JPH06128238A - New pyrimidinedione derivative - Google Patents

Abstract

PURPOSE:To provide a new pyrimidinedione derivative having potassium channel opening activity and applicable for the treatment and prevention of disorders caused by the constriction of vascular smooth muscle and other smooth muscle. CONSTITUTION:The compound of formula I [R1 and R2 are H, 1-6C alkyl or 1-6C alkenyl; R3 and R4 are 1-4C alkyl or together form 2-5C polymethylene; W is H or OH; A is group of formula II (Y1 and Y2 are H, alkylcarbonyl, NH2, NO2, CN, Cl, CF3, alkylsulfonyl, alkoxysulfinyl, alkoxy, cyanomethyl, etc.), 3-pyridyl or 4-pyridyl; X is 1-6C alkyl or NO2], e.g. 6-[4-[3(4- acetylphenoxy)-2-hydroxy-3-methylbutyl]piperazin-1-yl]-1,3-diisopropyl -2,4(1H,3H) pyrimidinedione. The compound of formula I wherein W is OH can be produced by reacting a uracilpiperazine derivative of formula III with a propane oxide derivative of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrimidinedione derivative and an acid addition salt thereof, an agent effective for treating or preventing a disorder associated with contraction of vascular smooth muscle and other smooth muscle containing the same, and a compound thereof. The present invention relates to a manufacturing method.

[0002]

2. Description of the Related Art Disorders associated with smooth muscle contraction, such as hypertension, congestive heart dysfunction, angina, peripheral and cerebrovascular disorders, urinary frequency, asthma, ischemic heart disease, and potassium channel opening as therapeutic agents for baldness The usefulness of the agent has been reported. (Gillian Edwards and
Arthur H. Western Trends in
Pharmacological Science19
90, 11, 417-422, Nigel S Coo
k Trends Pharmacol. Sci. , 1
988, 9, 21-28) Among them, the potassium channel openers that have been conventionally reported are roughly classified into the following three types. Benzopyran derivative (Cromakalim, JP-A-58-67683), cyanoguanidine derivative (Pinasidil, Br. J. Pharm)
acol. , 1987, 91, 421-429) and thioformamide derivatives (Apricalim, JP-A-59-59).
7188) However, there has been no report up to now on the potassium channel opening action of the pyrimidinedione derivative.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel pyrimidinedione derivative applicable to the treatment or prevention of disorders associated with contraction of vascular smooth muscle and other smooth muscles, a method for producing the same, and effective methods thereof. It is to provide a potassium channel opener containing as a component.

[0004]

[Means for Solving the Problems] The inventors of the present invention have extensively searched for a novel compound having a potassium channel opening action, and found that the compound represented by the general formula (1)

[0005]

[Chemical 16] (Wherein, R _1, R ₂ are the same or different, a hydrogen atom or a linear or branched alkyl group of C ₁ ~C _6, C ₁ ~
A C ₆ linear or branched alkenyl group is shown. R ₃ ,
R ₄ is the same or different and represents a C _{1 to} C ₄ alkyl group, or R ₃ and R ₄ are taken together to represent a C _{2 to} C ₅ polymethylene group. W represents a hydrogen atom or a hydroxyl group. A is the following group (2) [Chemical formula 17]

[0006]

[Chemical 17] Represents a benzene ring which may be substituted, a 3-pyridyl group, or a 4-pyridyl group. Where Y ₁ and Y ₂
Are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group, an amino group, a nitro group, a cyano group, a chloro atom, a trifluoromethyl group, or a C ₁ -C group. ₆ alkylsulfonyl groups, C ₁ ~
Alkoxysulfinyl sulfinyl group C _6, C ₁ -C alkoxy sulfonyl group of _6, alkylcarbonylamino group of C ₁ -C _6, an alkoxycarbonylamino group of C ₁ ~C _6, C ₁ ~
C ₆ alkylaminosulfinyl group, C _{1 to} C ₆ alkylaminosulfonyl group, C _{1 to} C ₆ alkylsulfinylamino group, C _{1 to} C ₆ alkylsulfonylamino group, C _{1 to} C ₆ alkoxy group, A cyanomethyl group, a 2-cyano-3-methylguanidine group, an S-methyl-N-cyanothioureido group and a 3-ethylureido group are shown. X represents a C ₁ -C ₆ alkyl group or a nitro group. The present invention has been completed by finding a potassium channel opening action and a smooth muscle relaxing action in the pyrimidinedione derivative represented by (4).

Specific examples of each substituent in the compound of the general formula (1) are shown below. Examples of the C _{1 to} C ₆ linear or branched alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, a cyclopropyl group, Isobutyl group, 1-methylpropyl group, t-butyl group, cyclobutyl group, cyclopentyl group, 3-methylbutyl group, 2-methylbutyl group, 1-methylbutyl group, 1,2-dimethylpropyl group, cyclohexyl group, 4-methylpentyl group Group, 3-methylpentyl group, 2-methylpentyl group, 1
-Methylpentyl group, 1,2,2-trimethylpropyl group and the like can be mentioned. Examples of the C _{1 to} C ₆ linear or branched alkenyl group include vinyl group, 2-propenyl group, 1-propenyl group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-pentenyl group, 1-pentenyl group, 5-hexenyl group, 4-hexenyl group, 3-hexenyl group, 2
-Hexenyl group, 1-hexenyl group, 1-methylethenyl group, 2-methyl-2-propenyl group, 2-methyl-1
-Propenyl group, 1-methyl-2-propenyl group, 1-
Methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 1,2-dimethyl-2-propenyl group, 1,2-dimethyl-1-propenyl group, 2-methyl-1-methylenepropenyl group, 2, 2-dimethyl-2-methylenepropenyl group etc. can be mentioned.

The C ₁ -C ₄ alkyl group includes a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an isopropyl group, a cyclopropyl group, an isobutyl group, a 1-methylpropyl group and a t-butyl group. , Cyclobutyl group and the like.

Examples of the C ₂ -C ₅ polymethylene group include ethylene group, trimethylene group, tetramethylene group, pentamethylene group and the like.

Examples of the C ₁ -C ₆ alkylcarbonyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a valeryl group, a hexanoyl group and a heptanoyl group.

The C ₁ -C ₆ alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, and n.
Examples thereof include a propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a t-butoxycarbonyl group, a pentyloxycarbonyl group and a hexyloxycarbonyl group.

Examples of the C ₁ -C ₆ alkylsulfonyl group include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group and a hexanesulfonyl group.

The C ₁ -C ₆ alkoxysulfinyl group includes methoxysulfinyl group, ethoxysulfinyl group, n-propoxysulfinyl group, isopropoxysulfinyl group, n-butoxysulfinyl group, isobutoxysulfinyl group, t-butoxysulfinyl group. , A pentyloxysulfinyl group, a hexyloxysulfinyl group, and the like.

The C ₁ -C ₆ alkoxysulfonyl group includes a methoxysulfonyl group, an ethoxysulfonyl group, and n.
Examples thereof include a propoxysulfonyl group, an isopropoxysulfonyl group, an n-butoxysulfonyl group, an isobutoxysulfonyl group, a t-butoxysulfonyl group, a pentyloxysulfonyl group and a hexyloxysulfonyl group.

Examples of the C ₁ -C ₆ alkylcarbonylamino group include acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, valerylamino group, hexanoylamino group and heptanoylamino group. Can be mentioned.

The C ₁ -C ₆ alkoxycarbonylamino group includes a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group,
Isopropoxycarbonylamino group, n-butoxycarbonylamino group, isobutoxycarbonylamino group, t
-Butoxycarbonylamino group, pentyloxycarbonylamino group, hexyloxycarbonylamino group and the like can be mentioned.

The C ₁ -C ₆ alkylaminosulfinyl group includes N-methylsulfinamoyl group, N-ethylsulfinamoyl group, N-propylsulfinamoyl group, N-butylsulfinamoyl group and N- Examples thereof include a pentylsulfinamoyl group and an N-hexylsulfinamoyl group.

Examples of the C ₁ -C ₆ alkylaminosulfonyl group include N-methylsulfamoyl group, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-butylsulfamoyl group and N- Examples thereof include a pentylsulfamoyl group and an N-hexylsulfamoyl group.

The C ₁ -C ₆ alkylsulfinylamino group includes methanesulfinylamino group, ethanesulfinylamino group, n-propanesulfinylamino group,
Isopropanesulfinylamino group, n-butanesulfinylamino group, isobutanesulfinylamino group, t
-Butansulfinylamino group, pentanesulfinylamino group, hexanesulfinylamino group and the like can be mentioned.

The C ₁ -C ₆ alkylsulfonylamino group includes methanesulfonylamino group, ethanesulfonylamino group, n-propylsulfonylamino group, isopropylsulfonylamino group, n-butanesulfonylamino group, isobutanesulfonylamino group, A t-butane sulfonylamino group, a pentane sulfonylamino group, a hexane sulfonylamino group etc. can be mentioned.

The C ₁ -C ₆ alkoxy group includes methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, pentyloxy group, hexyloxy group and the like. Can be mentioned.

The pyrimidinedione derivative represented by the general formula (1) may have optical isomers, but the present invention includes all these isomers. Specific examples of the compound represented by formula (1) will be given. 6- {4- [3- (4-acetylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methylbutyl 3- (4-propionylphenoxy)] piperazin-1-yl } -2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-butyrylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-pivaloylphenoxy) butyl] piperazine -1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-valerylphenoxy) butyl] piperazine-1 -Yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-hexanoylphenoxy) butyl] piperazine-1 -Yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-heptanoylphenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione

1,3-diisopropyl-6- {4- [2
-Hydroxy-3- (4-methoxycarbonylphenoxy) -3-methylbutyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxycarbonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propoxycarbonylphenoxy) butyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 6- {4-[(4-t-butoxycarbonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentyloxycarbonylphenoxy) butyl] piperazin-1-yl} -2,
4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-hexyloxycarbonylphenoxy) butyl] piperazin-1-yl} -2 ，
4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (3-nitrophenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-nitrophenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione

6- {4- [3- (3-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (3-chlorophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-chlorophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (3-trifluoromethylphenoxy) butyl] piperazine -1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-trifluoromethylphenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-methanesulfonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propanesulfonylphenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-t-butanesulfonylphenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentanesulfonylphenoxy) butyl] piperazin-1-yl} -2,4 ( 1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyclohexanesulfonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4
(1H, 3H) Pyrimidinedione

1,3-diisopropyl-6- {4- [2
-Hydroxy-3- (4-methoxysulfinylphenoxy) -3-methylbutyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxysulfinylphenoxy) -2-hydroxy-3-
Methylbutyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propoxysulfinylphenoxy) butyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-n-butylsulfinylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 ( 1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentyloxysulfinylphenoxy) butyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-n-
Hexyloxysulfinylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3- (4-methoxysulfonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxysulfonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propoxysulfonylphenoxy) butyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-n-butoxysulfonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 ( 1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentyloxysulfonylphenoxy) butyl] piperazin-1-yl} -2,
4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-n-
Hexyloxysulfonylphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,
4 (1H, 3H) Pyrimidinedione

6- {4- [3- (4-acetylaminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methylbutyl 3- (4-propionylaminophenoxy)] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- (4-butyrylaminophenoxy)-
2-Hydroxy-3-methylbutyl] piperazine-1-
Il} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-pivaloylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-valerylaminophenoxy))
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-hexanoylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-heptanoylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3- (4-methoxycarbonylaminophenoxy)-
3-Methylbutyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxycarbonylaminophenoxy) -2-hydroxy-
3-Methylbutyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propoxycarbonylaminophenoxy) butyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 6- {4-[(4-t-butoxycarbonylaminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2, Four
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentyloxycarbonylaminophenoxy) butyl] piperazin-1-yl}
-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-hexyloxycarbonylaminophenoxy) butyl] piperazine-1- Ill}
-2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [2
-Hydroxy-3-methyl-3- (4- (N-methylsulfinamoyl) phenoxy) butyl] piperazine-1
-Yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4- (N
-Ethylsulfinamoyl) phenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4- (N-n-propylsulfinamoyl) phenoxy) butyl] piperazine -1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4- (N-t-butylsulfinamoyl) phenoxy) -2-hydroxy-3-methyl-butyl] Piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4- (N -N-Pentylsulfinamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4- (N-cyclohexylsulfinamoyl) ) Phenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy -3-Methyl-3- (4- (N-methylsulfamoyl) phenoxy) butyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4- (N
-Ethylsulfamoyl) phenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,
4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4- (N-n-propylsulfamoyl) phenoxy) butyl] piperazine-1 -Il}
-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4- (N-t-butylsulfamoyl) phenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl } -1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4- (N-n-pentylsulfen) Famoyl) phenoxy) butyl] piperazin-1-yl}
-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4- (N-cyclohexylsulfamoyl) phenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1, 3-diisopropyl-2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [2
-Hydroxy-3-methyl-3- (4-methanesulfinylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfinylaminophenoxy) -2-hydroxy-
3-Methylbutyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propanesulfinylaminophenoxy) butyl] piperazin-1-yl}-
2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-t-butanesulfinylaminophenoxy) -2-hydroxy-3-methyl-butyl]
Piperazin-1-yl} -1,3-diisopropyl-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentanesulfinylaminophenoxy) butyl] piperazin-1-yl} −
2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyclohexanesulfinylaminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2, 4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-methanesulfonylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfonylaminophenoxy) -2-hydroxy-3
-Methylbutyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propanesulfonylaminophenoxy) butyl] piperazin-1-yl} -2,
4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-t-butanesulfonylaminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2, Four
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentanesulfonylaminophenoxy) butyl] piperazin-1-yl} -2,
4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyclohexanesulfonylaminophenoxy) -2-hydroxy-3-methylbutyl]
Piperazin-1-yl} -1,3-diisopropyl-
2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [2
-Hydroxy-3- (4-methoxyphenoxy) -3-
Methylbutyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxyphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-propoxyphenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 6- {4-[(4-t-butoxyphenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-pentyloxyphenoxy) butyl] Piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-n-hexyloxyphenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 6- {4- [3- (3-cyanomethylphenoxy) -2
-Hydroxy-3-methyl-butyl] piperazine-1-
Il} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- (4-cyanomethylphenoxy) -2
-Hydroxy-3-methyl-butyl] piperazine-1-
Il} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- <3- (2-cyano-3-methylguanidino) phenoxy> -2-hydroxybutyl-3-methyl] piperazin-1-yl} -1,3-diisopropyl- 2,4 (1H, 3H) pyrimidinedione 6- {4- [3- <4- (2-cyano-3-methylguanidino) phenoxy> -2-hydroxybutyl-3-methyl] piperazin-1-yl}- 1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- <3- (3
-Cyano-2-methylisothioureido) phenoxy>
-3-Methyl-2-hydroxybutyl] piperazine-1
-Yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- <4- (3
-Cyano-2-methylisothioureido) phenoxy>
-3-Methyl-2-hydroxybutyl] piperazine-1
-Yl} -2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [3
-<3- (3-ethylureido) phenoxy> -3-methyl-2-hydroxybutyl] piperazin-1-yl}
-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- <4- (3
-Ethylureido) phenoxy> -3-methyl-2-hydroxybutyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (3-pyridyloxy) -butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-pyridyloxy) -butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-acetylphenoxy) -3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2 , 4 (1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methylbutyl-3- (4-propionylphenoxy)] piperazin-1-yl} -2,4 (1H, 3H) pyrimidine Dione 6- {4- [3- (4-butyrylphenoxy) -3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl- 6- {4- [3-methyl-3
-(4-Pivaloylphenoxy) butyl] piperazine-
1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-valerylphenoxy) butyl] piperazine-1
-Yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Hexanoylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Heptanoylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [3
-(4-Methoxycarbonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxycarbonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3 -Diisopropyl-6- {4- [3-methyl-3
-(4-n-Propoxycarbonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4-[(4-t-butoxycarbonylphenoxy) -3-methylbutyl] piperazine -1-yl}-
1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentyloxycarbonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-hexyloxycarbonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(3-Nitrophenoxy) butyl] piperazine-1-
Il} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Nitrophenoxy) butyl] piperazine-1-
Ill} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (3-cyanophenoxy) -3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidine Dione 6- {4- [3- (3-chlorophenoxy) -3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-Chlorophenoxy) -3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione

1,3-diisopropyl-6- {4- [3
-Methyl-3- (3-trifluoromethylphenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Trifluoromethylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Methanesulfonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfonylphenoxy) -3 -Methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-propanesulfonylphenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-t-butanesulfonylphenoxy) -3-methyl-butyl] piperazin-1-yl}-
1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentanesulfonylphenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyclohexanesulfonylphenoxy) -3-methylbutyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-methoxysulfinylphenoxy) -3-methylbutyl] piperazin-1-yl}- 2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxysulfinylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H ) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Propoxysulfinylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-n-butanesulfinylphenoxy) -3-methylbutyl ] Piperazin-1-yl}-
1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-pentyloxysulfinylphenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-n-
Hexyloxysulfinylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione

1,3-diisopropyl-6- {4- [3
-(4-Methoxysulfonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxysulfonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3 -Diisopropyl-6- {4- [3-methyl-3
-(4-n-Propoxysulfonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-n-butylsulfonylphenoxy) -3-methylbutyl ] Piperazin-1-yl}-
1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentyloxysulfonylphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-n-
Hexyloxysulfonylphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-acetylaminophenoxy)-
3-Methylbutyl] piperazin-1-yl} -1,3-
Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methylbutyl-3- (4-propionylaminophenoxy)-] piperazin-1-yl} -2,4 ( 1H, 3H) Pyrimidinedione 6- {4- [3- (4-butyrylaminophenoxy)-
3-Methylbutyl] piperazin-1-yl} -1,3-
Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Pivaloylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-valerylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-hexanoylaminophenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-heptanoylaminophenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-methoxycarbonylaminophenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxycarbonylaminophenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H , 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-propoxycarbonylaminophenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 6- {4-[(4-t-butoxycarbonylaminophenoxy) -3-methylbutyl] piperazin-1-yl}
-1,3-Diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentyloxycarbonylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-hexyloxycarbonylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione

1,3-diisopropyl-6- {4- [3
-Methyl-3- (4- (N-methylsulfinamoyl))
Phenoxy) butyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4- (N
-Ethylsulfinamoyl) phenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4- (N-n-propylsulfinamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4- (N-t-butylsulfinamoyl) phenoxy) -3-methyl-butyl] piperazin-1-yl} -1,3-diisopropyl-2 , 4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4- (N-n-pentylsulfinamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyclohexylsulfinamoylphenoxy) -2-hydroxy-3-methylbutyl]
Piperazin-1-yl} -1,3-diisopropyl-
2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4- (N-Methylsulfamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4- (N
-Ethylsulfamoyl) phenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4- (N-n-propylsulfamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 6- {4- [3- (4- (N-t-butylsulfamoyl) phenoxy) -3-methyl-butyl] piperazine-
1-yl} -1,3-diisopropyl-2,4 (1H,
3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4- (N-n-pentylsulfamoyl) phenoxy) butyl] piperazin-1-yl} -2,4 (1H,
3H) Pyrimidinedione 6- {4- [3- (4-cyclohexylsulfamoylphenoxy) -3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione

1,3-diisopropyl-6- {4- [3
-Methyl-3- (4-methanesulfinylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1
H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfinylaminophenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-propanesulfinylaminophenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- (4-t-butanesulfinylaminophenoxy) -3-methyl-butyl] piperazine-1-
Il} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-pentanesulfinylaminophenoxy)
Butyl] piperazin-1-yl} -2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- (4-cyclohexanesulfinylaminophenoxy) -3-methylbutyl] piperazine-1
-Yl} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Methanesulfonylaminophenoxy) butyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethanesulfonylaminophenoxy) -3-methylbutyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Propanesulfonylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-t-butanesulfonylaminophenoxy) -3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentanesulfonylaminophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyclohexanesulfonylaminophenoxy) -3-methylbutyl] piperazine-1-
Il} -1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidinedione

1,3-diisopropyl-6- {4- [3
-(4-Methoxyphenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- (4-ethoxyphenoxy)- 3-Methylbutyl] piperazine-1
-Yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Propoxyphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4-[(4-t-butoxyphenoxy) -3-methylbutyl] piperazine-1 -Yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Pentyloxyphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-n-Hexyloxyphenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (3-cyanomethylphenoxy) -3
-Methyl-butyl] piperazin-1-yl} -1,3-
Diisopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanomethylphenoxy) -3
-Methyl-butyl] piperazin-1-yl} -1,3-
Diisopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- <3- (2-cyano-3-methylguanidino) phenoxy> -3-methylbutyl] piperazin-1-yl} -1,3 -Diisopropyl-2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- <4- (2-cyano-3-methylguanidino) phenoxy> -3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1
H, 3H) Pyrimidinedione

1,3-diisopropyl-6- {4- [3
-<3- (3-cyano-2-methylisothioureido)
Phenoxy> -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- <4- (3
-Cyano-2-methylisothioureido) phenoxy>
-3-Methylbutyl] piperazin-1-yl} -2,4
(1H, 3H) Pyrimidinedione 1,3-diisopropyl-6- {4- [3- <3- (3
-Ethylureido) phenoxy> -3-methylbutyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3- <4- (3
-Ethylureido) phenoxy> -3-methylbutyl]
Piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(3-Pyridyloxy) -butyl] piperazine-1-
Il} -2,4 (1H, 3H) pyrimidinedione 1,3-diisopropyl-6- {4- [3-methyl-3
-(4-Pyridyloxy) -butyl] piperazine-1-
Il} -2,4 (1H, 3H) pyrimidinedione

6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl} -1,3-dimethyl-2,4 (1H, 3
H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Diethyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Di-n-propyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazine-1- Ill}
-1,3-di-cyclopropyl-2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-Di-n-butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazine-1- Ill}
-1,3-Di-i-butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazine-1- Ill}
-1,3-Di-n-pentyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazine-1- Ill}
-1,3-Dicyclohexyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-di (1,2,2-trimethylpropyl)-
2,4 (1H, 3H) pyrimidinedione

6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl} -3-methyl-2,4 (1H, 3H) pyrimidinedione 6 -{4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-Ethyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-n-Propyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-Cyclopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-n-Butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-i-Butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-n-Pentyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3-Cyclohexyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-3- (1,2,2-trimethylpropyl) -2,4
(1H, 3H) Pyrimidinedione

6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl} -1-methyl-2,4 (1H, 3H) pyrimidinedione 6 -{4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-Ethyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-n-Propyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-Cyclopropyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-n-Butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-i-Butyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-n-Pentyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1-Cyclohexyl-2,4 (1H, 3H) pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1- (1,2,2-trimethylpropyl) -2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-pentyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H , 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-hexyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-heptyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-ethyl-pentyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-propyl-hexyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-butyl-heptyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
Pyrimidinedione

1- (4-cyanophenoxy) -1- [2
-{4- (1,3-diisopropyl-2,4 (1H, 3
H) Pyrimidindione-6-yl) piperazin-1-yl} -1-hydroxyethyl] cyclopropane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} -1
-Hydroxyethyl] cyclobutane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} -1
-Hydroxyethyl] cyclopentane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} -1
-Hydroxyethyl] cyclohexane 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-nitro-2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-methyl-2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-ethyl-2,4 (1
H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-n-propyl-2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-n-butyl-2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-n-pentyl-2,4
(1H, 3H) Pyrimidinedione 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methyl-butyl] piperazin-1-yl}
-1,3-diisopropyl-5-n-hexyl-2,4
(1H, 3H) Pyrimidinedione 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} ethyl] cyclopropane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} ethyl] cyclobutane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} ethyl] cyclopentane 1- (4-cyanophenoxy) -1- [2- {4-
(1,3-Diisopropyl-2,4 (1H, 3H) pyrimidindione-6-yl) piperazin-1-yl} ethyl] cyclohexane

The allylalkyl carbonate derivative represented by the general formula (6) is specifically exemplified below. Isobutyl carbonate 2-propen-1-yl isobutyl carbonate 2-methyl-3-buten-2-yl isobutyl carbonate 3-ethyl-1-penten-3-yl isobutyl carbonate 3-propyl-1-hexene-3-yl
Ile isobutyl 3-butyl-1-hepten-3-yl carbonate Isobutyl 3-buten-2-yl isobutyl carbonate 1-penten-3-yl isobutyl carbonate 1-hexen-3-yl isobutyl carbonate 1-hepten-3-yl Isobutyl carbonate 3-methyl-1-penten-3-yl isobutyl carbonate 3-methyl-1-hexen-3-yl isobutyl carbonate 3-methyl-1-hepten-3-yl isobutyl carbonate 3-ethyl-1-hexene-3 -Yl isobutyl carbonate 3-ethyl-1-hepten-3-yl isobutyl carbonate 3-propyl-1-heptene-3-
Il isobutyl carbonate 1-vinylcyclopropan-1-yl isobutyl carbonate 1-vinylcyclobutan-1-yl isobutyl carbonate 1-vinylcyclopentan-1-yl isobutyl carbonate 1-vinylcyclohexane-1-yl methyl carbonate 2-methyl-3 -Buten-2-yl ethyl carbonate 2-methyl-3-buten-2-yl carbonate n-propyl 2-methyl-3-buten-2-yl carbonate isopropyl carbonate 2-methyl-3-buten-2-yl carbonate 1- Methylpropyl 2-methyl-3-butene-
2-yl n-butyl carbonate 2-methyl-3-buten-2-yl t-butyl carbonate 2-methyl-3-buten-2-yl 3-methylbutyl carbonate 2-methyl-3-butene-2
-Yl 2-methylbutyl carbonate 2-methyl-3-butene-2
-Yl carbonate 1-methylbutyl 2-methyl-3-butene-2
-Yl carbonate 1,2-dimethylpropyl 2-methyl-3-buten-2-yl carbonate n-pentyl 2-methyl-3-buten-2-yl carbonate 4-methylpentyl carbonate 2-methyl-3-butene-
2-yl 3-methylpentyl carbonate 2-methyl-3-butene-
2-yl 2-methylpentyl carbonate 2-methyl-3-butene-
2-yl carbonate 1-methylpentyl 2-methyl-3-butene-
2-yl carbonate 1,2,2-trimethylpropyl 2-methyl-
3-buten-2-yl n-hexyl carbonate 2-methyl-3-buten-2-yl

Methyl carbonate 3-ethyl-1-penten-3-yl ethyl carbonate 3-ethyl-1-penten-3-yl carbonate n-propyl 3-ethyl-1-penten-3-yl carbonate
Isopropyl carbonate 3-ethyl-1-pentene-3-
1-Methylpropyl 3-ethyl-1-penten-3-yl carbonate n-butyl 3-ethyl-1-penten-3-yl carbonate t-butyl 3-ethyl-1-penten-3-yl carbonate 3-carbonate Methylbutyl 3-ethyl-1-pentene-
3-yl 2-methylbutyl carbonate 3-ethyl-1-pentene-
3-yl 1-methylbutyl carbonate 3-ethyl-1-pentene-
3-yl 1,2-dimethylpropyl 3-ethyl-1-penten-3-yl carbonate n-pentyl carbonate 3-ethyl-1-pentene-3-
4-methylpentyl 3-ethyl-1-penten-3-yl carbonate 3-methylpentyl 3-ethyl-1-penten-3-yl carbonate 2-methylpentyl 3-ethyl-1-penten-3-yl carbonate 1-Methylpentyl 3-ethyl-1-penten-3-yl carbonate 1,2,2-trimethylpropyl 3-ethyl-1
-Penten-3-yl methyl carbonate 3-propyl-1-hexen-3-yl ethyl carbonate 3-propyl-1-hexen-3-yl n-propyl carbonate 3-propyl-1-hexene-3
-Yl isopropyl carbonate 3-propyl-1-hexene-3
-Yl carbonate 1-methylpropyl 3-propyl-1-hexene-3-yl carbonate n-butyl 3-propyl-1-hexene-3-
Il t-butyl carbonate 3-propyl-1-hexene-3-
Ill

3-methylbutyl carbonate 3-propyl-
1-Hexen-3-yl 2-methylbutyl carbonate 3-propyl-1-hexen-3-yl 1-methylbutyl 3-propyl-1-hexen-3-yl carbonate 1,2-dimethylpropyl 3-propyl-1-
Hexen-3-yl n-pentyl carbonate 3-propyl-1-hexene-3
-Yl 4-methylpentyl 3-propyl-1-hexen-3-yl carbonate 3-methylpentyl 3-propyl-1-hexen-3-yl 2-methylpentyl carbonate 3-propyl-1-hexen-3-yl 1-methylpentyl 3-propyl-1-hexen-3-yl carbonate 1,2,2-trimethylpropyl 3-propyl-1-hexen-3-yl carbonate methyl 3-butyl-1-hepten-3-yl carbonate Ethyl 3-butyl-1-hepten-3-yl n-propyl carbonate 3-butyl-1-hepten-3-yl isopropyl carbonate 3-butyl-1-hepten-3-yl 1-methylpropyl 3-butyl carbonate -Hepten-
3-yl n-butyl carbonate 3-butyl-1-hepten-3-yl t-butyl carbonate 3-butyl-1-hepten-3-yl 3-methylbutyl carbonate 3-butyl-1-heptene-3
-Yl 2-methylbutyl carbonate 3-butyl-1-heptene-3
-Yl carbonate 1-methylbutyl 3-butyl-1-heptene-3
-Yl carbonate 1,2-dimethylpropyl 3-butyl-1-hepten-3-yl n-pentyl carbonate 3-butyl-1-hepten-3-yl 4-methylpentyl carbonate 3-butyl-1-heptene-
3-yl 3-methylpentyl carbonate 3-butyl-1-heptene-
3-yl 2-methylpentyl carbonate 3-butyl-1-heptene-
3-yl 1-methylpentyl carbonate 3-butyl-1-heptene-
3-yl carbonate 1,2,2-trimethylpropyl 3-butyl-1
-Hepten-3-yl

The alkene derivative represented by the general formula (7) is specifically exemplified below. 3- (4-acetylphenoxy) -3-methyl-1-butene 3- (4-ethylcarbonylphenoxy) -3-methyl-1-butene 3- (4-isopropionylphenoxy) -3-methyl-1-butene 3-Methyl-3- (4-pivaloylphenoxy) -1-
Butene 3-methyl-3- (4-valerylphenoxy) -1-butene 3- (4-n-hexylcarbonylphenoxy) -3-
Methyl-1-butene 3- (4-methoxycarbonylphenoxy) -3-methyl-1-butene 3- (4-ethoxycarbonylphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n- Propoxycarbonylphenoxy) -1-butene 3- (4-t-butoxycarbonylphenoxy) -3-
Methyl-1-butene 3-methyl-3- (4-n-pentyloxycarbonylphenoxy) -1-butene 3- (4-n-hexyloxycarbonylphenoxy)
-3-Methyl-1-butene 3-Methyl-3- (3-nitrophenoxy) -1-butene 3-Methyl-3- (4-nitrophenoxy) -1-butene 3- (3-cyanophenoxy) -3 -Methyl-1-butene 3- (4-cyanophenoxy) -3-methyl-1-butene 3- (3-chlorophenoxy) -3-methyl-1-butene 3- (4-chlorophenoxy) -3-methyl -1-Butene 3-methyl-3- (3-trifluoromethylphenoxy) -1-butene 3-methyl-3- (4-trifluoromethylphenoxy) -1-butene 3- (4-methanesulfonylphenoxy)- 3-Methyl-1-butene 3- (4-ethanesulfonylphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n-propanesulfonylphenoxy) -1-butene 3 (4-t-butane sulfonyl-phenoxy) -3-methyl-1-butene 3-methyl-3- (4-n-pentane sulfonyl) -l- butene 3- (4-cyclohexanesulfonyl phenoxy) -3
-Methyl-1-butene 3- (4-methanesulfinylphenoxy) -3-methyl-1-butene 3- (4-ethanesulfinylphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n -Propanesulfinylphenoxy) -1-butene 3- (4-t-butanesulfinylphenoxy) -3-
Methyl-1-butene 3-methyl-3- (4-n-pentanesulfinylphenoxy) -1-butene 3- (4-cyclohexanesulfinylphenoxy)-
3-Methyl-1-butene 3- (4-methoxysulfinylphenoxy) -3-methyl-1-butene 3- (4-ethoxysulfinylphenoxy) -3-methyl-1-butene 3-methyl-3- (4- n-Propoxysulfinylphenoxy) -1-butene 3- (4-n-butyloxysulfinylphenoxy)
-3-Methyl-1-butene 3-Methyl-3- (4-n-pentyloxysulfinylphenoxy) -1-butene 3- (4-n-hexyloxysulfinylphenoxy) -3-methyl-1-butene

3- (4-methoxysulfonylphenoxy) -3-methyl-1-butene 3- (4-ethoxysulfonylphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n-propoxysulfonyl) Phenoxy) -1-butene 3- (4-n-butylsulfonylphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n-pentyloxysulfonylphenoxy) -1-butene 3- (4- n-hexyloxysulfonylphenoxy)
-3-Methyl-1-butene 3- (4-acetylaminophenoxy) -3-methyl-
1-butene 3- (4-ethylcarbonylaminophenoxy) -3-
Methyl-1-butene 3- (4-isopropionylaminophenoxy) -3-
Methyl-1-butene 3-methyl-3- (4-pivaloylaminophenoxy)
-1-Butene 3-methyl-3- (4-valerylaminophenoxy)-
1-butene 3- (4-n-hexylcarbonylaminophenoxy)
-3-Methyl-1-butene 3- (4-methoxycarbonylaminophenoxy) -3
-Methyl-1-butene 3- (4-ethoxycarbonylaminophenoxy) -3
-Methyl-1-butene 3-methyl-3- (4-n-propoxycarbonylaminophenoxy) -1-butene 3- (4-t-butoxycarbonylaminophenoxy)
-3-Methyl-1-butene 3-Methyl- (4-n-pentyloxycarbonylaminophenoxy) -3-butene 3- (4-n-hexyloxycarbonylaminophenoxy) -3-methyl-1-butene 3-Methyl-3- (4-methylaminosulfinylphenoxy) -1-butene 3- (4-ethylaminosulfinylphenoxy) -3
-Methyl-1-butene 3-methyl-3- (4-n-propylaminosulfinylphenoxy) -1-butene 3- (4-t-butylaminosulfinylphenoxy)
-3-Methyl-1-butene 3-methyl-3- (4-n-pentylaminosulfinylphenoxy) -1-butene 3- (4-cyclohexylaminosulfinylphenoxy) -3-methyl-1-butene 3-methyl- 3- (4-methylaminosulfonylphenoxy) -1-butene 3- (4-ethylaminosulfonylphenoxy) -3-
Methyl-1-butene 3-methyl-3- (4-n-propylaminosulfonylphenoxy) -1-butene 3- (4-t-butylaminosulfonylphenoxy)-
3-Methyl-1-butene 3-Methyl-3- (4-n-pentylaminosulfonylphenoxy) -1-butene 3- (4-Cyclohexylaminosulfonylphenoxy) -3-methyl-1-butene 3-methyl-3 -(4-Methylsulfinylaminophenoxy) -1-butene 3- (4-ethylsulfinylaminophenoxy) -3
-Methyl-1-butene 3-methyl-3- (4-n-propylsulfinylaminophenoxy) -1-butene 3- (4-t-butylsulfinylaminophenoxy)
-3-Methyl-1-butene 3-methyl-3- (4-n-pentylsulfinylaminophenoxy) -1-butene 3- (4-cyclohexylsulfinylaminophenoxy) -3-methyl-1-butene 3-methyl- 3- (4-methylsulfonylaminophenoxy) -1-butene 3- (4-ethylsulfonylaminophenoxy) -3-
Methyl-1-butene 3-methyl-3- (4-n-propylsulfonylaminophenoxy) -1-butene 3- (4-t-butylsulfonylaminophenoxy)-
3-Methyl-1-butene 3-Methyl-3- (4-n-pentylsulfonylaminophenoxy) -1-butene 3- (4-Cyclohexylsulfonylaminophenoxy) -3-methyl-1-butene

3- (4-Methoxyphenoxy) -3-methyl-1-butene 3- (4-ethoxyphenoxy) -3-methyl-1-butene 3-methyl-3- (4-n-propoxyphenoxy)-
1-butene 3- (4-t-butoxyphenoxy) -3-methyl-1
-Butene 3-methyl-3- (4-n-pentyloxyphenoxy) -1-butene 3- (4-n-hexyloxyphenoxy) -3-methyl-1-butene 3- (3-cyanomethylphenoxy)- 3-methyl-1
-Butene 3- (4-cyanomethylphenoxy) -3-methyl-1
-Butene 3-methyl-3- (3-pyridyloxy) -1-butene 3-Methyl-3- (4-pyridyloxy) -1-butene 3- (4-cyanophenoxy) -3-ethyl-1-pentene 3- (4-Cyanophenoxy) -3-propyl-1-hexene 3-Butyl-3- (4-cyanophenoxy) -1-heptene 1- (4-cyanophenoxy) -1-vinylcyclopropane 1- (4 -Cyanophenoxy) -1-vinylcyclobutane 1- (4-cyanophenoxy) -1-vinylcyclopentane 1- (4-cyanophenoxy) -1-vinylcyclohexane {3-methyl-3- (3-pyridyloxy)- Butyl}
Piperazine {3-methyl-3- (4-pyridyloxy) -butyl}
Piperazine

The propane oxide derivative represented by the general formula (4) is specifically exemplified below. 3- (4-acetylphenoxy) -3-methyl-1,2
-Epoxybutane 3- (4-ethylcarbonylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-isopropionylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- ( 4-pivaloylphenoxy) -1,
2-epoxybutane 3-methyl-3- (4-valerylphenoxy) -1,2
-Epoxybutane 3- (4-n-hexylcarbonylphenoxy) -3-
Methyl-1,2-epoxybutane 3- (4-methoxycarbonylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-ethoxycarbonylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl -3- (4-n-propoxycarbonylphenoxy) -1,2-epoxybutane 3- (4-t-butoxycarbonylphenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentyloxycarbonylphenoxy) -1,2-epoxybutane 3- (4-n-hexyloxycarbonylphenoxy)
-3-Methyl-1,2-epoxybutane

3-Methyl-3- (3-nitrophenoxy) -1,2-epoxybutane 3-Methyl-3- (4-nitrophenoxy) -1,2-
Epoxy butane 3- (3-cyanophenoxy) -3-methyl-1,2-
Epoxy butane 3- (4-cyanophenoxy) -3-methyl-1,2-
Epoxy butane 3- (3-chlorophenoxy) -3-methyl-1,2-
Epoxy butane 3- (4-chlorophenoxy) -3-methyl-1,2-
Epoxy butane 3-Methyl-3- (3-trifluoromethylphenoxy) -1,2-epoxybutane 3-Methyl-3- (4-trifluoromethylphenoxy) -1,2-epoxybutane 3- (4-methane Sulfonylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-ethanesulfonylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- (4-n-propanesulfonylphenoxy)- 1,2-epoxybutane 3- (4-t-butanesulfonylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentanesulfonylphenoxy) -1,2-epoxybutane 3- (4-cyclohexylsulfonylphenoxy) -3
-Methyl-1,2-epoxybutane

3- (4-Methanesulfinylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-ethanesulfinylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- ( 4-n-propanesulfinylphenoxy) -1,2-epoxybutane 3- (4-t-butanesulfinylphenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentanesulfinylphenoxy) -1,2-epoxybutane 3- (4-cyclohexylsulfinylphenoxy)-
3-Methyl-1,2-epoxybutane 3- (4-methoxysulfinylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-ethoxysulfinylphenoxy) -3-methyl-1,2-epoxybutane 3-Methyl-3- (4-n-propoxysulfinylphenoxy) -1,2-epoxybutane 3- (4-n-butylsulfinylphenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentyloxysulfinylphenoxy) -1,2-epoxybutane 3- (4-n-hexyloxysulfinylphenoxy) -3-methyl-1, 2-epoxy butane

3- (4-methoxysulfonylphenoxy) -3-methyl-1,2-epoxybutane 3- (4-ethoxysulfonylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- ( 4-n-propoxysulfonylphenoxy) -1,2-epoxybutane 3- (4-n-butylsulfonylphenoxy) -3-methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentyloxy Sulfonylphenoxy) -1,2-epoxybutane 3- (4-n-hexyloxysulfonylphenoxy)
-3-Methyl-1,2-epoxybutane 3- (4-acetylaminophenoxy) -3-methyl-
1,2-epoxybutane 3- (4-ethylcarbonylaminophenoxy) -3-
Methyl-1,2-epoxybutane 3- (4-isopropionylaminophenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-pivaloylaminophenoxy)
-1,2-epoxybutane 3-methyl-3- (4-valerylaminophenoxy)-
1,2-epoxybutane 3- (4-n-hexylcarbonylaminophenoxy)
-3-Methyl-1,2-epoxybutane 3- (4-methoxycarbonylaminophenoxy) -3
-Methyl-1,2-epoxybutane 3- (4-ethoxycarbonylaminophenoxy) -3
-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-propoxycarbonylaminophenoxy) -1,2-epoxybutane 3- (4-t-butoxycarbonylaminophenoxy)
-3-Methyl-1,2-epoxybutane 3-Methyl-3- (4-n-pentyloxycarbonylaminophenoxy) -1,2-epoxybutane 3- (4-n-hexyloxycarbonylaminophenoxy) -3 -Methyl-1,2-epoxybutane

3-Methyl-3- (4-methylaminosulfinylphenoxy) -1,2-epoxybutane 3- (4-ethylaminosulfinylphenoxy) -3
-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-propylaminosulfinylphenoxy) -1,2-epoxybutane 3- (4-t-butylaminosulfinylphenoxy)
-3-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentylaminosulfinylphenoxy) -1,2-epoxybutane 3- (4-cyclohexylaminosulfinylphenoxy) -3-methyl-1 , 2-epoxybutane 3-methyl-3- (4-methylaminosulfonylphenoxy) -1,2-epoxybutane 3- (4-ethylaminosulfonylphenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-n-propylaminosulfonylphenoxy) -1,2-epoxybutane 3- (4-t-butylaminosulfonylphenoxy)-
3-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentylaminosulfonylphenoxy) -1,2-epoxybutane 3- (4-cyclohexylaminosulfonylphenoxy) -3-methyl-1, 2-epoxy butane

3-Methyl-3- (4-methylsulfinylaminophenoxy) -1,2-epoxybutane 3- (4-ethylsulfinylaminophenoxy) -3
-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-propylsulfinylaminophenoxy) -1,2-epoxybutane 3- (4-t-butylsulfinylaminophenoxy)
-3-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentylsulfinylaminophenoxy) -1,2-epoxybutane 3- (4-cyclohexylsulfinylaminophenoxy) -3-methyl-1 , 2-epoxybutane 3-methyl-3- (4-methylsulfonylaminophenoxy) -1,2-epoxybutane 3- (4-ethylsulfonylaminophenoxy) -3-
Methyl-1,2-epoxybutane 3-methyl-3- (4-n-propylsulfonylaminophenoxy) -1,2-epoxybutane 3- (4-t-butylsulfonylaminophenoxy)-
3-Methyl-1,2-epoxybutane 3-methyl-3- (4-n-pentylsulfonylaminophenoxy) -1,2-epoxybutane 3- (4-cyclohexylsulfonylaminophenoxy) -3-methyl-1, 2-epoxy butane

3-Methyl-3- (4-methoxyphenoxy) -1,2-epoxybutane 3-Methyl-3- (4-ethoxyphenoxy) -1,2
-Epoxybutane 3-methyl-3- (4-n-propoxyphenoxy)-
1,2-epoxybutane 3- (4-t-butoxyphenoxy) -3-methyl-
1,2-epoxybutane 3-methyl-3- (4-n-pentyloxyphenoxy) -1,2-epoxybutane 3- (4-n-hexyloxyphenoxy) -3-methyl-1,2-epoxybutane 3- (3-cyanomethylphenoxy) -3-methyl-
1,2-epoxybutane 3- (4-cyanomethylphenoxy) -3-methyl-
1,2-epoxybutane 3-methyl-3- (3-pyridyloxy) -1,2-epoxybutane 3-methyl-3- (4-pyridyloxy) -1,2-epoxybutane 3- (4-cyano Phenoxy) -3-ethyl-1,2-
Epoxy pentane 3- (4-cyanophenoxy) -3-propyl-1,2
-Epoxyhexane 3-butyl-3- (4-cyanophenoxy) -1,2-
Epoxyheptane 1- (4-cyanophenoxy) -1-epoxyethylcyclopropane 1- (4-cyanophenoxy) -1-epoxyethylcyclobutane 1- (4-cyanophenoxy) -1-epoxyethylcyclopentane 1- (4 -Cyanophenoxy) -1-epoxyethyl cyclohexane

The propyl alcohol derivative represented by the general formula (9) is specifically exemplified below. 3- (4-acetylphenoxy) -3-methylbutanol 3- (4-ethylcarbonylphenoxy) -3-methylbutanol 3- (4-isopropionylphenoxy) -3-methylbutanol 3-methyl-3- (4- Pivaloylphenoxy) butanol 3-methyl-3- (4-valerylphenoxy) butanol 3- (4-n-hexylcarbonylphenoxy) -3-
Methylbutanol 3- (4-methoxycarbonylphenoxy) -3-methylbutanol 3- (4-ethoxycarbonylphenoxy) -3-methylbutanol 3-methyl-3- (4-n-propoxycarbonylphenoxy) butanol 3- (4 -T-butoxycarbonylphenoxy) -3-
Methyl butanol 3-methyl-3- (4-n-pentyloxycarbonylphenoxy) butanol 3- (4-n-hexyloxycarbonylphenoxy)
-3-Methylbutanol 3-Methyl-3- (3-nitrophenoxy) butanol 3-Methyl-3- (4-nitrophenoxy) butanol 3- (3-Cyanophenoxy) -3-methylbutanol 3- (4-cyano Phenoxy) -3-methylbutanol 3- (3-Chlorophenoxy) -3-methylbutanol 3- (4-Chlorophenoxy) -3-methylbutanol

3-Methyl-3- (3-trifluoromethylphenoxy) butanol 3-Methyl-3- (4-trifluoromethylphenoxy) butanol 3- (4-methanesulfonylphenoxy) -3-methylbutanol 3- ( 4-ethanesulfonylphenoxy) -3-methylbutanol 3-methyl-3- (4-n-propanesulfonylphenoxy) butanol 3- (4-t-butanesulfonylphenoxy) -3-methylbutanol 3-methyl-3- ( 4-n-pentanesulfonylphenoxy) butanol 3- (4-cyclohexylsulfonylphenoxy) -3
-Methylbutanol 3- (4-methanesulfinylphenoxy) -3-methylbutanol 3- (4-ethanesulfinylphenoxy) -3-methylbutanol 3-methyl-3- (4-n-propanesulfinylphenoxy) butanol 3- ( 4-t-butanesulfinylphenoxy) -3-
Methyl butanol 3-methyl-3- (4-n-pentanesulfinylphenoxy) butanol 3- (4-cyclohexylsulfinylphenoxy)-
3-Methylbutanol 3- (4-Methoxysulfinylphenoxy) -3-methylbutanol 3- (4-Ethoxysulfinylphenoxy) -3-methylbutanol 3-Methyl-3- (4-n-propoxysulfinylphenoxy) butanol 3- (4-n-Butylsulfinylphenoxy) -3-
Methylbutanol 3-methyl-3- (4-n-pentyloxysulfinylphenoxy) butanol 3- (4-n-hexyloxysulfinylphenoxy) -3-methylbutanol

3- (4-Methoxysulfonylphenoxy) -3-methylbutanol 3- (4-ethoxysulfonylphenoxy) -3-methylbutanol 3-methyl-3- (4-n-propoxysulfonylphenoxy) butanol 3- ( 4-n-butylsulfonylphenoxy) -3-methylbutanol 3-methyl-3- (4-n-pentyloxysulfonylphenoxy) butanol 3- (4-n-hexyloxysulfonylphenoxy)
-3-Methylbutanol 3- (4-acetylaminophenoxy) -3-methylbutanol 3- (4-ethylcarbonylaminophenoxy) -3-
Methyl butanol 3- (4-isopropionylaminophenoxy) -3-
Methyl butanol 3-methyl-3- (4-pivaloylaminophenoxy)
Butanol 3-methyl-3- (4-valerylaminophenoxy) butanol 3- (4-n-hexylcarbonylaminophenoxy)
-3-Methyl-butanol 3- (4-methoxycarbonylaminophenoxy) -3
-Methylbutanol 3- (4-ethoxycarbonylaminophenoxy) -3
-Methyl butanol 3-methyl-3- (4-n-propoxycarbonylaminophenoxy) butanol 3- (4-t-butoxycarbonylaminophenoxy)
-3-Methylbutanol 3-Methyl-3- (4-n-pentyloxycarbonylaminophenoxy) butanol 3- (4-n-hexyloxycarbonylaminophenoxy) -3-methylbutanol

3-Methyl-3- (4-methylaminosulfinylphenoxy) butanol 3- (4-ethylaminosulfinylphenoxy) -3
-Methylbutanol 3-methyl-3- (4-n-propylaminosulfinylphenoxy) butanol 3- (4-t-butylaminosulfinylphenoxy)
-3-Methylbutanol 3-Methyl-3- (4-n-pentylaminosulfinylphenoxy) butanol 3- (4-Cyclohexylaminosulfinylphenoxy) -3-methylbutanol 3-Methyl-3- (4-methylaminosulfonylphenoxy) ) Butanol 3- (4-ethylaminosulfonylphenoxy) -3-
Methylbutanol 3-Methyl-3- (4-n-propylaminosulfonylphenoxy) butanol 3- (4-t-butylaminosulfonylphenoxy)-
3-Methylbutanol 3-Methyl-3- (4-n-pentylaminosulfonylphenoxy) butanol 3- (4-Cyclohexylaminosulfonylphenoxy) -3-methylbutanol 3-Methyl-3- (4-methylsulfinylaminophenoxy) Butanol 3- (4-ethylsulfinylaminophenoxy) -3
-Methylbutanol 3-methyl-3- (4-n-propylsulfinylaminophenoxy) butanol 3- (4-t-butylsulfinylaminophenoxy)
-3-Methylbutanol 3-Methyl-3- (4-n-pentylsulfinylaminophenoxy) butanol 3- (4-Cyclohexylsulfinylaminophenoxy) -3-methylbutanol

3-Methyl-3- (4-methylsulfonylaminophenoxy) butanol 3- (4-ethylsulfonylaminophenoxy) -3-
Methyl butanol 3-Methyl-3- (4-n-propylsulfonylaminophenoxy) butanol 3- (4-t-butylsulfonylaminophenoxy)-
3-Methylbutanol 3-Methyl-3- (4-n-pentylsulfonylaminophenoxy) butanol 3- (4-Cyclohexylsulfonylaminophenoxy) -3-methylbutanol 3- (4-Methoxyphenoxy) -3-methylbutanol 3 -(4-Ethoxyphenoxy) -3-methylbutanol 3-methyl-3- (4-n-propoxyphenoxy) butanol 3- (4-t-butoxyphenoxy) -3-methylbutanol 3-methyl-3- (4 -N-pentyloxyphenoxy) butanol 3-methyl-3- (4-n-hexyloxyphenoxy) butanol 3- (3-cyanomethylphenoxy) -3-methylbutanol 3- (4-cyanomethylphenoxy) -3- Methyl butanol 3-methyl-3- (3-pyridyloxy) Tanol 3-methyl-3- (4-pyridyloxy) butanol 3- (4-cyanophenoxy) -3-ethylpentanol 3- (4-cyanophenoxy) -3-propylhexanol 3-butyl-3- (4- Cyanophenoxy) -heptanol 1- (4-cyanophenoxy) -1-hydroxyethylcyclopropane 1- (4-cyanophenoxy) -1-hydroxyethylcyclobutane 1- (4-cyanophenoxy) -1-hydroxyethylcyclopentane 1 -(4-Cyanophenoxy) -1-hydroxyethylcyclohexane

Specific examples of the propane derivative represented by the general formula (8) will be given below. 3- (4-Acetylphenoxy) -3-methylbutane chloride 3- (4-Ethylcarbonylphenoxy) -3-methylbutane bromide 3- (4-Isopropionylphenoxy) -3-iodide
Methyl butane p-toluenesulfonic acid 3-methyl-3- (4-pivaloylphenoxy) butyl ester methanesulfonic acid 3-methyl-3- (4-valerylphenoxy) butyl ester trifluoromethanesulfonic acid 3- (4-n -Hexylcarbonylphenoxy) -3-methyl-butyl ester 3- (4-methoxycarbonylphenoxy) -3-chloride
Methyl butane 3- (4-ethoxycarbonylphenoxy) -3-bromide
Methyl butane iodide 3- (4-n-propoxycarbonylphenoxy) -3-methylbutane p-toluenesulfonic acid 3- (4-t-butoxycarbonylphenoxy) -3-methylbutyl ester methanesulfonic acid 3-methyl-3- ( 4-n-pentyloxycarbonylphenoxy) butyl ester trifluoromethanesulfonic acid 3-methyl-3- (4
-N-hexyloxycarbonylphenoxy) butyl ester

Chloromethyl-3-methyl-3- (3-nitrophenoxy) butane p-Toluenesulfonic acid 3-Methyl-3- (4-nitrophenoxy) butyl ester Methanesulfonic acid 3- (3-Cyanophenoxy) -3
-Methylbutyl ester 3- (4-cyanophenoxy) -3-methylbutane bromide 3- (3-Chlorophenoxy) -3-methylbutanol trifluoromethanesulfonic acid 3- (4-Chlorophenoxy) -3-methylbutyl Ester p-Toluenesulfonic acid 3-Methyl-3- (3-trifluoromethylphenoxy) butyl ester 3-Methyl-3- (4-trifluoromethylphenoxy) butane chloride 3-Methyl-3- (4-methane) Sulfonylphenoxy) butane iodide 3- (4-ethanesulfonylphenoxy) -3-
Methyl butane p-toluenesulfonic acid 3-methyl-3- (4-n-
Propanesulfonylphenoxy) butyl ester methanesulfonic acid 3- (4-t-butanesulfonylphenoxy) -3-methylbutyl ester trifluoromethanesulfonic acid 3-methyl-3- (4
-N-Pentanesulfonylphenoxy) butyl ester chloride 3- (4-cyclohexylsulfonylphenoxy)
-3-methylbutane

3-Methyl-3- (4-methanesulfinylphenoxy) butane bromide 3- (4-ethanesulfinylphenoxy) -3 iodide
-Methylbutane p-toluenesulfonic acid 3-methyl-3- (4-n-)
Propanesulfinylphenoxy) butyl ester methanesulfonic acid 3- (4-t-butanesulfinylphenoxy) -3-methylbutyl ester trifluoromethanesulfonic acid 3-methyl-3- (4
-N-pentanesulfinylphenoxy) butyl ester 3- (4-n-hexylsulfinylphenoxy) chloride
-3-Methylbutane chloride 3- (4-methoxysulfinylphenoxy) -3
-Methylbutane 3- (4-ethoxysulfinylphenoxy) -3 bromide
-Methylbutane 3-methyl-3- (4-n-propoxysulfinylphenoxy) butane p-toluenesulfonic acid 3- (4-n-butylsulfinylphenoxy) -3-methylbutyl ester methanesulfonic acid 3-methyl-3 -(4-n-Pentyloxysulfinylphenoxy) butyl ester trifluoromethanesulfonic acid 3- (4-n-hexyloxysulfinylphenoxy) -3-methylbutyl ester 3- (4-methoxysulfonylphenoxy) -3-chloride
Methylbutane 3- (4-ethoxysulfonylphenoxy) -3-bromide
Methyl butane 3-methyl-3- (4-n-propoxysulfonylphenoxy) butane p-toluenesulfonic acid 3- (4-n-butylsulfonylphenoxy) -3-methylbutyl ester methanesulfonic acid 3-methyl-3- (4-n-Pentyloxysulfonylphenoxy) butyl ester Trifluoromethanesulfonic acid 3- (4-n-hexyloxysulfonylphenoxy) -3-methylbutyl ester

3- (4-Acetylaminophenoxy) -3-methylbutane chloride 3- (4-Ethylcarbonylaminophenoxy) -bromide
3-Methylbutane iodide 3- (4-isopropionylaminophenoxy)
-3-Methylbutane p-toluenesulfonic acid 3-methyl-3- (4-pivaloylaminophenoxy) butyl ester methanesulfonic acid 3-methyl-3- (4-valerylaminophenoxy) butyl ester trifluoromethanesulfonic acid 3 -(4-n-hexylcarbonylaminophenoxy) -3-methyl-butyl ester 3- (4-methoxycarbonylaminophenoxy) chloride
-3-Methylbutane 3- (4-ethoxycarbonylaminophenoxy) bromide
-3-Methylbutane 3-methyl-3- (4-n-propoxycarbonylaminophenoxy) butane p-toluenesulfonic acid 3- (4-t-butoxycarbonylaminophenoxy) -3-methylbutyl ester methanesulfonic acid 3 -Methyl-3- (4-n-pentyloxycarbonylaminophenoxy) butyl ester trifluoromethanesulfonic acid 3- (4-n-hexyloxycarbonylaminophenoxy) -3-methyl-
Butyl ester 3-methyl-3- (4-methylaminosulfinylphenoxy) butane chloride 3- (4-ethylaminosulfinylphenoxy) bromide
-3-Methylbutanol 3-methyl-3- (4-n-propylaminosulfinylphenoxy) butane p-toluenesulfonic acid 3- (4-t-butylaminosulfinylphenoxy) -3-methylbutyl ester methanesulfonic acid 3-Methyl-3- (4-n-pentylaminosulfinylphenoxy) butyl ester Trifluoromethanesulfonic acid 3- (4-Cyclohexylaminosulfinylphenoxy) -3-methylbutyl ester

Trifluoromethanesulfonic acid 3-methyl-3- (4-methylaminosulfonylphenoxy) butyl ester Methanesulfonic acid 3- (4-ethylaminosulfonylphenoxy) -3-methylbutyl ester p-toluenesulfonic acid 3-methyl -3- (4-n-
Propylaminosulfonylphenoxy) butyl ester 3- (4-t-butylaminosulfonylphenoxy) -3-methylbutane chloride 3-Methyl-3- (4-n-pentylaminosulfonylphenoxy) butane bromide 3- (4- Cyclohexylaminosulfonylphenoxy) -3-methylbutane 3-methyl-3- (4-methylsulfinylaminophenoxy) butane chloride 3- (4-ethylsulfinylaminophenoxy) bromide
-3-Methylbutane 3-methyl-3- (4-n-propylsulfinylaminophenoxy) butane p-toluenesulfonic acid 3- (4-t-butylsulfinylaminophenoxy) -3-methylbutyl ester methanesulfonic acid 3 -Methyl-3- (4-n-pentylsulfinylaminophenoxy) butyl ester trifluoromethanesulfonic acid 3- (4-cyclohexylsulfinylaminophenoxy) -3-methylbutyl ester 3-methyl-3- (4-methanesulfonylamino chloride Phenoxy) butane 3- (4-ethanesulfonylaminophenoxy) -bromide
3-Methylbutane iodide 3-methyl-3- (4-n-propanesulfonylaminophenoxy) butane p-toluenesulfonic acid 3- (4-t-butanesulfonylaminophenoxy) -3-methylbutyl ester methanesulfonic acid 3- Methyl-3- (4-n-pentanesulfonylaminophenoxy) butyl ester Trifluoromethanesulfonic acid 3- (4-Cyclohexanesulfonylaminophenoxy) -3-methylbutyl ester

3- (4-methoxyphenoxy) -3 chloride
-Methylbutane 3- (4-ethoxyphenoxy) -3-methylbutane iodide 3-methyl-3- (4-n-propoxyphenoxy) butane p-toluenesulfonic acid 3- (4-t-butoxyphenoxy) -3 -Methylbutyl ester methanesulfonic acid 3-methyl-3- (4-n-pentyloxyphenoxy) butyl ester trifluoromethanesulfonic acid 3- (4-n-hexyloxyphenoxy) -3-methylbutyl ester chloride 3- (3 -Cyanomethylphenoxy) -3-methylbutane p-toluenesulfonic acid 3- (4-cyanomethylphenoxy) -3-methylbutyl ester bromide 3-methyl-3- (3-pyridyloxy) -butane methanesulfonic acid 3- Methyl-3- (4-pyridyloxy) -butyl ester methane sulfone 3- (4-cyanophenoxy) -3
-Ethylpentyl ester p-toluenesulfonic acid 3- (4-cyanophenoxy) -3-propylhexyl ester trifluoromethanesulfonic acid 3-butyl-3- (4
-Cyanophenoxy) -heptyl ester 1- (4-cyanophenoxy) -1-ethyl chloride cyclopropane 1- (4-cyanophenoxy) -1-ethylcyclobutane bromide 1- (4-cyanophenoxy) -1-iodinated Ethyl cyclopentane 1- (4-cyanophenoxy) -1-ethyl chloride cyclohexane

Specific examples of the piperazine derivative represented by the general formula (10) are shown below. The compounds in which W is a hydroxyl group are as follows. {3- (4-acetylphenoxy) -2-hydroxy-
3-Methylbutyl} piperazine {3- (4-ethylcarbonylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3- (4-isopropionylphenoxy) -3-methylbutyl} piperazine {2-hydroxy- 3-Methyl-3- (4-pivaloylphenoxy) butyl} piperazine {2-hydroxy-3-methyl-3- (4-valerylphenoxy) butyl} piperazine {2-hydroxy-3- (4-n- Hexylcarbonylphenoxy) -3-methylbutyl} piperazine {2-Hydroxy-3- (4-methoxycarbonylphenoxy) -3-methylbutyl} piperazine {3- (4-Ethoxycarbonylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- 4-n-propoxycarbonylphenoxy) butyl} piperazine {(4-t-butoxycarbonylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentyloxycarbonyl) Phenoxy) butyl} piperazine {2-hydroxy-3- (4-n-hexyloxycarbonylphenoxy) 3-methylbutyl} piperazine

{2-hydroxy-3-methyl-3- (3
-Nitrophenoxy) butyl} piperazine {2-hydroxy-3-methyl-3- (4-nitrophenoxy) butyl} piperazine {3- (3-cyanophenoxy) -2-hydroxy-3
-Methylbutyl} piperazine {3- (4-cyanophenoxy) -2-hydroxy-3
-Methylbutyl} piperazine {3- (3-chlorophenoxy) -2-hydroxy-3
-Methylbutyl} piperazine {3- (4-chlorophenoxy) -2-hydroxy-3
-Methylbutyl} piperazine {2-hydroxy-3-methyl-3- (3-trifluoromethylphenoxy) butyl} piperazine {2-hydroxy-3-methyl-3- (4-trifluoromethylphenoxy) butyl} piperazine {2 -Hydroxy-3-methyl-3- (4-methanesulfonylphenoxy) butyl} piperazine {3- (4-ethanesulfonylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-Propanesulfonylphenoxy) butyl} piperazine {3- (4-t-butanesulfonylphenoxy) -2-
Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentanesulfonylphenoxy) butyl} piperazine {3- (4-cyclohexylsulfonylphenoxy)-
2-hydroxy-3-methylbutyl} piperazine

{2-hydroxy-3-methyl-3- (4
-Methanesulfinylphenoxy) butyl} piperazine {3- (4-ethanesulfinylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propanesulfinylphenoxy) butyl} Piperazine {3- (4-t-butanesulfinylphenoxy) -2
-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentanesulfinylphenoxy) butyl} piperazine {3- (4-cyclohexylsulfinylphenoxy)
2-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3- (4-methoxysulfinylphenoxy) -3-methylbutyl} piperazine {3- (4-ethoxysulfinylphenoxy) -2-
Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propoxysulfinylphenoxy) butyl} piperazine {3- (4-n-butylsulfinylphenoxy) -2
-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentyloxysulfinylphenoxy) butyl} piperazine {3- (4-n-hexyloxysulfinylphenoxy) -2-hydroxy- 3-Methylbutyl} piperazine

{2-hydroxy-3- (4-methoxysulfonylphenoxy) -3-methylbutyl} piperazine {3- (4-ethoxysulfonylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3- Methyl-3- (4-n-propoxysulfonylphenoxy) butyl} piperazine {3- (4-n-butylsulfonylphenoxy) -2-
Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentyloxysulfonylphenoxy) butyl} piperazine {3- (4-n-hexyloxysulfonylphenoxy) -2-hydroxy-3 -Methylbutyl} piperazine {3- (4-acetylaminophenoxy) -2-hydroxy-3-methylbutyl} piperazine {3- (4-ethylcarbonylaminophenoxy) -2
-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3- (4-isopropionylaminophenoxy) -3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-pivaloylaminophenoxy) butyl } Piperazine {2-hydroxy-3-methyl-3- (4-valerylaminophenoxy) butyl} piperazine {2-hydroxy-3-methyl-3- (4-n-hexylcarbonylaminophenoxy) butyl} piperazine {2 -Hydroxy-3- (4-methoxycarbonylaminophenoxy) -3-methylbutyl} piperazine {3- (4-ethoxycarbonylaminophenoxy)-
2-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propoxycarbonylaminophenoxy) butyl} piperazine {(4-t-butoxycarbonylaminophenoxy)-
2-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentyloxycarbonylaminophenoxy) butyl} piperazine {3- (4-n-hexyloxycarbonylaminophenoxy) -2 -Hydroxy-3-methylbutyl} piperazine

{2-hydroxy-3-methyl-3- (4
-Methylaminosulfinylphenoxy) butyl} piperazine {3- (4-ethylaminosulfinylphenoxy)-
2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propylaminosulfinylphenoxy) butyl} piperazine {3- (4-t-butylaminosulfinylphenoxy) -2-hydroxy -3-Methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentylaminosulfinylphenoxy) butyl} piperazine {3- (4-cyclohexylaminosulfinylphenoxy) -2-hydroxy-3-methylbutyl} Piperazine {2-hydroxy-3-methyl-3- (4-methylaminosulfonylphenoxy) butyl} piperazine {3- (4-ethylaminosulfonylphenoxy) -2
-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propylaminosulfonylphenoxy) butyl} piperazine {3- (4-t-butylaminosulfonylphenoxy)
2-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentylaminosulfonylphenoxy) butyl} piperazine {3- (4-cyclohexylaminosulfonylphenoxy) -2-hydroxy- 3-Methylbutyl} piperazine

{2-hydroxy-3-methyl-3- (4
-Methylsulfinylaminophenoxy) butyl} piperazine {3- (4-ethylsulfinylaminophenoxy)-
2-hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propylsulfinylaminophenoxy) butyl} piperazine {3- (4-t-butylsulfinylaminophenoxy) -2-hydroxy -3-Methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentylsulfinylaminophenoxy) butyl} piperazine {3- (4-cyclohexylsulfinylaminophenoxy) -2-hydroxy-3-methylbutyl} Piperazine {2-hydroxy-3-methyl-3- (4-methanesulfonylaminophenoxy) butyl} piperazine {3- (4-ethanesulfonylaminophenoxy) -2
-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propanesulfonylaminophenoxy) butyl} piperazine {3- (4-t-butanesulfonylaminophenoxy)
2-Hydroxy-3-methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentanesulfonylaminophenoxy) butyl} piperazine {3- (4-Cyclohexanesulfonylaminophenoxy) -2-hydroxy- 3-Methylbutyl} piperazine {2-hydroxy-3- (4-methoxyphenoxy)-
3-Methylbutyl} piperazine {3- (4-ethoxyphenoxy) -2-hydroxy-
3-Methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-propoxyphenoxy) butyl} piperazine {(4-t-butoxyphenoxy) -2-hydroxy-
3-Methylbutyl} piperazine {2-hydroxy-3-methyl-3- (4-n-pentyloxyphenoxy) butyl} piperazine {3- (4-n-hexyloxyphenoxy) -2-hydroxy-3-methylbutyl} piperazine

{3- (3-cyanomethylphenoxy)-
2-Hydroxy-3-methylbutyl} piperazine {3- (4-Cyanomethylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {2-Hydroxy-3-methyl-3- (3-pyridyloxy) butyl} piperazine { 2-Hydroxy-3-methyl-3- (4-pyridyloxy) butyl} piperazine {3- (4-cyanophenoxy) -3-ethyl-2-hydroxypentyl} piperazine {3- (4-cyanophenoxy) -2 -Hydroxy-3
-Propylhexyl} piperazine {3-Butyl-3- (4-cyanophenoxy) -2-hydroxyheptyl} piperazine 1- (4-cyanophenoxy) -1- {1-hydroxy-2- (piperazin-1-yl) Ethyl} cyclopropane 1- (4-cyanophenoxy) -1- {1-hydroxy-2- (piperazin-1-yl) ethyl} cyclobutane 1- (4-cyanophenoxy) -1- {1-hydroxy-2- (Piperazin-1-yl) ethyl} cyclopentane 1- (4-cyanophenoxy) -1- {1-hydroxy-2- (piperazin-1-yl) ethyl} cyclohexane

The compounds in which W is a hydrogen atom are as follows. {3- (4-Acetylphenoxy) -3-methylbutyl} piperazine {3- (4-Ethylcarbonylphenoxy) -3-methylbutyl} piperazine {3- (4-Isopropionylphenoxy) -3-methylbutyl} piperazine {3- Methyl-3- (4-pivaloylphenoxy) butyl} piperazine {3-Methyl-3- (4-valerylphenoxy) butyl} piperazine {3-Methyl-3- (4-n-hexylcarbonylphenoxy) butyl} Piperazine {3- (4-methoxycarbonylphenoxy) -3-methylbutyl} piperazine {3- (4-Ethoxycarbonylphenoxy) -3-methylbutyl} piperazine {3-Methyl-3- (4-n-propoxycarbonylphenoxy) butyl } Piperazine {3- (4-t-butoxycarbonyl] Phenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-n-pentyloxycarbonylphenoxy) butyl} piperazine {3- (4-n-hexyloxycarbonylphenoxy) -3-methylbutyl} piperazine {3-methyl-3- (3-Nitrophenoxy) butyl}
Piperazine {3-methyl-3- (4-nitrophenoxy) butyl}
Piperazine {3- (3-cyanophenoxy) -3-methylbutyl}
Piperazine {3- (4-cyanophenoxy) -3-methylbutyl}
Piperazine {3- (3-chlorophenoxy) -3-methylbutyl}
Piperazine {3- (4-chlorophenoxy) -3-methylbutyl}
Piperazine {3-methyl-3- (3-trifluoromethylphenoxy) butyl} piperazine {3-Methyl-3- (4-trifluoromethylphenoxy) butyl} piperazine

{3- (4-Methanesulfonylphenoxy) -3-methylbutyl} piperazine {3- (4-ethanesulfonylphenoxy) -3-methylbutyl} piperazine {3-methyl-3- (4-n-propanesulfonylphenoxy) ) Butyl} piperazine {3- (4-t-butanesulfonylphenoxy) -3-
Methyl butyl} piperazine {3-methyl-3- (4-n-pentanesulfonylphenoxy) butyl} piperazine {3- (4-cyclohexylsulfonylphenoxy)-
3-Methylbutyl} piperazine {3- (4-methanesulfinylphenoxy) -3-methylbutyl} piperazine {3- (4-ethanesulfinylphenoxy) -3-methylbutyl} piperazine {3-methyl-3- (4-n-propane) Sulfinylphenoxy) butyl} piperazine {3- (4-t-butanesulfinylphenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-n-pentanesulfinylphenoxy) butyl} piperazine {3- (4-cyclohexylsulfinylphenoxy)
-3-Methylbutyl} piperazine {3- (4-methoxysulfinylphenoxy) -3-
Methylbutyl} piperazine {3- (4-ethoxysulfinylphenoxy) -3-
Methyl butyl} piperazine {3-methyl-3- (4-n-propoxysulfinylphenoxy) butyl} piperazine {3- (4-n-butylsulfinylphenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-n-pentyloxysulfinylphenoxy) butyl} piperazine {3- (4-n-hexyloxysulfinylphenoxy) -3-methylbutyl} piperazine

{3- (4-Methoxysulfonylphenoxy) -3-methylbutyl} piperazine {3- (4-Ethoxysulfonylphenoxy) -3-methylbutyl} piperazine {3-Methyl-3- (4-n-propoxysulfonylphenoxy) ) Butyl} piperazine {3- (4-n-butylsulfonylphenoxy) -3-
Methylbutyl} piperazine {3-methyl-3- (4-n-pentyloxysulfonylphenoxy) butyl} piperazine {3- (4-n-hexyloxysulfonylphenoxy) -3-methylbutyl} piperazine {3- (4-acetylamino Phenoxy) -3-methylbutyl} piperazine {3- (4-ethylcarbonylaminophenoxy) -3
-Methylbutyl} piperazine {3- (4-isopropionylaminophenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-pivaloylaminophenoxy) butyl} piperazine {3-Methyl-3- (4-valerylaminophenoxy)
Butyl} piperazine {3- (4-n-hexylcarbonylaminophenoxy) -3-methylbutyl} piperazine {3- (4-methoxycarbonylaminophenoxy)-
3-Methylbutyl} piperazine {3- (4-ethoxycarbonylaminophenoxy)-
3-Methylbutyl} piperazine {3-methyl-3- (4-n-propoxycarbonylaminophenoxy) butyl} piperazine {(4-t-butoxycarbonylaminophenoxy)-
3-Methylbutyl} piperazine {3-Methyl-3- (4-n-pentyloxycarbonylaminophenoxy) butyl} piperazine {3-Methyl-3- (4-n-hexyloxycarbonylaminophenoxy) butyl} piperazine

{3-Methyl-3- (4-methylaminosulfinylphenoxy) butyl} piperazine {3- (4-ethylaminosulfinylphenoxy)-
3-methylbutyl} piperazine {3-methyl-3- (4-n-propylaminosulfinylphenoxy) butyl} piperazine {3- (4-t-butylaminosulfinylphenoxy) -3-methylbutyl} piperazine {3-methyl- 3- (4-n-pentylaminosulfinylphenoxy) butyl} piperazine {3- (4-cyclohexylaminosulfinylphenoxy) -2-hydroxy-3-methylbutyl} piperazine {3-methyl-3- (4-methylaminosulfonylphenoxy) ) Butyl} piperazine {3- (4-ethylaminosulfonylphenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-n-propylaminosulfonylphenoxy) butyl} piperazine {3- (4-t-butylaminosulfonylphenoxy)
-3-Methylbutyl} piperazine {3-Methyl-3- (4-n-pentylaminosulfonylphenoxy) butyl} piperazine {3- (4-Cyclohexylaminosulfonylphenoxy) -3-methylbutyl} piperazine

{3-Methyl-3- (4-methylsulfinylaminophenoxy) butyl} piperazine {3- (4-Ethylsulfinylaminophenoxy)-
3-Methylbutyl} piperazine {3-methyl-3- (4-n-propylsulfinylaminophenoxy) butyl} piperazine {3- (4-t-butylsulfinylaminophenoxy) -3-methylbutyl} piperazine {3-methyl-3 -(4-n-Pentylsulfinylaminophenoxy) butyl} piperazine {3- (4-Cyclohexylsulfinylaminophenoxy) -3-methylbutyl} piperazine {3-Methyl-3- (4-methylsulfonylaminophenoxy) butyl} piperazine { 3- (4-ethylsulfonylaminophenoxy) -3
-Methylbutyl} piperazine {3-methyl-3- (4-n-propylsulfonylaminophenoxy) butyl} piperazine {3- (4-t-butylsulfonylaminophenoxy)
-3-Methylbutyl} piperazine {3-Methyl-3- (4-n-pentylsulfonylaminophenoxy) butyl} piperazine {3- (4-Cyclohexylsulfonylaminophenoxy) -3-methylbutyl} piperazine

{3- (4-methoxyphenoxy) -3-
Methylbutyl} piperazine {3- (4-ethoxyphenoxy) -3-methylbutyl} piperazine {3-methyl-3- (4-n-propoxyphenoxy)
Butyl} piperazine {3- (4-t-butoxyphenoxy) -3-methylbutyl} piperazine {3-Methyl-3- (4-n-pentyloxyphenoxy) butyl} piperazine {3- (4-n-hexyloxyphenoxy) ) -3-Methylbutyl} piperazine {3- (3-cyanomethylphenoxy) -3-methylbutyl} piperazine {3- (4-cyanomethylphenoxy) -3-methylbutyl} piperazine {3-methyl-3- (3-pyridyl) Oxy) -butyl}
Piperazine {3-methyl-3- (4-pyridyloxy) -butyl}
Piperazine {3- (4-cyanophenoxy) -3-ethylpentyl} piperazine {3- (4-Cyanophenoxy) -3-propylhexyl} piperazine {3-Butyl-3- (4-cyanophenoxy) heptyl} piperazine 1 -(4-Cyanophenoxy) -1- {2- (piperazin-1-yl) ethyl} cyclopropane 1- (4-Cyanophenoxy) -1- {2- (piperazin-1-yl) ethyl} cyclobutane 1- (4-Cyanophenoxy) -1- {2- (piperazin-1-yl) ethyl} cyclopentane 1- (4-cyanophenoxy) -1- {2- (piperazin-1-yl) ethyl} cyclohexane

Next, a method for producing the compound of the present invention will be described. First,
In the compound represented by the general formula (1), the compound in which W is a hydroxyl group can be synthesized by, for example, the method represented by the following formula [Chemical formula 18]. Manufacturing method 1

[0080]

[Chemical 18](In the formula, R₁, R₂Are the same or different and are a hydrogen atom, C
₁~ C₆A linear or branched alkyl group of, or C₁
~ C₆Represents a linear or branched alkenyl group.
R₃, R_FourAre the same or different and are a hydrogen atom, C₁~ C_Fourof
Alkyl group or R ₃, R_FourBecome together C₂~ C_FivePo
Indicates a rimethylene group. A is substituted by the group (2)
A benzene ring, a 3-pyridyl group, or a 4-pi
Indicates a lysyl group. Where Y₁, Y₂Are the same or different
, Hydrogen atom, C₁~ C₆An alkylcarbonyl group of C₁
~ C₆Alkoxycarbonyl group, amino group, nitro
Group, cyano group, chloro atom, trifluoromethyl group, C
₁~ C₆An alkylsulfonyl group of C₁~ C₆The alkoxy
Sulfinyl group, C₁~ C₆An alkoxysulfonyl group of
C₁~ C₆Alkylcarbonylamino group of C₁~ C₆A
Lucoxycarbonylamino group, C₁~ C₆The alkylami
Nosulfinyl group, C₁~ C₆Alkylaminosulfoni
Lu group, C₁~ C₆An alkylsulfinylamino group, C₁
~ C₆An alkylsulfonylamino group of C₁~ C₆The al
Coxy group, cyanomethyl group, 2-cyano-3-methyl group
Anidine group, S-methyl-N-cyanothioureido group,
A 3-ethylureido group is shown. X is C₁~ C₆The alkyl
Represents a group or a nitro group. ) A compound represented by the general formula (3) and a compound represented by the general formula (4)
Compound C₁~ C_FourAlcohol such as methanol,
Solvents such as ethanol, propanol, and isopropanol
It is obtained by heating to 10 to 100 ° C in a medium.

The uracil piperazine derivative represented by the general formula (3) is a known compound. Further, the propane oxide derivative represented by the general formula (4) is prepared by mixing the olefin represented by the general formula (7) with hydrogen peroxide, meta-chloroperbenzoic acid, or a peracid such as t-butyl hydroperoxide. The olefin represented by the general formula (7) can be converted to halohydrin by a conventional method at 30 ° C., or can be synthesized from halohydrin. The reaction is shown in the following formula [Formula 19].

[0082]

[Chemical 19] (In the formula, A represents a benzene ring which may be substituted represented by the group (2), a 3-pyridyl group, or a 4-pyridyl group. Here, Y ₁ and Y ₂ are the same or different and are hydrogen. Atom, C _{1 to} C ₆ alkylcarbonyl group, C _{1 to} C ₆ alkoxycarbonyl group, amino group, nitro group, cyano group,
Chlorine atom, trifluoromethyl group, C ₁ -C alkylsulfonyl group _6, C ₁ -C alkoxysulfinyl sulfinyl group _6, alkoxy sulfonyl group of C ₁ -C _6, alkyl carbonyl amino group of C ₁ -C _6, C alkoxycarbonylamino group ₁ -C _6, alkyl amino sulfinyl group C ₁ -C _6, alkyl aminosulfonyl group C _{1 ~C 6,} C ₁ ~
C ₆ alkylsulfinylamino group, C ₁ -C ₆ alkylsulfonylamino group, C ₁ -C ₆ alkoxy group, cyanomethyl group, 2-cyano-3-methylguanidine group,
An S-methyl-N-cyanothioureido group and a 3-ethylureido group are shown. R ₃ and R ₄ are the same or different and each represent a hydrogen atom, a C _{1 to} C ₄ alkyl group, or a combination of R ₃ and R ₄ to represent a C _{2 to} C ₅ polymethylene group. Z represents a bromine atom, a chlorine atom, or an iodine atom. )

The propene derivative represented by the general formula (7) is an allyl alkyl carbonate derivative represented by the general formula (6), for example, allyl isobutyl carbonate is tetrakis (triphenylphosphine) palladium complex 0.1 to 5 mol%, preferably Is in the presence of 0.5 mol% in a non-aqueous solvent such as the compound represented by the general formula (5) and anhydrous tetrahydrofuran, anhydrous ether, anhydrous dioxane, or anhydrous 1,2-dimethoxyethane, and is 0 to 30 ° C., preferably 25. It is obtained by reacting at 5 ° C. for 5 minutes to 1 hour, preferably 5 minutes, and then stopping the reaction by adding meta-chloroperbenzoic acid. The reaction is shown in the following formula [Formula 20].

[0084]

[Chemical 20] (In the formula, A represents a benzene ring which may be substituted represented by the group (2), a 3-pyridyl group, or a 4-pyridyl group. Here, Y ₁ and Y ₂ are the same or different and are hydrogen. Atom, C _{1 to} C ₆ alkylcarbonyl group, C _{1 to} C ₆ alkoxycarbonyl group, amino group, nitro group, cyano group,
Chlorine atom, trifluoromethyl group, C ₁ -C alkylsulfonyl group _6, C ₁ -C alkoxysulfinyl sulfinyl group _6, alkoxy sulfonyl group of C ₁ -C _6, alkyl carbonyl amino group of C ₁ -C _6, C alkoxycarbonylamino group ₁ -C _6, alkyl amino sulfinyl group C ₁ -C _6, alkyl aminosulfonyl group C _{1 ~C 6,} C ₁ ~
C ₆ alkylsulfinylamino group, C ₁ -C ₆ alkylsulfonylamino group, C ₁ -C ₆ alkoxy group, cyanomethyl group, 2-cyano-3-methylguanidine group,
An S-methyl-N-cyanothioureido group and a 3-ethylureido group are shown. R ₃ and R ₄ are the same or different and each represent a hydrogen atom, a C _{1 to} C ₄ alkyl group, or a combination of R ₃ and R ₄ to represent a C _{2 to} C ₅ polymethylene group. R ₅ is C _{1 to} C ₆
Represents a linear or branched alkyl group. In the reaction of allyl acetate and phenol, the target phenyl allyl ether can be obtained only in a low yield because the pKa of the leaving group acetate is larger than the pKa of the phenoxy group. By using an alkylallyl carboxylate, the leaving group from the palladium π-allyl complex can be removed by pK.
By converting a into an alkoxy group smaller than a phenoxy group, the equilibrium was biased toward the production system and the target product was obtained in high yield.

Next, in the compound represented by the general formula (1), wherein W is a hydrogen atom, the compound represented by the following formula:
It can be synthesized by the method shown in. Manufacturing method 2

[0086]

[Chemical 21](In the formula, R₁, R₂Are the same or different and are a hydrogen atom, C
₁~ C₆A linear or branched alkyl group of, or C₁
~ C₆Represents a linear or branched alkenyl group. A
Is an optionally substituted benzene ring represented by the group (2),
A 3-pyridyl group or a 4-pyridyl group is shown. here
And Y₁, Y₂Are the same or different and are a hydrogen atom, C₁~
C₆An alkylcarbonyl group of C₁~ C₆Alkoxyka
Rubonyl group, amino group, nitro group, cyano group, chlorine source
Child, trifluoromethyl group, C₁~ C₆Alkyl sulfo
Nyl group, C₁~ C₆An alkoxysulfinyl group of C₁~
C₆An alkoxysulfonyl group of C₁~ C₆Alkylka
Rubonylamino group, C₁~ C₆The alkoxycarbonyl
Mino group, C₁~ C₆An alkylaminosulfinyl group, C
₁~ C₆An alkylaminosulfonyl group of C₁~ C₆The al
Kirsulfinylamino group, C ₁~ C₆Alkyl sulfo
Nylamino group, C₁~ C₆Alkoxy group of cyanomethyl
Group, 2-cyano-3-methylguanidine group, S-methyl
-N-cyanothioureido group, 3-ethylureido group
Show. X is C₁~ C₆The alkyl or nitro group of
You R₃, R_FourAre the same or different and are a hydrogen atom, C₁~
C_FourAlkyl group of R, or R₃, R_FourBecome together C₂~ C
_FiveThe polymethylene group of is shown. L is chloro atom, Brom original
Child, iodine atom, p-toluenesulfonyloxy group,
Tansulphonyloxy group, trifluoromethanesulfoni
Shows a luoxy group. ) A compound represented by the general formula (3) and a compound represented by the general formula (8)
Compounds such as trialkylamine, pyridine, and imidazo
And organic bases such as potassium carbonate and sodium carbonate
In the presence of an inorganic base such as
Chloromethane, chloroform, dichloroethane, dioxy
Sun, DMF, THF, ether, 1,2-dimethoxy
For heating to 10 to 150 ° C in a solvent such as ethane
You get more.

The compound represented by the general formula (8) can be synthesized, for example, by the method represented by the following formula [Formula 22].

[0088]

[Chemical formula 22] (In the formula, A, X, R ₃ , R ₄ and L are the same as those described in [Formula 21] above.) The propane derivative represented by the general formula (8) is represented by the general formula (7). It is represented by the general formula (9), which is produced by reacting a propene derivative with a borane / THF complex, a borane / dimethyl sulfide complex, a boron compound such as 9-BBN, and further subjecting the resulting borane derivative to alkaline oxidation and hydrolysis. Halogenated propanol derivatives, or in the presence of organic bases such as trialkylamine, pyridine, imidazole and inorganic bases such as potassium carbonate and sodium carbonate, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, trifluoromethanesulfonic acid chloride, etc. It is produced by reacting with a sulfonic acid halide.

Next, a compound represented by the general formula (1) in which W is a hydrogen atom or a hydroxyl group can be synthesized by, for example, the method represented by the following formula [Chemical formula 23]. Manufacturing method 3

[0090]

[Chemical formula 23] (In the formula, A, X, R ₁ , R ₂ , R ₃ and R ₄ are the same as those described in [Formula 21]. W represents a hydrogen atom or a hydroxyl group. Z represents a chlorine atom, a bromine atom or an iodine atom. The compound represented by the general formula (10) and the compound represented by the general formula (11) are contained in a solvent such as dioxane, DMF, benzene, toluene, THF, ether, 1,2-dimethoxyethane or without solvent. Then, the compound represented by the general formula (1) is obtained by heating to 10 to 100 ° C. in the presence of a base or without using a base. When a base is used, examples of the base used include trialkylamine, pyridine, imidazole and the like.

Next, in the compound represented by the general formula (10), a compound in which W is a hydroxyl group is represented by the following formula:
It can be synthesized by the method shown in.

[0092]

[Chemical formula 24] (In the formula, A, R ₃ , and R ₄ are the same as those described in [Chemical Formula 21].) The epoxide and piperazine represented by the general formula (4) are replaced with C ₁
-C ₄ alcohols, such as methanol, ethanol,
Propanol, isopropanol, dioxane, DM
It can be obtained by heating to 10 to 100 ° C. in a solvent such as F, ether, THF or 1,2-dimethoxyethane.

The compound represented by the general formula (10) in which W is a hydrogen atom can be synthesized, for example, by the method represented by the following formula [Chem. 25].

[0094]

[Chemical 25] (In the formula, A, R ₃ , R ₄ , and L are the same as those described in [Chemical Formula 21] above.) The propane derivative represented by the general formula (8) and piperazine are converted into dichloromethane, chloroform, dichloroethane, dioxane, DMF, It can be obtained by heating to 10 to 150 ° C. in a solvent such as THF, ether, dimethoxyethane or the like without solvent. At this time, a base can be added if necessary. As the type of base, organic bases such as triethylamine, pyridine and imidazole and inorganic bases such as potassium carbonate and sodium carbonate can be used.

The uracil derivative represented by the general formula (11) is a known compound, for example, Journal of of
American Chemical Societ
y, 84, 1310 and the like.

The compound of the present invention represented by the general formula (1) and an acid addition salt thereof are used for hypertension, congestive heart dysfunction, angina, peripheral and cerebrovascular disorders, pollakiuria, asthma, ischemic heart. When used as a therapeutic agent for diseases and baldness, the dose and dosage form vary depending on the physical properties of the compound and the symptoms of the subject to be administered, but for example, 1 to 1000 mg per day orally for adults, tablets, granules, powders, It can be administered as a suspension, a capsule or the like, or parenterally, for example, as a suppository, an injection, an isotonic solution for infusion and the like.

The general method for producing the pharmaceutical composition of the present invention is, for example, a method of dissolving the compound of the present invention in an arbitrary amount of an oil selected from cottonseed oil, corn oil, peanut oil, olive oil and the like to give a non-aqueous injection. A method in which water is further added to the compound of the present invention to prepare an aqueous injection as an emulsion in the presence of a suitable surfactant; and in the case of tablets, crystalline cellulose and soft resin are added to the compound of the present invention as an adsorbent. Examples of the method include adding silicic acid anhydride, corn starch, etc. as an excipient, and finally adding magnesium stearate to prepare a preparation; It is possible to prepare a pharmaceutical preparation by the usual production method of.

[0098]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples. Example 1 1,3-Diisopropyl-6- {4- [2-hydroxy-3-methyl-3- (4-nitrophenoxy) butyl]
Process for producing piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione

[0099]

[Chemical formula 26] (1) 3-methyl-3- (4-nitrophenoxy) -1
-Synthesis of butene p-nitrophenol 3.0 g, isobutyl carbonate
2-Methyl-3-buten-2-yl 5.4 g (purity 85%) was dissolved in THF 60 ml, and [tetrakis (triphenylphosphine)] palladium (0) 520 m.
g was added and reacted at room temperature for 15 minutes and then at 30 ° C. for 20 minutes. When the generation of carbon dioxide stopped, 260 mg of m-chloroperbenzoic acid was added, and 1 hour later, 150 ml of water was added.
, Extracted with methylene chloride, and washed with 1N loading soda. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain oily 3-methyl-3- (4-nitrophenoxy) -1-butene. NMR (CDCl ₃ , δ): 8.11 (d, 2H),
7.03 (d, 2H), 6.12 (m, 1H), 5.2
6 (m, 2H), 1.55 (s, 6H) (2) 3-methyl-3- (4-nitrophenoxy)-
Synthesis of 1,2-epoxybutane 2.12 g of 3-methyl-3- (4-nitrophenoxy) -1-butene obtained in the above item (1) was added to 13 m of chloroform.
1, and added 2.65 g of m-chloroperbenzoic acid,
The reaction was carried out overnight at room temperature. Further, 10 ml of chloroform was added, and the mixture was heated under reflux for 3 hours. After cooling, it was washed with 1N sodium hydroxide and then with water, the organic layer was dried, concentrated, and then purified by silica gel column chromatography.
1.3 g of the target product, 3-methyl-3- (4-nitrophenoxy) -1,2-epoxybutane, was obtained. NMR (CDCl ₃ , δ): 8.17 (d, 2H),
7.17 (d, 2H), 3.21-3.22 (m, 1
H), 2.90 (t, 1H), 2.68-2.70.
(M, 1H), 1.46 (s, 3H), 1.31 (s,
3H) (3) 1,3-Diisopropyl-6- {4- [2-hydroxy-3- (4-nitrophenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 (1H, 3H)
Synthesis of Pyrimidinedione 3-Methyl-3- (4-nitrophenoxy) -1,2-
Epoxy butane 1.3 g and 1,3-diisopropyl-6
1.6 g of -piperazinyl-2,4 (1H, 3H) pyrimidinedione was heated to reflux in 20 ml of ethanol for 15 hours. After allowing to cool, the precipitated crystals were collected by filtration to obtain the desired product 1,
3-diisopropyl-6- {4- [2-hydroxy-3
2.2 g of -methyl-3- (4-nitrophenoxy) butyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione were obtained. According to a conventional method, 0.6 g of this pyrimidinedione derivative was dissolved in a small amount of ethanol, 0.3 g of oxalic acid dihydrate was added and dissolved, ether was added, and the precipitated crystals were collected by filtration to give 1,3-diisopropyl. -6- {4- [2-hydroxy-3-methyl-3- (4
-Nitrophenoxy) butyl] piperazin-1-yl}
0.69 g of crystals of -2,4 (1H, 3H) pyrimidinedione oxalate was obtained.

Example 2 6- {4- [3- (4-aminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}-
Process for producing 1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione

[0101]

[Chemical 27] 1,3-diisopropyl-6- {4 obtained in Example 1
-[2-Hydroxy-3-methyl-3- (4-nitrophenoxy) -butyl] piperazin-1-yl} -2,4
0.8 g of (1H, 3H) pyrimidinedione was suspended in 150 ml of methanol, 90 mg of 10% palladium carbon was added, and hydrogenation was carried out under atmospheric pressure. After completion of the reaction, the catalyst was filtered off by filtration, and the filtrate was concentrated and crystallized with ethanol / ether to give 6- {4-
[3- (4-aminophenoxy) -2-hydroxy-3
0.57 g of -methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione was obtained. In the same manner as in the item (3) of Example 1, this was made into oxalate in ethanol and crystallized,
0.71 g of the desired oxalate salt was obtained.

Example 3 1,3-Diisopropyl-6- {4- [2-hydroxy-3- (4-methoxycarbonylaminophenoxy)-
3-Methylbutyl] piperazin-1-yl} -2,4
Process for producing (1H, 3H) pyrimidinedione

[0103]

[Chemical 28] 0.76 g of 6- {4- [3- (4-aminophenoxy) -2-hydroxy-3-methyl-butyl] piperazine-1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione was added to 8 ml of THF. Was dissolved in water, 0.6 ml of triethylamine was added, and the mixture was ice-cooled. Next, a THF solution containing 0.24 g of methyl chloroformate was added dropwise, reacted for 30 minutes, and then concentrated. The residue is dissolved in chloroform, washed with water and concentrated,
Purified by silica gel column chromatography. The purified product was further crystallized with ether to give 1,3-diisopropyl-6- {4- [2-
Hydroxy-3- (4-methoxycarbonylaminophenoxy) -3-methylbutyl] piperazin-1-yl}
0.55 g of -2,4 (1H, 3H) pyrimidinedione was obtained. This was made into an oxalate salt in methanol by the same method as in the item (3) of Example 1 to obtain 0.56 g of oxalate crystal.

Example 4 1,3-Diisopropyl-6- {4- [2-hydroxy-3- (4-methanesulfonylaminophenoxy) -3
-Methylbutyl] piperazin-1-yl} -2,4 (1
Process for producing (H, 3H) pyrimidinedione

[0105]

[Chemical 29] 6- {4- [3- (4-aminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 obtained in Example (2)
To a chloroform (10 ml) solution of 600 mg of (1H, 3H) pyrimidinedione and 400 mg of triethylamine, 150 mg of methanesulfonyl chloride was added dropwise under ice cooling. After stirring the reaction mixture for 5 hours, a small amount of water was added to stop the reaction. Dilute this with 20 ml of chloroform,
After washing with water, the organic layer was dried and the solvent was distilled off. By purifying the residue by silica gel column chromatography,
As a light red crystal, the desired product, 1,3-diisopropyl-6- {4- [2-hydroxy-3- (4-methanesulfonylaminophenoxy) -3-methylbutyl] piperazin-1-yl} -2,4 580 mg of (1H, 3H) pyrimidinedione was obtained.

Example 5 1,3-Diisopropyl-6- {4- [3- <4- (3
-Ethylureido) phenoxy> -3-methyl-2-hydroxybutyl] piperazin-1-yl} -2,4 (1
Process for producing (H, 3H) pyrimidinedione

[0107]

[Chemical 30] 6- {4- [3- (4-aminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 obtained in Example (2)
(1H, 3H) Pyrimidinedione (500 mg) in chloroform (10 ml) was added with ethylisocyanate 73 under ice cooling.
mg was added dropwise. After stirring the reaction mixture for 10 hours, a small amount of water was added to stop the reaction. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product, 1,3-diisopropyl-6- {4- [3- <4- (3-ethylureido) phenoxy>. 460 mg of -3-methyl-2-hydroxybutyl] piperazin-1-yl} -2,4 (1H, 3H) pyrimidinedione were obtained.

Example 6 1,3-diisopropyl-6- {4- [3- <4- (3
-Cyano-2-methylisothioureido) phenoxy>
2-Hydroxy-3-methylbutyl] piperazine-1
-Yyl} -2,4 (1H, 3H) pyrimidinedione

[0109]

[Chemical 31] 6- {4- [3- (4-aminophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 obtained in Example (2)
1.0g of (1H, 3H) pyrimidinedione and dimethyl
A solution of 560 mg of N-cyanodithioiminocarbonate in 15 ml of ethanol was heated under reflux for 6 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 6- {4-
[3- <4- (3-cyano-2-methylisothioureido) phenoxy> -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H) 1.1 g of pyrimidinedione was obtained.

Example 7 6- {4- [3- <4- (2-cyano-3-methylguanidino) phenoxy> -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl Method for producing 2,4 (1H, 3H) pyrimidinedione

[0111]

[Chemical 32] 6- {4- [3- <4- (3-cyano-2-methylisothioureido) phenoxy> -2- obtained in Example (6)
Hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H)
1.0 g of pyrimidinedione and 5 ml of 40% methylamine aqueous solution were left in 15 ml of methanol for 1 week. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 6-
{4- [3- <4- (2-cyano-3-methylguanidino) phenoxy> -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1,3-diisopropyl-2,4 (1H, 3H ) Pyrimidinedione 400 mg
Was obtained.

Example 8 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl}-
Process for producing 1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione

[0113]

[Chemical 33] 3 synthesized in the same manner as in (1) and (2) of Example 1
0.8 g of-(4-cyanophenoxy) -3-methyl-1,2-epoxybutane and 1,3-diisopropyl-6-
1.0 g of (piperazinyl-1-yl) -2,4 (1H, 3H) pyrimidinedione in 16 ml of ethanol
Heated to reflux for hours. After cooling, the resulting crystals were collected by filtration and washed with ethanol to give 6- {4- [3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl] piperazin-1-yl} -1, 1.43 g of 3-diisopropyl-2,4 (1H, 3H) pyrimidinedione was obtained.

Example 9 Method for producing isobutyl 2-methyl-3-buten-2-yl carbonate

[0115]

[Chemical 34] A solution of 129.2 g of 2-methyl-3-buten-2-ol and 181.9 g of pyridine (11) in benzene (11) was added at room temperature to 204.87 g of benzene (50) of isobutyl chloroformate.
0 ml) solution was added dropwise while maintaining the reaction temperature at 20 to 30 ° C. After the dropping was completed, the mixture was stirred overnight at room temperature. Next, 750 ml of water was added to the reaction mixture, which was washed several times with 2N hydrochloric acid, and after liquid separation, the organic layer was concentrated to dryness. The residue was purified by distillation to give isobutyl carbonate 2-methyl-3-buten-2-yl 1
01 g was obtained as a colorless oil. IR (cm ^-1 , neat) 2966, 1748, 147
2,1398,1380,1259,1135,109
4,967,863,793 NMR (CDCl ₃ , δ): 6.01 (m, 1H),
4.93-5.30 (m, 2H), 3.81 (d, 2)
H), 1.93 (m, 1H), 1.55 (s, 6H),
1.00 (s, 3H), 0.87 (s, 3H)

Example 10 6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl]
Method for producing -1,3-diethyl-2,4 (1H, 3H) pyrimidinedione

[0117]

[Chemical 35] (1) Synthesis of 3- (4-cyanophenoxy) -2-hydroxy-3-methylbutylpiperazine 3- (4-cyanophenoxy) -3-methyl-1 was prepared in the same manner as in item (1) of Example 1. -Pentene was epoxidized and 5.35 g of the resulting 3- (4-cyanophenoxy) -3-methyl-1,2-epoxybutane and 11.4 g of anhydrous piperazine were heated to reflux in 30 ml of ethanol. After 2 hours, the reaction was completed, the reaction mixture was concentrated to dryness, the residue was dissolved in chloroform, and this was washed 3 times with 20 ml of saturated saline. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to give 1- [3-
5.36 g of (4-cyanophenoxy) -2-hydroxy-3-methylbutyl] piperazine were obtained. m. p.
92-95 ° C (2) 6- [4- {3- (4-cyanophenoxy) -2
Synthesis of -hydroxy-3-methylbutyl} piperazin-1-yl] -1,3-diethyl-2,4 (1H, 3H) pyrimidinedione 1- [3- (4-cyanophenoxy) obtained in item (1) ) -2-Hydroxy-3-methylbutyl] piperazine 0.72 g, 6-chloro-1,3-diethyl-2,4
0.51 g of (1H, 3H) pyrimidinedione and 1.0 g of triethylamine were heated to reflux in 10 ml of dioxane for 8 hours. After the reaction solution was concentrated to dryness, the residue was dissolved in chloroform and washed with water. After concentrating the chloroform layer, the residue was separated and purified by silica gel column chromatography to obtain the target 6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} piperazin-1-yl. ] -1,3-diethyl-2,4 (1
0.55 g of (H, 3H) pyrimidinedione was obtained.

Example 11 6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} piperazin-1-yl]-
Process for producing 1,3-dicyclohexyl-2,4 (1H, 3H) pyrimidinedione

[0119]

[Chemical 36] 1- [3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl] obtained in item (1) of Example 10
2 ml of triethylamine was added to a DMF (10 ml) solution of 1.45 g of piperazine and 1.55 g of 6-chloro-1,3-dicyclohexyl-2,4 (1H, 3H) pyrimidinedione, and the mixture was reacted at 80 to 90 ° C. for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform and washed with water. The chloroform layer is dried, concentrated, and purified by silica gel column chromatography to give the desired 6- [4- {3- (4-cyanophenoxy) -2-
Hydroxy-3-methylbutyl} piperazin-1-yl] -1,3-dicyclohexyl-2,4 (1H, 3
2.45 g of H) pyrimidinedione was obtained as white crystals.

Example 12 6- [4- {3- (4-cyanophenoxy) -3-ethyl-2-hydroxypentyl} piperazin-1-yl]
Method for producing -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione

[0121]

[Chemical 37] (1) 3- (4-cyanophenoxy) -3-methyl-1
-Synthesis of Pentin 8.1 g of 4-cyanophenol, 24.18 g of 3-chloro-3-ethyl-1-pentyne, 15 g of 40% benzyltrimethylammonium hydroxide methanol solution,
A mixed solution of 4.1 g of sodium hydroxide, 80 ml of water and 80 ml of dichloromethane was stirred at room temperature for 5 days under a nitrogen atmosphere. The organic layer was separated, the aqueous layer was further extracted with chloroform, and the combined organic layers were evaporated under reduced pressure. The residue is taken up in ether, washed with 2N aqueous sodium hydroxide solution and water, dried and concentrated, and the obtained orange oil is purified by silica gel column chromatography to give the desired 3- (4-cyanophenoxy). ) -3-Ethyl-
8.3 g of 1-pentyne was obtained. NMR (CDCl ₃ , δ): 7.55 (d, 2H),
7.28 (d, 2H), 2.68 (s, 1H), 1.9
5 (q, 2H), 1.94 (q, 2H), 1.03
(T, 6H) (2) 3- (4-cyanophenoxy) -3-ethyl-1
-Synthesis of pentene 3- (4-cyanophenoxy) -3-obtained in (1)
8 g of ethyl-1-pentyne was dissolved in 200 ml of methanol, and catalytic hydrogenation was carried out in the presence of 1.4 ml of quinoline and 1 g of a Lindlar catalyst. After completion of the reaction, the catalyst was filtered off by Celite filtration, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the desired 3- (4-cyanophenoxy) -3-ethyl-1. 8 g of pentene were obtained. NMR (CDCl ₃ , δ): 7.47 (d, 2H),
7.0 (d, 2H), 6.2-5.8 (m, 1H),
5.0-5.4 (m, 2H), 1.80 (m, 4H),
0.58 (t, 6H) (3) 3- (4-cyanophenoxy) -3-ethyl-1
—Synthesis of Pentene Oxide In the same manner as in (2) of Example 1, 0.8 g of 3- (4-cyanophenoxy) -3-ethyl-1-pentene was oxidized to give 3- (4-cyanophenoxy)- 3-ethyl-1-
0.41 g of pentene oxide was obtained. NMR (CDCl ₃ , δ): 7.55 (d, 2H),
7.18 (d, 2H), 3.18 (dd, 1H), 2.
89 (t, 1H), 2.79 (dd, 1H), 1.89
(M, 2H), 1.68 (m, 1H), 1.49 (m,
1H), 0.99 (t, 3H), 0.89 (t, 3H) (4) 6- [4- {3- (4-cyanophenoxy) -3
-Ethyl-2-hydroxypentyl} piperazine-1-
Il] -1,3-diisopropyl-2,4 (1H, 3
H) Synthesis of pyrimidinedione 3- (4-cyanophenoxy) -3-ethyl-1-pentene oxide 0.4 was prepared in the same manner as in (2) of Example 1.
From 1 g and 0.60 g of 1,3-diisopropyl-6- (piperazin-1-yl) -2,4 (1H, 3H) pyrimidinedione, 6- [4- {3- (4-cyanophenoxy) -3- Ethyl-2-hydroxypentyl} piperazin-1-yl] -1,3-diisopropyl-2,4
0.75 g of (1H, 3H) pyrimidinedione was obtained.

Example 13 Preparation of 6- [4- {3- (4-cyanophenoxy) -3-methylbutyl} piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione Law

[0123]

[Chemical 38] (1) Synthesis of 3- (4-cyanophenoxy) -3-methylbutanol 3 Synthesized by the same method as in (1) and (2) of Example 1.
-(4-Cyanophenoxy) -3-methylbutene 2.0
2 g was dissolved in 10 ml of anhydrous THF, and 0
0.4 ml of borane / methyl sulfide complex was added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, the temperature was further raised to room temperature, and the mixture was stirred for 4 hours. Next, ethanol 4 ml, 3N sodium hydroxide aqueous solution 1.2 ml and 35% hydrogen peroxide water 1.4.
ml was added and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with water and saturated brine, extracted twice with ethyl acetate,
After drying and concentration, the residue was purified by silica gel column chromatography to obtain 0.25 g of 3- (4-cyanophenoxy) -3-methyl-butanol. IR (cm ^-1 , neat): 3423, 2978, 22
26, 1602, 1502, 1254, 1128 NMR (CDCl ₃ , δ): 7.52 (d, 2H),
6.98 (d, 2H), 3.87 (t, 2H), 2.0
2 (t, 2H), 1.42 (s, 6H) (2) Synthesis of 3- (4-cyanophenoxy) -3-methylbutyl p-toluenesulfonic acid 3- (4-Cyanophenoxy) -3-methylbutanol 0.25 g was dissolved in 5 ml of dichloromethane, and 0.43 ml of triethylamine and 0.47 g of p-toluenesulfonic acid chloride were dissolved in dichloromethane (1.5 ml).
Was added at 0 ° C. After reacting at 0 ° C for 30 minutes and at room temperature for 2 hours,
The mixture was heated under reflux for another 5 hours. After allowing to cool, the reaction mixture is 5%
Wash with aqueous sodium hydroxide and wash with dichloromethane 3
Extracted twice. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain 0.29 g of the target 3-methyl-3- (4-cyanophenoxy) butyl p-toluenesulfonate as a brown oil. Was obtained. NMR (CDCl ₃ , δ): 7.67 (d, 2H),
7.41 (d, 2H), 7.22 (d, 2H), 6.8
3 (d, 2H), 4.22 (t, 2H), 2.43
(S, 3H), 2.08 (t, 2H), 1.33 (s,
6H) (3) 6- [4- {3- (4-cyanophenoxy) -3
-Methylbutyl} piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione synthesis p-toluenesulfonic acid 3- (4-cyanophenoxy) -3-methylbutyl 0.29 g and 1 , 3-Diisopropyl-6- (piperazin-1-yl) -2,4
0.5 g of (1H, 3H) pyrimidinedione was heated at 100 ° C. for 4 hours and a half. After cooling, the reaction mixture was purified by silica gel column chromatography to give the desired 6- [4- {3- (4-cyanophenoxy) -3-
0.2 g of methylbutyl} piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione was obtained.

Example 14 1,3-Diisopropyl-6- [4- {2-hydroxy-3-methyl-3- (4-pyridyloxy) butyl} piperazin-1-yl] -2,4 (1H, 3H ) Method for producing pyrimidinedione

[0125]

[Chemical Formula 39] (1) 3-methyl-3- (4-pyridyloxy) -1-
Synthesis of butyne 51 g of 4-hydroxypyridine, 59.5 g of 3-chloro-3-methyl-1-butyne, 100 g of 40% Triton B-methanol solution, 23 g of sodium hydroxide, 240 of water
A mixture of ml and 240 ml of dichloromethane was vigorously stirred for 4 days at room temperature. The reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, concentrated, and then the residue was purified by silica gel column chromatography.
Targeted 3-methyl-3- (4-pyridyloxy)-
16.2 g of 1-butyne was obtained. NMR (CDCl ₃ , δ): 8.31 (m, 2H),
2.65 (s, 1H), 1.68 (s, 6H) (2) 3-methyl-3- (4-pyridyloxy) -1-
Synthesis of butene 3-methyl-3- (4-pyridyloxy) -1-butyne 5.7 g, quinoline 1.4 ml, Pd-BaSO4 1
A mixture of g and 180 ml of methanol was hydrogenated for 30 minutes at room temperature and atmospheric pressure. After the reaction, the catalyst was filtered off by Celite filtration, and the filtrate was concentrated. After standing for several hours, the precipitated crystals were collected by filtration, and the mother liquor was purified by silica gel column chromatography to obtain the desired 3-methyl-3- (4
1.45 g of -pyridyloxy) -1-butene was obtained. NMR (CDCl ₃ , δ): 8.20 (m, 2H),
6.77 (m, 2H), 6.03 (dd, 1H), 5.
17 (m, 2H), 1.52 (s, 6H) (3) 1-bromo-2-hydroxy-3-methyl-3-
Synthesis of (4-pyridyloxy) -butane 3-methyl-3- (4-pyridyloxy) -1-butene 2 g, N-bromosuccinimide 2.6 g, water 20 ml
The mixture of and 30 ml of DMSO was stirred at room temperature for 2 hours. The reaction solution was poured into 35 ml of 0.01N hydrochloric acid and washed with ethyl acetate. The aqueous layer was then made alkaline and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to give the desired 1-bromo-2-hydroxy-3-methyl-3- (4-pyridyloxy) -butane 0. 0.42 g was obtained. NMR (CDCl ₃ , δ): 8.46 (m, 2H),
6.92 (m, 2H), 4.34 (dd, 1H), 4.
15 (dd, 1H), 3.98 (dd, 1H), 1.5
9 (s, 3H), 1.58 (s, 3H) (4) 1,3-diisopropyl-6- [4- {2-hydroxy-3-methyl-3- (4-pyridyloxy) butyl} piperazine- Synthesis of 1-yl] -2,4 (1H, 3H) pyrimidinedione 1-Bromo-2-hydroxy-3-methyl-3- (4-
Pyridyloxy) butane 0.4 g, potassium hydroxide 0.
A mixture of 4 g and 25 ml of ethanol was stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated to give 3-methyl-
0.3 g of a crude product of 3- (4-pyridyloxy) -1,2-epoxybutane was obtained. Next, this crude epoxide.
28 g, 1,3-diisopropyl-6- (piperazine-
A mixture of 1-yl) -2,4 (1H, 3H) pyrimidinedione (0.53 g) and ethanol (20 ml) was heated under reflux for 14 hours. After cooling, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain the desired 1,3-diisopropyl-6- [4-
{2-Hydroxy-3-methyl-3- (4-pyridyloxy) butyl} piperazin-1-yl] -2,4 (1
0.25 g of H, 3H) pyrimidinedione was obtained. The compounds of Examples 15 to 41 described in Table 1 [Table 1] were obtained in the same manner as in Examples 1 to 14 above. In Table 1, R
₁ , R ₂ , R ₃ , R ₄ , X, W and A are in the compound represented by the general formula (1).

[0126]

[Table 1] Table-1

[0127]

[Table 2] Continuation 1 of Table-1

[0128]

[Table 3] Continuation 2 of Table-1

[0129]

[Table 4] Continuation of Table-1 3

[0130]

[Table 5] Continuation 4 of Table-1

[0131]

[Table 6] Continuation of Table-1 5

[0132]

[Table 7] Continuation of Table-1 6

[0133]

[Table 8] Continuation 7 of Table-1

[0134]

[Table 9] Continuation of Table-1 8

[0135]

[Table 10] Continuation of Table-1 9

Example 42 (+)-6- [4- {3- (4-cyanophenoxy)-
2-hydroxy-3-methylbutyl} -piperazine-1
-Yl] -1,3-diisopropyl-2,4 (1H, 3
H) Preparation of pyrimidinedione 6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} obtained by the method of Example 8
-Piperazin-1-yl] -1,3-diisopropyl-
2,4 (1H, 3H) pyrimidinedione (2 g) and (+)-dibenzoyl-D-tartaric acid (1.56 g) were added to 100 ml of acetone, heated to reflux and dissolved, and then the insoluble matter was filtered off. The filtrate was left at room temperature for several hours, and then the precipitated crystals were collected by filtration. By recrystallizing 1.97 g of the obtained crystals twice from acetone and twice from ethanol, (+)-6-
[4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl]-
0.53 g of a salt of 1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione and (+)-dibenzoyl-D-tartaric acid was obtained. Dissolve this salt in chloroform and
The extract was washed with an aqueous solution of sodium hydroxide (%) and dried over anhydrous sodium sulfate. After concentration, the residue was dissolved in methanol, and (+)-6- was prepared by the same method as in item (3) of Example 1.
[4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl]-
0.21 g of crystals of 1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione oxalate were obtained. Enantiomeric excess rate 97.6% ee or more The enantiomeric excess rate was calculated by liquid chromatography using an optically active column.

Example 43 (-)-6- [4- {3- (4-cyanophenoxy)-
2-hydroxy-3-methylbutyl} -piperazine-1
-Yl] -1,3-diisopropyl-2,4 (1H, 3
H) Preparation of pyrimidinedione 6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} obtained by the method of Example 8
-Piperazin-1-yl] -1,3-diisopropyl-
1.23 g of 2,4 (1H, 3H) pyrimidinedione and 0.96 g of (−)-dibenzoyl-L-tartaric acid were added to 60 ml of acetone, heated to reflux and dissolved, and then the insoluble matter was filtered off. After standing at room temperature for several hours, the precipitated crystals were collected by filtration. By recrystallizing 1.33 g of the obtained crystal from ethanol twice, (-)-6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazine-1- Il] -1,3-diisopropyl-2,
0.21 g of a salt of 4 (1H, 3H) pyrimidinedione and (−)-dibenzoyl-L-tartaric acid was obtained. This salt was dissolved in chloroform, washed with a 5% aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. After filtration and concentration,
The residue was dissolved in methanol, and then (-)-6- [4- {3- (4-cyanophenoxy) -2-hydroxy-3-methylbutyl}-was prepared by the same method as in item (3) of Example 1.
Piperazin-1-yl] -1,3-diisopropyl-
0.08 g of crystals of 2,4 (1H, 3H) pyrimidinedione oxalate was obtained. Enantiomeric excess rate 96.2% ee or more The enantiomeric excess rate was calculated by liquid chromatography using an optically active column.

Example 44 6- [4- {3 obtainable by the method of Example 8
-(4-Cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione
Production of tablets containing oxalate as an active ingredient The pyrimidinedione derivative / oxalate 1 g, lactose 12
Mix 3g and corn starch 20g well,
Add 5 g of hydroxypropyl cellulose to 100 m of water.
The mixture was granulated with the liquid dissolved in 1 and dried at 50 ° C. for 4 hours. To this, 1 g of magnesium stearate was added and mixed well, and the tablets were obtained by tableting with a tableting machine at a weight of 150 mg per tablet.

Example 45 6- [4- {3 obtainable by the method of Example 8
-(4-Cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione
Production of capsules containing oxalate as an active ingredient The pyrimidinedione derivative / oxalate 5 g, lactose 12
Mix 0 g and corn starch 25 g well,
The obtained mixture is made into hard capsules by a capsule filling machine.
It was filled to 0 mg to obtain capsules.

Example 46 6- [4- {3 which can be obtained by the method of Example 8
-(4-Cyanophenoxy) -2-hydroxy-3-methylbutyl} -piperazin-1-yl] -1,3-diisopropyl-2,4 (1H, 3H) pyrimidinedione
Production of injection containing oxalate as an active ingredient 20 mg of the pyrimidinedione derivative / oxalate and 0.85 g of sodium chloride were taken and dissolved in an appropriate amount of distilled water for injection to make 100 ml to give an injection. .

[Pharmacological Test Example] Test Example 1 Effect on 20 mM KCl-induced contraction of isolated canine coronary artery Heparin (50) was carried out on an adult dog under pentobarbital anesthesia.
(00 U / Kg), the chest was opened and the heart was removed. The left convoluted branch was peeled and removed to obtain a ring-shaped sample having a width of about 5 mm. The sample was taken in 20 ml of Krebs-Henseleit solution (95
% O ₂ + 5% CO ₂ , 35 ° C.) and suspended in a Magnus bath to apply an initial tension of 1.5 g. The contraction reaction was measured on an equal scale via a tension transducer (TB-651, Nihon Kohden) and an amplifier (EF-601G, Nihon Kohden) and recorded on a recorder (MC-6623, GRAFTEC). The sample was left for 1 hour and propranolol (10 ^-6 M) and indomethacin (10 ^-5 M) were added to Kreb.
It was added to the s-Henzelet solution. After confirming that the sample was stable, the experiment was started. The relaxation rate is 20m
The tension induced by MKCl was defined as 100%, and the tension when the sample was completely relaxed by applying papaverine (10 ⁻⁵ M) after application of the test drug was determined as 0%. The test drug was dissolved in distilled water at the highest dose concentration and diluted with distilled water. The 50% relaxation concentration (ED ₅₀ ) of the sample by the test drug is shown in Table 2 [Table 11].

[0142]

[Table 11]

Test Example 2 Antagonism by Glyburide Using Canine Isolated Coronary Artery
Action In the same manner as in Test Example 1, induction of 20 mM KCl in the dog isolated coronary artery
Administration of the compound of Example 8 as a test drug against contraction and contraction
After confirming the relaxing action, glyburide10 ^-6M
After administration, the recovery rate for maximum relaxation was examined. That conclusion
As a result, the recovery rate after administration of glyburide was 39%.
It was. Test Example 3: Acute toxicity The compound of Example 8 of the present invention was intraperitoneally administered to a group of male mice 1
Administered 00 mg / kg, but no death was observed
It was

[0144]

As is clear from the above examples and various pharmacological tests, the pyrimidinedione derivative of the present invention has low toxicity, and has high blood pressure, congestive heart dysfunction, angina pectoris, peripheral and cerebrovascular disorders, and tachycardia. It is clinically highly expected as a therapeutic agent for urine, asthma, ischemic heart disease and baldness.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/505 ABU ACD ACV ADA AED 9360-4C C07C 43/215 7419-4H 43/225 7419-4H 43/235 7419-4H 69/62 9279-4H 69/96 Z 9279-4H 205/37 7188-4H 255/54 9357-4H 271/28 7188-4H 275/34 7188-4H 279/28 7188-4H 309 / 63 7419-4H 309/72 7419-4H 311/08 7419-4H 335/40 7106-4H C07D 213/64 213/65 301/12 301/14 301/19 303/16 401/12 239 8829-4C 405 / 12 213 8829-4C // (C07D 401/12 213: 00 239: 00) (C07D 405/12 213: 00 303: 00) (72) Inventor Junya Fujiwara 1144, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Tadahito Sho Mitsui Toatsu Chemical Co., Ltd. 1144, Togo, Mobara-shi, Chiba In-house (72) Hideo Odaka, 1144 Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Joji Kamiya, 1900, 1900, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Masahiko Maruyama 1 1900, Togo, Mobara, Chiba Prefecture Mitsui Toatsu Chemical Co., Ltd. (72) Inventor Tatsuro Sugawara 1900, 1900 Togo, Mobara City, Chiba Mitsui Toatsu Chemical Co., Ltd.

Claims (17)

[Claims] 1. General formula (1) [Chemical formula 1] (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, C
_{1 to} C ₆ linear or branched alkyl group, or C ₁
To C ₆ linear or branched alkenyl groups are shown.
R ₃ and R ₄ are the same or different and each represent a C _{1 to} C ₄ alkyl group, or R ₃ and R ₄ are taken together to represent a C _{2 to} C ₅ polymethylene group. W represents a hydrogen atom or a hydroxyl group. A is the following group (2) [Chemical formula 2] Represents a benzene ring which may be substituted, a 3-pyridyl group, or a 4-pyridyl group. Where Y ₁ and Y ₂
Are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group, a C ₁ -C ₆ alkoxycarbonyl group, an amino group, a nitro group, a cyano group, a chloro atom, a trifluoromethyl group, or a C ₁ -C group. ₆ alkylsulfonyl groups, C ₁ ~
Alkoxysulfinyl sulfinyl group C _6, C ₁ -C alkoxy sulfonyl group of _6, alkylcarbonylamino group of C ₁ -C _6, an alkoxycarbonylamino group of C ₁ ~C _6, C ₁ ~
C ₆ alkylaminosulfinyl group, C _{1 to} C ₆ alkylaminosulfonyl group, C _{1 to} C ₆ alkylsulfinylamino group, C _{1 to} C ₆ alkylsulfonylamino group, C _{1 to} C ₆ alkoxy group, A cyanomethyl group, a 2-cyano-3-methylguanidine group, an S-methyl-N-cyanothioureido group and a 3-ethylureido group are shown. X represents a C ₁ -C ₆ alkyl group or a nitro group. ) A pyrimidinedione derivative represented by: 2. General formula (3) [Chemical formula 3] (In the formula, R ₁ , R ₂ and X are the same as above.) And a uracil piperazine derivative represented by the general formula (4) [Chemical Formula 4] (In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom, C
_{1 to} C ₄ alkyl group, or R ₃ and R ₄ together form C ₂
Show a polymethylene group of ~C _5. A is the same as above. A propane oxide derivative represented by the formula (1) (wherein R ₃ and R ₄ are the same or different, a hydrogen atom, a C ₁ -C ₄ alkyl group, or R ₃ , R ₄ together represents a C ₂ -C ₅ polymethylene group, W is a hydroxyl group), and a method for producing a pharmaceutically acceptable acid addition salt thereof. 3. A compound represented by the general formula (5): [Chemical formula 5] A—OH (5) (wherein A is the same as above), and a compound represented by the general formula (6): 6] (In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom, C
_{1 to} C ₄ alkyl group, or R ₃ and R ₄ together form C ₂
Show a polymethylene group of ~C _5. R ₅ represents a C _{1 to} C ₆ linear or branched alkyl group. ) Is coupled with an allylalkyl carbonate derivative represented by the formula (1) in the presence of a palladium catalyst. (In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom, C
_{1 to} C ₄ alkyl group, or R ₃ and R ₄ together form C ₂
Show a polymethylene group of ~C _5. A is the same as above. The manufacturing method of the alkene derivative represented by these. 4. An allylalkyl carbonate derivative represented by the general formula (6). 5. General formula (7) [Chemical formula 8] [Chemical formula 8] (In the formula, R ₃ and R ₄ are the same or different and are a hydrogen atom,
Alkyl C ₁ -C _4, or an polymethylene group _R 3, _{R 4} is together C ₂ -C _5. A is the same as above. ) Alkene derivative represented by. 6. General formula (4) [Chemical formula 9] [Chemical formula 9] (In the formula, R ₃ and R ₄ are the same or different and are a hydrogen atom,
Alkyl C ₁ -C _4, or an polymethylene group _R 3, _{R 4} is together C ₂ -C _5. A is the same as above. ) Propane oxide derivative represented by. 7. A method for producing a propane oxide derivative represented by the general formula (4), which comprises oxidizing an alkene derivative represented by the general formula (7) with a peroxide. 8. A compound represented by the general formula (8): [Chemical Formula 10] (In the formula, R ₃ and R ₄ are the same or different, and a C _{1 to} C ₄ alkyl group or R ₃ and R ₄ are taken together to represent a C _{2 to} C ₅ polymethylene group. A is the same as above. L is a chloro atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group.) And a general formula (3). A method for producing a pyrimidinedione derivative represented by the general formula (1) (wherein W is a hydrogen atom) and a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a uracil piperazine derivative. 9. General formula (9) [Chemical formula 11] [Chemical formula 11] (In the formula, R ₃ and R ₄ are the same or different and are a hydrogen atom,
Alkyl C ₁ -C _4, or an polymethylene group _R 3, _{R 4} is together C ₂ -C _5. A is the same as above. ) Propyl alcohol derivative represented by. 10. A method for producing a propyl alcohol derivative represented by the general formula (9), which comprises hydroborating an alkene derivative represented by the general formula (7) with an organic boron compound. 11. A compound represented by the general formula (8): [Chemical Formula 12] (In the formula, R ₃ and R ₄ are the same or different and represent a C _{1 to} C ₄ alkyl group, or R ₃ and R ₄ are taken together to represent a C _{2 to} C ₅ polymethylene group. A is the same as above. L is a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, or a trifluoromethanesulfonyloxy group. 12. A process for producing a propane derivative represented by the general formula (8), which comprises halogenating a propyl alcohol derivative represented by the general formula (9) or reacting it with a sulfonic acid halide. 13. General formula (10) [Chemical formula 13] [Chemical formula 13](In the formula, R₃, R_FourAre the same or different and are a hydrogen atom, C
₁~ C_FourAlkyl group of R, or R₃, R_FourBecome together C₂
~ C_FiveThe polymethylene group of is shown. W and A are the same as above
is there. ) And a general formula (11)
[Chemical 14] [Chemical 14](In the formula, R₁, R₂And X are the same as above. Z is ku
A lole atom, a bromine atom, and an iodine atom are shown. )
General formula characterized by reacting a uracil derivative
(1) (However, R _Three, R_FourAre the same or different,
Child, C₁~ C_FourAlkyl group of R, or R_Three, R_FourTogether
Nari C₂~ C_FiveThe polymethylene group of is shown. ) Represented by
Limidinedione derivative and its pharmacologically acceptable
A method for producing an acid addition salt. 14. General formula (10) [Chemical formula 15] (In the formula, R ₃ and R ₄ are the same or different and are a hydrogen atom,
Alkyl C ₁ -C _4, or an polymethylene group _R 3, _{R 4} is together C ₂ -C _5. W and A are the same as above. ) The piperazine derivative represented by. 15. A process for producing a piperazine derivative represented by the general formula (10) (wherein W is a hydroxyl group), which comprises reacting piperazine with a propane oxide derivative represented by the general formula (4). . 16. A general formula (1) characterized by reacting a piperazine with a propane derivative represented by the general formula (8).
0) (however, W is a hydrogen atom) The manufacturing method of the piperazine derivative represented by this. 17. Hypertension, which comprises a pyrimidinedione derivative represented by the general formula (1) and a pharmacologically acceptable acid addition salt thereof as an active ingredient, and has a mechanism of action of opening a potassium channel, Congestive heart dysfunction, angina, peripheral and cerebrovascular disorders, pollakiuria, asthma, ischemic heart disease and baldness treatment.