JPH03173873A - New pyrimidinedione derivative and antiarrhythmic agent containing the same compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [A is (CH2)m, B-(CH2)k, formula II, etc., (m is 0-4; k is 2-4; B is O, S, NR<5>, etc.; R<5> is H, alkanoyl, alkyl, etc.); R<1> and R<2> are H, alkyloxycarbonyl, alkyl, etc., or together represent alkylene; R<3> and R<4> are H or alkyl; X<1> and X<2> are H or CO-R<6> (R<6> is alkyl, phenyl, etc.), halogen, alkyl, OH, alkoxy, alkylthio, etc.; X<3> is H, NO2, CH3 or CN]. EXAMPLE:1,3-Dimethyl-6-[2-(4-nitroanilino)ethylamino]-2,4(1H,3H)-pyrim idinedione. USE:Useful as an antiarrhythmic agent, especially as a class III type antiarrhythmic drug. PREPARATION:For example, a compound expressed by formula III is reacted with a compound expressed by formula IV (Y<3> is halogen or a substituent group capable of providing a leaving group in reaction), preferably in the presence of a base at 20-150 deg.C temperature to afford the compound expressed by formula I.

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to novel pyrimidinedione derivatives and acid addition salts thereof, methods for producing them, and drugs containing them that are effective in treating cardiac dysfunction such as arrhythmia and heart failure.

[Conventional technology]

The mechanism of arrhythmia is complex and is thought to involve abnormalities in stimulus generation, disorders in the conduction system, or a combination of these. The reentry theory is a typical example of disorders of excitatory conduction. The condition for its occurrence is the heterogeneity of the refractory period in each part of the heart.
This is thought to be caused by a combination of factors such as unidirectional block, shortened refractory period, conduction delay, and the existence of a turning path. Various antiarrhythmic drugs have been used to treat such arrhythmias. Antiarrhythmic drugs are classified into four groups depending on their mechanism of action. Namely, E. M. Vaughan Williams
(Advancesin drug rese
arch, vol, 9”, ed, by Harper
N.J., Simmondg A.B., Aca.
demic Press, London; 1974
, p. 69-101) classifies antiarrhythmic drugs into the following four groups according to their effects on myocardial action potentials or the ionic currents that generate them. Class I: Sodium channel inhibitors have the effect of suppressing sodium current. However, it usually has little or no effect on the action potential duration and the maximum rate of rise of the sodium current (
Vmax). Although antiarrhythmic drugs belonging to this class have strong antiarrhythmic effects, they also strongly suppress cardiac function, and care must be taken when administering them to patients with heart failure or hypotension. Class ■: β-blocker It has the effect of β-blocking action represented by propranolol, and is useful for arrhythmia involving sympathetic nerves. However, caution is required when using it as side effects include suppression of cardiac function due to β-blocking action, induction of bronchial asthma attacks, and induction of hypoglycemic attacks. Class ■: Drugs that prolong action potential duration These drugs have the effect of significantly prolonging the myocardial action potential duration and extending the effective refractory period. It is believed that this class of drugs can suppress reentry arrhythmia. Amiodarone, pretylium, etc. are known as this class ■ type antiarrhythmic drug. However, all of them have serious side effects and require sufficient caution when used. Class ■: Calcium antagonist Controls calcium channels and suppresses arrhythmia caused by automatic activation of the sinoatrial node and ventricular tachycardia that involves the atrioventricular node in the reentry circuit. Among these antiarrhythmic drugs, the class that is said to be effective against ventricular arrhythmias with the highest risk of life-threatening
Types are particularly important as they are the most useful.

[Problem to be solved by the invention]

Various antiarrhythmic drugs have already been developed or
is being used. However, it has a complex mechanism of development and a long history of antiarrhythmic drugs.
Ideal antiarrhythmia for arrhythmia therapy that requires periodic administration
The search for drugs continues, but there are no satisfactory results.
The current situation is that it has not been obtained. The present invention was developed in view of the current situation regarding such antiarrhythmic drugs.
The purpose of this drug is to treat it as a class ■ antiarrhythmic drug.
To provide a novel compound useful as a chemical compound and a method for producing the same.
It's there. Another object of the present invention is to improve cardiac dysfunction such as heart failure.
To provide a novel compound that is also effective in
It is in. Another object of the present invention is to use this novel compound as an active ingredient.
Treatment for cardiac dysfunction such as arrhythmia and heart failure
The goal is to provide medical treatment. [Means for Solving the Problems] In the course of intensive study to solve the above-mentioned problems, the present inventors
, the compound of the following general formula (1) and its acid addition salt are found.
However, as a result of studying the pharmacological properties of these compounds,
These compounds significantly affect the action potential duration of cardiac myocytes.
In animal experiments using adult dogs, their ventricles were lengthened.
We have discovered a pharmacological property that significantly extends the refractory period.
The invention has been completed. Furthermore, the compounds of the present invention have positive inotropic effects,
It was found to be useful as a total therapeutic agent. The compound of the present invention is a compound represented by the following general formula (1).
and its acid addition salts. [In the formula, A is -(CHz)-, -8-(cH2) 1
5 B represents an oxygen atom, a sulfur atom, -N-1]100-, 0HO D represents -N)IC-, -CH- or -C-, R1 and
and R2 each independently represent a hydrogen atom, a lower fluoryloxycarbonate
Rubonyl group, unsaturated lower alkyl group or lower alkyl group
group (any one hydrogen atom of the alkyl group is a hydroxyl group,
-lower alkylamino group, di-lower alkylamino group, lower
alkyloxy group, lower alkanoyloxy group, ben
Zoyloxy group, halogen atom or lower alkyloxy
benzoyloxy group substituted with cy group, phenyl group
, substituted by halogen atom or lower alkyloxy group
° phenyl group or lower alkyloxycarbohydrate
substituted with a substituent selected from the group consisting of
or R1 and R2 are connected to form an alkyl group.
-CNH- becomes a ren chain or may optionally form a heterocyclic structure, R3 and R4
independently represent a hydrogen atom or a lower alkyl group, XI and x2 independently represent a hydrogen atom, -CO-R'
, halogen atom, lower alkyl group, halogen-substituted lower atom
alkyl group, hydroxyl group, lower alkyloxy group, lower alkyl group
ruthio group, lower alkyloxycarbonyl group, carboxy
Syl group, cyano group, amino group, lower alkanoyloxy
group, lower alkanoylamino group, lower alkyl sulfone
Amide group, mono- or di-lower alkylamino group, phenyl
substituted lower alkylamino group or unsaturated lower alkyl
represents an oxy group, x3 represents a hydrogen atom, nitro group, methyl group or cyan group
and R5 is a hydrogen atom, a lower alkanoyl group, a lower alkyl group
represents a sulfonyl group or a lower alkyl group, or R1 and R5 are
Forms a heterocyclic structure by connecting to form an alkylene chain
R8 is a lower alkyl group, a cycloalkyl group,
(The phenyl group is a halogen atom, a lower alkyl group, a hydroxyl group,
l selected from the group consisting of groups and lower alkyloxy groups
It may be substituted with ~2 substituents. ) or
Indicates a heterocycle, n is 2 or 3, m is 0, 1, 2.3 or
or 4, k is 2.3 or 4, β is 0, 1.2.3 or
is 4]. In the compound of general formula (1) above, unsaturated lower alkyl
Examples of the group include vinyl group, allyl group, propargyl group, etc.
can be mentioned. As the lower alkyl group, a straight chain having 1 to 5 carbon atoms or
Branched alkyl groups, such as methyl, ethyl, propyl,
Butyl, isopropyl, isobutyl, tertiary butyl, tertiary butyl
Examples include secondary butyl group. In addition, as a lower alkyl group substituted with a hydroxyl group,
, 2-hydroxyethyl group, 3-hydroxypropyl group
, 2-hydroxypropyl group, 4-hydroxybutyl group
etc. can be mentioned. Furthermore, lower substituted by a mono-lower alkylamino group
As the alkyl group, 2-(methylamino)ethyl group,
3-(methylamino)propyl group, 2-(ethylamino)
) ethyl group, etc. Also, lower alkyl substituted by di-lower alkylamino group
As the alkyl group, 2-(dimethylamino)ethyl group,
2-(diethylamine)ethyl group, 3-(dimethylamine)
c) Propyl group, etc. can be mentioned. In addition, as the lower alkyloxy group, the lower alkyloxy group shown above is
It is possible to list oxygen atoms substituted by alkyl groups.
Wear. As the lower alkanoyloxy group, acetyloxy group
, propionyloxy group, butyryloxy group, isobutylene
Examples include lyloxy group, pivaloyloxy group, etc.
Wear. a lower alkyl group substituted with a benzoyloxy group and
For example, 2-benzoyloxyethyl group, 3-benzoyloxyethyl group,
2-benzoyloxyprobyl group, 2-benzoyloxyproyl group
Examples include biru group, 2-benzoyl-1-methylethyl group, etc.
can be done. As the lower alkyl group substituted with phenyl group, benzene
Zyl group, 2-phenylethyl group, 3-phenylpropyl group
Examples include groups. Lower alkyl in lower alkyloxycarbonyl group
is the same as the lower alkyl group exemplified above.
I can list things. Halogen atoms include fluorine, chlorine, and bromine atoms.
, an iodine atom. halogen-substituted lower alkyl group; lower alkyloxy group
Substituted lower alkyl group; lower alkanoyloxy group
Lower alkyl group substituted with: halogen atom or lower
a benzoyloxy group substituted with an alkyloxy group;
Substituted with halogen atom or lower alkyloxy group
Lower alkyl group substituted by benzoyloxy group
; Substituted with a halogen atom or lower alkyloxy group
phenyl group: halogen atom or lower alkyloxy
Lower alkyl substituted by phenyl group substituted by
substituted with a kyl group; and a lower alkyloxycarbonyl group
The substitution position of the substituent on the lower alkyl group
but not limited to. As the lower alkylthio group, the lower alkylthio group shown above is
Mention may be made of sulfur atoms substituted by kill groups
. The lower alkanoylamino group is an acetylamide group.
, propionylamino group, etc. As the lower alkylsulfonamide group, methanesulfonamide
amide group, ethanesulfonamide group, etc.
can. As the mono- or di-lower alkylamino group, methylal
mino group, ethylamino group, dimethylamino group, diethyl
Examples include amino groups. As the phenyl group-substituted lower alkylamino group, the above-mentioned
Those in which the lower alkylamino group is substituted with a phenyl group are listed.
The substitution position is not limited. Examples of unsaturated alkyloxy groups include vinyloxy group and alkyloxy group.
Listing lyloxy group, propargyloxy group, etc.
Can be done. R1 and R2 or R' and R8 are connected to each other.
Examples of the chain include ethylene chain, propylene chain, etc.
can be done. Lower alkanoyl groups include formyl group and acetyl group.
, propionyl group, butyryl group, etc.
. As a lower alkylsulfonyl group, methanesulfonyl
group, ethanesulfonyl group, etc. Examples of cycloalkyl groups include cyclopentyl group, cyclo
Examples include hexyl group. As the heterocycle for R6, pyridyl group, pyrazolyl
group, pyrimidinyl group, thienyl group, furyl group, pyrrolyl group
Examples include groups. Furthermore, the phenyl group in R6 is substituted with a substituent.
In the case of substitution, the substitution position is not particularly limited. Pharmaceutically acceptable compounds of the above general formula (1)
"Pharmaceutically acceptable" in acid addition salts refers to
Significant side effects or toxicity may occur when administered to
and that its pharmacological activity is not lost.
meaning that the acid addition salt can be prepared by neutralization of the free base.
I can do that. Acids that can constitute these pharmaceutically acceptable salts include:
Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonate
phosphoric acid, maleic acid, oxalic acid, malonic acid, succinic acid, fumaric acid
acid, tartaric acid, citric acid, lactic acid, benzenesulfonic acid, etc.
organic or inorganic acids. Specific examples of the compounds of the present invention are illustrated below. (1) 1,3-dimethyl-6-[2-(4-nitro
anilino)ethylamino] -2,4(1)1.3H)
-pyrimidinedione (2) 1,3-dimethyl-6-[
3-(4-nitroanilino)propylamino] -2,
4(1)1.3H)-pyrimidinedione (3) 1.3
-dimethyl-6-[4-(4-nitrophenyl)pipera
Zin-■-ilko2.4 (1)1.3H)-pirimi
Jindione (4) 1,3-dimethyl-6-[N-ethyl-2-(
4-nitroanilino)ethylamine] -2,4(18
,3)1)-pyrimidinedione (5) 1.3-dimethyl-6-[2-(N-methyl-
4-nitroanilino)ethylamino]-2,4(1)1
,3) 1)-pyrimidinedione (6) 1,3-dimethyl-6-[4-(4-nitroph)
phenyl) homopiperazin-1-yl] -2,4(1)
1.3H)-pyrimidinedione (7) 1.3-dimethyl-6-[2-(4-nitrobe)
-2,4(IH,3H
)-pyrimidinedione (8) 1,3-dimethyl-6-[3-(4-nitrobene)
-2,4(IH,3
H)-pyrimidinedione (9) 1,3-dimethyl-6-[4-(4-nitrobene)
piperazin-1-yl] -2,4(I)I,
3H)-pyrimidinedione (10) 1,3-dimethyl-6-[N-propyl-
2-(4-nitrobenzylamino)ethylamino] −
2,4(IH,3H)-pyrimidinedione (11) 1,3-dimethyl-6-(2-(N-ethyl
-4-nitrobenzylamino)ethylamino] -2,
4(1)1.3H)-pyrimidinedione (12) 1.3-dimethyl-6-(2-[N-(2-
hydroxyethyl)-4-nitrobenzylamino]ethyl
Ruamino)-2,4(+8.3H)-pyrimidinedione
(13) 1,3-dimethyl-6-(2-[2-(4-
Nitrophenyl)ethylaminoconitylamino) -2
,4(1)1,3)ri-pyrimidinedione (14) 1,3-dimethyl-6-(3-[2-(4-
Nitrophenyl)ethylaminocopropylamine)-2
,4(III, 3H)-pyrimidinedione (+5) 1.3-dimethyl-6-(N-(2-hydro
xyethyl)-2-(2-(4-nitrophenyl)ethyl
-2,4(IH,3H)-
Pyrimidinedione (16) 1,3-dimethyl-6-(
2-(N-ethyl-2-(4-nitrophenyl)ethyl
aminoconitylamino)-2,4(IH,3H)-pyri
Midinedione (17) 1,3-dimethyl-6-<2-[N-(2-
hydroxyethyl)-2-(4-nitrophenyl)ethyl
tylaminoconitylamino) -2,4(IH,3H)
-pyrimidinedione (18) 1,3-dimethyl-6-
(4-t2-(4-nitrophenyl)ethylcopiperadi
(1-yl)-2,4(IH,3H)-pyrimidine
dione (19) 1,3-dimethyl-6-(4-(2-(4-
nitrophenyl)ethyl]homopiperazin-1-yl)
-2,4(1)I. 3) 1)-Pyrimidinedione (20) 1.3-dimethyl-6-(2-[N-(2-
acetoxyethyl)-2-(4-nido-lophenyl)et
tylaminoconitylamino) -2,4(18,3H)
-pyrimidinedione (21) 1,3-dimethyl-6-
(2-[N-(3-hydroxypropyl)-2-(4-
Nitrophenyl)ethyl 7minocoethylamino)-2
,4(IH,3)1)-pyrimidinedione (22) 1
．． 3-dimethyl-6-(2-[N-(3-benzoyl)
xyprovir)-2-(4-nitrophenyl)ethylua
Minocoethylamino) -2,4(1)1.3)1)-
Pyrimidinedione (23) 1,3-dimethyl-6-(4-[2-(3-
nitrophenyl)ethylcopiperazin-1-yl) -
2,4(IH,3H) -pyrimidinedione (24) 1,3-dimethyl-6-(4-(2-(2-
nitrophenyl)ethylcopiperazin-1-yl) -
2,4(1)1.3H) -pyrimidinedione (25) 3-methyl-6-(4-[2-(4-nitro
phenyl)ethylcopiperazin-1-yl)-2,4(
IH,3H)-pyrimidinedione (26) l-methyl-6-(4-(2-(4-nitro)
phenyl)ethylcopiperazin-1-yl) -2,4
(IH,3H)-pyrimidinedione (27) 1.3-diethyl-6-(2-4N-(2-
hydroxyethyl)-2-(4-nitrophenyl)ethyl
-2,4(1)1.3)1
)-pyrimidinedione (28) 1,3-diisopropyl
Ru-6-(2-[N-(2-hydroxyethyl)-2-
(4-nitrophenyl)ethylaminocoethylamino)
-2,4(IH,3)1)-pyrimidinedione (29) 1,3-dimethyl-6-(2-[3-(4-
Nitrophenyl)propylaminocoethylamino)-2
,4(IH,3)1)-pyrimidinedione (30) 1.3-dimethyl-6-(3-[3-(4-
nitrophenyl) propylaminocopropylamino)
-2,4(IH. 3) 1)-pyrimidinedione (31) 1,3-dimethyl-6-(N-methyl-2-
[3-(4-nitrophenyl)propylaminocoethyl
amino)-2,4(IH,3)1)-pyrimidinedione
(32) 1,3-dimethyl-6-(N-ethyl-2-
[3-(4-nitrophenyl)propylaminocoethyl
amino)-2,4(1)1.3H)-pyrimidinedione
(33) 1,3-dimethyl-6-(N-propyl-2
-[3-(4-nitrophenyl)propylaminocoethyl
-2,4(II(,3)ri-pyrimidindi)
(34) 1,3-dimethyl-6-(N-(2-hypolymer)
droxyethyl)-2-(3-(4-nitrophenyl)
propylaminocoethylamino) -2,4(1)1.
3) 1)-Pyrimidinedione (35) 1.3-dimethyl-6-(N-(2-hydro
xypropyl)-2-[3-(4-nitrophenyl)propylene
ropylaminocoethylamino) -2,4(IH,3H
)-pyrimidinedione (36) 1,3-dimethyl-6-(N-(2-hydro
xy-I-methylethyl)-2-t3-(4-nitroph
phenyl)propylaminocoethylamino) -2,4(
IH, 3) 1)-pyrimidinedione (37) 1.3-dimethyl-6-(N-(2-aceto
xyethyl)-2-[3-(4-nitrophenyl)pro
pyraminocoethylamino)-2,4(1)1.3H)
-pyrimidinedione (38) 1,3-dimethyl-6-(N-methoxyl
Bonylmethyl-2-[3-(4-nitrophenyl)pro
pyraminocoethylamino) -2,4(lH,3H)
-pyrimidinedione (39) 1,3-dimethyl-6-(N-(2-phenylene)
(ethyl)-2-(3-(4-nitrophenyl)propyl)
-2,4(IH,3H)-
Pyrimidinedione (40) 1,3-dimethyl-6-(
2-[N-methyl-3-(4-nitrophenyl)propyl
-2,4(IH,3H)-pi
Rimidinedione (41) 1,3-dimethyl-6-(2
-(N-ethyl-N-[3-(4-nitrophenyl)propylene)
[ropyl]amine>ethylamino) -2,4(1)1.
3) 1)-pyrimidinedione (42) 1.3-dime
Chil-6-(2-[N-propyl-3-(4-nitroph)
phenyl)propylaminocoethylamino)-2,4(I
H,3H)-pyrimidinedione (43) 1,3-dime
Chyl-6-(2-[N-(1-methylethyl)-3-
(4-nitrophenyl)propylaminocoethylamino
) -2,4(Ill, 311)-pyrimidinedione
(44) 1,3-dimethyl-6-(2-[N-butyl
-3-(4-nitrophenyl)propylaminocoethyl
amino)-2,4(IH,3)1)-pyrimidinedione
(45) 1.3-dimethyl-6-(2-[N-(t-
butyl)-3-(4-nitrophenyl)propylamino
coethylamino) -2,4(1)1.3)1)-Biry
Midinedione (46) 1,3-dimethyl-6-(2-
(N-(2-hydroxyethyl)-N-[3-(4-ni)
trophenyl)propylcoamino>ethylamino) −
2,4(IH,3H)-pyrimidinedione (47) 1,3-dimethyl-6-(2-[N-(3-
Hydroxypropyl)-3-(4-nitrophenyl)
ropylaminocoethylamino)-2,4(I)I,
3H)-pyrimidinedione (48) 1.3-dimethyl-6-(2-[N-(2-
Hydroxy-1-methylethyl)-3-(4-nitroph
(enyl)propylamine]ethylamino) -2,4(
IH, 3) 1)-pyrimidinedione (49) 1.3-dimethyl-6-(2-(N-(2-
Hydroxypropyl)-3-(4-nitrophenyl)
(ropylaminocoethylamino) -2,4(1)! ,
381-pyrimidinedione (50) 1.3-dimethyl-6-(2-[N-(4-
hydroxybutyl)-3-(4-nitrophenyl)pyro
pyraminocoethylamino) -2,4(IH,3)1
)-pyrimidinedione (51) 1,3-dimethyl-6
-(2-[N-(2-acetoxyethyl)-3-(4-
nitrophenyl)propylaminocoethylamino) −
2,4(1)1,3)1)-pyrimidinedione (52)
1,3-dimethyl-6-(2-[N-(2-formyl
oxyethyl)-3-(4-nitrophenyl)propyl
aminocoethylamino)-2,4(IH,3H)-pi
Rimidinedione (53) 1,3-dimethyl-6-(2-(N-(2-
propionyloxyethyl)-3-(4-nitrophenyl)
(propylaminocoethylamino) -2,4(IH
,38)-pyrimidinedione (54) 1,3-dimethyl-6-(2-[N-(2-
isobutyryloxyethyl)-3-(4-nitrophenyl)
-2,4(I)propylamino]ethylamino)
H,3H)-pyrimidinedione (55) 1.3-dimethyl-6-(2-[N-(2-
pivaloyloxyethyl)-3-(4-nitrophenyl)
) propylaminocoethylamino) -2,4(IH,
3H)-pyrimidinedione (56) 1.3-dimethyl-6-(2-[N-(2-
Acetoxypropyl)-3-(4-nitrophenyl)
ropylaminocoethylamino) -2,4(IH,3H
)-pyrimidinedione (57) 1,3-dimethyl-6-(2-[N-(2-
acetoxy-1-methylethyl)-3-(4-nitroph
phenyl)propylaminocoethylamino) -2,4(
IH,3H)-pyrimidinedione (5811,3-dimethyl-6-(2-(N-(2-beta)
(nzoyloxyethyl)-3-(4-nitrophenyl)
Propylaminocoethylamino't -2,4(1)1
．． 3H)-pyrimidinedione (59) 1,3-dimethyl-6-(2-<N-[2-
(4-fluorobenzoyloxy)ethyl] -3-(
4-nitrophenyl)propylamino>ethylamino)
-2,4(IH,3H)pyrimidinedione (60) 1,3-dimethyl-6-(2-<N-[2-
(4-methoxybenzoyloxy)ethyl] -3-(
4-nitrophenyl)propylamine>ethylamino)
-2,4(IH,3H)-pyrimidinedione (61) 1,3-dimethyl-6-(2-<N-[2-
(2-chlorobenzoyloxy)ethyl] -3-(4
-nitrophenyl)propylamino>ethylamino)
-2,4(1)1,3H)-pyrimidinedione (62) 1,3-dimethyl-6-(2-(N-[2
-(3,5-dimethoxybenzoyloxy)ethyl]
-3-(4-nitrophenyl)propylamino〉ethyl
amino) -2,4(IH. 3H)-pyrimidinedione (63) 1,3-dimethyl-6-(2-<N-[2-
(3,4-dibromobenzoyloxy)ethyl]-3-
(4-nitrophenyl)propylamino)ethylamino
)-2,4(1)1.3)1'1-pyrimidinedione (64) 1,3-dimethyl-6-(2-[N-(2-
methoxyethyl)-3-(4-nitrophenyl)propyl
-2,4(IH,3H)-
Pyrimidinedione (65) 1,3-dimethyl-6-(
2-4N-(2-propyloxyethyl)-3-(4-
nitrophenyl)propylaminocoethylamino) −
2,4(IIL 3) 1)-pyrimidinedione (66) 1,3-dimethyl-6-(2-[N-benzi
Ru-3-(4-nitrophenyl)propylaminocoethyl
24(IH,3H)-pyrimidine (
67) 1,3-dimethyl-6-(2-[N-(4-methyl)
Toxybenzyl)-3-(4-nitrophenyl)propyl
-2,4 (IH, 3 days) -
Pyrimidinedione (68) 1,3-dimethyl-6-(
2-[N-(3,4,5-trimethoxybenzyl)-3
-(4-nitrophenyl)propylaminocoethylamide
-2,4(IH,3)1)-pyrimidinedione (69) 1,3-dimethyl-6-(2-[N-(2-
Chlorobenzyl)-3-(4-nitrophenyl)propyl
-2,4(1)1,3H)
-pyrimidinedione (70) 1,3-dimethyl-6-
(2-(N-(2-phenylethyl)-3-(4-nito)
lophenyl) propylaminocoethylamino) -2,
4(IH,3)1)-pyrimidinedione (71) 1.
3-dimethyl-6-(2-[N-vinyl-3-(4-di
trophenyl)propylaminocoethylamino)-2,
4(1)1.3H)-pyrimidinedione (72) 1
．． 3-dimethyl-6-(2-[N-allyl-3-(4-
Nitrophenyl)propylaminocoethylamino)-2
,4(1)I,3H)-pyrimidinedione (73)
1,3-dimethyl-6-(2-IN-propargyl-3
-(4-nitrophenyl)propylaminocoethylamide
-2,4(1)1.3H)-pyrimidinedione (
74) 1,3-dimethyl-6-(2-[N-ethoxy
Carbonylmethyl-3-(4-nitrophenyl)propyl
-2,4(IH,3)1)
-pyrimidinedione (75) 1,3-dimethyl-6-(2-[N-t-butylene
Toxycarbonylmethyl-3-(4-nitrophenyl)
propylaminocoethylamino)-2,4(IH,3
H)-pyrimidinedione (76) 1.3-dimethyl-6-(2-[N-(2-
Methoxycarbonylethyl-3-(4-nitrophenyl)
) propylaminocoethylamino) -2,4(IH,
3) 1)-Pyrimidinedione (77) 1.3-dimethyl-6-(N-methyl-2-
[N-methyl-3-(4-nitrophenyl)propyla
Minocoethylamino) -2,4(1)1z 3H)-
Pyrimidinedione (78) 1,3-dimethyl-6-(
N-ethyl-2-[N-(2-hydroxyethyl)-3
-(4-nitrophenyl)propylaminocoethylamide
-2,4(IH,3)1)-pyrimidinedione (79) 1,3-dimethyl-6-(2-(N-ethyl
-N-[3-(3-nitrophenyl)propylcoamino
〉ethylamino)-2,4(1)1.3H)-pyrimi
Jindione (80) 1,3-dimethyl-6-(2-I
N-methoxycarbonyl-3-(4-nitrophenyl)
propylaminocoethylamino)-2,4(IH,3
H)-pyrimidinedione (81) 1,3-dimethyl-
6-(2-[N-(t-butoxycarbonyl)-3-(
4-nitrophenyl)propylaminocoethylamino)
-2,4(IH,3H)-pyrimidinedione (82) 1,3-dimethyl-6-(2-(N-[2-
(N-methylamino)ethyl]-3-(4-nitrophe)
(I)propylamino>ethylamino)-2,4(I
H,3) 1)-pyrimidinedione (83) 1.3-dimethyl-6-(2-(N-[2-
(N,N-dimethylamino)ethyl]-3-(4-nito
lophenyl)propylamino>ethylamino)-2,4
(IH,38)-pyrimidinedione (84) 1.3-dimethyl-6-(2-<N-[2-
(N,N-diethylamino)ethyl]-3-(2-nito
lophenyl)propylamino〉ethylamino) -2,
4(1)1.3H)-pyrimidinedione (85) 1.3-dimethyl-6,(2-[N-[2-
hydroxyethyl)-3-(2-nitrophenyl)pro
pyraminocoethylamino) -2,4(IH,3H)
-pyrimidinedione (86) 1,3-dimethyl-6-
(4-(3-(4-nitrophenyl)propylcopipera)
din-1-yl)-2,4(IH,3H)-pyrimidine
Dione (87) 1,3-dimethyl-6-(4-(3-(4-
nitrophenyl)propyl] homopiperazin-1-yl
)-2,4(IH,3)1)-pyrimidinedione (88) 3-methyl-6-(4-[3-(4-nitro
phenyl)propylcopiperazin-1-yl) -2,
4(IH,38)-pyrimidinedione (89) 1-propyl-6-(2-[N-(2-hydro
(loxyethyl)-3-(4-nitrophenyl)propyl
aminocoethylamino) -2,4(1)1.3H)-
Pyrimidinedione (90) 6- (2-[N-ethyl
-3-(4-nitrophenyl)propylaminocoethyl
amino)-1,3,5-trimethyl-2.4 (IH,
38)-pyrimidinedione (91) 6- (2-[N
-(2-hydroxyethyl) -3-(4-nitrophe)
propylaminocoethylamino)-1,3,5-
Trimethyl-2,4(IH,31()-pyrimidinedio
(92) 1,3-dimethyl-6-(2-[N-ethyl
-3-(4-nitrophenyl)propylaminocoethyl
amino)-5nitro-2,4(II(,31()-pyri)
Midinedione (93) 1,3-dimethyl-6-(2-
[N-(2-hydroxyethyl)-3-(4-nitroph
phenyl)propylaminocoethylamino)-5-nitro
-2.4 (1)I, 3)1)-pyrimidinedione (94) 1.3-dimethyl-6-(2-[N-(meth)
(oxycarbonylmethyl)-3-(4-nitrophenyl)
propylaminocoethylamino)-5-cyano-2,4
(I) I, 3) 1)-pyrimidinedione (95) 1.3-dimethyl-6-(2-[N-(2-
hydroxyethyl)-3-(4-nitrophenyl)pro
pyraminocoethylamino)-5-cyano-2,4(1
)1.3)1)-pyrimidinedione (96) 1.3-dimethyl-6-(2-[4-(4-
nido, lophenyl)butylaminoconitylamino) −
2,4(IH,31()-pyrimidinedione(97) 6-(N-ethyl-N-(2-(4-(4
-nitrophenyl)butylaminocoethyl)amino)1
．． 3-dimethyl-2,4(II(,3)1)-pyrimidi
dione (98) 1,3-dimethyl-6-(N-(2
-Hydoxyethyl)-2-[4-(4-nitrophenyl)
) butylaminoconitylamino) -2,4(IH,3
H)-pyrimidinedione (99) 1,3-dimethyl-
6-(N-methoxycarbonylmethyl-2-[4-(4
-nitrophenyl)butyl7mino]ethylamino)=2
．． 4 (IH,31()-pyrimidine(+00) 1.3-dimethyl-6-(2-(N-ethyl)
Chyl-4-(4-nitrophenyl)butylaminoconiti
(Ruamino)-2,4(I)1.3)1)-Pyrimidine di
(101) 1,3-dimethyl-6-(2-[N-
(t-butyl)-4-(4-nitrophenyl)butyla
minoconithylamino) -2,4(IH,31-11-
Pyrimidinedione (102) 1,3-dimethyl-6-
(2-[N-(2-hydroxyethyl)-4-(4-ni
trophenyl)butylaminoconitylamino) -2,
4(1)I, 3)1)-pyrimidinedione (103)
1.3-dimethyl-6-(2-(N-(3-hydroxy)
cypropyl)-4-(4-nitrophenyl)butylamide
noconitylamino)-2,4(1)1,3H)-pyri
Midinedione (10411,3-dimethyl-6-(2-
[N-(2-acetoxyethyl)-4-(4-nitroph
phenyl)butylaminoconitylamino)-2,4(I
ll, 3H) ~ pyrimidinedione (105) 1,3
-dimethyl-6-(2-(N-(2-methoxyethyl)
-4-(4-nitrophenyl)butylaminoconytyl-a
-2,4CI)I, 31()-pyrimidine
(106) 1,3-dimethyl-6-(2-[N-
Benzyl-4-(4-nitrophenyl)butylaminoco
Nithylamino)-2,4(IH,3)1)-pyrimidine
Dione (107) 1,3-dimethyl-6-(2-(
N-allyl-4-(4-nitrophenyl)butylamino
conitylamino)-2,4(I)I, 3H)-pyrimi
Jindione (108) 1,3-dimethyl-6-(2-
(N-ethoxycarbonylmethyl-4-(4-nitroph)
phenyl)butylaminoconitylamino) -2,4(1
)1.3H)-pyrimidinedione (109) 1.3-
dimethyl-6-(N-methyl-2-[N-methyl-4-
(4-nitrophenyl)butylaminoconitylamino)
-2,4(IH,3)1)-pyrimidinedione (110
) 1.3-dimethyl-6-(2-(N-[2-(N,
N-diethylamine)ethyl]-4-(4-nitrophe)
nyl)butylamino>ethylamino) -2,4(It
(,3)1)-pyrimidinedione (+11) 1.3-dimethyl-6-(4-[4-(4
-nitrophenyl)butylcopiperazin-l-yl)
-2,4(IH,3H)-pyrimidinedione (112) 6- (2-[N-ethyl-4-(4-ni
trophenyl)butylaminoconitylamino) -1,
3,5-1-dimethyl-2,4(1)I, 3H)-pi
Rimidinedione (113) 1,3-dimethyl-6-(
2-[2-(4-nitrophenoxy)ethylaminochoe
thylamino)-2,4(1)1.3B)-pyrimidine di
(114) 1,3-dimethyl-6-(N-ethyl-2
-(2-(4-nitrophenoxy)ethylaminocoethyl)
Ruamino)-2,4(1)1.31()-pyrimidine di
(+15) 1,3-dimethyl-6-(4-[2-
(4-nitrophenoxy)ethylcopiperazine-1-y
)-2,4(IH,3H)-pyrimidinedione (116) 1,3-dimethyl-6-(2-[3-(4
-nitrophenoxy)propylaminoconitylamino)
-2,4(IH. 38)-pyrimidinedione (117) 1,3-dimethyl-6-(N-ethyl-2
-(3-(4-nitrophenoxy)propylaminoconi)
thylamino) -2,4(IH,3)1)-pyrimidine
Dione (118) 1,3-dimethyl-6-(2-(N
-ethyl-3-(4-nitrophenoxy)propylamide
noconitylamino)-2,4(IH,3H)-pyrimidine
dione (119) 1,3-dimethyl-6-(2-[
N-(2-hydroxyethyl)-3-(4-nitrophe)
(propylaminoconitylamino) -2,4(
1) 1,3H)-pyrimidinedione (+20) 1,3-dimethyl-6-(2-(N-(2
-acetoxyethyl)-3-(4-nitrophenoxy)
propylaminoconitylamino)-2,4(IH,3
)1)-pyrimidinedione (+21) 1.3-dimethyl-6-(N-methyl-2
-[N-methyl-3-(4-nitrophenoxy)propyl
-2,4(1)1.3)1
)-pyrimidinedione (122) 1,3-dimethyl-
6-(4-[3-(4-nitrophenoxy)propylco)
piperazin-1-yl) -2,4(IH. 38)-pyrimidinedione (123) 3-methyl-6-(4-(3-(4-nito)
lophenoxy)propylcopiperazin-1-yl)-2
,4(IH,3H)-pyrimidinedione (124) 1.3-dimethyl-6-(4-(3-(3
-nitrophenoxy)propylcopiperazin-1-yl
) -2,4(IH. 3H)-pyrimidinedione (125) 1,3-dimethyl-6-(4-[3-(2
-nitrophenoxy)propylcopiperazin-1-yl
) -2,4(IH. 3H)-pyrimidinedione (126) 1,3-dimethyl-6-(2-(4-(4
-nitrophenoxy)butylaminocoethylamine)
-2,4(IH. 3) 1)-pyrimidinedione (127) 1,3-dimethyl-6-(N-methyl-2
-[N-methyl-4-(4-nitrophenoxy)butyl
aminocoethylamino)-2,4(IH,3B)-pi
Rimidinedione (128) 1,3-dimethyl-6-(
4-(4-(4-nitrophenoxy)butylcopiperadi)
(1-yl)-2,4(11(,3H)-pyrimidine
Dione (129) 1,3-dimethyl-6-(2-[N-e
Thyl-2-(4-nitrophenylthio)ethylaminoco
ethylamino)-2,4(IH,3H)-pyrimidine di
(130) 1,3-dimethyl-6-(2-[N-
(2-hydroxyethyl)-3-(4-nitrophenyl)
thio)propylaminoconitylamino)-2,4(I
H,3H)-pyrimidinedione (131) 1.3-dimethyl-6-(4-[3-(4
-nitrophenylthio)propylcopiperazine-1-y
)-2,4(III,3H)-pyrimidinedione (13211,3-dimethyl-6-(N-methyl-2-
(N-methyl-4-(4-nitrophenylthio)butyl
aminocoethylamino) -2,4(IH,3)1)-
Pyrimidinedione (133) 1,3-dimethyl-6-
(4-(4-nitrophenacyl)piperazin-1-yl
] -2,4(IH,3H)-pyrimidinedione (134) 1,3-dimethyl-6-(4-[2-(4
-nitrobenzoyl)ethylcopiperazin-1-yl)
-2,4(1)l, 3+()-pyrimidinedione (135) 1,3-dimethyl-6-(N-methyl-2
-[N-methyl-4-(4-nitrophenylthio)buty
-2,4(I)1,3)1
)-pyrimidinedione (136) 1,3-dimethyl-
6-(4-[2-hydroxy-2-(4-nitropheny)
(l)ethylcopiperazin-1-yl)-2,4(IH,
3H)-pyrimidinedione (137) 1,3-dimethy
Ru-6-(4-(2-(4-nitrobenzoyloxy))
ethylcopiperazin-1-yl)-2,4(IH,3H
)-pyrimidinedione (138) 1,3-dimethyl-6-(2-(N-e
Chyl-3-(4-nitrobenzoyloxy)propyla
minoconithylamino)-2,4(18,3)1)-pi
Rimidinedione (139) 1,3-dimethyl-6-[
2-(4-nitrobenzoylamino)ethylamino]-
2,4(IH,3)1)-pyrimidinedione (140) 1,3-dimethyl-6-(4-(2-(4
-Nitrobenzoylamino)ethylcopiperazine-1-
yl)-2,4(1)I, 3H)-pyrimidinedione
(141) 1,3-dimethyl-6-(4-[N-(4
-Nitrophenyl)carbamoylmethylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione
(142) 1,3-dimethyl-6-(4-[N-(4
-nitrophenyl)carbamoylethyl]homopiperazi
(1-yl)-2,4(IH,3H)-pyrimidine
Dione (143) 1,3-dimethyl-6-(4-(3
-(4-nitroanilino)2-hydroxypropylcopi
perazin-1-yl)-2,4(1)1.3H)-p
Rimidinedione (144) 1,3-dimethyl-6-
(4-<4-[N-(4-nitrophenyl)carbamoy
Rucobutyl〉piperazin-1-yl) -2,4(1)
1,3H)-pyrimidinedione (+45) 1,3-di
Methyl-6-(N-methyl-2-[N-methyl-2-(
4-nitroanilino)ethylaminocoethylamino)-
2,4(IH,3)1)-pyrimidinedione (146)
1.3-dimethyl-6-(N-methyl-2-[N-(
2-hydroxyethyl)-2-(4-nitroanilino)
ethylaminocoethylamino) -2,4(IH,3H
)-pyrimidinedione (147) 1,3-dimethyl-6-(2-[N-ethyl
Ru-2-(4-nitroanilino)ethylaminocoethyl
amino)-2,4(IH,3H)-pyrimidinedione (148) 1,3-dimethyl-6-(3-[N-propylene)
Lopyl-2-(4-nitroanilino)ethylaminocop
(ropylamino)-2,4(1)I, 3H)-pyrimidine
dione (149) 1,3-dimethyl-6-(N-methyl
Chil-2-[N-methyl-2-(N-methyl-4-nito
roanilino)ethylaminocoethylamino) -2,4
(IH,3H)-pyrimidinedione (150) 1.3-dimethyl-6-(N-methyl-3
-[N-methyl-2-(4-nitroanilino)ethyl a
Minokopropylamino) -2,4(IH,311)-
Pyrimidinedione (151) 1,3-dimethyl-6
-(2-(N-ethyl-3-14-nitroanilino)propylene)
ropylaminocoethylamino)-2,4(IH,3H)
-pyrimidinedione (152) 1,3-dimethyl-6
-(2-[N-(2-hydroxyethyl)-3-(4-
nitroanilino)propylaminocopropylamino)
-2,4(IH,3)1)-pyrimidinedione (153
) 1,3-dimethyl-6-(2-[N-methoxycal
Bonylmethyl-3-(4-nitroanilino)propyla
Minocoethylamino)-2,4(IH,3H)-pyrimi
Zindione (154) 1,3-dimethyl-6-(4-(3-(4
-nitroanilino)propyl-1-piperazin-1-yl)
-2,4(IH,3H)-pyrimidinedione (155) 1,3-dimethyl-6-(4-(3-(N
-Methyl-4-nitroanilino)propylcopiperazine
-1-yl)-2,4(IH,3)1)-pyrimidine di
(+56) 1,3-dimethyl-6-(4-(3
-(N-propyl-4-nitroanilino)propylcopy
perazin-1-yl)-2,4(IH,3H)-pyrimi
Jindione (157) 1,3-dimethyl-6-(4-
(3-(N-methanesulfonyl-4-nitroanilino)
propylcopiperazin-1-yl)-2,4(IH,
3H)-pyrimidinedione (15B) 1,3-dimethy
-6-(4-[3-(N-ethanesulfonyl-4-ni)
(troanilino)propylcopiperazin-1-yl) -
2,4(IH,3H)-pyrimidinedione (159)
1,3-dimethyl-6-(4-[3-(N-acetyl-
4-nitroanilino)propylcopiperazin-1-yl
) -2,4(IH,3H)-pyrimidinedione (16
0) 1,3-dimethyl-6-(4-[3-(N-pro
Pionyl-4-nitroanilino)propylcopiperazine
-1-yl) -2,4(IH,3H)-pyrimidine di
(161) 1,3-dimethyl-6-(2-< [
1-(4-nitrophenyl)piperidin-4-yl core
Mino〉ethylamino)-2,4(1)1.3H)-p
Rimidinedione (162) 1,3-dimethyl-6-(
2-[4-(4-nitrophenyl)piperazine-l-y
luconitylamino)-2,4(IIl, 3)1)-pi
Rimidinedione (163) 1,3-dimethyl-6-(
3-(4-(4-nitrophenyl)piperazin-1-y)
luconitylamino)-2,4(1)1.3H)-pyrimi
Jindione (+64) 1,3-dimethyl-6-(N-(2-hydro
(oxyethyl)-2-(4-(4-nitrophenyl)pi)
perazin-1-ylconitylamino)-2,4(lH
,3)1)-pyrimidinedione (165) 1.3-dimethyl-6-(N-methyl-2
-[4-(4-nitrophenyl)piperazin-1-yl
conitylamino) -2,4(1)1.3)1)-pyri
Midinedione (166) 1,3-dimethyl-6-(4
-[3-(2-acetyl-4-nitrophenyl)propyl
rucopiperazin-1-yl)-2,4(1)1.3)
1)-pyrimidinedione (167) 1,3-dimethyl
-6-(2-[N-ethyl-2-(2-benzoyl-4
-nitrophenyl)ethylaminocoethylamino) -
2,4(IH,3H)-pyrimidinedione (16B)
1.3-dimethyl-6-[4-(3-acetyl-4-di
trophenyl)piperazin-1-yl]-2,4(I
H, 3) 1) -pyrimidinedione (+69) 1.3-dimethyl-6-(4-[4-(2
-acetyl-4-nitrophenoxy)butylcopiperazi
-2,4(IF+,3)1+-pyrimi
Jinjion (+70)! -Methyl-6-(4-[3-
(2-acetyl-4-nitrophenoxy)propyl]pi
Peragin! -yl)-2,4(1)1.3H)-pyri
Midinedione (171) 1,3-dimethyl-6-(4
-<3-[2-nitro-4-(2-pyridinecarbonyl
) phenoxy]propyl>piperazin-1-yl) −
2,4(IH,3)1)-pyrimidinedione (172) 1,3-dimethyl-6-(2-[N-(2
-hydroxyethyl)-3-(4-benzoyl-2-di
trophenoxy) propylaminocoethylamino) −
2,4(IH,3)1)-pyrimidinedione (173) 1,3-dimethyl-6-(4-(3-(2
-acetyl-4-di-troanilino)propylcopipera
di-1-yl)-2,4(Ill, 31()-pyri
Midinedione (174) 1,3-dimethyl-15-(
4-[3-(2-cyclopentanecarbonyl-4-nito
roanilino) propylcopiperazin-1-yl) -2
,4(IH,3H)-pyrimidinedione (175) 1.3-dimethyl-6-(4-<3-(2
-(2-chloroben'zoyl)-4-nitroanilinoj
propyl)piperazin-l-yl) -2,4(1)1
．． 3H)-pyrimidinedione (176) 1,3-dime
Chil-6-(4-<3-[2-(2-pyridinecarboni
)-4-nitroanilino]propyl>piperazine-1
-yl) -2,4(1)1,3H)-pyrimidinedio
(177) 1,3-dimethyl-6-(4-(3-
[2-(4-pyridinecarbonyl)-4-nitroanily
[propyl]piperazin-1-yl)-2,4(I
H,3H)-pyrimidinedione (178) 1,3-di
Methyl-6-(4-(3-(4-7cetyl-2-nitro)
anilino)propylcopiperazin-1-yl) -2,
4(IH,3)1)-pyrimidinedione (179) 1
．． 3-dimethyl-6-(4-[3-(4-propanoyl
-2-nitroanilino)propylcopiperazine-1-y
-2,4(IH,3B)-pyrimidinedione (1
80) 1,3-dimethyl-6-(4-[3-(4-beta)
nzoyl-2-nitroanilino)propylcopiperazine
-1-yl) -2,4(IH,3H)-pyrimidine di
(181) 1,3-dimethyl-6-(4-(3-
(3-acetyl-4-nitroanilino)propylcopipe
Radin-1-yl) -2,4(1)1.3)1)-P
Rimidinedione (182) 1,3-dimethyl-6-(
2-[3-(4-acetyl-2-nitroanilino)pro
pyraminocoethylamino)-2,4(Ill, 3
)1)-pyrimidinedione (183) 1,3-dimethy
Ru-6-(3-[N-(2-hydroxyethyl)-3-
(4-propanoyl-2-nitroanilino)propyla
Minokopropylamino)-2,4(IH,3H)-py
Rimidinedione (184) 1,3-dimethyl-6-(4-[3-(2
-benzoyl-4-nitroanilino)propylcopipera
di-l-yl)-2,4(I)I, 31()-p
Rimidinedione (185) 3-methyl-6-(4-(
3-(2-benzoyl-4-nitroanilino)propyl
Copiperazin-1-yl)-2,4(1)1.3H)-
Pyrimidinedione (186) 1,3-dimethyl-6-
(N-ethyl-2-[3-(2-formyl-4-nitro
anilino)propyl7mino]ethylamino) -2,4
(IH,3H)-pyrimidinedione (187) 1.3
-dimethyl-6-(4-(3-(3-fluoro-4-di)
trophenoxy)propylcopiperazin-1-yl)
-2,4(1)1,3H)-pyrimidinedione (188
) 1,3-dimethyl-6-(4-[3-(3-fluoro
rho-4=nitroanilino)propylcopiperazine-1-
yl)-2,4(IH,3H)-pyrimidinedione (1
89) 1,3-dimethyl-6-(4-[3-(3,5
-difluoro-4-nitrophenoxy)propyl copy
Radin-1-yl)-2,4(IH,3H)-pyrimi
Jindione (190) 1,3-dimethyl-6-(4-
(3-(3,5-difluoro-4-nitroanilino)propylene)
ropilcopiperazin-1-yl)-2,4(II(,3
)1)-pyrimidinedione (191) 1,3-dimethy
Ru-6-(4-[3-(2-fluoro-4-nitroani
lino)propyl]piperazin-1-yl) -2,4(
IH,3H)-pyrimidinedione (192) 1.3-
Dimethyl-6-(2-(3-(2-methoxy-4-nito)
lophenoxy) propylaminocoethylamino) -2
,4(IH,3)1)-pyrimidinedione (+93)
1.3-dimethyl-6-(3-[N-ethyl-3-(3
-trifluoromethyl-4-nitroanilino)propyl
aminocopropylamino) -2,4(1)1,3)1
)-pyrimidinedione (194) 1.3-dimethyl-6-(2-[4-(2
-acetyloxy-4-nitrophenoxy)butylamide
Nocoethylamino) -2,4(1)1.3)1)-P
Rimidinedione (195) 1,3-dimethyl-6-(
4-(3-(2-dimethylamino-4-nitroanilino)
) propyl] homopiperazin-1-yl) -2,4(
IH,3H)-pyrimidinedione (+96) 1.3-
Dimethyl-6-(2-[2-(2-diethylamino-4
−nitroanilino)ethylaminocoethylamino) −
2,4(II(,3)1)-pyrimidinedione (197
) 3-methyl-6-(2-[3-(2-hydroxy-
4-nitrophenoxy)propylaminocoethylamino
) -2,4(1)1.3H)-pyrimidinedione(1
98) 1-ethyl-6-(4-(3-(2-bromo-
4-nitroanilino)propylcopiperazin-1-yl
)-2,4(I)I, 3)1)-pyrimidinedione (
199) 6-(4-[2-(2-ethyl-4-nito
roanilino)ethylaminocopiperazin-1-yl)-
2,4(IH,31()-pyrimidinedione (200) 1,3-dimethyl-6-(4-[N-(3
-fluoro-4-nitrophenyl)carbamoylmethyl
Copiperazin-1-yl)-2,4(IH,3)1)
-pyrimidinedione (201) 1,3-dimethyl-6
-(2-[3-(2-ethoxy-4-nitrophenylthi)
e) propylaminocoethylamino) -2,4(1)
1,3H)-pyrimidinedione (202) 1,3-di
Methyl-6-(4-[3-(2-ethanesulfonamide)
-4-nitrophenoxy)propylcopiperazine-1-
-2,4(IH,3111-pyrimidinedione)
(203) 1,3-dimethyl-6-(4-[2-(3
-Fluoro-4-nitrophenyl)゛ethylcopiperadi
(1-yl)-2,4(IH,3)1)-pyrimidine
Dione (204) 1,3-dimethyl-6-(2-[N
-ethyl-3-(3-fluoro-4-nitrophenyl)
propylaminocoethylamino)-2,4(IH,3
H)-pyrimidinedione (205) 1,3-dimethyl
-6-(3-[N-(2-hydroxyethyl)-3-(
3,5-difluoro-4-nitrophenyl)propyla
minocopropylamine) -2,4(IH,3H) -
Pyrimidinedione (206) 1,3-dimethyl-6-(2-[N-(2
-acetoxyethyl)-3-(2-dimethylamine-4
-nitrophenyl)propylaminocoethylamino)-
2,4(IH,3H)-pyrimidinedione (207) 1,3-dimethyl-6-(2-[N-ethyl
-3-(2-ethoxy-4-nitrophenyl)propyl
-2,4(IH,3)1)
-pyrimidinedione (20B) 1,3-dimethyl-6
-(3-(N-(2-acetyloxyethyl)-3-(
2-ethanesulfonamido-4-nitrophenyl)pro
pyraminocopropylamino)-2,4(1)1.3)
1)-Pyrimidinedione (209) 1,3-dimethyl
-6-(4-(3-methyl-4-nitrobenzyl)pipe
Radin-1-yl] -2,4(1)I, 3H)-p
Rimidinedione (210) 1,3-dimethyl-6-<2-[N-(2
-hydroxyethyl)-3-(3-methoxy-4-nito
lophenyl) propylaminocoethylamino) -2,
4(1,H,3)1)-pyrimidinedione (211) 1,3-dimethyl-6-(2-[N-(3
-benzoyloxyprovir)-3-(2-ethoxyca
Rubonyl-4-nitrophenyl)propylaminocoethyl
Ruamino)-2,4(IH,3)1)-pyrimidinedio
(212) 1,3-dimethyl-6-(4-[3-(
2-acetyl-4-nitrophenoxy)propylcopipe
Radin-1-yl)-2,4(IH,3)1)-pyri
Midinedione (213) 1,3-dimethyl-6-(4
-(3-(4-acetyl-2-nitrophenoxy)pro
Pircopiperazin-1-yl) -2,4(IH,3)
1)-Pyrimidinedione (214) 1,3-dimethyl
-6-(4-(3-(4-benzoyl-2-nitrophe)
(noxy)propylcopiperazin-1-yl) -2,4
(1) 1.3H)-pyrimidinedione (215) 1.
3-dimethyl-6-(4-(3-(3-acetyl-4-
(nitrophenoxy)propylcopiperazin-1-yl)
-2,4(II(,3H)-pyrimidinedione (21
6) 1,3-dimethyl-6-(4-[3-(2-ben
Zoyl-4-nitrophenoxy)propylcopiperazine
-1-yl) -2,4(1B, 3H)-pyrimidine
Dione (217) 1,3-dimethyl-6-(4-<3
-(2-(4-bromobenzoyl)-4-nitropheno
xy]propyl>piperazin-1-yl) -2,4(
IH,31()-pyrimidinedione (218) 1.3
-dimethyl-6-(4-(3-[2-(3-pyrazolyl)
carbonyl)-4-nitrophenoxy]propyl>pipe
Radin-1-yl)-2,4(IH,3H)-pyrimi
Jindione (219) 1,3-dimethyl-6-(4-'<3-
[2-(2-pyrimidinecarbonyl)-4-nitrophe
noxy]propyl>piperazin-1-yl) -2,4
(1) 1.3H)-pyrimidinedione (220) 1.3-dimethyl-6-(4-<3-[2
-(3-pyridinecarbonyl)-4-nitrophenoxy
jpropyl)piperazin-1-yl) -2,4(IH
,3H)-pyrimidinedione (221) 1.3-dimethyl-6-(4-<3-[2
-(4-pyridinecarbonyl)-4-nitrophenoxy
]propyl>piperazin-1-yl)-2,4(IH
,3)1)-Pyrimidinedione (222) 1.3-dimethyl-6-(4-(3-[2
-(2-pyrimidinylcarbonyl)-4-nitropheno
xyJpropyl〉piperazin-1-yl) -2,4(
IH,3H)-pyrimidinedione (223) 1.3-dimethyl-6-(4-[2-(2
-acetyl-4-nitrophenoxy)ethylcopiperadi
(1-yl)-2,4(IH,3)1)-pyrimidine
Dione (224) 1,3-dimethyl-6-(4-(2
-(2-benzoyl-4-nitrophenoxy)ethylco
piperazin-1-yl) -2,4(1)1.38)-
Pyrimidinedione (225) 1,3-dimethyl-6-
(4-<2-[2-(4-bromobenzoyl)-4-di
trophenoxy]ethyl〉piperazin-1-yl) -
2,4(IH,3H)-pyrimidinedione (226)
1.3-dimethyl-6-(4-(2-(3-acetyl-
4-nitrophenyl)ethylcopiperazin-1-yl)
-2,4(1)1.31()-pyrimidinedione(22
7) 1,3-dimethyl-6-(4-[2-(2-nito
rho-4-acetyl)ethylcopiperazin-1-yl)
-2,4(It(.3)1)-pyrimidinedione (228) 1,3-dimethyl-6-(4-(2-(2
-Nitro-4-benzoyl)ethylcopiperazine-1-
yl)-2,4(1)1.3)1)-pyrimidinedione
(229) 1,3-dimethyl-6-(4-(3-[2
-(2-hydroxybenzoyl)-4-nitrophenoki
[C]propyl-1-piperazin-1-yl)-2,4(I
H,3) 1)-pyrimidinedione (230) 1.3-dimethyl-6-(4-(3-[2
-(2-chlorobenzoyl)-4-nitrophenoxy]
propyl)piperazin-1-yl)-2,4(IH,
3H)-pyrimidinedione (231) 1,3-dimethy
-6-(4-(3-(4-nitro-2-(2-pyridi)
carbonyl)phenylthio]propyl 1piperazine-
1-yl'j -2,4(IH,3H)-pyrimidine di
(232) 3-methyl-6-(4-[3-(4-nito)
rho-2-benzoylphenoxy)propylcopiperazine
-1-yl) -2,4(IH,31()-pyrimidine
Dione (233) 1,3-dimethyl-6-(2-[3
-(2-benzoyl-4-nitrophenoxy)propyl
aminocoethylamino) -2,4(IH,3)1)-
Pyrimidinedione (234) 1,3-dimethyl-6-
(2-(N-ethyl-3-(4-benzoyl-2-nito)
lophenoxy)propylaminocoethylamino') -
2,4(IH,3H)-pyrimidinedione (235)
1.3-dimethyl-6-(4-[2-(2-benzoy
-4-nitrophenylthio)ethyl J-piperazine-1-
-2,4(Ill, 3H)-pyrimidinedio
(236) 1,3-dimethyl-6-[4-(2-beta)
(nzoyl-4-nitrophenyl)piperazin-1-yl
] -2,4(IH. 3) 1)-pyrimidinedione (237) 1,3-dimethyl-6-(3-[4-di
Thoro-2-(3-pyridinecarbonyl)phenylamino
copropylamino) -2,4(18,3)1)-pyri
Midinedione (238) 1,3-dimethyl-6-[3
-(2-benzoyl-4-nitrophenylamino)pro
pyramino]-2,4(1)I. 3H)-pyrimidinedione (239) 1,3-dimethyl-6-[2-(2-ben
zoyl-4-nitrophenylamino)ethylamino]
-2,4(IH.3H)-pyrimidinedione (240) 1,3-dimethyl-6-(2-[4-di
Thoro-2-(3-pyridinecarbonyl)phenylamino
coethylamino) -2,4(IH,3)1)-pyrimi
Jindione (241) 1,3-dimethyl-6-(4-
(2-(2-benzoyl-4-nitrophenyl)ethyl
Copiperazin-l-yl)-2,4(Ill, 31
1)-Pyrimidinedione (242) 1,3-dimethyl
-6-(4-((2-benzoyl-4-nitrophenyl)
) methylcopiperazin-1-yl)-2,4(IH,3
)1)-pyrimidinedione (243) 1,3-dimethy
-6-(2-((2-benzoyl-4-nitrophenyl)
methylaminocoethylamino)-2,4(1)1.
3) 1)-pyrimidinedione (244) 1.3-dime
Chil-6-(4-[3-(4-benzoyl-2-nitro)
phenyl)propylcopiperazin-1-yl) -2,
4(IH,3H)-pyrimidinedione (245) 1,
3-dimethyl-6-(4-(2-(4-benzoyl-2
-nitrophenyl)ethylcopiperazin-1-yl)
-2,4(1)1.3)1)-pyrimidinedione (24
6) 1,3-dimethyl-6-(4-(3-(3-methy)
-4-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(Ill, 3)1)-pyrimi
Jindione (247) 1,3-dimethyl-6-(4-
(3-(4-chloro-2-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(IH,3H
)-pyrimidinedione (248) 1,3-dimethyl-
6-(4-(3-(2-chloro-4-nitrophenyl)
xy)propylcopiperazin-1-yl) -2,4(
II(,3)1)-pyrimidinedione (249) 1.
3-dimethyl-6-(4-(3-(4-methacylsulfonate)
Amido-2-nitrophenyloxy)propylcopype
Radin-1-yl)-2,4(1)1.3H)-pyri
Midinedione (250) 1,3-dimethyl-6-(4-(3-(4
-acetamido-2-nitrophenyloxy)propylco
piperazin-1-yl)-2,4(IH,3H)-pi
Rimidinedione (251) 1,3-dimethyl-6-(
4-(3-(2-hydroxy-5-nitrophenyloxy)
c) propylcopiperazin-1-yl) -2,4(I
H, 3) 1)-pyrimidinedione (252) 1.3-
dimethyl-6-(4-(3-(2-allyloxy-5-
Nitrophenyloxy)propylcopiperazine-1-y
-2,4(IH,3H)-pyrimidinedione (2
53) 1,3-dimethyl-6-(4-[3-(4-methyl
Tylthio-2-nitrophenyloxy)propyl copy paste
Radin-1-yl)-2,4(IH,3H)-pyrimi
Jindione (254) 1,3-dimethyl-6-(4-
<3-[2-(α-hydroxybenzyl)-4-nitro
phenyloxy]propyl>piperazine-■-yl)
-2,4(IH,3H)-pyrimidinedione (255) 1,3-dimethyl-6-(4-[3-(3
-trifluoromethyl-4-nitrophenyloxy)
ropilcopiperazin-1-yl)-2,4(IH,3
H)-pyrimidinedione (256) 1.3-dimethyl-6-(4-(3-(2
-methoxycarbonyl-4-nitrophenyloxy)
ropilcopiperazin-1-yl) -2,4(lH,3
H)-pyrimidinedione (257) 1,3-dimethyl-6-(4-(3-(2
-carboxy-4-nitrophenyloxy)propylco
piperazin-1-yl) -2,4(IH,3)1)-
Pyrimidinedione (25B) 1,3-dimethyl-6-
(4-[3-(2-amino-4-nitrophenyloxy
) propylcopiperazin-l-yl) -2,4(18
,3)1)-pyrimidinedione (259) 1,3-di
Methyl-6-(4-[3-(4-methoxycarbonyl-
2-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3)1)-pyrimidinedio
(260) 1,3-dimethyl-6-(4-(3-(2
-cyano-4-nitrophenyloxy)propyl copy paste
Radin-1-yl)-2,4(IH,38)-pyrimi
Jindione (261) 1,3-dimethyl-6-(4-
(3-(2-cyano-4-nitrophenylamino)pro
pyrcopiperazin-1-yl) -2,4(18,3H
)-pyrimidinedione (262) 1,3-dimethyl-
6-(4-(3-(2-ri-4-nitrophenyl)
(mino)propylcopiperazin-1-yl) -2,4(
IH, 3) 1)-pyrimidinedione (263) 1.3
-dimethyl-6-(4-(3-(2-methoxy-5-di
trophenyloxy)propyl 1-piperazin-1-yl
) -2,4(1)1.3H)-pyrimidinedione(2
64) 1,3-dimethyru6- (4-[3-(
2-allyloxy-4-nitrophenyloxy)propyl
rucopiperazin-1-yl)-2,4(IH,3)1
)-pyrimidinedione (265) 1,3-dimethyl-
6-(4-[3-(2-hydroxy-4-nitropheny)
((oxy)propylcopiperazin-1-yl) -2,
4(IH,3)1)-pyrimidinedione (266) 1
．． 3-dimethyl-6-(4-[3-(2-benzylamine)
No-4-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(IH,3)1)-pyrimidine
Dione (267) 1,3-dimethyl-6-(4-(3
-(2-methoxy-4-nitrophenyloxy)propyl
lucopiperazin-1-yl) -2,4(IH,3H)
-pyrimidinedione (268) 1,3-dimethyl-6
-(4-(3-(2,6-dichloro-4-nitrophenylate)
((oxy)propylcopiperazin-1-yl) -2,
4(1)1.3H)-pyrimidinedione Compounds of the invention
As shown in the above general formula (1), phenyl
moiety and pyrimidinedione moiety contain at least two nitrogen atoms.
Basics connected by a structure mainly composed of alkyl chains containing
This basic skeleton exerts pharmacological effects.
It is estimated that That is, the compound represented by the above general formula (1) is as follows:
When applied to arrhythmia pathology models such as
The compound also showed efficacy. Blood fake 1 u se Lヱ± Mongrel adult dog was treated with bentoparbital sodium (30 mg/
kg, intravenous administration), A, L, Goldb
The method of Erger et al. (International J
our own of Cardiology. 13, pp. 47-55, 1986).
Created a model. Using this atrial fibrillation model, we
The effect of the bright compound on the atrial fibrillation model is 0, I
Examined by intravenous administration at a dose of 10 mg/kg of N
However, all of the compounds of the present invention are effective against atrial fibrillation.
The therapeutic effect was observed. Blood 1 Ibarasako Ee mongrel adult dog was treated with bentoparbital sodium (30mg/
kg, intravenous administration). Left side under artificial respiration
Left anterior descending technique that opens the chest between the 4 costal spaces and locates near the tip of the auricle.
The coronary artery was ligated. Blood flow resumes 120 minutes after ligation
A myocardial infarction lesion that easily induces tachycardia was created. Below, Lynch's method (Journal Cardi
Ovascular Pharmacology, Volume 6
, pp. 1132-1141, 1984).
A ventricular tachycardia model was created by inducing heartbeats. For this model, the compound of the present invention was applied at 0.1 to 3 m
When administered intravenously at a dose of
The therapeutic effect was observed. Thus, the compound of the present invention is a model of arrhythmia pathology.
Effective treatment in atrial fibrillation and ventricular tachycardia models
It is effective in treating or preventing arrhythmia. Furthermore, the effects of the compounds of the present invention on cardiac function were investigated.
However, the following results were obtained. Ventoparbitalna mongrel dog (weight = 8-15 kg)
Anesthetized with thorium (30 mg/kg - intravenous administration) and
Insert the microsensor catheter into the left ventricle from the common artery.
The first derivative of left ventricular pressure (dp/dt) and electrocardiogram
Compounds of the present invention are tested using a test system that allows the recording of diagrams.
(di)/d by intravenous administration (1 mg/kg) of
t) and electrocardiogram changes were investigated. As a result, the compounds of the present invention significantly reduced dp/dt maX
and significantly prolong QTc on electrocardiogram.
I let it happen. Therefore, the compounds of the present invention have antiarrhythmic effects, especially class II type.
It was confirmed that it is useful as an antiarrhythmic drug. Also,
Significant increase in dp/dt max by compounds of the invention
The compound of the present invention has a positive inotropic effect and can be used for the treatment of heart failure.
It has been shown to be useful as a medicine. As mentioned earlier, in patients with arrhythmia, cardiac function
are often reduced, and in these patients, e.g.
Administer antiarrhythmic drugs classified as Class I and Class ■ mentioned above.
When used, these may have an antiarrhythmic effect as well as a negative inotropic effect.
Effects (effects that further reduce cardiac function) may be more or less
Therefore, sufficient care must be taken when using it (E
ivindS, Platous, Journal o
f Cardiovascular Pharma-c
ology, Vol. 8, No. 3, p. 459, 1986). In contrast, as mentioned above, the compounds of the present invention are antiarrhythmic.
Positive effect that significantly increases dp/dt max at the same time as action
Because it has an inotropic effect, it can be used in arrhythmia patients with decreased cardiac function.
It can be expected that this will bring good results to people as well. Next, representative methods for producing the compound of general formula (1) of the present invention
However, the present invention is not limited to these manufacturing methods.
It is not determined. Among the compounds of the general formula (1), the following general formula (2) ... (2) [wherein R1'' is a hydrogen atom, a lower alkyloxycarboxylic
Nyl group, unsaturated lower alkyl group or lower alkyl group (
If any one hydrogen atom of the alkyl group is a hydroxyl group,
alkylamino group, di-lower alkylamino group, lower alkylamino group,
alkyloxy group, lower alkanoyloxy group, benzoyloxy group
alkyloxy group, halogen atom or lower alkyloxy group
benzoyloxy group, phenyl group, halide substituted with
Substituted by rogene atom or lower alkyloxy group
phenyl group or lower alkyloxycarbonyl group
substituted with a substituent selected from the group consisting of
), and R1'' and R2 are connected to form an alkylene chain.
A heterocyclic structure may be formed by
Compounds defined in the same way as in (1)]
The product can be manufactured according to a method comprising the following step a):
Wear. Step a): The following general formula (9) [In this formula, xl and x2 are in the general formula (1) above]
A compound represented by the following general formula (1O) [wherein R1'' is defined as in the above general formula (2)]
, R'', R', R', X', n and k are the general formula
(defined in the same way as in (1))] in the presence of a dehydration condensation agent
Reacts while dissolved or suspended in a solvent or dispersant
(Application of Mitsunobu reaction; O, Mitun
obu, 5ynthesis, pp. 1-28, 1
(981), it was possible to obtain the compound of the general formula (2).
Wear. The reaction is carried out at a temperature below the reflux temperature of the solvent or dispersant used.
For example, more preferably in the range of -10 to 80°C.
selected from. As the dehydration condensation agent used in this reaction, ordinary ether
Various dehydration condensation agents used for bond formation
available, especially diethyl azodicarboxylate and truffles.
A mixed condensing agent of phenylphosphine is mentioned as a suitable one.
can be done. Suitable solvents or dispersants for this reaction include
Any solvent or dispersant that is inert to the reaction can be used without restriction.
For example, tetrahydrofuran, dimethylformamide
Hydrochloride, chloroform, dichloromethane, dioxane, etc.
Can be used. Next, among the compounds of the general formula (1), the following general formula (
4) B” represents an oxygen atom, a sulfur atom or -N-, and R6 represents water
Elementary atom, lower alkanoyl group, lower alkylsulfonyl
or lower alkyl group, or R1 and R6 are connected
Even if a heterocyclic structure is formed by forming an alkylene chain,
Often, k represents a number chosen from 2, 3.4, XI, X'',
R1, R'', R3, R', X3 and n are represented by the general formula (1
) is prepared according to a method comprising the following step b).
can be built. Step b): Following - Formula (11) [wherein, Y2 represents a halogen atom, Xl and x2 are
A compound represented by the following formula (12) [wherein A'' is defined as in formula (4) above]
and RI R2R3R4x3 and n are defined as above.
- defined in the same way as in formula (1) and represented by ] without using a solvent or by
Reacts while dissolved or suspended in a suitable solvent or dispersant.
to obtain the compound of formula (4) above.
Can be done. This reaction takes place from room temperature to below the reflux temperature of the reaction mixture.
temperature, for example, more preferably 20 to 150°C
selected from the range. In addition, by coexisting a base in the reaction solution, the reaction can be further enhanced.
This can be carried out favorably. Suitable solvents or dispersants for this reaction include
Any solvent or dispersant that is inert to the reaction may be used without restriction.
Alcohols such as methanol and ethanol can be used.
, tetrahydrofuran, dimethylformamide, chloro
loform, dichloromethane, dioxane, benzene, dichloroform,
Methyl sulfoxide etc. can be used. In addition, bases that have the effect of promoting this reaction include:
For example, triethylamine, pyridine, potassium carbonate, charcoal
Examples include sodium acid, sodium hydroxide, etc.
Ru. Next, among the compounds of the formula (1), the following formula (
3) [In the formula, A° is -(CH2)---8'-(CH*)k-
or R8° is a hydrogen atom, a lower alkanoyl group, a lower alkanoyl group,
Indicates a killsulfonyl group or a lower alkyl group, but
does not form a heterocyclic structure with R1''), m is 0, 1, 2,
From 3.4, k is chosen independently from 2 and 3.4.
R1'' is the number in formula (2) above.
Similarly defined, R2, R3, R4, XI, X2,
X3 and n are defined as in formula (1) above.
] The compound represented by is produced according to the method including the following step C)
can be built. Step C): The following formula (13) [wherein, Yl is a halogen atom or the following formula (14)]
Indicates a substituent that becomes a leaving group during the reaction with XI and
and x2 are - As in formula (1) above, Ao is
A compound represented by the following formula (14) [wherein R1'' is defined as in formula (2) above]
, R2, R3, R4, X3 and n are as shown in formula (1) above.
is defined in the same way as
Mix without a solvent or dissolve in a suitable solvent or dispersant.
The above-mentioned -
A compound of formula (3) can be obtained. This reaction takes place from room temperature to below the reflux temperature of the reaction mixture.
temperature, for example, more preferably from 20 to 170°C
selected from the range. In addition, by coexisting a base in the reaction solution, the reaction can be further enhanced.
It can be carried out favorably. Suitable solvents or dispersants for this reaction include
Any solvent or dispersant that is inert to the reaction may be used without restriction.
For example, those exemplified in the explanation of step b) above can be used.
Can be used. In addition, examples of bases useful for promoting this reaction include
For example, those exemplified in the description of step b) above can be used. Said - compound of formula (1) is subjected to a method comprising the following step d):
It can also be manufactured. Step d): The following formula (15) [wherein A,
and the following formula (16) [wherein, Y3 is a halogen atom]. is the above-formula (15
) represents a substituent that becomes a leaving group upon reaction with
Using a solvent with a compound represented by similarly defined
or dissolved or suspended in a suitable solvent or dispersant.
By reacting in a cloudy state, the above formula (1)
can be obtained. This reaction takes place from room temperature to below the reflux temperature of the reaction mixture.
temperature, for example, more preferably 20 to 150°C
selected from the range. In addition, by coexisting a base in the reaction solution, this reaction
can proceed more preferably. Suitable solvents or dispersants for this reaction include
Any solvent or dispersant that is inert to the reaction may be used without restriction.
For example, those exemplified in the explanation of step b) above can be used.
Can be used. In addition, examples of bases useful for promoting this reaction include
For example, those exemplified in the description of step b) above can be used. Next, among the compounds of the formula (1), the following formula (
5) [In the formula, A is -(C)12) ---8-(CH2)
k-, -CO-, Rlo is a hydrogen atom, a lower alkyloxycarbonyl group,
Unsaturated lower alkyl group or lower alkyl group (the alkyl
Any one hydrogen atom of the group is a hydroxyl group, a mono-lower alkyl group
lyamino group, di-lower alkylamino group, lower alkylamino group
xy group, lower alkanoyloxy group, benzoyloxy group
substituted by a group, a halogen atom or a lower alkyloxy group.
Substituted benzoyloxy group, phenyl group, halogen source
phenyloxy substituted with a lower alkyloxy group or a lower alkyloxy group
or lower alkyloxycarbonyl group
It may be substituted with a substituent selected from the group. ), and by linking with R8 to form an alkylene chain.
may form a heterocyclic structure, but it may be complex with other parts.
It does not form a ring structure, and R″ is a hydrogen atom, a lower alkanoyl group, or a lower alkyl group.
Represents a sulfonyl group or lower alkyl group, XI, X2
, X3, R3 and R4 are in the general formula (1) above.
The compound represented by [defined in the same manner as
). Step e): Following formula (17) [wherein XI and x2 are as in formula (1) above]
Similarly, A and Rl' are defined in the equation (5) above.
A compound represented by the following formula (18) [wherein R', R' and X3 are defined in the same manner as in formula (1)]
] without using a solvent or by mixing with a compound represented by
Reacts while dissolved or suspended in a suitable solvent or dispersant.
to obtain the compound of formula (5) above.
Can be done. This reaction takes place from room temperature to below the reflux temperature of the reaction mixture.
temperature, for example, more preferably 20 to 180°C
selected from the range. In addition, by coexisting an acid catalyst in the reaction solution, this reaction
This allows the reaction to proceed more favorably. Suitable solvents or dispersants for this reaction include
Any solvent or dispersant that is inert to the reaction may be used without restriction.
For example, those exemplified in the explanation of step b) above can be used.
Can be used. Further, as the acid catalyst, for example, p-toluenesulfonate
acidic acid, acidic ion exchange resin [e.g. trade name Amberlys]
(U.S. Rohm & Haas Company, product name Amberly)
15 etc.)]. Among the compounds of formula (1), the following formula (7) [wherein A is -(CHt), -1-B-(CHz) 1
, R' O B represents an oxygen atom, a sulfur atom, -N-, -CNH- or (1 100-), 0HO D represents -NHC-, -CH- or -C-, R1' Reach
and R2' each independently represent a hydrogen atom, lower alkyloxy
Carbonyl group, unsaturated lower alkyl group or lower alkyl group
group (any one hydrogen atom of the alkyl group is a hydroxyl group,
mono-lower alkylamino group, di-lower alkylamino group,
lower alkyloxy group, lower alkanoyloxy group,
Zoyloxy group, halogen atom or lower alkyl group
benzoyloxy group substituted by xy group, phenyl
substituted by a group, a halogen atom or a lower alkyloxy group.
substituted phenyl group or lower alkyloxycarboxylate
substituted with a substituent selected from the group consisting of
), R5 is a hydrogen atom, a lower alkanoyl group, a lower alkyl group
Represents a sulfonyl group or a lower alkyl group, or R1゛ and R1
A heterocyclic structure is created by connecting ゛ to form an alkylene chain.
In X', X'', X', R', R', m, A and n may form
The compound represented by - defined in the same manner as in formula (1) above is prepared by a method comprising the following step f).
can also be manufactured. Step f): That is, the compound represented by formula (17);
Below - Formula (19) [In the formula, R2' is a hydrogen atom, a lower alkyloxy group
Nyl group, unsaturated lower alkyl group or lower alkyl group (
If any one hydrogen atom of the alkyl group is a hydroxyl group,
alkylamino group, di-lower alkylamino group, lower alkylamino group,
alkyloxy group, lower alkanoyloxy group, benzoyloxy group
alkyloxy group, halogen atom or lower alkyloxy group
benzoyloxy group, phenyl group, halide substituted with
Substituted by rogene atom or lower alkyloxy group
phenyl group or lower alkyloxycarbonyl group
substituted with a substituent selected from the group consisting of
Good too. ) and does not combine with R' to form a heterocycle
, and R', R', X3 and n are the above formula (1
), and Y4 is a halogen atom or a reaction with the above-mentioned formula (17)
Indicates a substituent that becomes a leaving group when
and the compound according to the same method as in step C) above.
The compound of formula (7) above can be obtained by
Ru. Among the compounds of the above formula (1), the following formula (8) [wherein A°°゛ is -(CH2)--8"'-(C
H2) k-, and R''O B°゛° is an oxygen atom, a sulfur atom, -N-, -CNH-
or 100-, Rl''' and R2' independently represent a hydrogen atom, a lower alkali
Kyloxycarbonyl group, unsaturated lower alkyl group or
Lower alkyl group (any one hydrogen atom of the alkyl group)
is hydroxyl group, mono-lower alkylamino group, di-lower alkyl
Amino group, lower alkyloxy group, lower alkanoyl group
xy group, benzoyloxy group, halogen atom or lower
benzoyloxy group substituted by alkyloxy group
,) engineering nyl group, halogen atom or lower alkyloxy
phenyl group or lower alkyl group substituted with
by a substituent selected from the group consisting of xycarbonyl group.
), which may be substituted with R2'' and R′゛
and R′1° are not connected, and R2°c is similar to the above-mentioned formula (7),
, R3, R4 and n are R
'' is defined in the same way as the formula (3) above] The compound represented by
It can also be manufactured. Step g): Following formula (20) [wherein A and R2' are as in formula (7) above]
Similarly defined, XI, ) cm, X3, R
3R4 and n are defined as in formula (1) above.
defined] and a compound represented by the following formula (21) % formula % (21) [wherein Y4 is a halogen atom or the above formula (20)
Indicates a substituent that becomes a leaving group when reacting with R1=
``゛ is defined in the same way as in equation (8) above.
] in the same manner as in step C) above.
By treating according to the above formula (8), the compound of formula (8) can be obtained.
Obtainable. In addition, the compounds used in the above manufacturing method
In Yl, Y3 and Y4, it becomes a leaving group and
As a substituent, para-toluenesulfonyloxy group etc.
Arylsulfonyloxy group, methanesulfonyloxy
Examples include alkylsulfonyloxy groups such as
can. In each of the above formulas, R1 is multiple with each of R2 and R5.
Indicates a ring that may form a bare ring, and R' is a complex with only R5.
Indicates what may form an elementary ring, R1゛ is only R2
Indicates compounds that may form a heterocycle. Rl"', R2°, and R5' are each complex with other parts.
Indicates something that does not form a ring. The above-mentioned compound of formula (18) is prepared by a method comprising the following step f)
It can be manufactured in Step f): The compound represented by formula (15) and 2-amino
and ethanol according to the same method as in step d) above.
By doing so, the following formula (21) [where x3, R
1 and R4 are defined as in formula (1) above.
] After forming the compound represented by
chloride, tri-toluenesulfonyl chloride, etc.
sulfonate, or thionyl chloride, tribromine
converted into a halide by phosphorus, etc., and then converted to sodium hydride
, acetonitrile in the presence of a base such as sodium hydroxide
, chloroform, toluene, benzene, dimethyl sulfo
Stir in a solvent such as oxide or methanol at room temperature or under heat.
Then, the compound of formula (18) can be obtained.
. On the other hand, the pharmacologically acceptable compound of formula (1)
An acid addition salt is a compound of the above-mentioned formula (1) added to water or an organic compound.
in a solvent or a mixed solvent thereof, e.g. hydrochloric acid, water bromide
Basic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fluoric acid
Inorganic acids such as malic acid, oxalic acid, methanesulfonic acid, etc.
can be produced by reacting with an organic acid. The above-mentioned compound of formula (1) and its acid addition salt of the present invention
Cardiac dysfunction improving agents such as arrhythmia treatment agents and heart failure treatment agents.
When used as an active ingredient, the dosage and dosage form should be
This may vary depending on the physical properties of the compound of the present invention used and the symptoms of the subject to whom it is administered.
However, for example, 10 to 1000 mg per day for adults, preferably
Preferably 10 to 500 mg orally, tablets, granules,
As powders, suspensions, capsules, etc., and parenterally,
For example, waste drugs, injections, isotonic solutions for infusion, or inhalants,
It can be administered as a patch. In the case of intravenous injection, the dosage is, for example, for adults - 1 to 100 doses per day.
0mg, preferably 1-300mg
. The general method for producing the pharmaceutical composition of the present invention includes, for example, the pharmaceutical composition of the present invention.
compounds in cottonseed oil, corn oil, peanut oil,
Non-aqueous by dissolving in any amount of oil selected from leave oil etc.
Method for making an injection: Further, water is added to the compound of the present invention to dissolve it.
as a liquid or also as a suspended liquid in the presence of a suitable surfactant.
or as an emulsion, respectively, to form an aqueous injection;
In addition, when forming tablets, the compound of the present invention may contain lactose, corn, etc.
Adding oxidized starch, crystalline cellulose, etc., the final stage is
A method of preparing a preparation by adding magnesium alinate; etc.
However, it is not limited to the above manufacturing method,
It is also possible to create a drug using other normal manufacturing methods.
Ru. [Effect of the invention 1 Antiarrhythmic drugs and heart failure therapeutic drugs useful by the compounds of the present invention
is provided. [Example] Next, the present invention will be explained in more detail with reference to Examples.
However, the present invention is not limited to the following examples. Example 1 1.3-dimethyl-6-(4-(4-nitrophenyl)
piperazin-1-yl]-2,4(IN, 3)1)
-Production of pyrimidinedione (compound 1) First, 0.36 ml of 4-fluoronitrobenzene and 1
．． 3-dimethyl-6-(piperazin-I-yl)-2
,4(1)1゜3)1)-pyrimidinedione (compound 2
) and sodium bicarbonate Ig in dimethyl sulfate.
Add to 5 ml of Phoxide and react at 100℃ for 3 hours.
After that, the reaction mixture was poured into 50 ml of water, and this was
It was subjected to form extraction. Next, wash the chloroform extract with water and add anhydrous magnesium sulfate.
After drying with a vacuum, the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform/
Methanol = 40:l, volume ratio) and 1,3-dimethyl
-6-(4-(4-nitrophenyl)piperazine-1-
Illco2.4 (Ill, 3)1)-Pyrimidine
On (compound 1) 0.44 g was obtained. Analysis results of the obtained crystals of compound 1: Melting point = 249-250°C 1340, 840° NMR (da-DMSDI, δppm: 8.13.6
．． 98 (dx2, 2Hx21゜5, 23 (s, E)
. 3.23. 3.36 (Sx2, 3Hx2). 3,0 (m, 8)1) Elemental analysis value Cl11) Calculated as IlllN804
Value (%): C, 55, 65; H, 5, 55; N
, 20.28 Analysis value (%): C, 55, 34, H
,5,76,N, 20.46 Example 2 1.3-dimethyl-6-[4-(4-nitrobenzyl)
piperazin-1-yl]-2,4(IH93)1)-pi
Production of rimidinedione oxalate (compound 3) First, 0.48 g of 4-nitrobenzyl bromide, 1
．． 3-dimethyl-6-(piperazin-1-yl)-2
, 4(IH. 3) 1)-pyrimidinedione (compound 2) 0.5 g and
0.5ml of triethylamine and 5ml of isopropanol
After heating and refluxing the resulting suspension for 8 hours,
The solvent was distilled off from the resulting reaction mixture under reduced pressure, and the residue was
After dissolving in chloroform and washing with water, remove the washed organic layer.
Dry with sodium hydroxide sulfate. Furthermore, it is dried
The organic layer was treated under reduced pressure, the solvent was distilled off, and the residue was silicaed.
Kagel column chromatography purification (chloroform/methanol
= 50/1~2゜/1, capacity ratio), 1.3-dime
Chil-6-[4-(4-nitrobenzyl)piperazine-
1-ilco2.4 (1)1.3)1) -pyrimidi
0.88 g of dione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13), δppm: 2.6 (m,
2) 1) , 3. O(m, 2)1). 3.22. 3.34 (Sx2.3Hx2). 3, 36 (S, 2)ri, 5.14 (S,
1)1). 7.55. 8.17 (dx2, 2Hx2) Next,
This pyrimidinedione derivative was prepared using oxalic acid/method in a conventional manner.
1,3-dimethyl-6-[4-
(4-nitrobenzyl)piperazin-1-yl'J −
2,4(IH,3)1)-pyrimidinedione oxalic acid
A salt (compound 3) was obtained. Analysis results of the obtained crystals of Compound 3: Melting point = 211-212°C (decomposition) IRv (am-'): 2950.1720.16
70. +650°aX 1620, 1520. 1360. 760 elemental analysis
Value Cl7H21NSO4・(COOH)2 meter
Calculated value (%): C, 50, 78; H, 5, +6;
N, 15.58 Analysis value (%): C, 50,70,
H,5,44: N, 15.77 Example 3 1.3-dimethyl-6-(2-<N-ethyl-N-(3
-(4-nitrophenyl)propylcoaminoethyla
Mino)-2,4(IH,3H)-pyrimidinedione salt
Production of acid salt (compound 4) (1) 1.3-dimethyl-6-[2-(p-toluene)
sulfonyloxy)ethylamino] -2,4(IH
,3H)-pyrimidinedione (compound 5) 35.0 g of 2-2-amine ethanol was heated to 90°C,
Remove from oil bath and add 6-chloro-1,3-dimethyl-
Add 50.0 g of 2,4-dioxopyrimidine and
reacted. At this time, the addition is carried out at a reaction temperature of 90 to 11
The speed was such that the temperature was maintained in the 0°C range. End of addition
After the reaction mixture was stirred for 10 minutes, dioxicate was added to it.
San/methanol (=10/1.volume ratio) 300ml
- Add a small amount of dioxane to the crystals obtained by standing overnight.
1,3-dimethyl-6-(2-hydrochloride)
(oxyethylamino)-2,4(I)1,3H)-pi
49.0 g of white crystals of rimidinedione were obtained. Next, 49.0 g of this white crystal was suspended in 200 ml of pyridine.
The suspension was cooled to -5°C, and p-toluenesulfonyl was added to it.
40.0g of chloride was added without the reaction temperature rising above 5℃.
added at a fast speed. Even though the suspension in the reaction solution completely disappears
Furthermore, p-toluenesulfonyl chloride 51.0g
It was used. Furthermore, the obtained reaction mixture was added containing 70 g of KxCOs.
Pour into ice water 1.5β, leave overnight, and collect the resulting crystals.
Collected by filtration, washed with water, and dried under reduced pressure to obtain 1,3-dimethylene.
-6-[2-(p-toluenesulfonyloxy)ethyl
Ruamino]-2,4(IH,3-former-pyrimidinedione(
50.5 g of pale yellow crystals of compound 5) were obtained. Analysis results of the obtained crystals of Compound 5; Melting point: 146.0-149.0°C 1480, 1435. 1360. ．． 1190°1!
78. 1010,903. 780(2) 6-
(1-aziridinyl)-1,3-dimethyl-2,4(I
) Preparation of 13H)-pyrimidinedione (compound 6): Previous
47.2 g of anhydrous dimethyl sulfoxy of compound 5 obtained in
Add 60% oily sodium hydride to 150 ml of solution at room temperature.
6.24 g of lium was gradually added. The obtained mixture is
After further stirring vigorously for 5 hours at room temperature, it was cooled and a small amount of
Water was added to stop the reaction. Add 70g of potassium carbonate to this
Pour into 1β of water containing 20’Om of chloroform and 3
Extract twice and dry the combined organic layers with anhydrous sodium sulfate.
After concentration, add 300 ml of ether to the obtained concentrate.
I left it overnight. The pale yellow crystals precipitated by standing overnight were collected by filtration, and
After washing, dry under reduced pressure to obtain 6-(1-aziridine).
)-1,3-dimethyl-2,4(IH,311)-pi
15.2 g of rimidinedione (compound 6) was obtained. Analysis results of the obtained crystals of compound 6; Melting point: 126.0-126.5°C 1305, 1160,783,490'H-NMR (
CDC13), δppm+ 2.34 (s, 4H),
3.35 (s, 38). 3.56 (s, 3) 1), 5.25 (s, IH) (
3) 1,3-dimethyl-6-(2-(N-ethyl
-N-[3-(4-nitrophenyl)propylcoamino
〉ethylamino)-2,4(II(,3)1)pyrimidine
Preparation of Ndione Hydrochloride (Compound 4): N-Ethyl-N-(3-(4-nitrophenyl)propyl)
1.28 g of lucoamino (compound 7) and the previously obtained 6-
(l-aziridinyl)-1,3-dimethyl-2,4(I
H,31()-pyrimidinedione (compound 6) 1.1
After dissolving and mixing 1 g of chloroform in 5 ml of chloroform, the obtained
Concentrate the mixed solution under reduced pressure, and add amber to the residue (concentrate).
-List 15 (manufactured by Rohm and Haas) 10m
g and heated at 80° C. for 1 hour. Next, the resulting reaction mixture was dissolved in 20 ml of ethyl acetate.
After filtering off the amberlyst, add n-hexane to the filtrate.
Added 30ml. This was left overnight, and the precipitated pale yellow crystals were collected by filtration.
After washing, drying under reduced pressure to obtain 1,3-dimethyl-6
-(2-(N-ethyl-N-[3-(4-nitrophenylate)
(l)propylcoamino>ethylamino)-2,4(il)
l. 3) 2.20 g of 1)-pyrimidinedione was obtained. This was further recrystallized from ethyl acetate-〇-hexane,
It was collected by filtration, washed, and dried to obtain 1.85 g of pale yellow crystals. Analysis results of the crystals of this pyrimidinedione derivative obtained
: +600. 1545. 1515. 1345°12
05.770,755'H-NMR (CDCh), δppm: 1.07
ft, 3H,, b7.5Hz). 1,90 (m, 2H). 2, 17-3.27 (m, 10) 1). 3,37 (s, 3)1), 3.44 (s,
3+1). 4,90 (s, IH). 5, 64 (brs, I)I). 7,47 (m, 2H), 8.30 (m,
2H) Elemental analysis value Calculated value as CIJ2JsO4 (
%): C, 58, 60,) I, 6.99; N,
17.98 Analysis value (%): C, 58, 61, H, 7,
41, N, 17.57 Furthermore, the above ethyl acetate -〇-
Salt the pale yellow crystals recrystallized from hexane using a conventional method.
Treatment with acid/methanol gave 1,3-dimethyl-6-(
2-<N-ethyl-N-[3-(4-nitrophenyl)
propylcoamino〉ethylamino)-2,4(IH,3
H) Amorphous powder of pyrimidinedione hydrochloride (compound 4)
I got the end. Analysis result of the obtained amorphous powder of compound 4: 345 Elemental analysis value Cl9827N804 Calculated as 8CI
Calculated value (%): C, 53, 58, H, 6, 63, N,
16.44; C1,8,33 Analysis value (%): C,53,11; H,6,8+,
N, +6.12°CI, 7.95 Example 4 1.3-dimethyl-6-(2-<N-(2-hydroxy
ethyl) -N-[3-(4-nitrophenyl)propyl
rucoamino)ethylamino)-2,4(IH,3)1)
-Production of pyrimidinedione fumarate (compound 8) (compound 9) (□CHCOOH) 2/. H, oH (1) N-(2-hydroxyethyl) -N-(3
-(4-nitrophenyl)propyl]amine (compound 9
) Preparation of 3-(4-nitrophenyl)propyl p-toluene
Ruphonate 37.5g, aminoethanol 125g and
A mixture of 65 ml of dioxane and dioxane was heated at 90 to 100°C for 3 hours.
The mixture was heated and stirred for a while. After stirring, the mixture was treated under reduced pressure.
The solvent was distilled off, and the residue was dissolved in 800 ml of loloform.
, washed with water at 1°C. The organic layer washed with water is 0.5N hydroxy acid.
After washing with aqueous sodium chloride solution and again with water,
Dry with sodium hydroxide sulfate. The dried organic layer was treated under reduced pressure and the solvent was distilled off.
, the residue was mixed with benzene/hexane (=2/I, volume ratio).
The obtained crystals are collected by filtration, washed, dried and washed with N.
-(2-hydroxyethyl) -N-[3-C4-nito
21 g of lophenyl)propyl]amine (compound 9) was obtained.
Ta. Analysis results of the obtained crystals of Compound 9: Melting point: 80.5-81°C (2) 1.3-dimethyl-6-(2-(N-(2-
hydroxyethyl)-N-[3-(4-nitrophenyl)
) propylcoamino>ethylamino)-2,4(IH,
31()-pyrimidinedione fumarate (compound 8)
Preparation of: Example 3-1,3-dimethyl-6 synthesized in (1)
12-(P-toluenesulfonyloxy)ethylamino
1-2, 4 (1) 1.3) 1)-pyrimidinedione (
Compound 5) 23.2g was dissolved in 350ml of methanol.
Then, 2.76 g of sodium hydroxide was gradually added to this.
Ta. After stirring the resulting mixture at 50 to 60°C for 1 hour,
The solvent was distilled off from the mixture under reduced pressure, and 12% of chloroform was added to the residue.
After adding 0ml, insoluble matter was filtered off. The filtrate contains N-(2
-Hydroxyethyl) -N-[3-(4-nitrophe)
17 g of nyl)propyl]amine (compound 9) and p-t
After adding 0.66 g of luenesulfonic acid, reduce the mixture.
The solvent was distilled off under pressure. The residue after solvent distillation is
Heat and stir at 80°C for 1 hour, and add chloroform 480
ml and extracted twice with 300ml of 0.5N hydrochloric acid.
. Add potassium carbonate to the extract (hydrochloric acid solution) to make it alkaline.
After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration. The obtained crystals were dried, recrystallized from ethanol, and filtered.
1,3-dimethyl-6-(2-(
N-(2-hydroxyethyl) -N-(3-(4-ni)
Trophenyl)propylcoaminoethylamino)-2
, 22.1 g of 4(IH,311)-pyrimidinedione
Obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: Melting point: 117.5-118.5°C 'H-NMR (CDC13), δppm: 1.86
(m, :1I) 2,48~3.00 (m, I
1)I). 3,00-3.26 (m, 2H). 3,27 (s, 3)1), 3.39 (s,
3H). 3.71 (m, 2H), 4.78 (s, IH). 6,06 (m, IH), 7.38 (d,
2+1). 8,18 (d, 2H) This pyrimidinedione derivative was treated with fumaric acid/metallic acid according to a conventional method.
1,3-dimethyl-6-(2-
(N-(2-hydroxyethyl) -N-[3-(4-
Nitrophenyl)propyl]7minoethylamino)-
2゜4 (1)I, 3H)-pyrimidinedione fuma
The ruate salt (compound 8) was obtained. Analysis results of the obtained crystals of Compound 8: Melting point: I52.5-153.5°C +600°555 520 450 +355°250 070 990°80 (3) 1.3-dimethyl-6-(2-<N- (2
-hydroxyethyl) -N-[3-(4-nitrophe)
nil)propyl1amino>ethylamino)-2,4(I
H,3H)-pyrimidinedione hydrochloride (compound 8')
Preparation: 1,3-dimethyl-6-(2-
<N-(2-hydroxyethyl) -N-[3-(4-
Nitrophenyl)propyl 1aminoethylamino)-
2,4(IH,3)11-pyrimidinedione (compound 8
Dissolve 2.6g of educt) in 26ml of methanol by heating.
, keeping the internal temperature at 40°C 13% HCl/MeOH (weight ratio)
2.7 ml was added dropwise. After cooling on ice and leaving overnight, remove the precipitated crystals.
1.3 by vacuum drying the obtained crystals.
-dimethyl-6-(2-<N-(2-hydroxyethyl
) -N-(3-(4-nitrophenyl)propyl 1a)
Mino〉ethylamino)-2,4(IH,3)1)-pyri
2.5 g of midinedione hydrochloride (compound 8') was obtained. Analysis results of the obtained compound 8': mp, 172-174°C IR (KBr) vmax (am-') 3230, 1
640.1605. +540.1340.1240°
Example 5 1,3-dimethyl-6-(4-[2-(2-nitrophe)
tyrcopiperazin-1-yl)-2,4(IH,
3) 1)-Pyridinedione oxalate (compound 10)
(1) 2-(2-nitrophenyl)ethyl bromide
Preparation of compound 11: 2.5 ml of 2-(2-nitrophenyl)ethanol and P
Stir and mix 5.4 ml of Brs at 0°C for 30 minutes to react.
The resulting reaction mixture was diluted with 30ml of benzene.
This was then poured into 30 ml of water. Separate the organic layer
After drying with anhydrous sodium sulfate, it was treated under reduced pressure.
The solvent was distilled off and 2-(2-nitrophenyl)ethyl bromine was added.
3 g of a crude product of Mide (Compound 11) was obtained. (211,3-dimethyl-6-(4-[2-(2-nito
lophenyl)ethylcopiperazin-1-yl)-2,4
(IH,3B)-pyrimidinedione oxalate (compound
Preparation of compound 10): 3.0 g of compound 11 obtained previously, 1
．． 3-dimethyl-6-(piperazin-1-yl)-2
,4(IH,3H)-pyrimidinedione (compound 2)3
．． 2g of triethylamine and 4.2ml of isopropylamine
The prepared mixture was added to 15 ml of water in the same manner as in Example 2.
1,3-dimethyl-6-44-[2-
(2-nitrophenyl)ethylcopiperazin-1-yl
)-2,4(IH,3H)-pyrimidinedione 2.2g
I got it. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13), δppm: 2, 7-3.0
(m, 12)1). 3,39 (s, 3H), 3.41 (s,
3H)5, II (s, 1)1), 7.53
(m, 3H)7,96 (m, IH) Furthermore, this pyrimidione derivative was dehydrated according to a conventional method.
Treated with acid/methanol solution to give 1,3-dimethyl-6-
(4-[2-(2-nitrophenyl)ethylcopiperadi)
(l-yl)-2,4(IH,3)1)-pyrimidine
Dione oxalate (compound 10) was obtained. Analysis results of the obtained crystals of compound IO; melting point: 212~
214℃ Elemental analysis value C+aHzJs04・(COOH) 2・
Calculated value (%) as %H20: C, 50, 85,)l
, 5.55. N, 14.82 Analysis value (%): C
,50,57; H,5,54; N, 14.441
630, 1550°1380°70 Example 6 1.3-dimethyl-6-(2-(4-nitroanilino)
Ruamino]-2,4(IH,3)1)-pyrimidinedio
Preparation of ethyl 1,3-dimethyl-6-(piperazin-1-yl)-2 (compound 12)
,4(II(,3)1)-pyrimidinedione (compound 2
) instead of 6-(2-aminoethylamino)-1,3-
Dimethyl-2,4(IH,3H)-pyrimidinedione (
Compound 13) Same as Example 1 except that 0.45 g was used.
1,3-dimethyl-6-[2-(4-nitro)
Anilino) ethylamino 1-2゜4 (1)l, 31
()-pyrimidinedione (compound 12) 0.5g was obtained.
Ta. Analysis results of the obtained crystals of compound 12: Melting point: 308°C
(Decomposition) NMR (DMSO-da) 1320.850 δppm: 2.9 (m, 2H), 3.1 (m,
2H) 3, 29 (s, 3H), 3.38 (s
, 3H). 5,09 (s, 1)1), 7.04 (d,
2H). 8, 09 (d, 21 () CI4) 52.66 as 117N1104: ) I, 5.37; N, 2
1.9352.55. H, 5, 34: N, 2
1.82 Elemental analysis value calculation value (%): C1 Analysis value (%): C1 Example 7 13-dimethyl-6-(4-[2-(4-nitrophenyl)
) ethylcopiperazin-1-yl)-2,4(DI,
31()-pyrimidinedione hydrochloride (compound 14)
Preparation of HCI/C)IsOH (Compound 14) Using 4-nitrophenin instead of 4-nitrobenzyl bromide
Same as Example 2 except that 0.51 g of netyl bromide was used.
Similarly, 1,3-dimethyl-6-(4-[2-(4
-nitrophenyl)ethylcopiperazin-1-yl)-
2°4 (IH,3H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13), δppm: 2.8 (m,
12) 1), 3.22 (s, 3H). 3.36(s, 3H), 5.19(s, 1)I). 7.36 (d, 2H), 8.12 (d, 2H). Furthermore, this pyrimidinedione derivative was treated with hydrochloric acid according to a conventional method.
/methanol solution to give 1,3-dimethyl-6-(
4-[2-(4-nitrophenyl)ethylcopiperazine
-1-yl)-2,4(IH,3)1)-pyrimidine di
Crystals of On.hydrochloride (Compound 14) were obtained. Analysis results of the obtained crystals of compound 14: Melting point: 263~
266℃ (decomposition) Elemental analysis value C+aHisNs04・HCI・0.5H
Calculated value (%) as 20: C, 51, 61: H, 6
,02,N, 16.72°CI, 8.46 Analysis value (%): C,51,78,H,6,28,N,
16.93°CI, 8.60 1630, 1520. 1350. 805 Example 8 1,3-dimethyl-6-[2-(4-nitrobenzyl urethane)
ethylamino]-2,4(IH,38)-pyrimidy
Production of dione oxalate (compound 15) (COOH) z/CH:+OH 1.3-dimethyl-6-(piperazin-■-yl) -
2,4(IH,314)-pyrimidinedione (compound 2
) instead of 6-(2-aminoethylamino)-1,3-
Dimethyl-2,4(IH,3H)-pyrimidinedione (
Same as Example 2 except using 0.45 g of compound 13)
1゜3-dimethyl-6-[2-(4-nitrobene)
ethylamino]-2,4(IH,3!(
)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13:DMSO-da-1:1), δp
pm: 2, 9 (m, 28), 3.2 (
m, 2H), 3.30 (s, 3H). 3,38 (s, 3)1), 3.60 (m,
2)1), 5.07 (s, IH). 7, 42 (d, 2H), 8.06 (d,
2H) Furthermore, this pyrimidinedione derivative is added according to a conventional method.
treated with oxalic acid/methanol solution, dimethyl-6
-[2-(4-nitrobenzylamino)ruamino]-2
,4(IH,3H)-pyrimidinedione oxalate (compound
Crystals of product 15) were obtained. ■, 3- Analysis results of the obtained crystals of compound 15: Melting point: 203~
205°C (decomposition) IRvKBr (cm-'): 3150.2900.
1?10.1650゜ax 1640, 1630.870 Elemental analysis value C+sH+eNs04・(COOt()2
・Calculated value (%) as o, 5LO: C, 47, 22,
H, 5, 13, N, 16.20 analysis value (%): C,
47,04; H,4,40; N, 16.61 implementation
Example 9 1,3-dimethyl-6-(2-[2-(4-nitrophe)
nyl)ethylaminocoethylamino)-2,4(lH,
3) 1)-pyrimidinedione oxalate (compound 16
) (Compound 13) L=t13 (COO)1) z/CHsOH 4-nitrobenzyl bromide and 1,3-dimethyl-
6-Biverazin-1-yl) -2,4-(18,31
4)-pyrimidinedione (compound 2), 2-(
4-nitrophenyl)ethyl bromide 0.51g and 6
-(2-aminoethylamino)-1,3-dimethyl-2
,4(11(,3H)-pyrimidinedione (compound 13
) Same as Example 2 except that 0.45g was used.
, 1,3-dimethyl-6-(2-(2-(4-nitroph)
phenyl)ethylaminocoethylamino)-2,4(1)
1.3) 1)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCI, δppm: 2.7-3.2 (
m, 6) 1). 3,29 (s, 3)1), 3.37 (s,
3H). 3,51 (t, 2)1), 5.01 (s,
1)I). 8, 13 (d, 2) 1), 8.43 (d,
2) 1) Prepare this pyrimidinedione derivative according to the conventional method.
Treated with oxalic acid/methanol solution, 1,3-dimethyl
-6-(2-(2-(4-nitrophenyl)ethylamide)
Nocoethylamino)-2,4(1)1.38)-pyrimi
Crystals of jindione oxalate (compound 16) were obtained. Analysis results of the obtained crystals of compound 16: Melting point: 200~
202℃ (decomposition) Elemental analysis value C+sTo+N504・(COO)1)
Calculated value (%) as 2・÷820: C, 48, 43;
H, 5, 42: N, 15.69 Analysis value (%):
C, 48,52; H, 5,16; N, 16.25
1620, 1560. 1360. 850 Example 1
0 1,3-dimethyl-6-(N-methinoIL, 2-[N
-Methyl-3-(4-nitrophenyl) propylamino 1 ethylamino)-2,4 (IL 3) 1) - Production of pyrimidinedione oxalate (compound 17) (1) 1,3-dimethyl-6 -(N-methyl-N-[2-(meth)
Preparation of ethyl amino)-2,4(1)-pyrimidinedione (compound 18): 50 g of N,N'-dimethylethylenediamine and
rho-1,3-dimethyl-2,4(Ill, 3H)-pi
19.8g of rimidinedione in 200ml of chloroform
The mixture was dissolved and stirred under heating under reflux for 5 hours. After washing the reaction mixture with water, the separated organic layer was diluted with anhydrous sodium sulfate.
It was dried in a humidifier. The dried organic layer is further dried under reduced pressure.
The solvent was distilled off, ether was added to the residue, and crystallization
is precipitated, collected by filtration, washed, and dried to obtain 1.3-di
Methyl-6-(N-methyl-N-[2-(methylamino)
) ethylcoamino)-2,4(1)I. 3) 10g of 1)-pyrimidinedione (compound 18)
Obtained. Analysis results of the obtained crystals of compound 18: NMR (CDC
Is), δppm: 2.7 (s, 31(). 2, 5-3.3 (m, 4) 1). 3, 25 (s, 3H), 3.3 (s, 31
1). 3, 33 IS, 3)1), 5.25 (s,
1) Ri(2) 1.3-dimethyl-6-(N-methyl
-2-[N-methyl 3-(4nitrophenyl)propyl
Amino l ethylamino l-2,4(1)1.3)1)-
Preparation of pyrimidinedione oxalate (compound 17): 5.0 g of the previously obtained compound 18, 3-(4-nitroph)
5.5 g of propyl bromide and triethyl acetate
Prepare by adding 6 ml of minol to 60 ml of isopropanol.
The resulting mixture was treated in the same manner as in Example 2, and 1,3-dimethylene
-6-(N-methyl-2-[N-methyl-3-(4-
(nitrophenyl)propylamino/ethylamino) -
8.1 g of 2,4(IH.3H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 1.5-2
．． 2(m,2)1). 2, 25 (s, 3H). 2, 25-3.2 (m, 8) 1). 3, 3 (s, 3)1), 3.35 (s,
3H). 5, 25 (s, IH), 7.3 (d, 2
)1). 8, 15 (d, 2) 1) This pyrimidinedione derivative is further processed according to a conventional method.
Treated with uric acid/methanol solution, 1,3-dimethyl-6
-(N-methyl-2-

[N-methyl-3-(4-nitro
phenyl) propylamino l ethylamino) -2゜4
(1) 1.3H)-pyrimidinedione oxalate (chemical
Crystals of compound 17) were obtained. Analysis results of the obtained crystals of compound 17: Elemental analysis value C
+JztNs04・CC00H) Calculated value as 2 (%
): C, 52, 60, H, 6, 10, N, 14.
61 analysis value (%): C, 52, 41, H, 6, 33
: N, 14.21 Example 11 N-ethyl-N-(3-(4-nitrophenyl)propyl)
ruamino (compound 7), the ethyl group of said compound 7
An amino compound whose moiety (R”) is shown in Table 1 is
Same as Example 3-(3) except that each was used individually.
, Compounds 19 to 24 shown in Table 1 were obtained, respectively. Table 1 shows the physical properties of these compounds. Example 12 1.3-dimethyl-6-<2-<N-ethyl-N-(
3-(3-nitrophenyl)propylcoaminoethyl
amino)-2,4(IH,3)1)-pyrimidinedione
・Production of hydrochloride (compound 25) Starting materials include 5 g of 3-(3-nitrophenyl) propyl space P-toluenesulfonate, 120 g of ethylamine, and 1.3-dimethyl-6-(2-
(p-toluenesulfonyloxy)ethylamino-2,
4(1)1.3)1)-pyrimidinedione (compound 5)
1.3 in the same manner as in Example 4 except that 188 g was used.
-dimethyl-6-(2-<N-ethyl-N-(3-(3
-nitrophenyl)propylcoamino>ethylamino)
-2,4(IH,3)1)-pyrimidinedione crystals
Obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDC13), δppm: 1,00 (t, 3H). 1,6-2.0 (m, 2H). 2,4-2.8 (m, 8H). 2,9-3.1 (m, 2)1). 3, 2 (s, 3H), 3.3 (s, 3)
1). 4,75 (s, l11), 5.5 (br,
IH). 7, 3-7.4 (m, 2H). 7, 8-8.0 (m, 2H) This crystal was treated with a hydrochloric acid/methanol solution according to a conventional method.
, 1,3-dimethyl-6-(2-(N-ethyl-N-[
3-(3-nitrophenyl)propylcoaminoethyl
amino)-2,4(1)1.3)1)-pyrimidinedio
Crystals of N. hydrochloride (Compound 25) were obtained. Analysis results of the obtained crystals of compound 25: Elemental analysis value C
+J27Ns04・) Calculated value as IcI (%):
C, 53, 58: )l, 6.63; N, 16.
44; C1,8,33 Analysis value (%): C,53,02,)I,' 6.7
9. N, 16.01° CI, 7.98 Example 13 6-(N-ethyl-N-(2-[4-(4-nitrophe)
nyl)butylaminocoethyl〉amino)-1,3-dime
Chil-2,4(IH,3H)-pyrimidinedione
Preparation of urate salt (compound 26)NaH4.820 (1) 6-[N-ethyl-N-(2-hydroxyethyl)
ethyl)amine]-1,3-dimethyl-2,4(IH,3
Preparation of H)-pyrimidinedione (compound 27): 1 g of N-ethylaminoethanol was heated to 100°C.
, kept at the same temperature, and add 6-chloro-1,3-dimethyl to this.
-2,4(IH,3H)-pyrimidinedione (10g)
Added in portions. This reaction mixture was heated at the same temperature for 1 hour, and then diluted with
100ml of oxane was added and stirred for 1 hour under water cooling.
. The crystals precipitated by this stirring are filtered off, the filtrate is concentrated,
The residue (concentrate) was purified by silica gel column chromatography (acetic acid
Ethyl/methanol = 20/1, volume ratio) and 6-[N
-ethyl-N-(2-hydroxyethyl)amino]-1
,3-dimethyl-2,4(IH,3)1)-pyrimidine
7.2 g of dione (compound 27) was obtained. Analysis results of the obtained compound 27: NMR (CDC13), δppm: 1.15 (t
, 3) 1). 3, 0-3.3 (m, 4H). 3, 3 (s, 3H), 3.4 (s, 3H)
. 3,6-3.9 (m, 2H). 5,35 (s, IH) (2) 6-[N-ethyl-N-(2-aminoethyl
) amino]-1,3-dimethyl-2,4(IH,3H)
- Preparation of pyrimidinedione (compound 28): 16.8 g of compound 27 obtained as above, truffle
Phenylphosphine 8.6g and phthalimide 11.9
Suspension of 6g in 200ml of tetrahydrofuran
14.81 g of diethyl azodicarboxylate was added dropwise under water cooling.
I put it down. Next, after the dropwise addition is complete, the solvent is distilled off from the reaction mixture under reduced pressure.
and purified the residue by silica gel column chromatography (ethyl acetate).
), 6-[N-ethyl-N=(2-phthaloylamine
Noethyl)amino]-1,3-dimethyl-2,4(1)
1.311)-pyrimidinedione (compound 29) 22
．． 5g was obtained. Hydrogenate this in ethanol according to the usual method.
The phthaloyl group can be removed by treatment with radzine-hydrate.
6-[N-ethyl-N-(2-aminoethyl
) amino]-1,3-dimethyl-2,4(IH,3H)
-Crystals of pyrimidinedione (compound 28) were obtained. The analysis results of the obtained crystals of Compound 28 are as follows: 2 NMR (CDC)
Is:DMSO-ds=1:1), δppm: 1, 1
5 (t, 3H), 2.65 (q, 2H)
. 2.6-3.3 (m, 4) 1), 3.3 (s, 3H)
. 3, 4 (s, 3)1), 4.8 (s, I
H) (3) 6-(N-ethyl-N-<2-[4-(
4-nitrophenyl)butylaminocoethyl〉amino)
-1,3-dimethyl-2,4(IH,3H)-pyrimidine
Preparation of dione oxalate (compound 26): 6-(N-ethyl-N-(2-aminoethyl)amino
-1,3-dimethyl-2,4(IH,3H)-pyrimidine
1.58 g of dione (compound 28) and 4-(4-nito
1.35g of lophenyl)butanal in 25ml of ethanol
1 and add molecular sieves (3A) to this solution.
[Manufactured by Junsei Kagaku ■] Add 5g of o, and stir at room temperature for 3 hours.
Stirred. Add 0.8 g of sodium borohydride to the resulting reaction mixture.
After adding and stirring for 2 hours, add a small amount of water to this,
The solvent was distilled off from the resulting mixture under reduced pressure, and the residue was chromatographed.
Dissolved in loform. After washing this chloroform solution with water,
The separated organic layer was dried over anhydrous sodium sulfate and dried under reduced pressure.
The solvent was distilled off. The resulting residue was purified with silica gel.
Column chromatography purification (chloroform/methanol = 30
71, volume ratio), recrystallized from ethyl acetate, collected by filtration, and washed.
By cleaning and drying, 6-(N-ethyl-N-<
2-[4-(4-nitrophenyl)butylaminochoe
thyl>amino)-1,3-dimethyl-2,4(IH,3
0.78 g of H)-pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDCI, ), δppm: 1.05 (t
, 3H). 1,4-1.8 (m, 4)1). 2, 2-2.8 (m, 8) 1). 2,9-3.1 (m, 2N). 3,3 (s, 6H), 4.8 (s, II(
). 5, 6 (m, IH), 7.35 (d, 2)
1). 8,15 (d, 2H) This crystal was treated with an oxalic acid/methanol solution according to a conventional method.
and 6-(N-ethyl-N->2- [4-(4-ni
trophenyl)butylaminocoethyl〉amino)-1゜
3-dimethyl-2,4(IH,3H)-pyrimidinedio
oxalate (compound 26) was obtained. Analysis results of the obtained crystals of compound 25: Melting point: 164 ~
166℃ Elemental analysis value C2゜HaJsO4・(COOI() i
Calculated value (%): C, 53, 54: H, 6,
33,N, 14.19 Analysis value (%): C,53,
21; H,6,32,N, 13.98 Example 14 1.3-dimethyl-6-(3-(4-nitroanilino)
Propylamino l-2,4(1)1.3H)-pyrimidine
Production of dione oxalate (compound 30) (1) 1,3-dimethyl-6-(3-aminopropylene)
Ruamino)-2,4(IH,3)1)~pyrimidinedio
Preparation of compound 31: 1,3-diamine instead of N,N-dimethylethylenediamine
Example 10- except using 50 g of aminopropane
In the same manner as (1), 1,3-dimethyl-6-(3
-aminopropylamino l -2,4(IN, 3H)
-9.5 g of pyrimidinedione (compound 31) was obtained. Analysis results of the obtained compound 31: NMR (CDCIs), δPpm: 1.75-2.
10 (m, 2H). 2.75-3.48 (m, 41 (). 3, 12 (s, 3H), 3.35 (s, 3
)1). 4.75 (s, IH) (2) 1.3-dimethyl-6-[3-(4-nitroa)
nilino)propylamino]-2,4(1)1.38)-
Preparation of pyrimidinedione oxalate (compound 30): 0.5 g of compound 31 obtained as above was added to compound 2.
1.3-di in the same manner as in Example 1 except that it is used instead of
Methyl-6-[3-(4-nitroanilino)propyla
[mino]-2,4(18,3H)-pyrimidinedione was obtained.
After that, it was mixed with oxalic acid/methanol solution according to the usual method.
1,3-dimethyl-6-[3-(4-nitroa)
nilino)propylamino]-2,4(1)1.3)1)
-Crystals of pyrimidinedione oxalate (compound 30)
0.45g was obtained. Analysis results of the obtained crystals of compound 30: Melting point: 213~
214℃ (decomposition) 1560, 1320. 840 Elemental analysis value Cl5H1*N504・XA (C00H)
Calculated value (%) as 2: C, 50, 79; H, 5
, 33: N, 18.51 Analysis value (%): C, 5
0,95: H, 5,38; N, 18.82 Examples
15 1,3-dimethyl-6-[3-(4-nitrobenzyla)
Mino)propylamino] -2,4(IH,3)1)-
Production Example 14 of pyrimidinedione oxalate (compound 32) - (1,3-dimethyl-6 obtained with
-(3-aminopropylamino) -2,4(IH,3
H)-pyrimidinedione (compound 31) 1.45g
, p-nitrobenzyl bromide 1.44g and tri
1.5ml of ethylamine to 20ml of isopropanol
In addition, the prepared mixture was treated in the same manner as in Example 2, and 1.
3-dimethyl-6-[3-(4-nitrobenzylamino)
) propylamino 1-2゜4 (IH,3H)-pyrimi
Crystals of jindione oxalate (compound 32) were obtained. Analysis results of the obtained crystals of compound 32: Melting point: 175~
178℃ 1550, 1350. 850 Elemental analysis value C+aHz+N5O4・(COOFI)z
・Calculated value (%) as 3820: C, 43,99
: H, 5,95; N, 14.25 analysis value (%)
: C, 43, 52: H, 6, 05, N, 14.3
3 Example 16 3-(4-nitrobenzyl bromide was replaced with 4-nitrobenzyl bromide)
Using 0.51 g of lophenyl)propyl bromide
1,3-dimethyl-6-(4
-[3-(4-nitrophenyl)propylcopiperazine
-1-yl)-2,4(1)1.3H)-pyrimidine di
On oxalate (compound 33) was obtained. Also, instead of 4-nitrobenzyl bromide, 4-(4
- using 0.55 g of nitrophenyl)butyl bromide
, and hydrochloric acid/methanol solution instead of oxalic acid/methanol solution.
1.3-dimer was prepared in the same manner as in Example 2 except that 1.3-dimethyl
thyl-6-(4-[4-(4-nitrophenyl)butyl)
Copiperazin-1-yl)-2,4(1)1.3H)-
Pyrimidinedione hydrochloride (compound 34) was obtained. The physical properties of these compounds were as follows. (1) 1,3-dimethyl-6-(4-[3-(4-di
trophenyl)propylcopiperazin-1-yl)-2
,4(IH,3)1)-pyrimidinedione oxalate
(Compound 33) Melting point: 153-156°C (decomposition) 1590, 1510. 1340. 850 elemental analysis
Value CIJz5Ns04・(COOH)z・1.5)
Calculated value (%) as 120: C, 50,00; H
, 5,99; N, 13.88 Analysis value (%): C
,50,24,H,5,64; N, 13.23(2
) 1,3-dimethyl-6-(4-[4-(4-nitro
phenyl)butylcopiperazin-1-yl)-2,4(
18,3) 1)-Pyrimidinedione hydrochloride (compound 3
4) Melting point: 202-205.5°C IRv""(cm-'): 2920.2450.1
700.1650°ax 1615, 1440. 1345,791°762.
740 Elemental analysis value C2゜) Calculated as 127NS04・HCI
Calculated value (%): C, 54, 85, H, 6, 44: N
, 15.99C1,8,10 Analysis value (%): C,54,20,H,6,67,N
, +5.56° CI, 8.95 Example 17 1,3-dimethyl obtainable by the method of Example 2
Ru-6-(4-(4-nitrobenzyl)piperazine-1)
-yl] -2,4(IH,3)1)-pyrimidinedio
Production of tablets containing oxalate (compound 3) as an active ingredient
Preparation: The pyrimidinedione derivative/oxalate (compound 3) I
g, 123 g of lactose and 20 g of corn starch.
Mix well and add 5g of hydroxypropylcellulose
Mixed and granulated with a solution dissolved in 100ml of water, and heated to 50℃ for 4 hours.
Dry for an hour. Add magnesium stearate Ig to this.
Add, mix well, and use a tablet machine to make 150m per tablet.
The mixture was compressed into tablets with a weight of 1.5 g. Example 18 Obtainable by the method of Example 3! ,3-dimethy
-6-(2-(N-ethyl-N-(3-(4-nitro)
phenyl)propyl1amino>ethylamino)-2,4
(II-1゜31()-pyrimidinedione hydrochloride (chemical
Production of capsules containing compound 4) as an active ingredient: 5 g of the pyrimidinedione derivative hydrochloride (compound 4),
120g of lactose and 25g of corn starch
Mix and fill the resulting mixture into hard capsules using a capsule filling machine.
Capsules were obtained by filling 100 mg into a bottle. Example 19 1,3-dimethylene obtainable by the method of Example 4
Ru-6-(2-(N-(2-hydroxyethyl)-N
-[3-(4-nitrophenyl)propyl 1 amino]
thylamino)-2,4(IH,3H)-pyrimidinedio
Production of an injection containing the pyrimidinedione derivative fumarate (compound 8) as an active ingredient
Take 0mg and 0.85g of sodium chloride and
Dissolve with appropriate amount of distilled water for injection, make total volume 100ml, and inject.
It was used as a drug. Pharmacological test example 1 1) Effects on myocardial action potential duration (APD7)
Pendoparbital 30mg/kg intravenously administered to adult dogs
After anesthesia, the heart was removed and the right ventricular free wall was placed in Tyrode's solution.
I cut it out. The right ventricular free wall was cut out and fixed in a constant temperature bath at 37°C.
A nutrient solution (20 ml, Tyrode's solution) was perfused. In this state, each compound in Table 2 obtained in the above example and
and before and after administration of d-sotalol as a target drug.
The myocardial action potential duration (APIhs) is determined and obtained.
Based on the results, APD7! (%)of
Calculated. APD? B (%) = APD fs is a 1 Hz field effect on the right ventricular free wall.
stimulation, and changes in action potentials are transmitted to the Purkinje fibers.
Amplification from inserted glass microelectrode (1O ~ 20 MΩ)
drawn on an oscilloscope cathode ray tube through a computer
Waveform analysis was performed using
The time until polarization is calculated as the myocardial action potential duration.
Ta. Each compound shown in Table 2 and d-sotalol are each
individually added to perfusion nutrient solution (20 ml) for 20 min.
Changes in myocardial action potential duration after incubation of
APDys after administration was calculated from . This test was conducted using the method of Sahara et al. [H, 5ato, K. Hashimoto, Arzneimittel F
orschung, 34 (IJ. 3a, 376-380 (1984)).
became. The obtained results are summarized in Table 2 (2) Effect on the preventricular refractory period Each compound shown in Table 2 and d-sotalol were individually administered.
Before and after administration when administered intravenously or into the duodenum
The refractory period after administration is calculated according to the following method, and the obtained value is
Calculate ERP (%: refractory period extension rate) according to the formula below.
Ta. Administer pendoparbital 30mg/kg intravenously to an adult mongrel dog.
After administering anesthesia, inject silver-salt into the right ventricle of the right ventricle with a distance of 3 mm.
A silver oxide electrode was sewn, stimulation interval of 400 m5ec, 4
Electrical stimulation was performed with a current twice the threshold for the duration of m5ec.
After that, a small amount of alcohol is administered through the sinus artery and the paper is injected.
Ventricular failure occurs under ventricular basing by eliminating Smaker activity.
Response period (ERP) was measured. In other words, one training consists of 10 stimulations with a stimulation interval of 400m5ec.
The distance between trains is usually 400m5.
ec, but when measuring the refractory period, the interval is set to 10 m.
The response of the first stimulus of the train is shortened by 5 ec.
The refractory period was defined as the interval between trains when the train disappeared. Note that a cardiac stimulator (diameter) is used for these electrical stimulations.
Using Ikaru's DIM ~ 226-3), program stabilization.
I went by Geki. The results obtained are shown in Table 2. Toxicity test 1 Each compound obtained in the above example shown in Table 3 was
These were individually administered to mice (ddY strain, male). The administration is
300 mg/kg orally for each compound (p,o,)
and 250 mg/kg intraperitoneal administration (i, p, ) separately.
I did it many times. Mortality rate of mice 24 hours after administration (number of samples; − group
2 to 4) were determined, and the results are shown in Table 3. Table 3 Toxicity test results 0 2 3 6 4 0 0 Example 20 1.3-dimethyl-6-(4-(3-(4-nitrophe)
Production of 1)-pyrimidinedione hydrochloride (3 compounds) (Compound 37) (Compound 35) (1) 1.3 -dimethyl-6-[4-(3-hydroxylpropyl)piperazin-1-yl] -2,4(IH,3H)
-Preparation of pyrimidinedione (compound 36): 1,3-dimethyl-6-(l-piperazinyl)-2,4
(IH,3H)-pyrimidinedione (compound 37) 1
4.1 g, 3-bromo-1-propertool 11.7
g and 13 g of triethylamine, 250 m of ethanol
The reaction was carried out by heating under reflux for 20 hours in 1. Reaction completed
After that, the reaction mixture was concentrated to dryness, and the residue was dissolved in chloroform for 30 minutes.
Dissolve in 0 ml of water and wash it twice with 100 ml of water.
The organic layer after cleaning was dried over anhydrous magnesium sulfate. this
The organic layer was treated under reduced pressure, the solvent was distilled off, and the combined product 20
．． 5g was obtained. Add ether to this combined product and crystallize
Collect, wash, and dry the 1.3-di
Methyl-El-[4-<3-hydroxypropyl)pipe
Radin-■-yl]-2,4(IH,3H)-pyrimidine
Dione (Compound 36) 12.4g (Yield: 69
．． 8%). Analysis results of the obtained crystals of compound 36; melting point: 119~
121'C NMR (CDC13), δppm: 1.8 (d
t, 2l-1), 2.7 (m, 6H)3,0
2 (m, 4H), 3.36 (s, 3H)
. 3,43 (s, 3H), 3.82 (t,
2)1). 4,34 (br,,IH), 5.26 (s
, IH) IRvKB'(cm-'): 3380
．． 3180.2830.1695ax 1650, 1605. 1440. 1213°10
68, 1000. 921. 760 (2) 1,
3-dimethyl-6-(4-[3-(4-nitrophenoki)
c) Propylcopiperazin-1-yl l-2,4(1)
1.3H)-pyrimidinedione hydrochloride (compound 35)
Production: 1.0 g of the compound 36 obtained earlier, triphenylphosphine
1.1 g of alcohol and 0.57 g of 4-nitrophenol were added to
The suspension obtained by suspending and mixing in 15 ml of water and tetrahydrofuran
In the suspension, add 0.71 g of anhydrous diethyl azodicarboxylate.
10 ml of tetrahydrofuran solution were added at room temperature. Next, the resulting mixture was stirred for 10 minutes and then concentrated to dryness.
The residue was purified by silica gel column chromatography (methanol/vinegar
Ethyl acid = 1/15 to 1/7, volume ratio), 1.3
-dimethyl-6-(4-(3-(4-nitrophenoxy)
) propylcopiperazin-1-yl) -2,4(18
゜3F1)-pymidinedione 1.3g (yield: 80%
) was obtained. Analysis results of the obtained crystal of pyrimidinedione derivative: Melting point: 167-170°C Elemental analysis value: CIeHz8NsQ, calculated value C%
): C, 56, 57, H, 6, 25; N, 17
．． 36 analysis value (%): C, 56, 29,) I, 6
．． 17, N, 17.17Furthermore, obtained in this way
1,3-dimethyl-6-(4-[3-(4-nitroph)
(enoxy)propylcopiperazin-1-yl) -2,
4(LH,3H)-pyrimidinedione in hydrochloric acid/methanol
1,3-dimethyl-6-
(4-[3-(4-nitrophenoxy)propyl copy paste
Radin-1-yl)-2,4(1)1,31()-pi
Rimidinedione hydrochloride (compound 35) was obtained. Analysis results of the obtained crystals of compound 35: Melting point: 244 ~
246°C (decomposition) Example 21 1.3-dimethyl-6-(4-[3-(3-nitrophe)
(noxy)propylcopiperazin-1-yl) -2,4
(IH,3H)-pyrimidinedione hydrochloride (compound 3
8) Production (1) of 3-(3-nitrophenoxy)
Preparation of lopylbromide (compound 39): 13.9 g of 3-nitrophenol, 1,3-dibromo
101g of propane and 15.2g of anhydrous potassium carbonate,
Heating under reflux for 2 hours in 100ml of methyl ethyl ketone
Made it more responsive. After the reaction is complete, remove the insoluble matter from the reaction mixture.
It was filtered and the filtrate was concentrated. Next, the obtained concentrate was chromatographed.
Dissolve in 300 ml of chloroform, and then add
The solution was washed with water. Next, the water-washed organic layer is washed with anhydrous sulfuric acid.
Dry with magnesium, treat under reduced pressure to remove the solvent,
3-(3-nitrophenoxy)propyl bromide
Compound 39) 24.6 g were obtained as an oil. This is special
It was used in the next reaction without further purification. (2) 1,3-dimethyl-6-(4-[3-(3-
(nitrophenoxy)propylcopiperazin-1-yl)
-2,4(1)I. Production of 3H)-pyrimidinedione hydrochloride (compound 38)
Preparation: 1.69 g of the oily substance of compound 39 above, 1.3-
Dimethyl-6-(1-piperazinyl)-2,4(1)
I, 3) 1)-pyrimidinedione (compound 37) 1
．． 12 g and 1 ml of triethylamine, dioxane 2
0 incubation reacted by heating under reflux for 4 hours in 0 ml solution.
After the reaction is complete, insoluble materials are filtered from the reaction mixture and the filtrate is concentrated.
After that, the residue (concentrate) was dissolved in chloroform, and the obtained
The chloroform solution was washed with water. This washed organic layer
Dry over anhydrous magnesium sulfate and remove the solvent under reduced pressure.
was distilled off, and the residue was further purified by silica gel column chromatography (
Chloroform/methanol = 100/1 to 25/1, volume
(quantity ratio) and further recrystallized from methanol, the obtained crystals
By filtering, washing and drying, 1,3-dimethylene
Ru-6-(4-(3-(3-nitrophenoxy)propyl)
1.35 g of 2,4(Ill. 3H)-pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: Melting point = 164-165°C NMR (CDCI31, δppm: 1.8-2.
2(m, 2H). 2.4-2.8 (m, 6) 1). 2.8-3.8 (m, 4H). 3.34 (s, 3H). 3,42 (s, 3)1). 4, 15 (t, 2H). 5, 25 (s, IH). 7, 1~8.0 (m, 4H) Elemental analysis value C+ JzsNsOs To L/ Te calculation
Value (%): C, 56, 57: ) I, 6.25
: N, 17.36 Analysis value (%): C, 56,2
7,I(,6,69,N,17.21Then, like this
1,3-dimethyl-6-(4-[3-(3-
(nitrophenoxy)propylcopiperazin-1-yl)
-2,4(1)1.3H)-pyrimidinedione by conventional method
The 1,3-di
Methyl-6-(4-[3-(3-nitrophenoxy)propylene)
ropilcopiperazin-1-yl)-2,4(IH,3
1()-pyrimidinedione hydrochloride (compound 3B) was obtained.
Ta. Analysis results of the obtained crystals of compound 38: IRv “”
(am-'): ax 1690, 1650. +525. 1345°1
240, 1200. 1025,980°790.7
60,740,670 Elemental analysis value C+5HtsNs05]CI-MeOH
Calculated value (%): C, 51,00; H, 6,
21; N, 14.87CI, 7.53 Analysis value (%): C, 50, 60: H, 6, 71,
N, 14.81 CI, 7.74 Example 22 1.3-dimethyl-6-(4-(2-<4-nitroben
zoyloxy)ethylcopiperazin-1-yl)-2,
4(1)1.3H)-pyrimidinedione oxalate (
Production of compound 40) (compound 41) Hs 4-nitrobenzoyl chloride (1.5 g, 1
．． 3-dimethyl-6-[4-(2-hydroxyethyl)
piperazin-1-yl] -2,4(1)1.3)1)
-pyrimidinedione (compound 41) 0.47g and
1.5 ml of ethylamine and 5 ml of tetrahydrofuran
After stirring the added solution overnight at room temperature, the solvent was distilled off under reduced pressure.
The residue was dissolved in 30 ml of chloroform. obtained
After washing the chloroform solution with water, it was washed with anhydrous sodium sulfate.
A crude product was obtained by drying and further concentrating to dryness.
After that, it was purified by silica gel column chromatography (chloroform
methanol/methanol = 40/1, volume ratio), 1.3-
Dimethyl-6-(4-[2-(4-nitrobenzoyl)
xy)ethylcopiperazin-1-yl)-2,4(IH
, 3) 1)-pyrimidinedione was obtained. Next, this piri
The midinedione derivative was mixed with oxalic acid/methanol using a conventional method.
1,3-dimethyl-6-(4-(2-
(4-Nitrobenzoyloxy)ethylcopiperazine-
l-yl l-2,4(IH,3)1)-pyrimidinedio
0.84 g of oxalate (compound 40) was obtained. Analysis results of the obtained crystals of compound 40: Melting point = 171 ~
173°C (decomposition) IRvKBr (cm-'): 3100.2550.
1740.1700ax 1660, 1640.1540.1360゜50 Elemental analysis value C+eHzsNsOe・(COOH)
Calculated value (%) as z・2H20: C, 46, 24,
H,! 1.7:3: N, '12.84 analysis value (%)・
C, 46, 64, H, 5, 38, N, 12.83 implementation
Example 23 1,3-dimethyl-6-(4-(4-nitrophenacyl)
)piperazin-1-yl]-2,4(IH,314)-
Production of pyrimidinedione hydrochloride (compound 42) (compound 43) (compound 42) 8.25 g of 4-nitro-7cetophenone was dissolved in chloroform 2
00ml, and add 8g of bromine to this under cooling.
20ml of the solution was added dropwise. Concentrate the resulting mixture
, the residue (concentrate) was recrystallized from chloroform-ether.
, filtered, washed, dried, p-nitrophenacyl bromide
8.03 g of Mide was obtained. Next, 4.88 of this p-nitrophenacyl bromide
g, 1,3-dimethyl-6-(1-piperazinyl)-
2,4(II(,31()-pyrimidinedione (compound
37) 4.48g and 4.2ml of triethylamine
The solution added to 150ml of dioxane was heated under reflux for 1 hour.
did. After that, the reaction mixture is cooled and the precipitated crystals are filtered.
Dissolve in chloroform, wash with water, and dry (anhydrous sodium sulfate).
thorium), the solvent was distilled off, and methanol was added to the residue.
The resulting crystals are collected by filtration, washed, and dried.
1,3-dimethyl-6-[4-(4-nitrophenacyl)
)piperazin-1-yl]-2,4(IH,3)1)-
4.02 g of pyrimidinedione (compound 43) was obtained. Analysis results of the obtained crystals of compound 43: Melting point = 189 ~
192℃ Elemental analysis value Cl11821N8011 ・gcHJ
Calculated value as H (%): C, 55,08; H2S,
75: N, 17.313 Analysis value (%): C, 54
, 86; ) 1.5.44. N, 17.62NMR
(CFSCOOH), δppm: 3.63(s, 3H
), 3.73 (s, 3t (). 3, 7-4.3 (m, 8H). 5.21 (s, 2H), 6.12 (s, IH). 8, 28 (d, 2H) ), 8.52 (d,
2H). Furthermore, 0.9 g of compound 43 was added to hydrochloric acid/meth according to a conventional method.
1,3-dimethyl-6-[4-(
4-nitrophenacyl)piperazin-1-yl 1-2°
4 (Ill, 31()-pyrimidinedione hydrochloride
(Compound 42) 0.91 g was obtained. Analysis results of the obtained crystals of compound 42: Melting point = 257 ~
262℃ Elemental analysis calculated value (%): 1190, 960,845,790. 740C+a
C,50 as Hz+N5Os・HCl-lCH308
,52,H,5,50,N, 15.92°CI,
8.06 Analysis value (%): C1 50.77, H. 5.29°N. 15.82°CI. 7.61 Example 24 1.3-dimethyl-6-(4-(2-hydroxy-2-
(4-nitrophenyl)ethylcopiperazin-1-yl
)-2,4(1)1.3)1)-pyrimidinedione salt
Preparation of acid salt (compound 44). t, 3-dimethyl-6-(4-(4
-nitrophenacyl)piperazin-1-yl]-2,4
(IH,3H)-pyrimidinedione (compound 43)
8.12 g dry tetrahydrofuran 700 m I
3. Add lithium aluminum hydride to the FJ suspension under ice cooling.
46g was added, stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 minutes.
Stir for hours. After the stirring process is completed, the reaction mixture is cooled.
When rejected, 50ml of water was added to stop the reaction and remove the insoluble matter.
It was filtered and the filtrate was concentrated. Dissolve the residue (concentrate) in chloroform, wash with water, and dry (
anhydrous sodium sulfate), the organic layer was concentrated to a small volume,
Silica gel column chromatography purification (chloroform/methano
capacity ratio), 1.3
-dimethyl-6-(4-[2-hydroxy-2-(4-
Nitrophenyl)ethylcopiperazin-1-yl)-2
, 3.7 g of 4(IH,3H)-pyrimidinedione was obtained.
. Analysis results of the crystals of this pyrimidinedione derivative obtained
: Melting point: 205-207°C NMR (DMSO-d6), δppm knee 2.5-2.
7 (m, 6) 1). 2,7-2.95 (m, 4)1). 3,06 (s, 3H), 3.20 (s,
3H). 4,79 (t, IH), 7.47 (d,
2H). 8,04 (d, 2H) Next, 0.55 g of this pyrimidinedione derivative was added in a conventional manner.
1,3-dimer by treatment with hydrochloric acid/metal solution according to
Chil-6-(4-[2-hydroxy-2-(4-nitro
phenyl)ethylcopiperazin-1-yl)-2,4(
IH,3H)-pyrimidinedione hydrochloride (compound 44
) 0.53g was obtained. Analysis results of the obtained crystals of compound 44: Melting point: 250 ~
265℃ (gradually colored and decomposed) Elemental analysis value C+5H
Calculated value as zJsOs-1 (CI-'/4u2o (%
): C, 50, 23; ) I, 5.74. N,
16.27°CI, 8.24 Analysis value (%): C, 50,22, H, 6,07, N,
16.04; CI, 8.20 IRv""(cm-'): 1700. 1620.
1430.1340°ax 1190, 1!65,850,785Example 25 1.3-dimethyl-6-(4-(2-(4-nitroben)
zoylamino)ethylcopiperazin-1-yl)-2,
4(IH,3)1)-pyrimidinedione hydrochloride (compound
Production of product 45) Nt12C) IzCHJr ・) IBr
(Compound 46) HCI/Cll301 (CI. ・214C1 (Compound 45) (1) 2-(4-nitrobenzoylamino)ethyl
Preparation of bromide (compound 46): 3 g of 4-nitrobenzoyl chloride was
3.3 g of tylbromide/hydrobromic acid and 3. pyridine.
Add to 9 ml of 30 ml of chloroform solution under water cooling,
The mixture was stirred at the same temperature for 1 hour. Wash the reaction mixture with water and remove the organic layer.
Concentrate to 2-(4-nitrobenzoylamino)ethylbu
A crude lomide product was obtained. This is hexane-ethanol
Recrystallize from the crystals, collect the obtained crystals by filtration, wash, and dry.
2-(4-nitrobenzoylamino)ethyl bromide
2.9 g of crystals of (Compound 46) were obtained. Analysis results of the obtained crystals of compound 46: Melting point; 104~
108℃ (2) 1.3-dimethyl-6-(4-(2-(4
-Nitrobenzoylamino)ethylcopiperazine-1-
-2,4(IH.3)1)-pyrimidinedione hydrochloride (compound 45)
Preparation: 1.3 g of compound 46 obtained in section (1) above, 1.3-di
Methyl-6-(I-piperazinyl)-2,4(1)1
．． 31()pyrimidinedione (compound 37) 1.8g
, triethylamine 1.3 ml and isopropaz
A mixture of 10 ml of water was heated to reflux for 3 hours. Next, the solvent was distilled off from the resulting reaction mixture, and water was added.
and extracted with chloroform. Furthermore, after washing the chloroform extract with water, add anhydrous sodium sulfate to
After drying with a vacuum cleaner and condensing to obtain a crude product, this was
- Recrystallize from ethanol, collect the obtained crystals by filtration, and wash.
1,3-dimethy/L, -6-(4-(2
-(4-nitrobenzoylamino)ethylcopiperazine
-1-yl) -2,4(IH,3H)~pyrimidindi
1.77 g of on was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: Melting point = 169~+71'C Next, this pyrimidinedione derivative crystal was prepared according to a conventional method.
Treated with hydrochloric acid/methanol solution, 1,3-dimethyl-6
-(4-(2-(4-nitrobenzoylamino)ethyl
Copiperazin-1-yl)-2,4(IH,3l-1
)-pyrimidinedione hydrochloride (compound 45) was obtained. Analysis results of the obtained crystals of compound 45: Melting point: 283~
285℃ (decomposition) Elemental analysis value Calculated as C+-Hz4Naps・2HC1
Calculated value C%l: c, 46.62. ) I, 5.66
, N, +7.20°CI, 14.49 Analysis value (%): C, 46,45, H, 5,79; N
, 17.01CI, 14.67 Example 26 1.3-dimethyl-6-(4-(N-(4-nitrophe)
carbamoylmethyl]piperazin-l-yl)-
2,4f18.3) 1)-pyrimidinedione oxalic acid
Production of salt (Compound 47) (Compound 48) (Compound 47) 0.8 g of 4-nitroaniline, 0.6 ml of bromoacetylbromite, 1.5 g of anhydrous potassium carbonate, and 0 ml of dimethyl sulfoxide were mixed and stirred at 100°C for 4 hours. Then, the insoluble matter when heated was filtered off. Cool the filtrate and
4-(bromoacetamido)nitrobene precipitated during
The crystals of zene (compound 48) were separated by filtration and 1,3-di
Methyl-6-(1-piperazinyl)-2,4(IH,
3H)-pyrimidinedione (compound 37) 1.3g
, triethylamine 1.6 g and isopropanol 1
The mixture was heated under reflux for 15 hours with 5 ml of the mixture. After cooling, the solvent was distilled off and the residue was dissolved in chloroform.
After washing the resulting solution with water, dry it with anhydrous sodium sulfate.
Ta. Remove the solvent from this dried chloroform solution under reduced pressure.
The residue was purified by silica gel chromatography (chloroform
/methanol=lOO/1~25/l, volume ratio) and 1
．． 3-dimethyl-6-(4-[N-(4-nitropheny)
carbamoylmethyl]piperazin-1-yl>-2
, 0.85 g of 4(18,314)-pyrimidinedione
Obtained. Analysis results of this pyrimidine derivative obtained・NMR (D
MSO-d6), δppm: 2.5-2.9 (m,
10)1). 3,28 (s, 3)1), 3.37 (s,
3H) 5.00 (s, IH), 7.29 (d, 2
H). 8,01 (d, 2H) Next, 0.8 g of this pyrimidine derivative was syringed according to a conventional method.
Treated with oxalic acid/methanol solution! , 3-dimethyl-
6-(4-[N-(4-nitrophenyl)carbamoyl
Methyl l-piperazin-1-yl)-2,4(11(,3
1()-pyrimidinedione oxalate (compound 47)
0.8! , g was obtained. Analysis results of the obtained crystals of compound 47: Melting point: 281~
283℃ (decomposition) Elemental analysis value C+aL□News・(COON) z・
Calculated value as H2O (%): C, 47,06, H, 5
,13,N, +6.46; Analysis value (%): C,46
,90,) 1.5.34; N, 16.37 Example 2
7 1,3-dimethyl-6-(4-(3-(4-nitroani)
lino)-2-hydroxypropylcopiperazine = 1-y
)-2,4(1)1.310-pyrimidinedione
Production of oxalate (compound 49) First, 1,3-dimethyl-6-(4-(3-chloro-2
-hydroxypropyl)piperazin-1-yl]-2,
4(1)1.3H)-pyrimidinedione (compound 50)
2.0g ammonia methanol solution 20ml (0
, 1g/ml) was heated at 90°C for 8 hours. reaction mixture
was concentrated under reduced pressure, and the residue (concentrate) was added with 4-nitrofluorocarbon.
Add 0.9 g of triethylamine and 1 ml of triethylamine and mix at 90°C.
After heating for 2 hours at
1, the crystals precipitated at that time were collected by filtration, and diluted with methanol.
・Wash with ether, dry, 1,3-dimethyl-
6-(4-[3-(4-nitroanilino)-2-hydro
xypropylcopiperazin-1-yl)-2,4(IH
,3H)-pyrimidinedione yellow crystals were obtained.
Ta. Furthermore, the yellow crystals were treated with oxalic acid/methane using a conventional method.
1,3-dimethyl-6-(4-(
3-(4-nitroanilino)-2-hydroxypropyl
Copiperazine! -yl)-2,4(IH,3)1)-
Pyrimidinedione oxalate (compound 49) was obtained. Analysis results of the obtained crystals of compound 49: IRvKB'
(am"'): 3375 (br), 1693° ax 1470 (br), 1308° Elemental analysis value Cl9828N60B・(CO□H)2 total
Calculated value (%): C, 49,60; H, 5,55, N. Analysis value (%): C, 50,10; H, 5,98:
N. 1640, 16Q0°113 as 16,53 16.79 Example 28 1.3-dimethyl-6-(4-[3-(4-nitrophe)
Nylthio)propylcopiperazin-1-yl)-2,4
(18,3H)-pyrimidinedione oxalate (compound
Production of compound 51) 10zN@5C)I*C)IaCHzBr←(compound 5
2) (1) 3-(4-nitrophenylthio)propylbu
Preparation of Romide (Compound 52): 5,5 g of 4-nitrothiophenol and 1,3-dibro
In a solution of 28.3 g of mopropane in 50 ml of 2-butanone,
Add 9.0 g of anhydrous potassium carbonate and stir at room temperature for 30 minutes.
Ta. Insoluble materials were filtered off from the resulting reaction mixture, and the filtrate was concentrated.
After that, dissolve the concentrate in chloroform and dissolve the resulting chloroform.
The form solution was washed with water. Furthermore, the water-washed organic layer is dried
Dry over magnesium sulfate and remove the solvent under reduced pressure.
and 3-(4-nitrophenylthio)propylbro
8.0 g of Mide (Compound 18) was obtained as crystals. child
This was used in the next reaction without any particular purification. (2) 1,3-dimethyl-6-, (4-[3-(4-
Nitrophenylthio)propylcopiperazin-1-yl
)-2,4(IH,3H)-pyrimidinedione shu
Preparation of acid salt (compound 51): 2.0 g of compound 52 above, 1,3-dimethyl-6
-(1-piperazinyl)-2,4(IH,3H)-pyri
Midinedione (compound 37) 1.68g and triethyl
3 ml of amine was refluxed for 3 hours with 30 ml of ethanol.
The mixture was heated and stirred while flowing down. The resulting reaction mixture was concentrated to dryness and mixed with water too much.
The precipitate was collected by filtration and washed with ethanol. Furthermore, the washed precipitate was recrystallized from methanol,
1,3-dimethyl-6-(4-
(3-(4-nitrophenylthio)propylcopiperazi
(1-yl)-2,4(IH,311)-pyrimidine
2.4 g of dione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
2 Melting point: 145-147°C 2.2g of this crystal was suspended in 20ml of methanol.
Oxalic acid trihydrate 2. Og was added and stirred. - degree
After complete dissolution, stir for a while and add 30ml of ether to form a condensate.
Precipitate crystals, collect the precipitate by filtration, wash and dry, 1.
3-dimethyl-6-(4-[3-(4-nitrophenyl)
thio)propylcopiperazin-1-yl)-24(1)
1.3H)-pyrimidinedione oxalate (compound 5
1) 2.0g was obtained. Analysis results of the obtained crystals of compound 51: Melting point: 164 ~
168@(decomposition) Elemental analysis value C+JzsNsO4S・1.5 (COO
H) Calculated value (%) as t・H*o: C, 46,
15: ) I, 5.28: N, 12.23; S,
5.60 Analysis value (%): C, 45, 89: H, 5, 25,
N, 12.16; S, 6.12 1222, 978. 851. 745. 722 fruit
Example 29 1.3-dimethyl-6-(4-(2-(4-nitrophe)
noxy)ethylcopiperazin-1-yl)-2,4(1
) I, 3H)-pyrimidinedione hydrochloride (compound 5
Production of 3) (compound 41) H3 1,3-dimethyl-6-[4-(2-hydroxyethyl)
piperazin-1-yl-2,4(IH,3H)-pyri
Midinedione (compound 41) 5.37g, 4-=
3.20g of tff7znor and triphenylpho
Sphine 6.03g in anhydrous tetrahydrofuran 100ml
Example 20-(2) and the mixture prepared in addition to 1.
Treated in the same manner, 1,3-dimethyl-6-(4-(2
-(4-nitrophenoxy)ethylcopiperazine-1-
yl)-2,4(1)1.3H)-pyrimidinedione linkage
5.40 g of crystals were obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: 1340°1275°1213°! 180°1115, 1010,862,805.750
The crystals were treated with a hydrochloric acid/methanol solution according to a conventional method,
], 3-dimethyl-6-(4-[2-(4-nitrophe)
noxy)ethylcopiperazin-1-yl)-2,4(I
H,3) 1)-pyrimidinedione hydrochloride (compound 53
) was obtained. Analysis result of the obtained crystals of compound 53: +342. 1
267, 1112. 860°55 Elemental analysis value C1aHtsNsOs・HCI・O,5
Calculated value as Hzo (%): C, 49,71; H,
5,79; N, 16.10; CI, 8.15 Analysis value (%): C, 49,17, H, 6,05, N,
16.20°C1,8,40 Example 30 1.3-dimethyl-6-(4-[4-(4-nitrophe)
noxy)butylcopiperazin-1-yl)-2,4(1
)1.3H)-Preparation of pyrimidinedione hydrochloride (compound 54)
-Example 2O except that 12.9 g of butanol was used-
In the same manner as (1), 1,3-dimethyl-6-[4
-(4-hydroxybutyl)piperazin-1-yl]-
13.1 g of 2,4(IH,3H)-pyrimidinedione
Obtained. Furthermore, 1.05 g of this pyrimidinedione derivative,
1,3-dimethyl-6-[4-(3-hydroxypropylene)
Piper)piperazin-1-yl]-2,4(IH,3)1
)-pyrimidinedione (used in place of compound 36)
For the outside, 1.3-
Dimethyl-6-(4-[4-(4-nitrophenoxy)
butylcopiperazin-1-yl)-2,4(IH,3)
1) -Crystals of pyrimidinedione hydrochloride (compound 54)
1.2g was obtained. Analysis results of the obtained crystals of compound 54: Elemental analysis value C
2゜)127N60B・）ICI・0.5820
Calculated value (%): C, 51, 89, H, 6, 31, N,
15.13゜C1,7,66 Analysis value (%) 2C,52,01,H,6,24,N,
15.41; CI, 7.56 Example 31 1.3-dimethyl-6-(4-(3-(2-nitrophe)
noxy)propylcopiperazin-1-yl)-2,4(
IH,31()-pyrimidinedione, hydrochloride (compound
ES) Production of 2-nitrophenol instead of 3-nitrophenol
Example 2l-(1
) and 2l-(2), 1,3-dimethyl-
6-(4-(3-(2-nitrophenoxy)propylco)
piperazin-1-yl)-2,4(1)1.3H)-pi
Crystals of limidinedione were obtained. Analysis results of the obtained crystal of the pyrimidinedione derivative: Melting point: 123.5 to 125°C Elemental analysis value Calculated value as C + eHzsNsOs (%)
: C, 56, 57: H, 6, 25; N, 17.
36 analysis value (%): C, 56,74; H, 5,85
; N, 17.46 NMR (CDCIs), δ1)p
m: 2.03 (m, 2H), 2.66 (m, 6H
). 2,98 (m, 4)1), 3.32 (s,
38). 3,40 (s, 3H), 4.11 (t, 2
H). s, 22 (S, II (). 6, 9-7.9 (m, 48) The crystals were treated with a hydrochloric acid/methanol solution according to a conventional method.
and 1,3-dimethyl-6-(4-[3-(2-nito)
lophenoxy)propylcopiperazin-1-yl)-2
,4(1)1.38)-pyrimidinedione hydrochloride (chemical
Compound 55) was obtained. Analysis results of the obtained crystals of compound 55: Melting point: 251~
252℃ (decomposition) Elemental analysis value C+eH*5NsOs ・Calculated as HCI
Calculated value (%): C, 51, 88, H, 5, 96, N,
15.92°C1,8,06 Analysis value (%): C,51,29,H,5,84; N
, 16.06°C1,7,58 Example 32 1.3-dimethyl-6-[2-(4-nitrobenzoyl)
amino) ethylamino] -2,4(l H,3H)-
Preparation of pyrimidinedione (compound 56) 1.3-dimethyl-6-[4-(2-hydroxyethyl)
)piperazin-1-yl]-2,4(IH,3)1)-
1,3-dimethyl instead of pyrimidinedione (compound 41)
Thyl-6-(2-aminoethylamino)-2,4(I
H, 3) 1)-pyrimidinedione (compound 57) 0.
1.3 in the same manner as in Example 22 except that 35 g was used.
-dimethyl-6-[2-(4-nitrobenzoylamino)
) ethylamino] -2,4(II(,3)1)-pyri
0.49 g of crystals of midinedione (compound 56) was obtained. Analysis results of the obtained crystals of compound 56 Melting point: 284 ~
285℃ (decomposition) 1550, 1360. 86O NMR (DMSO-da), δppm: 3.3 (m
, 4) 1), 3.36(s, 3) 1). : 3.28 (s, 3)1), 4.98 (
s, 1N). : 8.18 (d, 2) 1), 8.41 (d, 2H)
Elemental analysis value C+a) Calculated value as IIyNsOs (%
): C, 51,87, H, 4,93; N, 20.
16 Analysis value (%): C, 51,89; H, s, tc
+; N, 19.73 Example 33 1,3-dimethyl which can be obtained by the method of Example 20
Chil-6-(4-[3-(4-nitrophenoxy)pro)
Pircopiperazin-1-yl)-2,4(1)1.3H
)-pyrimidinedione hydrochloride (compound 35) as the active ingredient
Manufacture of tablets for administration: The pyrimidinedione derivative hydrochloride (compound 35) Ig
, 123 g of milk and 20 g of corn starch.
Mix well and add 5g of hydroxypropylcellulose
Mixed and granulated with a solution dissolved in 100ml of water, and heated to 50℃ for 4 hours.
Dry for an hour. Add 1g of magnesium stearate to this.
Add, mix well, and use a tablet machine to make 150m per tablet.
The mixture was compressed into tablets with a weight of 1.5 g. Example 34 1,3-dimethyl obtainable by the method of Example 25
Chil-6-(4-[2-(4-nitrobenzoylamino)
) Ethyl 1-piperazin-1-yl)-2,4(IH,3
H)-pyrimidinedione hydrochloride (compound 45) is effective.
Production of capsules as ingredients: 5 g of the pyrimidinedione derivative hydrochloride (compound 45)
, 120 g of lactose and 25 g of corn starch.
The resulting mixture is packed into hard capsules using a capsule filling machine.
A cell was filled with 150 mg to obtain a capsule. Example 35 1,3-dimethyl obtainable by the method of Example 27
Chil-6-(4-(3-(4-nitrophenyl)-2-
hydroxypropyl] piperazin-1-yl)-2,
4(1)1.3H) -pyrimidinedione oxalate
Production of an injection containing (Compound 49) as an active ingredient: The pyrimidinedione derivative/oxalate (Compound 49)
Take 20 mg and 0.85 g of sodium chloride.
Dissolve this in an appropriate amount of distilled water for injection to make a total volume of 100ml.
It was made into an injection. Pharmacological Test Example 2 In the same manner as Pharmacological Test Example I, the above-mentioned implementation shown in Table 4 was carried out.
APD of each compound obtained in the example? 11 and find ERP
Ta. The results are shown in Table 4. Toxicity test 2 Similar to toxicity test 1, the results obtained in the above examples shown in Table 5 were
The toxicity of each compound was tested and the mortality rate of mice was determined.
Ta. Administration was 300 mg/Kg orally for each compound (p
,. ,). Surface toxicity test results Example 36 1.3-dimethyl-6-(4-[3-(4-nitroanidine)
Production of pyrimidinedione hydrochloride (compound 58) (compound 60) hydrazine H,0 (1) 1,3-dimethyl-6-[4 -(3-ami
nopropyl)piperazin-1-yl]-2,4(IH
,3H)-pyrimidinedione (compound 59): 18.52 g of potassium phthalimide and 1,3-dibro
200g of mopropane 100ml of dimethylformamide
The suspension in 1 was heated and stirred at 120°C for 6 hours, and these
Next, remove the insoluble matter from the resulting reaction mixture.
It was filtered and the filtrate was concentrated to dryness under reduced pressure. After washing the residue with hexane, it was reconstituted with ethanol-water.
The crystals obtained are collected by filtration, washed, dried, and N-
Obtained 13.8 g of (3-bromopropyl)phthalimide.
. Next, this N-(3-bromopropyl)phthalimide
13.0 g, 1,3-dimethyl-6-(l-pipera
(dinyl)-2,4(1)1.3H)-pyrimidinedione
(Compound 60) 10.3g and triethylamine 20g
was suspended in 200 ml of dioxane.
The liquid was heated to reflux for 6 hours. Furthermore, insoluble matter was filtered from the obtained reaction mixture, and the filtrate was
Concentrate to dryness under reduced pressure, and dissolve the residue (concentrated to dryness) in ethyl acetate.
- Recrystallize from hexane, collect the obtained crystals by filtration, and wash.
Clean, dry and give 1,3-dimethyl-6-[4-(3-ph).
taloyl7minobrovir)piperazin-1-yl]-2
, 12.5 g of 4(LH,3H)-pyrimidinedione was obtained.
Ta. Next, 12.5 g of this crystal and 6.0 g of hydrazine hydrate
A suspension of g in 200ml of ethanol was heated for 4 hours.
Heat under reflux, and after cooling, insoluble matter generated is filtered off, and the filtrate is depressurized.
The mixture was concentrated to dryness. Furthermore, the residue (concentrated dry matter) was dissolved in water.
Add dilute hydrochloric acid to this to adjust the pH to about 3, and then
The insoluble matter generated during the process is removed by filtration, and the filtrate is added with potassium carbonate.
After adding a large amount of, this was extracted with chloroform. Extraction operation
After completion of cropping, dry the obtained organic layer with anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and 1,3-dimethyl
-6-(4-(3-aminopropyl)piperazine-1-
]-2,4(IH,38)-pyrimidinedione (
Compound 59) 6.80 g was obtained as a colorless syrup. This was crystallized by overnight incubation. (2) 1,3-dimethyl-6-(4-(3-(4
-nitroanilino)propylcopiperazin-1-yl)
-2,4(IH,3H)-pyrimidinedione hydrochloride
Preparation of (Compound 58): 2.50 of the previously obtained Compound 59
g and 1.90 g of 4-nitrofluorobenzene were
Added to 20 ml of methyl sulfoxide and the resulting mixture
The solution was heated to 80°C for 3 hours, and after cooling, a crystalline filtrate was precipitated.
1,3-dimethyl-6-(4-(
3-(4-nitroanilino)propylcopiperazine-1
-yl) -2,4(IH. 3H)-pyrimidinedione (compound 58°) 2.7
5g was obtained. Analysis results of the obtained compound 58° crystals: 1425, 1295. 1105,990゜40 Elemental analysis value Calculated value as C+eH*5NsO4 (%
): C, 56, 70, H, 6, 51, N, 20.
88 analysis value (%): C, 56°19, H, 6,88
, N , 20.50 Next, the compound obtained as above
58° was treated with hydrochloric acid/methanol solution according to the conventional method.
, 1,3-dimethyl-6-(4-[3-(4-nitro
(nilino)propylcopiperazin-1-yl) -2,4
(IH,3H)-pyrimidinedione hydrochloride (compound 5
8) was obtained. Analysis results of the obtained crystals of compound 58: Melting point: 270°C
Above 1315, 1105. 837゜45 Elemental analysis value Calculated as C19828N604・HCl
Calculated value (%): C, 51,99,) I, 6.20:
N, 19.15. (:l 8.08 Analysis value (%): C, 52,30: H, 6,56;
N, +8.91; CI, 8.56 Example 37 1.3-dimethyl-6-(2-[[1-(4-nitroph
phenyl)piperidin-4-yl]amino]ethylamino
)-2゜4 (IH,3)i)-pyrimidinedione cy
Production of oxalate (compound 61) (1) 1-(4-nitrophenyl)-4-oxopi
Preparation of peridine (compound 62): 2.8 g of 4-nitrofluorobenzene, 4-piperi
Add 3 g of Don hydrochloride and 6.9 ml of triethylamine.
It was dissolved in 20 ml of setonitrile and heated under reflux for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water to precipitate
The crystals were collected by filtration. After washing the crystals with water, wash with ether and isolate
Recrystallized from propatool/hexane (1/1, volume ratio)
filtered, washed and dried to obtain 1-(4-nitrophenyl).
)-4-oxopiperidine (compound 62) 3.47g
I got it. (2) 1,3-dimethyl-6-(2-[(1-(4
-nitrophenyl)piperidin-4-yl]amino]et
thylamino)-2,4(IH,3H)-pyrimidinedio
Preparation of oxalate (compound 61): O, 5 g of the compound 62 obtained earlier and 6-(2-amino
ethylamino)-1,3-dimethyl-2,4(1)1.
3N)-pyrimidinedione (compound 63) 1.8 g
Suspend in 30 ml of methanol and cool the resulting suspension to 0°C.
Add 0.58ml of 4N HCI/dioxane solution dropwise.
The mixture was stirred at the same temperature for 1 hour. Next, keep the internal temperature of the reaction mixture at 0°C, and add cyano water to it.
Add 0.14 g of sodium boronate little by little, and
The mixture was stirred at the same temperature for 3 hours. Add a small amount of water to the reaction mixture, then remove the methanol under reduced pressure.
The residue obtained was dissolved in 0.5N hydrochloric acid. Add potassium carbonate to this hydrochloric acid solution to make it alkaline.
Extracted with chloroform. After washing the extract (organic layer) with water, dry it with anhydrous sodium sulfate.
Then, the solvent was distilled off under reduced pressure, and the residue was transferred to a silica gel column.
Chromatographic purification (chloroform/methanol = 50/1~
25/1, volume ratio) and 1,3-dimethyl-6-(2
-[[1-(4-nitrophenyl)piperidin-4-y
rucoamino)ethylamino)-2,4(IH,3H)
-0.6 g of pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDCIg) δppm: 1.5 (m,
4H) 2,2~3.2 (m, 7H) 3,30 (s, 3H) 3.41 (s, 3H
)4,0 (m, 2H) 4.86 (s, IH
) 6.93 (d, 2H) 8.17 (d, 21 () next
Then, this pyrimidinedione derivative was desiccated according to a conventional method.
Treatment with acid/methanol solution gives 1,3-dimethyl-6
-(2-([1-<4-nitrophenyl)piperidine-
4-yl]amino J ethylamino)-2゜4 (IH,
3H)-pyrimidinedione oxalate (compound 61)
0.52g was obtained. Analysis results of the obtained crystals of compound 61: Melting point: 216 ~
217℃ (decomposition) 1540, 1330. 810 Elemental analysis value C+eHzNa04・(COOH) 2
Calculated value (%): C, 51, 22, H, 5, 7
3: N, 17.06 Analysis value (%): C, 51,
08: H, 5,69; N, 16.58 Example 38 1.3-dimethyl-6-(2-(4-(4-nitrophe)
(nyl)piperazin-1-yl]ethylamino) -2,
4(IH,3)1) -pyrimidinedione oxalate
Production of (Compound 64) (Compound 66) (1) 1,3-dimethyl-6-[2-(p-toluene)
sulfonyloxy)ethylamino] -2,4(IH
,3H)-pyrimidinedione (compound 65): Heating 35.0 g of 2-aminoethanol to 90°C,
Remove from oil bath and add 6-chloro-1,3-dimethyl-
2,4(1)1.3H)-pyrimidinedione 50. O
g was added, and these were allowed to react. The addition at this time is
Perform at a speed that maintains the temperature within the range of 90-110°C.
I was told. After the addition was complete, the reaction mixture was stirred for 10 minutes.
After that, dioxane/methanol (=1071, volume
ratio) 300ml was added, and the resulting crystals were left overnight.
Washed with a small amount of dioxane, dried and 1,3-dimethyl
-6-(2-hydroxyethylamine) -2,4(I
49.0 g of white crystals of H,3H)-pyrimidinedione
Obtained. Next, 49.0 g of this white crystal was suspended in 200 ml of pyridine.
The suspension was cooled to -5°C, and p-toluenesulfonyl was added to it.
The reaction temperature of chloride 40, Og does not rise above 5℃.
The suspension in the reaction solution added at the same speed completely disappears.
Additionally, 51.0 g of p-toluenesulfonyl chloride was used.
did. Furthermore, the obtained reaction mixture was poured into ice containing 370 g of KxCO.
Pour into water at 1.5℃, leave overnight, and filter the resulting crystals.
After washing with water and drying under reduced pressure, 1,3-dimethyl-
6-[2-(p-toluenesulfonyloxy)ethyl a
-2,4(1)1.3H)-pyrimidinedione
50.5 g of pale yellow crystals of (Compound 65) were obtained. Analysis results of the obtained crystals of Compound 65: Melting point: 146.
0-149.0°C Br IR (am-'): 3270. 1682.
16+5. 1550°ax 1480, 1435. 1350, 1190°117
8, 1010,903,780(2)1-(4-nito
Preparation of piperazine (compound 66): 2.8 g of 4-nitrofluorobenzene, 15 g of piperazine
Heat a mixture of g and 20 ml of acetonitrile for 6 hours.
After refluxing and cooling, chloroform was added to the reaction mixture to obtain a
After washing the solution with water and drying (anhydrous sodium sulfate)
, concentrated under reduced pressure to give N-(4-nitrophenyl)pipe
Radin (compound 66) was obtained. (3) 1,3-dimethyl-6-(2-[4-(4-di
trophenyl)piperazin-1-yl]ethylamino)
-2,4(I)I. 3H)-pyrimidinedione oxalate (compound 64)
Preparation of the previously obtained N-(4-nitrophenyl)piperazine (compound
66) 0.6g and 1,3-dimethyl-6-(2-
(P-toluenesulfonyloxy)ethylamino]-2
,4(])1.3H) Pyrimidinedione (Compound 65
) 0.5g were mixed and heated at 80°C for 1 hour. Cooling
Afterwards, the reaction mixture was diluted with 5 ml of acetonitrile. Next, add this diluted solution to 20ml of diluted sodium hydroxide water.
The resulting mixture was extracted with chloroform, and the organic layer was
After washing with water and drying (anhydrous sodium sulfate), concentrate to dryness.
did. The residue (concentrated to dryness) was purified by silica gel column chromatography (
Chloroform/methanol = 30:1. capacity ratio),
1,3-dimethyl-6-(2-(4-(4-nitrophe)
piperazin-1-yl]ethylamino)-2,4
(IH,3H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13) δppm: 2.8-3
．． 8 (m, 12H). 3, 36 (s, 3H), 3.41 (s,
3)1). 4,86 (s, 1)1), 6.87 (d,
21(). 8, 16 (d, 28) This pyrimidinedione derivative was treated with oxalic acid/
Treatment with methanol solution gave 1,3-dimethyl-6-(
2-(4-(4-nitrophenyl)piperazin-1-y)
]ethylamino)-2,4(1)1.3H)-pyri
Midindione oxalate (compound 64) 0.36g
I got it. Analysis results of the obtained crystals of compound 64: 1320, 8
30 Elemental analysis value C2゜HiJaO4・2 (COOH)
141 (calculated value (%) as 20: C, 43, 38,
) I, 5.46: N, 12.65 Analysis value (%):
'C, 42, 91,) I, 5.19. N, 13.
24 Example 39 1,3-dimethyl-6-(N-methyl-2-[N-methyl
Ru-2-(N-methyl-4-nitro7nilino)ethylua
(mino)ethylamino)-2,4(IH,3H)-pyrimi
Production of jindione oxalate (compound 67) (1) N,N',N''-trimethyl-N-(4-ni
trophenyl) diethylenetriamine (compound 68)
Preparation: 1.41 g of p-fluoronitrobenzene and N,N
', N-trimethyldiethylenetriamine 14g
Dissolved in 7 ml of methyl sulfoxide and heated at 120°C for 3 hours.
Stir for a while. The solvent was distilled off from the resulting reaction mixture under reduced pressure, and the residue was
Dissolved in chloroform. A small amount of this chloroform solution
of water, dried over anhydrous sodium sulfate, and dried under reduced pressure.
The solvent is distilled off to give N,N',N''-trimethyl-
N-(4-nitrophenyl)diethylenetriamine
2.1 g of compound 68) were obtained as a yellow oil. (2) 1,3-dimethyl-6-(N-methyl-2-[
N~methyl-2-(N-methyl-4-nitroanilino)
ethylamino 1 ethylamino)-2,4(1)I, 3
H)-pyrimidinedione oxalate (compound 67)
Production: The previously obtained N,N',N"-trimethyl-N-(4-nito
lophenyl) diethylenetriamine (compound 68) 2
．． 1g, 6-chloro-1,3-dimethyl-2,4(1)
1.3) 1)-pyrimidinedione 1.22g and tri
Suspend 2 ml of ethylamine in 10 ml of ethanol,
The mixture was heated under reflux for 1 hour. The resulting reaction mixture was concentrated to dryness.
, the residue was purified by silica gel column chromatography (chloroform
/methanol = 50/1 to 25/1, volume ratio) and acetic acid
Recrystallize from ton/water (1/1, volume ratio) to obtain 1.3
-dimethyl-6-(N-methyl-2-[N-methyl-2
-(N-methyl-4-nitroanilino)ethylamino 1
ethylamino)-2,4(IL 3H)-pyrimidine di
1.87 g of on was obtained. Analysis results of the obtained crystals: Melting point 265°C NMR (CDC13), δppm: 2.40 (s
, 3H). 3, 38 (s, 3) 1). 3,54 (s, 3)1). 3,13 (m, 2)1). 2, 82 (s, 3) 1). 3,50 (s, 3H). 2,78 (m, 2H). 3,80 (m, 2H). 5,40 (s, IH), 6.78 (m,
28) 8, 62 (m, 2H) Elemental analysis value Calculated value (%) as C+JzaNs04
: C, 5B, 42; H, 6,98, N, 20.7
8 Analysis value (%): C, 56, 63: H, 7, 31
; N, 19.98 1,3-di obtained as above
Methyl-6-(N-methyl-2-[N-methyl-2-(
N-methyl-4-nitroanilino)ethylamino 1ethyl
Ruamino)-2,4(IH,3H)-pyrimidinedione
was treated with an oxalic acid/methanol solution according to a conventional method to obtain 1
．． 3-dimethyl-6-(N-methyl-2-[N-methyl
-2-(N-methyl-4-nitroanilide ethylamino
1ethylamino)-2,4(IH,3)1)-pyrimidine
Obtained 1.91 g of dione oxalate (compound 67).
Ta. Analysis results of the obtained crystals of compound 67: Melting point = 184 ~
185℃ (decomposition) 1480°1310°1200°1100°833.722 Elemental analysis value C+J2sNaO4・(COOH) 1 station
Calculated value as LO (%): C, 50, 09, H, 6
,21,N, 16.69 Analysis value (%): C,50
, 29: H, 6, 29: N, 16.11 Example 4
0 1.3-dimethyl-6-(4-(3-(N-methyl-4
-nitroanilino)propylcopiperazin-1-yl)
-2,4(IH13H)-pyrimidinedione oxalic acid
Preparation of salt (compound 69) (compound 69) H3 1,3-dimethyl-6-(4-(3-
(4-nitroanilino)propylcopiperazine-1-y
)-2゜4 (IH,3)1)-pyrimidinedione (
Compound 58') 0.7 g of anhydrous dimethylformamide 1
0.12 60% oily sodium hydride in 5 ml suspension
g at room temperature, stirred for 30 minutes, and added 0.0 g of methyl iodide.
．． An additional 29g was added. After stirring this mixture at room temperature for 10 minutes, add a small amount of
Added methanol and further added 50ml of chloroform.
Thereafter, the resulting reaction mixture was poured into 50 ml of water. separation
The organic layer was separated, washed with water, and dried (anhydrous sodium sulfate).
), the solvent was distilled off and the residue was dissolved in methanol/ether.
crystallize from a solution (1/1, volume ratio), filter, wash,
By drying, 1,3-dimethyl-6-(4-
(3-(N-methyl-4-nitroanilino)propyl)
piperazin-1-yl)-2,4(1)1.3)1)-
0.62 g of pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: 1480, 1425. 1282. 1205°11
01. 815 NMR (do-DMSO), δppm: 1.82
(m, 2H). 2,13-2.73 (m, 6)1). 2,7:3-3.07 (m, 4)1). 3, 10 (s, 3H), 3.17 (s, 3H). 3,30 (s, 3H), 3.57 (t, 2
H). 5, 22 (s, IH), 6.87 (d, 2
H). 8. I O (d, 2H) Elemental analysis value Calculated as C2゜HzNa04・2H20
Calculated value (%): C, 57, 13,) I, 7.67;
N, 19.99 Analysis value (%): C, 57,49,)
! , ? , 02; Pyrimidine geo in N, 20.1
The carbon derivative was treated with an oxalic acid/methanol solution according to a conventional method.
1,3-dimethyl-6-(4-[3-(N-methyl)
Chil-4-nitro7nilinopropylpiperazine-1
-yl)-2,4(II(,3)1)-pyrimidinedio
oxalate (compound 69) was obtained. Analysis result of the obtained crystal of compound 69: Elemental analysis value C2
゜HiaNsO4・(COOH) 2・2H20
Calculated value (%): C, 51, 76: H, 6, 71, N
, 16.46 Analysis value (%): C, 52,05, H,
6,08; N, 16.56 Example 41 1.3-dimethyl-6-(4-[3-(N-methanesulfur)
Honyl-4nitro7nilino)propyl1piperazine-1
-yl)-2,4(1)1.3H)-pyrimidinedione
・Production of oxalate (compound 70) CH3S03C1 (COOH) */C)IsO)I 1,3-dimethyl-6-(4-[3-
(4-nitroanilinopropylcopiperazin-1-yl
)-2,4(IH,3H)-pyrimidinedione (compound
58') 0.4g and triethylamine 0.4g.
Dissolve in 20ml of loloform, add methane to this solution under water cooling.
0.2 g of sulfonyl chloride was added. Let this mixture stand overnight at room temperature, then add a small amount of water to it.
The mixture was added and stirred at room temperature for 30 minutes. Furthermore, add 20ml of dilute alkaline water to this mixture and separate the liquid.
, the chloroform layer was washed with water and dried with anhydrous sodium sulfate.
did. Afterwards, the dried chloroform layer is treated under reduced pressure.
The solvent was distilled off, and the residue was purified using silica gel column chromatography.
purification (chloroform/methanol = 100/1-2
5/1, volume ratio) and 1,3-dimethyl-6-(4-(
3-(N-methanesulfonyl-4-nitroanilino)p
ropyru]piperazin-1-yl)-2,4(IL 3H
)-pyrimidinedione (0.35 g) was obtained. This pyrimidinedione derivative was mixed with oxalic acid/
1,3-dimethyl-6-(4
-[3-(N-methanesulfonyl-4-nitroanilino
)propyl]piperazin-1-yl)-2,4(1)1
．． 3H)-pyrimidinedione oxalate (compound 70
) was obtained. Analysis results of the obtained crystals of compound 70: Melting point: 20
4.0~204.5℃ Elemental analysis value C2゜H2llN606S・(COOH)
Calculated value (%) as 2.2H20: C, 43, 56
,) I, 5.65; N, 13.85; S, 5.
29 Analysis value (%): C, 43, 81, It, 5.24
．． N, 13.35°S, 5.52 1350, 1340°1205°155 Example 42 1.3-dimethyl-6-(2-[N-ethyl-2-(4
-nitroanilino)ethylamino]ethyl,amino)-
2,4 (IH,3H) - Production of pyrimidinedione oxalate (compound 71)11111110) ICI/CH,0)11111111→ (compound 71 ) CH. (1) 6-(l-aziridinyl)-1,3-dimethyl-2,4
(1) 1゜3) Preparation of 1)-pyrimidinedione (compound 72): Example 38 - 47.2 g of compound 65 obtained in (1)
Add to 150ml solution of anhydrous dimethyl sulfoxide at room temperature.
, gradually add 6.24 g of 60% oily sodium hydride.
Ta. The resulting mixture was further stirred vigorously at room temperature for 5 hours.
Thereafter, the mixture was cooled and a small amount of water was added to stop the reaction. Charcoal
Pour into 1f2 of water containing 70g of potassium acid, and add chloroform.
Extracted three times with 200ml of
After drying with sodium and concentrating, ether was added to the resulting concentrate.
300 ml of the solution was added and left overnight. The pale yellow crystals precipitated by standing overnight were collected by filtration, and
After washing, dry under reduced pressure to obtain 6-(1-azirid
nyl)-1,3-dimethyl-2,4(1)1.38)-
15.2 g of pyrimidinedione (compound 72) was obtained. Analysis results of the obtained crystals of compound 72; melting point: 12
6.0-126.5℃ 0r IRv 1705. 1650. 1&12.
1470. 1440°ax 1305, 1150.783 490'H-NIII
R(CDC131, δppm: 2.34(s, 4H
), 3.35 (s, 3H) 3, 56 (s, 38
), 5.25 (s, 3) 1) (2) 1,
3-dimethyl-6-(2-[N-ethyl-2-(4-di
troanilino)ethylamino]ethylamino)-2,4
(IH, 31()-pyrimidinedione oxalate (chemical
Preparation of compound 71) N-ethyl-N'14-nitrophenyl)ethylenedia
1.32 g of min and the previously obtained 6-(1-aziridinyl)
-1,3-dimethyl-2,4(IH,3H)-pyrimidine
1.12 g of dione (compound 72) and chloroform
After dissolving in 5 ml, the resulting mixed solution was concentrated under reduced pressure.
Concentrate and add Amberlyst 15 (trade name) to the residue (concentrate).
(manufactured by Rohm and Haas) 1 (add 1 mg, 8
Heated at 0°C for 1 hour. Next, the resulting reaction mixture was dissolved in 5 ml of ethyl acetate.
After removing Amberlyst 15 by filtration, add n-hex to the filtrate.
Added Sun. Further, this was left overnight, the precipitated crystals were collected by filtration, and n-
After washing with hexane and drying under reduced pressure, 1,3-dimethyl
thyl-6-(2-(N-ethyl-2-(4-nitroani)
Lino)ethylamino J ethylamino)-2,4(IH,
3) 1.5 g of 1)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: 'H-NMR (CDCIs), δppm: 1.12
(t, 3)1). 2,52-2.98 (m, 6H). 2,98-3.25 (m, 2H). 3, 28 (s, 6H). 3,28-3.48 (m, 2Hl. 4,78 (s, 1)1), 5.27 (m,
IH) 5-45 (m, IH), 6.59 (d, 2
)1). 8,08 (d, 2) 1) Furthermore, this pyrimidinedione derivative was subjected to a conventional method.
1,3-dimethyl- by treatment with uric acid/methanol solution
6-(2-[N-ethyl-2-(4-nitroanilino)
dithylamino]ethylamino)-2,4(IH, 38)
-Pyrimidinedione oxalate (compound 71) 1.
4g was obtained. Analysis results of the obtained crystals of compound 71: Melting point: 17
5.0-176, 5℃ Elemental analysis value C3 mountain. N604・(Cool-1) 2
Calculated value (%); C, so, oo; ) I,
5.87. N, 17.49 Analysis value (%):
C, 49, 81; ) I, 6.02. N, 17.
22 Example 43 1.3-dimethyl-6-(2-[N-ethyl-3-(4
-nitroanilino)propylamino]ethylamino)-
2,4(IH13H)-pyrimidinedione hydrochloride (chemical
Production of compound 73) (compound 72) HCI/CH,OH -1111111> As a starting material, N-ethyl-N-(4-nitrophenyl
N-ethyl-N-(4-
Nitrophenyl)-1,3-propylene diamine 1.4
Same strainer as in Example 42-(2) except that 5g was used.
and 1,3-dimethyl-6-(2-[N-ethyl-3-
(4-nitro7nilino)propylamino]ethylamino
)-2,4(IH,3)1)-pyrimidinedione crystal
(I asked Akira Kiyoshi's analytical results of this pyrimidinedione derivative obtained.
Results: NMR (DMSO-ds), δppm: 1.05 (
t, 3H). 1,6-1.9 (m, 2H). 2,4-2.8 (m, 6H). 3, 0-3.4 (m, 4H). 3, 1 (s, 3)1), 3.25 (s,
3H). 4,65 (s, IH), 6.4 (br, 1
)1). 6, 6 (d, 2H), 7.2 (br, I
H). 8,0 (d, 2H) This crystal was further treated with a hydrochloric acid/methanol solution according to a conventional method.
1,3-dimethyl-6-(2-[N-ethyl-
3-(4-nitroanilino)propylamino J ethyla
(mino)-2,4(18,3H)-pyrimidinedione salt
An acid salt (compound 73) was obtained. Analysis results of the obtained crystals of compound 73: Elemental analysis value C
Calculated value (%) as +eH*aNs04・2HC1:
C, 47,80: H, 6,33; N, 17.6
0CL 14.85 Analysis value (%): C, 47,52, H, 6,49;
N, 17.31C1,14,76 Example 44 1.3-dimethyl-6-(N-(2-hydroxyethyl
)-2-(4-(4-nitrophenyl)piperazine-1
-yl]ethylamino)-2,4(IH,3H)-pyri
Production of midinedione oxalate (compound 74) (compound 74) CI(3 (1) 1-[2-(2-hydroxyethylamino)ethyl
Thirj-4-(4-nitrophenyl)piperazine (compound
Preparation of product 75): ! -(4-nitrophenyl)piperazine (compound 66)
4g and 1-(2-hydroxylethyl)aziridine 0
．． 52 ml was dissolved in 20 ml of chloroform to obtain
The solvent was distilled off from the mixed solution under reduced pressure. Amber on the remainder
List 15 (Product name: Rohm & Haas) 1
0mg was added, heated and stirred at 100℃ for 3 hours, and the reaction mixture was
Return the mixture to room temperature and add 20ml of chloroform to it.
Insoluble materials were filtered off from the resulting mixture. Concentrate the filtrate
, the residue (concentrate) was purified by silica gel column chromatography.
Roloform/methanol = 100/1~25/l, volume
1-[2-(2-hydroxyethylamine)
ethyl]-4-(4-nitrophenyl)piperazine
1 g of (Compound 75) was obtained. (2) 1,3-dimethyl-6-(N-(2-hydroxy)
ethyl)-2-[4-(4-nitrophenyl)pipera
Zin-1-yl]ethylamino)-2,4(IH,3)
1)-pyrimidinedione oxalate (compound 74)
Preparation: Compound 7 obtained as above as starting material
1.0 g of 5, 6-chloro-1,3-dimethyl-2,
4(IH,31()-pyrimidinedione 0.52g and
Add 2 ml of triethylamine and 2 ml of triethylamine to 10 ml of ethanol.
The mixture prepared was treated in the same manner as in Example 39-(2).
and 1,3-dimethyl-6-(N-(2-hydroxyethyl)
chill)-2-[4-(4-nitrophenyl)piperazine
-1-yl]ethylamino)-2,4(1)1.3H)
-0.73 g of pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 2,65 (m, 68), 2.9-3.4 (m
, 8)1). 3, 31 (s, 3)1), 3.47 (s,
3t1). 3,82 (m, 21(), 5.32 (s,
1)1). 6,86 (d, 2H), 8.12 (d,
2H) Further add 0.7 g of this pyrimidinedione derivative in a conventional manner.
treated with oxalic acid/methanol solution according to l. 3-dimethyl-6-(N-(2-hydroxyethyl)
-2-[4-(4-nitrophenyl)piperazine-1-
yl]ethylamino)-2,4(IH,3H)-pyri
Crystals of midinedione oxalate (compound 74) 0.3
5g was obtained. Analysis results of the obtained crystals of compound 74: Elemental analysis value C
3゜) 1211N8011.5 (COOH) 1LO
Calculated value (%): C, 47, 18; H, 5,
68; N, 14.35 Analysis value (%): C, 47
, 37: H, 5, 94: N, 14.08 Example 4
5 1,3-dimethyl obtainable by the method of Example 36
Chil-6-(4-(3-(4-nitroanilino)propyl)
lucopiperazin-1-yl)-2,4(IH,3H)-
Pyrimidinedione hydrochloride (compound 58) as active ingredient
Production of tablets: The pyrimidinedione derivative hydrochloride (compound 58) Ig
, 123 g of lactose and 20 g of corn starch.
Mix well and add 5g of hydroxypropyl cellulose.
Mix and granulate with a solution dissolved in 100ml of water and heat at 50℃ for 4 hours.
Dry for a while. Add 1g of magnesium stearate to this.
Mix well and use a tablet machine to give 150mg per tablet.
Tablets were obtained by compression with a weight of . Example 46 1,3-dimethyl obtainable by the method of Example 37
Chil-6-(2-[[1-(4-nitrophenyl)pipe
Lysin-4-yl]amino]ethylamino)-2,4(
1)1.3)1)-Birimidinedione hydrochloride (compound
Production of capsules containing 61) as an active ingredient: 5 g of the pyrimidinedione derivative hydrochloride (compound 61)
, 120 g of lactose and 25 g of corn starch.
The resulting mixture is packed into hard capsules using a capsule filling machine.
A cell was filled with 150 mg to obtain a capsule. Example 47 1,3-dimethyl obtainable by the method of Example 43
-6-(2-(N-methyl-N-[3-(4-nitroa)
nilino)propyl 1-amino]ethylamino)-2,4(
1) 1.31() -pyrimidinedione hydrochloride (compound
Production of an injection containing compound 73) as an active ingredient: Said pyrimidinedione derivative/hydrochloride (compound ?3) 2
Take 0mg and 0.85g of sodium chloride and
Dissolve with appropriate amount of distilled water for injection, make total volume 100ml, and inject.
It was used as a drug. Pharmacological Test Example 3 In the same manner as Pharmacological Test Example 1, the above-mentioned implementation shown in Table 6 was carried out.
Find ADP7S and ERP of each compound obtained in the example.
I met. The results are shown in Table 6. Toxicity Experiment 3 In the same manner as Toxicity Test 1, the results obtained in the above example shown in Table 7 were
The toxicity of each compound was tested and the mortality rate of mice was determined.
Ta. The results are shown in Table 7. The administration was 300mg/Kg orally for each compound.
Administration (p,o,) was performed. Surface toxicity test results 1 Example 48 1.3-dimethyl-6-(4-[3-(2-acetyl-
4-nitrophenoxy)propylcopiperazine-1-y
)-2,4(II, 3H)-pyrimidinedione
Production of oxalate (compound 76) (compound 76) (1) 1.3-dimethyl-6-(4-(3-hydro)
xypropyl)piperazin-1-yl]-2,4(I
Preparation of H,3H)-pyrimidinedione: 1.3-dimethyl-6-(1-piperazinyl)-2,
14.1 g of 4(IH,3H)-pyrimidinedione,
11.7 g of 3-bromo-1-propatool and triethyl
13 g of Ruamine in 250 ml of ethanol at 20 hours.
After the completion of 6 reactions, the reaction mixture was heated under reflux for a while.
was concentrated to dryness, and the residue was dissolved in 300 ml of chloroform.
This was washed twice with 100 ml of water. After this cleaning,
The organic layer was dried over anhydrous magnesium sulfate. This organic layer
Treated under reduced pressure, the solvent was distilled off, and 20.5 g of the crude product was
Obtained. Add ether to this crude product to crystallize it,
It was filtered, washed with cold ether, dried and
．． 3-dimethyl-6-[4-(3-hydroxypuchubiru)
) piperazin-1-yl]-2,4(IH,3H)-pi
12.4g of rimidinedione (yield: 69.8%)
Obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
; Melting point: 119-121'C NMR (CDC13), δppm: 1.8 (dt
, 2H). 2,7 (m, 6)1), 3.02 (m, 4
H). 3, 36 (s, 3)1), 3.43 (s,
3H). 3,82 (t, 211), 4.34 (br,
18). 5, 26 (s, l11) 1695, 1650, 1605. 1440°121
3, 1068. 1000. 921°60 (2) 1.3-dimethyl-6-(4-[3-(2-
Acetyl-4-nitrophenoxy)propylcopiperazi
(1-yl)-2,4(1)1.3H)-pyrimidine
Production of dione oxalate (compound 76); 0.6 g of the pyrimidinedione derivative obtained in the above (Section 11)
, 2-hydroxy-5-nitroacetophenone 0,5
4 g and triphenylphosphine 0.69 g in anhydrous tetane
Suspension obtained by mixing in 10ml of lahydrofuran
Add 0.42 mβ of diethyl azodicarboxylate to the inside at room temperature.
It was added dropwise while stirring. Next, the resulting mixture was stirred at room temperature for 30 minutes, then concentrated and dried.
solidify, and purify the residue by silica gel column chromatography (chlorophore).
lum/methanol = 50/1, volume ratio), 1.3-
Dimethyl-6-(4-[3-(2-acetyl-4-nito)
lophenoxy)propylcopiperazin-1-yl) -
0.7 g of 2,4(IH,3)1)-pyrimidinedione
Obtained as an oil. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 8.47 (
m, 1) I) 7.54 (m, IH), 6.91 (
d, IH), 5, 23 (s, IH), 4.26
(m, 2) 1), 3, 37 (s, 31(),
3.30 (s, 3H), 2,98 (m, 4H
), 2.60 (m, 6H), 2,6
3 (s, 3H), 2.16 (m, 2H
) Furthermore, this pyrimidinedione derivative was treated with oxalic acid/meth
1,3-dimethyl-
6-(4-(3-(2-acetyl-4-nitrophenoki)
c) propylcopiperazin-l-yl) -2,4(1
8,3H)-pyrimidinedione oxalate (compound 7
6) Obtained 0.73g. Analysis results of the obtained compound 76; Melting point: 122-124°C (decomposition) +640. 1520. 1340. +280°1
120.820,750,700 Elemental analysis value C2+H2JsOs・(CO□H)12
Calculated value (%) as H20: C, 48, 33; H
,5,82: N, 12.25 Analysis value (%): C
,48,22,H,5,69,N, 11.93 Examples
49 1.3-dimethyl-6-(4-[3-(4-acetyl-
2-nitrophenoxy)propyl] biverazine-1-
yl)-2,4(IH13)1)-pyrimidinedione・
Production of oxalate (compound 77) (compound 77) Example 48 - 2-hydroxy-5-ni
Instead of troacetophenone, 4-hydroxy-3-ni
Example 48- (2
), 1,3-dimethyl-6-(4-
(3-(4-acetyl-2-nitrophenoxy)propyl
rucopiperazin-1-yl) -2,4(1)I, 3
H)-pyrimidinedione oxalate (compound 77)
Obtained. Analysis of the obtained pyrimidinedione derivative (compound 77)
Results; Melting point: 119-123℃ (decomposition) 1530, 1350, 1020.760゜00 Elemental analysis value Cz+HzJsOs・(CO□H)2・
Calculated value (%) as 3H20: C, 46, 86, H
, 5,98, N , 11.88 Analysis value (%): C,
46,79; H, 5,43; N, 11.51 implementation
Example 50 1,3-dimethyl-6-(4-[3-(4-benzoyl)
-2-nitrophenoxy)propylcopiperazine-1-
yl)-2,4(IH,3)1)-pyrimidinedione
Preparation of oxalate (compound 78)
4-hydroxy-3-nito instead of loacetophenone
Example 48-(2) except for using lobenzophenone
By the same operation as above, 1,3-dimethyl-6-(4-(
3-(4-benzoyl-2-nitrophenoxy)propyl
rucopiperazin-1-yl)-2,4(1B, 3H
)-pyrimidinedione oxalate (compound 78) was obtained.
Ta. Analysis of the obtained pyrimidinedione derivative (compound 78)
Result; Melting point = 168-171'C (decomposition) +540. 1350. 1080,760゜00 Elemental analysis value C26H2QNs06・(C02H)2
・Calculated value as H2O (%): C, 54, 63, H
,5,40,N,11.38 Analysis value (%): C,
54,99, H, 5,29: N, 11.30 Example
51 1.3-dimethyl-6-(4-[3-(3-acetyl-
4-nitrophenoxy)propylcopiperazine-1-y
)-2,4(IH,3H)-pyrimidinedione
Production Example 48 of Urate Salt (Compound 79) - In the step (2), 2-hydroxy-5-ni
Instead of troacetophenone, 5-hydroxy-2-ni
Example 48- (2
), 1,3-dimethyl-6-(4-
[3-(3-acetyl-4-nitrophenoxy)propyl
biverazin-1-yl)-2゜4 (IH, 38)
- Pyrimidinedione: oxalate (compound 79) was obtained
. Analysis of the obtained pyrimidinedione derivative (compound 79)
Results; Melting point = 223-224°C (decomposition) 1600, 1520. 1350. 1020゜10 Elemental analysis value Cz+HzJsOs・(COz)1)
12) Calculated as 1tO (I! (%): C, 48,
33;) I, 5.82; N, 12.25 analysis
Value (%): C, 48, 17, H, 5, 62, N,
12.05 Example 52 1.3-dimethyl-6-(4-[3-(2-benzoyl
-4-nitrophenoxy)propylcopiperazine-1-
yl)-2,4(IH,31()-pyrimidinedione・
Oxalate (compound 80) (1) Preparation of 2-hydroxy-5-nitrobenzophenone
3g of 2-chloro-5-nitrobenzophenone, potassium hydroxide
A suspension obtained by suspending 1.1 g of Rium in 30 ml of water,
The mixture was heated and stirred in an autoclave at 150°C for 5 hours. After stirring, leave to cool and add 30ml of water to the resulting reaction solution.
Further, hydrochloric acid was added to make the reaction solution acidic, and at that time, the precipitated
The crystals were collected by filtration. Furthermore, the obtained crystals were recrystallized from ethanol to
2.3 g of droxy-5-nitrobenzophenone was obtained. Analysis results of the obtained crystals; Melting point: 125-126°C NMR (CDCIs), δppm: 7.21
(m, 2H). 7,68 (m, 4H). 8, 41 (m, 2H) 1280, 1210. 1080. 960°90 (2) 1.3-dimethyl-6-(4-(3-(2-beta)
Nzoyl-4-nitrophenoxy)propylcopiperadi
(1-yl)-2,4(11-1,3H)-pyrimidine
dione oxalate (manufacture of compound 80; 2-hydroxy-5-nitrobenzo obtained in section (1) above)
Phenone 0.73g, 1,3-dimethyl-6-(4
-(3-hydroxypropyl)piperazine-■-yl
-2,4(IH.3H)-pyrimidinedione 0.5g, triphenyl
Phosphine 0.58g, diethyl azodicarboxylate 0.
34 ml in anhydrous tetrahydrofuran 10 mβ
React and treat in the same manner as in Example 48-(2), 1.
3-dimethyl-6-(4-[3-(2-benzoyl-4
-nitrophenoxy)propylcopiperazin-1-yl
) -2,4(E,3H)-pyrimidinedione
Obtained as a cup (0.7 g). Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 8.36 (m
, 2H). 7.0-7.8 (m, 6H) 5.14 (s, IH 4,14 (t, 2) 1. 3.26 (s, 3) 1. 3.34 (s, 3H. 3.0 (m, 4H). 2.2-2.5 (m, 6H). 1,9 (m, 2H) Next, this pyrimidinedione derivative was synthesized according to a conventional method.
1゜3-dimethyl by treatment with oxalic acid/methanol solution
-6-(4-(3-(2-benzoyl-4-nitrophe)
noxy)propylcopiperazin-1-yl)-2,4(
1) 1,3) 1)-Pyrimidinedione oxalate (chemical
Compound 80) 0.71 g was obtained. Analysis of the obtained pyrimidinedione derivative (compound 80)
Results; Melting point: 200-202°C (decomposition) 1510, 1330.12g0. 1150°10B
0. 760. 700 Elemental analysis value Czs)12sNsOa・%(CO□o
) Calculated value (%) for 1 station 820: C, 57, 85; ) I, 5.3
9; N, 12.49 Analysis value (%): C, 57
, 71; H, 5, 54; N, 12.24 Example 5
3 Production of compounds 87 to 92; instead of 2-chloro-5-nitrobenzophenone, the following
Each compound 81 in which XI of structural formula (I) is a group shown below
Example 52-(1) and 86 were used, respectively.
By the same operation, Xl of the following structural formula (E') is
Different phenol derivative compounds 81' to 86' were obtained. Compound no. 1 81. 81' -CO%Br Analysis results of the obtained compound 81': NMR (CDCIs), δppm: 8.3+3(
m, 2N). 7,70 (m, 4H). 7,41 (m, 1)1). Elemental analysis value Calculated value (%) as C+5HaNOJr
: C, 48, 47: H, 2, 50; Br, 24
．． 81 Analysis value (%): C, 48, 52; H, 2, 31;
Br, 24.42 Analysis results of the obtained compound 83': , 4.35 4.45 770, 750 Analysis results of the obtained compound 84; 1040, 730 Next, the substitute for 2-hydroxy-5-nitrobenzophenone
In addition, each phenol derivative compound 81' to 86' was
The same operation as in Example 52-(2) except for using each
Accordingly, XI in the following structural formula (rr) is the group shown below.
Oxalic acid, a pyrimidinedione derivative with the following physical properties:
Salts (compounds 87 to 92) were obtained respectively. (II) Compound 87 (X' is the same as compound 81); Melting point; 13
4-135℃ (decomposition) Elemental analysis value 1340, 840,790 CzaH*aNsOJt” (CO2H) 13HJ
Calculated value (%): C, 46,04, H, 4,97, N
, 9.59Br, 10.94 Analysis value (%'): C, 46,26, H, 5,16,
N, 9.92Br, 10.53 Compound aa (x' is the same as compound 82): Melting point; 1
71-174°C (decomposition) 1440, 1350. 1200.760 elemental analysis value
C2JatNtOs・2 (CO2H) as z
Calculated value (%): C, 47,86; H, 4,61,
N, 14.47 Analysis value (%): C, 47,38:
H, 5, 17, N , 14.40 Compound 89 (X'
is the same as compound 83): Melting point; 149-151''C (
decomposition) 1340, 850. 800 Elemental analysis value CzJztN70g・2 (CO2H)
Calculated value (%) as 24HJ: C, 45, 22;
H, 5,02, N, 13.19 Analysis value (%):
C, 45,60; H, 5,18; N, 13.59
Compound 90 (X' is the same as compound 84); Melting point: 177
~178℃ (decomposition) 1320, 126 (1,860,760 elemental analysis value
CC211) 128N60・2(CO□D)128z
Calculated value (%) as O: C, 48,07, H, 5,01:
N, 11.60 analysis value (%): C, 48,02:
H, 5,05; N, 11.31 Compound 91 (X'
is the same as compound 85); melting point, 104-107°C (min.
Solution) 1340, 1280.800 Elemental analysis value C25Hz? LsOm・2 (COJ
) Calculated value (%) as i・3H20: C, 46,
90; H, 5, 16; N, 11.32 analysis value (%
): C,46,88,)I,5.42,N
, 11.38 compound 92 (X' is the same as compound 86);
Melting point; amorphous 1350, 1260. 780. 700 elemental analysis values
C15tlzaNaOs・2(COJ)11HJ and
Calculated value (%): C, 49,29, H, 4,85
, N, 11.89 Analysis value (%): C, 4B, 85
, H, 4,97, N, 11.44 Example 54 1.3-dimethyl-6-(4-[2-(2-acetyl-
4-nitrophenoxy)ethylcopiperazin-l-yl
)-2,4(II-1,3)1)-pyrimidinedione・
Production of oxalate (compound 93) (1) 1.3-dimethyl-6-[4-(2-hydroxy
ethyl)piperazin-1-yl]-2,4(Ill,
3) Preparation of 1)-pyrimidinedione; 6-chloro-1,3-dimethyl-2,4(1)1,31
1) 2.7 g of -pyrimidinedione and 1-(2-hydroxy
ethyl)piperazine 4 ml and triethylamine 12
ml was dissolved in 70 ml of isopropanol and the obtained
The solution was stirred under reflux for 3 hours. After the stirring process is completed, the reaction solution is allowed to cool, and then the solvent is removed from the reaction solution.
was removed under reduced pressure, and the residue was dissolved in 60 ml of chloroform.
I understand. After washing the obtained chloroform solution with water, immerse it in anhydrous sulfur.
dried over sodium chloride, further concentrated to dryness under reduced pressure,
A crude product was obtained. Next, add ethanol/ethyl ether mixture to the crude product.
The crystals precipitated at that time were collected by filtration. This crystal was further recrystallized from hexane/ethanol to give 1
．． 3-dimethyl-6-[4-(2-hydroxyethyl)
piperazin-1-yl)-2,4(IH,3H)-pyri
3.72 g of midinedione was obtained. Analysis results of this pyrimidinedione derivative obtained; NMR (CDC13), δppm: 5.21 (s
, 1)1). 3.69 (t, 2l-1). 3, 35 (s, 38). 3, 26 (s, 3H). 2.5-3.1 (m, 10H) (2) 1.3-dimethyl-6-(4-[2-(2-a
Cetyl-4-nitrophenoxy)ethylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione
- Production of oxalate (compound 93); pyrimidinedione derivative obtained by the operation in item (1) above.
5g, 2-hydroxy-5-nitroacetophenone 0.
65g, triphenylphosphine 0.6g, azodi
Example 48-(2) 0.36 ml of diethyl carboxylate
1,3-dimethyl-6-(4-[2-
(2-acetyl-4-nitrophenoxy)ethylcopipe
Radin-l-yl)-2,4(IH,3H)-pyrimidine
Obtained dione (0.65 g). Analysis results of this pyrimidinedione derivative obtained; NMR (CDC1a), δppm: 8.2-8.
6 (m, 2H). 7, 08 (m, 1) 1 5, 26 (s, 18 4.35 (m, 2H. 3.42 (s, 3H. 3.34 (s, 3H. 2, 72 (s, 3) 1) 2,7-3.2 (m, 10H) Next, this pyrimidinedione derivative was subjected to a conventional method.
Treated with uric acid/methanol solution, 1,3-dimethyl-6
-(4-(2-(2-acetyl-4-nitrophenoxy)
) Ethylcopiperazin-1-yl)-2,4(IH. 3H)-pyrimidinedione oxalate (Compound 93)
0.68g was obtained. Analysis of the obtained pyrimidinedione derivative (compound 93)
Results; Melting point: 193-195°C (decomposition) +520. 1340. 1270. 1120°83
0.760,700 Elemental analysis value C2゜H2sNsO+・(COOH)
Calculated value (%) as 11HJ: C, 48, 98, H,
5,42,N, 12.98 Analysis value (%): C,49
,02; H,5,22: N, 12.90 Example 5
5 Production of compounds 99 to 103; R7, R8 and Be in the following structural formula (III) are as follows.
Each phenol derivative compound 94-98 which is a group shown below
Proceed in the same manner as in Example 54-(2) using
R7, R8 and R9 in the structural formula (IV) are each
Pyrimidinedione derivatives with different physical properties shown below.
Oxalate compounds 99-103 were obtained. 8 e 7 Compound 94 Compound 95 H H -CO@ -co(t[3r -No□ NO2 Compound 96 C0CHs H NO2 Compound 97 10-NO! C0CHs Compound 98 H No2 COO Compound q de (R?, R8, R9 is the same as compound 94)
: Melting point: 160~162℃ (decomposition) +340°760°00 Elemental analysis value C25827N606・(COO)I) 12820
Calculated value C%): C, 52, 34: H, 5, 37:
N, 11.30 Analysis value (%): C, 52,14;
H, 5, 1B, N, 11.42 compound 100 (
R', R8, R9 are the same as compound 95); Melting point: 136
~138℃ (decomposition) Elemental analysis value 1340, 800. 700 Czs) liJrNaoa' (COOH) i'2H
Calculated value (%) as z0: C1 Br. Analysis value (%): C1 Br. 46.43°11.44 46.64°11.25 Hl Hl 4.62°4.43°? (1, (13. 10.30° Compound 101 (R', R', R1+ are the same as compound 96)
Di); Melting point: 110°C (amorphous) Elemental analysis value 1520, 1320. 1180.800C Goose H
-a N s Os・(COO)IL4)IJ
Calculated value C%: C, 45, 91, H, 5, 78, N,
12.17 Analysis value (%): C, 45,76; I(,
5,54,N, 12.07 Compound 102 (R7, Ra
, R9 compound 97); Melting point: 139-141
"C (decomposition) 1530, 1360. +270. 800゜60 Elemental analysis value C2゜HssNsOs・(COOH)
1! (Calculated value (%) assuming 20: C, 48, 98:
H, 5, 42: N, 12.98 Analysis value (%) IC
,49,08; H,5,97; N, 12.97
Compound 103 (R', R8, R9 are the same as compound 98)
); Melting point: 133-135°C (decomposition) 1540, 1340. 12B0,760゜00 Elemental analysis value C1JztNaOa・(COOH12・
I (calculated value C%' as 20): C, 53, 91, H
,5,19,N, 11.64 Analysis value (%): C,5
3,66: H, 4,96; N, 11.86 Example
56 1.3-dimethyl-6-(4-<3-[2-(2-hydro
(roxybenzoyl)-4-nitrophenoxyjpropyl
〉Piperazin-1-yl)-2,4(IH,3H)-pi
Production of rimidinedione oxalate (compound 104) (compound 104) (1) 2.2'-dihydroxy-5-nitrobenzof
Preparation of phenone (compound 104'); 2.3 g of 2°-dichloro-5-nitrobenzophenone and
Suspend 1.1 g of potassium hydroxide in 30 mI2 of water.
The obtained reaction solution was heated in an autoclave at 150°C for 5 hours.
The mixture was heated and stirred. After cooling, add 30 mI2 of water to the reaction solution, and then add hydrochloric acid.
The reaction solution was made acidic, and the precipitated product was collected by filtration. The crystals were dried under reduced pressure and 2,2°-dihydroxy-5-
1.9 g of nitrobenzophenone (compound 104°)
Obtained. This crystal can be used for the following reaction without further purification.
used for the operation. (2) 1,3-dimethyl-6-(4-゛(3-[
2-(2-hydroxybenzoyl)-4-nitropheno
xy]propyl)piperazine-! -il)-2,4(1
) I, 3H)-pyrimidinedione oxalate (compound
Production of product 104);
Droxy-5-nitrobenzophenone 0.75g%1.
3-dimethyl-6-[4-(3-hydroxypropyl)
piperazin-1-yl)-2,4(IH,3)1)-pi
Rimidinedione 0.5g, triphenylphosphine
0.58g, diethyl azodicarboxylate 0.34mI
Example 4
8- React and process in the same manner as in (2) to obtain 1.3
-dimethyl-6-(4-<3- [2-(2-hydroxy
cybenzoyl)-4-nitrophenoxylpropyl
perazin-1-yl)-2,4(IH,3H)-pyrimi
0.6 g of jindione was obtained. Next, this pyrimidinedione derivative was synthesized using a conventional method.
1,3-dimethyl- by treatment with oxalic acid/methanol solution
6-(4-(3-[2-(2-hydroxybenzoyl)
-4-nitrophenoxy1propyl]piperazine-1-
yl)-2,4(I14.3H)-pyrimidinedione.
0.6 g of oxalate (compound IQ4) was obtained. The amount of the obtained pyrimidinedione derivative (compound 104)
Analysis results: Melting point: 144-146°C (decomposition) 1640, 1530. 134G, 840°730.
700 Elemental analysis value Cz6H*J@Ot・2 (COO)1
) Calculated value (%) as 1HaO: C, 49,93, H, 4,89, N,
9.73 Analysis value (%): C, 49,83; H,
5,07,N, 9.43 Example 57 1.3-dimethyl-6-(4-<3- [2-(2-k
lorobenzoyl)-4-nitrophenoxylpropyl>
piperazin-1-yl)-2,4(IH,3H)-pyri
Production of midinedione oxalate (compound IQ9) (113-(2-chlorobenzoyl)-4-methoxyni
Preparation of Trobenzene: 2-Methoxy-5-nitrobenzoic acid chloride4. Og
was dissolved in 100ml of anhydrous tetrahydrofuran, and added to it.
4-(N,N-dimethylamino)pyridine 2.72
g was added at room temperature and stirred vigorously for an additional hour. After the stirring process is completed, 2-chlorobromobenzene 3 is added to the reaction solution.
．． 82g and 0.48g of metallic magnesium to ethyl ethyl
28 ml of Grignard reagent prepared in ether
It was added dropwise at ℃. After dropping, the temperature of the reaction solution was gradually raised to room temperature over 3 hours.
After reconstitution, water was added to this and concentrated to dryness. Next, get
The obtained residue was dissolved in 50 ml of chloroform, and the obtained
After washing the solution with water, add 50ml of IN sodium hydroxide aqueous solution.
Washed with 50 ml of IN hydrochloric acid and saturated saline in this order. After drying the washed solution (anhydrous sodium sulfate), remove the solvent.
was distilled off, and the resulting residue was purified by silica gel column chromatography.
(chloroform/hexane = 1750~l/20)
3-(2-chlorobenzoyl)-4-methoxyni
Trobenzene (1.55 g) was obtained. Obtained analysis results of this compound; NMR (CDCIs), δppm: 3.80 (8
,2)1). 6.92-7.75 (m, 5) 1). 8, 28-8.69 (m, 21()(2) 3-(
2-chlorobenzoyl)-4-hydroxynitrobenze
Preparation of 3-(2-chlorobenzoyl)-4 obtained in section (1) above
- 1.55 g of methoxynitrobenzene in chloroform
0ml of trimethylsilane iodide.
Then, the resulting solution was heated under reflux for 2 hours.
After heating and stirring for a while, the reaction solution was allowed to cool, washed with 30 ml of water,
Further, the mixture was extracted twice with IN aqueous sodium hydroxide solution. Hydrochloric acid was added to the alkaline layer obtained from the extraction, and chloro
Extracted with form. The organic material obtained from the chloroform extraction
After washing the layer with water and drying (anhydrous sodium sulfate), the organic layer
The solvent was distilled off under reduced pressure to give 3-(2-chlorobenzoyl)
-4-Hydroxynitrobenzene in the form of a pale yellow oil (0
, 5g). Analysis results of this pale yellow oily compound obtained; NMR
(CDC13) , δppm + 7.33 (d,
LH, J-10,0Hz) 7.46-7.83 (m,
5H). 8.35 (d, IH, J=2.5Hz). 8.50 (dd, IH, J=2.5. IO, 0Hz
)(3) 1,3-dimethyl-6-(4-<3- [2
-(2-chlorobenzoyl)-4-nitrophenoxyl
propyl〉piperazin-I-yl)-2,4(IH,3
H)-pyrimidinedione oxalate (compound 105)
Production: 3-(2-chlorobenzoyl)-4 obtained in section (2) above
-Hydroxynitrobenzene, 2-hydroxy-5-
Example 48 except that it is used in place of nitroacetophenone
- By the same operation as (2), 1,3-dimethyl-
6-(4-(3-[2-(2-chlorobenzoyl)-4
-nitrophenoxy1propyl]piperazin-1-yl
)-2,4(IH93H)-pyrimidinedione shu
White crystals (0.5 g) of the acid salt (compound 105) were obtained. Analysis results of the obtained crystals of compound 105: Melting point: amol
Fas 1335° 1285° 1 mouth 80 Elemental analysis value Czs) IzaCINsOa・(CO□H)!・Hl0
Calculated value (%): C1 51,74: Hl 4.96°N. 10, 77 CI. 5.45 Analysis value (%): C1 51,50: Hl 5.1+. N. 10, 97 CI. 5.71 Example 58 1.3-dimethyl-6-(4-<3-[4-nitro-
2-(2-biwazinecarbonyl)phenylthiopropyl
l〉piperazin-1-yl)-2,4(IH,3H)-
Pyrimidinedione (Compound 106) (1) 1-chloro-3-[2-(2-pyridinecarboni
Preparation of 4-chloro-3-(2-pyridinecarbonyl)-4-nitrophenylthio]propane;
1.58g of mercaptan, 3-chloropropyl mercaptan
0.66g and 2ml of triethylamine in dimethylsulfate.
Dissolved in 5 ml of sulfoxide, heated and stirred at 80°C for 3 hours.
Ta. After stirring, the reaction solution was concentrated, and the resulting concentrate was chloroformed.
Dissolve in form, wash with water, and dry (anhydrous sodium sulfate).
Ta. Next, the solvent was distilled off from the dried solution, and the obtained
Purify the residue by silica gel column chromatography (chloroform)
and further crystallized with a hexane/ether mixture to obtain 1-
Chloro-3-[2-(2-pyridinecarbonyl)-4-
1.0 g of ditrophenylthio]propane was obtained. Analysis results of the obtained crystals of this compound; elemental analysis value C
Calculated value (%) as IsH+5CINJsS: C,
53,49: l(, 3,89; N, 8.32°S
, 9.52. C1,10,53 Analysis value (%): C,53,29: H,3,79;
N, 8.25; S, 9.35. CI, 10.
37(2) 1,3-dimethyl-6-(4-<3-
[4-Nitro-2-(2-pyridinecarbonyl)phenylene
ruthiolpropyl〉piperazin-1-yl)-2,4(
IH, 3) 1)-Virimidinedione oxalate (compound
Preparation of product 106): l-chloro-3 obtained in section (1) above
-[2-(2-pyridinecarbonyl)-4-nitrophe
Nilti primary propane 0.93g, 1,3-dimethyl
-6-(piperazin-1-yl)-2゜4 (IH, 3
)1)-pyrimidinedione 0.62g and triethyl acetate
Dissolve 2 ml of amine in 10 ml of dimethyl sulfoxide.
The mixture was heated and stirred at 120° C. for 4 hours. After stirring, the reaction solution was allowed to cool, and then the reaction solution was drained under reduced pressure.
The solvent was distilled off, the residue was dissolved in chloroform, and the obtained
After washing the solution with water and drying (anhydrous sodium sulfate),
Purification by silica gel column chromatography (chlorowaform/method)
1,3-dimethyl-6-(4
-[3-[4-nitro-2-(2-pyridinecarbonyl
) phenylthyl(1-propyl)piperazin-1-yl)-
2,4(LH,3)1)-pyrimidinedione 0.69g
was obtained as a yellow solid. Analysis results of this pyrimidinedione derivative obtained: Melting point = 182°C (decomposition) NMR (CDCl2), δppm: 1.89 (m
, 2) 1), 2.56 (m, 6H) 3.0 + (m,
4H), 3.36 (s, 3H) 3,42 (s,
3H), 3.46 (m, 2H)5, 28 (
s, IH). 7,5~8.9 (m, 7H) Elemental analysis value CzsHzsNaOaS-%H20
Calculated value (%”): C, 56,27; H, 5,48
; N, 15.75; S, 6.01 Analysis value (%): C, 56,37: H, 5,36:
N, 15.55:S, 5.79 The pyrimidinedione derivative obtained as a yellow solid was
treatment with oxalic acid/methanol according to the method
Methyl-6-(4-(3-[4-nitro-2-(2-pi)
lysinecarbonyl)phenylthiopropyl]piperazi
(1-yl)-2,4(1)1.3)1)-pyrimidine
Dione oxalate (compound +06) 0.62g
I got it. Analysis results of the obtained compound 106; Melting point = 138°C (decomposition) IRv""(cm-'): 3460.1693.
1648. +600°ax 1454, 1435. 1346. 722゜00 Elemental analysis value C15HzNaOsS・(COOH)
1!4) Calculated value (%) as t20: C, 52,00, H, 5,01:
N, 13.48; S, 5.14 Analysis value (%): C, 51,81; H, 4,86;
N, 13.24:S 5.06 Example 59 3-Methyl-6-(4-<3-(4-nitro-2-beta)
(zoylphenoxy)propyl〉piperazin-1yl)
-2,4(IH,3)1)-pyrimidinedione shu
Production of acid salt (compound 107) (1) l-[3-(2-benzoyl-4-nitrophe)
Preparation of 3-benzoyl-4-(3-bromopropyloxy)piperazine
3.5 g of trobenzene and 7.8 g of piperazine were
The mixture was dissolved in 30 ml of aluminum and heated under reflux for 4 hours. After cooling the resulting reaction solution, it was washed with water and dried (anhydrous sodium sulfate).
After treatment, the solvent is distilled off from the reaction solution to obtain
The resulting residue was crystallized from hexane/ethanol, and 1-
[3-(2-benzoyl-4-nitrophenoxy)pro
Pill I 3.5 g of piperazine was obtained. (2) 3-methyl-6-(4-[3-(4-nitro-2
-benzoylphenoxy)propyl 1 piperazine-1
-yl)-2゜4 (IH,3)1)-pyrimidinedio
Production of benzoyl oxalate (compound 107); 1-(3-(2-benzoyl-4-
Nitrophenoxy)propyl 1 Piperazine Ig, 6
-chloro-3-methyl-2,4(1)1.31()-pi
0.34 g of rimidinedione and 0.7 g of triethylamine
Dissolve 2ml in 3ml of 2-propatool and heat for 6 hours.
It refluxed. Filter the precipitated crystals from the reaction solution and recrystallize with isopropanol.
and 3-methyl-6-(4-(3-(4-nitro-2-
benzoylphenoxy)propyl-1piperazin-1yl
)-2,4(IH,3)1)-pyrimidinedione 1.9
I got g. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 8.41 (m
, 2H). 7.1-7.9 (m, 6H). 4,77 (s, 1)1) , 4.13 (m,
21(). 3.15 (s, 3H). 2.0-2.4 (m, 10) 1). 1,74 (m, 2)1) Next, this pyrimidinedione derivative was dried according to a conventional method.
Treatment with uric acid/methanol resulted in 3-methyl-6-(4-[
3-(4-nitro-2-benzoylphenoxy)propyl
l piperazin-1yl)-2,4(1)1.31(
)-pyrimidinedione oxalate (compound 107)
0.67g was obtained. Analysis results of the obtained compound 107; Melting point: 144-146°C (decomposition) 1610, 1520. 1350. 1290°11
00, 750.700 Elemental analysis value C□)I17N808・(COOH) z
Calculated value (%) as 4HJ: C, 52, 34, H, 5
,37: N, 11.30 Analysis value (%): C,5
1,89; H, 5, mouth 4; N, 11.23 Example
60 1.3-dimethyl-6-(2-(3-(2-benzoyl)
-4-nitrophenoxy)propylamino 1-ethylamide
-2,4(IH,3H)-pyrimidinedione
Preparation of Urate Salt (Compound 108) Preparation of Rubromide; 1.5 g of 2-hydroxy-5-nitrobenzophenone. 1.3-dibromopropane 6mβ, anhydrous potassium carbonate 3
g was heated under reflux for 6 hours in 10 mQ of 2-butanone.
I responded. After the reaction is completed, the reaction solution is allowed to cool, unnecessary substances are filtered, and the filtrate is
Silica gel column chromatography of the concentrated silica
Purify with filtrate (hexane/ethyl acetate = 471) and
Crystallized from xane to give 3-(2-benzoyl-4-nito)
1.0 g of lophenoxy)propyl bromide was obtained. Analysis results of the obtained propyl bromide derivative; Melting point = 86°C (2) 1.3-dimethyl-6-(2-[3-(2-beta)
Nzoyl-4-nitrophenoxy) propylamino 1e
thylamino)-2,4(IH,3)1)-pyrimidine di
Production of on oxalate (compound 108): Propyl bromide derivative obtained in section (1) above 0.77
g, 1,3-dimethyl-6-(2-aminoethyla
mino)-2,4(IH,3H)-pyrimidinedione 0.
5g, t-ethylamine 0.7mf2 in dimethyl
The reaction was carried out at 80° C. for 4 hours in formamide 10 mβ. After distilling off the solvent from the resulting reaction solution under reduced pressure, the residue was
The solution containing roform was washed with water, dried, and further concentrated.
I got Shiratsubu. This sillage was further subjected to silica gel column chromatography.
- (Chloroform/methanol = 40/1)
and 1,3-dimethyl-6-(2-(3-(2-benzo
yl-4-nitrophenoxy)propylamino 1-ethyl
amino)-2,4(Ill, 3H)-pyrimidinedio
Obtained 0.51 g. Analysis results of this pyrimidinedione derivative compound obtained
: NMR (CDC13), δppm: 7.1-8.1
(m, 8H). 5.14 (s, IH), 4.33 (t, 28). 3,22 (s, 3)1), 3.36 (s,
3)1). 2,7-3.2 (m, 6)1). 2.1 (m, 2H). Next, this pyrimidinedione derivative was processed using a conventional method.
Treatment with uric acid/methanol resulted in 1,3-dimethyl-6-(
2-[3-(2-benzoyl-4-nitrophenoxy)
propylamino]ethylamino)-2,4(1)1.3
)1)-pyrimidinedione oxalate (compound 108
) 0.43g was obtained. Analysis results of the obtained compound 1 '08: Melting point: 11
1-113℃ (decomposition) KBr-IRv (cm'): 3050.1?30.
1700.1640°ax 1520, 1360. 770. 700 elemental analysis values
Cz<Hz7NsOa・(COO)I)z・3HzO
b T: Calculated value (%): C, 49, 92; )l
, 5.69. N, 11.20 analysis value (%):
C, 50, 11; H, 5, 35: N, 11.00
Example 61 1.3-dimethyl-6-(2-(N-ethyl-3-(4
-benzoyl-2-nitrophenoxy)propylamino
]ethylamino)-2,4(It(,3H)-pyrimidi
Production of dione oxalate (compound 109) (1) 5-benzoyl-2-(3-bromopropyloxide)
c) Preparation of nitrobenzene; 1.5 g of 4-hydroxy-3-nitrobenzophenone. Add 1g of K2CO3 to 5mβ of methyl ethyl ketone and add 3
Stir under heating and reflux for 0 minutes, then add dibromopropane 2.
After adding Omj2 and stirring the 0 reaction solution for further 4 hours, let it cool.
Insoluble matter was removed by filtration, concentrated, and cooled to 0°C. In that state, add 10 mβ of hexane to the reaction solution and sludge.
The resulting 5-benzoyl-2-(3-bromopropylene)
The precipitate of pyruoxy)nitrobenzene was collected by filtration. Analysis results of this precipitate; NMR (CDCIs), δppm: 7.2-8.3
(m, 8H). 4.40 (t, 2H), 3.69 (t, 2H). 2,47 (m, 2H) This 5-benzoyl-2-(3-bromopropyloxy
) 2.0 g of nitrobenzene precipitate was sent to the next reaction without purification.
It was used accordingly. (2) 1,3-dimethyl-6-(2-[N-ethyl-
3-(4-benzoyl-2-nitrophenoxy)propyl
[ruamino]ethylamino)-2,4(IH,3H)-pi
Production of rimidinedione oxalate (compound 109); 5-benzoyl-2-(3-bromo
1.8 g of the precipitate of propyloxy)nitrobenzene was
Thylamine (70%) 10 autocracked with mj2
After reacting for 1 hour at 70°C in a Rebe, excess ethyl
The amine was distilled off, and 30 mj2 of chloroform was added to the reaction solution.
was added and then washed twice with water. Next, the water-washed chloroform layer was concentrated and the 5-benzo
yl-2-(3-ethylaminopropyloxy)nitro
2.1 g of oily crude benzene was obtained. 1.0 g of this oily crude product and 6-(1-aziridine)
)-1,3-dimethyl-2,4(I)l, 3)1
)-pyrimidinedione (compound 6) 0.4g% p-tolu
005g of ensulfonic acid in a solvent-free state at 80℃ for 3 hours
React and directly purify by silica gel column chromatography (C
HCIs /CH30)1 =40/1), 1
．． 3-dimethyl-6-(2-(N-ethyl-3-(4-
Benzoyl-2-nitrophenoxy)propylaminoco
Nithylamino)-2,4(IH,3H)-pyrimidine di
0.61 g of on was obtained. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 7.4-8.2
(m, 8H). 4,99 (s, 1)1) , 4.16 (t,
2H). 3, 36.3.44 (s, 3H). 2.4-3.0 (+n, 8H). 2.11 (m, 2H), 1.10 (t, 3H) order
Then, this pyrimidinedione derivative was desiccated according to a conventional method.
Treatment with acid/methanol gave 1,3-dimethyl-6-(
2-[N-ethyl-3-(4-benzoyl-2-nitro
phenoxy)propylamino)-2,4(1)1,3H
)-pyrimidinedione oxalate (compound 109)
0.5g was obtained. Analysis results of the obtained compound 109; 1360, 1250. 720. 700 elemental analysis values
C1aHs +NaOs・(COO)I) 2・2H
Calculated value (%) as 20: C, 52, 91: H,
5,87,N, 11.02 Analysis value (%): C,
52,50; H, 5,77; N, 10.92 implementation
Example 62 6-(4-[2-(2-benzoyl-4-nitrophe)
Nylthio)ethyl piperazin-1-yl)-1,3
-dimethyl-2,4(1)l, 3H)-pyrimidine di
on oxalate ((1) 2-(2-hydroxyethyl
Preparation of thio)-5-nitrobenzophenone; 2-chloro-5-nitrobenzophenone2. Og and To
Add 2.0g of ethylamine to 10m of dimethyl sulfoxide.
Dissolve in β and add 0.63g of 2-mercaptoethanol.
Then, the reaction mixture heated and stirred at 80°C for 5 hours was poured into water.
After extracting with 100 mβ of chloroform and washing the extract with water,
After drying with anhydrous sodium sulfate, remove the solvent under reduced pressure.
Distill to give 2-(2-hydroxyethylthio)-5-ni
2.0 g of trobenzophenone was obtained as pale yellow crystals. Analysis results of this nitrobenzophenone derivative obtained: NMR (CDCIs), δppm: 8.16-8.
50 (m, 2H). 7, 2:3-8.06 (m, 68). 3.86(t, 21(), 3.21(t, 2Ffl
. 2,63 (br, s, IH) (2) 6-(4-[2-(2-benzoyl-4-nito
lophenylthio)ethyl] piperazin-1-yl)-
1,3-dimethyl-2,4(1)1.3)1)-pyrimi
Production of jindione oxalate (compound 110): 2-(2-hydroxyethylthio) obtained in section (1) above
-2.0 g of 5-nitrobenzophenone in chloroform 2
Dissolve in 0 mβ and add 1.6 g of triethylamine to it.
In addition, 0.91 g of methanesulfonyl chloride was added at 0°C.
was added. The mixture was stirred at 0°C for 00 min and then further kept at room temperature for 16 h.
The resulting reaction mixture was diluted with chloroform 80+
After diluting with nI2, pour into water, separate the layers, and add the organic layer to IN-water.
Washed with sodium oxide aqueous solution, water, and saturated saline in this order.
. Next, wash the organic layer with anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain the crude mesylate product.
2.50g was obtained. Dissolve this mesylate in dimethyl sulfoxide 15 nI2.
Add 1,3-dimethyl-6-(l-piperadi) to the dissolved solution.
-2,4(I)1,3)1)-pyrimidinedio
1.80 g of water was added and heated at 80° C. for 6 hours. obtained
The reaction mixture was added to 100ml of water containing 2.0g of potassium carbonate.
j2 and extracted twice with 50 mβ of chloroform. Combine the extracts, wash with water, and dry with anhydrous sodium sulfate.
After that, the solvent was distilled off under reduced pressure. The resulting residue is poured into silicage.
column chromatography purification (chloroform/methanol = 5
0/1~25/1)L,,6-(4-[2-(2-ben
Zoyl-4-nitrophenylthio)ethyl piperazine
-1-yl)-1,3-dimethyl-2,4(I)I,
3H)-pyrimidinedione 2. Og as pale yellow crystal
Obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 8.27 ~
8.54 (m, 2H). 7°44~8°07 (m, 6H). 5, 28 (s, 1f(), 3.39 (s
, 3) 1). 3, 35 (s, 3H). 2,44~3.27 (m, 12H) Next, this pi
Add methanol solution of rimidinedione derivative according to conventional method.
Treated with oxalic acid/methanol solution, 6-(4-[2
-(2-benzoyl-4-nitrophenylthio)ethyl
1-piperazin-1-yl)-1,3-dimethyl-2,4
(IH,3H)-pyrimidinedione oxalate (compound
White crystals of product 110) were obtained. Analysis results of the obtained compound 110; Melting point: 201.0-202.5°C Elemental analysis value C25HatNsO4S・(COOH)
Calculated value (%) as 2: C, 55, 57; H, 5
,, pl; N, 12.00: S, 5.49 Analysis value (%): C, 55,51; H, 5,55:
S, 5.38 Example 63 1,3-dimethane obtainable by the method of Example 50
Chil-6-(4-(3-(4-benzoyl-2-nitro)
phenoxy)propylcopiperazin-1-yl)-2,
4(IH. 3H)-pyrimidinedione oxalate (compound 78)
Production of tablets containing as an active ingredient: the pyrimidinedione derivative/oxalate (compound 78)
Ig, 123g lactose and 20g corn starch
Mix well and add hydroxypropylcellulose 5
g was dissolved in 100ml of water, mixed and granulated, and heated at 50℃.
It was dried for 4 hours. Add this to 1g of magnesium stearate.
150 per tablet using a tablet press.
The mixture was compressed into tablets with a weight of mg. Example 64 1,3-dimethyl obtainable by the method of Example 52
Chil-6-(4-(3-(2-benzoyl-4-nitro)
phenoxy)propyl piperazine-! -il)-2,
4(1)1゜3H)-pyrimidinedione oxalate (
Production of capsules containing compound 81) as an active ingredient: The pyrimidinedione derivative/oxalate (compound 81)
5g, 120g lactose and 25g corn starch
Mix well and harden the resulting mixture using a capsule filling machine.
Capsules were filled to 150 mg to obtain capsules. Example 65 1,3-dimethyl obtainable by the method of Example 57
Chil-6-(4-[3-[2-(2-chlorobenzoyl)
)-4-nitrophenoxy]propyl]piperazine-1
-il)-2,4CI)! , 3H)-pyrimidinedione
・Injection containing oxalate (compound 105) as an active ingredient
Production of: the pyrimidinedione derivative/oxalate (compound
105) 20mg, and sodium chloride 0.8
Take 5g, dissolve it in an appropriate amount of distilled water for injection, and reduce the total amount to 1.
00ml and used as an injection. Pharmacological Test Example 4 In the same manner as Pharmacological Test Example 1, the above-mentioned implementation shown in Table 8 was carried out.
Calculate ADP7s and ERP of each compound obtained in the example.
I met. The results are shown in Table 8. Toxicity test 4 Similar to toxicity test 1, the results obtained in the above example shown in Table 9 were
The toxicity of each compound was tested and the mortality rate of mice was determined.
Ta. The results are shown in Table 9. The administration was 300mg/Kg orally for each compound.
Administration (p,o,) was performed. Table Example 66 1.3-dimethyl-6-(4-[3-(2-benzoyl)
-4-nitroanilino)propylcopiperazine-1-y
)-2,4(1)1.3H)-pyrimidinedione
Production of oxalate salt (compound 111) (compound 1m (1) 1.3-dimethyl-6-(4-(3-amino)
propyl)piperazin-1-yl]-2,4(IH,3
) 1) Preparation of -pyrimidinedione (compound 158); 18.52 g of potassium phthalimide and 1,3-dibro
200g of mopropane 100ml of dimethylformamide
The suspension in 1 was heated and stirred at 120°C for 6 hours, and these
reacted. Next, remove the insoluble matter from the resulting reaction mixture.
It was filtered and the filtrate was concentrated to dryness under reduced pressure. After washing the residue with hexane, it was reconstituted with ethanol-water.
The crystals obtained are collected by filtration, washed, dried, and N-
Obtained 13.8 g of (3-bromopropyl)phthalimide.
. Next, this N-(3-bromopropyl)phthalimide
13.0 g, 1,3-dimethyl-6-(1-pipera
(dinyl)-2,4(lH,3)1)-pyrimidinedione
(Compound 157) 10.3g and triethylamine 2
obtained by suspending 0 g in 200 ml of dioxane.
The suspension was heated to reflux for 6 hours. Furthermore, insoluble matter was filtered from the obtained reaction mixture, and the filtrate was
Concentrate to dryness under reduced pressure, and dissolve the residue (concentrated to dryness) in ethyl acetate.
- Recrystallize from hexane, collect the obtained crystals by filtration, and wash.
After cleaning and drying, 1,3-dimethyl-6-(4-(3-ph)
taloylaminopropyl)piperazin-1-yl]-2
, 12.5 g of 4(IH,3H)-pyrimidinedione was obtained.
Ta. Next, 12.5 g of this crystal and 6.0 g of hydrazine hydrate
A suspension of g in 200ml of ethanol was heated for 4 hours.
After refluxing and cooling, the insoluble matter containing raw acid was filtered off, and the filtrate was filtered under reduced pressure.
It was concentrated to dryness. Furthermore, dissolve the residue (concentrated dry product) in water.
Then, add dilute hydrochloric acid to adjust the pH to about 3, and at that time
The generated insoluble matter is removed by filtration, and potassium carbonate is added to the filtrate.
After adding a large amount, this was extracted with chloroform. extraction
After completion of the operation, the obtained organic layer was dried with anhydrous sodium sulfate.
After drying and removing the solvent under reduced pressure, the 1,3-dimethylene
Le-6-(4-(3-aminopropyl)pivepdin-l)
-yl]-2,4(IH,3H)-pyrimidinedione (
Compound 158) 6.80 g was obtained as a colorless syrup.
Ta. This was crystallized by overnight incubation. (2) 1,3-dimethyl-6-(4-[3-(2
-benzoyl-4-nitroanilino)propylcopipera
Zin-1-yl)-2,4(1)1.3)1)-pyrimi
Preparation of jindione oxalate (compound 111); 1,3-dimethyl-6-[4-(3
-aminopropyl)piperazin-1-yl]-2,4(
LH, 3) 0.9 g of 11-pyrimidinedione and 2-k
1.0 g of lolo-5-nitrobenzophenone and dimethylene
Added to 10 ml of Rusulfoxide and the resulting mixture solution
was heated to 110°C for 20 hours, and after cooling, the reaction mixture was saturated.
Pour the resulting mixture into aqueous sodium bicarbonate solution.
Extracted with loloform. Separate the organic layer (chloroform layer) obtained from the extraction process.
After washing with water and drying (anhydrous sodium sulfate), concentrate and dry.
The resulting residue was purified by silica gel column chromatography (
Chloroform/methanol = 50/1 to 20/1) L,
1.3-dimethyl-6-(4-(3-(2-benzoyl)
-4-nitroanilino)propylcopiperazine-1-y
-2,4(IH,3)1)-pyrimidinedione
0.95 g was obtained as a yellow oil. Analytical results of the oily substance obtained from this pyrimidinedione derivative
Results: NMR (CDC13) δppm: 2.04 (m,
2H), 2.65 (m, 6H). 3,04 (m, 4H), 3.36 (s, 3
H). 3,42 (s, 3H), 3.57 (t, 2
H). 5.30 (s, IH), 6.90 (d, 18). 7, 69 (s, 5) 1). 8.35 (dd, IH), 8.95 (d, l11). 9,50 (S, IH) Furthermore, this oil was mixed with oxalic acid/methanol according to a conventional method.
solution to produce 1,3-dimethyl-6-(4-[3-
(2-benzoyl-4-nitroanilino)propylcopy
perazin-1-yl)-2,4(IH,31()-p
1.0 rimidinedione oxalate (compound 111)
I got g. Analysis results of the obtained compound 111: Melting point: Amorphous elemental analysis value Cx5) IsoNeol (COJ) z
Calculated value (%): C, 56, 37, H, 5, 4
1; N, 14.09 Analysis value (%): C, 56.9
2; H, 5,40; N, 14.20 Example 67 Production of compounds 120 to 127; In the step of Example 66-(2), 2-chloro-5-nitro
In place of benzophenone, R7 and R of the following structural formula (I)
Compounds 112 to 11 in which 8 and R9 are the groups shown below
Same as Example 66-(2) except that 9 is used respectively.
R7, R in the following structural formula (I'1) by the operation of
8 and R9 have different physical properties as shown below.
Rimidinedione derivative oxalate compounds 120-127
were obtained respectively. 7 R8 1 Compound 112 -COCH. -NO□ H Compound 117 -No□ C0CHs H Compound +19 H -N(]2 C0CHs Compound 120 (R', R', R' are compound 11
Same as 2); Melting point: 135-137°C (decomposition) +560° 1320° 1250° Elemental analysis value C2 + HzaNgO1 (COOH) 2
・Calculated value (%) as 2H20: C, 48, 42; ) 1.6.01.
N, 14.73 Analysis value (%): C, 48, 14:
H, 5, 82, N, 14.32 compound 121 (R'
, R11, R9 are the same as compound 113); Melting point: ■82
~183℃ (decomposition) 1540゜1350゜1290゜100 810゜Elemental analysis value CzsHs4Na01 (COOH) 2
・Calculated value (%) as 2.5LO: C, 50, 46, H, 6, 59; N
, 13.08 Analysis value (%): C, 51,04,H,
6,77, N, 12.90 Compound 122 (R', Ra
, R (1 is the same as compound 114); melting point = (amol
Fass) Elemental analysis value C*6H2eNsOnCI・(COOH
) 1'A LO and calculated value (%): C, 52, 54, H, 5, 04, N,
13.13° CI, 5.54 Analysis value (%) C, 52,36, H, 5,05; N,
13. +4; C1,5,23 compound 123 (R', Ra, Ra are compound 11
Melting point: 151'C (decomposition) 1496°1441°1333°1200°768°722°00 Elemental analysis value C25HzJhOs・1.5 (CO□H)2・)12
Calculated value (%) as 0: C, 50,91: H, 5,19;
N, 14.84 Analysis value (%): C, 51, +2;
)l, 5.10: N, 14.81 compound 124
(R', R", R'4; i Compound 116 1.
;) Melting point = 162-165℃ (decomposition) +350゜00 1260゜1150.780゜Elemental analysis value C25H29N7012 (C0011)
Calculated value (%) as 2 H, O: C, 48,00; )I, 4.83
．． N, 13.06 Analysis value (%): C, 48,38
,H,4,92,N, 12.91 compound 125(R'
, R8, R9 are the same as compound 117); Melting point: 148~
150°C (decomposition) 1530, 1330, 1240.980°760.7
00 Elemental analysis value CzaHsJaol (COOH) 13
Calculated value as HJ (%): C, 50,46; H, 6,59, N
, 13.08 Analysis value (%): C, 51,04; I
t, 6.77, N, 12.90 compound 126 (
R', R11, R9 are the same as compound 118) Melting point: 20
2-203℃ (decomposition) +530. 1320. 1280. 11+0°81
0, 710 Elemental analysis value CzsHsaNaOs・(COO)I)
Calculated value (%) as 1HJ: C, 54, 72; H,
5,58,N, 13.67 Analysis value (%): C,54
,68,H,5,21; N, 13.47 Compound 12
7 (R', R@, Rs are the same as compound!19);
Point: ~140°C (amorphous) 1540° 1320° + 220° 1110° 810° Elemental analysis value CzlHzaNsOl (COJ) 2.
Calculated value (%) as 2H20: C, 48, 24: H, 5, 57:
N, 14.06 Analysis value (%): C, 48, 11, H
,5,90,N, 13.89 Example 68 1,3-dimethyl obtainable by the method of Example 66
Chil-6-(4-[3-(2-benzoyl-4-nitro)
anilino)propylcopiperazin-1-yl) -2,
4(IH. 3) 1)-pyrimidinedione oxalate (compound 11
Production of tablets containing 1) as an active ingredient: The pyrimidinedione derivative/oxalate (compound 1) I
g. Breasts? 1123g and corn starch 20g
Mix well and add hydroxypropylcellulose 5
g was dissolved in 100ml of water, mixed and granulated, and heated at 50℃.
It was dried for 4 hours. Add this to 1g of magnesium stearate.
Add, mix well, and use a tablet machine to make 1 tablet.150
The mixture was compressed into tablets with a weight of mg. Example 69 1,3-dimethyl obtainable by the method of Example 67
Tyl-6-(4-(3-(2-acetyl-4-nitroa)
(nilino)propylcopiperazin-1-yl) -2,4
(IH. 3) 1)-pyrimidinedione oxalate (compound 12
0) as an active ingredient: The pyrimidinedione derivative/oxalate (compound 120)
) 5g, lactose 120g and corn starch 25g
Mix well and fill the resulting mixture with a capsule filling machine.
Hard capsules were filled to 150 mg to obtain capsules. Example 70 1,3-dimethyl obtainable by the method of Example 66
Chil-6-(4-(3-(2-benzoyl-4-nitro)
anilino)propylcopiperazin-1-yl) -2,
4(1)1゜3H)-pyrimidinedione oxalate (
Production of an injection containing compound 111) as an active ingredient: The birymidinedione derivative/oxalate (compound 11)
1) 20mg and 0.85g of sodium chloride
Dissolve this in an appropriate amount of distilled water for injection and make a total volume of 100ml.
1 and used as an injection. Pharmacological Test Example 5 In the same manner as Pharmacological Test Example 1, the above-mentioned substances shown in Table 1O were prepared.
Calculate ADPys and ERP of each compound obtained in the example.
I met. The results are shown in Table 10. Toxicity Test 5 In the same manner as Toxicity Test 1, the above examples shown in Table 11 were carried out.
The toxicity of each compound obtained was tested and the mortality rate of mice was determined.
I met. The results are shown in Table 11. The administration was 300 mg/kg orally for each compound.
Administration (p,o,) was performed. Table 11 Compound number Mortality rate 22 26 Example 71 1.3-dimethyl-6-[4-(2-benzoyl-4-
Nitrophenyl)piperazine-! -il] -2,4(
IH,3H)-pyrimidinedione oxalate (compound
128) (Compound 15 (Compound 128) 1.3-dimethyl-6-(piperazin-1-yl)-2
,4(II(,3H)-pyrimidinedione (compound 15)
7) 0.5g and 3-benzoyl-4-chloronitro
0.6 g of benzene in 5 ml of dimethyl sulfoxide
and heated the resulting mixture solution to 110°C for 20 hours.
After cooling, the reaction mixture was dissolved in saturated aqueous sodium bicarbonate solution.
The resulting mixture was extracted with chloroform. Separate the organic layer (chloroform layer) obtained from the extraction process.
After washing with water and drying (anhydrous sodium sulfate), concentrate to dryness.
The resulting residue was purified by silica gel column chromatography.
loloform/methanol = 50/1 to 20/1) I.
1,3-dimethyl-6-[4-(2-benzoyl-4-
(nitrophenyl)piperazin-1-yl]-2,4(I
H,3) 0.2g of 1)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (d, -DMSO) δppm: 2.64 (m,
4H), 3.18 (m, 4H). 3,28 (s, 3H), 3.17 (s, 3
)1). 5,00 (s, IH). 7, 3-8.0 (m, 5) 1). 8,2-8.6 (m, 3)1) Furthermore, this pyrimidinedione derivative was subjected to a conventional method.
1゜3-dimethyl-
6-[4-(2-benzoyl-4-nitrophenyl)pi
perazin-l-yl]-2,4(IH,3H)-pyrimi
0.18g of Zindione oxalate (Compound 128)
Obtained. Analysis results of the obtained compound 128: Melting point = 178-179°C (decomposition) 1520° 1320, 1260. 1130 950°860, 760. 700 Elemental analysis value C*5lbsNsOs・% (C02H)
Calculated value (%') as 1% HtO: C, 57,25, H, 5,01, N
, 13.91 Analysis value (%): C, 57, 55, H,
4,80,N, 13.56 Example 72 1.3-dimethyl-6-(3-[4-nitro-2-(3
-pyridinecarbonyl)anilino1propylamino)-
2゜4 (Ill, 3H)-pyrimidinedione
Production of urate salt (compound 129) (compound I29) 4-chloro-3-(3-pyridinecarbonyl)nitrobe
0.67 g, 1,3-dimethyl-6-(3-
aminopropylamino)-2,4(IH,3H)-pyri
Add 0.6 g of midinedione to 3 ml of dimethylformamide.
Dissolve and further add 0.79 ml of triethylamine.
The mixture was heated and stirred at 80° C. for 5 hours. After stirring, the reaction solution was allowed to cool, the solvent was distilled off, and the obtained
The residue was purified by silica gel column chromatography (chloroform/
methanol = 40/1) L, 1,3-dimethyl-6-
(3-[4-nitro-2-(3-pyridinecarbonyl)
7nilino] propylamino) -2,4(IH,3)1
)-pyrimidinedione (0.39 g) was obtained as an oil. Analysis results of this pyrimidinedione derivative obtained; MR (CDCIs), δppm: 9, 40 (m, IH), 8.84 (m,
2H). 7, 86-8.57 (m, 3H). 7.50 (dd, 1B), 6.85 (d, IH). 5,90 (m, IH), 4.86 (s,
IH). 3,23 (s, 3H), 3.38 (s,
3)1). 3,40 (m, 4H), 2.1 (m, 2
)1) Furthermore, this pyrimidinedione derivative is treated with oxalic acid/
Treat with methanol in a conventional manner to obtain 1,3-dimethyl-
6-(3-[4-nitro-2-(3-pyridinecarboni
)-! 1 hair 11 propylamino) -2,4(1)!
, 3) 1) -pyrimidinedione oxalate (compound
0.36 g of product 129) was obtained. Analysis results of the obtained compound +29; Melting point: 136-139°C (decomposition) 155G, 1330. 1260. 1110°7
70, 700 Elemental analysis value Ca+HtJsOs・(COO)I)*
Calculated value (%'): C, 52, 27, H, 4, 5
8,N, 15.90 Analysis value (%): C,52,2
5,H,4,92,N, 15.51 Example 73 1.3-dimethyl-6-(3-(2-benzoyl-4-
nitroanilino)propylamino]-2,4(1)1,
3H)-pyrimidinedione oxalate (compound 130
) (Compound 130) 3-benzoyl-4-chloronitrobenzene was used instead of 4-chloro-3-(3-pyridinecarbonyl)nitrobenzene.
1. The same procedure as in Example 72 was carried out except that 1.
3-dimethyl-6-(3-(2-benzoyl-4-nito)
roanilino)propylamino]-2,4(1)1.3H
)-pyrimidinedione oxalate was obtained. Analysis results of the obtained compound 130; Melting point: amorphous 1330, 1110. 990. 850°760,
700 Elemental analysis value C1JasN@Os-'A (COOH)
! Calculated value (%): C, 57, 26: H,
5,01; N, 14.52 Analysis value (%): C,
57,16; H, 4,63; N, 14.76 implemented
Example 74 1,3-dimethyl-6-[2-(2-benzoyl-4-
nitroanilino)ethylamino]-2,4(IH,3)
1) Production of -pyrimidinedione (compound 131) 1.3-dimethyl-6-(3-aminopropylamino)
-2゜4- (IIl, 3)1)-pyrimidinedione
1,3-dimethyl-6-(2-aminoethyl
amino) -2,4(IH,31()-pyrimidinedio
was reacted with 3-benzoyl-4-chloronitrobenzene.
1.3-dimethyl was prepared in the same manner as in Example 73 except that
Chil-6-[2-(2-benzoyl-4-nitroanili)
) ethylamino]-2,4(IH,3H)-pyrimidine
This yielded dione (compound 131). Analysis results of the obtained compound 131: Melting point: 207-209°C (decomposition) 1560° 1340° 110 760°00 Elemental analysis value Ci + Ht + N501 (COzH) 1H2
Calculated value (%) assuming 0: C, st, (Is: )l
, 4.74. N, 13.18 Analysis value (%):
C, 51, 81: H, 4, 87, N, 12.97 fruit
Example 75 1.3-dimethyl-6-(2-[4-nitro-2-(3
-pyridinecarbonyl)aminoethylamino) 2.4
-(IH. 3) 1) Production of -pyrimidinedione (compound 132) (
Compound 132) 1,3-dimethyl-6-(3-aminopropylamino)
-2゜4- (IH,3H)-pyrimidinedione replacement
, 1,3-dimethyl-6-(2-aminoethylamino
) -2,4(1)1.31()-pyrimidinedione
1.3-dimethane was used in the same manner as in Example 72 except for using
Chil-6-(2-[4-nitro-2-(3-pyridine)
(rubonyl)phenylamino1ethylamino)-2,4(
IH,3) 1)-pyrimidinedione (compound 132)
Obtained. Analysis results of the obtained compound 132; Melting point: 148°C (decomposition) 1587, 1333. 1265. 1155°11
5 Elemental analysis value Calculated value as C2゜H2゜N501LO (
%): C, 54,30; H, 5,01: N,
19.00 Analysis value (%): C, 54,04: )I
, 4.71. N, 18.84 Example 76 1.3-dimethyl-6-(4-[2-(2-benzoyl
-4-nitrophenyl)ethyl 1piperazin-1-yl
)-2,4(IH,3H)-pyrimidinedione shu
Production of acid salt (Compound 133) (Compound 133) (1) 1-[2-(4-nitrophenyl)ethyl]-
Preparation of 4-tert-butyloxycarbonylpiperazine
manufactured by: 1.7 g of 4-nitrophenethyl bromide and pipette
Dissolve 5 g of Radin in 15 ml of chloroform and heat to reflux.
The mixture was stirred for 3 hours. After the reaction is completed, the reaction solution is allowed to cool, and then washed with water three times to remove the excess.
of piperazine was removed from the reaction solution, and the chloroform layer was added.
was separated. Next, the solvent was removed from the chloroform layer under reduced pressure, and the obtained
The resulting residue was dissolved in 15 ml of anhydrous tetrahydrofuran.
, 1.6 g of di-tert-butyl dicarbonate was added to this
After stirring at room temperature for 1 hour, the solvent was distilled off from the reaction solution.
Ta. Add hexane/ethanol mixture to the obtained residue, and
The precipitated crystals were collected by filtration, and then mixed with hexane/ethanol.
It is recrystallized in liquid to give 1-(2-(4-nitrophe)
ethyl]-4-tert-butyloxycarbonyl
2.4 g of rubiverazine was obtained. Analysis results of this piperazine derivative obtained; Melting point: Amo
Rufus NMR (CDC13), δppm: 8.14 (d,
2H), 7.34(d,2)1). 3,41 (m, 4H), 2.74 (m, 4
t()2, 43 (m, 4H), 1.45 (s
, 9H)(2) 1,3-dimethyl-6-(4-[2
-(2-benzoyl-4-nitrophenyl)ethyl 1-pi
perazin-1-yl)-2,4(1)1.3H)-pyri
Production of midinedione oxalate (compound 133); 1-(2-(4-nitrophenyl) obtained in section (1) above)
ethyl]-4-tert-butyloxycarbonylpipe
Dissolve 0.8g of Radin in 20ml of anhydrous tetrahydrofuran.
Dissolve and add 1 ml of hexamethylphosphorus triamide to this.
was added, and the resulting mixed solution was cooled to -78°C.
IM lithium diisopropylamide
2.9 ml of water-tetrahydrofuran solution was added. One hour after the end of the addition, the temperature of the reaction solution was lowered to -78°C.
Add another drop of 0.83 ml of benzoyl chloride to this.
I put it down. After the dropwise addition was completed, the temperature of the reaction solution was gradually raised to -30°C.
After stirring for an hour, the reaction solution was poured into ice water and extracted with chloroform.
did. The extract was washed with water, dried (anhydrous sodium sulfate), and then dried under reduced pressure.
It solidified to give a syrupy substance. Dissolve this syrup in 30ml of ethyl ether.
, 2 ml of hydrochloric acid/dioxane (4N) was added to this, and the mixture was heated to room temperature.
The mixture was stirred for 30 minutes. The crystals that precipitated at that time were collected by filtration and diluted with ethyl ether.
Washed. Next, this crystal was dissolved in 20 ml of isopropanol,
This was added to 1,3-dimethyl-6-chloro-2,4 (IIl
, 3) 1) -pyrimidinedione 0.5g, l-
Add 3 ml of realylamine and stir under heating and reflux for 6 hours.
did. After stirring, the solvent was distilled off from the reaction solution, and the resulting residue was
The solution dissolved in chloroform was washed with water and dried (anhydrous sulfuric acid).
sodium) and then dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloro
Form/methanol = 50/1) L, 1,3-dimethyl
-6-(4-[2-(2-benzoyl-4-nitrophe)
Nyl)ethyl 1piperazin-1-yl)-2,4(1)
0.33 g of 1.3H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCI, ), δppm: 7.3-8.2
(m, 8t(). 5, Ofi (s, IH), 3.28 (s,
3t()3, 39(s, 3)1). 2,4-3.0 (m, 12H) Next, this pyrimidinedione derivative was treated with oxalic acid/methano
1,3-dimethyl-6-(
4-[2-(2-benzoyl-4-nitrophenyl)et
Chil-1-piperazin-1-yl)-2,4(IH, 38)
-0 pyrimidinedione oxalate (compound 133)
．． 34g was obtained. Analysis results of the obtained compound 133; Melting point: 183-185°C (decomposition) 1660, 1520. 1340. +210°8
40, 800. 750. 700 elemental analysis values
Calculated value as C15Hz7NaO1(CO□H)1HJ
(%): C, 55, 38, H, 5, 34, N, 1
1.96 Analysis value (%): C, 55, 16, H, 5,
11,N, 12.01 Example 77 1.3-dimethyl-6-(4-[(2-benzoyl-4
-nitrophenyl)methyl 1piperazin-1-yl)-
2,4(IH,3H)-pyrimidinedione oxalate
Production of (compound 134) (1) 1-[(4-nitrophenyl)methyl]-4-
Preparation of tert-butyloxycarbonylpiperazine:
4-nitrobe instead of 4-nitrophenethyl bromide
Njiru bromide! , Example 76 except that 6 g was used.
- In the same manner as in (1), to[(4-nitrophenyl)methyl
[chill]-4-tert-butyloxycarbonyl bibera
1.1 g of gin was obtained. Analysis results of this piperazine derivative obtained; NMR (C
DCIs), δppm: 8.11 (d, 28),
7.44(d,2)1). 2,96 (m, 4N), 2.73 (m,
4H). 1,51 (s, 9H) (2) 1,3-dimethyl-6-(4-((2-benzo
yl-4-nitrophenyl)methyl] piperazine-1-
yl)-2,4(ill, 3H)-pyrimidinedione
・Production of oxalate (compound 134); 1-[2-(4-nitrophenyl)ethyl]-4-te
Instead of rt-butyloxycarbonylpiperazine, the above
1-((4-nitrophenyl)methyl obtained in section (1) above
]-4-tert-butyloxylponylbiverazine
Same as Example 76-(2) except that 0.77g was used.
Similarly, 1,3-dimethyl-6-(4-((2-benzene)
zoyl-4-nitrophenyl)methyl piperazine-1
-yl)-2,4(II(,3)1)-pyrimidinedio
0.10 g of oxalate (compound 134) was obtained. Analysis results of the obtained compound 134; Melting point: Amorphous IRv KBr (cm-'): ax 3350, 1700. 1630. 1530°+3
60. 1120. 860. 760゜00 Elemental analysis value CZ4H2Js011/2 (CO2H)
Calculated value (%) as 2-3/2H20: C, 56,42, H, 4,92, N
, 12.65 Analysis value (%): C, 56, 12;
H,4,77: N, 12.39 Example 78 1.3-dimethyl-6-(2-((2-benzoyl-4
-nitrophenyl)methylaminolethylamino)-2
,4(IH,3F+)-pyrimidinedione oxalate
Production of (compound 135) (1) 2-benzoyl-4-nitrobenzaldehyde
Preparation: 3.72g of bisthiophenylmethane was added to tetrahydrofurane.
The resulting solution was cooled to -20°C.
, to which n-butyllithium (1,6M hexane solution
) 12ml was added dropwise and stirred at -20°C for 1 hour. After stirring, while maintaining the temperature of the reaction solution at -20°C,
Pensoyl-4-chloronitrobenzene 4g
A solution dissolved in 20 ml of Dorofuran was added dropwise. After completing the dropwise addition, the temperature of the reaction solution was set to -78°C to -20°C.
These were allowed to react for 1 hour. After the reaction was completed, the reaction solution was poured into water and diluted with 400ml of ether.
Extract and wash the extract (ether layer) twice with 200ml of water.
The mixture was washed with water and dried over anhydrous magnesium sulfate. Next, the solvent was distilled off from the extract under reduced pressure, and the resulting residue was
The residue (crude product) was purified by silica gel column chromatography (hexyl
San/ethyl acetate=lO/1) to obtain an oily substance. Dissolve this oil in 40ml of acetonitrile and
In addition, a solution of 2.0 g of mercuric chloride dissolved in 20 ml of water was added.
The liquid was dropped. After dropping, add O,Ig p-toluenesulfonic acid.
In addition, the mixture was reacted at 60° C. for 4 hours. After the reaction is complete, insoluble materials are filtered from the reaction solution, and the filtrate is concentrated.
and purified by silica gel column chromatography (hexane/acetic acid ether).
chill = 10/1) and 2-benzoyl-4-nitrobene
1.1 g of crude dualdehyde was obtained as an oil. (2) 1,3-dimethyl-6-(2-[(2-benzo
yl-4-nitrophenyl)methylamino-1ethylamide
)-2,4(IH,31()-pyrimidinedione cy
Production of oxalate salt (compound 135); 1.3-dimethyl-6-(2-aminoethylamino)-
1.0 g of 2,4(IH,3H)-pyrimidinedione was
A solution dissolved in 20 ml of tanol, obtained in the above (1)
Crude production of 2-benzoyl-4-nitrobenzaldehyde
A solution prepared by adding 1.1 g of the substance to 10 ml of methanol
and 0.3 ml of a 4N dioxane solution of hydrochloric acid in each
The solution was cooled to 0°C, mixed, and reacted for 1 hour at 0°C.
. After the reaction is complete, add sodium cyanoborohydride to the reaction solution.
, Ig was added and allowed to react at a temperature of 0±5°C for 3 hours. After the reaction was completed, the reaction solution was made acidic with IN hydrochloric acid and poured into ice water.
, further made basic with sodium hydrogen carbonate, and added with chloroform.
Extracted twice with 50ml. After the extraction process, the chloroform layer was washed with 30ml of water.
, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (chromatography).
Roform/methanol = 50/1) l, 1,3-dime
Chil-6-(2-((2-benzoyl-4-nitrophe)
methylamino)-2,4(IH,
3H)-pyrimidinedione was obtained as an oil, 0.7 g.
. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 7.2-8.1
(m,8)1). 5.68 (b, IH), 4.89 (s, II (). 3.61 (s, 2) 1), 3.34 (s, 3H) 3,
39 (s, 3H), 3.06 (m, 4H) next
Then, add 0.5 g of this pyrimidinedione derivative to oxalic acid/
Treat with methanol in a conventional manner to obtain 1,3-dimethyl-
6-(2-[(2-benzoyl-4-nitrophenyl)
Methylamino 1ethylamino)-2,4(1)1,3H
)-pyrimidinedione oxalate (compound 135) 0
．． 11g was obtained6 Analytical results of the obtained compound 135; Melting point: hygroscopic amorphous 1700, 1620. 1530. 1340°11
20, 820. 720. ．． 700 elemental analysis value C2
Calculated as □1bsNs012(Co□H)13820
Value (%): C, 46, 50, H, 4, 95, N,
10.43 Analysis value (%): C, 46, 82: H,
4,65: N, 10.25 Example 79 1.3. -dimethyl-6-(4-(3-(4-benzoy)
-2-nitrophenyl)propyl-piperazine-1-
yl)-2,4(IH,3l-1)-pyrimidinedione
・Production of hydrochloride (compound 136) @-(@CII□C1I□CI+2011NO. (Compound 136) (1) Preparation of 4-iodo-3-nitrobenzophenone;
10.44 g of 4-chloro-3-nitrobenzophenone and
A mixture of 60 g of sodium iodide was heated under reflux for 15 hours.
Ta. After cooling the reaction mixture, it was poured into 800ml of water and the precipitated crystals
was collected by filtration. Next, this precipitate was washed with water, dried under reduced pressure, and silica gel
Column chromatography purification (chloroform/hexane = 271
~10/1) L,4-iodo-3-nitropenzofe
10.17 g of non was obtained as yellow crystals. Analysis results of this benzophenone derivative obtained; NMR
(CDCIs), δppm: 8.35 (d, IH
). 8.26(d, IH). 7, 40-8.10 (m, 6H). (2) Preparation of methyl 4-benzoyl-2-nitrocinnamate
; above (4-iodo-3-nitrobenzof obtained in Section 11)
Enone 10.17g, methyl acrylate 4.10g and
Triethylamine 4.70g Acetonitrile 130ml
After dissolving in and degassing, add 0.65 g of palladium acetate.
, heated under reflux for 6 hours under a nitrogen stream to react them.
Ta. After cooling the reaction solution, the solvent was distilled off from the reaction solution under reduced pressure.
, add benzene to the residue, add water, IN hydrochloric acid, saturated sodium bicarbonate solution
This was then washed with saturated saline. The washed organic layer was dried with anhydrous sodium sulfate and vacuum
The solvent was distilled off and the residue was purified by silica gel column chromatography.
(chloroform) and 4-benzoyl-2-nitro Katsura
7.12 g of methyl oxide was obtained as pale yellow crystals. Analysis results of the obtained cinnamic acid derivative: NMR (CDCIs), δppm: 8.43 (d,
IH). 7, 48-8.38 (m, 8) 1). 6.51 (d, IH), 3.84 (s, 3) 1) (3
)2-nitro-4-(α-hydroxybenzyl)cinnamic acid
Preparation; 4-benzoyl-2-nitrocinnamic acid obtained in section (2) above
Dissolve 7.12g of methyl in 120ml of methanol, and
Add 0.90 g of sodium borohydride to this at room temperature,
After stirring at the same temperature for 10 hours, add a small amount of water to stop the reaction.
I made it stop. The solvent was distilled off from the resulting reaction solution under reduced pressure, and the residue was vented.
Dissolve in Zen, 200ml of water, 200ml of saturated saline
Washed in this order. The washed organic layer was dried with anhydrous sodium sulfate and vacuum
The solvent was evaporated under
Methyl 4-(a-hydroxybenzyl)cinnamate 7,12
I got g. Furthermore, 7.12 g of this pale yellow oil was added to 60 g of methanol.
m1, and add 40 m of IN potassium hydroxide aqueous solution to this.
1 was added at room temperature, and the mixture was vigorously stirred at the same temperature for 3 hours. stirring
After completion, the reaction solution was poured into water, neutralized with IN hydrochloric acid, and precipitated.
The resulting crystals were collected by filtration and further washed with water. The obtained crystals were dried under reduced pressure to obtain 2-nitro-4-(α-hyperoxygenate).
6.95 g of purified cinnamic acid (droxybenzyl) was obtained. Analysis results of the obtained purified product; Elemental analysis value Calculated value (%) as C+J+5NOs: C, 64,21; H, 4,38;
N, 4.68 Analysis value (%): C, 63,79
: H,4,95,N, 4.21(4) 3-(4
-benzoyl-2-nitrophenyl)-1-propazyl
Preparation of 2-nitro-4-(α-hydroxy
benzyl) cinnamic acid 3.54g, hydroxyamine-〇-
13.38 g of sulfonic acid, 9. hydroxylamine sulfate.
69 g was suspended in 180 ml of water, and the resulting suspension was cooled.
and keep the internal temperature at 20~30℃, and add 50% hydroxy acid to this.
An aqueous sodium chloride solution (22 ml in total) was added dropwise. After stirring the mixed solution for 3 hours at the same temperature to react, the reaction solution was
Water cooled. Next, add 6N sulfuric acid to the reaction solution to make it acidic.
The precipitated product was collected by filtration. After further washing the obtained crystals with water,
Dry under reduced pressure to obtain 3-[2-nitro-4-(α-hydroxy).
Crystallized 3.48 g of phenyl (cybenzyl) propionic acid.
I got it. Crystals of phenylpropionic acid derivatives obtained in this way
Dissolve 3.3g in 70ml of tetrahydrofuran to obtain
Add borane dimethyl sulfide complex 1 to the solution at room temperature.
．． 4 ml was added and stirred. After 6 hours, add 5 liters of water to the reaction solution.
ml to stop the reaction, and remove the solvent from the reaction solution under reduced pressure.
was distilled off, and the residue was dissolved in chloroform room. This chloroform solution was mixed with water and IN sodium hydroxide.
Wash with aqueous solution and saturated saline in that order, and remove the washed organic layer.
Dry over anhydrous sodium sulfate, remove the solvent under reduced pressure,
Crude 3-[2-nitro-4-(α-hydroxybenzyl)fluorocarbon
2.90 g of phenyl 1-propertool was obtained. 2.90g of this crude product was added to 100ml of chloroform.
Dissolve and add 20 g of Celite, 9 manganese dioxide, and O
g and stirred vigorously at room temperature for 24 hours. After stirring, the reaction mixture was filtered and the filtrate was concentrated to dryness.
, 3-(4-benzoyl-2-nitrophenyl)-1-
2.87 g of propatool was obtained. Analysis results of this phenylpropatol derivative obtained. NMR (CDCl2), 699m: 8.12(d,
IH), 7.80 (dd, 1B). ? , OO~7.72 (m, 6H). 3,64 (t, 2H), 3.00 (t, 2H)
1 () 1.92 (m, 2H), 1.84 (brs, I
H) (5) 1,3. -dimethyl-6-(4-(3
-(4-benzoyl-2-nitrophenyl)propyl 1
piperazin-1-yl)-2,4(1)1.31()-
Production of pyrimidinedione hydrochloride (compound 136);
phenyl)-1-propatool1. og and pyridine 1.
Dissolve 38g in 20ml of chloroform to obtain a mixed solution
of p-toluenesulfonic acid chloride under water cooling.
g and stirred at the same temperature for 10 minutes, then further stirred at room temperature.
The mixture was stirred for 16 hours. Add 2 ml of water to the resulting reaction mixture and stir at room temperature for 3 hours.
After stirring and further adding 50 ml of chloroform, the reaction mixture
The material was poured into 50ml of water. Separate the layers and add the organic layer to IN hydrochloric acid.
Wash with IN sodium hydroxide aqueous solution and saturated saline in this order.
and dry with anhydrous sodium sulfate, then remove the solvent under reduced pressure.
Distill, 3-(4-benzoyl-2-nitrophenyl)
-1-propyl p-toluenesulfothyi H, 51g yellow
Obtained as a colored oil. 1.51 g of this yellow oil was dissolved in 1.5 g of dimethyl sulfoxide.
1,3-dimethyl-6 to the resulting solution.
-(1-piperazinyl) -2,4(IH,3)1)-
Add 1.10g of pyrimidinedione and heat at 80℃ for 6 hours.
Heated and caused them to react. The resulting reaction mixture was dissolved in 100 ml of water and 2.0 ml of potassium carbonate.
Pour into the solution obtained by adding 0g of
Extracted twice with m1. Combine the organic layers separated in these two pumping processes and wash with water.
After further drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloro
Form/methanol = 50/l ~ 20/1) L, ,■,
3. -dimethyl-6-(4-(3-(4-benzoyl-
2-nitrophenyl)propyl]piperazin-1-yl
)-2,4(II(,3)1)-pyrimidinedione 0.
92 g of pale yellow crystals were obtained. Analysis results of this pyrimidine derivative obtained; NMR (C
DC13), δppm: 8.23(d, It()
. 7.16-8.10 (m, 7H). 5.21 (s, IH), 3.36 (s, 3H) 3, 2
9 (s, 3H). 2, 26-3.26 (m, 12H). 1,96 (m, 2H) Next, this pyrimidinedione derivative was dissolved in hydrochloric acid/methanol.
1.3. -dimethyl-6-(4
-[3-(4-benzoyl-2-nitrophenyl)pro
Pill 1 piperazin-1-yl)-2,4(IH,3)1
)-pyrimidinedione hydrochloride (compound 136) 0.9 g was obtained as white crystals. Analysis results of the obtained compound l゛36; Elemental analysis value Calculated value as CzsHtJsolHCl (
%): C, 59,14: H, 5,73; N,
13.26CI, 6.71 Analysis value (%): C,59,56,)l, 6.09
．． N, 13.16C1,6,21 Example 80 1.3-dimethyl-6-(4-[2-(4-benzoyl
-2-nitrophenyl)ethylcopiperazin-1-yl
)-2,4(IH,3H)-pyrimidinedione shu
Preparation of acid salt (Compound 137) BrCIIaCOOC2H5 (Compound 137) (+) 2-(4-chloro-3-nitrophenyl)-2
- Preparation of phenyl-1,3-dioxane; 4-chloro-3-nitrobenzophenone lOg, 1.
15ml of 3-propanediol and camphorsulfone
Dissolve 0.5 g of acid in 50 ml of benzene and stir under heating under reflux.
Recular sieves (genuine chemical ■, molecular sieves)
3A, +/+6 pellets)
The mixture was allowed to react for 12 hours. The obtained reaction solution was allowed to cool, and IN aqueous sodium hydroxide solution was added.
Washed with liquid, further washed with water, dried, and concentrated to obtain an oily substance.
. Next, this oil was purified by silica gel column chromatography (he
xane/ethyl acetate = 4/1)L, 2-(4-chloro-
3-nitrophenyl)-2-phenyl-1,3-dioxy
7.8 g of sun was obtained. Analysis result of this compound obtained; Elemental analysis value Calculated value as C+aH+5N04C1 (%
): C, 60, 29, H, 4, 11; N, 4.
39CI, 11.12 Analysis value (%): C, 60,09, H, 4,56, N
, 4.0IC1,11,29 (2) 4-(2-phenyl-1,3-dioxane-2
-yl)-2=Preparation of ethyl nitrophenyl acetate; Mixing of 10 ml of benzene and 10 ml of trimethyl borate
5.2 g of zinc powder was suspended in the solution, and the suspension was placed in a nitrogen atmosphere.
Under ambient atmosphere, 9 ml of ethyl bromoacetate was added dropwise at room temperature to react.
I set it. After 1 hour, 2-( obtained in the above (1)) was added to the reaction solution.
4-chloro-3-nitrophenyl)-2-phenyl=1
．． Dissolve 7.8g of 3-dioxane in 40ml of benzene
solution, 0.9 ml of dimethylformamide and trichloride.
listriphenylphosphine palladium (II) 0,
22g was added and left overnight at room temperature to react.
. Next, insoluble matter was removed from the reaction solution by filtration, and the filtrate was concentrated.
The resulting concentrate was purified by silica gel column chromatography.
(hexane/ethyl acetate = 371) and oily 4-(2
-phenyl-1,3-dioxan-2-yl)-2-di
4.4 g of ethyl trophenylacetate was obtained. Analysis results of the obtained ethyl phenylacetate derivative; NMR (CDCIs), δppm: 7.3-8.2
(m, 8)1). 4, 15 (q, 2H), 3.22 (s, 2H
). 1,40 (t, 3) 1) (3) Preparation of 4-benzoyl-2-nitrophenylacetic acid
; 4-(2-phenyl-1,3-di obtained in section (2) above)
Ethyl oxan-2-yl)-2-nitrophenylacetate
4.48 was dissolved in 30 ml of methanol, and IN
Added 15 ml of hydrochloric acid and reacted under heating under reflux for 1 hour.
. After the reaction was completed, the reaction solution was allowed to cool, the solvent was distilled off, and the obtained
The residue was extracted with ether. Furthermore, the organic layer obtained in the extraction process was washed with water, concentrated, and oil
3.5 g of a solid substance was obtained. Next, dissolve this oil in 20 ml of ethanol to obtain
Add 5 ml of 10% sodium hydroxide aqueous solution to the solution.
The reaction mixture was allowed to react overnight at room temperature, and the solvent was distilled off from the reaction solution. profit
Add 10ml of water to the resulting residue, and add 3N hydrochloric acid to this.
The precipitated crystals were collected by filtration and 4-benzoyl-2-ni
2.8 g of trophenylacetic acid was obtained. Analysis results of this nitrophenylacetic acid derivative obtained: NMR (CDCl2), δp'pm: 7.2-8.
3(m, 8)1). 3,73 (s, 28) (4) 2-(4-benzoyl-2-nitrophenyl)
Preparation of ethyl alcohol; 4-benzoyl-2-nitrophenyl obtained in section (3) above
Dissolve 2.8 g of acetic acid in 50 ml of tetrahydrofuran.
The solution was cooled on ice, and the borane methyl sulfide complex was added to it.
2.3 ml of the solution was dropped and left to stand. After 1 hour, add water to stop the reaction and remove the solution from the reaction solution.
The medium was distilled off, ether was added to the residue, and the resulting ether
The solution was washed with aqueous hydrogen oxide solution. After washing, concentrate the ether solution and activate the resulting sillage.
50ml of chloroform with 17g of manganese dioxide
and stirred vigorously for 30 hours.
. After stirring, manganese dioxide is filtered from the reaction solution, and the filtrate is
Concentrate and purify using silica gel chromatography (hexane)
/ethyl acetate = 3/1), oily 2-(4-benzoylene)
1.9 g of (2-nitrophenyl)ethyl alcohol
Obtained. Obtained analysis results of this compound; NMR (CDCl2), δppm: 7.2-8.3
(m, 8)1). 4.05(t, 2H), 3.11(t, 2)1
)(5) 1,3-dimethyl-6-(4-(2-(4-
Benzoyl-2-nitrophenyl)ethyl]piperazine
-■-yl)-2,4(IH,3H)-pyrimidinedio
Production of 2-(4-benzoyl-2-nitro) oxalate (compound 137): 2-(4-benzoyl-2-nitro
phenyl)ethyl alcohol 1.9g, p-toluene
1.5 g of sulfonyl chloride and 1.8 ml of pyridine
was dissolved in 30 ml of chloroform and reacted at room temperature for 1 day.
Ta. Next, water was added to the reaction mixture and stirred vigorously for 3 hours.
After that, the chloroform layer was separated and first diluted with IN aqueous hydrochloric acid solution.
, then washed with 1N aqueous sodium hydroxide solution, and then with water.
, further dried with sodium sulfate and concentrated to a brown oil.
I got something. This brown oil was dissolved in 1,3-dimethyl-6-(pipera
din-1-yl)-2,4(IH,38)-pyrimidine
Injected with 0.6 g of dione and 3 ml of triethylamine.
React for 6 hours under heating reflux in 20 mI of sopropatol.
I set it. After cooling, the reaction solution was concentrated, dissolved in chloroform, and diluted with water.
After washing and concentrating, silica gel column chromatography purification (clean
loloform/methanol = 40/1) and oily 1.
3-dimethyl-6-(4-[2-(4-benzoyl-2
-nitrophenyl)ethylcopiperazin-1-yl)
-2,4(18,3)1)-pyrimidinedione 0.7g
I got it. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13), δppm: 8. Old (d,
IH). 7, 3-7.8 (m, 7t(). 5, 12 (s, I) I), 4.55 (m,
2H). 3,22 (s, 3H), 3.30 (s, 2
)1). 2,6-3.3 (m, 10)1) Next, 0.6 g of this oily pyrimidinedione derivative was
Treatment with uric acid/methanol according to a conventional method. 3-dimethyl-6-(4-[2-(4-benzoyl-2
-nitrophenyl)ethylcopiperazin-1-yl)-
2,4(IH,3)1)-pyrimidinedione oxalic acid
0.6 g of salt (compound 137) was obtained. Analysis results of the obtained compound 137; IRv" (cm-1): 2550.1740.1
700.1650°ax 1530, +340.1200.1030830,
760. 700 Elemental analysis value CzsHzJsOl(CO□H)2.3H
Calculated value (%) as 20: C, 52, 17: )I
, 5.68; N, 11.27 Analysis value (%):
C, 52, 57,) I, 6.01: N, 11.3
0 Example 8I 1,3-dimethyl obtainable by the method of Example 76
Chil-6-(4-[2-(2-benzoyl-4-nitro)
phenyl)ethyl 1piperazin-1-yl)-2,4(
IH,3H)-pyrimidinedione oxalate (compound
133) as an active ingredient: The pyrimidinedione derivative/oxalate (compound 133)
) 1 g, milk frM 123 g and chickpeas
Mix 20g of Tenbun well and add it to hydroxypropylene.
Mixed with a solution of 5g of cellulose dissolved in 100ml of water.
It was granulated and dried at 50°C for 4 hours. This is combined with stearic acid
Add gnesium Ig, mix well, and use a tablet machine to make one tablet.
Tablets were obtained by compression with a weight of 150 mg. Example 82 1,3-dimethyl obtainable by the method of Example 74
Chil-6-[2-(2-benzoyl-4-nitroanili)
) ethylamino]-2,4(IH,3)1)-pyrimi
Capsule containing jindione (compound 131) as an active ingredient
Production of agent: 5 g of the pyrimidinedione derivative (compound 131),
120g of lactose and 25g of corn starch
Mix and fill the resulting mixture into hard capsules using a capsule filling machine.
Capsules were obtained by filling 150 mg into a bottle. Example 83 1,3-dimethyl obtainable by the method of Example 72
Chil-6-(3-[4-nitro-2-(3-pyridine)
2.4
-(IH. 3H)-pyrimidinedione oxalate (compound 129
) as an active ingredient: Production of an injection containing the pyrimidinedione derivative/oxalate (compound 129
) 20mg and 0.85g of sodium chloride
Dissolve this in an appropriate amount of distilled water for injection to bring the total volume to 100ml.
It was made into an injection. Pharmacological Test Example 6 In the same manner as Pharmacological Test Example 1, the above-mentioned substances shown in Table 12 were
Calculate ADP7S and ERP of each compound obtained in the example.
I met. The results are shown in Table 12. Toxicity Test 6 In the same manner as Toxicity Test 1, the above examples shown in Table 13 were used.
The toxicity of each compound obtained was tested and the mortality rate of mice was determined.
I met. The results are shown in Table 13. The administration was 300 mg/kg orally for each compound.
Administration (p,o,) was performed. Table 12 Pharmacological test results table 28 1 33 Example 84 1.3-dimethyl-6-(4-[3-(3-methyl-4
-nitrophenyloxy)propylcopiperazine-1-
-2,4(1)1.3H)-pyrimidinedione
Preparation of hydrochloride salt (Compound 138) (Compound 157) (Compound 139) H3CH. (Compound 138) (1) 1.3-dimethyl-6-(4-(3-hydro
xypropyl)piperazin-l-yl] -2,4(I
Preparation of H,311)-pyrimidinedione (compound 139)
Manufactured by: 1,3-dimethyl-6-(l-piperazinyl) -
2,4(IH3H)-pyrimidinedione (compound 157
) 14.1 g, 3-bromo-1-propatool 1
1.7 g and 13 g of triethylamine, 2 ethanol
The reaction was carried out by heating under reflux in 50 ml for 20 hours. anti
After the reaction, the reaction mixture was concentrated to dryness and the residue was dissolved in chloroform.
Dissolve it in 300ml of water and wash it twice with 100ml of water.
After that, the washed organic layer was dried with anhydrous magnesium sulfate.
. This organic layer was treated under reduced pressure, the solvent was distilled off, and the crude product
20.5 g of product was obtained. Add ether to this crude product,
Crystallize it, collect it, wash it, dry it, 1.
3-dimethyl-6-[4-(3-hydroxypropyl)
piperazin-1-yl]-2,4(IH,3H)-pyri
Midinedione (Compound 139) 12.4g (Yield:
69.8%). Analysis results of the obtained crystals of compound +39: Melting point: 119
~121°C NMR (CDCIs) δppm: 1.8 (d, 2H
), 2.7 (m, 6H). 3,02 (m, 4H), 3.36 (s, 3
H). 3,43 (s, 3)1), 3.82 (t,
2)1). 4.34 (br, 1) 1), 5.26 (s, IH) 16
05.1440. +213.1068. 1000°9
21.750 (2) 1,3-dimethyl-6-(4-(3-(3-methyl)
thyl-4-nitrophenyloxy)propylcopiperazi
-2,4([1,3)1)-pyrimidine
Production of dione hydrochloride (compound 138): 1.13 g of the previously obtained compound 139,
1.21 g of sphine and 3-methyl-4-nitropheno
0.70 g of alcohol in 15 ml of anhydrous tetrahydrofuran
In the suspension obtained by suspending and mixing, azodicarboxylic acid di
10ml solution of 0.8g ethyl in anhydrous tetrahydrofuran
was added at room temperature. Next, the resulting mixture was stirred for 10 minutes and then concentrated to dryness.
The residue was purified by silica gel column chromatography (methanol/vinegar
Ethyl acid = 1/15 to 1/7, volume ratio), 1.3
-dimethyl-5-(4-[3-(3-methyl-4-nito
lophenyloxy)propylcopiperazin-1-yl)
-2,4(1)1.3H)-pyrimidinedione 0.9
2 g was obtained. Analysis results of the obtained crystal of pyrimidinedione derivative: Melting point: 178.5-181°C Elemental analysis value Calculated value as C2°HaJiOs (%)
: C57,54, H6,52, N16.78 analysis value
(%): C57.30, H6.56, N16.6
4NMR (CDCIs) δppm: 1.9-2.3
(m, 2H), 2.6~2,8 (m, 9H),
3.0-3.2 (m4)1), 3.44 (s,
3H), 3.54 (s. 3H), 4.28 (t, 2H), 5.44
(s. IH), 7.0-7.16 (m, 2H). 8,40 (d, IH) Furthermore, the 1,3-dimethyl-6-(4
-[3-(3-methyl-4-nitrophenyloxy)propylene
ropilcopiperazin-1-yl)-2,4(1)I,
3H)-pyrimidinedione Q, 8(l g to HCI
/methanol solution according to a conventional method to obtain 1,3-di
Methyl-6-(4-(3-(3-methyl-4-nitroph)
phenyloxy)propylcopiperazin-1-yl) -
2,4(IH,3H)-pyrimidinedione hydrochloride (chemical
Compound 138) 0.60 g was obtained. Analysis results of the obtained crystals of compound 138: Melting point: 224
°C (decomposition) Elemental analysis value C2゜HzJsO1)1cI・2H30 meter
Calculated value (%): C49,03, H6,58, N14
．． 29°CI 7.24 Analysis value (%): C48,82, H6,88, N1
4.18°CI 7.31 Example 85 1.3-dimethyl-6-(4-[3-(4-chloro-2
-nitrophenyloxy>propylcopiperazine-1-
-2,4(IH,38)-pyrimidinedione
Preparation of hydrochloride (compound 140) 4-chloro-2-ditrophenol 0.80 g, 1.
3-dimethyl-6-(4-(3-hydroxypropyl)
piperazin-1-yl)-2,4(IH,3H)-pi
Rimidinedione (Compound 139) 1.13g,
1.21 g of rifhenylphosphine was added to anhydrous tetrahydrophosphine.
Suspended in 15 ml of run, diethyl azodicarboxylate o,
Example s4-(
2) to obtain 1,3-dimethyl-6-(4-
[3-(4-chloro-2-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(IH,3H
)-pyrimidinedione crystals (1.43 g) were obtained. Analysis result of the obtained crystal of this pyrimidinedione derivative mp, 162-163°C Elemental analysis value C+e) 1z4NsOaC1-1/2LO
Calculated value (%): C51.07, N5.64
．． N15.67CI 7.93 Analysis value (%): C51.11, N5.68. N
15.64°C17,94 NIIIR (CDCI δppm: 1.8-2.2
(m, 2) 1), 2.4-2.8 (m, 6N), 2.8
~3.04 (m. 41(), 3.2~3.4 (m, 2) 1). 3,52 (s, 3H), 3.80 (s, 3
)1). 4,18 (t, 2)1), 5.20 (s,
IH). 7.20 (d, IH), 7.45 (dd, 1l (). 7,81 (d, IH) Next, 1.2 g of this pyrimidinedione derivative was added to 15%
Treated with HCI/methanol solution according to a conventional method, 1.
3-dimethyl-6-(4-(3-(4-chloro-2-di
trophenyloxy)propylcopiperazin-l-yl
)-2,4(1)1,3)1)-pyrimidinedione salt
1.13 g of crystals of the acid salt (Compound 140) were obtained. Analysis results of the obtained crystals of compound 140 mp, 271 (
Decomposition) Elemental analysis value C+ Calculated as eHiJsOsclHcl
Calculated value (%): C48.11, N5.31. N1
4.76°CI 14.95 Analysis value (%): C47.80, N5.33. N
14.62°CI 14.86 Example 86 1.3-dimethyl-6-(4-[3-(2-chloro-4
-nitrophenyloxy)propylcopiperazine-1-
yl)-2,4(1)1,3H)-pyrimidinedione.
Preparation of hydrochloride (compound 141) 1 (CI/CHsO)I 2-chloro-4-ditrophenol 2.4 g, 1.3-
Dimethyl-6-(4-(3-hydroxypropyl)pipe)
Radin-1-yl) -2,4(1)1,3)1)-pi
Rimidinedione (Compound 139) 3.38g, )
3.62 g of liphenylphosphine was added to anhydrous tetrahydrochloride.
Suspended in 70ml of furan, diethyl azodicarboxylate 2
．． Example 84-(2) The mixture prepared by adding 4 g
2.5 g of pale yellow crystals were obtained. This conclusion
The crystals were recrystallized from ethanol to give 1,3-dimethyl-6-(
4-[3-(2-chloro-4-nitrophenyloxy)
propylcopiperazin-1-yl)-2,4(IH,
2.07 g of crystals of 3H)-pyrimidinedione were obtained. Analysis result of the obtained crystal of this pyrimidinedione derivative mp, 133-134°C Elemental analysis value Calculated value as C+eHaJsOaCI (%
): C52,12,N5.52. N13.99
゜CI8.10 Analysis value (%): C51.99, N5.72. N
15.70°CI 8.06 NMR (CDCIs) δppm: 1.8-2.3
(m, 2H), 2.3-3, 1 (m, 10)1)
, 3.33 (s, 3H). 3.41 (s, 3H), 4.24 (t, 2t1). 5, 26 (s, 1) I), 7.0-8.4 (
m. 3H) Next, 0.5g of this pyrimidinedione derivative was added to 15%
Treated with HC1/methanol solution according to a conventional method to give 1.3
-dimethyl-6-(4-[3-(2-chloro-4-nito)
lophenyloxy)propyl]piperazin-1-yl)
-2,4(IH,3)ri-pyrimidinedione hydrochloride
0.5 g of crystals of (Compound 141) were obtained. Analysis results of the obtained crystals of compound 141 mp, 11
5-120℃ Elemental analysis value as C+JiJsOsC1HC1HzO
Calculated value (%): C46, 35, H5, 53, N1
4.22゜CI 14.40 Analysis value (%): C46,25,H5,29,N1
4.46°CI 14.69 +055,900,830,750 Example 87 1.3-dimethyl-6-(4-(3-(4-methanesulfur)
Honamido-2-nitrophenyloxy)propylcopy
perazin-l-yl)-2,4(IH,3H)-pyri
Production of midinedione hydrochloride (compound 142) 1) 2N HCI (compound 157) (1) 4-acetamido-2-ditrophenol (compound
143> 10.1 g of 4-amino-2-nitrophenol was dissolved in 8 g of acetic acid.
0ml and added 6.7g of acetic anhydride over 5 minutes.
Ta. After stirring for 1 hour, the solvent was distilled off under reduced pressure, and water was added to precipitate.
A dark brown solid was collected by filtration. After washing this with water, use water-containing ethanol.
4-acetamido-2-nito
Obtained 10.2 g of crystals of lophenol (compound 143).
Ta. Analysis results of the obtained crystals of compound 143 mp, 158~
159℃ (2) 3-(4-acetamido-2-nitrophenyl)
Preparation of 4-acetamido-2-nitrophenol (xy)propyl bromide obtained above.
Compound +43) Io, 2g and potassium carbonate 13.9
g, 100 ml of methyl ethyl ketone, 1,3-dibro
A mixture of 40.2 g of mopropane was reacted under reflux for 6 hours.
I set it. Insoluble materials were filtered from the reaction mixture, and the filtrate was concentrated under reduced pressure.
Dissolve the residue in chloroform, wash with water, and soak in an anhydrous sulfuric acid mug.
It was dried with sodium chloride, and the solvent was distilled off under reduced pressure. Siri this
Kagel column chromatography for purification with chloroform/methanol
(volume ratio = 100/1), and dichloromethane-hexane
3-(4-acetamide)
-2-ditrophenyloxy)propyl bromide
5.2 g of crystals were obtained. Analysis result mp of the crystal of the obtained propyl bromide derivative, 134°C Elemental analysis value Calculated value as C++H + 5NtOsBr (
%): C41,66, H4,13, H8,83,
Br25.13 analysis value (%): C41,84,H
4,35,H8,92,Br24.73(3) 3-(
4-Methanesulfonamido-2-nitrophenyloxy
) Preparation of propyl chloride The 3-(4-acetyl chloride obtained above)
Tamido-2-nitrophenyloxy)propyl bromide
Suspend 1.0g in 15ml of 2N hydrochloric acid and heat reflux for 30 minutes.
After the flow, 10 ml of acetic acid was added, and the mixture was further heated under reflux for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and sodium carbonate was added to the residue.
Add p) to adjust to 17-8, and extract with chloroform.
I put it out. Dry this extract with anhydrous sodium sulfate and
The desiccant was filtered off, 1 ml of pyridine was added to the filtrate, and the mixture was cooled with water.
Drop a solution of 0.5 g of silk chloride in 5 ml of chloroform.
I put it down. After stirring for 2 hours under water cooling, stirring at room temperature for 2 hours,
Extract twice with N sodium hydroxide solution, and the resulting aqueous layer
Washed with chloroform. This aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate.
did. The extract was concentrated under reduced pressure, and the residue was reconcentrated with ethanol.
By crystallizing, 3-(4-methanesulfonamide-
Crystals of 2-nitrophenyloxy)propyl chloride
0.7g was obtained. Analysis results of the crystals of the obtained propyl chloride derivative Elemental analysis value Calculated value as C1°H + 5CINzOsS
(%): C38,90, H4,24, H9,07
°C111,49, S10.38 Analysis value (%): C38,90, H4,30, N8
．． 94. C110°72. S10.03 (4) 1,3-dimethyl-6-(4-(3-(4-methyl)
Tansulfonamido-2-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(18,38
)-Production of pyrimidinedione hydrochloride (compound 142)
3-(4-methanesulfonamido-2-nitrophenyl
0.31 g of oxy)propyl chloride, 1,3-di
Methyl-6-(l-piperazinyl)-2,4(1)1
．． 3) 1)-pyrimidinedione (compound +57) 0
．． 22g, triethylamine 0.5ml in ethanol 1
After heating and dissolving in 0ml to make a homogeneous solution, the solvent was distilled off under reduced pressure.
I left. After heating the residue at 110°C for 2 hours, n-butano
10 ml of water was added thereto, and the mixture was further heated and stirred at 110°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dilute sodium hydroxide solution.
Dissolved and washed with chloroform. This aqueous layer is diluted with dilute hydrochloric acid.
Adjust the pH to 1-2, wash with ethyl acetate, then add carbonated water.
Add sodium to adjust the pH to 7-8, and remove the precipitated solids.
The solution was collected by filtration. After drying this filtered material under reduced pressure, methanol
Dissolve 15%) ICI/methanol in the usual manner.
1,3-dimethyl-6-(4
-[3-(4-methanesulfonamido-2-nitrophe)
nyloxy)propylcopiperazin-1-yl) -2
,4(1)1,3H)-pyrimidinedione hydrochloride (chemical
0.2 g of crystals of compound 142) were obtained. Analysis result mp of the obtained crystal of compound 142, 239°C Elemental analysis value C2°H2aNsOtS-HC1l/2H
Calculated value as J (C%): C44,32,H5,5
8, N15.51°CI 6.54, 35.9
2 Analysis value (%): C44, 30, H5, 58, N1
5.45°C16,96,S 5.94 Example 88 1.3-dimethyl-6-(4-(3-(4-acetamide)
-2-ditrophenyloxy)propylcopiperazine-
1-yl) -2,4(IH,3H)-pyrimidinedio
4-acetamido-2-nitrohydrochloride (compound 144) obtained in Example 87-(1)
Phenol (compound 143) 2.71g and 1.3-
Dimethyl-6-[4-(3-hidyloxybrovir)pipe
Radin-1-yl]-2,4(IH,3)1)-pyri
Midinedione (Compound 139) 3.38g,
3.62 g of rifhenylphosphine was added to anhydrous tetrahydrofosphine.
Suspend in 70 ml of run, diethyl azodicarboxylate 2.
The mixture prepared by adding 4g was prepared as Example 84-(2).
The same treatment yielded 2.7 g of pale yellow crystals. this crystal
2.0g in 15% lIC1/methanol solution according to the usual method.
I, 3-dimethyl-6-(4-(3-(
4-acetamido-2-nitrophenyloxy)propyl
] Piperazin-■-yl)-2,4(Ill, 3) 1)
-Crystals of pyrimidinedione hydrochloride (compound 144)
2.5g was obtained. Analysis results of the obtained crystals of compound 144 mp, 228
．． 5～230℃ Elemental analysis value Calculated as Ca+HzaNaOa・HCI
Value (%): C50,76, H5,8B, N16
．． 91°CI 7.13 Analysis value (%): C50,67, H6,27, N1
7.07°CI 6.81 Example 89 1.3-dimethyl-6-(4-(3-(2-hydroxy)
-5-nitrophenyloxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione
・Production of hydrochloride (compound 145) (compound 145) 2-nitrocatechol 0.63 g% 1.3-dimethyl
-6-[4=(3-hydroxypropyl)piperazine-
1-yl]-2,4(11(,3H)-pyrimidinedio
(Compound 139) 1.0 g, triphenyl
1.06 g of phosphine in 15 g of anhydrous tetrahydrofuran
ml, and 0.71 g of diethyl azodicarboxylate was suspended in
In addition, the prepared mixture was prepared in the same manner as in Example 84-(2).
Upon treatment, 0.65 g of pale yellow crystals were obtained. This crystal is
Recrystallized from tanol and 1,3-dimethyl-6-(4-(
3-(2-hydroxy-5-nitrophenyloxy)
ropilcopiperazin-1-yl) -2,4(18,
3) 1)-pyrimidinedione (compound 145)
0.55 g of crystals of ) were obtained. Analysis result of the obtained crystal of this pyrimidinedione derivative mp, 171-173°C Elemental analysis value Calculated value as C+5HtaNsOs (%)
: C54,40,H6,OO,N16.69 analysis
Value (%): C54, 40, H6, 28, N16.
48HMR (CDCIs) δppm: 1.9-2.
2 (m, 2H), 2.6-3.2 (m, 10H)
, 3.3 (s, 3H). 3, 4 (S, 3H), 4.1 (t, 2H
). 5.24 (s, 1) 1), 6.88-7.08 (m
, IH), 7.60-7.80 (m, 2H)
1280.114 (1,990,870 then this piri
0.5 g of midinedione derivative was dissolved in 20% HCI/meth
1,3-dimethyl-
6-(4-[3-(2-hydroxy-5-nitropheny)
((oxy)propylcopiperazin-1-yl) -2,
4(111,3H)-pyrimidinedione hydrochloride (compound
0.5 g of crystals of product 145) were obtained. Analysis results of the obtained crystals of compound 145 mp, 246~
249℃ Elemental analysis value C+e)I*5NaOs-)IC1・2H
Calculated value as J (%): C46,39,H6,1
5,N14.24゜CI 7.21 Analysis value (%): C46,83,1 (5,97,N
I4.55°CI 7.77 Example 90 1.3-dimethyl-6-(4-(3-(2-allyloki)
C-5-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(1)1.3H)-pyrimidine
Preparation of dione hydrochloride (compound 146) HCI/C) 130) 1 1.3-Dimethyl-6-(4-
[3-(2-hydroxy-5-nitrophenyloxy)
propylcopiperazin-1-yl)-2,4(IH,
31()-pyrimidinedione (free monomer of compound 145)
) 1g, allyl bromide 0.3+ g, potassium carbonate
Suspend 0.36 g of aluminum in 10 ml of dry acetone and add
The mixture was heated to reflux for a while. Pour the reaction solution into 60ml of water and add chloro
Extract 3 times with 30ml of form, and add this extract to 0.5N water.
It was washed with an aqueous sodium oxide solution and then with water. This black
Dry the loform solution over anhydrous sodium sulfate to reduce the solvent.
Evaporate under pressure and purify the residue using silica gel column chromatography.
Loloform/methanol = 20/1 volume ratio) Obtained oil
By crystallizing the product using ethanol, 1.3-
Dimethyl-6-<4- [3-(2-allyloxy-5
-nitrophenyloxy)propylcopiperazine-1-
-2,4(IH,3H)-pyrimidinedione
0.78 g of crystals were obtained. Analysis results of the obtained crystals of this pyrimidinedione derivative mp, 120-121 HMR (CDCI δppm: °C 2.08 (t, 2H), 2.5-3.0 (m. 10H), 3.3 (s, 3H), 3.3
6 (s. 3) 1), 4.16 (t, 2N), 4.5-4
, 7 (m, 2) 1) , 5.2 (s, IH)
. 5.16-5. [i(m, 2H), 5.8-6, 2
4 (m, IH), 6.9 (d, IH)
. 7, 68-7.92 (m, 2) 1) 1.280.
1000 Next, 0.5g of this pyrimidinedione derivative was added to 20%
) Treated with ICI/methanol solution according to a conventional method, 1
．． 3-dimethyl-6-(4-[3-(2-allyloxy)
-5 nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3)1)-pyrimidinedio
0.5 g of crystals of N. hydrochloride (Compound 146) were obtained. Analysis results of the obtained crystals of compound 146 mp, 161.
5-180°C Example 91 1.3-dimethyl-6-(4-(3-(4-methylthio)
-2-nitrophenyloxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione
- Production of hydrochloride (compound 147)) ICI10H308 4-methylthio-2-ditrophenol 1.5g, 1.
3-dimethyl-6-[4-(3-hydroxypropyl)
piperazin-I-yl]-2,4(IH,3)1)-pi
Rimidinedione (compound +39) 2.0 g,
Add 2.2 g of Riphenylphosphine to anhydrous tetrahydrofura
Suspended in 30 ml of water, 1.3 diethyl azodicarboxylate
Example 84-(2) The mixture prepared by adding 5 ml of
1,3-dimethyl-6-(4-(3
-(4-methylthio-2-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(18,38
)-pyrimidinedione crystals (2.9 g) were obtained. Analysis results of the obtained crystals of this pyrimidinedione derivative NMR (CDCIs) δppm: 1.9-2.2 (
m, 2) 1), 2.48 (s. 3) 1), 2.4-2.7 (m, 6H),
2.8-3.0 (m, 4H), 3.28 (s
, 3H). 3.36 (s, 3H), 4.14 (m, 2H). 5, 16 (s, 1) 1), 7.0 (d, I
H). 7,36 (dd, IH), 7.62 (d,
IH) Next, 0.5 g of this pyrimidinedione derivative
20% 1 (treated with C1/methanol solution according to the usual method)
, 1,3-dimethyl-6-(4-[3-(4-methylthi
O-2-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(1)1.3H)-pyrimidine
0.4g of crystals of dione hydrochloride (compound 147) was obtained.
. Analysis results of the obtained crystals of compound 147 mρ, 224 ~
226℃ Elemental analysis value Calculated as C1oHatNaOsS-HCI
Calculated value (%): C49,43N5.81; N14
．． 41. C1,7,30,S,6.60 Analysis value (%): C49,20H,5,97N,
14.28CI, ? , 23. S, 6.84 Example 92 1.3-dimethyl-6-(4-<3-[2-(α-
hydroxybenzyl)-4-nitrophenyloxy]
Lopil〉piperazin-1-yl)-2,4(IH,3
)1)-pyrimidinedione oxalate (compound 148
) Production (1) 1.3-dimethyl-6-(4-(3-
(2-benzoyl-4nitrophenyloxy)propyl
Copiperazin-1-yl) -2,4'(1)1,3H
)-Preparation of pyrimidinedione (compound 149) 3.74 g of 2-benzoyl-4-nitrophenol,
1,3-dimethyl-6-[4-(3-hydroxypropyl)
) piperazin-1-yl] -2,4(IH, 38)
-pyrimidinedione (compound +39) 3.5 g,
3.3 g of triphenylphosphine was added to anhydrous tetrahydrophosphine.
Suspend in 50 ml of run, diethyl azodicarboxylate 2.
Example 84-(2) The mixture prepared by adding 40 ml of
1,3-dimethyl-6-(4-[3
-(2-benzoyl-4-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(IH,3H
)-pyrimidinedione (compound I49) crystals 3.9 g
I got it. This pyrimidinedione derivative (compound 149) obtained
Analysis results of crystals NMR (CDCIs) δppm: 1.9 ~ 2.2 (
m, 2H), 2.4-2,7 (m, 6H),
2.8-3.0 (m. 4H), 3.26 (s, 3H), 3.36
(s. 3H), 4.14 (m, 2H), 5.14
(s. IH), 7.0-7.8 (m, 8N), 8.36 (
d, 2H) (2) 1,3-dimethyl-6-(4-<3-[2
-(α-hydroxybenzyl)-4-nitrophenyl
xy]propyl>piperazin-1-yl) -2,4(
IH, 38)-pyrimidinedione oxalate (compound
148) Production of the pyrimidinedione derivative (chemical compound) obtained above.
0.2 g of compound 149) and 15 m of sodium borohydride
0 reaction in which g was dissolved in ethanol and stirred at room temperature for 6 hours.
Pour the liquid into water, extract with chloroform, and remove the chloroform layer.
After washing with water, it was dried over anhydrous sodium sulfate. solvent
The residue was purified by silica gel column chromatography (chlorophore).
lum/methanol = 40/1 volume ratio) L/1.3-dime
Chil-6-(4-<3-(2-(a-hydroxybeta)
(ditrophenyl)-4-nitrophenyloxy]propyl>pipe
Radin-1-yl)-2,4(IH,311)-pyri
0.15 g of midinedione was obtained. Analysis result of the obtained crystal of this pyrimidinedione derivative NMR (CDCIs) δppm: 2.0 (m, 2H
), 2.5-2.9 (m. 10H), 3.26 (s, 3H), 3.3
7 (s. 3) 1), 4.11 (m, 2) 1), 5.
16 (s. 1) 1), 6.04 (s, III), 6.88 (d
. 1l1), 8.14 (dd, IH), 8.52 (d
, IH) Next, 0.15 g of this pyrimidinedione derivative was
Treated with uric acid/methanol solution according to a conventional method to obtain 1.3-
Dimethyl-6-(4-<3- (2-(α-hydroxy)
(cybenzyl)-4-nitrophenyloxy]propyl
piperazin-1-yl) -2,4(1)I, 3)1
)-pyrimidinedione oxalate (compound 148)
0.15 g of crystals were obtained. Analysis results of the obtained crystals of compound 148 mp, 1
1 1~115℃ Elemental analysis value C25H5INS06・(COO)I)
Calculated value (%) as 22820: C52,91,
H5, 87, N11.02 analysis value (%): C52
,74,H5,65,N10.941340.760 00 Example 93 1.3-dimethyl-6-(4-(3-(3-trifluoro)
lomethyl-4-nitrophenyloxy)propyl copy paste
Radin-1-yl)-2,4(IH,3)
Preparation of Zindione Oxalate (Compound 150) 4-2
Thoro-3-trifluoromethylphenol 1.9 g%
1,3-dimethyl-6-(4-(3-hydroxypropyl)
piperazin-1-yl]-2,4(1)1.3)1
)-pyrimidinedione (compound 139) 2.25g
, 2.41 g of triphenylphosphine was added to anhydrous tetrahydrogen
Suspended in Dorofuran 60ml, diethyl azodicarboxylate
Example 84-(
It was treated in the same manner as in 2) to obtain 3.50 g of pale yellow crystals. These crystals were recrystallized from ethanol and 1,3-dimethyl-
6-(4-(3-(3-trifluoromethyl-4-nito)
lophenyloxy)propylcopiperazin-1-yl)
-2,4(IH,3H)-pyrimidinedione crystal 3
．． 31 g was obtained. Analysis results of the obtained crystals of this pyrimidinedione derivative NMR (CDCIs) δ p, pm:
1.9 ~ 2.2 (m, 2H), 2.5 ~ 2.75 (
m, 6H), 2.9-3.1<m. 48), 3.3 (s, 3H), 3.4 (
s. 3H), 4.15 (t, 2H), 5.3
(s. 1) 1), 7.1-7.4 (m, 2H). 8,15 (d, IH) Next, 3.2 g of this pyrimidinedione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(4-[3-(3-trifluoromethyl-
4-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3)1)-pyrimidinedio
Obtained 3.22g of crystals of oxalate (compound 150).
Ta. Analysis results of the obtained crystals of compound 150 mp, 187~
189℃ Elemental analysis value C2゜HzJsNaOs・(COD)I)
, Calculated value (%): C47.06, H4°67,
N12.47°F 10.15 Analysis value (%): C47.51, H5.24, N12.6
7°Flo, 49 Example 94 1.3-dimethyl-6-(4-(3-(2-methoxyca)
Rubonyl-4-nitrophenyloxy)propyl copy paste
Radin-1-yl) -2,4(1)1.3)1)-P
Production of rimidinedione oxalate (compound 151)
(1) Preparation of methyl 5-nitrosalcylate 5-nitrosa
Add 80ml of methanol and Log concentrated sulfuric acid to 5g of lytic acid.
Then, the mixture was heated under reflux for 8 hours while methanol was distilled off. solvent
was distilled off under reduced pressure, the residue was dissolved in chloroform, and the chloroform
The loform solution was washed with water and then concentrated to dryness. the residue obtained
Purify using shiso gel and ram chromatography (chloroform),
Further, crystallization was performed using chloroform-ether.
5.1 g of crystals of methyl 5-nitrosalicylate were obtained.
. Analysis results of the obtained crystals of methyl 5-nitrosalicylate mp, 114-116°C (2) 1.3-dimethyl-6-(4-[3-(2-methyl)
Toxycarbonyl-4-nitrophenyloxy)propyl
rucopiperazin-1-yl)-2,4(1)1.3)
1)-pyrimidinedione oxalate (compound 151)
Production of methyl 5-nitrosalicylate 2 obtained by the above procedure
, 96 g and 1,3-dimethyl-6-(4-(3-hypolymer)
droxypropyl)piperazin-1-yl) -2,4
(IH,3H)-pyrimidinedione (compound 139)
4.23g, triphenylphosphine 3.93g
Suspend in 50 ml of water and tetrahydrofuran, and
A mixture prepared by adding 2.6 g of diethyl phosphate was used as an example.
84- Treat in the same manner as (2) to obtain 6.5 g of pale yellow crystals.
I got it. This crystal was recrystallized from methanol and 1,3-di
Methyl-6-(4-[3-(2-methoxycarbonyl-
4-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3H)-pyrimidinedione
Obtained 5.74 g of crystals of (Furi-integrated compound 151)
. This pyrimidinedione derivative (compound 151) obtained
Results of analysis of crystals of Furi-integrated) mp, 145-146°C NMR (CDCIs) δ1) H+: 1.8-2.2 (
m, 2) 1), 2.4-3.0 (m, 10H)
, 3.27 (s, 3H) , 3.36 (s
. 31(), 3.87 (s, 3H) 4.17
(t, 2H). 5, 24 (s, IH), 7.0-8.7 (m
, 3H) Next, 5.5 of this pyrimidinedione derivative
g with an oxalic acid/methanol solution according to a conventional method,
1,3-dimethyl-6-(4-[3-(2-methoxyca)
Rubonyl-4-nitrophenyloxy)propyl copy paste
Radin-1-yl)-2,4(IH,31()-pyri
5 crystals of midinedione oxalate (compound 151)
．． 6g was obtained. Analysis results of the obtained crystals of compound 151 rnp, tea
~187℃ (decomposition) Elemental analysis value Cz+Hz, N5Ot・(COO)I)
1cHsOH L/1” Calculated value (%): C47,
92,) (5,86,N11.64 analysis value (%):
C47,74, H6,66, N11.4310B0.
820,765,750 Example 95 1.3-dimethyl-6-(4-[3-(2-carboxy
-4-nitrophenyloxy)propylcopiperazine-
1-yl)-2,4(1B, 3H)-pyrimidine di
Preparation of oxalate (compound 152)
Ru-6-(4-(3-(2-methoxycarbonyl-4-
Nitrophenyloxy)propylcopiperazine-1-a
)-2,4(1)1,3H)-pyrimidinedione (chemical
1.38g of compound 151) and methanol 20g
0ml of 1.5N aqueous sodium hydroxide solution
Add 0ml and stir at 60℃ for 30 minutes. Leave the reaction solution to cool.
Afterwards, it was neutralized with dilute hydrochloric acid and concentrated under reduced pressure to bring the total volume to 50ml.
1 by cooling on ice and collecting the precipitated crystals by filtration. 3-dimethyl-6-(4-[3-(2-carboxy-4
-nitrophenyloxy)propylcopiperazine-1-
-2,4(II(,3)1)-pyrimidinedio
1.16 g of ion was obtained. Analysis results of the obtained crystals of this pyrimidinedione derivative mp, 155-158°C NMR (DMSO-d6) δppm: 1.8-2.3
(m, 2H), 2.4~3, 2 (m, 10H) 3
．． 13 (s, 3) 1). 3, 27 (s, 3H), 4.2 (t, 2H
). 5, 2 (s, 1) 1), 7.3~8.5 (m
. 3H) Next, 1.0 g of this pyrimidinedione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(4-(3-(2-carboxy-4-nito)
lophenyloxy)propylcopiperazin-1-yl)
-2,4(IH,3H)-pyrimidinedione shu
0.9 g of crystals of the acid salt (Compound 152) were obtained. Analysis results of the obtained crystals of compound 152 mp, 191~
193℃ (decomposition) Elemental analysis value C*oHtsNsOt・(COOH)1)
Calculated value C% as 1aO): C47,57,N5.
26. N12J2 analysis value (%): C47,85,
N5.32. N12.491135.1075,76
0,750 Example 96 1.3-dimethyl-6-(4-[3-(2-amino-4
-nitrophenyloxy)propylcopiperazine-l-
-2,4(IH,3)1)-pyrimidinedione
- Production of oxalate (compound 153) 1.54 g of 2-7 minnow 4-nitrophenol. 1,3-dimethyl-6-[4-(3-hydroxypropyl)
piperazin-1-yl] -2,4(1)1.3)
1)-pyrimidinedione (compound 139) 2.82
g, triphenylphosphine 2.88 g in anhydrous tetra
Suspend in 20ml of hydrofuran and add azodicarboxylic acid diethyl
Add 1.92 g of chilli and stir at room temperature for 1 hour to remove the precipitate.
was collected by filtration, washed with chloroform-ether, and condensed.
1.44 g of crystals were obtained. The crystals were mixed with ethanol-chlorophore.
1,3-dimethyl-6-(4-[3-
(2-amino-4-nitrophenyloxy)propylco
piperazin-1-yl)-2,4(IH,3H)-pi
0.6 g of limidinedione crystals were obtained. Analysis results of the obtained crystals of this pyrimidinedione derivative mp, 188°C NMR (DMSO-d6) δppm: 1.9-2.
0 (m, 2H), 2.4-3, 0 (m, 10)1)
, 3.1 (s, 3)1). 3,24 (s, 3H), 4.08 (m, 2
H). 5, 15 (s, 1) 1), 5.35 (br, 2H) 6
, 8 to 7.5 (m, 3H) Next, 0.2 g of this pyrimidinedione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(4-[3-(2?amino-4nitrophe)
nyloxy)propylcopiperazin-1-yl) -2
, 4CI8.3) 1)-pyrimidinedione oxalate
0.21 g of crystals of (Compound 153) were obtained. Analysis result mp of the obtained crystal of compound 153, 145°C Elemental analysis value C + JzsNs01 (COOH) x
Calculated value (%): C49.60, N5.55. N
16.53 analysis value (%): C49.53, N5.9
6. N13.491510.1435,1340.1
290,1235°075 Example 97 1.3-dimethyl-6-(4-(3-(4-methoxyca)
Rubonyl-2-nitrophenyloxy)propyl copy paste
Radin-1-yl) -2,4(u+, 3)1)-p
Production of rimidinedione oxalate (compound 154) (
Compound! 54) Methyl 4-hydroxy-3-nitrobenzoate 0,84
g and 1,3-dimethyl-6-[4-(3-hydroxypropylene)
-2,4(11(,
311) -pyrimidinedione (compound 139) 0
．． 8 g, triphenylphosphine 0.88 g anhydrous
Suspended in 14 ml of tetrahydrofuran, 7zodicarbonate
A mixture prepared by adding 0.54 ml of diethyl acid was carried out.
In the same manner as in Example 84-(2), 1,3-dimethyl-
6-(4-[3-(4-methoxycarbonyl-2-nito)
lophenyloxy)propylcopiperazin-1-yl)
-2,4(IH,3H)-pyrimidinedione oil 1
．． 1g was obtained. Analysis results of this pyrimidinedione derivative obtained NMR (CDCIs) δppm: 2.1 (m, 2H), 2.3-3.0 (m
, 10) 1) 3, 3 (s, 3H) , 3.4
(s, 3)1) , 3.95(s, 3)1) ,
4.3 (t, 2H), 5.25 (s. IH), 7.25 (d, IH), 8.27
(dd. 1) 1), 8.61 (d, IH) Next, 1.0 g of this pyrimidinedione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(4-[3-(4-methoxycarbonyl-
2-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3H)-pyrimidinedione
・T, o g of crystals of oxalate (compound 154) were obtained.
. Analysis results of the obtained crystals of compound 154 mp, 19
0-193℃ (decomposition) Elemental analysis value C□HitNsOγ・(COOH) 13
) Calculated value as IJ (%): C45,62,N5.
83. N11.57 analysis value (%): C45,92
, N5.21. N11.841640.1620,1
530.1340.800 Example 98 1.3-dimethyl-6-(4-[3-(2-cyano-4
-nitrophenyloxy)propylcopiperazine-1-
-2,4(1)1.3H)-pyrimidinedione
・Production of oxalate (compound 155) 2-chloro-5-nitrobenzonitrile (1,82 g and
1,3-dimethyl-6-[4-(3-hydroxypropyl)
piperazin-1-yl]-2゜4 (18,311
)-pyrimidinedione (compound 139) 1.0 g
, 0.22 g of sodium hydride in dimethylformamide
After reacting for 1 hour at 0°C in 5 ml of water, water was added to remove the precipitated insoluble
The material was filtered and washed with water. The obtained crystals were vacuum dried, and 1.
3-dimethyl-6-(4-(3-(2-cyano-4-di
trophenyloxy)propyl]piperazin-1-yl
) -2,4(IH,3H)-pyrimidinedione at 0.
I got 9g. Analysis result of the obtained crystal of this pyrimidinedione derivative NMR (CDC13) δppm: 2.1 (m, 2
H), 2.6-3.0 (m. 10H), 3.3 (s, 3H), 3.35
(s. 38), 4.6 (t, 2)1), 5.1
(s. IH), 7.5 (d, IH), 8.6 (
m. 2H) Next, 0.9 g of this pyrimidinedione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(4-(3-(2-cyano-4nitrophe)
nyloxy)propyl]piperazine=1-yl) -2
,4(+)1,3H)-pyrimidinedione oxalate
0.87 g of crystals of (Compound 155) were obtained. Analysis results of the obtained crystals of compound 155 mp, 191~
193℃ (decomposition) Elemental analysis value C2゜)lz4Na01(COOH)13
Calculated value (%) as 8zO: C4B, 15. N5.
63. N14.68 analysis value (%): C4S, 89
．． N5.3B, N14.29IRνK"(cm-')
: 2200.1680.1630.1600.15
80°aX +520.1340.840 Example 99 1.3-dimethyl-6-(4-[3-(2-cyano-4
-nitroanilino)propyl]piperazin-1-yl)
-2,4(1)1,38)-pyrimidinedione
Production of urate salt (compound 156) (+) 1.3-dimethyl-6-[4-(3-amino)
propyl) piperazin-1-yl”J-2,4(IH
,3H)-pyrimidinedione (compound 158):
18.52 g of potash phthalimide and 1,3-dibromo
200g of propane to 100ml of dimethylformamide
The suspended liquid was heated and stirred at 120°C for 6 hours, and then
Next, insoluble matter was filtered from the resulting reaction mixture.
The filtrate was concentrated to dryness under reduced pressure. Wash the residue with hexane.
After cleaning, recrystallization from ethanol-water yielded
The crystals are collected by filtration, washed and dried to give N-(3-bromopropylene).
13.8 g of phthalimide was obtained. Next, this N-(3-bromopropyl)phthalimide
13.0 g, 1,3-dimethyl-6-(1-piperazi
)-2,4(IH,3H)-pyrimidinedione (
compound +57) 10.3g and triethylamine 20
A suspension obtained by suspending g in 200 ml of dioxane
The liquid was heated to reflux for 6 hours. Furthermore, insoluble matter was filtered from the obtained reaction mixture, and the filtrate was
Concentrate to dryness under reduced pressure, and dissolve the residue (concentrated to dryness) in ethyl acetate.
- Recrystallize from n-hexane, collect the obtained crystals by filtration, and wash.
Clean, dry and give 1,3-dimethyl-6-[4-(3-ph).
taloylaminopropyl)piperazin-1-yl]-2
,4(IH,31()-pyrimidinedione 1.25g
Obtained. Next, 12.5 g of this crystal and 6.0 g of hydrazine hydrate
g in 200ml of ethanol! Q Add the cloudy liquid for 4 hours.
Heat under reflux, and after cooling, insoluble matter generated is filtered off, and the filtrate is depressurized.
The mixture was concentrated to dryness. Furthermore, the residue ('a condensed to dryness) was added to water.
Dissolve it, add dilute hydrochloric acid to adjust the pH to about 3, and then
The insoluble matter generated during the process is removed by filtration, and the filtrate is added with potassium carbonate.
After adding a large amount of aluminum, this was extracted with chloroform. After the extraction operation is completed, the obtained organic layer is added to anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the 1,3-di
Methyl-6-[4-(3-aminopropyl)piperazine
-1-yl-]-2,4(1)I, 3)1)-pyrimi
Zindione (Compound 158) 6.80g as a colorless white powder
It was obtained as a cup. This can be achieved by using the device at night.
Crystallized. Analysis results of the obtained crystals of compound 158 mp, 85-8
8°C NMR (CDCIs) δppm: 1.58 (br,
2) 1), 1.66 (m, 2) 1). 2,48 (t, 2H), 2.59 (m, 4
H). 2,78 (t, 2H), 2.97 (m, 4
H). 3, 32 (s, 3H), 3.38 (s, 3
H). 5,24 (s, IH) (2) 1,3-dimethyl-6-(4-[3-(2-syl)
Ano-4-nitroanilino)propylcopiperazine-1
-yl) -2,4(1)1.3)1)-pyrimidine di
0.3 g of compound 158 obtained from the manufacturer of on oxalate (compound 156) and 2-chloro-5 nitrate
Lobenzonitrile 0.3 g, triethylamine 0.
31 ml in 5 ml of dimethylformamide at 80°C.
The reaction solution was stirred for an hour, concentrated under reduced pressure, and the residue was purified using silica gel.
Column chromatography purification (chloroform/methanol =
40/1 volume ratio) 1.3-dimethyl-6-(4-(3-
(2-cyano-4-nitroanilino)propyl]pipera
di-l-yl)-2,4(1)1.3H)-pyrimi
0.4 g of jindione was obtained. Analysis result of this pyrimidinedione derivative obtained NMR (CDCIs) δppm: 2.0 (m
, 2H), 2.6-3.3 (m. 12) 1), 3.35 (s, 3H), 3.
45 (s. 3H), 5.33 (s, IH), 7.28
(m. H1), 8.4~B, 6 (m, 2) 1) Then
, 0.4g of this biwamidinedione derivative was mixed with oxalic acid/
Treat with methanol solution in a conventional manner to obtain 1,3-dimethylene
Ru-6-(4-(3-(2-cyano-4-nitroanili)
(n) propylcopiperazin-1-yl) -2,4(I
H,3H)-pyrimidinedione oxalate (compound 1
0.41 g of crystals of 56) were obtained. Analysis results of the obtained crystals of compound 156 mp, 156~
158℃ (decomposition) Elemental analysis value C2゜H*5Ny04・(COOH) 1
Calculated value (%) as 8to: C49, 41, N5.
43. N17.94 analysis value (%'): C49.3
4, N5.46. N18.31Br-IRV,,, (cm'): 77g13. ij,
iQo total 09o5530.1340゜Example 1 [10 1,3-dimethyl-6-(4-[3-(2-chloro-4
-nitroanilino)propylcopiperazin-1-yl)
-2,4(IH,3)1)-pyrimidinedione
Production Example 99 of Urate Salt (Compound 159) - 0.4 g of Compound 158 obtained in (1)
3゜4-dichloronitrobenzene 0.4 g, )ri
Ethylamine 0.43ml. Mix 6 ml of DMF
The material was treated in the same manner as in Example 99-(2), and 1.3-di
Methyl-6-(4-[3-(2-chloro-4-nitroa)
(nilino)propylcopiperazin-1-yl) -2,4
(1)1.3) 0.55g of 1)-pyrimidinedione was obtained.
Ta. Analysis result of this pyrimidinedione derivative obtained NMR (CDCIs) δppm: 2.0 (m, 2
H), 2.5-3.3 (m. 10H), 3.28 (s, 3H), 3.3
9 (s, 3H), 3.4 (m, 2H),
5, 23 (s, IH), 6.77 (m, I
JI), 8.11 (m, lH), 8.20
(m, lH) Next, 0 of this pyrimidinedione derivative
．． Treat 5g with oxalic acid/methanol solution according to conventional method.
and 1,3-dimethyl-6-(4-[3-(2-chloro
-4nitroanilino)propylcopiperazin-1-yl
)-2,4(1)1.3)1)-pyrimidinedione cy
0.53 g of crystals of oxalate (compound 159) were obtained.
Analysis result mp of the obtained crystal of compound 159, 153-155°C (decomposition) Elemental analysis value C+JisCINeO4・(COO)1)
Calculated value (%) as 12.5H*0: C44,10,N
5.64. N14.69. CI 6.20 Analysis value (%
): C44, 14, H5, 20°N 14.63.
CI 6.13 1530.1330,800,740 Example 101 1.3 Monodimethyl-6-(4-[3-(2-methoxy-5 nitrophenyloxy) propyl] piperazin-1-yl) -2,4 (1)1.3)1)-pyrimidinedione/hydrochloric acid
Preparation of salt (Compound 160) HCI/C) 1308 (Compound 160) 2-methoxy-5-nitrophenol 0.9 g, 1.3
-dimethyl-6-(4-(3-hydroxypropyl)pi)
perazin-1-yl]-2,4(1)1.3H)-p
rimidinedione (compound 139') 1.0 g,
1.1 g of triphenylphosphine was added to anhydrous tetrahydrofosphine.
Suspended in 20ml of run, 0.0% diethyl azodicarboxylate.
Example 84-(2
) to give 1,3-dimethyl-6-(4-[
3-(2-methoxy-5-nitrophenyloxy)pro
pyrcopiperazin-1-yl) -2,4(IH,3H
)-pyrimidinedione (1.2 g) was obtained as an oil. Analysis results of the obtained pyrimidinedione derivative NMR (CDCls) δppm: 2. +5 (m
, 28), 2.5-3.2 (m. 10H), 3.3 (s, 3H), 3.4
(s, 3H)3, 97 (s, 3)1), 4.
23 (t, 2H). 5,26 (s, IH), 6.96 (d, I
H). 7,86 (m, 2H) Next, 1.1 g of this pyrimidinedione derivative was added to 10%
Treated with HCI/methanol solution according to a conventional method, 1.3
-dimethyl-6-(4-[3-(2-methoxy-5-di
Trophenyloxy)propylcopiperazin-1-yl
) -2,4(IH,3H)-pyrimidinedione/hydrochloric acid
1.17 g of crystals of the salt (compound 160) were obtained. Analysis results of the obtained crystals of compound 160 mp, 15
8-162℃ (decomposition) Elemental analysis value C2゜HzvNaOs・HClToQ
Calculated values (%): C49.23, H6.20, N14.
35. CI 7.27 Analysis value (%): C49.04,H
6, 28, N14.26. CI 7.541350.1
260,1010,810,770 Example 102 1.3-dimethyl-6-(4-[3-(2-allylox
C-4-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(IH,3)1)-pyrimidine
Preparation of dione hydrochloride (compound 161) HCI/CH,0H 0 (1) Preparation of 2-allyloxy-4-ditrophenol 1.7 g of 4-nitrocatechol, 0.0 g of allyl alcohol.
74ml, triphenylphosphine 2.4g anhydrous tet
Suspend in 40ml of lahydrofuran and
After adding 1.5 ml of ethyl and stirring at room temperature for 11 hours, silica
5 g of gel was added and concentrated under reduced pressure. Dab the residue with silica gel
Muchromato purified hexane/ethyl acetate = 3/1 volume
ratio) 2-allyloxy-4-nitrophenol oil
1.5g was obtained. The analysis result of this phenol derivative obtained is NMR (CD
CIs) δppm: 4.76 (m, 2H), 5.2
2 (m, IH). 5,35 (m, IH), 5.96 (m, 1
)1). 6,99 (d, IH), 7.91 (m, 2
)1)(2) 1.3-dimethyl-6-(4-(3-(
2-allyloxy-4-nitrophenyloxy)propyl
rucopiperazin-1-yl)-2,4(II(,3H
)-pyrimidinedione hydrochloride (compound 161)
2-allyloxy-4-nitrophenol 1.5
g, 1,3-dimethyl-6-[4-(3-hydroxy
propyl)piperazin-1-yl]-2,4(IH,
3) 1)-pyrimidinedione (compound 139) 1.
0 g, l-rifelphosphine 1.1 g in anhydrous tea.
Disturbed by 20ml of trahydrofuran, azodicarboxylic acid
Example: A mixture prepared by adding 0.67 ml of diethyl
84- Treat in the same manner as (2) to obtain 1,3-dimethyl-
6-(4-(3-(2-allyloxy-4-nitrophe)
nyloxy)propylcopiperazin-1-yl) -2
,4(IH,3H)-pyrimidinedione (compound 161
1.1 g of an oily substance was obtained. This pyrimidinedione derivative (compound 161) obtained
NMR (CDCIs) δppm: 2.1 (m, 2
H) 2.5-3.3 (m. 10H), 3.35 (s, 3H), 3.4
3 (s, 3H), 4.76 (m, 211)
, 5.3 (s, IH), 5.6 (m, 2H), 6.
15 (m, IH), 7.0 (m, 1)1)
, 7.8 (m, 28) Next, 0.5 g of this pyrimidinedione derivative was added to 10%
Treated with HCI/methanol solution according to a conventional method, 1.
3-dimethyl-6-(4-[3-(2-allyloxy-
4-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,31()-pyrimidinedio
0.4 g of crystals of N. hydrochloride (Compound 161) were obtained. Analysis results of the obtained crystals of compound 161 mp, 134~
136℃ (decomposition) Elemental analysis value C2□)IzsNsOa・)ICI・2.
Calculated value (%) as 5H20: C48,84,H6,5
2, NI2.95. CI 6.55 analysis value (%):
C48, 97, H6, 27°N 12.74. C1 6,75 1340, 1280, 1090, 810, 760 Examples
103 1.3-dimethyl-6-(4-(3-(2-hydroxy)
-4-nitrophenyloxy)propylcopiperazine-
1-yl) -2,4(IH,3H)-pyrimidinedio
HC1/C) 1308 (Compound 162) Example 102, - 1,3-dimethyl-6 obtained in (2)
-(4-(3-(2-allyloxy-4-nitropheny)
(oxy)propylcopiperazin-1-yl)-2,4
(IH,3H)-pyrimidinedione (compound 161)
Dissolve 0.6g of 10ml of methanol,
%Pd/activated carbon 0.1g, p-1 luenesulfonic acid -
Add 0.1 g of hydrate and 2 ml of water and heat for 15 hours while stirring.
It refluxed. After cooling, insoluble materials were removed by filtration, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography and purified with chloroform.
m/methanol = 50/1 volume ratio) l, 3-dimethyl-
6-(4-[3-(2-hydroxy-4-nitropheny)
((oxy)propylcopiperazin-1-yl) -2,
4(11(,3H)-pyrimidinedione 0.4g was obtained.
. Analysis result of this pyrimidinedione derivative obtained NMR (C, DC13) δppm: 2.15 (m,
21 (), 2.7-3.3 (m. 10H), 3.34 (s, 3H), 3.4
3 (s. 3) 1), 4.13 ft, 2H), 5.3
4 (s. 1) 1), 7.0 (m, 1) 1), 8.03 (m. 21 ()) Next, 0.4 g of this pyrimidinedione derivative was added to 10%
Treated with hydrochloric acid/methanol solution according to a conventional method to obtain 1.3-
dimethyl-6-(4-[3-(2-hydroxy-4-di
Trophenyloxy)propylcopiperazin-1-yl
) -2,4(IH,3)1)-pyrimidinedione salt
0.33 g of amorphous powder of the acid salt (Compound 162) was obtained. Analysis result of the obtained crystal of compound 162 Elemental analysis value C
+oH2sNsOa・) Totaled as ICI-1,5820
Calculated value (%): C47.26, H6.05, N14.05
．． CI 7.34 analysis value (%): C47,53,H6,
21, N13.75. C17, 9 Example 104 1.3-dimethyl-6-(4-[3-(2-benzyl acetate)
Mino-4-nitrophenyloxy)propylcopiperazi
(1-yl)-2,4(IH,3H)-pyrimidine
Production of dione oxalate (compound 163) (1) 2-benzylamino-4-ditrophenol
Preparation of 2-amino-4-nitrophenol 4.4 g, benzua
Rudehyde 5.2g% p-toluenesulfonic acid-hydrate
Dissolve 0.4g in 300ml of benzene and remove the water.
The mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was
Xane was added and the precipitated crystals were collected by filtration to obtain 6.6 g of crystals. child
The crystals were dissolved in 55ml of dimethylformamide and cooled with water.
Add 2.2g of sodium borohydride and leave at the same temperature for 2 hours.
Stirred. Add ether to this reaction solution and make the ether solution
After washing with water, drying with anhydrous sodium sulfate, and distilling off the solvent.
4.2 g of 2-benzylamino-4-nitrophenol
Obtained. This 2-benzylamino-4-nitrophenol was subjected to the next reaction without purification.
NMR (CDCl2) δppm: 4.5 (s,
2H), 6.8-7.0 (d1)1), 7.3-7
．． 6 (m, 2H). 7,4 (s, 1)1) (2) 1.3-dimethyl-6-(4-(3-(2-
benzylamino-4-nitrophenyloxy)propyl
Copiperazin-1-yl) -2,4(1)1.3H)
-Production of pyrimidinedione oxalate (compound 163)
Manufactured 2-benzylamino-4-nitrophenol 0.7g
, 1,3-dimethyl-6-[4-(3-hydroxypropylene)
(ropyru)piperazin-1-yl) -2,4(1)I,
3H)-pyrimidinedione (compound 139) 0.
8 g, triphenylphosphine 0.9 g in anhydrous tetra
Suspend in 20ml of hydrofuran and add azodicarboxylic acid diethyl
Example 84- The mixture prepared by adding 0.65 g of chilli
Treated in the same manner as (2), 1,3-dimethyl-6-(
4-[3-(2-benzylamino-4-nitrophenyl
oxy)propylcopiperazin-1-yl)-2,4(
IH, 3) 0.93 g of Ri-pyrimidinedione crystals
Obtained. Analysis result of this pyrimidinedione derivative obtained NMR (CDCl2) δppm: 2.05 (m, 2
H, 2, 6 (m, 6H). 2,95 (m, 4H, 3,3(s, 3H). 3,35 (s, 3H), 4.15 (t, 2
)1). 4, 35 (d, 2H, 4, 8 (m, 1) 1). 5,25 (s, 1) I) 6.75 (d, 1) I)
. 7, 2-7.45 (m, 1) 1). 7, 35 (s, 5H), 7.6 (m, IH
) Next, 0.8 g of this pyrimidinedione derivative was
Treated with uric acid/methanol solution according to a conventional method to obtain 1.3-
dimethyl-6-(4-(3-(2-benzylamino-4
-nitrophenyloxy)propylcopiperazine-1-
-2,4(1)1.3H)-pyrimidinedio
0.81 g of crystals of oxalate (compound 163) (
85%) was obtained. Analysis result of the obtained crystal of compound 163 Elemental analysis value C
zJsJaol(COOH) t・0.5t120
Calculated value (%): C55, 35, H5, 81, N1
3.83 Analysis value (%): C55,73, H5,78
, N13.87 Example 105 1.3-dimethyl-6-(4-(3-(2-methoxy-
4-nitrophenyloxy)propylcopiperazine-1-
-2,4(1)I, 3)1)-pyrimidine
Preparation of On hydrochloride (Compound 164) (1) Preparation of 2-methoxy-4-nitrophenol 50 g of 2-amino-5-nitroanisole and sodium hydroxide
Dissolve 50g of aluminum in 450ml of water and heat under reflux for 3 hours.
did. Cool on ice, collect the precipitated crystals by filtration, and dissolve them in water.
After neutralization with 6N hydrochloric acid, the precipitated crystals were collected by filtration.
(Also, dissolve these crystals in chloroform, wash with water, and then
Dry with sodium sulfate and concentrate the chloroform layer under reduced pressure.
2-methoxy-4-nitrophenol by condensation
4.5 g of crystals were obtained. The amount of this 2-methoxy-4-nitrophenol obtained
Analysis result mp, 102-103°C (2) 1.3-dimethyl-6-(4-[3-(2-
methoxy-4-nitrophenyloxy)propyl copy paste
Radin-1-yl)-2,4(IH,3)1)-pyri
Preparation of midinedione hydrochloride (compound 164) 2-methoxy-4-nitrophenol 0.68 g. 1,3-dimethyl-6-[4-(3-hydroxypropyl)
) piperazin-1-yl't-2,4(IH, 31
1)-pyrimidinedione (compound 139) 1.0
g, 1.1 g of triphenylphosphine in anhydrous tetrahydride
Suspended in 20 ml of Lofuran, diethyl azodicarboxylate
Example 84-(
2), and then recrystallize using methanol.
1,3-dimethyl-6-(4-(3-(2
-methoxy-4-nitrophenyloxy)propylcopy
perazin-1-yl) -2,4(1)l, 3)1)
-1.35 g of crystals of pyrimidinedione were obtained. Analysis results of this pyrimidinedione derivative obtained NMR (CDCIs) δppm: 1.9-3.3 (
m, 12H). 3, 43 (S, 3) 1), 3.5 (s, 3
)1). 4,06 (s, 3H), 4.26 (t, 2
! (). 5.35 (s, 11(), 7.05 (d,
IH). 7,8-8.15 (m, 2H) Next, 1.3g of this pyrimidinedione derivative was added to 10%
Treated with HCI/methanol solution according to a conventional method, 1.
3-dimethyl-6-(4-(3-(2-methoxy-4-
Nitrophenyloxy)propylcopiperazine-1-y
-2,4(1)1.3)1)-pyrimidinedione
- 1.17 g of crystals of hydrochloride (compound 164) were obtained. Analysis results of the obtained crystals of compound 164 mp, 135~
138℃ Elemental analysis value C2゜Hx7NsO-・)ICI-1,5
Calculated value (%) as H,0: C48,34, H6,29
, N14.09. CI 7.13 analysis value (%): C48
, 20, H6, 61, N14.27. CI 7.38 fruit
Example 106 1,3-dimethyl-6-(4-[3-(2,6-dichloro)
rho-4-nitrophenyloxy)propylcopiperazine
-1-yl) -2,4(IH,3H)-pyrimidine di
1cI/CH,ON (Compound 157) (1) 1-Bromo-3-(2,6-dichloro-4-
Preparation of nitrophenyloxy)propane 2.4.16 g of 6-dichloro-4-ditrophenol,
1,3-dibromopropane 40.4g, potassium carbonate 2
．． 76 g% t-butoxypotassium (2,46 g)
The mixture was heated to reflux in 50 ml of methyl ethyl ketone for 4 hours.
The reaction solution was filtered off after being allowed to cool. Concentrate the filtrate under reduced pressure to remove the residue.
Dissolve the residue in chloroform, wash with water, and then distill off the chloroform.
did. The obtained residue was purified by silica gel column chromatography.
(Chloroform/hexane = 4/1 volume ratio)
mo-3-(2,6-dichloro-4-nitrophenyloxy)
c) 6.24 g of propane was obtained. This compound is
It was used in the next reaction without further purification. (2) 1,3-dimethyl-6-(4-[3-(2,
6-dichloro-4-nitrophenyloxy)propylco
piperazin-1-yl) -2,4(1)1.3)1)
-Production of pyrimidinedione hydrochloride (compound 165)
4.94 g of trophenyloxy)propane, 1.3-
Dimethyl-6-(l-piperazinyl)-2,4(IH
,3H)-pyrimidinedione (compound 157) 3
．． 36 g, triethylamine 4 ml dioxane 100
The solution was dissolved in ml and stirred under heating under reflux for 2 hours. Reaction after cooling
The liquid was filtered to remove insoluble materials, and the filtrate was dried under reduced pressure to obtain the
The residue was dissolved in chloroform. Chloroform solution in water
After washing, the solvent was distilled off and the residue was purified by silica gel chromatography.
Chloroform/methanol Lumi 10010-2 volume ratio
〉, further recrystallized using ethanol to obtain 1.3
-dimethyl-6-(4-(3-(2,6-dichloro-4
-nitrophenyloxy)propylcopiperazine-1-
-2,4(1)1,3H)-pyrimidinedione
3.57 g of crystals were obtained. Analysis results of the obtained pyrimidinedione derivative NMR (CDCIs) δppm: 1.95-2.2
5 (m, 2H), 2.5~2,8 (m, 6N)
, 2.9-3.1 (m. 4H), 3.3 (s, 3H), 3.4 (
s, 38) 4, 2 (t, 21(), 5.35
(s, IH). 8,25 (s, 2)1) Next, 0.5g of this pyrimidinedione derivative was added to 10%
1 (treated with C1/methanol solution according to a conventional method, 1.
3-dimethyl-6-(4-[3-(2,6-dichloro-
4-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(1)1,3H)-pyrimidinedio
0.45 g of crystals of N. hydrochloride (Compound 165) were obtained. Analysis results of the obtained crystals of compound 165 mp, 200~
202℃ Elemental analysis value CreH2sCI□N5011 (CI・0
．． Calculated value (%) as 25LO: C44, 46, H4,
81, N13.64. C120,72 analysis value (%):
C44,47,H4,87,N 13.55. C.I.
20.73 Example 107 l,3-dimethyl obtainable by the method of Example 85
Chil-6-(4-[3-(4-chloro-2-nitrophe)
nyloxy)propylcopiperazin-1-yl) -2
,4(IH,3H)-pyrimidinedione hydrochloride (compound
Production of tablets containing substance 140) as an active ingredient: the pyrimidine
Dione derivative/hydrochloride (compound 140) Ig, lactose 12
Mix well 3g and 20g of corn starch,
Add 5g of hydroxypropyl cellulose to 1OOI of water.
Mix and granulate with the solution dissolved in T+1 and dry at 50°C for 4 hours.
did. Add 1g of magnesium stearate to this.
Mix thoroughly and use a tablet machine to make 150 mg per tablet.
Tablets were obtained by compression. Example tOa 1,3-dimethyl obtainable by the method of Example 86
Chil-6-(4-(3-(2-chloro-4-nitrophe)
nyloxy)propylcopiperazin-1-yl) -2
,4(11(,3H)-pyrimidinedione hydrochloride (chemical
Production of capsules containing Compound 141) as an active ingredient: The pyrimidinedione derivative/hydrochloride (Compound 141) 5
g, breasts f! 120g and 25g corn starch
Mix well and harden the resulting mixture using a capsule filling machine.
Capsules were filled to 150 mg to obtain capsules. Example 109 l,3-dimethyl obtainable by the method of Example 87
Chil-6-(4-[3-(4-methanesulfonamide-
2-nitrophenyloxy)propylcopiperazine-1
-yl) -2,4(IH,3H)-pyrimidinedione
・Production of injections containing hydrochloride (compound 142) as an active ingredient
Preparation: The pyrimidinedione derivative/hydrochloride (Compound 142)
Take 20ml and 0.85g of sodium chloride.
Dissolve this in an appropriate amount of distilled water for injection to make a total volume of 1゜Oml.
It was made into an injection. Pharmacological Test Example 7 In the same manner as Pharmacological Test Example 1, the above-mentioned substances shown in Table 14 were
A1) P? of each compound obtained in Examples B, and ERP
The results are shown in Table 14. Toxicity Test 7 Similar to Toxicity Test 1, the above examples shown in Table 15 were used.
The toxicity of each compound obtained was tested and the mortality rate of mice was determined.
I met. The results are shown in Table 15. The administration was 300 mg/g orally for each compound.
Administration (p,o,) was performed. Table 4 Pharmacochemical test results of new pyrimidine derivative A compound
15 Toxicity test results for novel pyrimidine derivative compounds Example 110 1.3-dimethyl-6-(2-[N-methoxycarbonyl
methyl-3-(4-nitroanilino)propylamino
coethylamino)-2,4(1)1.3H)-pyrimi
Production of jindione hydrochloride (compound 166) C) +3 Hs 2-aminoethanol 35.0 g Heating to 90°C,
Remove from oil bath and add 6-chloro-1,3-dimethyl-
2,4-(IH,3H)-pyrimidinedione 50.0g
were added and allowed to react. The addition at this time is
Perform at a speed that maintains the temperature within the range of 90-110°C.
I was disappointed. After the addition was complete and the reaction mixture was stirred for 10 minutes.
, to which dioxane/methanol (=10/1.volume ratio
) Add 300 m4 and add a small amount of the crystals obtained by incubating at night.
Wash with dioxane and dry 1,3-dimethyl-6
-(2-hydroxyethylamino)-2,4uH,3)
1) 49.0 g of white crystals of -pyrimidinedione were obtained. Next, 49.0 g of this white crystal in 200 ml of pyridine
2. The suspension was cooled to -5°C, and p-toluenesulfonate was added to it.
Reaction temperature of 40.0g of nil space chloride is 5℃ or higher.
added at a rate that does not increase. The suspension in the reaction solution has completely disappeared.
Add p-toluenesulfonyl space chloride to remove
51.0 g of lido was used. Furthermore, the obtained reaction mixture was added containing 70 g of KzCOs.
Pour into ice water at 1.5°C, set aside overnight, and collect the resulting crystals.
Collected by filtration, washed with water, and dried under reduced pressure to obtain 1,3-dimethylene.
-6-[2-(p-toluenesulfonyloxy)ethyl
Ruamino]-2,4(IH,3H)-pyrimidinedione
50.5 g of pale yellow crystals were obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: Melting point: 146.0-149.0°C IRyW:; (cm-'): 3270, 1682.16
15.1550, 1480°1435, 1360.11
90.1178.1010.903.780° obtained earlier
1,3-dimethyl-8-[2-(p-toluenesulfony)
2,4(IH,3H)-pyloxy)ethylamino]-2,4(IH,3H)-
47.2 g of anhydrous dimethyl sulfochloride of rimidinedione
6.24 g of 150% oily sodium hydride were gradually added. The resulting mixture was further stirred vigorously at room temperature for 5 hours.
Thereafter, the mixture was cooled and a small amount of water was added to stop the reaction. Charcoal
Pour into water containing 70 g of potassium acid at 1°C, and add chloroform.
Extracted 3 times with 200 mβ and combined organic layers with anhydrous sulfuric acid.
After drying with sodium and concentrating, ether was added to the resulting concentrate.
A 300 mf2 filter was added and the unit was turned off overnight. This night, the pale yellow crystals precipitated by the apparatus were collected by filtration, and
After washing, dry under reduced pressure to obtain 6-(1-aziridine).
15.2 g of 3H)-1,3-dimethyl-2,4(IH.3H)-pyrimidinedione (compound a) was obtained.
Ta. Analysis results of the obtained crystals of compound a: Melting point: 126.0-126.5°C 1305, 1160.783.490') I-NMR (CDC13), δppm: 2
．． 34 (s, 4) 1), 3.35 (s, 3H). 3,56 (s, 3H), 5.25 (s, I
H) 2.8g of 4-nitrofluorobenzene in propylene
29.6 g of diamine was heated to 80°C and stirred for 1 hour.
. The reaction mixture was poured into water, the precipitated crystals were collected by filtration, and N-(4-ni
3.6 g of crystals of propylene diamine (trophenyl) were obtained.
Ta. This N-(4-nitrophenyl)propylene diamine 1
．． 2g and 6-(1-aziridinyl) obtained in (2) above.
-1,3-dimethyl-2,4(IH,3H)-pyrimidine
1.1 g of dione (compound a) in chloroform 5n+j
2, the resulting mixture was concentrated under reduced pressure to obtain a residue.
Amberlyst 15 (manufactured by Rohm and Haas)
10 mg was added and stirred at 80°C for 1 hour. The resulting mixture
Dissolve the compound in chloroform 20mβ, add Amberlyst
After filtering off, the filtrate was washed with water, and the solvent was reduced after drying with sodium sulfate.
Crude 1,3-dimethyl-6-(2-
[3-(4-nitroanilino)propylaminoconityl
amino) -2,4(IH,3H)-pyrimidinedione
(Compound b) was obtained. What is obtained from this process is an impurity
contains, but it can be used in the next reaction without purification.
did. 1,3-dimethyl-6-(2-[3-
(4-nitroanilino) propylaminoconitylamino
) -2,4(2)1.3)1)-pyrimidinedione (
Dissolve 1.5 g of compound b) in DMSO12++I2
Methyl loroacetate 1.2g, triethylamine 1.5mI
2 was added, stirred at 50℃ for 2 hours, and dissolved in chloroform.
After washing with water, it was dried with mirabilite, and the solvent was distilled off under reduced pressure. Silica residue
Gel column chromatography purification (chloroform/methanol =
30/l, volume ratio) and 1,3-dimethyl-6-(2-
[N-methoxycarbonylmethyl-3-(4-nitro
(nilino) propylaminoconitylamino) -2,4(
1) 1.8 g of 1.3H)-pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (1) MSO-d6) δppm: 1.70 (
m, 2H). 2.6-2.9 (m, 4) 1), 2.95-3.4 (
m, 4H). 3, 25 (s, 3)1), 3.3 (s, 3
)1), 3.45 (s, 2)1). 3,65 (s, IH), 4.6 (s, I)
1), 6.45 (m, IH), 6.6 (
d, 2H). 7, 2 (m, 1) 1), 7.95 (d, 2
)1) Furthermore, 1.5 g of this pyrimidinedione derivative was constantly added.
1.3-
Dimethyl-6-(2-[N-methoxycarbonylmethyl
-3-(4-nitroanilino)propylaminoconityl
amino) -2,4(IH,3H)-pyrimidinedione
・Hydrochloride (Compound 166) 1.4 g amorphous powder
I got it. Elemental analysis value C2゜) IaaNsOa・HClHzO
Calculated value (%): C47.76, H6.21, N 1
6°71. CI 7.05 analysis value (%): C47.0
6, H5, 91, N 16.05. C17,58 implementation
Example 111 1.3-dimethyl-6-(2-[N-(2-acetoxy
ethyl)-3-(4-nitrophenyl)propylamino
conitylamino)-2,4(IH,311)-pyrimi
Production of jindione oxalic acid (compound 167) - C) 60 g of 13-(4-nitrophenyl)propionic acid was suspended in 360 mβ of chloroform, and 2.25 g of dimethylformamide was added to the reaction mixture.
Warm at ℃ and gradually drop thionyl chloride 33.5n+42.
After adding 0 drops, the mixture was heated under reflux for 1 hour, and the solvent was distilled off under reduced pressure.
The resulting oil is dissolved in 150 mβ of chloroform. Separately, add this chloroform solution to ethanolamine 28.
2 g and 42.5 g of potassium carbonate in 450 mI2 of water.
1 hour after the completion of 0 drops into the dissolved solution under water cooling
Stir and collect the precipitated crystals by filtration, which are further diluted with ethyl acetate.
N-(2-hydroxyethyl)-3
-(4-nitrophenyl)propionamide crystal 56
．． 1g was obtained. mp, 122-125°C N-(2-hydroxyethyl)-3-(4-ni
50 g of trophenyl) propionamide with boron hydride
31.8 g of thorium was dissolved in THF (tetrahydrofuran)
) Suspended in 500 mj2 and added dropwise with 50.5 g of acetic acid under water cooling.
After the completion of the dropwise addition, heat under reflux for 2 hours, cool again with water, and add 50% water.
0 ml was added dropwise. Add 4N hydrochloric acid to p) 15-6
THF was distilled off under reduced pressure, and 4N salt was added to the resulting aqueous solution.
Add 425 mj2 of acid and heat and stir at 60 to 70°C for 1 hour.
Stirred. After cooling, return to room temperature and wash with chloroform.
, pll the aqueous solution with 16% sodium hydroxide solution.
1 and extracted twice with 500 mβ of chloroform. By combining the chloroform extracts and concentrating under reduced pressure.
Crystallize the obtained residue using 900 mJ2 of toluene.
N-(2-hydroxyethyl)-3-(4nit)
Obtained 38.6 g of crystals of (lofenyl)propylamine.
. mp, 82.5-84,5°C 6-chloro-1,3-dimethyl-2,4(IH,3)1
)-pyrimidinedione 52.4g to pyridine 280mβ
45.5 g of triethylamine and aminoethylamine dissolved in
Add 21.3g of alcohol and heat and stir at 90℃ for 4 hours.
. The reaction solution was ice-cooled and kept at an internal temperature of 0 to 4°C, and methanesulfonyl
55.8 g of chloride was added dropwise, stirred at the same temperature for 3 hours,
To this was added 1.24 g of methanol, and the mixture was further stirred for 2 hours. The crystals precipitated in this reaction solution were collected by filtration, and further methanol
1.3-dimethyl by recrystallization with 3.5!2
-6-(2-methanesulfonyloxyethylamino)
-2,4(1)1,3)1)-pyrimidinedione (compound
70.0 g of crystals of substance C) were obtained. mp, 169-170°C 1,3-dimethyl-6-(2-methyl) synthesized in (3) above
tansulfonyloxyethylamino)-2,4(IH,
3) 20.2 g of 1)-pyrimidinedione (compound c) and
15.1g of potassium carbonate and 300mfl of acetonitrile
The suspension was suspended in water and heated under reflux for 4 hours. Remove insoluble matter by filtration and reduce the filtrate.
Concentrate under pressure to bring the total volume to about 60ml, and add the above (2) to this solution.
) N-(2-hydroxyethyl)-3-(4-
18g of (nitrophenyl)propylamine and 36m of DMF
4. 0.69 g of p-toluenesulfonic acid-hydrate
The acetonitrile was distilled off under reduced pressure, and the residue was heated at 80°C for 2 hours.
The mixture was heated and stirred for hours. The reaction solution was returned to room temperature and 0. INN
Add an aqueous solution of hydrochloric acid 90 to make it alkaline and stir at room temperature for 3 hours.
The crystals precipitated by stirring are collected by filtration and dried.
, 1,3-dimethylene was obtained by recrystallizing from ethanol.
Ru-6-(2-[N- (2-hydroxyethyl)-3
- (4-nitrophenyl)propylaminocoethyl acetate
Mino)-2. 4 (IH, 3H)-pyrimidinedio
Crystals of (compound d) 26. 6 g was obtained. mp. 125-126℃ 1,3-dimethyl-6-(2-(N-(2
-hydroxyethyl)-3- (4-nitrophenyl)
propylaminocoethylamino)-2.4(1)1.
1.6 g of 3H)-pyrimidinedione (compound d) and anhydrous
Dissolve 0.8 g of acetic acid in 5 mJ2 of pyridine and stir at room temperature for 2
After stirring for 4 hours, the reaction was further stirred at 60°C for 1 hour.
Pour the liquid into water, extract with chloroform, and pour the extract into water.
After washing, the resulting residue was purified using silica gel column chromatography.
Chloroform/methanol = 25/1-1
0/l, volume ratio) 1.3-dimethyl-6- (2- (
N-(2-acetoxyethyl)-3-(4-nitrophe
(propylaminocoethylamino) -2. 4
(IH. 3H)-pyrimidinedione crystals 1.65 g
I got it. Analysis results of the crystals of this pyrimidinedione derivative obtained
: mp. 90.5-92.0°C NMR (CDCIs) δppm: l'. 85 (
m, 2H), 2. 15 (s, 38). 2,5 ~3.3(n+,108), 3.26(s,
3H). 3, 37 (s, 3H), 4. 3 (t,
2H), 4. 78 (s, 1) 1). 7, 2-8. 2 (m, 4H) Next, this piri
165g of midinedione derivative in oxalic acid/methanol
1,3-dimethyl-6-
(2- (N- (2-acetoxyethyl)-3- (
4-nitrophenyl)propylaminocoethylamino)
-2.4(+)1.3)1) -pyrimidinedione・
1.6 g of crystals of oxalate (compound 167) were obtained. Analysis results of the obtained crystals of compound 167 Two-element analysis values
(,1)119NS08・(COO)1)1)120
Calculated value (%): C 49.73 H 5.9
9 N 12.61 Analysis value (%): C 50.22
H 5.75 N 12.98 Example 112 1,3-dimethyl-6- (2-[:N- (2-ben
zoyloxyethyl)-3- (4-nitrophenyl)
propylaminocoethylamino)-2. 4 (IH,
3H)-pyrimidinedione oxalate (compound 16
8> Production C) Is In the above Example 111-(5), in place of acetic anhydride,
The same process was carried out except that 1.6 g of aqueous benzoic acid was used, and 1
．． 3-dimethyl-6-(2- (N-(2-benzoyl)
(oxyethyl) -3-(4-nitrophenyl)propyl
1.85 g of 2.4(IH. 3H)-pyrimidinedione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDCIs) δppm: 1.93 (m, 2) 1
), 2.5-3.4 (m, 10) 1). 3,29 (s, 3H), 3.38 (s, 3
B), 4.45 (t, 2H). 4.77ft, 2)1), 7.0~8.2(m, 9H
) Next, 1.5 g of this pyrimidinedione derivative was
Treat with uric acid/methanol solution according to the conventional method, 1.3
-dimethyl-6-(2-(N-(2-benzoyloxy)
ethyl)-3-(4-nitrophenyl)propylamino
coethylamino)-2,4(lit. 3H)-pyrimidinedione oxalate (compound 16
1.4 g of crystals of 8) were obtained. Analysis results of the obtained crystals of compound 168 Two-element analysis values
Czslb+N5Os・(COOf() z・H2O and
Calculated value (%): C54,45H5,71N 11.
34 Analysis value (%): C54,90H5,55N 11.
55 Example 113 1.3-dimethyl-6-(2-<N-[2-(4-flu
(obenzoyloxy)ethyl] -3-(4-nitro
phenyl)propylamino〉ethylamino)-2,4(
Preparation H3 of IH,3H)-pyrimidinedione oxalate (compound 169) 1,3-dimethyl-6 obtained in Example 111-(4) above
-(2-[N-(2-hydroxyethyl)-3-(4-
nitrophenyl)propylaminocoethylamino) −
2,4(IH,3H)-pyrimidinedione (compound d)
1.0g and 0°8g of p-fluorobenzoyl chloride.
Dissolved in 5 ml of pyridine and stirred at room temperature for 12 hours.
After that, the reaction solution was poured into water and extracted with chloroform. After washing the extract with water, concentrate and filter the resulting residue with silica gel color.
Muchromato purified chloroform/methanol = 40/
1, volume ratio), 1.3-dimethyl-6-(2-<N-[
2-(4-fluorobenzoyloxy)ethyl]-3-
(4-nitrophenyl)propylamino>ethylamino
) -2,4(IH,3H)-pyrimidinedione 1.0
I got g. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDC13) δppm: 1.9 to 3.1 (m
, 12) 1). 3,29 (s, 1)() , 3.38 (3,3
8), 4.59 (t, 2H). 4.78 (t, 2H), 7.1-8.0 (m, 8H)
Next, 0.95 g of this pyrimidinedione derivative was added to the syringe.
Treated with oxalic acid/methanol solution according to a conventional method, 1.
3-dimethyl-6-(2-<N-[2-(4-fluoro
benzoyloxy)ethyl]-3-(4-nitropheny)
propylamino>ethylamino)-2,4(1)1
, 3) 1)-pyrimidinedione oxalate (compound 1
1.07 g of crystals of 69) were obtained. Analysis results of the obtained crystals of compound 169=mp, 96~
99℃ (decomposition) Elemental analysis value C*5HsoNJaF・(Coo1)12
1 (calculated value (%) as 20: C51,4585,55
N 10.71 Analysis value (%): C51,82H5,40
N 10.821620, 1530. 1330.
1000. 850. 760 Example 114 1.3-dimethyl-6-(2-<N-[2-(4-meth)
xybenzoyloxy)ethyl]-3-(4-nitroph
(enyl)propylamino〉ethylamino)-2,4(I
H, 3) 1)-pyrimidinedione oxalate (compound
170) Production of p-fluorobenzoyl chlora in Example 113 above
p-methoxybenzoyl chloride is used instead of
Treated in the same manner except that 1,3-dimethyl-6'-
(2-<N-[2-(4-methoxybenzoyloxy)
ethyl]-3-(4-nitrophenyl)propylamide
〉ethylamino)-2,4(IH,3H)-pyrimidine
1.1 g of dione was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDCIs) δppm: 2.0 (m, 2H),
2.4-3.0 (n+, 10H). 3, 31 (s, 3H), 3.42 (s, 3
H), 3.50 (s, 3H). 4, 4 (t, 2H), 4.77 (s, 1)
1), 5.31(br,1)I). 7.18 (m, 4) 1), 8.0 (m, 4) 1) then
, 1.0 g of this pyrimidinedione derivative was mixed with oxalic acid/
Treat with methanol solution according to a conventional method to obtain 1,3-dimethyl
Chil-6-(2-<N-[2-(4-methoxybenzoy
(oxy)ethyl]-3-(4-nitrophenyl)pro
Pyramino〉ethylamino) -2,4(1)1.3)
1)-pyrimidinedione oxalate (compound 170)
1.05g of crystals were obtained. Analysis results of the obtained crystals of compound 170: Elemental analysis values
C27H33NSO?・(COO)I) 2・0.51
(Calculated value (%) assuming 20: C54, 54H5, 68N
10.97 Analysis value (%): C54,21) 15.99
N 10.921520, 1350. 1250
．． 1020. 850. 760 Example 115 1.3-dimethyl-6-(2-[N-(2-methoxyethyl)
(thyl)-3-(4-nitrophenyl)propylaminoco
ethylamino)-2,4(IH,3H)-pyrimidine di
Production of on oxalate (compound 115) (COOH)
i/C)IsO)1 3-(4-nitrophenyl)propyl p-toluene
Ruphonate 1g 12-methoxyethylamine 6.5mβ
and 5 nu of dioxane was heated to reflux for 3 hours.
After that, add 100 mI2 of chloroform, wash with water, and then add anhydrous sulfuric acid.
Dry with sodium. In the resulting chloroform solution
Example with 10 mg of p-toluenesulfonic acid! 10- (
6-(l-aziridinyl)-1,3-dimethylene obtained in 2)
-2,4(IH,3H)-pyrimidinedione (compound
a) 0.54 g was added, and the solvent was distilled off under reduced pressure. This mixture
Heat something at 80℃ for 2 hours, cool it, and let it return to room temperature.
Silica gel column chromatography purification (chloroform/meth)
1,3-dimethyl-6-
(2-(N-(2-methoxyethyl)-3-(4-ni)
trophenyl) propylaminocoethylamino) -2
,4(IH,311)-pyrimidinedione oil 0.
82 g of the resulting pyrimidinedione crystals were obtained.
Analysis results: NMR (CDCIs) δppm: 1.9 (m, 2H),
2.4-3.6 (m, 12H). 3, 23 (s, 3)1), 3.30 (s,
3)1), 3.33 (s, 3)1). 4.71 (s, IH), 5.74 (br, IH), 7
．． 19(d, 2H). 8,03 (d, 2H) Next, 0.80 g of this pyrimidinedione derivative was added to the syringe.
1. Treat with an acid/methanol solution according to a conventional method.
．． 3-dimethyl-6-(2-(N-(2-methoxyethyl)
)-3-(4-nitrophenyl)propylaminochoe
thylamino)-2,4(1)1.3H)-pyrimidine
Dione oxalate (compound 171) crystals at 0.85
I got g. Analysis results of the obtained crystals of compound 171: Elemental analysis values
CaoH2, N5O1(COO)I) 1HJ and shite meter
Calculated value (%): C50,09H6,31N 13.28 minutes
Analysis value (%): C50, 14H6, 39N 13.30I
RvKBr(am-'): 3300.3000.16
80.1630°aX 1510, 1430. +350.1200.770.
700 Example 116 1.3-dimethyl-6-(2-[N-benzyl-3-(
4-nitrophenyl)propylamine] ethylamino)
-2,4(IH,3H)-pyrimidinedione (COO
N) 2/CH30)1 Substituted for 2-methoxyethylamine in Example 115
Using 0.36 mJ2 of benzylamine,
Same procedure except adding 1 ml of ethylamine.
, 1,3-dimethyl-6-(2-[N-benzyl-3
-(4-nitrophenyl)propylaminocoethylamide
-2,4(II(,3H)-pyrimidinedione) 1.
6g was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR (CDC13) δppm: 2.0 (m, 2H
), 2.4-3.3 (m, 8) 1). 3.21 (s, 3H), 3.25 (s, 3H), 3
．． 58(s, 2) 1). 4,67 (s, IH), 5.22 (br,
1) I), 7.22 (d, 2H). 7, 30 (s, 5H), 8.03 (d, 2
)1) Next, 1.50 g of this pyrimidinedione derivative
was treated with an oxalic acid/methanol solution according to a conventional method,
1,3-dimethyl-6-(2-[N-benzyl-3-
(4-nitrophenyl)propylaminocoethylamino
)-2,4(IH,3H)-pyrimidinedione shu
1.55 g of crystals of the acid salt (Compound 172) were obtained. Analysis results of the obtained crystals of compound 172: Elemental analysis values
CiJgJs04・(COOH)tJ, 5)1*O
Calculated value (%): C56,72H5,86N 12
．． 72 analysis value (%): C56,4+) 15.82
N 12.24I RvKB'(cm-'): 330
0.2950.1680.1630°ax 1540, 1340. +200.770.700 implemented
Example 117 1.3-dimethyl-6-(2-[N-(t-butoxyca
nyl)-3-(4-nitrophenyl)propylamide
Nocoethylamino)-2,4(IH,3)1)-pyrimi
Production of jindione (compound 8) 3-(4-nitrophenyl)propionyl chloride 2
A solution of 1 g dissolved in 30++ liters of chloroform is poured into a concentrated aqueous solution.
Drop into a mixture of 75 mI2 of ammonia water and 75 mI2 of ice water.
After that, the mixture was stirred for 2 hours under water cooling. Filter the precipitate,
Air-dried and recrystallized from ethyl acetate to obtain 3-(4-nitrophyte).
13.7 g of phenyl)propanamide were obtained. This amide form io, o g and sodium borohydride 9
．． Suspend 5g in 250nl of dioxane, add acetic acid at 15m℃
was added dropwise and stirred under reflux for 10 hours. Methanol in the reaction solution
10111J2 was added, concentrated to dryness, and the residue was dissolved in chloroform.
After washing with water and concentrating to dryness, 3-(4-nitrophenylate) was obtained.
6.0 g of propylamine oil was obtained. This compound
was subjected to the next reaction without further purification. NMR (CDCl2) δppm: 1.9 (m, 2) 1)
, 2.4-3.0 (m, 4H). 6.70 (br, 28), 8.21 (d, l11),
8.10(d,2H) 3-(4-ni) obtained in (1) above
6.0 g of trophenyl)propylamine and Example n above.
o - 6-(1-aziridinyl)-1,3 obtained in (2)
-dimethyl-2,4(lH,3)1)-pyrimidinedio
(compound a) 3.98g in chloroform 50mI2
After dissolution, the resulting mixture was concentrated under reduced pressure and the residue was
- Add 50 mg of toluenesulfonic acid and heat at 90°C for 2 hours.
Stirred. This mixture was diluted with tetrahydrofuran 60+nj
2 and added 3.0 g of di-t-butyl carbonate.
After stirring at room temperature for 1 hour, concentrate and apply to a silica gel column.
Chromatographic purification (chloroform/methanol = 40/1)
1,3-dimethyl-6-(2-[N-(t-buto)
(oxycarbonyl)-3-(4-nitrophenyl)propyl
-2,4 (Ill, 31
1) -Crystal of pyrimidinedione (compound 173) 5.0
I got g. Analysis results of the obtained compound 173: mp, 111-112°C NMR (CDC13) δppm: 1.51 (s, 9N
), 1.9 (m, 2H). 2.5-3.0 (m, 6) 1), 3.3-3.4 (m
, 2) 1). 3,28 (s, 3)1), 3.36 (s,
3H), 4.68 (s, IH). 6,54 (br, IH), 7.39 (d,
2H), 8.20 (d, 2H) elemental analysis value C
Calculated value (%) as zzH□N, 06: C57,251
46,77N 15.17 Analysis value (%): C57,29
H6,76N 15.13 Example 118 1.3-dimethyl-6-(2-[N-(4-methoxybenzene)
nitrophenyl)-3-(4-nitrophenyl)propylamino
coethylamino) -2,4(IH,3H) -pyrimi
Zindione oxalate (preparation of compound 9) f-) ICIlo 0°C-(1) 1-dimethyl-6--14-nitrophenyl propylamino ethylamide Previous example
1,3-dimethyl-6-(2-[N-(t-butylene) obtained in step 8
carbonyl)-3-(4nitrophenyl)pro
pyraminocoethylamino) -2,4(II(,3)
1)-pyrimidinedione (compound 173) 4.9
Add 1 cI/dioxane (30 nl)
The mixture was stirred at room temperature for 24 hours. Filter the precipitate and convert it into ethanol.
By washing with a cold solvent of ether (1/2)
, 1,3-dimethyl-6-(2-[3-(4-nitroph)
phenyl)propylaminocoethylamino) -2,4(
IH,3H)-pyrimidinedione hydrochloride (compound e)
3.9 g of crystals were obtained. Analysis results of the obtained crystal of compound e: mp, 230-231°C (decomposition) Elemental analysis value C+, H*5Ns04・2) ICI-82
Calculated value (%) as 0: C45,14,H6,02,N
15.48. CI 15.68 Analysis value (%): C45
,31,115,87,N 15.54 C115,6
7(2) 1,3-dimethyl-6-2-N-4-meth
Obtained from xybenzyl-3-4-nitrophenyl (1)
1,3-dimethyl-6-(2-[3-(4-nitroph)
phenyl)propylaminoconitylamino) -2,4(
IH,3H)-pyrimidinedione hydrochloride (compound e)
Dissolve 1.4 g in 5 mI2 of water and add potassium carbonate.
The mixture was made alkaline and extracted with chloroform. The obtained
The loloform solution was concentrated to dryness, and the residue contained p-methoxy
Benzyl bromide 0.6g, triethylamine
Add 3 mI2 and 20+yl isopanol and heat for 8 hours.
It refluxed. The solvent was distilled off under reduced pressure and the residue was directly transferred to silica gel.
Column chromatography purification (chloroform/methanol = 40
/1, volume ratio) and 1,3-dimethyl-6-(2-(
N-(4-methoxybenzyl)-3-(4-nitrophe
propylaminoconitylamino)-2,4(1)
! , 0.55 g of 3H)-pyrimidinedione was obtained.
. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCl2) δppm: 2.0 (m, 2) 1
), 2.5-3.1 (m, 8H) 3.24 (s, 3
8), 3.30 (s, 30), 3.64 (s,
2H). 4.59 (s, IH), 5.16 (m, IH),
7.16 (m, 4H). 7,94 (m, 4H) Next, 0.52 g of this pyrimidinedione derivative was
Treated with oxalic acid/methanol solution according to a conventional method, 1.
3-dimethyl-6-(2-[N-(4-methoxybenzi
)-3-(4-nitrophenyl)propylaminoconi
thylamino) -2,4(IH,3H)pyrimidinedio
Obtained 0.54g of crystals of oxalate (compound 174).
Ta. Analysis results of the obtained crystals of compound 174: mp, 104
~106°C (decomposition) I RvKBr (cm-'): 3300.2950.1
710.1700゜max! 630.1520.1340.1250.10?0.
770.700 Elemental analysis value CzsHs+N501 (C
Calculated value (%) as OON)z4.5HJ: C54,1
8H6゜06N 11.70 Analysis value (%): C54
,,74H5,97N 11.37 Example 119 1.3-dimethyl-6-(2-[N-ethoxycarbonyl
(methyl)-3-(4-nitrophenyl)propylamide
noconitylamino)-2,4(IH,3H)-pyri
Preparation of midinedione oxalate (compound 175) In Example 118-(2) above, p-methoxyben
Ethyl bromoacetate 0.4mβ instead of dilbromide
1,3-dimethyl-6-(2
-(N-ethoxycarbonylmethyl)-3-(4-nito
lophenyl) propylaminoconitylamino) -2,
0.77 g of 4(IH,31()-pyrimidinedione)
Obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: NMR(CDC1,)δI)I)m+ 1.30 (
t, 3) 1), 1.9 (m, 2H). 2.4-3.0 (m, 6) 1), 3.0-3.4 (
m, 48). 3, 3 (s, 3H), 3.5 (s, 3)
() , 4.22 (q, 2H) 4.74 (s,
IH), 7.31 (d, 2H), 8.12 (d
, 2) 1) Next, 0.7 of this pyrimidinedione derivative
g with an oxalic acid/methanol solution according to a conventional method,
1,3-dimethyl-6-(2-[N-ethoxycarbo
Nylmethyl)-3-(4-nitrophenyl)propyla
minoconithylamino)-2,4(11(,3H)-bily
0 crystals of midinedione oxalate (compound 175)
．． Obtained 72 g. Analysis results of the obtained crystals of compound 175 = mp, 148
~149°C (decomposition) IR'm'a;(am-'): 293
0.2450. I 730. I 7 Q 01600.
1540. +340.1250. +200.850.
700 elemental analysis value C211 (29NSO8・(COO
H) Calculated value (%) as 10.5H20: C50.5
51 (5,90N 12.81 analysis value (%): C50,
89H5,81N 12.62 Example 120 1.3-dimethyl-6-(N-(2-phenylethyl)
-2-[3-(4-nitrophenyl)propylaminoco
ethylamino)-2,4(IH,3H)-pyrimidine
Production of dione hydrochloride (compound 176) 1 cl/C)
IsO) 1 CI (3 Phenethyl bromide 3ml 11. Ethanolamine 13
A mixture of mβ and isopropanol 15 mI2 for 2 hours.
Heat to reflux, and after cooling, add 50 ml of chloroform.
After washing with water and concentrating, 6-chloro-1,3 was added to the resulting oil.
-dimethyl-2,4(1)1,3H) -pyrimidine di
Add 3.5 g of onion and 3.3 m12 of triethylamine,
The solution was dissolved in 15 mn of DMF and stirred at 110°C for 4 hours. room temperature
Add 150 mβ of chloroform, wash with water, and concentrate.
The resulting oil is crystallized using ether.
By this, 1,3-dimethyl-6-[N-(2-hydro
(oxyethyl)-2-phenylethylamino]-2,4
4.1 g of (18,3)1)-pyrimidinedione crystals
I got it. Analysis results of the obtained crystals of this pyrimidione derivative: mp, 77-78°C NMR (CDCI31δppm: 2.4-3.2 (m
, 6H), 3.18 (s, 38). 3.22 (s, 3H), 3.50 (t, 2H), 5
．． 28(s, IH). 7, 18 (br, 5) 1) Elemental analysis value C + 5l (calculated value as z + N5Os (
%): C63,35) 16.98 N 13.85
Analysis value (%): C63,01H6,78N 13.9
1 solution of 0.26 mβ of oxalyl chloride and 5 parts of dichloromethane
Dissolved in n+12, cooled to -78°C, DMSOo, 2
1 mI2 of dichloromethane 5 mA solution was added dropwise. After stirring at the same temperature for 15 minutes,
Methyl-6-[N-(2-hydroxyethyl)-2-ph
phenylethylamino]-2,4(1)1゜3H)-p
0.6 g of rimidinedione in 10 mβ solution of dichloromethane
was added dropwise and further stirred for 15 minutes. After adding 0.84 mβ of triethylamine, the temperature was gradually increased to room temperature.
Return to room temperature, stir for 5 minutes, add 30mβ of chloroform, and add water.
After washing and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
0.51 g of oil was obtained. The obtained oil was dissolved in 10 mI2 of methanol.
Example 117-3-(4-nitrophenyl)propylene obtained in (1)
0.72 g of lopylamine and 4 N-HCl/dioxylene
After adding 0.5 mI2 of San and stirring at room temperature for 30 minutes,
Add 1g of sodium borohydride in small portions several times.
did. After stirring at room temperature for 12 hours, 1N hydrochloric acid was added to the reaction mixture.
The reaction solution is made acidic, methanol is distilled off, and potassium carbonate is removed.
In addition, it was neutralized. Chloroform extraction was performed from this solution, and chloroform was extracted.
The loform layer was concentrated to dryness. The resulting residue is sifted with silica gel.
Lamb chromatography purification (chloroform/methanol = 40/
1, volume ratio) and 1,3-dimethyl-6-(N-(2-
phenylethyl)-2-[3-(4-nitrophenyl)
propylaminocoethylamino)-2,4(IH,3
0.2 g of H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDC13) δppm: 1.9 (m, 2H),
2.6-3.6 (m, 12H). 3.18(s, 31(), 3.26(s, 3H),
5.28 (s, 1) I). 7,18 (s, 5H), 7.30 (d,
2H), 8.09 (d, 2) 1) Next, this
0.198 of the pyrimidinedione derivative in lN-HCl/
Treat with methanol solution in a conventional manner to obtain 1,3-dimethylene
Ru-6-(N-(2-phenylethyl)-2-(3-(
4-nitrophenyl)propylaminoconitylamino)
-2,4(1)1.38)-pyrimidinedione/hydrochloric acid
0.12 g of crystals of the salt (Compound 176) were obtained. Analysis results of the obtained crystals of compound 176: Elemental analysis values
C15Hs+N504・IIcI・3H20 calculated value (%
) :C54,0006,89N12.59 Cl3
6.38 Analysis value (%): C53,81) 16.74
N12.11 C425,911RvKBr(am-
') ;3420.2610.1700.1650°
ax 1620, 1550.1320.1010.820.7
81), 750 Example 121 1.3-dimethyl-6-(2-[N-allyl-3-(4
-nitrophenyl)propylaminoconitylamino)
-2,4(IH,3)1)-pyrimidinedione shu
Preparation of acid salt (compound 177) In Example 118-(2) above, p-methoxybenzene
Allyl bromide 0638ml instead of rubromide
1,3-dimethyl-6-(2
-[N-7 lylu-3-(4-nitrophenyl)propyl
aminoconitylamino)-2゜4 (IH,3H)-pi
0.9 g of rimidinedione was obtained. This pirimiji obtained
Analysis results of crystals of pyrimidine dione derivative: mp, 109-111°C 8,04 (d, 28) Next, 0.80 g of this pyrimidine dione derivative was
Treat with acid/methanol solution in a conventional manner to obtain 1,3-di
Methyl-6-(2-[N-allyl-3-(4-nitroph)
phenyl)propylaminoconitylamino)-2,4(L
H,3H)-pyrimidinedione oxalate (compound 1
0.75 g of crystals of 77) were obtained. Analysis results of the obtained crystals of compound 177: mp, 85~
90℃ Analysis value (%): C51,3086,26N13.241
540.1340,1160,990,850,770
,700 Example 122 1.3-dimethyl-6-(2-[N-propargyl-3
-(4-nitrophenyl)propylaminoconitylamide
-2,4(LH,3H)-pyrimidinedione
Preparation of Urate Salt (Compound 178) Previous Example 118- (
In 2), instead of p-methoxybenzyl bromide
The same except that 0.37ml of propargyl bromide was used.
1,3-dimethyl-8-[2-(N-propyl)
Lugyl-3-(4-nitrophenyl)propylaminoco
Nithylamino)-2,4(IH,3H)-pyrimidine di
0.85 g of On was obtained. Analysis results of the crystals of this pyrimidinedione derivative obtained
: mp, 156-157°C NMR (CDCIs) δppm: 1.9 (m, 2) 1)
, 2.23 (m, 1l-1). 2.4-3.1(s, 10)1), 3.25(s,
3H). 3,34 (s, 3H), 4.73 (s,
IH), 5.22 (br, 1l-1). 7, 27 (d, 2B), 8.04 (d,
2H) Next, 80g of this pyrimidinedione derivative
was treated with an oxalic acid/methanol solution according to a conventional method, and 1
．． 3-dimethyl-6-(2-[N-propargyl-3-
(4-nitrophenyl)propylamine]ethylamino
)-2,4(IH,3H)-pyrimidinedione shu
0.75 g of crystals of the acid salt (Compound 178) were obtained. Analysis results of the obtained crystals of compound 17B: mp, 1
7C) N172℃ Elemental analysis value C2゜H2SNSO4・(COOH) 1
0.5H20 calculated value (%): C53,01I5.66
N14.05 analysis value (%): C53,31I5.63
N14.18I Rv""(cm-'); 32
50.2600.1640.1620°ax 1530, +340. 770. 700 Example 1
23 1,3-di obtained by the method of Example 111
Methyl-6-(2-(N-(2-acetoxyethyl)-
3-(4-nitrophenyl)propylamino]ethyl 7
-2,4(IH,3H)-pyrimidinedione
Production of tablets containing oxalate (compound 167) as an active ingredient
Preparation: The pyrimidinedione derivative/oxalate (compound 167
') l g, milk [123 g and maize starch]
Mix 20g of starch powder well and add hydroxypropylcetate.
Mix and granulate 5g of lullose with a solution dissolved in water Loomβ.
, and dried at 50° C. for 4 hours. In this, stearic acid magne
Add 1 g of Silum, mix well, and use a tablet machine to make 1 tablet.
The mixture was compressed into tablets weighing 150 mg. Example 124 1,3-di obtained by the method of Example 116
Methyl-6-(2-[N-benzyl-3-(4-nitro)
phenyl)propylaminocoethylamino) -2,4
(IH,3H)-pyrimidinedione oxalate (compound
Production of capsules containing Compound 172) as an active ingredient: The pyrimidinedione derivative/oxalate (Compound 172)
) 5 g, lactose 120 g and corn starch
Mix 25g of the ingredients well and fill the resulting mixture into capsules.
Fill hard capsules to 150mg using a machine, and then fill the capsules with
Obtained. Example 125 1,3-di obtainable by the method of Example 119
Methyl-6-(2-[N-ethoxycarbonylethyl-
3-(4-nitrophenyl)propylaminocoethyla
-2,4(IH,38)-pyrimidinedione
An injection containing oxalate (compound 175) as an active ingredient
Production: The pyrimidinedione derivative/oxalate (compound 175
) 20 mg, and 0.85 g of sodium chloride
Dissolve this in an appropriate amount of distilled water for injection to bring the total amount to 100%.
It was given as an injection as mI2. Pharmacological Test Example 8 In the same manner as Pharmacological Test Example 1, the above-mentioned substances shown in Table 16 were
ADP of each compound obtained in the example? 8, and ERP
I asked for it. The results are shown in Table 16. Toxicity Test 8 Similar to Toxicity Test 1, the above examples shown in Table 17 were used.
The toxicity of each compound obtained was tested and the mortality rate of mice was determined.
I met. The results are shown in Table 17. The administration was 300mg/Kg for each compound.
Oral administration (p,o,) was performed. Table 17 Chemical No. Mortality Example 126 6- (2-[N-(2-hydroxyethyl) -3-
(4-nitrophenyl)propylamino1ethylamino
)-1,3゜5-trimethyl-2,4(IH,3H)-
Production of pyrimidinedione hydrochloride (compound 179) (compound 179) (1) 6-(2-hydroxyethylamine)-1,3
,5-trimethyl-2,4(01,3)1)-pyrimidine
Preparation of 6-chloro-1,3,5-trimethyl-
3.4 g of 2,4(IH,3)1)-pyrimidinedione
Suspend ethanolamine in 30 ml of isopropanol
1.26+nj2 and 3.8ml of triethylamine
The mixture was added and reacted for 3 hours under heating and reflux. left at room temperature overnight
After that, the precipitated crystals were collected by filtration, washed with water, and mixed with water-ethanol (1
: Recrystallized from 1) to give 6-(2-hydroxyethyl acetate)
mino)-1,3,5-trimethyl-2,4(IH,3H
)-pyrimidinedione (2.9 g) was obtained. Analysis results of this pyrimidinedione derivative obtained; Melting point: 159-160°C NMR (CDCl2), δppm: 4.71 (t,
2H), 3.55 (m, 2)1) 3, 21
(s, 3H) , 3.39 (s, 3)1) ,
1.93 (s, 3H) elemental analysis value C9H+5N
Calculated value as sOs (%): C, 50, 69,) 1,
7.09; N, 19.71 Analysis value (%): C, 50
,89,)1,7.1+,N,+9.90(216-
(2-methanesulfonyloxyethylamino)-1,3
,5-trimethyl-2,4(IH,3H)-pyrimidine
Preparation of dione 6-(2-hydroxyethylamino)-1,3,5-
Trimethyl-2,4(fH,31()-pyrimidinedio
Dissolve 2.9 g of pyridine in 20 m4 of pyridine and chloride at 0°C.
1.20 mI2 of methanesulfonyl was added dropwise. At 0℃
After 4 hours of reaction, pour into ice water Iomβ and extract with chloroform.
After washing with water, dry with anhydrous sodium sulfate and concentrate under reduced pressure.
The oily substance obtained was purified by silica gel column chromatography.
Roloform/methanol = 30:l volume ratio) and 6-C
2-methanesulfonyloxyethylamino)-1,3,
5-trimethyl-2,4(1)1.3H)-pyrimidine
3.0 g of dione was obtained. Analysis results of this pyrimidinedione derivative obtained; NMR (COCIs), δ ppm: 5.0
2 (t, 2H), 3.48 (m, 2N). 3, 30 (s, 3H), 3.41 (s, 3
H), 2.14 (s, 3)i), 1.99
(s, 3) 1) Elemental analysis value Calculated value as C0°H + tNsOsS (%
): C, 41,23; H, 5,88; N, 14.
42:S, 11.01 Analysis value (%): C, 40,97; H, 5,91:
N, 14.65°S, 11.07 (3) 6-(2-4N-(2-hydroxyethyl)-
3-(4-nitrophenyl)propylamino 1 ethyl acetate
(IH,3)-1゜3,5-trimethyl-2,4(IH,3
)1)-pyrimidinedione hydrochloride (compound 179)
Production 6-(2-methanesulfonyloxyethylamino)-1
, 3,5-trimethyl-2,4(1)1.3)1)-pi
3.0g of rimidinedione and 36m of acetonitrile! to 2
Dissolve, add 2.1 g of potassium carbonate and heat under reflux for 6 hours.
After the reaction, the mixture was left at room temperature overnight, and insoluble materials were filtered.
and the filtrate was diluted in acetonitrile loOmj2.
. Of these, Ionβ is taken and N-(2-hydroxyethyl
)-3-(4-nitrophenyl)propylamine 0.2
3g. Add 50 mg of p-toluenesulfone, dissolve and reduce under reduced pressure.
After reacting the concentrated oil at 80°C for 6 hours, the reaction mixture was
The compound was purified by silica gel column chromatography (chloroform/
methanol = 40:l volume ratio), 6-(2-[N-(
2-hydroxyethyl)-3-(4-nitrophenyl
)propylamino]ethylamino)-1,3,5-tri
Methyl-2,4(IH,3)1)-pyrimidinedione 0
．． 29 g was obtained. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 8.05 (d, 2
H), 7.30(d, 2H). 4,32 (m, 2H), 3.25 (s, 3
)1), 3.31 (s, 3H), 2.6-
3.1 (m, 10) 1), 2.06 (s, 3
H) , 1.9 (m, 2H) Then, this pyrimidium
Treat the dione derivative with hydrochloric acid/methanol according to the conventional method.
The hygroscopic amorphous 6-(2-[N-(2-H)
Droxyethyl)-3-(4-nitrophenyl)propyl
ethylamino)-1,3,5-trimethyl-
2,4(I)l,3H)-pyrimidinedione hydrochloride
0.12 g of (Compound 1) was obtained. Analysis results of the obtained compound 1; IRv, (cm-'): 3300.264
0.1690.1590.1555°1340.122
0.930,750.700 Elemental analysis value C2゜HiJ
Calculated value (%) as solHCI・HzO: C, 50
,68,H,6,81; N, 14.78°CI, 7
．． 48 Analysis value (%): C, 51,22; H, 6,94;
N, 14.29; CI, 7.73 Example 127 1.3-dimethyl-6-(2-[N-(2-hydroxy
ethyl)-3-(4-nitrophenyl)propylamino
1ethylamino)5-nitro-2,4(IH,3H)-
Production of pyrimidinedione hydrochloride (compound 180) (1) (compound 180) 6-(2-methanesulfonyloxyethylamino)-1
,3-dimethyl-5-nitro-2,4(IH,3H)-
Preparation of pyrimidinedione 6-chloro-1,3-dimethyl-5-2nitro-2,4
(III. 3) 4.0 g of 1)-pyrimidinedione was dissolved in dichloromethane.
13 mβ and ethanolamine at 1.26 m℃ and
and 3.8 mA of triethylamine in dichloromethane 13
It was slowly added dropwise to the solution obtained by dissolving mβ at 0°C. The mixture was reacted at 0° C. for 1 hour and left at room temperature for 5 hours. This reaction solution was cooled again to 0°C, and 3.8% of triethylamine was added.
Add mβ and add methanesulfonyl chloride 2.28+n
j2 was added dropwise. After reacting at 0℃ for 5 hours, add 30m4 of ice water.
was added and stirred vigorously for 30 minutes. Separate the dichloromethane layer
The aqueous layer is extracted with loloform, the organic layer is combined and washed with water.
, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The product was purified by silica gel column chromatography (chloroform/
Methanol = 301 volume ratio), 6-(2-methane sulfur)
(honyloxyethylamino)-1,3-dimethyl-5-
5.8 g of nitro-2,4(IH.3)1)-pyrimidinedione were obtained. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 5.12 (t,
2H), 3.44 (s, 3H). 3,22 (m, 2H), 3.16 (s, 3
H)(2) 6-(aziridin-1-yl)-1,3
-dimethyl-5-nitro2.4 (I)I, 3)1
)-Pyrimidinedione Preparation 6-(2-Methanesulfoni
(dioxyethylamino)-1,3-dimethyl-5-nito
Rho-2,4(IH,3H)-pyrimidinedione 5.8g
was dissolved in 70 mβ of acetonitrile, and 3.
8 g was added and the mixture was reacted for 3 hours under heating and reflux. Cool to room temperature
After that, insoluble materials were removed by filtration, and the filtrate was concentrated to 20m℃.
After condensing, 100 ml of ether was added and refrigerated for 2 days. The precipitated crystals were filtered and washed with hexane to form a fine powder of 6-
(aziridin-1-yl)-1,3-dimethyl-5-di
Thoro-2,4(IH,3)1)-pyrimidinedione 1
．． Obtained 0g. Analysis results of this pyrimidinedione derivative obtained: NMR (CDCIs), δppm: 3.37 (s, 3H
), 3.18 (s, 3) 1). 2,1-2.2 (m, 4H) (3) 1,3-dimethyl-6-(2-[N-
Droxyethyl)-3-(4-nitrophenyl)propyl
(1 ethylamino)5-nitro-2,4(IH,
3H)-pyrimidinedione hydrochloride (compound 180)
Production 6-(aziridin-1-yl)-1,3-dimethyl-5
-nitro-2,4(IH,3H)-pyrimidinedione 1
．． 0g, N-(2-(hydroxyethyl)-3-(4
-nitrophenyl)propyl 7mine 0.99g, p-
50mg of toluenesulfonic acid to 11g of dimethylformamide
．． The oily substance obtained by dissolving in On+n was heated to 90°C.
After reacting for an hour, the reaction mixture was left to cool, and 10 ml of water was added to stir.
The mixture was thoroughly stirred and the precipitated crystals were collected by filtration. Add this to chloroform
Dissolved in silica gel column chromatography (chloroform)
methanol/methanol = 40:1 volume ratio) and 1,3-dimethylene
Ru-6-(2-[N-(2-hydroxyethyl)-3-
(4-nitrophenyl)propylamino1ethylamino
)5-nitro-2,4(IH,3H)-pyrimidinedio
0.44 g of compound 180 (educt) was obtained. Analysis results of this pyrimidinedione derivative obtained; NMR (CDCIs), δppm: 8.01 (d,
2H), 7.31 (d, 2H). 3,66 (t, 2)1), 3.45 (s,
3H), 3.35 (s, 3H), 2.6-
3.6 (m, 10H), 2.0 (+n, 21
() Next, this pyrimidinedione derivative was mixed with hydrochloric acid/methanol.
A hygroscopic amorphous 1
．． 3-dimethyl-6-(2-[N-(2-hydroxyethyl)
-3-(4-nitrophenyl)propylamino
1ethylamino)5-nitro-2,4(I)l, 31
()-pyrimidinedione hydrochloride (compound 180)
31 g of O was obtained. Analysis results of the obtained compound 180; 1350.1110.930.750 Elemental analysis value C1,H26N607・Hcl・3H2o
Calculated value (%): C, 42, 19,) 1.6. +
5. N, 15.54°C1,6,55 Analysis value (%): C,41,79: )1,6.41;
N, 14.83: CI, 6.02 Example 128 1,3-di obtainable by the method of Example 127
Methyl-6-(2-[N-(2-hydroxyethyl)
-3-(4-nitrophenyl)propyl-7mino]ethyl
amino)-5-nitro-2,4(1)1.3H)-pyri
The active ingredient is midinedione (free form of compound 180).
Preparation of tablets of the pyrimidinedione derivative (compound 180)
(educt) 1g, lactose 123g and corn starch
Mix 20g of pull well and add it to hydroxypropylcetate.
Mix and granulate 5g of lulose dissolved in 100ml of water.
, and dried at 50° C. for 4 hours. In this, stearic acid magne
Add SiIg, mix well, and use a tablet machine to make 1 tablet.
The mixture was compressed into tablets weighing 150 mg. Example 129 6-(2-
[N-(2-hydroxyethyl)-3-(4-nitro
phenyl)propyl 7mino]ethylamino)-1,3,
5-trimethyl-2,4(IH,3H)-pyrimidine di
Capsules containing On hydrochloride (compound 179) as the active ingredient
Production of the pyrimidinedione derivative hydrochloride (compound 179)
5g, lactose 120g and corn starch 25g
Mix well and fill the resulting mixture with a capsule filling machine.
Hard capsules were filled to 150 mg to obtain capsules. Example 130 1,3-di obtainable by the method of Example 127
Methyl-6-(2-[N-(2-hydroxyethyl)
-3-(4-nitrophenyl)propylamino 1-ethyl
amino)-5-nitro-2,4(IH,3-pyrimidium)
Injection containing undione hydrochloride (compound 180) as the active ingredient
Production of propellant: The pyrimidinedione derivative/hydrochloride (compound 180)
Take 20 mg and 0.85 g of sodium chloride.
Dissolve it in an appropriate amount of distilled water for injection and make the total volume 100ml.
It was used as a propellant. Pharmacological Test Example 9 Compound 180 obtained in Example +27 was subjected to a pharmacological test.
When the ADP7B was determined in the same manner as Experimental Example 1, Table 18
The results were obtained. Table 8 Example 131 1.3-dimethyl-6-(4-(3-[2-nitro-4
-(2-pyridinecarbonyl)phenoxy]propyl>
piperazin-1-yl)-2,4(18,3)1)-pi
Production method 1 of rimidinedione oxalate (compound 181) (compound 36) (compound 181) (I) 2-chloro-5-(2-pyridinecarbonyl) di
Preparation of trobenzene 3.3mβ of 2-bromopyridine in ether 30n+j2
Butyllithium (1,6M hexane) was dissolved in -30°C.
22.1 mI2 of solution) was added dropwise. Here at the same temperature,
5.0 g of 4-chlorobenzonitrile to 10 ml of ether
2 and added dropwise. After stirring for 1 hour, the reaction solution was placed in ice water.
The ether was removed under reduced pressure. Add 6N salt to the resulting aqueous layer.
Add acid to make it acidic, stir at 100℃ for 1 hour, then cool.
Cool, add sodium hydroxide to make the solution basic, and add ether.
Extracted using a . Concentrate the ether layer to obtain an oily
Dissolve the substance in 10 mβ of concentrated sulfuric acid at 0°C, and add it to this solution.
After dropping 1.2 mI2 of fuming nitric acid, the mixture was stirred at the same temperature for 1 hour.
Ta. Pour the reaction solution into ice water, collect the precipitated crystals by filtration, and further evaporate.
By recrystallizing from alcohol, 2-chloro-5-(2
-pyridinecarbonyl)nitrobenzene crystals 3.6g
I got it. (2) 1,3-dimethyl-6-(4-(3-[2-
Nitro-4-(2-pyridinecarbonyl)phenoxy]
propyl〉piperazin-1-yl)-2,4(IH,3
H)-Production of pyrimidinedione oxalate (compound 181)
Manufacturing method Sodium hydroxide (60% oil-based) 0.17g in hexane
Wash it with
Cool to 1,3-dimethyl-6-[4-(3-hydro
xypropyl) piperazine-! -il]-2,4(1)
I, 3H)-pyrimidinedione (compound 36) 1
．． 0 g was added and stirred for 30 minutes. here 2-chloro-5
-(2-pyridinecarbonyl)nitrobenzene 1.1g
After stirring for another hour, pour the reaction mixture into ice water to remove the precipitate.
It was filtered and washed with water. By drying this filtered material, 1
．． 3-dimethyl-6-(4-(3-[2-nitro-4-
(2-pyridinecarbonyl)phenoxy]propyl>pyridine
perazin-1-yl)-2,4(II(,3H)-pyri
1.0 g of amorphous powder of midindione was obtained. Analysis results of this pyrimidinedione derivative obtained NMR
(CDC13) δppm: 2.1 (m, 2) 1)
2.4-3.1 (m, +08) 3, 25 (s, 3H
) 3.34 (s, 3H) 4.28 (t,
21()5.14(s, 18) 7.1~8.9(
m, 7H) 0.98 g of this pyrimidinedione derivative
According to a conventional method, treated with oxalic acid/methanol solution, 1
．． 3-dimethyl-6-(4-(3-[2-nitro-4-
(2-pyridinecarbonyl)phenoxy]propyl>pyridine
perazin-1-yl)-2,4(IH,3H)-pyrimi
Crystal of jindione oxalate (compound 181) 0.76
I got g. Analysis result of this compound 181 obtained IRv (cm-'): 3450.2500.17
00.1650.1600.1520゜1310, 12
80.800.740.700 Elemental analysis value Cx5Hz
aNaOa・(COOH) Calculated value as 12HJ (%
): C51,10H5,40N 13.24 analysis value (
%): C51,32H5,40N 13.15 Examples
132 1.3-dimethyl-6-(2-(N-(3-hydroxy
propyl)-3-(4-nitrophenyl)propyla
Minocoethylamino)-2,4-(IH,38)-pyri
Process for producing midinedione/oxalate (compound 182) (1) N-(3-hydroxypropyl)-3-(
Preparation of 4-nitrophenyl)propylamine 3-(4-nitrophenyl)propyl p-toluenesulfur
phonate Ig, 3-hydroxypropylamine 4,1n
Dissolve j2 in dioxane lOmβ and stir at 80°C for 30 minutes.
Stirred. Water 100mβ, chloroform 100+nI2
Add, separate the layers, remove the chloroform layer, wash with water, and add sulfuric anhydride.
After drying with sodium, the solvent was distilled off and the N-(3-hydroxy
cypropyl)-3-(4-nitrophenyl)propyla
0.7 g of min oil was obtained. Analysis result of this amine derivative obtained NMR (CDCIs) δppm: 1.9-2.1 (m
, 4) 1) 2.83-3.2 (m, 6H) 4
．． 18 (t, 2f1) 7.62 (d, 2H
) 8, 01 (d, 2H) (2) 1,3-dimethyl-6-(2-[N-(3-hy-
Droxypropyl)-3-(4-nitrophenyl)pro
pyramino]-2,4(IH,3)1)
-Production method of pyrimidinedione oxalate (compound 182)N-(3-hydroxypropyl)-3-(4-nitroph
6-(1-azily) propylamine 0.7 g, 6-(1-azily)
(dinyl)-1,3-dimethyl-2,4(1)1.3H)
-pyrimidinedione (compound 6) 0.53g and p-t
50 mg of luenesulfonic acid-hydrate in acetonitrile
Dissolve in 30 mJ2, then remove the solvent under reduced pressure to obtain
The resulting oil was reacted at 80°C for 3 hours, and then converted into silica gel.
Column chromatography purification (chloroform/methanol = 40
71 Volume ratio) L, 1.3-dimethyl-6-(2-[
N-(3-hydroxypropyl)-3-(4-nitroph
phenyl)propylaminocoethylamino) -2,4(
1) Obtained 0.68 g of 1,3H)-pyrimidinedione.
Ta. Analysis results of this pyrimidinedione derivative obtained NMR
(CDCIs) δppm: 1.7 (m, 4H)
2.4-3.1 (m, 8H) 3.21 (s, 3H
) 3.34 (s, 3) 1) 3.70 (br, 2
)1) 4,0 (m, 2)1) 4.71 (s,
IH) 5.81 (br, 18)? , 25
(d, 2) 1) 8.06 (d, 2H) This pin
0.65 g of rimidinedione derivative was added to the cylinder according to a conventional method.
1,3-dimethyl by treatment with oxalic acid/methanol solution
-6-(2-[N-(3-hydroxypropyl)-3-
(4-nitrophenyl)propylaminocoethylamino
)-2,4-(IH,3)1)-pyrimidinedione
0.62 g of crystals of the acid salt (Compound 182) were obtained. Analysis result of this compound 182 obtained mp, 103-105°C (decomposition) IRυ (cm-'): 3300.1690.162
0.1540.1410.1330゜1050, 850
．． 770.740.690 Elemental analysis value C2゜HiJs
Ol(COOH) Calculated value (%) as 1HJ: C5
0,09H6,31N 13.28 Analysis value (%): C
50,37H6,25N 12.79 Example 133 1.3-dimethyl-6-(2-(N-(1-methylethyl)
)-3-(4-nitrophenyl)propylaminochoe
thylamino)-2,4(1)1.3H)-pyrimidine
Production method of dione oxalate (compound 183) NotI□C) IzCHzCHzO3GCHs filtration (1)
Preparation of trophenyl)propylamine 3-(4-nitrophenyl)propyl P-)luensur
1 g of honate, 5 ml of isopropylamine in dioxane
The mixture was dissolved in 15 mJ2 of water and stirred under heating and reflux for 4 hours. Add 100++j2 of water and 100mJ2 of chloroform,
Separate the layers, remove the chloroform layer, wash with water, and add anhydrous sodium sulfate.
The solvent was distilled off and N-(1-methylethyl)
-3-(4-nitrophenyl)propylamine oil
0.61g was obtained. Analysis result of this amine derivative obtained NMR (CDCIs) δppm: 1.22 (d, 61
() 2.0 (m, 2) 1) 2, 9-3.3 (m,
5) 1) 7.28 (d, 2H) 8, 09 (
d, 211) (2) 1,3-dimethyl-6-(2-[N-(1-methyl
ethyl)-3-(4-nitrophenyl)propyla
minocoethylamino)-2,4(1)1.3H)-pi
Production method of rimidinedione oxalate (compound 183) N-(1-methylethyl)-3-(4-nitrophenylate)
l)propylamine 0.6 g, 6-(l-aziridinyl)
)-1,3-dimethyl-2,4(IH,3)1)-pyri
Midinedione (compound 6) 0.5g and p-toluene
50mg of sulfonic acid-hydrate in 30mf of acetonitrile
2, and then the solvent was distilled off under reduced pressure to obtain an oily substance.
was reacted at 80°C for 3 hours, and then directly transferred to a silica gel column.
Romato purification (chloroform/methanol = 40/1 volume)
quantitative ratio) L, 1.3-dimethyl-6-(2-[N-(1-
methylethyl)-3-(4-nitrophenyl)propyl
aminocoethylamino)-2,4-(1)1.3H)-
1.0 g of pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained NMR
(CDCIs) δppm: 1.45 (d, 68)
2.0 (m, 2) 1) 3.29 (s, 38)
3.40 (s, 3H) 2.5-3.1 (m, 78
)3,8~4.1 (m, 4H) 4.80 (s
, IH) 5.5 (m, 1) 1) 7.31 (d
, 2H) 8.00 (d, 2H) This pyrimidinedio
0.95g of oxalic acid/methano derivative according to the conventional method.
1,3-dimethyl-6-(2-(
N-(1-methylethyl)-3-(4-nitropheny)
(propylaminocoethylamino)-2,4-(IH
, 311)-pyrimidinedione oxalate (compound 183
0.88 g of crystals of ) were obtained. Analysis result of this compound 183 obtained IRv (cm-'): 3250.2600.17
00.1640.1590.1510゜1330, 12
20.760.750.700 Elemental analysis value C2゜Ht
s N s Oa・1.5 (COO)I) 10.
Calculated value (%) as 5LO: C50,45) 16.08 N 1
2.79 Analysis value (%): C50,25) 15.81
N 12.52 Example 134 1.3-dimethyl-6-(2-[N-(2-hydroxy
-1-methylethyl)-3-(4-nitrophenyl)
ropylaminocoethylamino)-2,4(IH,3H)
-Production method of pyrimidinedione hydrochloride (compound 187) (compound 187) (1) N-(2-hydroxy-1-methylethyl)
-3-(4-nitrophenyl)propionic acid amide
Preparation 3-(4-nitrophenyl)propionic acid 5g salt
Suspended in 40 mβ of thionyl chloride and stirred under heating and reflux for 2 hours.
, then excess thionyl chloride was distilled off under reduced pressure to obtain
The oil was dissolved in 15 m4 of chloroform. Separately, 3.8 g of 2-amino-1-propatool and potassium carbonate
Dissolve 3.5 g of um in 35 mβ of water and bring this solution to 0°C.
After cooling, the previously obtained chloroform solution was added dropwise. to 5℃
After stirring for 1 hour, the precipitated product was collected by filtration and washed with water. Furthermore, acetic acid
Recrystallized from ethyl/chloroform = 1/1 (volume ratio)
N-(2-hydroxy-1-methylethyl)-3-(
Crystals of 4-nitrophenyl)propionic acid amide 3.4
6 g was obtained. Analysis results of this amine derivative obtained: mp, 174°C (2) N-(2-hydroxy-1-methylethyl)
-Preparation of 3-(4-nitrophenyl)propylamine
N-(2-hydroxy-1-methyl ether obtained in (1) above)
Chyl)-3-(4-nitrophenyl)propionic acid amide
3.4g of sodium hydride and 2.1g of sodium borohydride 71F! :
Suspend in 32 mI2 of THF, and add 3.3 g of acetic acid to this.
After dropping the F32m℃ solution, stir under heating under reflux for 10 hours.
The stirred reaction solution was cooled to 5℃ and 20mJ2 of methanol was added.
After stirring for 30 minutes, the mixture was concentrated to dryness, and the residue was diluted with 50% IN-hydrochloric acid.
mJ2 and chloroform 50mJl! and stir vigorously.
Stirred. After standing still, separate the layers and add sodium hydroxide to the aqueous layer.
Make basic, extract with chloroform, and remove the chloroform layer.
After washing with water, drying with anhydrous sodium sulfate and concentrating to dryness, an oily
N-(2-hydroxy-1-methylethyl)-3-(4
-nitrophenyl)propylamine 2.96 g were obtained.
. This was used in the next reaction without purification. (3) 1,3-dimethyl-6-(2-(N-(2-hypolymer)
Droxy-1-methylethyl)-3-(4-nitrophe)
propylaminocoethylamino) -2,4(1
B, 3) 1)-pyrimidinedione hydrochloride (compound 1
87) Production method N-(2-hydroxy obtained in (2) above)
-1-methylethyl)-3-(4-nitrophenyl)
Lopylamine 2.2g, 6-(1-aziridinyl)-
1,3-dimethyl-2,4(Ill, 3H)-pyrimi
1.6 g of jindione (compound 6) and p-toluenesul
0.1g of fonic acid-hydrate in 100mJ of acetonitrile
2, and then the solvent was distilled off under reduced pressure to obtain an oily substance.
was reacted at 80°C for 3 hours, and then directly transferred to a silica gel column.
Romato purification (chloroform/methanol = 40/1
volume ratio) and 1,3-dimethyl-6-(2-[N-(2-
Hydroxy-1-methylethyl)-3-(4-nitroph
phenyl)propylaminocoethylamino) -2,4(
3.0 g of IH,3H)-pyrimidinedione was obtained. Analysis results of this pyrimidinedione derivative obtained NMR
(CDCIs) δppm: 1.04 (d, 3H)
1.9 (m, 2H) 2.5~3.0 (m
, 9)1) 3.28 (s, 3)1) 3.
40 (S, 3t()4, 13 (m, 2H)
4.69 (s, IH) 6.47 (m, IH
)7゜29 (d, 2H) 8.06 (d, 2
1 () 2.95g of this pyrimidinedione derivative was added using a conventional method.
1.3 by treatment with HCI/methanol solution according to
-dimethyl-6-(2-[N-(2-hydroxy-1-
methylethyl)-3-(4-nitrophenyl)propyl
amine]ethylamino)-2,4(IH,3H)-p
Crystals of rimidinedione hydrochloride (compound 187) 3.0
2 g was obtained. Analysis result of this compound 187 obtained mp, 154-155°C IRv (cm-'); 3250.2900.1
690.1600.1550.1340°1240, 1
060.840.760.700 Example 135 1.3-dimethyl-6-[4-(3-methyl-4-nito
lobenzyl)piperazin-1-yl]-2,4(IH
,3H)-pyrimidinedione hydrochloride (compound 188)
(Compound 188) (1) Preparation of 3-methyl-4-nitrobenzyl chloride
2 g of 3-methyl-4-nitrobenzyl alcohol and D
Dissolve MF 0.2mj2 in toluene 20mI2,
Add thionyl chloride In+42 and stir under heating under reflux for 3 hours.
The stirred reaction solution was concentrated and 3-methyl-4-nitrobendi
2.2 g of oily chloride was obtained. This will be refined
It was used in the next reaction without any reaction. (2) 1,3-dimethyl-6-(4-(3-methyl-
4-nitrobenzyl)piperazin-1-yl] -2,
4(IH,3H)-pyrimidinedione hydrochloride (compound
188) Production method 3-methyl-4-di obtained in the above (1)
Trobenzyl chloride 2.2g, 1,3-dimethyl
-6-(piperazin-1-yl) -2,4(IH,3
) 1)-pyrimidinedione (compound 2) 2.2 g and
ethylamine 4. Inn to Improper Tools 40m
A zero-reaction solution was dissolved in β and stirred for 2.5 hours under heating and reflux.
The solvent was distilled off under reduced pressure, and the residue was dissolved in 50 mβ of chloroform.
Dissolve, wash this chloroform solution with water, and dilute with anhydrous sodium sulfate.
After drying with aluminum, the solvent was distilled off. This from ethanol
By crystallization, 1,3-dimethyl-6-[4
-(3-methyl-4-nitrobenzyl)piperazine-1
-yl]-2,4(IH,3H)-pyrimidinedione
2.76 g of crystals were obtained. Analysis results of this pyrimidinedione derivative obtained mp,
162-164℃ NMR (CDCIs) δppm: 2.5, 3
(m, 8H) 2.61 (s, 3H) 3.26
(s, 3H) 3.36(s, 3H) 3.61(
br, 2t1) 5.15 (s, IH) 7.35 (m
, 2J1) 7.87(d,1)1) This pyrimidine
2.4g of the dione derivative was mixed with HCI/meth according to a conventional method.
1,3-dimethyl-6-(4-
(3-methyl-4-nitrobenzyl)piperazine-1-
-2,4(IH,3H)-pyrimidinedione
2.34 g of crystals of hydrochloride (compound 188) were obtained. Analysis result of this compound 188 obtained IRv (cm-1); 3360.2540.16
90.1640.1520.1440°1340, 12
00.980.840.760.700 Elemental analysis value C
Calculated value (%
): C50,52H6,12N 16°36CI 8
．． 28 Analysis value (%): C50,8786,64N 16.4
4CI 7.68 Example 136 1.3-dimethyl-6-(2-(N-(2-hydroxy
ethyl)-3-(4-benzoyl-2-nitrophenoki)
C) propylaminocoethylamino) -2,4(1)
1.3) Method for producing 1)-pyrimidinedione oxalate (compound 189) (1) 1.3-dimethyl-6-(2-(2-hydroxy)
ethylamino]-2,4(I) 1.3
Preparation of H)-pyrimidinedione 6-(l-aziridinyl)-1,3-dimethyl-2,4
(IH, 3) 1)-pyrimidinedione (compound 6) 0.
81g. Ethanolamine 1mI2 and p-toluenesulfonic acid
・-Dissolve 50 mg of hydrate in 200 mβ of acetonitrile
Then, the solvent was distilled off under reduced pressure, and the resulting oil was heated at 90°C.
The 0 reaction solution reacted for 3 hours was left to cool, then ethanol was added to dissolve it.
crystals precipitated by adding ether to this
was collected by filtration, and the crystals were further purified using ethanol/ether.
By recrystallization, 1,3-dimethyl-6-(2-(
2- and droxyethylamino)ethyl7mino]-2,4
(IH,3H)-pyrimidinedione crystals 1.02 g
I got it. Analysis results of this pyrimidinedione derivative obtained mp,
146-148°C (2) 4-(3-bromopropyloxy)-3-nito
Preparation of lobenzophenone 2.5 g of 4-hydroxy-3-nitrobenzophenone and
7.1g of potassium carbonate to 15mβ of methyl ethyl ketone
After stirring for 30 minutes under heating and reflux, 1,3-dibromo
Propane was added and the mixture was further heated under reflux for 6 hours. The reaction solution was allowed to cool, the insoluble matter was filtered off, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography (hexane/vinegar
Ethyl acid = 3/1 volume ratio) and 4-(3-bromopropylene)
3-nitrobenzophenone oil 2.0
8g was obtained. NMR (CDC1,) δppm: 2.40 (m,
2) 1) 3.66 (t, 2H) 4, 39 (
t, 2H) 7.13-8.34 (m, 8H)
(3) 1,3-dimethyl-6-(2-[N-(2-hypolymer)
droxyethyl)-3-(4-benzoyl-2-nitro
phenoxy)propylaminocoethylamino) -2,
4(IH,3)1)-pyrimidinedione oxalate (
Method for producing compound 189) The 1,3-dimethyl obtained in the above (1)
thyl-6-(2-(2-hydroxyethylamino)ethyl
Ruamino]-2,4(IH,3H)-pyrimidinedione
0.67 g, 4-(3-bromopropylene) obtained in (2)
1.0 g of (lopyloxy)-3-nitrobenzophenone,
1.5 ml of triethylamine and 3 mβ of DMF
The mixture was heated and stirred at 100° C. for 1 hour. After cooling, add chloroform 50n+12 and wash with water.
By drying with anhydrous sodium sulfate and distilling off the solvent,
The resulting residue was dissolved in a mixed solvent of ethanol/ether.
1,3-dimethyl-6-
(2-(N-(2-hydroxyethyl)-3-(4-
Benzoyl-2-nitrophenoxy)propylaminoco
ethylamino) -2,4(IH,3)1)-pyrimidine
0.59 g of crystals of dione were obtained. Analysis results of this pyrimidinedione derivative obtained mp,
180-181'C NMR (CDCIS/DMSO-d6=1/1 capacity ratio)
δppm: 2.0 (m, 2H) 2.6 to 3.1 (
m, 8H) 3.21 (s, 3) 1) 3, 34 (s,
3H) 3.67 (t, 28) 4.39
(t, 2H) 4,58 (s, IH) 6.25
(br, IH) 7.31 (d, IH)7.
5~8.1 (m, 6H) 8゜26 (d, 1
8) 0.55g of this pyrimidinedione derivative was added in a conventional manner.
Therefore, by treatment with oxalic acid/methanol solution, 1.3-
Dimethyl-6-(2-[N-(2-hydroxyethyl)
-3-(4-benzoyl-2-nitrophenoxy)pro
pyraminocoethylamino)-2,4(18,3H)-
Crystals of pyrimidinedione oxalate (compound 189)
0.62 g was obtained. Analysis result of this compound 189 obtained mp, 144-147°C (decomposition) IRν(am-'); 3300.2590.172
0.1680.1630.1530°1340, 128
0.1070.780.710 Elemental analysis value C*a)I
s+N5Oy・(COO)I) J, as 5HzO
Calculated value (%): C53,8485,49N 11.2
1 Analysis value (%): C5, 3, 88) 15.26 N
11.27 Example 137 1.3-dimethyl-6-(2-IN-(2-hydroxy
ethyl)-3-(3-methoxy-4-nitrophenyl)
propylaminocoethylamino)-2,4(IH,3
H)-pyrimidinedione oxalate (compound 190)
Production method of (COa)I) t/CHsO)1 (1) (Compound 190) 3-(3-me)+C4-nitrophenyl)propio
Preparation of 3-methoxy-4-nitrocinnamic acid and 6.2 g of sulfuric acid
Dissolve 12.3 g of xylamine in 250 mI2 of water, and
Add 7.1g of sodium hydroxide to this, and then add sodium hydroxide.
A solution of 18 g of lithium in 27 mβ of water and hydroxylamine-
〇- Keep 19.2g of sulfonic acid at pH 9 and add small amounts alternately.
added to. After stirring at 5°C for 6 hours, insoluble matter was filtered off.
The filtrate was cooled with water, adjusted to pH 2 by adding 6N sulfuric acid, and precipitated.
By filtering the crystals, washing with water, and drying, 3-(
3-Methoxy-4-nitrophenyl)propionic acid linkage
1.27 g of crystal was obtained. Analysis results of the crystals of this propionic acid derivative obtained: mp, 137-139°C (2) N-(2-hydroxyethyl)-3-(3-methyl)
Preparation of toxy-4nitrophenyl)propionic acid 7mide
3-(3-methoxy-4-nitrophe obtained in (1) above)
1.2g of propionic acid to 20mβ of thionyl chloride
After suspending and stirring under heating and reflux for 2 hours, the solvent was distilled off and the remaining
The residue was dissolved in 3ml chloroform. Separately, 0.52 g of ethanolamine and 0.7 g of potassium carbonate
Dissolve 8 g in 8 m4 of water, cool to 0°C, and dissolve the previously obtained chlorine.
3 mJl+ of loform solution was added dropwise. Steep for 1 hour at the same temperature
Stir well, collect the precipitated crystals by filtration, wash the crystals with water, dry them, and then
By recrystallizing with ethyl acetate,
Droxyethyl)-3-(3-methoxy-4-nitroph
1.14 g of crystals of (phenyl) propionic acid amide were obtained. Analysis results of the obtained crystals of this amide, mp, 155°C (decomposition) (3) N-(2-hydroxyethyl)-3-(3-methane)
Preparation of Toxy-4-nitrophenyl)propylamine water
Suspend 0.78g of sodium boron chloride in THFI2mβ
Then, to this, the N-(2-hydroxyethyl
)-3-(3-methoxy-4-nitrophenyl)pro
Add 1.1 g of pionic acid amide and add 1.2 mI2 of acetic acid.
was added dropwise little by little. Stir until foaming stops, then heat.
Stir under reflux for 10 hours, cool and add 10 mβ of methanol.
Added little by little. The solvent was distilled off under reduced pressure, and chloroform 2
0 m°C was added, and the mixture was extracted with IN aqueous hydrochloric acid solution. salt
Add sodium hydroxide to the acid extract under water cooling to make it basic.
Extract with chloroform, and remove the chloroform layer with saturated saline.
After washing, dry with anhydrous sodium sulfate and distill off the solvent.
Possibly N-(2-hydroxyethyl)-3-(3-
Methoxy-4-nitrophenyl)propylamine oil
0.72 g of product was obtained. This is the next reaction without purification.
It was used for. (4) 1,3-dimethyl-6-(2-[N-(2-hypolymer)
droxyethyl)-3-(3-methoxy-4-nitroff)
phenyl)propylaminocoethylamino) -2,4(
IH,3) 1)-pyrimidinedione (compound 190)
Production method 6-(1-7 diridinyl)-1,3-dimethyl-2,4
(1) 1°38)-pyrimidinedione (compound 6) 0.
45g, N-(2-hydroxyethyl obtained in (3) above)
)-3-(3-methoxy-4-nitrophenyl)propyl
0.7g of amine and p-toluenesulfonic acid.-
Dissolve 50 mg of hydrate in 25 mβ of acetonitrile and
After that, the solvent was distilled off under reduced pressure, and the obtained oil was heated at 80°C for 3 hours.
silica gel column chromatography (resolution).
Chloroform/methanol = 40/1 volume ratio) 1.
3-dimethyl-6-(2-[N-(2-hydroxyethyl)
)-3-(3-methoxy-4-nitrophenyl)pro
pyraminoconitylamino) -2,4(IH,3)1
)-pyrimidinedione (0.38 g) was obtained. Analysis results of this pyrimidinedione derivative obtained NMR
(CDCIs) δppm: 1.9 (m, 2H)
2.4=3.8 (m, 12H)3,20 (s,
3)1) 3.33 (s, 3H) 3.83
(s, 3H) 4.63 (s, 1) 1) 6.11
(m, IH) 6.75 (m, 2H) 7, 26 (m
, IH) 0.33 g of this pyrimidinedione derivative was added according to a conventional method.
, treated with oxalic acid/methanol solution to obtain 1,3-dimethyl
thyl-6-(2-[N-(2-hydroxyethyl)-3
-(3-methoxy-4-nitrophenyl)propylamide
noconitylamino)-2,4(IH,3)1)-pyrimi
Amorphous powder of jindione oxalate (compound l90)
0.22 g was obtained. Analysis result of this compound 190 obtained IRv (cm-'); 3300.2550,169
0,1640,1540.1350°1280,760
．． 700 Elemental analysis value C8゜LJsOs・2 (COOH)・2
Calculated value (%) as H30: C44,24N 5.7
2N 10.75 Analysis value (%): C43,93H
5,85N 11.10 Example 13g 1.3-dimethyl-6-(2-[N-(2-diethyla
mino)ethyl-3-(4-nitrophenyl)propyla
minoconithylamino)-2,4(1)1.3H)-pi
Production of rimidinedione oxalate (compound 191) (compound 191) 1.3-dimethyl-6-(2-[3-(4-nitrophe)
(propylaminoconitylamino) -2,4(1
)1.3H)-pyrimidinedione, hydrochloride (compound e)
Dissolve 1.4 g in water 5rn12 and add potassium carbonate.
In addition, the mixture was made alkaline and extracted with chloroform. obtained
The chloroform solution was concentrated to dryness, and 2-dietate was added to the residue.
thylaminoethyl chloride 1.0g,) diethylamide
Add 3 mβ and 20 mβ of isopropanol for 10 hours.
The mixture was heated to reflux. The solvent was distilled off under reduced pressure, and the residue was directly transferred to silica.
Gel column chromatography purification (chloroform/methanol =
2071 volume ratio) and 1,3-dimethyl-6-(2
-[N-(2-diethylamino)ethyl-3-(4-ni
Trophenyl) propylaminoconitylamino) -2゜
4 (1)1.3H)-pyrimidinedione 0.60 g
Obtained. 0.50g of this pyrimidinedione derivative was
Treated with uric acid/methanol solution according to a conventional method to obtain 1.3-
Dimethyl-6-(2-[N-(2-diethylamino)ethyl
Chil-3-(4-nitrophenyl)propylaminoconi
thylamino)-2,4(1)I, 3H)-pyrimidine
0.52 crystals of dione oxalate (compound 191)
I got g. Analysis results of the obtained crystals of compound 191 mp, 19
7-199℃

Claims (1)

[Claims] 1) The following general formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (1) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1 and R^2 are each independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group,
phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a substituent selected from the group consisting of a lower alkyloxycarbonyl group), or R^1 and R^2 may be linked to form an alkylene chain to form a heterocyclic structure, R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^1 and X^2 are independently , a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
represents a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group; R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or Indicates a lower alkyl group, or R^1 and R
^5 may be linked to form an alkylene chain to form a heterocyclic structure, and R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, a lower alkyl group, a hydroxyl group, (optionally substituted with 1 to 2 substituents selected from the group consisting of lower alkyloxy groups) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4, k is 2
, 3 or 4, l is 0, 1, 2, 3 or 4]. 2) The following general formula (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (2) [In the formula, R^1'' and R^2 independently represent a hydrogen atom,
Lower alkyloxycarbonyl group, unsaturated lower alkyl group or lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower alkanoyloxy group) , a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a lower alkyloxycarbonyl group. ) or R^1
'' and R^2 may be linked to form an alkylene chain to form a heterocyclic structure, R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^1 and X ^2 is independently a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
Represents a phenyl-substituted lower alkylamino group or unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, nitro group, methyl group or cyano group, R^6 represents a lower alkyl group, cycloalkyl group, phenyl group (such as The phenyl group may be substituted with 1 to 2 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) or a heterocycle, and n is 2 or 3. , k is 2, 3 or 4]. The pyrimidinedione derivative according to claim 1. 3) General formula (3) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(3) [In the formula, A' is -(CH_2)_m-, -B'-(CH_
2) ＿k- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, B' indicates oxygen atoms, sulfur atoms, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^1'' and R^2 are mutually exclusive. independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a saturated lower alkyl group (wherein any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group,
Substituted with a substituent selected from the group consisting of a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a lower alkyloxycarbonyl group. You can. ), or R^1'' and R^2 may be connected to form an alkylene chain to form a heterocyclic structure, and R^3 and R^4 are each independently a hydrogen atom or a lower alkyl group. , X^1 and X^2 are each independently a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
Represents a phenyl-substituted lower alkylamino group or unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, nitro group, methyl group, or cyano group, and R^5' represents a hydrogen atom, lower alkanoyl group, or lower alkylsulfonyl group. or a lower alkyl group, R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is one or two selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) ) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4, k is 2
, 3 or 4] The pyrimidinedione derivative according to claim 1. 4) The following general formula (4) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(4) [In the formula, A'' is -B''-(CH_2)_k- or ▲Mathematical formula,
Chemical formulas, tables, etc. are available ▼, B'' indicates oxygen atoms, sulfur atoms, or ▲numerical formulas, chemical formulas, tables, etc. are available▼,
R^1 and R^2 are each independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (wherein any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di- Lower alkylamino group, lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group, phenyl group substituted with a halogen atom or lower alkyloxy group or may be substituted with a substituent selected from the group consisting of lower alkyloxycarbonyl groups), or R^1 and R^2 are linked to form an alkylene chain to form a heterocyclic structure. R^3 and R^4 each independently represent a hydrogen atom or a lower alkyl group, and X^1 and X^2 each independently represent a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
represents a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group; R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or Indicates a lower alkyl group, or R^1 and R
^5 may be linked to form an alkylene chain to form a heterocyclic structure, and R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, a lower alkyl group, a hydroxyl group, (optionally substituted with 1 to 2 substituents selected from the group consisting of lower alkyloxy groups) or a heterocycle, n is 2 or 3, k is 2, 3 or 4] The pyrimidinedione derivative according to claim 1. 5) The following general formula (5) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(5) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1' is a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyl group) From an oxy group, a lower alkanoyloxy group, a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group ), R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^1 and X^2 independently represent , a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
represents a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group; R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or It may represent a lower alkyl group, or R^1' and R^5 may be linked to form an alkylene chain to form a heterocyclic structure, and R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group ( The phenyl group may be substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) or a heterocycle, and m is 0, 1, 2, 3 or 4, k is 2, 3 or 4, l
is 0, 1, 2, 3 or 4] The pyrimidinedione derivative according to claim 1, characterized in that it is represented by the following formula. 6) The following general formula (6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(6) [In the formula, R^1'' and R^2 independently represent a hydrogen atom,
Lower alkyloxycarbonyl group, unsaturated lower alkyl group or lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower alkanoyloxy group) , a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a lower alkyloxycarbonyl group. ), or R^1'' and R^2 may be linked to form an alkylene chain to form a heterocyclic structure, and R^3 and R^4 are Each independently represents a hydrogen atom or a lower alkyl group, and X^1 and X^2 each independently represent a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
A phenyl-substituted lower alkylamino group or an unsaturated alkyloxy group, R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is a group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) ) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4] Item 1. The pyrimidinedione derivative according to item 1. 7) The following general formula (7) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(7) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1' and R^2' are each independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (wherein any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, di-lower alkylamino group, lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group, phenyl group substituted with a halogen atom or lower alkyloxy group or a lower alkyloxycarbonyl group), R^3 and R^4 each independently represent a hydrogen atom or a lower alkyl group, 1 and X^2 each independently represent a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
represents a phenyl-substituted lower alkylamino group or an unsaturated alkyloxy group, X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group; R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or a lower It may represent an alkyl group, or R^1' and R^5 may be linked to form an alkylene chain to form a heterocyclic structure, and R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (such as The phenyl group may be substituted with 1 to 2 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) or a heterocycle, and n is 2 or 3. , m is 0, 1, 2, 3 or 4, k is 2
, 3 or 4, l is 0, 1, 2, 3 or 4]. The pyrimidinedione derivative according to claim 1. 8) The following general formula (8) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(8) [In the formula, A''' is -(CH_2)_m-, -B'''-(C
H_2)_k-, -D-(CH_2)_l-, ▲ Formula,
There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and B''′ is an oxygen atom, a sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. Yes▼or▲
D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1''' and R^2' are each independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group) , di-lower alkylamino group, lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group, substituted with a halogen atom or lower alkyloxy group ), R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X ^1 and X^ are each independently a hydrogen atom, -CO-R
^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoylamino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group, phenyl-substituted lower alkylamino group or unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, nitro group, methyl group or cyano group, R^5' represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or a lower alkyl group, and R^6 represents a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, a lower alkyl group, a hydroxyl group) and a lower alkyloxy group) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4, k is 2
, 3 or 4, l is 0, 1, 2, 3 or 4]. The pyrimidinedione derivative according to claim 1. 9) A pharmaceutically acceptable acid addition salt of the pyrimidinedione derivative according to any one of claims 1 to 8. 10) The following general formula (9) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(9) [X^1 and X^2 are each independently a hydrogen atom, -CO
-R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group,
Represents a carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoylamino group, lower alkylsulfonamido group, mono- or di-lower alkylamino group, phenyl-substituted lower alkylamino group or unsaturated alkyloxy group, R^ 6 is a lower alkyl group, a cycloalkyl group, a phenyl group (even if the phenyl group is substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) ) or a heterocycle] and the following general formula (10) ▲There are numerical formulas, chemical formulas, tables, etc.▼...(10) [R^1'' and R^2 are independently of each other A hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (wherein any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower Selected from the group consisting of an alkanoyloxy group, a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group. ), or R^1'' and R
^2 may be linked to form an alkylene chain to form a heterocyclic structure, R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^3 is a hydrogen atom, a nitro methyl group or cyano group, n is 2 or 3, and k is 2, 3 or 4] in the presence of a dehydration condensation agent. A method for producing the described pyrimidinedione derivative. 11) The following general formula (11) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(11) [X^1 and X^2 are each independently a hydrogen atom, -CO
-R^8, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group,
Represents a carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoylamino group, lower alkylsulfonamido group, mono- or di-lower alkylamino group, phenyl-substituted lower alkylamino group or unsaturated lower alkyloxy group, R ^8 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) ) or a heterocycle, and Y^2 represents a halogen atom] and the following general formula (12) ▲There are numerical formulas, chemical formulas, tables, etc.▼...(12) [In the formula A″ is −B″−(CH_2)_k− or ▲formula,
Chemical formulas, tables, etc. are available▼, B'' is an oxygen atom, sulfur atom, or ▲numeric formulas, chemical formulas, tables, etc. are available▼, and R^1 and R^2 are each independently a hydrogen atom, lower alkyloxycarbonyl group, unsaturated lower alkyl group or lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower alkanoyloxy group, a benzoyloxy group) , a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a lower alkyloxycarbonyl group substituted with a substituent selected from the group consisting of ), or R^1 and R^2 may be linked to form an alkylene chain to form a heterocyclic structure, and R^3 and R^4 independently represent hydrogen atoms. or represents a lower alkyl group; 1 and R
^5 may be linked to form an alkylene chain to form a heterocyclic structure, n is 2 or 3, k is 2, 3 or 4]. The method for producing a pyrimidinedione derivative according to claim 4. 12) The following general formula (13) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(13) [In the formula, A' is -(CH_2)_m-, -B'-(CH_
2) Indicates ___k- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, B' indicates an oxygen atom, sulfur atom, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and X^1 and X^2 are independent of each other. To,
Hydrogen atom, -CO-R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower represents an alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a mono- or di-lower alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated alkyloxy group, R^5' is a hydrogen atom, a lower alkanoyl group, represents a lower alkylsulfonyl group or a lower alkyl group, R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) may be substituted with 1 to 2 substituents) or a heterocycle, and Y^1 represents a halogen atom or a substituent that can become a leaving group during the reaction with the following general formula (14). , n is 2 or 3, m is 0, 1, 2, 3 or 4, k is 2, 3 or 4
] and the following general formula (14) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(14) [R^1'' and R^2 are each independently a hydrogen atom, lower alkyloxy Carbonyl group, unsaturated lower alkyl group or lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower alkanoyloxy group, a benzoyloxy group) substituted with a substituent selected from the group consisting of a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group substituted with a halogen atom or a lower alkyloxy group, or a lower alkyloxycarbonyl group ) or R^1'' and R
^2 may be linked to form an alkylene chain to form a heterocyclic structure, R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^3 is a hydrogen atom, a nitro methyl group or cyano group, and n is 2 or 3]
A method for producing the compound according to claim 3. 13) The following general formula (15) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(15) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1 and R^2 are each independently a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower Alkylamino group, lower alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group, phenyl group substituted with a halogen atom or lower alkyloxy group, or may be substituted with a substituent selected from the group consisting of lower alkyloxycarbonyl groups), or form a heterocyclic structure by connecting R^1 and R^2 to form an alkylene chain. X^1 and X^2 may each independently represent a hydrogen atom, -CO-R^8, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoylamino group,
It represents a lower alkylsulfonamide group, a mono- or di-lower alkylamino group, a phenyl-substituted lower alkylamino group, or an unsaturated alkyloxy group, and R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or a lower alkyl group. Or R^1 and R
^5 may be linked to form an alkylene chain to form a heterocyclic structure, and R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is a halogen atom, a lower alkyl group, a hydroxyl group, may be substituted with 1 to 2 substituents selected from the group consisting of lower alkyloxy groups) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4 , k is 2
, 3 or 4, l is 0, 1, 2, 3 or 4] and the following general formula (16) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(16) [R^3 and R^4 each independently represent a hydrogen atom or a lower alkyl group; 2. The method for producing a pyrimidinedione derivative according to claim 1, which comprises reacting with a compound represented by the following formula, which represents a substituent that can become a leaving group during the reaction. 14) The following general formula (17) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (17) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1' is a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyl group) From an oxy group, a lower alkanoyloxy group, a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group ), and X^1 and X^2 each independently represent a hydrogen atom, -CO-
R^8, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
It represents a phenyl-substituted lower alkylamino group or an unsaturated alkyloxy group, and R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or a lower alkyl group, or R^1' and R^5 are connected A heterocyclic structure may be formed by forming an alkylene chain. ) or a heterocycle, m is 0, 1, 2, 3 or 4, k is 2, 3 or 4, l
is 0, 1, 2, 3 or 4] and the following general formula (18) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(18) [R^3 and R^4 are mutually The pyrimidinedione derivative according to claim 5, wherein the pyrimidinedione derivative is reacted with a compound represented by: independently representing a hydrogen atom or a lower alkyl group, and X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group. manufacturing method. 15) The following general formula (17) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(17) [In the formula, A is -(CH_2)_m-, -B-(CH_2)
＿k-, -D-(CH_2)_l-, ▲mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, B is oxygen atom, sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^1' is a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyl group) From an oxy group, a lower alkanoyloxy group, a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group ), and X^1 and X^2 each independently represent a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
It represents a phenyl-substituted lower alkylamino group or an unsaturated alkyloxy group, and R^5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, or a lower alkyl group, or R^1' and R^5 are connected A heterocyclic structure may be formed by forming an alkylene chain. ) or a heterocycle, m is 0, 1, 2, 3 or 4, k is 2, 3 or 4, l
is 0, 1, 2, 3 or 4] and the following general formula (19) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(19) [In the formula, R^2' is hydrogen atom, lower alkyloxycarbonyl group, unsaturated lower alkyl group, or lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyloxy group, a lower alkanoyl group) Oxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group,
It may be substituted with a substituent selected from the group consisting of a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group. ), R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, X^3 represents a hydrogen atom, a nitro group, a methyl group, or a cyano group, n is 2 or 3, 8. The pyrimidinedione according to claim 7, wherein Y^4 represents a halogen atom or a substituent that can become a leaving group upon reaction with the general formula (17). Method for producing derivatives. 16) The following general formula (20) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(20) [In the formula, A''' is -(CH_2)_m-, -B'''-(C
H_2)_k-, -D-(CH_2)_l-, ▲ Formula,
There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and B''′ is an oxygen atom, a sulfur atom, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. Yes▼or▲
D indicates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, R ^2' is a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkyl group) From an oxy group, a lower alkanoyloxy group, a benzoyloxy group, a benzoyloxy group substituted with a halogen atom or a lower alkyloxy group, a phenyl group, a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group ), R^3 and R^4 independently represent a hydrogen atom or a lower alkyl group, and X^1 and X^2 independently represent , a hydrogen atom, -CO-
R^6, halogen atom, lower alkyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkyloxy group, lower alkylthio group, lower alkyloxycarbonyl group, carboxyl group, cyano group, amino group, lower alkanoyloxy group, lower alkanoyl amino group, lower alkylsulfonamide group, mono- or di-lower alkylamino group,
Represents a phenyl-substituted lower alkylamino group or unsaturated lower alkyloxy group, X^3 represents a hydrogen atom, nitro group, methyl group, or cyano group, and R^5' represents a hydrogen atom, lower alkanoyl group, or lower alkylsulfonyl group. or a lower alkyl group, R^6 is a lower alkyl group, a cycloalkyl group, a phenyl group (the phenyl group is one or two selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, and a lower alkyloxy group) ) or a heterocycle, n is 2 or 3, m is 0, 1, 2, 3 or 4, k is 2
, 3 or 4, l is 0, 1, 2, 3 or 4] and the following general formula (21) R^1'''-Y^4... (21) [wherein R ^1''' is a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group, or a lower alkyl group (wherein any one hydrogen atom of the alkyl group is a hydroxyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower Alkyloxy group, lower alkanoyloxy group, benzoyloxy group, benzoyloxy group substituted with a halogen atom or lower alkyloxy group, phenyl group,
It may be substituted with a substituent selected from the group consisting of a phenyl group or a lower alkyloxycarbonyl group substituted with a halogen atom or a lower alkyloxy group. ), and Y^4 represents a halogen atom or a substituent that can become a leaving group when reacting with the general formula (20)]. 8. The method for producing a pyrimidinedione derivative according to 8. 17) A pharmaceutically acceptable method of producing a pyrimidinedione derivative, which comprises a step of reacting the pyrimidinedione derivative obtained by the production method according to any one of claims 10 to 16 with an acid to form a pharmaceutically acceptable acid addition salt. A method for producing an acid addition salt. 18) An antiarrhythmic agent comprising the pyrimidinedione derivative according to any one of claims 1 to 8 as an active ingredient. 19) An antiarrhythmic agent comprising a pharmaceutically acceptable acid addition salt of the pyrimidinedione derivative according to any one of claims 1 to 8 as an active ingredient.