JPH01221367A - Propanol derivative, production thereof and drug composition containing said derivative - Google Patents

Abstract

NEW MATERIAL:A propanol derivative shown by formula I (R<1> and R<2> are H, lower alkyl or aryl; X is H, halogen, nitro, amino, hydroxyl group, cyano, trifluoromethyl, carbamoyl, lower alkyl, acyl, acylamino, alkylsulfonylamino, alkylsulfonyl, alkylcarbamoyl, alkylsulfamoyl, lower alkylthio, alkoxycarbonyl or aryloxy) and an acid addition salt thereof. EXAMPLE:1,3-Dimethyl-6-{4-[2-hydroxy-3(4-nitrophenoxy)propyl]piperazin-1- yl}-2,4(1H,3H)-pyrimidinedione. USE:Useful as an antiarrhythmic drug. Prolonging voltage duration time of cardiac muscle action. PREPARATION:A compound shown by formula II [Y is group shown by formula III or formula IV (Hal is halogen)] is reacted with a compound shown by formula V to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (1) (wherein R1 and H1 independently represent a hydrogen atom, a lower alkyl group, or an aryl group; X is a hydrogen atom) , halogen atom, nitro group, amino group, hydroxyl group, cyano group, trifluoromethyl group, carbamoyl group, lower alkyl group, acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group, alkylsulfamoyl group group, lower alkylthio group, alkoxycarbonyl group or aryloxy group,
) or its acid adducts, their production methods, and antiarrhythmic agents containing them as active ingredients.

More specifically, the present invention provides a class 1 type antiarrhythmic agent.

[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.

Regarding disorders of excitatory conduction, the reentry theory is typical.
The condition for its occurrence is the heterogeneity of the refractory period in each part of the heart.
It is caused by a combination of unidirectional block, shortened refractory period, conduction delay, and the presence of a circular pathway.

The search for an ideal antiarrhythmic drug for arrhythmia therapy, which has a complex developmental mechanism and requires long-term administration of an antiarrhythmic drug, continues, but such a compound is not yet known.

Antiarrhythmic drugs are classified into four groups depending on their mechanism of action. That is, E., M., and Vaughan Williams classified antiarrhythmic drugs into the following four groups according to their action on myocardial action potential or ionic current that generates it.

Class I: Sodium channel blocker An antiarrhythmic drug that suppresses sodium current, usually has no effect on action potential duration, and has no effect on the maximum rise velocity of sodium current (Vm
ax).

Although antiarrhythmia belonging to the second class has a strong antiarrhythmia effect, it also strongly suppresses cardiac function, and care must be taken when administering to patients with heart failure or hypotension.

Class ■: β-blockers β-blockers represented by propranolol are useful for arrhythmia involving sympathetic nerves. Side effects include suppression of cardiac function due to β-blocking action, induction of bronchial asthma attacks, and induction of hypoglycemic attacks, so care must be taken when using it.

Class ■: Drugs that prolong action potential duration. These drugs significantly prolong the myocardial action potential duration and extend the effective refractory period. Therefore, reentry arrhythmia is thought to be suppressed. Amiodarone and pretylium are known as representative drugs, but both have serious side effects and must be used with caution.

Class ■: Calcium antagonist. Suppresses calcium channels and suppresses arrhythmia caused by hyperactivity of the sinoatrial node and ventricular moribund that involves the atrioventricular node in the reentry circuit.

[Problem that the invention seeks to solve]

As mentioned above, there is no known drug that is ideal for arrhythmia therapy, which has a complex pathogenic mechanism and requires long-term administration of antiarrhythmic drugs.Among these, there are class II antiarrhythmic drugs that are useful for life-threatening ventricular arrhythmias. An arrhythmic drug is close to ideal.An object of the present invention is to provide an antiarrhythmic drug with excellent medicinal efficacy.

[Means for solving problems]

The present inventors conducted extensive pharmacological research on the compound of general formula (1), and surprisingly found that the compound of general formula (1) markedly prolongs the duration of myocardial action potential.

Furthermore, in a test against ventricular arrhythmia in adults, the compound (maximum 1) exhibited a significant effect of prolonging the refractory period in both intravenous and intraduodenal administration.

Due to these pharmacological properties, the compound of -S formula (1) is classified as a class 1 antiarrhythmic drug in the E, N, Vaughan Williams classification.

The compound of the present invention has - maximum (N) (wherein R1 and R1 independently represent a hydrogen atom, a lower alkyl group, or an aryl group, Cyano group, trifluoromethyl group, carbamoyl group, lower alkyl group,
Acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group,
Indicates an alkylsulfamoyl group, a lower alkylthio group, an alkoxycarbonyl group, or an alkyloxy group;)
Specifically, it is a compound represented by
4(IH, 3H)-pyrimidinedione, 1,3-dimethyl-6-(4-(2-hydroxy-3-(3-nitrophenoxy)propylcopiperazin-1-yl) -2,
4(IH, 3B)-pyrimidinedione, 1,3-dimethyl-6-(4-(2-hydroxy-3-(2-nitrophenoxy)propyl)piperazin-1-yl+ -2,
4-(IH,3+1)-pyrimidinedione, 1,3-dimethyl-6-(4-(3-(2-fluorophenoxy)
-2-hydroxypropylcopiperazin-1-yl
-2,4(IH,3H)-pyrimidinedione, 6-(
4-(3-(4-acetoxyphenoxy)-2-hydroxypropylcopiperazin-1-yl l-1,3-dimethyl-2,4(Ill, 38)-pyrimidinedione,
1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-hydroxymethyl)phenoxypropyl)piperazin-1-yl) -2,4(IH,3+1)-pyrimidinedione, 6- (4-(3-(4-acetylphenoxy)-2-hydroxypropylcopiperazine- 1-yl)l, 3-dimethyl2.4(11(,3H)-pyrimidinedione, 6-(4-(3-(3-acetylphenoxy)-2-hydroxypropyl]piperazin=1-yl)1. 3-dimethyl 2.4(11(,3H)-pyrimidinedione, 1°3-dimethyl-6-+4-(2-hydroxy-3-(4-)lifluoromethylphenoxy)propylcopiperazin-1-yl) -2,4(IH,3
H)-pyrimidinedione, 1°3-dimethyl-6-(4
-(2-hydroxy-3-(2-trifluoromethylphenoxy)propylcopiperazin-1-yl l -2,
4(IH,3H)-pyrimidinedione, 6-(4-(3
-(4-t-butylphenoxy)-2-hydroxypropylcopiperazin-1-yl) -1,3dimethyl-2
,4(IH,3H)-pyrimidinedione,6-(4-
(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3dimethyl-2
,4(IH,311)-pyrimidinedione,3-(4
-(1,3-dimethyl2,4-dioxo-1,2,3,
4-tetrahydropyrimidin-6-yl)piperazine-
1-yl2-hydroxypropoxyphenylmethanesulfonic acid, 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-methoxycarbonylphenoxy)propylcopiperazin-1-yl-2,4( IH, 3
)1)-pyrimidinedione, 6-(4-(3-(2-
chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3 dimethyl-2,4(IH,
38) -pyrimidinedione, 6- (4-(3-chloro2-hydroxypropyl)piperazin-1-yl) -
1,3 dimethyl-2,4(1B,3H)-pyrimidinedione, 1,3-dimethyl-6-(4-[2-hydroxy-3-(4-phenoxyphenoxy)propylcopiperazin-1-yl) - 2,4(1)1.31()-pyrimidinedione, 6-(4-(3-(4-acetylaminophenoxy)-2-hydroxypropylcopiperazin-1-yl l-1,3dimethyl-2, 4 (1■, 3H)
-pyrimidinedione, 1,3-dimethyl-6-(4-(
2-Hydroxy-3-(4-phenylsulfonylphenoxy)propylcopiperazin-1-yl) -2,4(
11(,3H)-pyrimidinedione, 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-hydroxyphenoxy)propylcopiperazin-1-yl l-2
,4-(LH,3H)-pyrimidinedione, N,N-dimethyl-3-(4-(2,4-dioxo-113-dimethyl-1,2,3,4-tetrahydropyrimidine-6-
yl)piperazin-1-yl]-2-hydroxypropyloxybenzenesulfonic acid amide, 1,3-dimethyl-6-[4-[2-hydroxy-3-(4-methylthiophenoxy)propylcopiperazin-1-yl] ) −2
,4(1B,31()-pyrimidinedione,6-(
4-(3-(4-carbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl l -1,3-
Dimethyl-2,4 (IH.

311)-pyrimidinedione, 6- +4- (3-(
2-Carbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-dimethyl-2
,4(II(,311)-pyrimidinedione, 1.3-
Dimethyl-6-+4- (3-(4-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl) -2,4(IH,3H)-pyrimidinedione, 1,3-dimethyl-6-( 4-(3-(2-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl) -2,4(Ill,
3H)-pyrimidinedione, 1,3-dimethyl-6-(
4-(2-hydroxy-3-(2-methylcarbamoylphenoxy)propylcopiperazin-1-yl) -2
,4(18,3)1)-pyrimidinedione,6-(4
-(2-hydroxy-3-phenoxy)piperazine-1
-yl) 4,3-diisopropyl-2,4(Ill
, 311) Pyrimidinedione, 1,3-diphenyl-6-(4-(2-hydroxy-3-phenoxypropyl)piperazin-1-yl]-2,4(IH,3H)
Pyrimidinedione, 6-(4-(3-(4-chloroenoxy)-2-hydroxypropylcopiperazine-1-
yl)-3-methyl-2,4(18,38)-pyrimidinedione, 6-(4-(2-hydroxy-3-phenoxypropyl)piperazin-1-yl), 1-methyl-
2,4(IH,3H)-pyrimidinedione, 6-[4
-(2-hydroxy-3-phenoxypropyl)piperazin-1-yl]-3-methyl-2,4(1!1.3H
)-pyrimidinedione, 6-(4-(3-'(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1-isopropyl-3-methyl-2,
4(IN, 38)-pyrimidinedione, 6-(4-
(3-(4-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl) -1,3dimethyl-2
,4(IH13■)-pyrimidinedione,6-(4-
(3-(2-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl) -1,3-dimethyl-
2,4(IH,3H)-pyrimidinedione, 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-methanesulfonylaminophenoxy)propylcopiperazin-1-yl) -2,4 (18,3H)-pyrimidinedione, 1,3-dinotyl-6-[4-(2-hydroxy-3-(4-methanesulfonylaminophenoxy)propylcopiperazin-1-yl)-2,4(IH, 3H
)-pyrimidinedione, 1,3-dimethyl-6-(4-
(2-hydroxy-3-(4-methanesulfinylphenoxy)propyl]piperazin-yl) -2,4
(IN, 3H)-pyrimidinedione, 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-methanesulfonylphenoxy)propylcopiperazin-1-yl l-2,4(IH, 311 )-pyrimidinedione and the like.

The compound of general formula (1) of the present invention has the formula -i (I[) (wherein Y is -CIl-CI or -CIlCIIJal
\o' 6H (in the formula, Hal means a halogen atom), X is -C
Substituent corresponding to formula (1) The compound is reacted in the presence of a suitable solvent and, if necessary, a dispersant. Solvents used include, for example, water, aromatic hydrocarbons (e.g. benzene, toluene, xylene); ketones (e.g. acetone, methyl ethyl ketone); halogenated hydrocarbons (e.g. chloroform, carbon tetrachloride, chlorobenzene, dichloromethane); ethers. (eg tetrahydrofuran, dioxane); sulfoxides (eg dimethylformamide or N-methylpyrrolidone). As a solvent, especially when using a polar solvent,
For example, alcohols are preferably used. Suitable alcohols include, for example, methanol, ethanol, isopropanol, tert-butanol, and the like.

The reaction is usually carried out at a temperature up to the reflux temperature of the solvent or dispersant used, preferably in the temperature range of 60 to 100°C.

In addition, the reaction can be carried out in the presence of a base, and as the base, common bases such as potassium carbonate, sodium carbonate, and triethylamine can be used. It can be synthesized at will.

First, the compound of the general formula (Ill) is reacted with epichlorohydrin or epibromohydrin, and the compound of the general formula (Ill) is reacted with the compound of the general formula (Ill).
IV) (In the formula, R1 and R2 independently represent a hydrogen atom or a lower alkylaryl group.

Y is -CL-CI or 1IalCIlz-CH-\0
'011 (in the formula, Hat means a halogen atom)) is synthesized, and then a compound of the general formula (V), rho1 (wherein, X is replaced by X in the general formula (1)) is synthesized. ) indicating the corresponding substituent in a suitable solvent or dispersant, such as penzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, chlorobenzene, dioxane, ether, tetrahydrofuran, water, dimethylsulfoxide, dimethylformamide, N- The 0 reaction obtained by reacting with a solvent or suspension in methylpyrrolidone etc. proceeds at the reflux temperature of the solvent or dispersant. Further, it is preferable to carry out the reaction in the presence of at least the same amount of a base such as potassium carbonate, sodium carbonate, or triethylamine.

Furthermore, as an alternative method, the compound of general formula (1) can also be obtained by the following method. That is, - the compound of maximum (II) and piperazine are reacted under the same conditions as the reaction with (I[I) described above, and the compound of the general formula (Vl) (wherein, X corresponds to X of the general formula (1) (indicating a substituent) is synthesized, followed by -maximum % formula % (wherein R1 and R1 independently represent a hydrogen atom or a lower alkyl group; l1al represents a halogen atom.

) can be synthesized by reacting them under the same conditions as the reactions (2) and (3) above.

-S Among the compounds of formula (T'), the compounds in which X is an alkylsulfonylamino group may be combined with alcohols such as methanol, ethanol, propatool, or ethyl acetate, acetic acid, dimethylacetamide. After hydrogenation using a hydrogenation catalyst such as Pd/C in a solvent such as dichloromethane, dioxane,
triethylamine in a solvent such as dimethylformamide,
It can be synthesized by reacting an alkylsulfonyl chloride in the presence of a base such as pyridine.

-a Among the compounds of formula (1), the compounds in which X is alkylsulfinyl or alkylsulfonyl are the compounds in which X is an alkylthio group, in a solvent such as acetic acid, dichloromethane, or chloroform, in hydrogen peroxide or t-butyl hydrogen peroxide. ,m
-Can be synthesized by oxidation with chloroperbenzoic acid, etc.

- At least one asymmetric carbon exists in the maximum (1) compound, and optical isomers exist. Two types of beta-adrenergic receptor inhibitory activity are dominant.

The class Ⅰ antiarrhythmic effect of the present invention shows approximately the same activity for the 1-, 6-, and racemic forms.

As a class ■ type antiarrhythmia drug, it is preferable that it does not have a β-adrenergic receptor inhibitory effect that suppresses cardiac function.

Separation of optical isomers is achieved by common chemical methods.
For example, (1) a method of forming a diastereomer salt with an optically active acid such as tartaric acid or camphorsulfonic acid and the compound of general formula (1) and fractionally recrystallizing it to obtain one of the optical activities;
2) - Maximum (1) method of using an optically active intermediate in the production process, and (3) use of column chromatography for separating optical isomers; using these methods, it is possible to produce the desired optically active substance. Can be done.

When converting the compound of general formula ([) into its pharmacologically acceptable salt, -a the compound of formula (1) is mixed with an inorganic or organic acid, such as hydrochloric acid, in water or an organic solvent or a mixed solvent thereof. , hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, etc.

When the compound of the present invention is used as a therapeutic agent for arrhythmia, the dosage and dosage form vary depending on the physical properties of the compound and the symptoms to be administered, but 1 to 1,000 μg per adult day can be administered orally, for example, in tablets, granules, or powders. It can be administered parenterally, for example, as a suppository, injection, or isotonic solution for infusion.

A general method for producing the pharmaceutical composition of the present invention includes, for example, dissolving the compound of the present invention in an arbitrary amount of oil selected from cottonseed oil, corn oil, peanut oil, and olive oil to prepare a non-aqueous injection; Aqueous injections can be obtained by adding water to form an emulsion in the presence of a suitable surfactant, or tablets can be prepared by adding crystalline cellulose and pure silicic anhydride as adsorbents to the compound of the present invention, and further excipients. Examples include a method of adding corn starch or the like as an excipient and finally adding magnesium stearate to prepare a preparation.

〔Effect of the invention〕

The compounds of the present invention provide useful Las type antiarrhythmic agents.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.

Example 1 1.3-dimethyl-6-+4- (2-hydroxy-3
(4-nitrophenoxy)propylcopiperazine-1-
yl)-2,4(IH,3T()-pyrimidinedione・
Hydrochloride 4-nitrophenoxydibricidyl ether (1°6g)
and 1,3-dimethyl-6-(1-piperazinyl)-2,
4(IH13H)-pyrimidinedione (1,94g)
was dissolved in ethanol (70d) and heated under reflux for 2 hours. After concentration, silica gel column (MeOH/CHCl5-1
/100 to 3/100) purified to 1,3-dimethyl-6
-(4-(2-hydroxy-3(4-nitrophenoxy)propyl)piperazin-1-yl)-2,4(LH,
3H)-pyrimidinedione (2.75 g, 80%) was obtained.

mp 180-181°C 1,3-dimethyl-6-(4-[2-hydroxy-3(
4-nitrophenoxy)propylcopiperazin-1-yl)-2,4(IH13H)-pyrimidinedione (3,
3g) was dissolved in chloroform (70IR1), methanol (150mffi) was added, and an excess molar amount of hydrochloric acid/methanol was added. After condensing this solution to 70 d, ethanol (70 d) was added, and further concentrated to about 50 d,
After cooling, the precipitated crystals were collected by filtration, and 1,3-dimethyl-6-
(4-(2-hydroxy-3-(4-nitrophenoxy)propylcopiperazin-1-yl)-2,4(IH,
3H)-pyrimidinedione hydrochloride (3.14 g) was obtained.

mp 226-228°C Elemental bone Fr C+*thsNs(h ・IIcI calculated value C: 50.06, ll: 5.57, N: 15.36
, C1 near, 78 analysis value C: 49.43, H: 6
．． 16, N: 15.0? , C1:8.05IR(KB
r) cm-': 1700.1630.1490
．． 1430. 1265.1110.965.840.
795.745.660 Example 2 1.3-dimethyl-6-(4-(2-hydroxy-3-
(3-nitrophenoxy)propylcopiperazine-1-
yl)-2,4(IH,3H)-pyrimidinedione hydrochloride 3-nitrophenoxyglycidyl ether (1°37g
) and 1,3-dimethyl-6-(l-piperazinyl)-2
,4(IH,3)I)-pyrimidinedione (1,57g
) was dissolved in ethanol (30rd) and heated under reflux for 2 hours. The crystals precipitated by cooling were collected by filtration and recrystallized with ethanol to give 1,3-dimethyl-6-(4-(2-hydroxy-3(3-nitrophenoxy)propyl)piperazin-1-yl)- 2,4(LH,3H)-pyrimidinedione (2.36 g, 80%) was obtained.

89142-144°C NMR (CDCh) δppm: 2.5-3.2 (IO
H, m), 3.34 (s, 3H), 3.42 (s,
3H), 4.0-4.3 (m, 3H), 5.26
(s, IH), 7.2-8.0 (+w, 4H) 1.3-dimethyl-6-[4-(2-hydroxy-3-
(3-nitrophenoxy)propylcopiperazine-1-
)-2,4(IH,3H)-pyrimidinedione was treated with hydrochloric acid/methanol to give 1,3-dimethyl-6-(4
-C2-hydroxy-3-(3-nitrophenoxy)propylcopiperazin-1-yl)-2,4(IH,3H
)-pyrimidinedione hydrochloride was obtained.

all 241-243℃ Elemental bone Fr C+, HzsNsOh-) ICI calculation value
C: 50.06, old 5.75, N: 15.36, C
h7.78 analysis value C: 49.90, H: 5.90,
N: 15.24, C1 near, 76IR (KBr)
cva-': 1700, 1645, 1525,
1345, 1255.1200.970.810.76
0.740.6706-(4-(3-(4-cyanophenoxy)-2-hydroxypropyl)piperazine-1
-yl1-1,3-dimethyl-2,4(LH,3H)-
Pyrimidinedione hydrochloride 4-cyanophenyl glycidyl ether (1,4 g) and 1,3-dimethyl-6-(1-piperazinyl)-2,4
(IH,3H)-pyrimidinedione (1.59 g) was dissolved in ethanol (20d) and heated under reflux for 2 hours.

After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane/ethanol to give 6-(4-(3-(4-cyanophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1°3 -Dimethyl-2,4(IH,3H)-pyrimidinedione (2,67 g, 95.5%) was obtained.

mp 198-200°C NMR (CDCIx) δpp+*: 2.6-3.4 (
m, l0H), 3.38 (s, 3H), 3.46 (s,
3H), 4.14 (m, 3B), 5.32 (s, IH
), 7.0-7.8 (■, 4H) Elemental analysis C8°Hg511sO4・1/2CIHsOH
Calculated values C: 59.70, H: 6.68, N: 16
．． 58 analysis value (:59.42, HF2.18, N:
14.7B The above non-hydrochloride salt was treated with hydrochloric acid/methanol to give 6-(4-(3-(4-cyanophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-dimethyl-2, 4(IH,3H)-pyrimidinedione hydrochloride was obtained.

MP 228°C (decomposition) Elemental analysis C:. H□NSO,・1.8CI -CI!
OH calculation value C: 50.74, H: 6.25, N: 1
4.09, Ct: 12.84 Analysis value C: 50.28
, H: 6.73, N: 14.26, C1: 12.5
6IR(KBr) cm-': 3300.2950
．． 2680.2230.1690.1630.1600
．． 1500.1436.1389.1295.1255
, 1172.1025 Example 3 1.3-dimethyl-6-(4-(2-hydroxy-3-
(2-nitrophenoxy)propylcopiperazine-1-
Hydrochloride of 1,3-dimethyl-6-(4-(2-hydroxy-3-
(2-nitrophenoxy)propyl)piperazine-1-
yl)-2,4(IH,3H)-pyrimidinedione Synthesized in the same manner as in Example 1.

Rinp 168-170°C 11MR (CDCI) δpp-: 2.75 (m,
108), 3.25 (s, 3B), 3.40 (s,
3H), 4.20(s, 3H), 5.26(s, I
R), 7.50 (m, 4H) IR (KBr) cta-': 1680.1640
．． 1600.1520.1430.1340.1270
．． 1200 Elemental analysis CIH□N, 0 & Calculated value C: 54.41, H: 6.01, N: 16
．． 70 Analysis value C: 54.12, H: 5.99, N:
16.60 The non-hydrochloride salt is treated with hydrochloric acid/methanol to
3-dimethyl-6-(4-(2-hydroxy-3-(2
-nitrophenoxy)propylcopiperazin-1-yl) -2,4(IH13H)-pyrimidinedione hydrochloride.

12242-245°C Elemental analysis CIqNzsNsCh・HCI calculated value C:5
0.05, H: 5.74, N: 15.36, C1
Near, 77 analysis value C: 49.75, lh5.85,
N: 15.29, C1 near, 93 Example 4 1.3-dimethyl-6-(4-(3-(2-fluorophenoxy)-2-hydroxypropylcopiperazine-1
-yl)-2,4(IH,3H)-pyrimidinedione
Hydrochloride was synthesized in the same manner as in Example 1.

1.3-dimethyl-6-(4-(3-(2-fluorophenoxy)-2-hydroxypropylcopiperazine-1
-yl)-2,4(IH13H)-pyrimidinedione NMR (CDCI δppm: 2.5-2.85(m
, 5H), 2.85-3゜1 (s, 5H), 3.2
8 (s, 3H), 3.34 (s, 3) 1) -14,0~
4.25 (s, 3H), 5.22 (s,, LH),
6.9 - 7.2 (m, 4H) 1,3-dimethyl-6-
(4-(3-(2-fluorophenoxy)-2-hydroxypropyl)piperazin-1-yl l-2,4(IH
,3H)-pyrimidinedione/hydrochloride ■p230-234℃ Elemental analysis C+*lI□N404/HCI calculated value C:5
3.21, H: 6.11, N: 13.06, F: 4.
43, CI: 8.27 Analysis value C: 53.25, H: 6.40. N:13
．． 04, F: 4.11, CI: 8.44 rR (KBr) cm-': 1710.1650.
1280%1215.1130°1050,. 1000
．． 800 Example 5 6-(4-(3-(4-acetoxyphenoxy)-2
-hydroxypropylcopiperazin-1-yl)-1,
3-Dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

6- (4-(3-(4-acetoxyphenoxy)=2
-hydroxypropylcopiperazin-1-yl)-1,
3-dimethyl-2,4(IH,3H)-pyrimidinedione NMR (CDC1i) δppm: 2.3(s, 3
H), 2.5-3.5 (m, 8H), 3.35 (s,
3H), 3.4(s, 3H), 3.9-4.3(m,
3H), 5.3(s, 111), 6.8-7.2(
s,4H)IR(KBr)am-': 1760
．． 1660.1640.16o5.15o56- (4
-(3-(4-acetoxyphenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-dimethyl-2,4(LH,3H)-pyrimidinedione hydrochloride 1Iip 238-241℃ Elemental analysis C□111□N40.・HCI・H,0 calculated value C: 51.80, H: 6.24, N: 11.51.
Cl near, 28 analysis value C: 51.63, II: 6.78
, N: 11.95, C1: 8.42 Example 6 1.3-dimethyl-6-[4-(2-hydroxy-3-
(4-Hydroxymethyl)phenoxyprobylcopiperazin-1-yl l-2,4(IH13H)-pyrimidinedione 19m 4-(2,3-epoxy)propyloxybenzyl alcohol 4-hydroxybenzyl alcohol (2,48g) and epichlorohydrin (9,2 g) and potassium carbonate (1,6
g) was added to acetone (10m) and heated under reflux for 6 hours. After removing the precipitate by filtration and concentrating the filtrate, the residue was purified with a silica gel column to obtain 4-(2,3-epoxy)propyloxybenzyl alcohol (1.43 g, 40%).
I got it.

NMR (CDCIm) δppm: 1.90 (t, J 5H, IH), 2.7-3.1 (m, 2H), 3.
3 ~ 3.6 (s, IH), 4.13 (8 Bq, J
-11Hz, 18Hz, 18), 4.22 (ABQ, J
= 11H2, 18H2, 4.70 (d, J-5
H2, 2H), 7.00 (d, J=9Hz, 2H), 7
．． 37(d, J-911z, 2H) Subsequently, the same reaction as in Example 1 was carried out to obtain 1,3-dimethyl-6-(4-(2
-Hydroxy-3-(4-hydroxymethyl)phenoxyprobilcopiperazin-1-yl)-2,4(IH1
3H)-pyrimidinedione was synthesized.

NMR (DMSO-d δppm: 2.3-3.1
(m, 101), 3.12 (s, 3H), 3.27
(s, 3B), 3.88 (brs, 2H), 3.7
~4.1 (m, 18), 4.38 (d, J-6Hz
, 2H), 4.80 (d, J-4Hz, 1ll), 4.
94 (t, J=6Hz, IH), 5.12 (s, LH)
, 6.81 (d, J=9Hz, 2H), 7.08 (d,
J = 9Hz, 2H) Treatment of the non-hydrochloride with hydrochloric acid/methanol to give 1,3-dimethyl-6-(4-[2-hydroxy-3-(4-hydroxymethyl)phenoxyprobilcopiperazin-1-yl) -2,4(IH,3H)-pyrimidinedione hydrochloride.

19202~204℃ Elemental analysis calculation value C150.37,! (:6.97, N:11.7
5, Cl near, 43 analysis value C: 51.33, H near, 3
9, N: 11.97, Cl nia, 62 Example 7 6- (4-(3-(4-acetylphenoxy)-2-
hydroxypropylcopiperazin-1-yl)l,3-
Dimethyl2.4 (LH,3H)-pyrimidinedione・
Hydrochloride example! was synthesized in a similar manner.

6-(4-(3-(4-acetylphenoxy)-2-hydroxypropyl)piperazin-1-yl) 1.3-
Dimethyl 2.4 (IH,3H)-pyrimidinedione mp 12a~132°C 6-(4-(3-(4-acetylphenoxy)-2-hydroxypropylcopiperazin-1-yl)1,3-dimethyl 2 .4(LH13H)-pyrimidinedione hydrochloride mp 229-231℃ Elemental analysis C+HisNaOs・1(C1・!1□0
Calculated value C: 53.56, th6.64, )l: 11.9
0, Cl near, 53 analysis value C: 53.37, F15.8
3, lJ: 11.56, Cl nia, 87 Example 8 6- (4-(3-(2-acetylphenoxy)-2-
hydroxypropylcopiperazin-1-yl) 1.3
-Dimethyl2.4 (LH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

6- (4-(3-(2-acetylphenoxy)-2-
hydroxypropylcopiperazin-1-yl) 1.3
-Dimethyl 2.4 (IH,3H)-pyrimidinedione mp 133-134°C Elemental analysis C□HzsNaOs Calculated value C: 60.56, lI: 6.78, N: 13.4
5 Analysis value C: 60.80, H near, 40, N: 13.4
16- (4-(3-(2-acetylphenoxy)-2
-hydroxypropyl)piperazin-1-yl) 1.
3-dimethyl 2.4 (LH,3H)-pyrimidinedione hydrochloride mp 125-128°C Elemental analysis Cz+l1raN40s・)ICI・th.

Calculated value C: 53.56, ll: 6.64, ) hll, 9
0, Cl near, 53 analysis value C: 53.10, H near, 2
8, +l: 11.41, C1: 8.59 Example 9 6- +4- (3-(3-acetylphenoxy)-2
-hydroxypropylcopiperazin-1-yl)1,3
-Dimethyl2.4 (IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

6- (4-(3-(3-acetylphenoxy)-2-
hydroxypropylcopiperazin-1-yl) 1,3
-Dimethyl2.4(IH13H)-pyrimidinedione mp 134-136°C Elemental analysis Cz+HiJ40s Calculated value C: 60.56, old 6678,! 1:13.45
Analysis value C: 60.32, H near, 27, N! 13.42
6- (4-(3-(3-acetylphenoxy)-2-
hydroxypropylcopiperazin-1-yl) 1.3
-Dimethyl2.4 (LH,3H)-pyrimidinedione hydrochloride mp 217-219°C Elemental analysis Cz+l1zsN40s·HCI -uz.

Calculated values C: 53.56, H: 6.64, N: 11.90
, C1 near, 53 analysis value C: 53.92, H: 6.98
, N: 11.90, C1: 8.24 Example 10 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-1-Lifluoromethylphenoxy)propylcopiperazin-1-yl l-2,4(IH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-Trifluoromethylphenoxy)propylcopiperazin-1-yl)-2,4(LH13H)-pyrimidinedione mp 143-1'45°C NAR(CDCl2)δpp+m: 2.6-3.4
(m, 10'n), 3.36 (s, 3H), 3.44
(s, 3Q), 4.11 (s, 3H), 5.30 (s,
LH), 7.0-7.7 (+m, 411) Elemental analysis C2°H□F, N404 Calculated value C: 54.29, old 5.70. F: 12.8B
, N: 12.66 Analysis value C: 54.11, H: 5.80
．． F: 12.25, N: 12.80 1.3-dimethyl-6-(4-(2-hydroxy-3-(4-)lifluoromethylphenoxy)propylcopiperazin-1-yl]-2,'4 (LH13H)-pyrimidinedione hydrochloride mp 233-235°C (decomposition) Elemental analysis C8°HtsFJaOa・IIcI calculated value C
: 50.16, H: 5.47, F: 11.90, C1 near, 4ON: 11.70 Analysis value C: 50.37, ll: 6.55, F: 11.8
0, Cl near, 28N? 11.80 IRCKBr) cya-': 3400.3250
．． 1708.1640.1616.1495.1443
．． 1255.1163.1114.1070.991.
848.765 Example 11 1.3-dimethyl-6-(4-(2-hydroxy-3-
(3-1-Lifluoromethylphenoxy)propylcopiperazin-1-yl)-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(3-Trifluoromethylphenoxy)propylcopiperazin-1-yl)-2,4(LH13H)-pyrimidinedione mp 113-115"C NMR (CDCl2) δppm: 2.5-3.5 (m
, 118), 3.38 (s, 311), 3.46 (s
, 311), 4.0-4.4 (m, 3H), 5.33
(s, IH), 7.1-7.6 (monk, 4+1) Elemental analysis C2゜HtsFJaOa Calculated value C: 54.29, old 5.70, F: 12.8B,
N: 12.66 Analysis value C: 55.14, R: 6.54,
F: 13.86, N: 11.571.3-dimethyl-6
-(4-(2-hydroxy-3-(3-trifluoromethylphenoxy)propylcopiperazin-1-yl)
-2,4(IH13H)-pyrimidinedione hydrochloride 1wp 115°C (decomposition) Elemental analysis CxoHzsPxNaOa ・1.6HC1
Calculated values C: 41.91, II: 5.35, t': 11.
38, C1: 11.33 N: 11.19 Analysis value C: 47.92, H near, 52, F: 12.44
, C1:11.52N:9.80 IR (MBr) cm-': 3420.2950
．． 2700.1700.1648.1496.1450
．． 1330. ．． 1240. 1170.1125.1
069.800.763.701 Example 12 1.3-dimethyl-6-(4-(2-hydroxy-3-
(2-)Lifluoromethylphenoxy)propylcopiperazin-1-yl)-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

1,3-dimethyl-62[4-(2-hydroxy-3-
(2-) Lifluoromethylphenoxy)propylcopiperazin-1-yl l-2,4(LH13H)-pyrimidinedione m9 170-173°C NMR (CDCl2) δppm: 2.5-3.1 (
a+, 10) 1), 3.25 (s, 38), 3.33
(s, 3H), 4.02 (s, 3H), 5.18 (s,
IH), 6.8-7.6 (m, 4H) Elemental analysis CztrHzsFrNaO.

Calculated values C: 54.29, H: 5.70, F: 12.8B
, N: 12.66 Analysis value C: 54.22, ) I: 6.0
9, p: 1z, so, N: 12,471.3-dimethyl-6-(4-(2-hydroxy-3-(2-trifluoromethylphenoxy)propylcopiperazin-1-yl)-2,4 (IH13H)-pyrimidinedione hydrochloride sp 159-160°C (decomposition) Elemental analysis C2゜ll□F4NaOa・)ICI calculated value C: 47.97, )l: 5.35, F: 11.90.
C1 near, 4ON: 11.70 Analysis value C: 47.92, H near, 52, F: 11.20
．． C1:8.11N:11.32 IR(KBr) C1: 3400.3250.17
01.1642.1610゜1497.1455.13
24.1275.1248.1160, 1120.10
37.772.762 Example 13 6-(4-(3-(4-t-butylphenoxy)-2
-hydroxypropylcopiperazin-1-yl)-1,
3dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

6- (4-(3-(4-t-butylphenoxy)-2
-hydroxypropylcopiperazin-1-yl)-1,
3dimethyl-2,4(11(,3H)-pyrimidinedione mp 110-112°C !1MR(CDC13) δppm: 1.37(
s, 98), 2.6-3.1 (s, 10H), 3.4
0 (s, 3H), 3.47 (s, 3H), 4.10 (m
, 38), 5.35 (s, IH), 6.9-7.5 (+
+, 4H) Elemental analysis CzxIIzaNaOa Calculated value C: 64.16, H near, 96, N: 13.01
Analysis value C: 63.76, H near, 90. , N: 12.8
26- (4-(3-(4-t-butylphenoxy)-
2-hydroxypropylcopiperazin-1-yl)-1
,3dimethyl-2,4(11-1,3H)-pyrimidinedione hydrochloride mp 264-265°C (decomposition) Elemental analysis CzsHsaNaOa・IIcI calculated value C:
59.15, H near, 55, Cl near, 59, N:1
2. OO analysis value C: 58.75, H: 8.25, C1 near, 87, N: 12.0? IR(KBr)C11-'
: 3220.2960.2300.1702.16
30°1608.1515.1490.1440.12
45.1208.1192.990.832.795,
Example 14 6-+4- (3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl 1-1.3 dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride Example It was synthesized in the same manner as 1.

6-(4-(3-(4-chlorophenoxy)-2-hydroxyprobyl]piperazin-1-yl)-1,3dimethyl-2,4(IH,3H)-pyrimidinedione NMR (CDC13) δppm: 2.4-3.3
(II, 8H), 3.3(s, 3H), 3.3
3 (s, 3H), 3.9-4.3 (m, 3H),
5.23 (s, In), 6.9 (d, J=8Hz, 2
H) ,7.3(d,J-8Hz,211)6-(4
-(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3dimethyl-2
,4(IH,3H)-pyrimidinedione hydrochloride mp 215-218℃ Elemental analysis Cl9H□N404C1・IIcI -1,
.

Calculated value C: 49.25, H: 6.09, N: tz, oq
, CI: 15.30 Analysis value C: 49.12.116.4
1, N: 11.99, CI: 15.69 Example 15 3-(4-(1,3-dimethyl 2,4-dioxo-1,
2,3,4-tetrahydropyrimidin-6-yl)piperazin-1-yl]-2-hydroxypropoxyphenyl methanesulfonic acid hydrochloride Synthesized in the same manner as in Example 1.

3-(4-(1,3-dimethyl2,4-dioxo-1
,2,3,4-tetrahydropyrimidin-6-yl)piperazin-1-yl2-hydroxypropoxyphenylmethanesulfonic acid NMR (CDC13) δ1111
111: 2.5-3.4 (II, 10H), 3.1 (
s, 3H), 3.3(s, 3H), 3.4(s, 3H)
), 3.9-4.2 (m, 3H), 5.23 (s, I
H), 6.9 (d, J=8Hz, 2H), 7.
2 (d, J-8Hz.

2I() 3-(4-(1,3-dimethyl2,4-dioxo-1
,2,3,4-tetrahydropyrimidin-6-yl)piperazin-1-yl2-hydroxypropoxyphenylmethanesulfonic acid hydrochloride mp 229-232
°C Elemental analysis C. HxsNnOyS -HCl・■O0
Calculated value C: 45.93.115.97, N: 10.71
, C1: 6.78 S: 6.13 Analysis value C: 46.22, H: 6.22, N: 10.24
, C1:6.72S:6.89 Example 16 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-methoxycarbonylphenoxy)propylcopiperazin-1-yl)-2,4(LH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 1.

1.3-zume. Chil-6-(4-(2-hydroxy-3
-(4-methoxycarbonylphenoxy)propylcopiperazin-1-yl)-2,4(IH.

3H)-pyrimidinedione NMR (CDCI δppm: 2.5-3.2(m,
8H), 3.33 (s, 3■), 3.4 (s, 3H)
, 3.9 (s, 3H), 3.9-4.3 (m, 5H)
,5.3(s,IH) ,? , 0(d, J=811z,
211), 8.06 (d, J=8Hz, 2■) 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-Methoxycarbonylphenoxy)propylcopiperazin-1-yl) -2,4(IH13H)-pyrimidinedione hydrochloride up 239-241°C Elemental analysis C□HtmN401HCI Calculated value C: 53.78, H: 6. 23, N: 11.95
, Cl near, 56 analysis value C: 53.64, H: 6.42
, N: 11.65, C1 near, 59 Example 17 6-(4-(3-(2-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3dimethyl-2,4( IH,3H)-pyrimidinedione hydrochloride 6-(4-(3-chloro2-hydroxybutopyr)piperazin-1-yl)-1,3dimethyl-2,4(IH
13H)-pyrimidinedione 1,3-dimethyl 6-(1
-piperazinyl)-2,4(IH13H)-pyrimidinedione (30g) in chloroform (150d), add epichlorohydrin (123g),
Heated at 65°C for 7 hours. This reaction solution was concentrated, dichloromethane (300 d) was added to the residue, and saturated aqueous sodium bicarbonate (15 d) was added to the residue.
0F! After drying with Glauber's salt washed with 1x2), it was concentrated, crystallized with ether, and the crystals were collected by filtration to give 6-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)-1,3- Dimethyl-2,4(IH,3H)-pyrimidinedione (34 g) was obtained.

6-(4-(3-(2-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl 1-1.3 dimethyl-2,4(LH,3H)-pyrimidinedione m-chlorophenol (0, 39g) was dissolved in 6% caustic soda (2me) and ethanol (2d) was added to give 6-(4-(2-chloro-2-hydroxypropyl)piperazin-1-yl)-1,3-dimethyl-2. ,4
(LH,3H)-pyrimidinedione (0.56 g) was added and heated at 80°C for 2 hours.

Additional m-chlorophenol (0.26 g) was added and the mixture was heated for a further 2 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in chloroform and washed with water. The chloroform layer was dried with Glauber's salt and then concentrated. The residue was filtered onto a silica gel column (MeoH/C
6-(4-(3-(2-chlorophenoxy)-2-hydroxypropyl)piperazin-1-yl)-1,3 dimethyl- 2,4(LH,3H)-pyrimidinedione (0
, 21g, 26%) was obtained.

sp 133-134°C Elemental analysis C+ qHtsNaOacI calculated value C: 55
．． 31. H: 6.16, N: 13.70. C1:8
．． 67 analysis value C: 55.57, H: 6.48, N: 13
．． 71. C1:8.67 The above non-hydrochloride salt was treated with hydrochloric acid/methanol to give 6-(4-(3-(2-chlorophenoxy)-2-hydroxypropylcopiperazine-1-
yl)-1,3 dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride.

1llp 230-232.5°C Elemental analysis C+JzsN40aC1-HCI calculated value C:
51.24, H: 5.88, N: 12.58, C1:1
5.92 Analysis value C: 51.20, H: 6.31, N: 1
2.43, C1:16.98IR(KBr) CI-'
: 3400.2530.2450.1696.16
40.1595.1485.1439.1392.12
95.1242.1192.1033.982.775
, Example 18 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-phenoxyphenoxy)propylcopiperazine-
1-yl)-2,4(LH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-phenoxyphenoxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione ■p 161-162°C NMR (CDCh) δppm: 2.5-3.3
(+s, 10H), 3.32 (s, 3H), 3.38
(s, 3H), 3.8-4.3 (m, 311), 5
．． 23 (s, 1) 1), 6.9-7.2 (m, 9B) Elemental analysis CgsHsJaOs Calculated value C: 61.36.11: 6.48, N: 12.0
1 analysis value Ω64.28, I(:6.62, N:12.0
61.3-dimethyl-6-(4-(2-hydroxy-3
-(4-phenoxyphenoxy)propylcopiperazin-1-yl)-2,4(LH,3H)-pyrimidinedione hydrochloride sp 215-218°C Elemental analysis C-poly5HsoN40s ・1.2HC1 Calculated value C: 58. 84, H: 5.96, N: 10.98, C
1:8.34 Analysis value C:59.14, H:6.05, N
:11.09, C1:8.35IR(lBr) cm-
': 1705.1640.1435.1220.9
80.845.755.690 Example 19 6- (4-(3-(4-acetylaminophenoxy)
-2-hydroxypropyl]biperazin-1-yl l-
1,3 dimethyl-2,4(LH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

6- (4-(3-(4-acetylaminophenoxy)
-2-hydroxypropyl)piperazin-1-yl)-
1,3 dimethyl-2,4(IH13H)-pyrimidinedione mp 178-180″C NMR (CDCIz+DMSO-di) δppm: 2
．． 11 (s, 3H), 2.5-2.8 (m, 4H),
2.8-3.2 (m, 6tl), 3.28 (s, 3H
), 3°38(s, 3H), 3.8~4.2(m, 3H
), 5.18(s, LH), 6.83(d, 21()
, 7.48 (d, 2B), 9.34 (s, IH) 6-
(4-(3-(4-acetylaminophenoxy)-2-
Hydroxypropylcopiperazin-1-yl l-1,3
Dimethyl-2,4(IH13H)-pyrimidinedione
Hydrochloride 1266-269°C Elemental analysis Ct+H*qNsOs・HCI calculated value C: 5
3.90, H: 6.46, N: 14.96, C117,
58 analysis values C: 53.59, H: 6.67, N: 14.
80, C1 near, 60IR (KBr) C+++-1:
1700.1660.1510.1240.1040
．． 830.760.520 Example 20 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-Phenylsulfonylphenoxy)propylcopiperazin-1-yl l-2,4(IH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-Phenylsulfonylphenoxy)propylcopiperazin-1-yl l-2,4(LH13H)-pyrimidinedione NMli (CDCl ff) δppm: 2.5-3
．． 2 (m, 8H), 3.33 (m, 511), 3.4 (
s, 3H), 4.0-4.3 (m, 3tl), 5.3
(s, IH), 7.0-8.1 (cut, 9■) 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-Phenylsulfonylphenoxy)propylcopiperazin-1-yl -2,4(If(,3H)-pyrimidinedione hydrochloride amorphous crystal elemental analysis CtsHs.Na0aS ・1'/JCB
・3H! 0 calculated value C: 50.78, H: 6.39,
N: 9.47, C1: 8.99 S: 5.42 Analysis value C: 50.66, H: 6.48, ll: 9.43
, C1:9.15S:5.41 Example 21 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-hydroxyphenoxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-hydroxyphenoxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione NMR (CDCIs) δppm: 2.4-3.1(m
+10H), 3.32 (s, 31), 3.38 (s,
3H), 3.8-4.2 (m, 3)1), 5.
24 (s, LH), 6.7-6.9 (m, 4H) 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-hydroxyphenoxy)propyl)piperazine-
1-yl)-2,4(LH13H)-pyrimidinedione/hydrochloride elemental analysis C+JzhNaOs/HCI-HfO calculated values C: 51.29, II: 6.57, N: 12.59
, C1 near, 97 analysis value C: 51.39, H: 6.92
, N: 13.03, C1: 8.19 Example 22 N,N-dimethyl-3-(4-(2,4-dioxo-1
, 3-dimethyl-1,2,3,4-tetrahydropyrimidin-6-yl)piperazin-1-yl]-2-hydroxypropyloxybenzenesulfonic acid amide hydrochloride It was synthesized in the same manner as in Example 17.

N,N-dimethyl-3-[4-(2,4-dioxo-1
,3-dimethyl-1,2,3,4-tetrahydropyrimidin-6-yl)piperazin-1-yl]-2-hydroxypropyloxybenzenesulfonic acid amide NMR (CDCIs) δpp+w: 2.4-3
．． 1 (m, 811), 2.7 (s, 6H), 3.2~
3.5 (m, 3H), 3.36 (s, 3H), 3.4
(s, 3H), 4.15 (+s, 2H), 5.3 (s,
IH), 7.1 (d, J=8Hz, 2+1), 7
．． 7(d, J=8Hz, 2H)N,N-dimethyl-3-(4-(2,4-dioxo-1,3-dimethyl-
1,2,3,4-tetrahydropyrimidin-6-yl)
piperazin-1-yl]-2-hydroxypropyloxybenzenesulfonic acid amide hydrochloride mp 155-157°C Elemental analysis C, Jx + N5ObS ・HCI ・2
■20 Calculated value C: 45.52, II: 6.55, N: 1
2.64, C1: 6.40 S: 5.79 Analysis value C: 45.74, H: 6.69, N: 12.74
, CI:6.33S:5.72 Example 23 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-methylthiophenoxy)propylcopiperazine-
[1-yl]-2,4(IH,3H)-pyrimidinedione hydrochloride It was synthesized in the same manner as in Example 17.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-methylthiophenoxy)propylcopiperazine-
1-yl l-2,4(LH13H)-pyrimidinedione NMR (CIICh) δppm: 2.4-3.1 (
m, 10H), 2.43 (s, 3H), 2.4-3.
1 (m, 10H), 3.37 (s, 38), 3.
8-4.2 (fall.

3H), 5.20 (s, IH), 6.82 (d, 28
), 7.23(d,2H)1.3-dimethyl-6-+4
- (2-hydroxy-3-(4-methylthiophenoxy)propylcopiperazin-1-yl l-2,4(IH
,3H)-pyrimidinedione hydrochloride mp 120-122°C Elemental analysis CzoHtsN404S ・HCI ・'/
1HtO calculation value C: 51.55, old 6.49, N: 12
．． 02, S: 6.88C1 near, 61 Analysis value C: 51.82, H: 6.81, N: 12.04
, S:6.68C1:8.03 IR(KBr) ell-': 1700.1620
．． 1240.990.960.820.800.760 Example 24 6-(4-(3-(4-rubamoylphenoxy)-
2-hydroxypropylcopiperazin-1-yl l-1
, 3-dimethyl-2,4(LH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

6- (4-(3-(4-carbamoylphenoxy)-
2-hydroxypropyl)piperazin-1-yl l-1
,3-dimethyl-2,4(IH,3H)-pyrimidinedione NMR (CDCl2) δppm: 2.48-3.24
(s+, 9M), 3.12 (s, 3H), 3.26 (s
, 3H), 4.00 (s, 48), 4.96 (s, IH
), 5.20 (s, 18), 7.00 (d, J=8Hz
, 28), 7.00 (s, IH), 7.86 (d,
J = 8Hz, 2H), 7.86 (s, 18) Elemental analysis C8゜HtJ, Os II eight to ZO calculated value C: 54
．． 04, H: 6.80. N: 15.75 Analysis value C: 5
4.38, H: 6.71, N: 15.336- +4-
'(3-(4-carbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride mp 252-254°C Element Analysis C2゜O,,N,O,・IIcI-H,0
Calculated values C: 50.90, H: 6.40, N: 14.83
, C1 near, 51 analysis value C: 50.65, ll: 6.6
4, N: 14.42, Cl nia, 51 Example 25 6-(4-(3-(2-carbamoylphenoxy)-2
-hydroxypropylcopiperazin-1-yl l-1,
3-dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

6- (4-(3-(2-carbamoylphenoxy)-
2-hydroxypropylcopiperazin-1-yl]-1
,3-dimethyl-2,4(IH,3H)-pyrimidinedione NMR (DMSO-di) δppm: 2.50~
3.08 (Ugu, l0H), 3.12 (s, 38)
, 3.26 (s, 3H), 4.06 (s, 3H), 5.
16 (s, 2) 1), 6.92-7.96 (m, 6H) Elemental analysis CgollttNsOs Calculated value C: 57.54.11: 6.51, N: 16.7
7 Analysis values C: 57.21, H: 6.71, N: 16.4
9IR(KBr) cta-': 3450.315
0.1700.1640.1600°1490.145
0 6- (4-(3-(2-carbamoylphenoxy)-
2-hydroxypropyl)piperazin-1-yl)-1
,3-dimethyl-2,4(IH,3H)-pyrimidinedione hydrochloride mp 140-145"C Elemental analysis C2゜1hJsos・lIcl-1'811
10 Calculated value C: 49.94, old 6.49.11:14.
56, CI near, 37 analysis value C: 49.9L H: 6.
80, N: 14.19, CI Near, 60 Example 26 1.3-dimethyl-6-(4-(3-(4-zintylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl l-2 ,4(lH13H)-pyrimidinedione hydrochloride It was synthesized in the same manner as in Example 17.

1.3-dimethyl-6-(4-(3-(4-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl l-2,4(IH,3H)-pyrimidinedione NMR (DMSO-dh ) δppm: 2.40~
2.94 (m, 11H), 2.98 (s, 6H)
, 3.14 (s, 3H), 3.28 (s, 3H), 4.
00 (s, 3H), 4.94 (s, IH), 5.16 (
s, 111), 6.98 (d, J=811z, 21ri,
7°38 (d, J=8Hz, 28) 1.3-dimethyl-6-(4-(3-(4-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl l-2,4( IH, 3H)-pyrimidinedione/hydrochloride mp 164-166°C Elemental analysis CzJs+N5OsS/2HCI/2H
20 Calculated value C: 41.65, Il: 6.72, N: 12
．． 63, CI: 12.78 Analysis value C: 47.41, H near, 80. N: 12.53, CI: 12.47 Example 27 1.3-dimethyl-6-+4- (3-(2-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl l-2,4 (IH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

1.3-dimethyl-6-+4- (3-(2-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazin-1-yl)-2,4(LH,3H)-pyrimidinedione NMR (DMSO-di) δpp■: 2.40-2.
76 (#, 7H), 2.80 (s, 3H), 2.84~
3.00 (■, 3■), 3.00 (s, 38), 3.1
4 (s, 3H), 3.30 (s, 38), 4.00 (s
, 3H), 4.84 (s, IH), 5.16 (s, IH)
), 7.00-7.50 (+s, 411) 1.3-dimethyl-6-(4-(3-(2-dimethylcarbamoylphenoxy)-2-hydroxypropylcopiperazine-1
-yl)-2,4(IH13H)-pyrimidinedione amorphous crystal elemental analysis C*dh+N5Os・118HCI・118■! O calculated value C: 50.11, H: 6.78, N: 13
．． 28, C1: 10.08 Analysis value C: 50.58, H near, 44, N: 12.9 OSC 1: 9.35 Example 2B 1.3-dimethyl-6-+4-(2-hydroxy-3-
(2-Methylcarbamoylphenoxy)propylcopiperazin-1-yl 1-2,4(IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 17.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(2-Methylcarbamoylphenoxy)propylcopiperazin-1-yl)-2,4(IH13H)-pyrimidinedione mp 192-193°C NMR (DMSO-di) δpp: 2.40-3.
00(s+, 17H), 2.82(s, J=4Hz,
3H), 3.10 (s, 3H), 3.24 (s, 3H)
, 4.00 (m, 3H), 5.14 (s, 18), 5
．． 24 (s, LH), 6.90-8.36 (m, 5H) Elemental analysis C*+HtJsOs・Calculated value C: 58.45, H: 6.77, N: 16.23
Analysis value C: 58.15, H: 6.72, N: 16.25
1,3-dimethyl-6-(4-(2-hydroxy-3-
(2-Methylcarbamoylphenoxy)propylcopiperazin-1-yl)-2,4(IH13H)-pyrimidinedione hydrochloride elemental analysis Cg+IbJsos・2+1CI・t'/,
+1. Q calculated value C: 47.46, H: 6.44, N: 1
3.17, C1: 13.34 Analysis value C: 47.28, H
Nia, 61. N: 13.36, C1: 11.28 Example 29 6-(4-(2-hydroxy-3-phenoxy)piperazin-1-yl)-1,3-diisopropyl-2,4
(IH-,3H)-pyrimidinedione hydrochloride 1-(2-hydroxy-3-phenoxypropyl)piperazine (1,0 g) and 6-chloro-1,3-diisopropyl-2,4(IH,3H)- Pyrimidinedione (1,
47g) was dissolved in ethanol (10d) and heated under reflux for 18 hours. Ethanol was distilled off, the residue was purified with a silica gel column, and crystallized from ether/hexane to give 6-
[4-(2-hydroxy-3-phenoxy)piperazin-1-yl]-1,3-diisopropyl-2,4(IH
13H)-pyrimidinedione (1.17 g, 63%) was obtained.

NMR (CDC1i) δppm: 1.46 (d, J=
71Lz, 6H), 1.52 (d, J=711z, 6H
), 2.4-3.1 (m, 10H), 3.1 (brs
, 18), 3°97 (s, 2H), 4.0 (m, LH
), 4.54 (septet, J=7Hz, LH),
5.12 (septet, J=7Hz+IH), 5.
12(s, IH), 6.7-7.4(s, 5H) Non-hydrochloride was treated with hydrochloric acid/methanol to form 6-[4-(2
-hydroxy-3-phenoxy)piperazin-1-yl)-1,3-diisopropyl-2゜4 (LH,3H)
- Pyrimidinedione hydrochloride was obtained.

mp 198-203°C Elemental analysis CtJH34NaOa・)IcI calculated value (:
59.15, H Near, 55, N: 12. OO, CI near, 59 analysis value C: 60.13, H near, 74.1h12
．． 22, C1:5.34 Example 30 1.3-diphenyl-6-(4-(2-hydroxy-3
-phenoxypropyl)piperazin-1-yl)-2,
4(IH13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 29.

1.3-diphenyl-6-(4-(2-hydroxy-3
-phenoxypropyl)piperazin-l-yl)-2,
4(IH,3H)-pyrimidinedione NMR (CDCh) δppm: 2.0-2.5(m
, 6H), 2.95(t, 41(), 3.04(br,
s, IH), 3.85 (br, s, 3N), 5
．． 50(s, II()6.7-7.6(m, 15H) 1.3-diphenyl-6-(4-(2-hydroxy-3
-phenoxypropyl)piperazin-1-yl] ~2.
4 (IH,3H)-pyrimidinedione-hydrochloride mp 140-143°C Elemental analysis C*JsoNaO41 (CI ・1'/l
Hz.

Calculated values C: 61.97, Il: 6.10, N: 9.97
, C1: 6.31 Analysis value C: 62.19, ) I: 6.2
6, N: 9.96, C1: 5.7B Example 31 6-(4-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperazin-1-yl)-3-methyl-2,4 (IH,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 29.

6-(4-(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-3-methyl-2,4(IM, 3H)-pyrimidinedione N-group R (DMSO-di) δppm: 2.2~2
．． 7 (m, 6H), 3.0~3゜4 (m, 4H)
, 3.8-4.1 (s+, 3H), 4.
8 (br, s, Hl), 4°8 (s, IH), 6.
96 (d, J-8Hz, 2H), 7.30 (d, J=8
Hz, 2H), 10.5 (br, s, IH) 6- (4-(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-3-methyl-2,4( IH, 3H)-pyrimidinedione hydrochloride sp 225-226℃ (decomposition) Elemental analysis C+5HtsN40aC1-HCI ・U
ZO calculation value CF48.12, H:5.83, N:12.
47, C1: 15.78 Analysis value C: 48.15, H: 6
．． 02, Nj12.00. CI=15.11 Example 3
2 6-(4-(2-hydroxy-3-phenoxypropyl)piperazin-1-yl2-1-methyl-2,4(L
H13H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 29.

6-(4-(2-hydroxy-3-phenoxypropyl)piperazin-1-yl)-1-methyl-2,4(I
T(,3H)-pyrimidinedione NMR (CD!00)
δppm: 2.4 to 2.7 (m+108), 3
．． 30 (s, 3H), 4.3 (m, 3H), 5.06
(s, IH), 7.0-7.7 (m, 5H) elemental analysis
C+st+zaN404 Calculated value C:59.97, l(:6.71, tb15.5
8 analysis value C: 60.37, H near, 14, N: 14.7
26-(4-(2-hydroxy-3-phenoxyprobyl)piperazin-1-yl]~l-methyl-2,4(
IH,3H)-pyrimidinedione hydrochloride, amorphous crystal Example 33 6-(4-(2-hydroxy-3-phenoxyprobyl)piperazin-1-yl]-3-methyl-2,4(L
H,3H)-pyrimidinedione hydrochloride Synthesized in the same manner as in Example 29.

mp 160-165°C Elemental analysis C15HzNaOa・HCl-1'8H aO calculated value C: 51#, H: 1silp, N: /3
．． 22, ct: g, 34 analysis value C: 50,67, H
Near, 09, N: 13.23, C1: 8.36 Example 3
4 6- (4-(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin=1-yl)-1-isopropyl-3-methyl-2,4(IH,3H)-pyrimidinedione hydrochloride It was synthesized in the same manner as in Example 29.

6-(4-(3-(4-chlorophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1-isopropyl-3-methyl-2,4(LH13H)-pyrimidinedione NMR (CDC1a) δpptm: 1.4(d
, J=6+1z, 6H), 2.3~2.8(w+, 6
8), 3.3(s, 3H), 3.4-3.9(n+
, 411) , 3.9-4.3 (m, 3H) , 5.2
(s, IH), 5.3 (m, LH), 6.86 (d
, J=10Hz, 2H), 7.3(d, J=10Hz
, 211) 6-(4-(3-(4-chlorophenoxy)
-2-hydroxypropylcopiperazin-1-yl)-
1-isopropyl-3-methyl-2,4 (IH53H)
-Pyrimidinedione hydrochloride mρ183°C (decomposition) Elemental analysis Cz+HzJ4C, +04・211CI calculated value C: 4B, 43, H: 6.06, N: 10.76, C
1: 22.46 analysis value C: 48.64, H: 6.06,
N: 10.73, CI: 22.84 Example 35 6-(4-(3-(4-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3dimethyl-2,4( LH,3H)-pyrimidinedione hydrochloride 1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-nitrophenoxy)propylcopiperazine-1-
yl)-2,4(IH13H)-pyrimidinedione (2
, 7g) Dissolved in a mixed solvent of dimethylacetamide (150d) and methanol (70d), 10% pd/c
(0.3 g) was added and hydrogenated under normal pressure. The catalyst was filtered off, the solvent was distilled off, and ethanol was added and concentrated to crystallize.

Ether was added, the crystals were collected by filtration, and 6-(4-(3-
(4-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-dimethyl-2,4(
LH23H)-pyrimidinedione (2,37g, 94%
) was obtained.

sap 185-187°C NMR (DMSO-da) δppm: 2.2-5.0
(m, 148), 3.15 (s, 3H), 3.29 (s
, 3H), 5.17 (s, 1) 1), 6.55 (d, 2
+1), 6.72 (d, 2H) The non-hydrochloride salt is treated with hydrochloric acid/methanol to form 6-(4-(3
-(4-aminophenoxy)-2-hydroxypropylcopiperazin-1-yll-1,3-dimethyl-2,4
(IH,3H)-pyrimidinedione hydrochloride.

mp 239-240'C Elemental analysis CIJzJs04・2HCI・1'/zll
zO calculation value C: 46.63, H: 6.59, N: I4.
31, CI: 14.49 analysis value (:: 46.87, old 6
．． 77, N: 14.23, ct: t4.67IR (KB
r) cm-': 1700.1640.1510.
1445.1390.1260.1205.975.8
05.760 Example 36 6-(4-(3-(2-aminophenoxy)-2-hydroxypropyl]piperazin-1-yl 1-1.3-
Dimethyl-2,4(IH23H)-pyrimidinedione
It was synthesized in the same manner as in Hydrochloride Example 35.

6- (4-(3-(2-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-
Dimethyl-2,4(LH,3H)-pyrimidinedione mp 145-150°C NMR (DMSO-da) δppa+: 2.75(m
, ), 3.15 (s, 38), 3.28 (m, 4B
), 3.80 (s, 4H), 4.80 (drs, 2H)
, 4.96 (d, J=28.IH) , 5.16 (s,
18), 6.64 (m, 4H) elemental analysis C+JxtN
sOa・010 calculation (i C:56.OO, H near, 1
? , N: 17.18 Analysis value C: 55.88, H near, 3
3, N: 17.13IR (KBr) Cm-': 3
400.3300.1680.1640.1220.1
000.760.740 6- (4-(3-(2-aminophenoxy)-2-hydroxypropylcopiperazin-1-yl)-1,3-
Dimethyl-2,4(IH,3H)-pyrimidinedione
Hydrochloride elemental analysis C+JtJsOa・2HCI-'nz.

Calculated values C: 48.41, H: 6.41, N: 14.85
, C1115,04 analysis value C: 48.56, H: 6.
45, N: 14.97, C1: 14.74 Example 37 ■, 3-dimethyl-6-+4-(2-hydroxy-3-
(4-methanesulfonylaminophenoxy)propylcopiperazin-1-yl)-2,4(IH,3H)-pyrimidinedione hydrochloride 6-(4-(3-(4-aminophenoxy)-2-hydroxybro Pill] Piperazine
1-yl)1,3-dimethyl-2,4(IH13H)-
Dissolve pyrimidinedione (0.39 g) in dry dimethylformamide (8 ml) and dissolve methanesulfonyl chloride (0.78 μ2) in dry dimethylformamide (3 ml).
5d) The solution was added under water cooling. - hours later methanesulfonyl chloride (16 μl) and triethylamine (28 μl)
m)/dry dimethylformamide (3,5d) was added. The solvent was distilled off, ethanol (lOIni) and triethylamine (0,2IRl'') were added to the residue, and the residue was concentrated again.
=1/100~6/100) Shita. Crystallization from ethanol gave 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-methanesulfonylaminophenoxy)).
propylcopiperazin-1-yl)-2,4(IH,3
H)-pyrimidinedio7 (0.33 g, 71%) was obtained.

mp 15B-16C NMR (CDCI 3+DMSO-di) δpI) II
: 2.4~4.2 (m, 13H), 2°84 (s
, 311), 2.84 (s, 38), 3.33 (s,
3H), 4.6 (drs, II), 5.17 (s,
1B), 6.88 (d, 211), 7.23 (d, 2)
1), 9.2 (s, 11) Treating the non-hydrochloride with hydrochloric acid/methanol to produce 1,3-dimethyl-6-(4-(2-hydroxy-3-(4-methanesulfonylaminophenoxy)) Propylcopiperazine
1-yl)-2,4(LH,3H)-pyrimidinedione hydrochloride.

mp 255-258°C (field) Elemental analysis C2°HzqNsObS-HCI calculated value C:
47.66, H:6. OO, N: 13.90, C1 near, 03 analysis value CF47.57, H: 6.41. N:1
3.79, C1 near, 19IR (KBr) CI-'
: 1700.1655.1450.1390.132
5.1150, 920.520 Examples 38 and 39 1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-Methanesulfinylphenoxy)propyl)piperazin-1-yl)-2,4(IH,3H)-pyrimidinedione hydrochloride (Example and 1,3-dimethyl-6
-(4-(2-hydroxy-3-(4-methanesulfonylphenoxy)propylcopiperazin-1-yl)-2
, t(IH,3H)-pyrimidinedione hydrochloride (Example 39) 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-methylthiophenoxy)propylcopiperazine-
1-yl)-2,4(IH,3H)-pyrimidinedione (4.9 g) was dissolved in acetic acid (50d), 30% hydrogen oxide (3.97 g) was added, and the mixture was reacted overnight at room temperature. After adding water (LooIIll) and concentrating to about 20d, neutralizing with aqueous caustic soda solution, chloroform (150d
7) Extracted and purified with silica gel column, 1.3
-dimethyl-6-(4-(2-hydroxy-3-(4-
Methanesulfinylphenoxy)propylcopiperazin-1-yl)-2,4(IH,3H)-pyrimidinedione (1,52g, 30%) and 1,3-dimethyl-6-(
4-(2-hydroxy-3-(4-methanesulfonylphenoxy)propylcopiperazin-1-yl)-2,4
(IH13H)-pyrimidinedione (0.44g, 8%
) was obtained.

1,3-dimethyl-6-(4-(2-hydroxy-3-
(4-methanesulfinylphenoxy)propyl]piperazin-1-yl)-2,4(IH13H)-pyrimidinedione mp 1B8-190°C NMR (CDCI δpp so = 2.5-3.1 (m
, l0H), 2.72 (s, 3■), 3.28 (s,
31), 3.36 (s, 3H), 3.8-4.2 (s,
3H), 5, 23 (s, 1B), 7.04 (d,
2H), 7.57 (d, 2H) Elemental analysis CgJz
JaOsS.

Calculated value C: 55.03, I(: 6.46, N: 12.8
3. S near, 34 analysis value C: 54.5? ,H:6.8B
, N: 12.59, s: t, asl, 3-dimethyl-6
-(4-(2-hydroxy-3-(4-methanesulfonylphenoxy)propylcopiperazin-1-yl)-2
, 4 (IH.

3H)-pyrimidinedione NMR (CDCl s) δPPII: 2.4-3.2
(II+, 1011), 3.07 (s, 311), 3.
36 (s, 3H), 3.43 (s, 38), 4.0-4
．． 4 (m, 3H), 5.27 (s, LH), 7.11
(d, 2B), 7.93 (d, 2H) elemental analysis Czo
llzsNaOaS・Calculated value C: 53.08, H: 6.
24, N: 12.3B analysis value C: 52.63, H: 6.
49, N:12.191.3-dimethyl-6-(4-(
2-Hydroxy-3-(4-methanesulfinylphenoxy)propylcopiperazin-1-yl -2,4(
LH13H)-pyrimidinedione hydrochloride mp 238-240℃ (decomposition) Elemental analysis C2゜HzsN40sS・IIcI calculated value C
:50.79, H:6.18.11:11.84, S:
6.78C1 near, 43 Analysis value C: 50.60,) I: 6.41, N: 11.7
3, S: 6.86 CI near, 57 IR (KBr) cta-direct: 1690.1625.14
80.1235.1040.980,830 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-methanesulfonylphenoxy)propylcopiperazin-1-yl)-2,4(1)(.

3H)-pyrimidinedione hydrochloride Q 262-265℃ (decomposition) Elemental analysis C2゜H*5N40hS-HCI calculated value C:
49.13, +(:5.98, s:it, 4s, S:6
．． 56Cl Near, 25 Analysis value C: 49.16, ll: 5.52, ? l11.5
6, S: 6.91 (:I near, 31 1R (KBr) cm-': 1700.1630.
1310.1145.970.840.760 Example 40 1,3-dimethyl〒6-(4-(2-hydroxy-3-
(4-nitrophenoxy)propylcopiperazine-1-
yl-2,4(IH,3H)-pyrimidinedione・
Method for manufacturing tablets containing hydrochloride as an active ingredient: Mix 1 g of the title compound, 1123 g of milk, and 20 g of corn starch, mix and granulate with a solution of 5 g of hydroxypropyl cellulose dissolved in 100 d of water, and heat at 50°C. Dry for 4 hours. Magnesium stearate Ig is added to this, mixed well, and then compressed using a tablet machine at a weight of 150 square meters per tablet to obtain tablets.

Example 41 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-nitrophenoxy)propylcopiperazine-1-
Method for producing capsules containing yl-2,4(IH13H)-pyrimidinedione hydrochloride as an active ingredient 5 g of the title compound, 1120 g of milk, and 25 g of corn starch are thoroughly mixed. This is filled into 150 square hard capsules using a capsule filling machine to obtain capsules.

Example 42 1.3-dimethyl-6-(4-(2-hydroxy-3-
(4-nitrophenoxy)propylcopiperazine-1-
20 ■ of the title compound and 0.85 g of sodium chloride
Dissolve this in an appropriate amount of distilled water for injection and make the total amount 100%
1R1 and used as an injection.

(Test example) Effect on myocardial action potential duration After anesthetizing a hybrid adult adult with bendoparbital 30 μ/kg intravenously, the heart was removed and the right ventricular free wall was excised in Tyrode's solution. The free wall was fixed in a constant temperature bath at 37°C, and field stimulation was performed at 1 Hz.Action potential was detected by inserting a glass microelectrode (10-20M) into the Purkinje fiber and transmitting it to an oscilloscope cathode ray tube via an amplifier. The myocardial action potential duration was defined as the time from the occurrence of the action potential to 75% repolarization (APD75).

The compound of the present invention was added to the nutrient solution (20d) that perfuses the specimen, and the change in myocardial action potential duration after 20 minutes of incubation was expressed as a percentage with the value before drug administration as 100%, and the effect of the drug was determined. .

The results are shown in Table 1 Pharmacological Test Results as APD.

Effect on ventricular myocardial refractory period After anesthetizing a mongrel adult with bendoparbital 30 μ/kg intravenously, a silver-silver chloride electrode with a pole spacing of 3 m was sewn into the right ventricle through a right thoracotomy, and a stimulation interval of 400 Llsec, 4 m5
Electrical stimulation is performed with a current twice the darkness value for the duration of EC,
Thereafter, a small amount of alcohol is intravenously injected into the sinus artery to extinguish pacemaker activity, and the ventricular refractory period (ERP) is measured under ventricular pacing. That is, 10 stimulations constitute one train, and the interval between trains is usually 400 m5ec.
However, when measuring the refractory period, the interval is set as lQmse.
The train interval was shortened by c increments, and the refractory period was defined as the interval between trains when the response to the first stimulus in the train disappeared. For these electrical stimulations, a heart stimulator (DH made by Diamond Medical Co., Ltd.) was used.
M-226-3) and programmed stimulation. The refractory period prolonging effect of the drug was expressed as a percentage, with the refractory period before drug administration being taken as 100%. Drugs were administered intravenously or intraduodenally.

The results are shown in Table 1 Pharmacological Test Results as ERP.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 and R^2 are each independently a hydrogen atom, a lower alkyl group, or an aryl group. X represents a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group,
trifluoromethyl group, carbamoyl group, lower alkyl group, acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group, alkylsulfamoyl group, lower alkylthio group,
Propanol derivatives represented by (representing an alkoxycarbonyl group or an aryloxy group) and acid adducts thereof. 2. General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, X is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, a trifluoromethyl group, a carbamoyl group) , lower alkyl group, acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group, alkylsulfamoyl group, lower alkylthio group, alkoxycarbonyl group, or aryloxy group. Y is ▲ mathematical formula, chemical formula , tables, etc. ▼ or ▲ formulas,
There are chemical formulas, tables, etc. ▼ Compounds represented by (in the formula, Hal indicates a halogen atom) and general formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (III) Indicates a lower alkyl group or aryl group ) A method for producing the compound according to claim 1, which comprises reacting with a compound represented by: 3. General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, X is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, a trifluoromethyl group, a carbamoyl group) , a lower alkyl group, an acyl group, an acylamino group, an alkylsulfonylamino group, an alkylsulfonyl group, an alkylcarbamoyl group, an alkylsulfamoyl group, a lower alkylthio group, an alkoxycarbonyl group, or an aryloxy group. ,
General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^1 and R^2 independently represent a hydrogen atom, a lower alkyl group, or an aryl group, and Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼or▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ A method for producing the compound described in patent item 1, which is characterized by reacting a compound represented by (in the formula, Hal represents a halogen atom). 4. Compounds represented by the general formula (VI) and ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (wherein, X is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, a trifluoro group) Indicates a methyl group, carbamoyl group, lower alkyl group, acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group, alkylsulfamoyl group, lower alkylthio group, alkoxycarbonyl group, or aryloxy group.) General formula (VII) ▲Mathematical formulas, chemical formulas, tables, etc.▼(VII) (In the formula, R^1 and R^2 are independent of each other and represent a hydrogen atom, lower alkyl, or aryl group, and Hal represents a halogen 1. A method for producing a compound according to claim 1, which comprises reacting a compound represented by (indicates an atom). 5. General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R^1 and R^2 independently represent a hydrogen atom, a lower alkyl group, or an aryl group. hydrogen atom,
Halogen atom, nitro group, amino group, hydroxyl group, cyano group, trifluoromethyl group, carbamoyl group, lower alkyl group, acyl group, acylamino group, alkylsulfonylamino group, alkylsulfonyl group, alkylcarbamoyl group, alkylsulfamoyl group , lower alkylthio group, alkoxycarbonyl group or aryloxy group. ) or an acid adduct thereof as an active ingredient.