JP2997536B2 - Pantothenic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I {R<1> and R<2> are each H or protective group for OH; R<3> is (aromatic group-substituted)5-25C monovalent aliphatic hydrocarbon group or NH-R<4> [R<4> is (aromatic group-substituted)5-25C monovalent aliphatic hydrocarbon group); (m) is 2 or 3; (n) is 1-4}. EXAMPLE:1-Hexanoyl-4-{1-oxo-3-[N-(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino]propyl}piperazine. USE:Having inhibitory activity for acyl CoA-cholesterol-acyl transferase, thus useful for the therapies for hyperlipemia, arteriosclerosis, etc. PREPARATION:The objective compound of the formula I can be obtained by reaction between (A) a compound of formula II (R<11> and R<12> are each protected OH) and (B) a compound of formula R<3>-COZ<1> (Z<1> is H, halogen, alkoxy, etc.) or formula R<4>-NCO using, as necessary, a catalyst or reaction promoter in a solvent such as methylene chloride at temperatures ranging from -78 deg.C to the boiling point of the solvent.

Description

The present invention relates to a pantothenic acid derivative having excellent inhibitory activity on acyl-CoA-cholesterol-acyltransferase (Acyl CoA-Cholesterol-Acyltransferase—hereinafter abbreviated as “ACAT”).

<Prior art and problems> In recent years, in atherosclerosis, which is commonly seen in arteriosclerosis, fat deposition is recognized from the earliest stage of the onset of arteriosclerosis, and the main component of the accumulated fat is cholesterol, In addition, numerous histopathological and biochemical studies have revealed that this cholesterol is derived from plasma lipids. Also, various epidemiological studies have shown that hyperlipidemia is a major risk factor for atherosclerotic disease. Therefore, the treatment of hyperlipidemia is becoming more and more important in reducing the risk of atherosclerotic diseases, and the therapeutic agent not only lowers serum lipid levels but also improves serum lipid balance, There is a demand for a drug capable of positively preventing the onset of sclerosis.

Numerous drugs are already available for the treatment of hyperlipidemia, with some clinical effect on lowering total serum cholesterol, but not necessarily on reducing mortality from atherosclerotic disease. No effect has been observed. In recent years, along with elucidation of the lipid metabolism system, a drug that controls serum lipid balance, that is, effective in increasing the serum level of high-density lipoprotein (HDL) and decreasing the level of low-density lipoprotein (LDL). Drugs or drugs that inhibit cholesterol biosynthesis and consequently lower serum lipid levels (HMG CoA reductase inhibi
tors) is under development. However, while these drugs are also effective in improving blood lipid levels, they have little effect on controlling the absorption of dietary cholesterol from the intestinal wall and, moreover, actively inhibit the development or progression of arteriosclerosis. It does not have a preventable effect and whether it can reduce the risk of atherosclerotic disease has to be studied further.

On the other hand, ACAT, known as an integral membrane enzyme, is abundantly present in intracellular microsomes of the liver and small intestine, and controls the synthesis of cholesterol esters. Also, this enzyme has
At present, the existence of two types of isozymes is known, but their structures and their physiological roles have not been elucidated yet because isolation and purification of this enzyme are difficult. But AC
It is known that AT is involved in absorption of cholesterol in the intestine and accumulation as cholesterol ester in cells, and its activity is promoted in atherosclerotic lesions,
The inhibitor of this enzyme is expected to be useful as a drug having a blood lipid lowering effect and an anti-atherosclerotic effect based on the inhibition of cholesterol absorption.

The present inventors have conducted intensive studies to synthesize a substance having an excellent ACAT inhibitory activity, and as a result, the present invention has been completed.

<Disclosure of the Invention> According to the present invention, the following general formula In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group; R ³ is substituted with a saturated or unsaturated and linear, branched or cyclic aromatic group as needed. which may C ₅ even though ~C
Represents ₂₅ monovalent aliphatic hydrocarbon group or a group -NH-R ^4, wherein, R ⁴ is and saturated or unsaturated linear, optionally substituted by branched or cyclic optionally aromatic group It represents a good C ₅ -C ₂₅ monovalent aliphatic hydrocarbon group, m is 2 or 3; n is an integer of 1 to 4, in the compounds represented is provided.

In the present invention, the term "lower" is used to indicate that the atomic group or the compound modified by this term has 6 or less, preferably 4 or less carbon atoms.

The “protecting group for a hydroxyl group” can be any protecting group that can be eliminated by hydrolysis or hydrogenolysis, and examples thereof include those exemplified below. Methyl, methoxyethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
Bis (2-chloroethoxy) methyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, cinnamyl, benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-
Chlorobenzyl, o-chlorobenzyl, p-cyanobenzyl, diphenylmethyl, α-naphthyldiphenylmethyl, triphenylmethyl, di (p-methoxyphenyl)
A substituted or unsubstituted alkyl or alkenyl group such as methyl;
Tetrahydropyranyl, tetrahydrothiopyranyl, 4
Heterocyclic groups such as -methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, and tetrahydrothiofuranyl; trimethylsilyl,
Triethylsilyl, isopropyldimethylsilyl, t-
Butyldimethylsilyl, t-butyldiphenylsilyl,
Substituted silyl groups such as methyldiisopropylsilyl, methyldi-tert-butylsilyl, tribenzylsilyl, triphenylsilyl and triisopropylsilyl; formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, triphenyl Methoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl, 2,6-dichloro-4-methylphenoxyacetyl, phenylacetyl, chlorodiphenylacetyl, 3-phenylpropionyl, 3-benzoylpropionyl, isobutyroyl, monosuccinoyl, 4-oxopentanoyl , Pivaloyl, 2-butenoyl, (E) -2-methyl-2-butenoyl, benzoyl, 2-chlorobenzoyl, 3-nitrobenzoyl, 2-phenyl Acyl groups such as lobenzoyl, 3-trifluorobenzoyl, 3-trichlorobenzoyl, 4-phenylbenzoyl, 2,4,6-trimethylbenzoyl and α-naphthoyl; methoxycarbonyl, ethoxycarbonyl, 2,2,2-triethoxy Carbonyl, isobutoxycarbonyl, vinyloxycarbonyl, aryloxycarbonyl, cinnamyloxycarbonyl, p-
Substituted oxycarbonyl groups such as nitrophenoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; phenylcarbamoyl, naphthylcarbamoyl, Toluylcarbamoyl, fluorophenylcarbamoyl, difluorophenylcarbamoyl, nitrophenylcarbamoyl, cyanophenylcarbamoyl, benzylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl,
Butylcarbamoyl, cyclohexylcarbamoyl, cyclopropylmethylcarbamoyl, phenylthiocarbamoyl, naphthylthiocarbamoyl, toluylthiocarbamoyl, fluorophenylthiocarbamoyl, difluorophenylthiocarbamoyl, nitrophenylthiocarbamoyl, cyanophenylthiocarbamoyl, benzylthiocarbamoyl, propylthio Substituted carbamoyl groups such as carbamoyl and butylthiocarbamoyl;

When R ¹ and R ² in the formula (I) represent a protecting group for a hydroxyl group, R ¹ and R ² together form methylene, ethylidene, 1-t-butylethylidene, 1-phenyl Ethylidene, 2,2,2-trichloroethylidene, isopropylidene, butylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene,
p-methoxybenzylidene, 2,4-dimethoxybenzylidene, p-dimethylaminobenzylidene, o-nitrobenzylidene, methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene and the like An ylidene group can also be formed.

Examples of the “saturated or unsaturated, linear, branched or cyclic, monovalent aliphatic hydrocarbon group” include the following.

(1) Alkyl group: For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, isopentyl, t-pentyl, 1-ethylpentyl, 1-isopropylpentyl, 1-t-butylpentyl , 2-ethylpentyl, 2-isopropylpentyl, 2-t-butylpentyl, 3-ethylpentyl, 3-isopropylpentyl, 3-t-butylpentyl, hexyl, 1-ethylhexyl, 1-isopropylhexyl, 1-t- Butylhexyl, 2-ethylhexyl, 2-isopropylhexyl, 2-t-butylhexyl, 3-ethylhexyl, 3-isopropylhexyl, 3-t-butylhexyl, heptyl, 1-ethylheptyl, 1-isopropylheptyl, 1-neo Pentylheptyl, 2- Ethylheptyl, 2-isopropylheptyl, 2-neopentylheptyl, 3-ethylheptyl, 3-isopropylheptyl, 3-neopentylheptyl, octyl, 1-ethyloctyl, 1-isopropyloctyl, 1-t-butyloctyl, 2 -Ethyloctyl, 3-isopropyloctyl, 4-t-butyloctyl, nonyl, 1-methylnonyl, 1-ethylnonyl, 1-isopropylnonyl,
-Isobutylnonyl, 2-methylnonyl, 2-ethylnonyl, 3-isopropylnonyl, 4-isobutylnonyl, decyl, 1-ethyldecyl, 1,1-diethyldecyl, 1-t-butyldecyl, 3-ethyldecyl, 1,3-
Diethyldecyl, 2-t-butyldecyl, undecyl,
1-isopropylundecyl, 1,1-diethylundecyl, 2-isopropylundecyl, 1,2-diethylundecyl, dodecyl, 1-t-butyldodecyl, 1-isopropyldodecyl, 1,1-diethyldodecyl, 2 -T-
Butyl dodecyl, 3-isopropyldodecyl, 2,4-diethyldodecyl, tridecyl, 1,1-diethyltridecyl, 1-t-butyltridecyl, 1,5-diethyltridecyl, 3-t-butyltridecyl, tetradecyl , 1-
Isobutyltetradecyl, pentadecyl, 1-methylpentadecyl, 1,1-dimethylpentadecyl, 1-ethylpentadecyl, 1,1-diethylpentadecyl, 1-isopropylpentadecyl, 1-t-butylpentadecyl,
2-isobutyltetradecyl, 3-methylpentadecyl, 2,6-dimethylpentadecyl, 2-ethylpentadecyl, 1,4-diethylpentadecyl, 3-isopropylpentadecyl, 2-t-butylpentadecyl, hexadecyl, 1,1-dimethylhexadecyl, 1-methylhexadecyl, 1-ethylhexadecyl, 1-isopropylhexadecyl, 1-t-butylhexadecyl, 1,3-dimethylhexadecyl, 2-methylhexadecyl, 4- Ethylhexadecyl, 3-isopropylhexadecyl, 4-
t-butylhexadecyl, heptadecyl, 1-methylheptadecyl, 1,1-dimethylheptadecyl, 1-ethylheptadecyl, 1-isopropylheptadecyl, 1-t
-Butylheptadecyl, 2-methylheptadecyl, 3,5
-Dimethylheptadecyl, 2-ethylheptadecyl, 5
-Isopropylheptadecyl, 3-t-butylheptadecyl, octadecyl, 1-methyloctadecyl, 1,1-
Dimethyl octadecyl, 1-ethyl octadecyl, 1,1
-Diethyloctadecyl, 2-methyloctadecyl, 2,
3-dimethyloctadecyl, 5-ethyloctadecyl,
1,2-diethyloctadecyl, nonadecyl, 1-methylnonadecyl, 1,1-dimethylnonadecyl, 1-t-butylnonadecyl, 2-methylnonadecyl, 2,3-dimethylnonadecyl, 3-t-butylnonadecyl, icosyl,
-Methyl icosyl, 1,1-dimethyl icosyl, 1-ethyl icosyl, 1-t-butyl icosyl, 4-methyl icosyl, 2,2-dimethyl icosyl, 3-ethyl icosyl,
2-t-butyl icosyl and the like.

(2) Alkenyl group: for example, vinyl, 1-propenyl, 1-methyl-2-propenyl, 1-methyl-1-butenyl, 2-butenyl, 1-methyl-3-butenyl, 1-pentenyl, 1-methyl-2
-Pentenyl, 1-ethyl-3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl,
1-hexenyl, 1-methyl-2-hexenyl, 3-hexenyl, 4-hexenyl, 1-butyl-5-hexenyl, 1,3-hexadienyl, 2,4-hexadienyl, 1-
Heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1,3-heptadienyl, 2,4-heptadienyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-
Nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 9-decenyl, 1-methyl-9-decenyl, 1,1-dimethyl-9-decenyl, 1-ethyl-
9-decenyl, 6-undecenyl, 1-methyl-6-undecenyl, 1,1-dimethyl-6-undecenyl, 6-
Tridecenyl, 1-methyl-6-tridecenyl, 1,1-
Dimethyl-6-tridecenyl, 8-tridecenyl, 1-
Methyl-8-tridecenyl, 1,1-dimethyl-8-tridecenyl, 10-tridecenyl, 1-methyl-10-tridecenyl, 1,1-dimethyl-10-tridecenyl, 10-pentadecenyl, 1-methyl-10-pentadecenyl, 1,1−
Dimethyl-10-pentadecenyl, 8-pentadecenyl,
1-methyl-8-pentadecenyl, 1,1-dimethyl-8
-Pentadecenyl, 12-heptadecenyl, 1-methyl-
12-heptadecenyl, 1,1-dimethyl-12-heptadecenyl, 10-heptadecenyl, 1-methyl-10-heptadecenyl, 1,1-dimethyl-10-heptadecenyl, 8-heptadecenyl, 1-methyl-8-heptadecenyl, 1, 1
-Dimethyl-8-heptadecenyl, 1-ethyl-8-heptadecenyl, 8,11-heptadecadienyl, 1-methyl-8,11-heptadecadienyl, 8,11,14-heptadecatrienyl and the like.

(3) alkynyl group: for example, propargyl, 2-butynyl, 1-methyl-3-butynyl, 2-pentynyl, 1-ethyl-3-pentynyl, 1
-Isopropyl-4-pentynyl, 1,3-pentadiynyl, 2,4-pentadiynyl, 1-hexynyl, 1-methyl-2-hexynyl, 2-methyl-3-hexynyl, 1
-Ethyl-4-hexynyl, 5-hexynyl, 1,3-hexadiynyl, 2,4-hexadiynyl, 1-heptynyl, 1-methyl-2-heptynyl, 3-heptynyl, 1
-Ethyl-4-heptynyl, 2-propyl-5-heptynyl, 2-ethyl-6-heptynyl, 1,3-heptadiynyl, 2,4-heptadiynyl, 1-octynyl, 1-methyl-2-octynyl, 3-methyl -1-octynyl,
4-methyl-1-octynyl, 1-methyl-5-octynyl, 6-methyl-1-octynyl, 7-octynyl,
1-noninyl, 2-methyl-1-noninyl, 3-methyl-1-noninyl, 1-methyl-4-noninyl, 5-noninyl, 6-methyl-1-noninyl, 1-methyl-7-noninyl, 8- Noninyl, 9-decynyl, 1-methyl-9
-Decinyl, 1,1-dimethyl-9-decynyl, 1-ethyl-9-decynyl, 6-undecinyl, 1-methyl-6
-Undecinyl, 1,1-dimethyl-6-undecinyl,
6-tridecynyl, 1-methyl-6-tridecynyl, 1,
1-dimethyl-6-tridecynyl, 8-tridecynyl,
1-methyl-8-tridecynyl, 1,1-dimethyl-8-
Tridecinyl, 10-tridecinyl, 1-methyl-10-tridecinyl, 1,1-dimethyl-10-tridecynyl, 10-
Pentadecynyl, 1-methyl-10-pentadecynyl, 1,
1-dimethyl-10-pentadecynyl, 8-pentadecynyl, 1-methyl-8-pentadecynyl, 1,1-dimethyl-8-pentadecynyl, 12-heptadecynyl, 1-methyl-12-heptadecynyl, 1,1-dimethyl-12- Heptadecynyl, 10-heptadecynyl, 1-methyl-10-heptadecynyl, 1,1-dimethyl-10-heptadecynyl, 8
-Heptadecynyl, 1-methyl-8-heptadecynyl,
1,1-dimethyl-8-heptadecynyl, 1-ethyl-8
-Heptadecynyl, 8,11-heptadecadinyl, 1-methyl-8,11-heptadecadinyl, 8,11,14-heptadecatriynyl and the like.

(4) Cycloalkyl group: For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, perhydronaphthyl and the like.

(5) Cycloalkenyl group: for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentakienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl and the like.

(6) cycloalkylalkyl group: for example, cyclohexylmethyl, cyclopentylmethyl, (4-
(Isopropylcyclohexyl) methyl, (4-t-butylcyclohexyl) methyl, (4-neopanthycyclohexyl) methyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopentylpropyl, 3
-Cyclohexylpropyl, 1-cyclopentylpentyl, 1-cyclohexylpentyl, 1-cyclohexylmethylpentyl, 3-cyclopentylpentyl, 2-cyclohexylpentyl, 2-cyclohexylmethylpentyl, 1- (4-t-butylcyclohexyl) methylpentyl, 1 -Cyclopentylhexyl, 1-cyclohexylhexyl, 1-cyclopentylmethylhexyl, 2
-Cyclopentylhexyl, 2-cyclohexylhexyl, 3-cyclopentylmethylhexyl, 1- (4-neopentylcyclohexyl) methylhexyl, 1-cyclopentylheptyl, 1-cyclohexylmethylheptyl, 1- (4-isopropylcyclohexyl) methylheptyl, 3 -Cyclopentylheptyl, 2-cyclohexylmethylheptyl, 4- (4-isopropylcyclohexyl) methylheptyl, 1-cyclopentyloctyl, 1-cyclohexyloctyl, 1-cyclopentylmethyloctyl, 2-cyclopentyloctyl, 3-cyclohexyloctyl, 2-cyclopentyl Methyloctyl, 1-cyclopentylnonyl, 1-cyclohexylnonyl, 1-cyclohexylmethylnonyl, 3-cyclopentylnonyl, 2 Cyclohexyl nonyl, 2-cyclohexylmethyl-nonyl, 1-cyclopentyl-decyl,
1-cyclopentyl undecyl, 1-cyclohexyl undecyl, 1-cyclopentyl dodecyl, 1-cyclopentyl tridecyl, 2-cyclopentyl decyl, 3-cyclopentyl undecyl, 3-cyclohexyl undecyl, 2-cyclopentyl dodecyl, 2-cyclopentyl tridecyl , 1-cyclopentyltetradecyl, 1-cyclohexyltetradecyl, 2-cyclopentyltetradecyl, 3-cyclohexyltetradecyl and the like.

(7) cycloalkenylalkyl group: for example, 2-cyclohexen-1-ylmethyl, 1-cyclopenten-1-ylmethyl, 2- (2-cyclopenten-1
-Yl) ethyl, 2- (1-cyclohexen-1-yl) ethyl, 3- (1-cyclopenten-1-yl) propyl, 3- (1-cyclohexen-1-yl) propyl, 4- (1-cyclohexene -1-yl) butyl, 1
-(1-cyclopenten-1-yl) pentyl, 5-
(1-cyclopenten-1-yl) pentyl, 1-1
(Cyclohexen-1-yl) pentyl, 5- (1-cyclohexen-1-yl) pentyl, 1- (1-cyclohexen-1-ylmethyl) pentyl, 1- (1-cyclopenten-1-yl) hexyl, 6- (1-cyclopenten-1-yl) hexyl, 1- (1-cyclohexen-1-yl) hexyl, 6- (1-cyclohexen-
1-yl) hexyl, 1- (2-cyclopentene-1-
Ylmethyl) hexyl, 1- (1-cyclopentene-1)
-Yl) heptyl, 7- (1-cyclopenten-1-yl) heptyl, 1- (1-cyclohexen-1-ylmethyl) heptyl, 1- (1-cyclopenten-1-yl) octyl, 1- (2-cyclopentene -1-yl)
Octyl, 1- (2-cyclohexen-1-yl) octyl, 8- (2-cyclohexen-1-yl) octyl, 1- (1-cyclopenten-1-ylmethyl) octyl, 1- (1-cyclopenten-1-) Il) nonyl,
9- (1-cyclopenten-1-yl) nonyl, 1-
(1-cyclohexen-1-yl) nonyl, 9- (1-
Cyclohexen-1-yl) nonyl, 1- (1-cyclohexen-1-ylmethyl) nonyl, 1- (1-cyclopenten-1-yl) decyl, 10- (1-cyclopenten-1-yl) decyl, 1- ( 2-cyclopentene-1
-Yl) undecyl, 1- (2-cyclohexene-1-)
Yl) undecyl, 1- (1-cyclopenten-1-yl) dodecyl, 1- (1-cyclopenten-1-yl)
Tridecyl, 1- (2-cyclopenten-1-yl) tetradecyl, 1- (3-cyclohexen-1-yl) tetradecyl and the like.

(8) alkylcycloalkyl group and alkenylcycloalkyl group: for example, 1-methylcyclobutyl, 2-ethylcyclobutyl,
-Propylcyclobutyl, 1-butylcyclobutyl, 1
-Pentylcyclobutyl, 1-hexylcyclobutyl,
1-heptylcyclobutyl, 1-octylcyclobutyl, 1-nonylcyclobutyl, 2-pentylcyclobutyl, 2-hexylcyclobutyl, 2-heptylcyclobutyl, 2-octylcyclobutyl, 2-nonylcyclobutyl, 1- Decylcyclobutyl, 1-undecylcyclobutyl, 1-dodecylcyclobutyl, 1-pentadecylcyclobutyl, 1- (9-octadecenyl) cyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 1-ethylcyclopentyl, 1- Propylcyclopentyl, 1-butylcyclopentyl, 2-butylcyclopentyl, 1-pentylcyclopentyl, 1-hexylcyclopentyl, 3-hexylcyclopentyl, 1-
Heptylcyclopentyl, 1-octylcyclopentyl, 2-octylcyclopentyl, 1-decylcyclopentyl, 1-dodecylcyclopentyl, 1-tridecylcyclopentyl, 1-tetradecylcyclopentyl, 1
-(9-octadecenyl) cyclopentyl, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 2-methylcyclohexyl, 3-
Ethylcyclohexyl, 4-propylcyclohexyl, 1
-Butylcyclohexyl, 1-pentylcyclohexyl, 1-hexylcyclohexyl, 4-butylcyclohexyl, 4-pentylcyclohexyl, 4-hexylcyclohexyl, 1-heptylcyclohexyl, 1-octylcyclohexyl, 1-nonylcyclohexyl, 1-
Undecylcyclohexyl, 1-hexadecylcyclohexyl, 1- (9-octadecenyl) cyclohexyl and the like.

(9) alkylcycloalkenyl group and alkenylcycloalkenyl group: for example, 1-methyl-2-cyclopentenyl, 1-ethyl-2-
Cyclopentenyl, 1-propyl-2-cyclopentenyl, 1-butyl-2-cyclopentenyl, 1-pentyl-2-cyclopentenyl, 1-hexyl-2-cyclopentenyl, 1-heptyl-2-cyclopentenyl, 1-
Octyl-2-cyclopentenyl, 2-methyl-2-cyclopentenyl, 3-ethyl-2-cyclopentenyl,
2-propyl-3-cyclopentenyl, 3-butyl-2
-Cyclopentenyl, 2-pentyl-2-cyclopentenyl, 3-hexyl-3-cyclopentenyl, 2-heptyl-2-cyclopentenyl, 2-octyl-3-cyclopentenyl, 1-decyl-2-cyclopentenyl, 1
-Dodecyl-2-cyclopentenyl, 1-tridecyl-
2-cyclopentenyl, 1-tetradecyl-2-cyclopentenyl, 1- (9-octadecenyl) -2-cyclopentenyl, 1-methyl-2-cyclohexenyl, 1-
Ethyl-2-cyclohexenyl, 1-propyl-2-cyclohexenyl, 1-butyl-2-cyclohexenyl,
1-pentyl-2-cyclohexenyl, 1-hexyl-
2-cyclohexenyl, 1-heptyl-2-cyclohexenyl, 4-methyl-2-cyclohexenyl, 2-ethyl-2-cyclohexenyl, 3-propyl-2-cyclohexenyl, 4-butyl-3-cyclohexenyl, 3-
Pentyl-3-cyclohexenyl, 4-hexyl-3-
Cyclohexenyl, 4-heptyl-3-cyclohexenyl, 1-octyl-2-cyclohexenyl, 1-nonyl-2-cyclohexenyl, 1-undecyl-2-cyclohexenyl, 1-hexadecyl-2-cyclohexenyl, 1- (9-octadecenyl) -2-cyclohexenyl and the like.

"Aromatic group" in "saturated or unsaturated and linear, branched or cyclic monovalent aliphatic hydrocarbon group optionally substituted with an aromatic group" includes, for example, phenyl, naphthyl Aromatic hydrocarbon groups such as freel, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, benzooxadiazolyl, imidazolyl, benzothiadiazolyl, triazolyl, tetrazolyl and the like; You.
These aromatic groups may be substituted. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom, a lower alkyl group, a lower alkoxy group, a cyano group, a nitro group and a trichloromethyl group. , A trifluoromethyl group, a hydroxy group, a phenyl group, a phenoxy group, and a lower alkylthio group.

As the saturated or unsaturated and linear, branched or cyclic monovalent aliphatic hydrocarbon group represented by R ³ or R ⁴ in the above general formula, among the above, those having a relatively long chain That is, having 5 to 25 carbon atoms, preferably 8 carbon atoms.
~ 22 are used.

Specific examples of the group —NH—R ⁴ that can be represented by R ³ in the general formula (I) include, for example, 2-cyclopentylethylamino, 2-cyclohexylethylamino, 3-cyclopentylpropylamino, -Cyclohexylpropylamino, 2-cyclopentyl-1-methylethylamino, 2-cyclopentyl-1,1-dimethylethylamino, 2-cyclohexyl-1-methylethylamino, 3-cyclopentylpropylamino, 3-cyclohexylpropylamino, 4 -Cyclohexyl-1,
1-dimethylbutylamino, 1-methylpentylamino, 1,1-dimethylpentylamino, 1-ethylpentylamino, 1-cyclohexyl-4-methylpentylamino, 1-cyclopentyl-4-methylpentylamino, 2-methylpentyl Amino, 1,2-dimethylpentylamino, 2-ethylpentylamino, 2-cyclohexyl-4-methylpentylamino, 2-cyclopentyl-4-methylpentylamino, 3-methylpentylamino, 1,3-dimethylpentylamino, 3-ethylpentylamino, 1-cyclohexyl-3-methylpentylamino, 1-cyclopentyl-3-methylpentylamino, hexylamino, 1-methylhexylamino, 1,1
-Dimethylhexylamino, 1-ethylhexylamino, 1,1-diethylhexylamino, 1-propylhexylamino, 1-butylhexylamino, 1-cyclopentylhexylamino, 2-methylhexylamino,
2-dimethylhexylamino, 2-ethylhexylamino, 1,2-diethylhexylamino, 2-propylhexylamino, 2-butylhexylamino, 6-cyclopentylhexylamino, 6-cyclohexylhexylamino, heptylamino, 1-ethylheptyl Amino, 1,
1-dimethylheptylamino, 1-cyclohexylheptylamino, 1-cyclopentylheptylamino, 1-
Cyclohexylmethylheptylamino, 1-cyclopentylmethylheptylamino, octylamino, 1,1-dimethyloctylamino, 1-methyloctylamino, 1
-Ethyloctylamino, 1,1-diethyloctylamino, 1-propyloctylamino, 1-butyloctylamino, 1-cyclopentyloctylamino, 1-cyclohexyloctylamino, 1-cyclopentylmethyloctylamino, 1-cyclohexylmethyloctylamino , Nonylamino, 1-methylnonylamino, 1,1-
Dimethylnonylamino, 1-ethylnonylamino, 1,1
-Diethylnonylamino, decylamino, 1-methyldecylamino, 1,1-dimethyldecylamino, 1-ethyldecylamino, 1,1-diethyldecylamino, 1-cyclopentyldecylamino, 1-cyclohexyldecylamino, 1-cyclopentyl Methyldecylamino, 1-cyclohexylmethyldecylamino, undecylamino,
1-methylundecylamino, 1,1-dimethylundecylamino, dodecylamino, 1-methyldodecylamino, 1,1-dimethyldodecylamino, tetradecylamino, 1-methyltetradecylamino, 1,1-dimethyltetra Decylamino, pentadecylamino, 1-methylpentadecylamino, 1,1-dimethylpentadecylamino, hexadecylamino, 1-methylhexadecylamino, 1,1-dimethylhexadecylamino, heptadecylamino, 1-methyl Heptadecylamino, 1,1-dimethylheptadecylamino, octadecylamino, 1-methyloctadecylamino, 1,1-dimethyloctadecylamino, 3-cyclopentyl-2-propenylamino, 3
-Cyclohexyl-2-propenylamino, 1,1-dimethyl-3-butenylamino, 1-ethyl-3-butenylamino, 1-cyclopropyl-3-butenylamino, 1
-Methyl-2-pentenylamino, 1,1-dimethyl-2
-Pentenylamino, 1-ethyl-2-pentenylamino, 1-cyclopropyl-2-pentenylamino, 2-
Hexenylamino, 1-methyl-2-hexenylamino, 1,1-dimethyl-2-hexenylamino, 3-hexenylamino, 1-methyl-3-hexenylamino,
1-dimethyl-3-hexenylamino, 2-heptenylamino, 1-methyl-2-heptenylamino, 2-octenylamino, 1-methyl-2-octenylamino, 3
-Nonenylamino, 1-methyl-3-nonenylamino,
1,1-dimethyl-3-nonenylamino, 1-ethyl-3
-Nonenylamino, 1-propyl-3-nonenylamino, 8-nonenylamino, 1-methyl-8-nonenylamino, 1,1-dimethyl-8-nonenylamino, 1-ethyl-8-nonenylamino, 9-decenylamino, 1-methyl-9 -Decenylamino, 1,1-dimethyl-9-decenylamino, 1-ethyl-9-decenylamino, 6-undecenylamino, 1-methyl-6-undecenylamino, 1,1-dimethyl-6-undecenyl Amino, 6-tridecenylamino, 1-methyl-6-tridecenylamino, 1,1-dimethyl-6-tridecenylamino, 8-tridecenylamino, 1-methyl-8-tridecenylamino , 1,1-dimethyl-8-tridecenylamino, 10-tridecenylamino, 1-methyl-10-tridecenylamino, 1,1-dimethyl-10-tridecenylamino Arylamino, 10-pentadecenyl amino, 1-methyl-10-pentadecenyl amino, 1,1-dimethyl-10-pentadecenyl amino,
8-pentadecenylamino, 1-methyl-8-pentadecenylamino, 1,1-dimethyl-8-pentadecenylamino, 12-heptadecenylamino, 1-methyl-12-heptade Cenylamino, 1,1-dimethyl-12-heptadecenylamino, 10-heptadecenylamino, 1-methyl-
10-heptadecenylamino, 1,1-dimethyl-10-heptadecenylamino, 8-heptadecenylamino, 1-methyl-8-heptadecenylamino, 1,1-dimethyl-8
-Heptadecenylamino, 1-ethyl-8-heptadecenylamino, 8,11-heptadecadienylamino, 1-methyl-8,11-heptadecadienylamino, 8,11,14-hepta Decatrienylamino, 1-ethylcyclobutylamino, 1-propylcyclobutylamino, 1-butylcyclobutylamino, 1-pentylcyclobutylamino,
1-hexylcyclobutylamino, 1-pentylcyclobutylamino, 1-octylcyclobutylamino, 1-
Nonylcyclobutylamino, 1-decylcyclobutylamino, 1-undecylcyclobutylamino, 1-dodecylcyclobutylamino, 1-pentadecylcyclobutylamino, 1- (9-octadecenyl) cyclobutylamino, 1-methylcyclopentyl Amino, 1-ethylcyclopentylamino, 1-propylcyclopentylamino, 1-butylcyclopentylamino, 1-hexylcyclopentylamino, 1-octylcyclopentylamino, 1-decylcyclopentylamino, 1-dodecylcyclopentylamino, 1-tridecylcyclopentylamino , 1-tetradecylcyclopentylamino, 1-
(9-octadecenyl) cyclopentylamino, cyclohexylamino, 1-methylcyclohexylamino, 1
-Propylcyclohexylamino, 1-pentylcyclohexylamino, 1-heptylcyclohexylamino,
Monosubstituted amino groups such as 1-nonylcyclohexylamino, 1-undecylcyclohexylamino, 1-hexadecylcyclohexylamino, 1- (9-octadecenyl) cyclohexylamino; 1-benzylhexylamino,
1-benzylheptylamino, 1-benzyloctylamino, 1-benzylnonylamino, 1-benzyldecylamino, 1-benzylundecylamino, 1-benzyldodecylamino, 1-benzyltetradecylamino, 1
-Benzylhexadecylamino, 1-phenyldecylamino, 1-benzyl-8-heptadecenylamino group.

Among the compounds provided by the present invention, it is preferable that in the general formula (I), R ¹ and R ² are the same or different and each is a hydrogen atom;
Lower alkyl groups, particularly t-butyl groups; benzyl groups optionally substituted with halogen atoms, lower alkoxy groups, nitro groups or cyano groups, especially benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-chlorobenzyl, o-chlorobenzyl, p-cyanobenzyl group; diphenylmethyl group; allyl group; cinnamyl group; tetrahydropyranyl, tetrahydrothiopyranyl, 4
A heterocyclic group selected from -methoxytetrahydropyranyl, 4-methoxytetrahydrohythiopyranyl, tetrahydrofuranyl and tetrahydrothiofuranyl; or an acyl group, especially acetyl, propionyl, phenylacetyl, chlorodiphenylacetyl, 3-phenyl Propionyl, 3-benzoylpropionyl, isobutyroyl,
Pivaloyl, 2-butenoyl, (E) -2-methyl-2
-Butenoyl, benzoyl, 2-chlorobenzoyl, 3
-Nitrobenzoyl, 2-fluorobenzoyl, 3-trifluoromethylbenzoyl, 3-trichloromethylbenzoyl, 4-phenylbenzoyl, 2,4,6-trimethylbenzoyl, α-naphthoyl, or R ¹ and R ² are Together, 1-t-butylethylidene, 1
-Ylidene selected from phenylethylidene, isopropylidene, butylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, p-dimethylaminobenzylidene and o-nitrobenzylidene R ³ represents (1) a linear or branched C ₅ -C ₂₅ alkyl group, particularly, pentyl, 1-isopropylpentyl, 1-t-butylpentyl, hexyl, 1-isopropyl Hexyl, 1-t-butylhexyl, heptyl, 1
-Isopropylheptyl, 1-t-butylheptyl, octyl, 1-t-butyloctyl, nonyl, 1-isobutylnonyl, decyl, 1-ethyldecyl, 1,1-diethyldecyl, 1-t-butyldecyl, undecyl, 1- Isopropylundecyl, 1,1-diethylundecyl, dodecyl, 1-tert-butyldodecyl, 1-isopropyldodecyl, 1,1-diethyldodecyl, tridecyl, 1,1-diethyltridecyl, 1-tert-butyltridecyl , Tetradecyl, 1-isobutyltetradecyl, pentadecyl,
1-methylpentadecyl, 1,1-dimethylpentadecyl, 1-ethylpentadecyl, 1,1-diethylpentadecyl, 1-isopropylpentadecyl, 1-t-butylpentadecyl, hexadecyl, 1,1-dimethylhexa Decyl, 1-methylhexadecyl, 1-ethylhexadecyl, 1-isopropylhexadecyl, 1-t-butylhexadecyl, heptadecyl, 1-methylheptadecyl,
1,1-dimethylheptadecyl, 1-ethylheptadecyl, 1-isopropylheptadecyl, 1-t-butylheptadecyl, octadecyl, 1-methyloctadecyl,
1,1-dimethyl octadecyl, 1-ethyl octadecyl or 1,1-diethyl octadecyl; (2) C ₁₂ ~C ₁₈ alkenyl group having a branched chain to straight chain or 1-position, in particular, 1,1-dimethyl - 9-decenyl, 1
-Ethyl-9-decenyl, 1-methyl-6-undecenyl, 1,1-dimethyl-6-undecenyl, 6-tridecenyl, 1-methyl-6-tridecenyl, 1,1-dimethyl-6-tridecenyl, 8-tridecenyl , 1-methyl-
8-tridecenyl, 1,1-dimethyl-8-tridecenyl, 10-tridecenyl, 1-methyl-10-tridecenyl, 1,1-dimethyl-10-tridecenyl, 10-pentadecenyl, 1-methyl-10-pentadecenyl, 1, 1-dimethyl-10-pentadecenyl, 8-pentadecenyl, 1-
Methyl-8-pentadecenyl, 1,1-dimethyl-8-pentadecenyl, 12-heptadecenyl, 1-methyl-12-
Heptadecenyl, 1,1-dimethyl-12-heptadecenyl, 10-heptadecenyl, 1-methyl-10-heptadecenyl, 1,1-dimethyl-10-heptadecenyl, 8-heptadecenyl, 1-methyl-8-heptadecenyl, 1,1-
Dimethyl-8-heptadecenyl, 1-ethyl-8-heptadecenyl, 8,11-heptadecadienyl, 1-methyl-
8,11-heptadecadienyl or 8,11,14- hept tetradecatrienyl _{group; (3) C 8 ~C 18} - alkyl -C ₄ -C ₆ cycloalkyl group,
In particular, 1-octylcyclobutyl, 1-nonylcyclobutyl, 1-decylcyclobutyl, 1-undecylcyclobutyl, 1-dodecylcyclobutyl, 1-pentadecylcyclobutyl, 1- (9-octadecenyl) cyclobutyl, -Octylcyclopentyl, 1-decylcyclopentyl, 1-dodecylcyclopentyl, 1-tridecylcyclopentyl, 1-tetradecylcyclopentyl, 1
-(9-octadecenyl) cyclopentyl, 1-nonylcyclohexyl, 1-undecylcyclohexyl, 1-
Hexadecylcyclohexyl or 1- (9-octadecenyl) cyclohexyl group; or (4) an amino group monosubstituted by an alkyl or alkenyl group having 8 to 22 carbon atoms, for example, 1-isopropylpentylamino, 1-t-butylpentyl Amino, 1-isopropylhexylamino, 1-t-butylhexylamino, 1-isopropylheptylamino, 1-t-butylheptylamino, 1-t-butyloctylamino, 1-
Isobutylnonylamino, decylamino, 1-ethyldecylamino, 1,1-diethyldecylamino, 1-t-butyldecylamino, undecylamino, 1-isopropylundecylamino, 1,1-diethylundecylamino, dodecylamino , 1-t-butyl dodecylamino,
1-isopropyldodecylamino, 1,1-diethyldodecylamino, tridecylamino, 1,1-diethyltridecylamino, 1-t-butyltridecylamino, tetradecylamino, 1-isobutyltetradecylamino, pentadecylamino , 1-methylpentadecylamino, 1,
1-dimethylpentadecylamino, 1-ethylpentadecylamino, 1,1-diethylpentadecylamino, 1-
Isopropylpentadecylamino, 1-t-butylpentadecylamino, hexadecylamino, 1,1-dimethylhexadecylamino, 1-methylhexadecylamino,
1-ethylhexadecylamino, 1-isopropylhexadecylamino, 1-t-butylhexadecylamino,
Heptadecylamino, 1-methylheptadecylamino,
1,1-dimethylheptadecylamino, 1-ethylheptadecylamino, 1-isopropylheptadecylamino,
1-t-butylheptadecylamino, octadecylamino, 1-methyloctadecylamino, 1,1-dimethyloctadecylamino, 1-ethyloctadecylamino, 1,
1-diethyloctadecylamino, 1,1-dimethyl-9-
Decenylamino, 1-ethyl-9-decenylamino, 1
-Methyl-6-undecenylamino, 1,1-dimethyl-
6-undecenylamino, 1-methyl-6-tridecenylamino, 1,1-dimethyl-6-tridecenylamino,
8-tridecenylamino, 1-methyl-8-tridecenylamino, 1,1-dimethyl-8-tridecenylamino, 1
0-tridecenylamino, 1-methyl-10-tridecenylamino, 1,1-dimethyl-10-tridecenylamino, 1
0-pentadecenylamino, 1-methyl-10-pentadecenylamino, 1,1-dimethyl-10-pentadecenylamino, 8-pentadecenylamino, 1-methyl-8-pentade Cenylamino, 1,1-dimethyl-8-pentadecenylamino, 12-heptadecenylamino, 1-methyl-
12-heptadecenylamino, 1,1-dimethyl-12-heptadecenylamino, 10-heptadecenylamino, 1-methyl-10-heptadecenylamino, 1,1-dimethyl-10
-Heptadecenylamino, 8-heptadecenylamino,
1-methyl-8-heptadecenylamino, 1,1-dimethyl-8-heptadecenylamino, 1-ethyl-8-heptadecenylamino, 8,11-heptadecadienylamino,
1-methyl-8,11-heptadecadienylamino, 8,11,1
4-heptadecatrienylamino, 1-hexylcyclobutylamino, 1-heptylcyclobutylamino, 1-
Octylcyclobutylamino, 1-nonylcyclobutylamino, 1-decylcyclobutylamino, 1-undecylcyclobutylamino, 1-dodecylcyclobutylamino, 1-pentadecylcyclobutylamino, 1- (9-
Octadecenyl) cyclobutylamino, 1-pentylcyclopentylamino, 1-hexylcyclopentylamino, 1-heptylcyclopentylamino, 1-octylcyclopentylamino, 1-decylcyclopentylamino, 1-dodecylcyclopentylamino, 1-tridecylcyclopentylamino , 1-tetradecylcyclopentylamino, 1- (9-octadecenyl) cyclopentylamino, 1-nonylcyclohexylamino, 1-undecylcyclohexylamino, 1-hexadecylcyclohexylamino, 1- (9-octadecenyl) cyclohexylamino, 1- Benzylhexylamino, 1-benzylheptylamino, 1-benzyloctylamino, 1
-Benzylnonylamino, 1-benzyldecylamino,
1-benzylundecylamino, 1-benzyldodecylamino, 1-benzyltetradecylamino, 1-benzylhexadecylamino, 1-phenyldecylamino, 1
-Benzyl-8-heptadecenylamino and the like, wherein m is 2 or 3, and n is an integer of 1 to 4.

Thus, the general formula (I) provided by the present invention
The following are representative examples of the compound represented by.

-1-hexanoyl-4- [1-oxo-3- [N-
(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-heptanoyl-4- [1-oxo-3- [N-
(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-octanoyl-4- [1-oxo-3- [N-
(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-decanoyl-4- [1-oxo-3- [N- (1
-Oxo-2,4-diacetoxy-3,3-dimethylbutyl)
Amino] propyl] piperazine 1-dodecanoyl-4- [1-oxo-3- [N-
(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-tetradecanoyl-4- [1-oxo-3- [N
-(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-hexadecanoyl-4- [1-oxo-3- [N
-(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-octadecanoyl-4- [1-oxo-3- [N
-(1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (7-tetradecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (10-hexadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (13-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (9,12-octadecadienoyl) -4- [1-oxo-3 -[N- (1-oxo-2,4-diacetoxy-
3,3-dimethylbutyl) amino] propyl] piperazine 1- (9,12,15-octadecatrienoyl) -4-
[1-oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (2-methylheptadecanoyl) -4- [1- Oxo-3- [N- (1-oxo-2,4-diacetoxy-
3,3-dimethylbutyl) amino] propyl] piperazine 1- (2,2-dimethylheptadecanoyl) -4- [1
-Oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (2-methyloctadecanoyl) -4- [1-oxo- 3- [N- (1-oxo-2,4-diacetoxy-
3,3-dimethylbutyl) amino] propyl] piperazine 1- (2,2-dimethyloctadecanoyl) -4- [1
-Oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (2-methyl-9-octadecenoyl) -4-
[1-oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (2-ethyl-9-octadecenoyl) -4-
[1-oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (2,2-dimethyl-9-octadecenoyl) -4
-[1-oxo-3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl]
Piperazine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-dihydroxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2-hydroxy-4-benzoyloxy-3,3-dimethylbutyl) amino] propyl] piperazine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-dibenzoyloxy-
3,3-dimethylbutyl) amino] propyl] piperazine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2-hydroxy-4-pivaloyloxy-3,3-dimethylbutyl) amino] propyl] piperazine.1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-dibenzyloxy-3,3
-Dimethylbutyl) amino] propyl] piperazine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] tetrahydro-1,4
-Diazepine 1- (9-octadecenoyl) -4- [1-oxo-
3- [N- (1-oxo-2,4-dihydroxy-3,3-dimethylbutyl) amino] propyl] tetrahydro-1,4
-Diazepine 1- (9-octadecenoyl) -4- [3- [N-
(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propanoyl] piperazine 1-octadecanoyl-4- [3- [N- (2,2,5,5
-Tetramethyl-1,3-dioxane-4-carbonyl)
Amino] propanoyl] piperazine 1- (9-octadecenoyl) -4- [3- [N-
(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propanoyl] tetrahydro-1,4-
Diazepine 1- (9-octadecenoyl) -4- [3- [N-
(2-phenyl-5,5-dimethyl-1,3-dioxane-4
-Carbonyl) amino] propanoyl] piperazine 1- (8-heptadecenyl) carbamoyl-4- [3
-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonylamino) propanoyl] piperazine 1- (8,11-heptadecadienyl) carbamoyl-4
-[3- (2,2,5,5-tetramethyl-1,3-dioxane-
4-carbonylamino) propanoyl] piperazine 1- (8,11,14-heptadecatrienyl) carbamoyl-4- [3- (2,2,5,5-tetramethyl-1,3-dioxane-4- Carbonylamino) propanoyl] piperazine 1- (8-heptadecenyl) carbamoyl-4- [3
-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonylamino) propanoyl] tetrahydro-1,4-
Diazepine 1- (2-benzylundecanoyl) -4- [3-
[N- (2,2,5,5-tetramethyl-1,3-dioxane-4
-Carbonyl) amino] propanoyl] piperazine 1- (1-benzyldecyl) carbamoyl-4- [3
-(N- (2,2,5,5-tetramethyl-1,3-dioxane-
4-carbonyl) amino] propanoyl] piperazine The compound of the present invention contains at least one asymmetric carbon atom as shown by the asterisk (*) in the general formula (I), and contains an optically active compound (R-form or (S-form) or racemic form.

The compounds of the present invention include, for example, (a) In the formula, R ¹¹ and R ²¹ are the same or different and each represents a protected hydroxyl group; m and n are as defined above, and a compound represented by the following formula R ³ —COZ ¹ (III) or R ^4- NCO (IV) wherein Z ¹ is a hydrogen atom; a halogen atom such as Cl or Br; an alkoxy group such as methoxy or ethoxy; a substituted or unsubstituted group such as phenoxy, p-nitrophenoxy, 2,4-dinitrophenoxy R ³ and R ⁴ are as defined above, or a compound represented by the following formula is reacted, or (b) Wherein R ¹¹ , R ²¹ , n and Z ¹ are as defined above. Wherein R ³ and m are as defined above, and reacting with a compound represented by the following formula. In the formula, R ¹¹ , R ²¹ , R ³ , m and n are as defined above, and can be produced by removing a hydroxyl-protecting group from a compound represented by the formula:

The reaction between the compound of the formula (II) and the compound of the formula (III) in the method (a) and the reaction of the compound of the formula (V) and the compound of the formula (VI) in the method (b) are usually carried out in a suitable solvent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. And high-boiling polar solvents such as dimethylformamide and dimethylsulfoxide; alcohols such as methanol and ethanol; and single or mixed solvents such as water. This reaction is generally -78
C. to the boiling point of the working solvent, preferably from about -10.degree. C. to the boiling point of the working solvent. Also,
In the method (a) and the method (b), a catalyst or a reaction accelerator can be used for the reaction. Examples of the catalyst or reaction accelerator that can be used include dicyclohexylcarbodiimide, diisopropylcarbodiimide,
Carbodiimides such as -ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; acid anhydrides such as acetic anhydride and benzoic anhydride; inorganics such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Bases: organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, pyridine and the like. These catalysts or reaction accelerators can be used in the range of 0.01 to 10 equivalents, preferably 0.1 to 1.1 equivalents, relative to compound (II) or compound (IV).

The ratio of the compound (III) or (IV) to the compound (II) is not strictly limited, but the compound (III) or (IV) is usually used in an amount of 0.8 to 1 mol per mol of the compound (II). It can be used in a range of 1.2 mol, preferably 1.0 to 1.1 mol. Similarly, compound (V) is generally used in an amount of 0.8 to 1.2 mol, preferably 1. mol, per 1 mol of compound (VI).
It can be used within the range of 0 to 1.1 mol.

In the method (c), the reaction for removing the hydroxyl-protecting group from the compound (I-1) can be carried out by hydrolysis in a solvent in the presence of a suitable catalyst. For example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride High-boiling polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohols such as methanol and ethanol; water; organic acids such as acetic acid and propionic acid; ketones such as acetone and methyl ethyl ketone alone or in a mixed solvent at -78. C. to the boiling point of the working solvent, preferably from about -10.degree. C. to the boiling point of the working solvent. Examples of usable catalysts include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine; and mineral bases such as hydrochloric acid, nitric acid and sulfuric acid. Acids; hydrogen halides such as hydrogen fluoride, hydrogen bromide and hydrogen iodide; and organic acids such as trifluoroacetic acid and trichloroacetic acid. The protective group can also be eliminated by catalytic hydrogenation using a suitable metal catalyst according to a conventional method. As a metal catalyst that can be used at that time, a normal hydrogenation catalyst such as nickel, palladium, rhodium, and platinum is used.

The product obtained by each of the above methods can be separated or purified from the reaction mixture by using a method known per se, for example, crystallization, chromatography, extraction, or an appropriate combination of methods. it can.

The compounds of formulas (V), (II) and (VI) used as starting materials in the above method can be prepared as described below.

[Production of Compound of Formula (V)] Step 1: Process 2: Process 3: Process 4: Process 5: Step 6: (Va) → (Vd) In the above formula, M represents a hydrogen atom; an alkali metal atom such as sodium or potassium or an alkaline earth metal atom such as magnesium or calcium; and L represents OH or Cl. , Br, represents I or _{^{n 2, R 11, R 21}} , n and Z ¹ are as defined above.

Step 1: In this step, compound (Va) is synthesized by reacting pantoyl lactone with ω-aminocarboxylic acid. Pantoyl lactone may be any of the (D)-, (L)-and (DL) -forms. Examples of ω-aminocarboxylic acids include aminoacetic acid (glycine), 3-aminopropionic acid (β-alanine), and 4-aminobutyric acid (γ
-Aminobutyric acid, GABA), 5-aminovaleric acid and the like. The reaction is preferably carried out using a solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; high-boiling polar solvents such as dimethylformamide and dimethylsulfoxide; Alcohols such as methanol and ethanol; water can be used alone or as a mixture. The reaction can generally be carried out at a temperature in the range from about 0 ° C. to the boiling point of the working solvent, preferably from room temperature to the boiling point of the working solvent. It is preferable to use a catalyst for this reaction. Examples of such a catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, and pyridine. Kind. These catalysts are used in an amount of 0.01 to 10 equivalents, preferably 0.1 to 1.1 equivalents, based on pantoyl lactone.
It can be used within the equivalent range.

Step 2: In this step, the compound (Va) synthesized in Step 1 is benzylated to be converted to a compound (Vb). As the benzylation reagent, benzyl halides such as benzyl chloride, benzyl bromide and benzyl iodide; benzyl alcohol; phenyldiazomethane and the like are used. This reaction is carried out in a suitable solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane;
Esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohols such as methanol and ethanol; acetone and methyl ethyl ketone Ketones;
The reaction can be carried out in a single or mixed solvent such as water at a temperature usually ranging from -78 ° C to the boiling point of the solvent used, preferably from -10 ° C to the boiling point of the solvent used. In this reaction, a catalyst or a reaction accelerator may be used. Examples of such a catalyst or reaction accelerator include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; acid anhydrides such as acetic anhydride and benzoic anhydride; Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; and organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine. These catalysts or reaction accelerators can be used in the range of 0.01 to 10 equivalents, preferably 0.1 to 1.1 equivalents, relative to compound (Va).

Step 3: In this step, the compound synthesized in the previous step 2 (V
In this step, compound (Vc) is synthesized by protecting the hydroxyl group in (b). As a reaction reagent for introducing a protecting group (R ¹¹ , R ²¹ ), for example, acid anhydrides such as acetic anhydride and benzoic anhydride; acid chlorides such as acetyl chloride and benzoyl chloride; acetic acid, benzoic acid, p- Organic acids such as toluenesulfonic acid; orthoesters such as ethyl orthoformate and methyl orthoformate; ketones such as acetone and cyclohexanone; aldehydes such as benzaldehyde and acetaldehyde; silylating agents such as trimethylsilyl chloride and dimethylphenylsilyl chloride; Alkylating agents such as diazomethane and dimethyl sulfate; alkyl halides such as methyl iodide and benzyl chloride are used. This reaction is carried out in a suitable solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; methylene chloride, chlorophohelm, Halogenated hydrocarbons such as carbon tetrachloride; dimethylformamide,
High-boiling polar solvents such as dimethyl sulfoxide; alcohols such as methanol and ethanol; ketones such as acetone and methyl ethyl ketone; in a solvent alone or in a mixed solvent such as water from -78 ° C to the boiling point of the solvent used, preferably about-
The reaction can be performed at a temperature in the range of 10 ° C. to the boiling point of the solvent used. In this reaction, a catalyst or a reaction accelerator may be used. Examples of such a catalyst or reaction accelerator include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-
Carbodiimides such as dimethylaminopropyl) -carbodiimide hydrochloride; acid anhydrides such as acetic anhydride and benzoic anhydride; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; triethylamine, diethylamine, dimethyl Organic bases such as amine, diisopropylamine, and pyridine; and organic acids such as acetic acid, p-toluenesulfonic acid, and camphorsulfonic acid. These catalysts or reaction accelerators are compound (V-
It can be used in the range of 0.01 to 10 equivalents, preferably 0.1 to 1.1 equivalents to b).

Step 4: In this step, compound (Vc) is converted to compound (Vd) by hydrolysis or catalytic hydrogenation.
This reaction can be performed using a suitable catalyst in a solvent. Hydrolysis is carried out, for example, by aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; methylene chloride, chloroform and carbon tetrachloride. Halogenated hydrocarbons; polyvalent boiling polar solvents such as dimethylformamide and dimethylsulfoxide; alcohols such as methanol and ethanol; water;
Organic acids such as acetic acid and propionic acid; -78 in a single or mixed solvent of ketones such as acetone and methyl ethyl ketone;
The reaction can be carried out at a temperature in the range of from 0 ° C to the boiling point of the working solvent, preferably from about -10 ° C to the boiling point of the working solvent.
Examples of usable catalysts include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine; hydrochloric acid, nitric acid and sulfuric acid Mineral acids such as hydrogen fluoride, hydrogen bromide, and hydrogen iodide; and organic acids such as trifluoroacetic acid and trichloroacetic acid. on the other hand,
The catalytic hydrogenation can be carried out by a usual method known per se, and nickel, palladium, rhodium, platinum or the like is used as a metal catalyst.

Step 5: This step is a step of converting compound (Vd) into compound (V). Examples of the reagent used in this reaction include halogenating reagents such as thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride; or alcohols such as methanol and ethanol; phenols such as p-nitrophenol and 2,4-dinitrophenol. Esterifying reagents such as In this step, in an appropriate solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; methylene chloride, chloroform; Halogenated hydrocarbons such as carbon tetrachloride; high-boiling polar solvents such as dimethylformamide and dimethylsulfoxide; alcohols such as methanol and ethanol; -78 ° C in a single or mixed solvent such as water.
To the boiling point of the solvent used, preferably from about -10 ° C to the boiling point of the solvent used. Further, a catalyst or a reaction accelerator can be used in the reaction. Examples of such a catalyst or reaction accelerator include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)
-Carbodiimides such as carbodiimide hydrochloride; acid anhydrides such as acetic anhydride and benzoic anhydride; sodium hydroxide;
Inorganic bases such as potassium hydroxide, sodium carbonate and potassium carbonate; and organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine. These catalysts or reaction accelerators are used in an amount of 0.01 to 10 equivalents, preferably 0.1 to 10 equivalents, based on compound (Vd).
It can be used within the range of ~ 1.1 equivalents.

Step 6: This step is a step of synthesizing the compound (Vd) from the compound (Va). Reagents that can react with compound (Va) include anhydrides such as acetic anhydride and benzoic anhydride; acid chlorides such as acetyl chloride and benzoyl chloride; organic acids such as acetic acid, benzoic acid and p-toluenesulfonic acid. Orthoesters such as ethyl orthoformate and methyl orthoformate; ketones such as acetone and cyclohexanone; aldehydes such as benzaldehyde and acetaldehyde; silylating agents such as trimethylsilyl chloride and dimethylphenylsilyl chloride; alkyls such as diazomethane and dimethyl sulfate. Agents: alkyl halides such as methyl iodide and benzyl chloride are used. This reaction is carried out in a suitable solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; high boiling polar solvents such as dimethylformamide and dimethyl sulfoxide; alcohols such as methanol and ethanol; ketones such as acetone and methyl ethyl ketone; −78
The reaction can be carried out at a temperature in the range of from 0 ° C to the boiling point of the working solvent, preferably from about -10 ° C to the boiling point of the working solvent.
In this reaction, a catalyst or a reaction accelerator may be used. Examples of such catalysts or reaction accelerators include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; and acid anhydrides such as acetic anhydride and benzoic anhydride. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine; acetic acid, p-toluenesulfonic acid,
Organic acids such as camphorsulfonic acid can be mentioned. These catalysts or reaction accelerators are used for compound (Vb).
It can be used in the range of 0.01 to 10 equivalents, preferably 0.1 to 1.1 equivalents.

[Production of Compound of Formula (II)] The compound (II) is produced by the following formula produced as described above. Wherein R ¹¹ , R ²¹ , n and Z ¹ are as defined above. In the formula, m is as defined above, and is obtained by reacting with a compound represented by

This reaction is carried out in an appropriate solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethyl ether,
Ethers such as tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; high-boiling polar solvents such as dimethylformamide and dimethyl sulfoxide; methanol and ethanol The reaction can be carried out in a solvent alone or in a mixed solvent such as water at a temperature in the range of -78 ° C to the boiling point of the solvent used, preferably from about -10 ° C to the boiling point of the solvent used. Further, a catalyst or a reaction accelerator can be used in the reaction. Examples of such a catalyst or reaction accelerator include dicyclohexylcarbodiimide, diisopropylcarbodiimide,
Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; halogenating reagents such as thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride; acid anhydrides such as acetic anhydride and benzoic anhydride Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; Organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine and pyridine; acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like Organic acids. These catalysts or reaction accelerators are used in an amount of 0.01 to 10 based on the compound (V).
It can be used in equivalents, preferably in the range of 0.1 to 1.1 equivalents.

[Production of Compound of Formula (VI)] Compound (VI) is represented by the following formula Wherein m is as defined above, and a compound represented by the following formula: R ³ —CO—Z ¹ (VIII) wherein R ³ and Z ¹ are as defined above, It is obtained by reacting.

This reaction is carried out in an appropriate solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethyl ether,
Ethers such as tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; high-boiling polar solvents such as dimethylformamide and dimethyl sulfoxide; methanol and ethanol The reaction can be carried out in a solvent alone or in a mixed solvent such as water at a temperature in the range of -78 ° C to the boiling point of the solvent used, preferably from about -10 ° C to the boiling point of the solvent used. Further, a catalyst or a reaction accelerator can be used in the reaction. Examples of such a catalyst or reaction accelerator include dicyclohexylcarbodiimide, diisopropylcarbodiimide,
Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride; halogenating reagents such as thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride; acid anhydrides such as acetic anhydride and benzoic anhydride , Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, pyridine; acetic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. Organic acids. These catalysts or reaction accelerators are used in an amount of 0.01 to 10 based on the compound (V).
It can be used in equivalents, preferably in the range of 0.1 to 1.1 equivalents.

The compound of the formula (I) provided by the present invention has excellent ACAT inhibitory activity, and can be used for the treatment and treatment of hyperlipidemia, arteriosclerosis, angina, myocardial infarction, thrombosis and the like. It is expected to be used as a drug for prevention.

The ACAT inhibitory activity of the compound of the present invention can be confirmed by the test methods described below.

The ACAT inhibition test was performed according to the method of Helgerud et al. [Journal of L.
ipid Research, 22, 497 (1981)] and the method of Folch et al. [Journal of Biological Chemistry, 226, 497 (195)
According to 7) Reference was accomplished by measuring the cholesteryl oleate produced by the intracellular cholesterol ^[1-14 C] oleoyl CoA.

In other words, 2μM bovine serum albumin and 2μM [1- ¹⁴ C]
Oleoyl-CoA and 0.514M potassium phosphate buffer (pH
In 0.5 ml of the solution dissolved in 7.4), a microsomal fraction (0.3 mg protein) prepared from rat liver was dissolved in a 0.514 M potassium phosphate buffer (pH 7.4), and a 10 μM solution and 10 ^-7 M of a reagent were prepared.
Is added to 5 μl of a solution of dimethyl sulfoxide in dimethyl sulfoxide, and reacted at 37 ° C. for 4 minutes.

Thereafter, 4.2 ml of methanol and 8.3 ml of chloroform were added to stop the reaction, and 2.5 ml of water was added. After sufficient shaking, the chloroform layer was separated. After concentrating the chloroform layer, the resultant is subjected to thin-layer chromatography, and the produced cholesteryl oleate is collected, and the radioactivity is measured with a liquid scintillation counter.

In addition, the ACAT inhibitory activity of each test compound is calculated based on the radioactivity of the control obtained by performing the same test as above without using a sample.

 The results are shown in Table 1 below.

Hyperlipidemia, arteriosclerosis, a compound of the present invention as a drug,
When used for the treatment, treatment, prevention and the like of diseases such as angina pectoris, myocardial infarction and thrombosis, the compound is used as a pharmaceutical auxiliary, for example, a pharmaceutically acceptable carrier, diluent, excipient, binder. Along with disintegrants, lubricants, preservatives, stabilizers, dissolution aids, flavoring agents, etc., in dosage forms suitable for administration, such as tablets, capsules, powders, granules, microcapsules, syrups, elixirs , Suppositories and the like can be formulated into unit dosage forms.

The content of the active ingredient in these preparations can be varied in a wide range depending on the type of the compound of the present invention, the type of preparation, the purpose of use, etc., but generally 0.5 to 90% by weight,
Preferably, it can be in the range of 5 to 60% by weight.

Tablets, capsules, powders, solid preparations such as granules, the compound of the present invention, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose, starch, polyvinylpyrrolidone, aluminum metasilicate, Carrier or diluent such as talc; lubricant such as magnesium stearate;
It can be formulated according to a conventional method together with a disintegrating agent such as calcium cellulose gluconate; a solubilizing agent such as glutamic acid and aspartic acid; and a stabilizer such as lactose. Further, if necessary, tablets may be coated with a gastric or enteric substance of sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose sugar, and the capsule may be a hard capsule.
Alternatively, a soft capsule may be used.

In the case of liquid preparations such as syrups, elixirs, solutions, emulsions and suspensions, the compounds of the present invention can be used in pharmaceutically acceptable liquid media such as purified water, saline,
The preparation can be prepared by dissolving or dispersing in a buffer solution, ethanol, or the like, and further, if necessary, appropriately mixing a surfactant, a sweetener, a flavor, a fragrance, a preservative, and the like.

On the other hand, injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Such injections may be prepared by mixing the compound of the present invention with distilled water for injection, an aqueous diluent such as physiological saline or polyethylene glycol,
It can be prepared by mixing with a non-aqueous diluent such as propylene glycol, olive oil, ethanol, and Polysorbate 80 (registered trademark). In addition, preservatives, wetting agents, surfactants, dispersants,
Auxiliary agents such as stabilizers and solubilizing agents can also be included.
These injections can usually be sterilized by filtration using a bacteria-retaining filter or the like, blending of a bactericide or irradiation, etc., and after these treatments, a solid preparation is obtained by a method such as freeze-drying. Just before use, sterile water or a sterile injectable diluent can be added for use.

The compounds of the present invention can be administered orally or rectally or by parenteral administration, such as intravenous, intramuscular, subcutaneous, and the like. The dosage depends on the type of compound used,
It can be changed according to the method of administration, the severity of the condition of the patient to be treated, the age and weight of the patient, the judgment of the doctor, etc.
In general, it is appropriate to administer about 2 to about 500 mg / kg of body weight per day, once or in 2 to 4 divided doses. However, the above dose range is only a rough guide, and it is of course possible to administer a dose above or below the above range according to the judgment of the doctor, the severity of the symptoms, and the like.

Reference Example-1 1-oleoylpiperazine 4.3 g of piperazine was dissolved in 30 ml of methylene chloride, and a solution of 3.0 g of oleic chloride dissolved in 10 ml of methylene chloride was added dropwise with stirring under ice cooling. After stirring for 2 hours,
10 ml of water was added to the reaction solution, and the organic layer was separated. The organic layer was further washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (2.68 g, yield 76%).

Properties; oily mass spectrometry molecular formula; C ₂₂ H ₄₂ N ₂ O theory 350.3297 Found _{350.3308 NMR (δ, CDCl 3)} ; 088 (3H, t, J = 7Hz), 1.18-1.39 (20
H, m), 1.62-1.78 (2H, m), 1.91-2.07 (4H, m), 2.31
(2H, t, J = 7Hz), 2.90−3.00 (4H, m), 3.62−3.73 (4H,
m), 3.62-3.73 (4H, m), 5.28-5.41 (2H, m) Reference Example-2 1-oleoyl-tetrahydro-1,4-diazepine 5.0 g of tetrahydro-1,4-diazepine was dissolved in 30 ml of methylene chloride, and stirred under ice-cooling, oleic acid chloride 3.
A solution of 0 g in 10 ml of methylene chloride was added dropwise. After stirring for 2 hours as it was, 10 ml of water was added to the reaction solution, and the organic layer was separated. The organic layer was further washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, and 2.76 g of the title compound was obtained.
(75% yield).

Properties; oil Mass spectrometry Molecular formula: C ₂₃ H ₄₄ N ₂ O Theoretical 364.3453 Observed 364.3451 NMR (δ, CDCl ₃ ); 088 (3H, t, J = 7 Hz), 1.21-1.39 (20
H, m), 1.59−2.08 (8H, m), 2.27−2.38 (2H, m), 2.85−
3.01 (4H, m), 3.50-3.68 (4H, m), 5.29-5.40 (2H, m) Reference Example-3 (A) 1-benzyloxycarbonyl-4- [1-oxo-3- [N- ( 2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propyl] piperazine 5.18 g of 3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionic acid and 1
-Dissolve 6.60 g of benzyloxycarbonylpiperazine in 50 ml of methylene chloride and, with stirring under ice-cooling, add 1-ethyl hydrochloride-
4.42 g of 3- (3-dimethylaminopropyl) carbodiimide (WSC) was added and stirred overnight. After completion of the reaction, the reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 8.60 g (yield 94%) of the title compound.

Properties; oily IR (cm ^-1 , neat); ν _co 1706,1648 mass spectrometry molecular formula; C ₂₄ H ₃₅ N ₃ O ₆ theoretical 461.2525 found 461.2537 NMR (δ, CDCl ₃ ); 1.03 (3H, s), 1.41 (3
H, s), 1.46 (3H, s), 2.49-2.64 (2H, m), 3.27 (1H, d, J
= 12Hz), 3.35-3.62 (10H, m), 3.67 (1H, d, J = 12Hz),
4.06 (1H, s), 5.15 (2H, s), 7.09 (1H, t, J = 6Hz), 7.28
-7.43 (5H, m) (B) 1- [1-oxo-3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propyl] piperazine 1-benzyloxycarbonyl-4- [1-oxo-
1.4 g of 3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propyl] piperazine
Is dissolved in 30 ml of methanol, and 10% palladium on carbon carrier 20
0 mg was added, and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere.
After completion of the reaction, insolubles were filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.993 g (yield: 100%) of the title compound.

Properties; oil Mass spectrometry Molecular formula; C ₁₆ H ₂₉ N ₃ O ₄ theoretical 327.2158 found 327.2166 NMR (δ, CDCl ₃ ); 0.97 (3H, s), 1.04 (3H, s), 1.42 (3
H, s), 1.47 (3H, s), 2.47-2.63 (2H, m), 2.79-2.97
(4H, m), 3.40-3.76 (7H, m), 3.28 (1H, d, J = 12Hz),
4.07 (1H, s), 7.12 (1H, t, J = 6Hz) Reference Example-4 Benzyl 3- [N- (2,4-dihydroxy-3,3-dimethyl-1-oxo) amino] propionate 75 g of calcium pantothenate and 53.8 g of benzyl bromide were dissolved in dimethylformamide 11 and stirred at 100 ° C. overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 90.3 g (yield: 93%) of the title compound as a residue.

Properties; oil ^{IR (cm -1, neat);} ν CO 1738,1662 Mass spectrometry molecular formula; C ₁₈ H ₂₃ NO ₅ theory 309.1576 Found _{309.1577 NMR (δ, CDCl 3)} ; 0.88 (3H, s), 1.00 ( 3H, s), 2.62 (2
H, t, J = 7 Hz), 3.45 (1H, d, J = 11 Hz), 3.48 (1 H, d, J = 11)
Hz), 3.52-3.64 (2H, m), 3.99 (1H, s), 5.14 (2H, s),
7.10-7.20 (1H, m), 7.33-7.42 (5H, m) Reference Example-5 Benzyl 3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino ] Propionate 90 g of benzyl 3-[(2,4-dihydroxy-3,3-dimethyl-1-oxo) amino] propionate is added to acetone 7
The mixture was dissolved in 00 ml, p-toluenesulfonic acid monohydrate (5.6 g) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
Washed with water and then with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (85 g) was obtained as a residue.
(84% yield).

Properties; oily IR (cm ^-1 , neat); ν _NH 3456, ν _CO 1740, 1676 Mass spectrometry Molecular formula; C ₁₉ H ₂₇ NO ₅ theoretical 349.1889 found 349.1882 NMR (δ, CDCl ₃ ); 0.94 (3H, s ), 1.03 (3H, s), 1.41 (3
H, s), 1.44 (3H, s), 2.62 (2H, t, J = 7Hz), 3.28 (1H, d,
J = 12Hz), 3.67 (1H, d, J = 12Hz), 3.42-3.65 (2H, m),
4.07 (1H, s), 5.14 (2H, s), 6.90-7.10 (1H, m), 7.30
-7.40 (5H, m) Reference Example-6 3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionic acid Benzyl 3- [N- (2,2,5,5-tetramethyl-1,3-
Dioxane-4-carbonyl) amino] propionate
35 g was dissolved in 350 ml of methanol, and 100 ml of a 1N aqueous solution of sodium hydroxide was added under ice cooling and stirring, followed by stirring for 1 hour. After completion of the reaction, methanol was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate. Add 1N hydrochloric acid to the aqueous layer to make it acidic,
Extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (20.4 g, yield 78%) was obtained as a residue.
I got

Property: Melting point: 87.2 to 89.2 ° C IR (cm ⁻¹ , neat); ν _NH 3420, ν _CO 1743, 1636 Mass spectrometry Molecular formula: C ₁₂ H ₂₁ NO ₅ Theoretical value 259.1419 Actual value 259.1425 NMR (δ, CDCl ₃ ); 0.98 (3H, s), 1.04 (3H, s), 1.43 (3
H, s), 1.46 (3H, s), 2.62 (2H, t, J = 7Hz), 3.29 (1H, d,
J = 12Hz), 3.68 (1H, d, J = 12Hz), 3.43-3.66 (2H, m),
4.11 (1H, s), 6.90-7.10 (1H, m) Reference Example-7 Benzyl 3- [N- (5,5-dimethyl-2-phenyl-
1,3-dioxane-4-carbonyl) amino] propionate Dissolve 3.09 g of benzyl 3- [N- (2,4-dihydroxy-3,3-dimethyl-1-oxo) amino] propionate in 6.09 g of benzaldehyde dimethyl acetal and 0.19 g of p-toluenesulfonic acid in 100 ml of benzene and azeotrope. The mixture was refluxed for 2 hours while removing the water generated in the above. After completion of the reaction, the reaction solution was washed with a saturated aqueous solution of sodium bicarbonate, water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography to produce, thereby obtaining 3.18 g (yield: 80%) of the title compound.

Properties; oily IR (cm ^-1 , neat); ν _NH 3456, ν _CO 1740, 1676 Mass spectrometry Molecular formula; C ₁₉ H ₂₇ NO ₅ theoretical 397.1889 found 397.1882 NMR (δ, CDCl ₃ ); 1.08 (3H, s ), 1.10 (3H, s), 2.62 (2
H, t, J = 6Hz), 3.68 (1H, d, J = 11Hz), 3.45-3.64 (2H,
m), 3.72 (1H, d, 11Hz), 4.09 (1H, s), 5.10 (2H, s), 5.
51 (1H, s), 6.92-7.04 (1H, m), 7.38-7.52 (10H, m) Reference Example-8 Benzyl 3- [N- (3,3-dimethyl-1,5-dioxaspiro [5,5 ] Dodecane-2-carbonyl) amino] propionate Benzyl 3- [N- (2,4-dihydroxy-3,3-dimethyl-1-oxo) amino] propionate 3.09 g, cyclohexanone 1.47 g and p-toluenesulfonic acid 0.19 g
Was dissolved in 100 ml of benzene and refluxed for 2 hours while removing water generated by boiling. After completion of the reaction, the reaction solution was washed with a saturated aqueous solution of sodium bicarbonate, water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography to produce, thereby obtaining 3.07 g (yield 79%) of the title compound.

Properties; oily IR (cm ^-1 , neat); ν _CO 1738,1680 mass spectrometry molecular formula; C ₂₂ H ₃₁ NO ₅ theoretical value 389.2202 actual value 389.2214 NMR (δ, CDCl ₃ ); 0.95 (3H, s), 1.03 ( 3H, s), 1.32-
1.50 (4H, m), 1.54-1.70 (4H, m), 1.78-1.90 (2H,
m), 2.62 (2H, t, J = 7Hz), 3.25 (1H, d, J = 12Hz), 3.46
−3.66 (2H, m), 3.69 (1H, d, J = 12Hz), 4.08 (1H, s),
5.14 (2H, s), 7.00-7.10 (1H, m), 7.03-7.42 (5H, m) Reference Example-9 3- [N- (5,5-dimethyl-2-phenyl-1,3-dioxane- 4-carbonyl) amino] propionic acid Dissolve 1.0 g of benzyl 3- [N- (5,5-dimethyl-2-phenyl-1,3-dioxane-4-carbonyl) amino) propionate in 20 ml of methanol, and add 10 ml of 1N aqueous sodium hydroxide solution under ice-cooling and stirring. The mixture was stirred for 2 hours. After completion of the reaction, methanol was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 0.77 g (yield quantitative) of the title compound as a residue.

Properties; oily IR (cm ^-1 , neat); ν _NH 3420, ν _CO 1732, 1636 mass spectrometry molecular formula; C ₁₆ H ₂₁ NO ₅ theoretical 307.1419 found 307.1423 NMR (δ, CDCl ₃ ); 1.11 (3H, s ), 2.62 (2H, t, J = 7Hz),
3.28 (1H, d, J = 12Hz), 3.44-3.64 (2H, m), 3.68 (1H,
d, J = 11Hz) N, 3.73 (1H, d, J = 11Hz), 4.12 (1H, s), 5.5
1 (1H, s), 7.00-7.10 (1H, m), 7.38-7.45 (3H, m), 7.
45-7.52 (2H, m) Reference Example-10 3- [N- (3,3-dimethyl-1.5-dioxaspiro [5,
5] dodecane-2-carbonyl) amino) propionic acid 1.95 g of benzyl 3- [N- (3,3-dimethyl-1.5-dioxaspiro [5,5] dodecane-2-carbonyl) amino] propionate was dissolved in 20 ml of methanol, and 20 mg of a 10% palladium-carbon carrier was suspended. The mixture was stirred overnight at room temperature under a hydrogen gas atmosphere. After completion of the reaction, insolubles were filtered off and the solvent was distilled off, thereby obtaining 1.50 g of the title compound.

Properties; oily IR (cm ^-1 , neat); ν _CO 1728,1670 mass spectrometry molecular formula; C ₁₅ H ₂₅ NO ₅ theoretical 299.1732 found 299.1718 NMR (δ, CDCl ₃ ); 0.99 (3H, s), 1.04 ( 3H, s), 1.32-
1.54 (4H, m), 1.54-1.94 (7H, m), 2.64 (2H, t, J = 6H
z), 3.26 (1H, d, J = 12Hz), 3.71 (1H, d, J = 12Hz), 3.46
−3.64 (2H, m), 4.12 (1H, s), 7.08−7.14 (1H, m) Reference Example-11 3- [N- (2,4-diacetoxy-3,3-dimethyl-1-)
Oxobutyl) amino] propionic acid 4.47 g of calcium pantetonate was suspended in 20 ml of pyridine, 10.2 g of acetic anhydride was added, and the mixture was stirred overnight. After completion of the reaction, the reaction solution was poured into ice water and stirred for 2 hours, and then adjusted to pH 2 by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off, and 4.19 g (yield 69) of the title compound was obtained as a residue.
%).

Properties; oily IR (cm ^-1 , neat); ν _CO 1742,1664, ν _OH 3384 mass spectrometry molecular formula; C ₁₃ H ₂₁ NO ₇ theoretical 303.1317 actual 303.1326 NMR (δ, CDCl ₃ ); ), 1.07 (3H, s), 2.08 (3
H, s), 2.14 (3H, s), 2.60 (2H, t, J = 6Hz), 3.40-3.64
(2H, m), 3.84 (1H, d, J = 11Hz), 4.04 (1H, d, J = 11H
z), 4.98 (1H, s), 6.62 to 6.72 (1 H, m) Reference Example-12 4-nitrophenyl 3- [N- (2,4-diacetoxy-
3,3-Dimethyl-1-oxobutyl) amino] propionate 3- [N- (2,4-diacetoxy-3,3-dimethyl-1
[Oxobutyl) amino] propionic acid (22.6 g) and p-nitrophenol (10.4 g) were dissolved in tetrahydrofuran (500 ml), dicyclohexylcarbodiimide (15.5 g) was added, and the mixture was stirred overnight. After the reaction was completed, insolubles were removed, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 10.2 g (yield 32%) of the title compound as a residue.

Properties; oily IR (cm ^-1 , neat); ν _NH 3456, ν _CO 1740, 1676 Mass spectrometry Molecular formula; C ₁₉ H ₂₄ N ₂ O ₉ theoretical value 424.1481 found 424.1467 NMR (δ, CDCl ₃ ); 1.04 (3H , s), 1.08 (3H, s), 2.06 (3
H, s), 2.10 (3H, s), 2,84-2.91 (2H, m), 3.50-3.76
(2H, m), 3.86 (1H, d, J = 11Hz), 4.04 (1H, d, J = 11H
z), 4.93 (1H, s), 6.50-6.60 (1H, m), 7.29 (2H, d, 7H
z), 8,28 (2H, d, 7Hz) Reference Example-13 Benzyl 2- [N- (2,4-dihydroxy-3,3-dimethylbutanoyl) amino] acetate 13.0 g of pantoyl lactone, 8.3 g of glycine and 85% potassium hydroxide were dissolved in 100 ml of methanol, and the mixture was heated under reflux for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure. After drying the residue, the residue was dissolved in dimethylformamide (150 ml), benzyl bromide (18.8 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was evaporated under reduced pressure, and the residue was dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 12.8 g (43%) of the title compound. .

NMR (δ, CDCl ₃ ); 0.95 (3H, s), 1.06 (3H, s), 2.73
(2H, brs), 3.51 (1H, d, J = 11Hz), 3.56 (1H, d, J = 11H
z), 4.03-4.21 (2H, m), 4.09 (1H, s), 5.19 (2H, s),
7.23-7.28 (1H, m), 7.33-7.42 (5H, m) Example 1 1-Oleoyl-4- [1-oxo-3- [N- (1-
Oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] piperazine 980 mg of 1-oleoylpiperazine and 3- [N- (2,4-
836 mg of diacetoxy-3,3-dimethyl-1-oxobutyl) amino] propionic acid were dissolved in 10 ml of methylene chloride, and under ice-cooling and stirring, 530 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added. Stir at room temperature for 18 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (900 mg, 51%)
I got

Properties; oil Optical rotation [α] _D; +20.2 DEG _{(C = 1.0, CHCl 3)} IR (cm -1, neat); ν NH 3360, ν CO 1748,1644 Mass spectrometry molecular formula; C ₃₅ H ₆₁ N ₃ O ₇ theoretical 635.4509 found 635.4517 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 1.03 (3H, s),
1.06 (3H, s), 1.23-1.38 (20H, m), 1.58-1.68 (2H,
m), 1.95−2.08 (4H, m), 2.05 (3H, s), 2.11 (3H, s),
2.31 (2H, t, J = 7Hz), 2.42−2.59 (2H, m), 3.35−3.69
(10H, m), 3.83 (1H, d, J = 12Hz), 4.02 (1H, d, J = 12H
z), 4.88 (1H, s), 5.28-5.40 (2H, m), 6.73 (1H, t, J =
6 Hz) Example 2 1-oleoyl-4- [1-oxo-3- [N- (1-
Oxo-2,4-dihydroxy-3,3-dimethylbutyl) amino] propyl] piperazine 1-oleoyl-4- [1-oxo-3- [N- (1
-Oxo-2,4-diacetoxy-3,3-dimethylbutyl)
Amino] propyl] piperazine (635 mg) was dissolved in methanol (5 ml), 1N NaOH aqueous solution (2 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Methylene chloride and water were added to the reaction solution, and the organic layer was separated, washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 482 mg (87%) of the title compound.

Properties; oil rotation [α] _D ; +16.11 (C = 1.0, CHCl ₃ ) IR (cm ⁻¹ , neat); ν _NH , ν _CO 1646 Mass spectrometry Molecular formula; C ₃₁ H ₅₇ N ₃ O ₅ theory Value 605.4767 found 605.4787 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.92 (3H, s),
1.02 (3H, s), 1.22-1.41 (20H, m), 1.57-1.68 (2H,
m), 1.92-2.08 (4H, m), 2.33 (2H, t, J = 7Hz), 2.54 (2
H, brs), 3.12−3.21 (1H, m), 2.59 (2H, t, J = 6Hz), 3.4
1−3.68 (10H, m), 3.99 (1H, s), 5.28−5.40 (2H, m),
7.30-7.39 (1H, m) Example 3 1-Oleoyl-4- [1-oxo-3- [N- (1-
Oxo-2,4-diacetoxy-3,3-dimethylbutyl) amino] propyl] tetrahydro-1,4-diazepine 919 mg of 1-oleoyl homopiperazine and 3- [N-
(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl) amino] propionic acid 755 mg and methylene chloride 10m
1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide (477 mg) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off.The residue was purified by silica gel column chromatography to obtain 930 mg of the title compound.
(57%).

Properties; Oil rotation [α] _D ; + 27.3 ° (C = 1.0, CHCl ₃ ) IR (cm ⁻¹ , neat); ν _NH , ν _CO 1748,1644 Mass spectrometry Molecular formula; C ₃₆ H ₆₃ N ₃ O ₇ theoretical 649.4665 found 649.4652 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 1.02 (3H, s),
1.06 (3H, s), 1.23-1.40 (20H, m), 1.56-1.70 (2H,
m), 1.78-1.91 (2H, m), 1.92-2.06 (4H, m), 2.04 (3
H, s), 2.11 (3H, s), 2.28 (2H, t, J = 7Hz), 2.42-2.56
(2H, m), 3.35-3.76 (1H, m), 3.84 (1H, d, J = 12Hz),
4.03 (1H, d, J = 12Hz), 4.91 (1H, brs), 5.27-5.40 (2
H, m), 6.74-6.83 (1H, m) Example 4 1-Oleoyl-4- [1-oxo-3- [N- (1-
Oxo-2,4-dihydroxy-3,3-dimethylbutyl) amino] propyl] tetrahydro-1,4-diazepine 1-oleoyl-4- [1-oxo-3- [N- (1
-Oxo-2,4-diacetoxy-3,3-dimethylbutyl)
Amino] propyl] tetrahydro-1,4-diazepine 6
49 mg was dissolved in 5 ml of methanol, 2 ml of a 1NNaOH aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. Methylene chloride and water were added to the reaction solution, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 515 mg of the title compound.

Properties; oil rotation [α] _D ; + 14.0 ° (C = 1.0, CHCl ₃ ) IR (cm ⁻¹ , neat); ν _NH , ν _CO 1642 mass spectrometry molecular formula; C ₃₂ H ₅₉ N ₃ O ₅ theory Value 565.4454 found 565.4440 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.92 (3H, s),
1.02 (3H, s), 1.21-1.39 (20H, m), 1.55-1.68 (2H,
m), 1.72-1.88 (2H, m), 1.92-2.08 (4H, m), 2.12-2.
62 (6H, m), 3.25-3.85 (10H, m), 3.96 (1H, brs), 5.28
-5.40 (2H, m), 7.12-7.22 (1H, m) Example 5 1-stearoyl-4- [3- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonylamino ) Propanoyl] piperazine 1- [3- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonylamino) propanoyl] piperazine
326 mg and stearic acid chloride 303 mg with methylene chloride
Dissolved in 20 ml, suspended 106 mg of sodium carbonate and reacted for 2 hours. After filtration of the insolubles, the solvent was distilled off.The residue was subjected to silica gel column chromatography to give the title compound 49.
8 mg (84%) were obtained.

Properties; oil Optical rotation [α] _D; +28.9 DEG _{(C = 1.0, CHCl 3)} IR (cm -1, neat); ν NH 3408, ν CO 1656,1638 Mass spectrometry molecular formula; C ₃₄ H ₆₃ N ₃ O ₅ theoretical 593.4767 found 593.4776 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.96 (3H, s),
1.04 (3H, s), 1.19-1.39 (28H, m), 1.56-1.73 (2H,
m), 2.33 (2H, t, J = 7 Hz), 2.56-2.66 (2H, m) 3.28 (1
H, d, J = 12Hz), 3.39-3.68 (5H, m), 3.37-3.71 (10H,
m), 3.68 (1H, d, J = 12Hz), 4.07 (1H, s), 7.05-7.14
(1H, m) Example 6 1-linoleoyl-4- [3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propanoyl] piperazine 1- [3- [N- (2,2,5,5-tetramethyl-1,3-dioxan-4-carbonyl) amino] propanoyl] piperazine (489 mg) and linoleic acid (421 mg) in methylene chloride (30 ml)
In 1-ethyl-3- (3- (3-hydrochloric acid) under ice-cooling and stirring.
216 mg of dimethylaminotopyr) carbodiimide was added, and the mixture was stirred for 16 hours. Next, the reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography to obtain 496 mg (56%) of the title compound.

Properties; oil rotation [α] _D ; +26.7 ゜ (C = 1.0, CHCl ₃ ) IR (cm ⁻¹ , neat); ν _CO 1646, mass spectrometry Molecular formula; C ₃₄ H ₅₉ N ₃ O ₅ theoretical 589.4454 Found 589.4431 NMR (δ, CDCl ₃ ); 0.89 (3H, t, J = 7 Hz), 0.96 (3H, s),
1.04 (3H, s), 1.22-1.42 (14H, m), 1.98-2.09 (2H,
m), 2.33 (2H, t, J = 7 Hz), 2.52-2.63 (2H, m), 2.77 (2
H, d, J = 12 Hz), 3.28 (1 H, d, J = 12 Hz), 3.36-3.72 (10
H, m), 3.68 (1H, d, J = 12Hz), 4.07 (1H, s), 5.29-5.44
(4H, m), 7.05-7.13 (1H, m) Example 7 1- (8-heptadecenyl) carbamoyl-4- [3-
[N- (2,2,5,5-tetramethyl-1,3-dioxane-4
-Carbonyl) amino] propanoyl] piperazine 489 mg of 1- [3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propanoyl] piperazine is dissolved in 30 ml of methylene chloride, and heptadecane is stirred under ice-cooling and stirring. 419 mg of nyl isocyanate were added. Next, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain 900 mg of the title compound.

Properties; Oil rotation [α] _D ; +27.0 ゜ (C = 1.0, CHCl ₃ ) IR (cm ⁻¹ , neat); ν _CO 1648 Mass spectrometry Molecular formula; C ₃₄ H ₆₂ N ₄ O ₅ Theoretical value 606.4820 Actual measurement Value 606.4719 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.90 (3H, s),
1.04 (3H, s), 1.21-1.38 (20H, m), 1.40-1.57 (2H,
m), 1.42 (3H, s), 1.46 (3H, s), 2.33 (2H, t, J = 7Hz),
1.92−2.04 (4H, m), 2.49−2.65 (2H, m), 3.17−3.73
(14H, m), 4.07 (1H, s), 4.43 (1H, brs), 5.29-5.40
(2H, m), 7.08 (1H, t, J = 6 Hz) Example 8 1- (2-benzylundecanoyl) -4- [3- [N
-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propanoyl] piperazine The reaction was carried out in the same manner as in Example 5 using 2-benzylundecanoyl chloride instead of stearic acid chloride to obtain the title compound.

Properties; oily molecular _{formula; C 34 H 55 N 3 O} 5 Molecular weight: 585.83 Mass spectrometry Calculated 585.4141 Found 585.4130 optical rotation [α] ²⁷ _D; 25.0 ° _{(C = 1.0, CHCl 3)} IR (ν, cm -1) 2928,2860,1648 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.94 (3H, s),
1.03 (3H, s), 1.16-1.35 (14H, m), 1.41 (3H, s), 1.45
(3H, s), 1.49-1.78 (2H, m), 2.24-2.58 (3H, m), 2.7
2−3.93 (14H, m), 4.06 (1H, s), 7.03 (1H, t, J = 5Hz),
7.13-7.29 (5H, m) Example 9 1- (1-benzyldecyl) carbamoyl-4- [3-
[N- (2,2,5,5-tetramethyl-1,3-dioxane-4
-Carbonyl) amino] propanoyl] piperazine 553 mg of 2-benzylundecanoic acid and 550 mg of diphenylphosphorylamide were dissolved in 3 ml of anhydrous toluene, and a solution of 223 mg of triethylamine in 3 ml of anhydrous toluene was added dropwise with stirring at room temperature. The reaction was stirred at 80 ° C. for another 2 hours. After completion of the reaction, the temperature is returned to room temperature, and 1- [1-oxo-3
-[N- (2,2,5,5-tetramethyl-1,3-dioxane-
4-carbonyl) amino] propyl] piperazine 655 mg
Was dissolved in 2 ml of chloroform, and the mixture was stirred at room temperature for 18 hours. The reaction solution was saturated aqueous sodium hydrogen carbonate,
Subsequently, the extract was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to give 599 mg (yield 50 mg) of the title compound.
%).

Properties; oily molecular _{formula; C 34 H 56 N 4 O} 5 Molecular weight: 600.85 Mass spectrometry Calculated 600.4250 Found 600.4244 optical rotation [α] ²⁷ _D; 25.8 ° _{(C = 1.0, CHCl 3)} IR (νneat, cm -1) _{; 2932,2860,1636 NMR (δ, CDCl 3} ); 0.88 (3H, t, J = 7Hz), 0.96 (3H, s),
1.04 (3H, s), 1.17-1.40 (16H, m), 1.42 (3H, s), 1.46
(3H, s), 1.47-2.64 (2H, m), 2.72-2.88 (2H, m), 3.1
5−3.65 (1H, m), 3.28 (1H, d, J = 12Hz), 3.68 (1H, d, J
= 12Hz), 4.07 (1H, s), 4.08-4.17 (1H, m), 7.18 (1H,
t, J = 5 Hz), 7.12-7.33 (5H, m) Example 10 1- (2-methyllauroyl) -4- [3- [N- (2,
2,5,5-tetramethyl-1,3-dioxane) amino] propanoyl] piperazine The title compound was obtained by reacting in the same manner as in Example 5 except that 2-methyllauroyl chloride was used instead of stearic acid chloride.

Properties; oily molecular _{formula; C 29 H 55 N 3 O} 5 Molecular weight: 523.76 Mass spectrometry Calculated 523.3985 Found 523.3974 optical rotation [α] ²⁷ _D; 30.3 ° _{(C = 1.0, CHCl 3)} IR (νneat, cm -1) 2928,2860,1646 NMR (δ, CDCl ₃ ); 0.88 (3H, t, J = 7 Hz), 0.96 (3H, s),
1.04 (3H, s), 1.11 (3H, d, J = 7Hz), 1.15-1.34 (16H,
m), 1.42 (3H, s), 1.46 (3H, s), 1.54-1.62 (2H, m),
2.54-2.72 (3H, m), 3.28 (1H, d, J = 12Hz), 3.38-3.70
(10H, m), 3.68 (1H, d, J = 12Hz), 4.07 (1H, s), 7.15-
7.23 (1H, m) Example 11 1- (1-decylcyclobutanecarbonyl) -4- [3
-[N- (2,2,5,5-tetramethyl-1,3-dioxane-
4-carbonyl) amino] propanoyl] piperidine The same procedure as in Example 5 was carried out except that 2-decylcyclobutanecarbonyl chloride was used instead of stearic acid chloride, to obtain the title compound.

Properties; oily molecular _{formula; C 31 H 55 N 3 O} 5 Molecular weight: 549.80 Mass spectrometry Calculated 549.4141 Found 549.4119 optical rotation [α] ²⁷ _D; 29.6 ° _{(C = 1.0, CHCl 3)} IR (νneat, cm -1) _{; 2932,2860,1642 NMR (δ, CDCl 3} ); 0.88 (3H, t, J = 7Hz), 0.96 (3H, s),
1.04 (3H, s), 1.16-1.35 (16H, m), 1.42 (3H, s), 1.46
(3H, s), 1.68-1.98 (6H, m), 2.42-2.60 (4H, m), 3.2
6−3.68 (10H, m), 3.28 (1H, d, J = 12Hz), 3.68 (1H, d, J
= 12Hz), 4.07 (1H, s), 7.08 (1H, t, J = 5Hz)

Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/495 A61K 31/495 31/551 31/55 601 (72) Inventor Jun Kusunoki 4-6-7 Shimochiai, Shinjuku-ku, Tokyo Fuji (56) References JP-A-61-151190 (JP, A) JP-A-3-218340 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 243 / 08 C07D 295/18 C07D 319/06 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a protecting group for a hydroxyl group; R ³ is substituted with a saturated or unsaturated and optionally linear, branched or cyclic aromatic group It may be C ₅ -C ₂₅
Monovalent represents an aliphatic hydrocarbon group or a group -NH-R ^4, wherein, R ⁴ is and linear saturated or unsaturated, optionally substituted by branched or cyclic optionally aromatic group
C ₅ -C represents the ₂₅ monovalent aliphatic hydrocarbon group, m is 2 or 3; n is an integer of 1 to 4, in the compounds represented.