JPH02179A - Saturated heterocyclic carboxylic acid amide derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 5-6-membered heterocyclic group which may be condensed with benzene ring; R<2> is H, alkyl or R<1>; X<1> is O, S or CH2; Y<1> is O, S or NR<4> (R<4> is H, alkyl or carboxy); A<1> is methylene or ethylene; R<3> is NR<5>R<6>, group of formula II, formula III (one of R<5> and R<6> is H or hydrocarbon group and the other is hydrocarbon group or R<1>; A<2> and A<3> are alkylene; Z is CH or N; R<7> is H, hydrocarbon group, carboxy, acyl, carbamoyl, etc.), etc.] or its salt. EXAMPLE:[N-tert-butoxycarbonyl-2-(3-pyridyl) thiazolidine-4-carbo-nyl]-L-methio- nine methyl ester. USE:A drug composition having antagonistic action against platelet activating factor. PREPARATION:The compound of formula I can be produced by reacting a compound of formula IV [R<12>, R<13> and Y<2> are (protected) R<1>, R<2> and Y<1>) with a compound of formula H-R<14> [R<14> is (protected) R<3>] and, as necessary, removing the protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel saturated heterocyclic carboxylic acid amide derivative having platelet activating factor (PAF) antagonistic activity and a salt thereof.

(Prior Art) PAF is a chemical substance released from human and animal cells, and is acetylglyceryl ether of phosphorylcholine represented by the following formula.

(In the formula, t means 15 or 17.) PAF has physiological activities such as contraction of airway smooth muscle, enhancement of vascular permeability, aggregation of platelets, and lowering of blood pressure. It is thought to be a factor that causes various symptoms such as shock. Therefore.

Research into substances that antagonize the physiological activity of PAF is underway, and several anti-PAF drugs have been reported (for example, JP-A-61-93191, JP-A-60-11667).
No. 9, JP-A-60-142932, JP-A-59-13
No. 4798, JP-A-61-87684, JP-A-61
-37726).

The present inventors completed the present invention by recognizing the excellent anti-PAF activity of a novel saturated heterocyclic carboxylic acid amide derivative having a chemical structure different from that of conventional anti-PAF drugs.

(Means for Solving the Problems) The saturated heterocyclic carboxylic acid amide derivative of the present invention is represented by the following general formula (I).

(The symbols in the formula have the following meanings.

R1: a substituted or unsubstituted 5- to 6-membered heterocyclic group which may be fused with a benzene ring.

R2: hydrogen atom, lower alkyl group, or the same group as R1.

X'=methylene group optionally substituted with oxygen atom, sulfur atom, or lower alkyl group.

YI: an oxygen atom, a sulfur atom, or a group represented by the formula)NR'.

A1: Methylene group or ethylene group each optionally substituted with a lower alkyl group.

R4: hydrogen atom, lower alkyl group, carboxy group, lower alkoxycarbonyl group, acyl group.

R5 and R6: one is a hydrogen atom or a substituted or unsubstituted hydrocarbon group, the other is a substituted or unsubstituted hydrocarbon group, or a 5- to 6-membered heterocyclic group to which a benzene ring may be fused.

A2 and A3: Same or different substituted/substituted or unsubstituted lower alkylene groups.

Z: methine group (>CH-), or nitrogen atom R7: hydrogen atom, substituted or unsubstituted hydrocarbon group, carboxy group,
Lower alkoxycarbonyl group, acyl group, carno (moyl group).

or a mono- or di-lower alkyl aminocarbonyl group.

R8, RQ, Rlo and R11: Same or different, hydrogen atom.

A lower alkyl group, an aralkyl group, or an aryl group. ) The chemical structural feature of the compound of the present invention is that it is a saturated heterocyclic carboxylic acid amide derivative in which a specific position of a specific saturated heterocycle is necessarily substituted with a specific heterocycle and a specific carboxamide. . That is, the compound represented by Formula 1 (I) Ro: Alkyl group having 2 to 17 carbon atoms R2: Carboxyl group or its ester or amide has a stone-removing action.

In U.S. Pat. No. 3,592,905, a specific position of a saturated heterocycle, i.e., a 5- or 6-membered saturated heterocycle, may be fused with a specific heterocycle, i.e., a 5- or 6-membered benzene ring represented by R1. It has a chemical structural feature in that the -tero ring and the specific amine group represented by -COR' are always substituted with a substituted carboxamide.

Various compounds have been known as saturated heterocyclic carboxylic acid amide derivatives such as the compound (I) of the present invention.

For example, Rooster German patent 2729414 has formula %formula%) The compound represented by has an anti-inflammatory effect.

Although each of them has been disclosed, a compound having the above-mentioned chemical structural characteristics has not been specifically known.

A more detailed explanation of the compound of the present invention is as follows.

In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, the "lower alkyl group" specifically includes, for example, a methyl group, an ethyl group, and a propyl group.

Isopropyl group, butyl group, isobutyl group, 5ee-
Butyl group, tert-butyl group, pentyl (amyl) group, impentyl group, neopentyl group, tert
-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group.

2-methylpentyl group, 3-methylpentyl group.

1.1-dimethylbutyl group, 1.2-dimethylbutyl group, 2.2-dimethylbutyl group, 1.3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group,
1,1.2-) IJ methylpropyl group.

1.2.2-)! J Methylglobil group, 1-ethyl-1
-methylpropyl group, 1-ethyl-2-methylpropyl group, etc.

Moreover, "mono- or di-lower alkylaminocarbonyl group" means a group in which the amine group of a carbamoyl group is mono- or di-substituted with the above-mentioned "lower alkyl group". Therefore, specifically, for example.

Methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, inbutylaminocarbonyl group.

Be/thylaminocarbonyl group, impentylaminocarbonyl group, hexylaminocarbonyl group, inhexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, dibutylaminocarbonyl group group, dibentylaminocarbonyl group, dihexylaminocarbonyl group, ethylmethylaminocarbonyl group, methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, ethylisopropylaminocarbonyl group, butylmethylaminocarbonyl group, butylpropylaminocarbonyl group etc.

In the present invention, the term "hydrocarbon group" refers to a monovalent group obtained by removing one hydrogen atom from a hydrocarbon molecule, which is a general term for compounds consisting only of carbon and hydrogen. Suitable examples thereof include saturated carbonized chloroalkyl groups, aromatic monocyclic and polycyclic hydrocarbon aralkyl groups, and aralkenyl groups.

Here, the "alkyl group" is preferably a straight chain or branched one having 1 to 20 carbon atoms, and specifically, in addition to the specific examples of the "lower alkyl group" above, it further includes a heptyl group, 5
-Methylhexyl group.

Octyl group, 6-methylheptyl group, nonyl group.

7-methyloctyl group, decyl group, 8-methylnonyl group, undecyl group, 9-methyldecyl group.

dodecyl group, 10-methylcundecyl group, tridecyl group, 11-methyldodecyl group, tetradecyl group,
12-methyltridecyl group, pentadecyl group, 1
3-methyltetradecyl group, hexadecyl group, 14-
Examples include methylpentadecyl group, heptadecyl group, 15-methylhexadecyl group, octadecyl group, 16-methylheptadecyl group, nonadecyl group, 17-methyloctadecyl group, eicosyl group, and 18-methylnonadecyl group.

The "cycloalkyl group" preferably has 3 to 7 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

Preferred examples of the "aryl group" include phenyl and naphthyl groups.

The "aralkyl group" is preferably a group in which any hydrogen atom of the "lower alkyl group" is substituted with the "aryl group", and specifically, a benzyl group, a phenethyl group, a 1-
Phenylethyl group.

3-phenylpropyl group, 2-phenylpropyl group, 1
-phenylpropyl group, 1-mef-2-phenylethyl group, 4-phenylbutyl group.

3-phenylbutyl group, 2-phenylbutyl group.

1-phenylbutyl group, 2-methyl-3-7enylpropyl group, 2-methyl-2-phenylpropyl group, 2-methyl-1-phenylpropyl group, 1-methyl-3-phenylpropyl group, 1-methyl -2-phenylpropyl group, 1-methyl-1-7enylpropyl group, 1-ethyl-
2-phenylethyl group, 1.1-dimethyl-2-phenyl ether group, 5-72dylpentyl group, 4-phenylpentyl group, 3-phenyl/thyl group, 2-phenylpentyl group, 1: l;'z Nylpentyl group, 3-methyl-4
-phenylbutyl group.

3-methyl-3-phenylbutyl group, 3-methyl-2-
phenylbutyl a, 3-mef-1-phenyl phthyl group, 6-phenylhexyl group.

5-phenylhexyl group, 4-phenylhexyl group, 3
-phenylhexyl group, 2-7enylhexyl group, l-
Phenylhexyl group, 4-methyl-5-phenylpentyl group, 4-methyl-4-phenylpentyl group, 4-methyl-3-phenylpentyl group, 4-methyl-2-phenylpentyl group, 4-methyl-1- phenylpentyl group,
1-naphthylmethyl group, 2-naphthylmethyl group, 2-(
1-naphthyl)ethyl group, 2-(2-naphthyl)ethyl group, 1-(1-naphthyl)ethyl, M, 1-(2-naphthyl)ethyl group.

3-(1-naphthyl)propyl group, 3-(2-naphthyl)propyl group, 2-(1-naphthyl)propyl group, 2-
(2-naphthyl)propyl group.

1-(1-naphthyl)propyl group, 1-(2-naphthyl)propyl group, 1-methyl-2-(1-naphthyl)ethyl group, 1-methyl-2-(2-naphthyl)ethyl group, 4
-(1-naphthyl)butyl group, 4-(2-naphthyl)butyl group, 3-(1-naphthyl)butyl group, 3-(2-naphthyl)butyl group, 2-(1-naphthyl)butyl group, 2
-(2-naphthyl)butyl group, 1-(1-naphthyl)butyl group, 1-(2-naphthyl)butyl group, 2-methyl-
3-(1-naphthyl)propyl group, 2-methyl-3-(
2-naphthyl)propyl group, 2-methyl-2-(1-naphthyl)propyl group, 2-methyl-2-(2-naphthyl)propyl group, 2-methyl-1-(1-+butyl)propyl group, 2-methyl-1-(2-naphthyl)propyl group, 5-(1-naphthyl)pentyl group.

5-(2-naphthyl)pentyl group, 4-(1-naphthyl)pentyl group, 4-(2-naphthyl)pentyl group, 3-
Methyl-4-(1-naphthyl)butyl group, 3-methyl-
4-(2-naphthyl)butyl group, 6-(1-naphthyl/I
/) Hexyl group.

6-(2-su7tyl)hexyl group, 5-(1-su7tyl)hexyl group, 5-(2-naphthyl)hexyl group, 4-
Examples thereof include methyl-5-(1-naphthyl)pentyl group, 4-methyl-5-(2-su7tyl)pentyl group, diphenylmethyl group (pensethyl group), and trityl group.

``r-aralkenyl group'' is one in which the above-mentioned ``aryl group'' is bonded to a lower alkenyl group.

Specifically, for example, 2-7 2-22-ethenyl group.

3-7 x nyl-1-furobenyl group, 3-722-2
-Flobenyl group, 1-methyl-2-phenyl-1-butenyl group, 4-phenyl-2-phthynyl group, 4-phenyl-3-ph2/14.5 phenyl-1-pentenyl group,
5-phenyl-2-pentenyl group, 5-phenyl-3-
pentenyl group, 5-7enyl-4-pentenyl group.

6-phenyl-1-hexenyl group, 6-7 euru 2-
hexenyl group, 6-phenyl-3-hexenyl group, 6-
Phenyl-4-hexenyl group.

6-phenyl-5-hexenyl group, 2-(1-naphthyl)ethynyl group, 2-(2-naphthyl)ethynyl group, 3-
(1-naphthyl)-2-7'robenyl group, 3-(2-naphthyl)-2-globeni/14.4-(1-naphthyl)
-3-phnyl group, 4-(2-su7tyl)-3-butenyl group.

5-(1-naphthyl)-2-pentenyl group, 5(2-naphthyl)-2-pentenyl group, 5-(1-naphthyl)-
4-pentenyl group, 5-(2-naphthyl)-4-pentenyl group, 6-(1-naphthyl)-2-hexenyl group, 6-(2-naphthyl)-2-hexenyl group, 6-(1
-naphthyl)-5-hexenyl group, 6-(2-naphthyl)-5-hexenyl group, and the like.

The "non-aromatic condensed polycyclic hydrocarbon group" specifically refers to an indenyl group (C), however, the bond may be bonded to either a benzene ring or a saturated ring.

(Hereinafter, similar bonds have the same meaning), indenyl group, specifically pyrrolyl group, pyrrolinyl group, pyrrolidinyl group, imidazolyl group, imigzolinyl group, imidazolidinyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, triazolyl group , tetrazolyl group, indolyl group, benzimidazolyl group, indazolyl group, pyridyl group.

Dihydropyridyl group, tetrahydropyridyl group.

-1-cyclohebutenyl group (Ge-), fluorenyl group (()乎≧e-,), 2.3-dihydro-IH-benz[f]indenyl group ((EζB)L H-hair, <
[r] Indenyl group 3. ．． ) and other fused polycyclic hydrocarbon groups that are not included in aromatic hydrocarbon groups.

In the compound of the present invention, when R2, R5 or R6 is the same group as R1 or R1, the "5- or 6-membered heterocyclic group which may be fused with a benzene ring" is:

Saturated or unsaturated heterocyclic groups containing oxygen, sulfur, and/or nitrogen atoms are preferred.

Quinazolinyl group, quinoxalinyl group, phthalazinyl group 7
cinnolinyl group, monocyclic or bicyclic saturated or unsaturated heterocyclic group containing only nitrogen atoms, thiazolyl group,
Monocyclic or bicyclic saturated or unsaturated heterocyclic groups containing nitrogen atoms and sulfur atoms, such as thiazolinyl group, thiazolidinyl group, isothiazolyl group, thiadiazolyl group, benzothiazolyl group, benzisothiazolyl group, oxacyl group, oxazolinyl group Containing monocyclic or bicyclic saturated or unsaturated heterocyclic groups containing nitrogen atoms and oxygen atoms such as , oxazolidinyl group, inoxasilyl group, oxadiazolyl group, benzoxasilyl group, penzisoxazolyl group, etc. In addition to nitrogen heterocyclic groups, money-making heterocyclic groups such as thienyl group and tetrahydrothienyl group, furyl group, tetrahydrofuryl group, pyranyl group, tetradropyranyl group, dioxylyl group, benzofuryl group, benzopyranyl group, benzodioxoline Examples include oxygen-containing heterocyclic groups such as groups.

These heterocyclic groups may have a bond on either a ring carbon atom or a ring nitrogen atom, or on a heterocycle or benzene ring.

The "lower alkylene group" represented by A2 or A3 is preferably a linear alkylene group having 1 to 3 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, and a trimethylene group.

Furthermore, the "acyl group" is particularly a formyl group.

Acetyl group, propionyl group, butyryl group, inbutyryl group, valeryl group, invaleryl group.

Lower alkameyl groups such as hivaloyl group and hexanoyl group, benzylcarbonyl group, 3-phenylpropanoyl group, 2-phenylpropanoyl group, 1-7enylpropanoyl group, 4-phenylbutanoyl group, 3-phenylbutanoyl group Base.

2-phenylbutanoyl group, 1-7enylbutanoyl group, 2-methyl-3-7enylprobanoyl group, 5-7enylpentanoyl group, 4-7enylpentanoyl group, 3-
Phenylpentanoyl group, 2-phenylpentanoyl group, 1-phenylpentanoyl group, 3-methyl-4-phenylbutanoyl group, 3-methyl-2-phenylphtanoyl group, 6-7enylhexanoyl group, 5 Phenylhexanoyl group, 4-7enylhexanoyl group, 3-phenylhexanoyl group, 2-phenylhexanoyl group, 1-phenylhexanoyl group, 4-methyl-5-phenylpentanoyl group, 4-methyl-3 -7enylhexanoyl group, aralkayl group such as 4-methyl-2-phenylhexanoyl group, benzoyl group, 1-naphthoyl group, 2-naphthoyl group and (I, m, or p) toluoyl group, (
o, m or tt-p)-fluorobenzoyl group.

Substituted or unsubstituted arylcarbonyl groups such as (o, m or p)-chlorobenzoyl group, (0゜m or p)-bromobenzoyl group, various fluoronaphthoyl groups, various chloronaphthoyl groups, various bromonaphthoyl groups, etc. are preferred.

Examples of the "lower alkoxycarbonyl group" include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, impropoxycarbonyl group, butoxycarbonyl group, imbutoxycarbonyl group, 5ec-butoxycarbonyl group, tert 7')oxycarbonyl group, pentyl group oxycarbonyl group, 3-methylbutoxycarbonyl group, hexyloxycarbonyl f, 4
-methylpentyloxycarbonyl group and the like.

The "aralkyl group" or "aryl group" of R8 to R1+ is preferably a group exemplified by the aralkyl group or aryl group shown in the above-mentioned hydrocarbon group.

The above-mentioned "hydrocarbon group" and "5- to 6-membered beterocyclic group which may be fused with a benzene ring" are.

R5, R6 and R7 as well as R1 and R2 may further have substituents (・These substituents are)・Rogen atom, lower alkyl group, hydroxyl group (hydroxyl group, mercapto group, alkoxy group, lower Alkylthio group, cycloalkyl lower alkoxy group.

Cycloalkyl lower alkylthio group, aralkyloxy group, aralkylthio group, aryloxy group.

Arylthio group, aryloxy lower alkoxy group, aryloxy lower alkylthio group, arylthio lower alkoxy group, arylthio lower alkylthio group), oxo group (oxo group).

thioxo group), carboxy group (carboxy group).

(lower alkoxycarbonyl group, acyl group), cyan group,
Carbamoyl group (carbamoyl group, mono- or di-lower alkylaminocarbonyl group).

Nitrogen-containing hetero group, amino group (amino group, mono- or di-lower alkylamino group, mono- or dialkylamino group, N-aralkyl-grade alkylamino group) and R5 and R6 Selected from cyclic groups.

Here, the "halogen atom" is preferably a fluorine atom, a chlorine atom, or a bromine atom. "Lower alkyl group" means the above-mentioned group.

The "alkoxy group" is preferably a linear or branched one having 1 to 10 carbon atoms, and specifically includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutoxy group.

5ec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, impentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1- Ethylpropoxy group.

hexyloxy group, heptyloxy group, 5-methylhexyloxy group, octyloxy group, 6-methylhebutyloxy group, nonyloxy group.

7-methyloctyloxy group, decyloxy group.

Examples include 8-methylnonyloxy group.

In addition, "lower alkoxy group" refers to the above "alkoxy group"
Among these, those having 1 to 6 carbon atoms are mentioned.

A "lower alkylthio group" is one in which the oxygen atom of the above "lower alkoxy group" has become a sulfur atom, and specifically, a methylthio group, an ethylthio group, a propylthio group,
Isopropylthio group.

butylthio group, 5ec-butylthio group, ter
Examples include t-butylthio group, pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylglobylthio group, 1-ethylpropylthio group, and hexylthio group.

As a "cycloalkyl lower alkoxy group" or "cycloalkyl lower alkylthio group".

It means a group in which any hydrogen atom of the above "lower alkoxy group" or "lower alkylthio group" is substituted with the above "cycloalkyl group", specifically, for example, a cyclopropyl-methoxy (or methylthio) group (cyclopropyl -Meaning of methoxy group or cyclopropyl-methylthio group (the same applies hereinafter).

2-cyclopropyl-ethoxy (also haethylthio) group,
1-cyclopropyl-ethoxy (or ethylthio) group,
3-cycloprobyl-proboxy (or propylthio)
group, 2-cyclopropyl-proboxy (or propylthio) group, 1-cyclopropyl-proboxy (or propylthio) group, 2-cyclopropyl-1-methyl-ethoxy (or ethylthio) group, 4-cyclopropyl-butoxy (or butylthio) group, 5-cyclopropylbenthyloxy (or thio) group, 6-cyclobrobylhexyloxy (or thio) group, cyclobutyl-methoxy (or methylthio) group, 2-cyclobutyl-ethoxy (or ethylthio) group, ) group, 1-cyclobutyl-ethoxy (or ethylthio) group, 3-cyclobutyl-propoxy (or propylthio) group, 2-cyclobutylzuloboxy (or propylthio) group.

1-Cyclobutyl-1-methyl-ethoxy (or ethylthio) group, 4-cyclobutyl-butoxy (or butylthio) group, 5-cyclobutylbenthyloxy (or thio) group, 6-cyclobutylhexyloxy (or thio) group
group, cyclopentyl-methoxy (or methylthio) group,
2-cyclopentyl-ethoxy (or ethylthio) group,
l-cyclopentyl-ethoxy (or ethylthio) group,
3-cyclopentyl-propoxy (or propylthio)
group, 2-cyclopentyl-propoxy (or propylthio) group, 1-cyclopentyl-propoxy (or propylthio) group, 2-cyclopentyl-1-methyl-ethoxy (also haethylthio) group, 4-cyclopentyl-butoxy (or butylthio) group, 5-cyclopentylpentyloxy (or thio) group, 6-cyclopentylhexyl-oxy (or hathio) group, cyclohexyl-methoxy (or methylthio) group, 2-cyclohexyl-ethoxy (or ethylthio) group, 1-cyclohexyl-ethoxy ( Also, ethylthio) group, 3-cyclohexyl-propoxy (or propylthio) group, 2-cyclohexyl-propoxy (or propylthio) group, 1-cyclohexyl-
Propoxy (or propylthio) group, 2-cyclohexyl-1-methyl-ethoxy (or ethylthio) group, 4-
Cyclohexyl-butoxy (or butylthio) group.

5-cyclohexylbenzenyloxy (also hachio) group,
6-cyclohexylhexyloxy (or thio) group,
cycloheptyl-methoxy (or methylthio) group, 2-
cycloheptyl-ethoxy (or ethylthio) group, 1-
cycloheptyl-ethoxy (or ethylthio) group, 3-
cycloheptyl-propoxy (or propylthio) group,
2-cycloheptylpropoxy (or propylthio)
group, 1-cyclohebutyl-propoxy (or propylthio) group, 2-cycloheptyl-1-methyl-ethoxy (
or ethylthio) group, 4-cyclohebutyl-butoxy (
or butylthio) group, 5-cycloheptylpentyloxy (or thio) group, 6-cyclohebutylhexyloxy (or thio) group, and the like.

"Aralkyloxy group" and "aralkylthio group" mean a group in which any hydrogen atom of the above "lower alkoxy group" or "lower alkylthio group" is substituted with the above "IJ-R group", and specifically Specifically, examples of "aryl groups" include phenyl groups, such as benzyl-oxy (or thio) groups.

phenethyl-oxy (or thio) group, 1-7 enyl-ethoxy (or ethylthio) group, 3-7 enyl-propoxy (or propylthio) group.

2-7 enylpropoxy (or propylthio) group, 1
-phenyl-propoxy (or propylthio) group, 2-
Phenyl-1-methyl-ethoxy (or ethylthio) group, 4-phenyl-butoxy (or butylthio) group, 5-
These include phenylbenzenyloxy (or thio) group, 6-phenylhexyloxy (or thio) group, and the like.

Specifically, the "aryloxy group" and "arylthio" group are derived from aromatic monocyclic or polycyclic hydrocarbon hydroxy or mercapto compounds such as phenoxy (or phenylthio) group and naphthyl-oxy (or thio) group. Examples include ether or thioether residues.

"Aryloxy lower alkoxy group", "aryloxy lower alkylthio group", "arylthio lower alkoxy group" or "arylthio lower alkylthio group" means that the above-mentioned "lower alkoxy group" or "lower alkylthio group" has any hydrogen atom attached to it. It means a group substituted with an "aryloxy group" or "arylthio group", and if only a phenoxy (or phenylthio) group is used as an example of an "aryloxy group" or "arylthio group", phenoxy (or phenylthio)-methoxy (or methylthio) group, 2-phenoxy (or phenylthio)-ethoxy (or ethylthio) group, 1-phenoxy (or phenylthio)-ethoxy (or ethylthio) group, 3-phenoxy (or phenylthio)-propoxy (or propylthio) group, 2 -phenoxy (or phenylthio) -propoxy (or propylthio) group, 1-phenoxy (or phenylthio) -propoxy (or propylthio) group, 2-phenoxy (or)
(enylthio)-1-methyl-ethoxy (or ethylthio) group, 4-phenoxy (or phenylthio)-butoxy (or butylthio) group, 5-phenoxy (or phenylthio) pentyl-oxy (or thio) group, 6-phenoxy ( or phenylthio)hexyl-oxy(or thio)
These are the basics.

Specific substituents for the "acyl group" and "mono- or di-lower alkylaminocarbonyl group" include the same groups as mentioned above.

[Mono- or di-lower alkylamino group].

It means a group in which one or two hydrogen atoms of an amine group are substituted with the above-mentioned "lower alkyl group". Specifically, methylamine group, ethylamino group, propylamine group, isopropylamino' group, butylamino group, inbutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, etc. Number of carbon atoms is 1 to 6
A monoalkylamino group or a dimethylamino group substituted with straight-chain or branched alkyl groups.

diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dibentylamino group,
A symmetric dialkylamino group, an ethylmethylamino group, a methylpropylamino group di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, such as a dihexylamino group.

An asymmetric type di-substituted with a different alkyl group among linear or branched alkyl groups having 1 to 6 carbon atoms such as ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropylamino group, etc. A dialkylamino group is mentioned.

The "mono- or dialkylamino group" includes a benzylamino group and a phenethyl amino group.

3; 7z nylpropylamine/group, 4-phenylbutylamino group, 5-phenylpentylamino group, 6-phenylhexylamine group, 1-naphthylmethylamino group, 2-
naphthylmethylamino group, 1-naphthylethylamino group, 2-naphthylethylamino group, 1-naphthylpropylamino group, 2-naphthylglopylamino group, 1-naphthylbutylamino group, 2-naphthylbutylamino group, diphenylmethyl Amino group, 2.2-diphenylethylamino group, 3.3-diphenylpropylamino group, 4.4-
Monoaralkyl amino groups such as diphenylbutylamino groups and triphenylmethylamine groups, dibenzylamino groups,
Diphenethylamino group, bis(3-phenylpropyl)
Amine group, bis(4-phenylbutyl)amine group, bis(5-phenylpentyl)amine group, symmetric dialkylamino group such as bis(6-phenylhexyl)amine group, N-benzylphenethylamino group, N- benzyl
3-phenylbropylamine group, N-benzyl-4-phenylbutylamino group, N-benzyl-5-phenylpentylamino group, N-benzyl-6-phenylhexylamine group, N-7enethyl-3- Phenylpropylamino group, N-phenethyl-4-phenylbutylamino group,
N-phenethyl-5-phenylpentylamino M,
N-phenethyl-6-phenylhexylamine group.

N-(3-7enylpropyl)-4-phenylbutylamino group, N-(3-phenylpropyl)-5-phenylpentylamino group, N-(3-7enylpropyl)-6
-Phenylhexylamine group, N-(4-phenylbutyl)-5-phenylpentylamino group, N-(4-phenylbutyl)-6-7enylhexylamino group, N-(
Examples include asymmetric dialkylamino groups such as 5-phenylpentyl)-67xnylhexylamino groups.

"N-aralkyl-N-lower alkyl group" is.

Refers to an amine group obtained by substituting the amine group of the above-mentioned "monoaralkylamino group" with the above-mentioned "lower alkyl group" to tertiaryize it, and includes N-methylbenzylamino group, N-ethylbenzylamino group, N-propylbenzylamino group. group, N-butylbenzylamino group, N-pentylbenzylamino group, N
-hexylbenzylamino group, N-methylphenethylamino group, N-ethylphenethylamino group.

N-propylphenethylamino group, N-butylphenethylamino group, N-pentylphenethylamino group, N-hexylphenethylamino group.

N-methyl-3-7enylpropylamino group.

N-ethyl-3-phenylpropylamine group.

N-propyl-3-7enylpropylamino group.

N-butyl-3-7enylpropylamino group.

N-pentyl-3-phenylpropylamine group.

N-hexyl-3-phenylpropylamine group.

N-methyl-4-phenylbutylamino group, N-ethyl-4-7enylbutylamino group, N-propyl-4-phenylbutylamino group, N-butyl-4-phenylbutylamino group, N-hentyl-4 Typical specific groups include -7enylbutylamino group and N-hexyl-4-phenylbutylamino group.

"Nitrogen-containing, terocyclic group" as a substituent for R5 and R6
contains a nitrogen atom as a hetero atom, may also contain a sulfur shoji or an oxygen atom, and may be fused with a benzene ring. It means a saturated or unsaturated 5- to 6-membered heterocyclic group, specifically a 5- to 6-membered heterocyclic group that may have a benzene ring fused thereto, and has at least one nitrogen atom. Examples include heterocyclic groups.

Regarding the bonds of these heterocycles, as above, either the ring carbon atom or the ring nitrogen atom.

Further, it may be bonded to either a hetero ring or a benzene ring.

In addition, as substituents that Am and A3 may have,
Lower alkyl groups, aralkyl groups and aryl groups are preferred, and specifically, the groups exemplified in the above-mentioned "lower alkyl groups" and the aral, kyl and aryl groups among the "hydrocarbon groups". The exemplified groups are suitable.

Compound (I) of the present invention forms a salt. The present invention includes salts of compound (I). Examples of such salts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, as well as acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apple acid. acid, acid addition salts with organic acids such as fumaric acid, tartaric acid, picric acid, methanesulfonic acid, and ethanesulfonic acid, salts with acidic amino acids such as glutamic acid and aspartic acid, and methyl chloride.

Examples include quaternary ammonium salts formed by bonding with alkyl halides such as methyl bromide and methyl iodide.

Furthermore, the compound (I) provided by the present invention has at least two or more asymmetric carbon atoms, and isomers exist based on the presence of the asymmetric carbon atoms.

Further, a compound in which a hydroxyl group or a mercapto group is bonded to a heterocycle and a compound in which an oxo group or a thioxo group is bonded may be a keto-enol type tautomer.

The present invention includes each of these separated isomers and mixtures thereof.

(Production method) The compound (I) of the present invention can be produced by applying various synthetic methods using the characteristics of the basic skeleton and various substituents. Typical manufacturing methods are illustrated below.

1st production method (amidation A) 3rd production method (amidation C) (TI) (nT) or its reactive derivative (V) or its reactive derivative (Vl) 2nd production method (amidation B) 4th production method ( N-acylation A) QV) (■) (■) or its reactive derivative (b) (■c) No. 518! Process (N-acylation B) (IX) (X) or its reactive derivative (rd) Sixth production process (N-acylation C) αD αD or its reactive derivative (Ie) Ninth production process (ether or thioetherification C) (X%) (XIX) 10th production method (cyclization) (XX) (xlxI) (Ii) 7th production method (ether or thioetherification A) (X[V
) (XV) Eighth production method (ether or thioetherification B) (X%'I
) (8'II) (Ig) Eleventh production method (N-alkylation A) Twelfth production method (N-alkylation B) < xxrv ) (3) Removal of protecting group if necessary (Ik) Thirteenth production method (N- Alkylation C) No. 15! Method A (N-alkylation E) ○■■) ○■■) (Xα■ 14th production method (N-alkylation D) 16th production method (XXIX) (XXX) (XXXIV) (XXXV) 17th production method (reduction ) (In the reaction formula, Rゝ, R2, R3, R', R', X
', A', Y' and Z have the above meanings, and other symbols have the following meanings.

R12: The same group as R1 which may have a protecting group.

R13: The same group as R2 which may have a protecting group.

Y2: The same group as yl which may have a protecting group.

R14: The same group as R3 which may have a protecting group.

R15: The same group as R5 which may have a protecting group.

A4: Hydrocarbon divalent group.

R16 and R1? : Same or different, hydrogen atom or lower alkyl group.

R18 A residue obtained by removing the carbonyl group from the nearacyl group.

@5- to 6-membered nitrogen-containing heterocyclic group which may be fused with a non-tertiary benzene ring.

R19: a hydrogen atom, a lower alkyl group, or a group represented by formula H-0.

R20: The same group as R1 which may have a protecting group.

R2' = the same group as R2 which may have a protecting group.

Y3: The same group as Yl which may have a protecting group.

R22 = the same group as R5 which may have a protecting group.

As: the same group or formula as A4 -A4 X2 A
A divalent group represented by S-.

X2: oxygen atom or sulfur atom.

H6: Lower alkylene group.

One of Dl and D2 is a hydroxyl group, a mercapto group, or an alkali metal substituted product thereof, and the other is a halogen atom or an organic sulfonic acid residue.

R23: an alkyl group having 1 to 10 carbon atoms, a cycloalkyl lower alkyl group, an aralkyl group.

An aryl group or an aryloxy lower alkyl 6-membered heterocyclic divalent group, or a group represented by the formula -A6X2-Aδ-.

A8 = 5- to 6-membered heterocyclic divalent group which may be fused with a benzene ring.

R24: The same group as R3 which may have a protecting group.

X4: oxygen atom or sulfur atom Y4=oxygen atom, sulfur atom or imino group (-NH-).

D3: halogen atom or organic sulfonic acid residue.

R25: lower alkyl group, lower alkoxycarbonyl group, or acyl group.

One of D4 and D5 may have a protecting group - an amine group, and the other a halogen atom or an organic sulfonic acid residue.

A lower alkyl group or a group which is the same as or different from 52, .

R31: hydrogen atom, lower alkyl group, aralkyl group, or aryl group.

X5: an oxygen atom, a sulfur atom, a methylene group which may have a lower alkyl group as a substituent, or a methine group which may have a lower alkyl group as a substituent.

When , it is a hydrogen atom or a lower alkyl group.

or an aralkyl group When p5 is a halogen atom or an organic sulfonic acid residue, it is a lower alkyl group or an aralkyl group, or potassium phthalic acid imide (provided that D5-R'' is combined with potassium phthalate).

D4 is a halogen atom or an organic sulfonic acid residue).

...Bond in either side is a double bond. ) Here, the protecting group is a protecting group for an amine group.

Carboxy group protecting group, mercapto group protecting group.

Examples of protecting groups for amine groups include bersyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-methylbenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, and p-nitrobenzyloxy group. Carbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazopenzyloxine carbonyl 75. 3.5-dimethoxybenzyloxycarbonyl group, 3,4.5-trimethoxybenzyloxycarbonyl group.

Urethane-type protecting groups such as tert-butoxycarginyl group, tert-amyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group.

Formyl group, trifluoroacetyl group, phthalyl group, tosyl group, o-nitrophenylsulfenyl group, p
-meth*cy0-nitrophenylsulfenyl group, benzoyl group, acyl-type protecting group such as chloroacetyl group,
Trityl group, benzyl group, 2-benzoyl-1-methylvinyl group.

Alkyl-type protecting groups such as trimethylsilyl groups.

Examples include allylidene-type protecting groups such as benzylidene group and 2-hydroxyallylidene group.

In addition, as a protecting group for a carboxyl group, a benzyl group r
p-nitrobenzyl group, p-methoxybenzyl group,
21416-drimethylpenzyl group.

Pentamethylbenzyl group, methyl group, ethyl group.

tert-butyl group, benzhydryl group, trityl group,
Examples include ester residues such as a phthalimidomethyl group, a cyclopentyl group, a 2-methylthioethyl group, a phenacyl group, and a 4-picolyl group.

A benzyl group is used as a protecting group for a mercapto group.

p-methoxybenzyl group r p-nitrobenzyl group,
Benzhydryl group, trityl group, benzyloxycarbonyl group, benzoyl group, ethylcarbamoyl group, acetamidomethyl group, ethylthio group, benzylthiomethyl group, etc., and as protecting groups for hydroxyl group, benzyl group,
Examples include a tert-butyl group, an acetyl group, a trifluorocetyl group, and a benzyloxycarbonyl group.

"Hydrocarbon divalent group" is R5, R6, R? It corresponds to a hydrocarbon group substituted in , and includes an alkylene group, a cycloalkanediyl group, an arylene group, and a non-aromatic condensed polycyclic hydrocarbon divalent group.

Aralkylene groups are preferred.

The "alkylene group" is preferably a linear or branched group having 1 to 20 carbon atoms, and specifically includes a methylene group, a methylmethylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group.

1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, pentamethylene group, l-
Methyltetramethylene group, 4methyltetramethylene group,
Hexamethylene group.

5-methylpentamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene group, tridecamethylene group, tetradecamethylene group, pentadecamethylene group, hexadecamethylene group, Examples include heptadecamethylene group, octadecamethylene group, nonadecamethylene group, and icosameethylene group.

Examples of "cycloalkanediyl groups" include various cyclopropanediyl groups, various cyclobutanediyl groups, various cyclopentanediyl groups, various cyclohexanediyl groups, and various cyclohebutanediyl groups, and "non-aromatic fused polycyclic hydrocarbon divalent Specifically, the "group" includes various indandiyl groups.

Various indenediyl groups, various tetrahydronaphthalenediyl groups, various dihydronaphthalenediyl groups, various 1.2
-benzo-1-cycloheptenediyl group, various fluorenediyl groups, various 2,3-dihydro-IH-benz [f
] indendiyl group.

Various IH-benz[f]indendiyl groups are exemplified as suitable ones. Examples of the "arylene group" include a phenylene group (0+m+I), various naphthalenediyl groups, and the like. "Aralkylene group" means a divalent group of arylalkane in which a lower alkylene group having 1 to 6 carbon atoms and the above "arylene group" are bonded, and the arylene group is a phenylene group, and the lower alkylene group is a methylene group. An example is -CH2-43-.

Furthermore, examples of the alkali metal atoms forming alcoholade (phenolate) and thiolate (thiophenolate) include potassium and sodium.

Examples of "residues obtained by removing a carbonyl group from an acyl group" include lower alkyl groups and aralkyl groups.

Preferred are halogen-substituted or unsubstituted aryl groups and lower alkoxy groups, and specific examples thereof include the same groups as mentioned above.

"A 5- to 6-membered nitrogen-containing heterocyclic group which may be fused with a non-tertiary benzene ring" is.

When R2 is the same group as R1 and R1, "5- or 6-membered benzene ring may be fused to Δ2 or Δ2"
3-pyrrolinyl group, pyrrolidinyl group, imidazolyl group,
imidazolinyl group, imidazolidinyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, IH-1,
2,3-) riazolyl group.

2 H-1,2,3-triazolyl group, IH-1,
2,4-triazolyl group, 4H-1,2,4-triazolyl group, IH-1,2,3,4-tetrazolyl group, indolyl group, benzimidazolyl group, IH-imidazolyl group, 2T(-indazolyl group, 1.4-dihydropyridyl group, tetrahydropyridyl group, piperidul group, piperazinyl group, Δ4-thiazolinyl group, thiazolidinyl group, Δ4-oxazolinyl group, oxazolidinyl group, Δ4-isoxasilyl group, inoxazolidinyl group, etc. It will be done.

DI, D2. D3. The "...rogen atom" represented by p4 and D5 includes an iodine atom, a bromine atom, a chlorine atom, etc.

Examples of organic sulfonic acid residues include alkylsulfonyloxy groups such as methanesulfonyloxy group and ethanesulfonyloxy group, and benzenesulfonyloxy groups.
Examples include arylsulfonyloxy groups such as K p-)luene)sulfonyloxy group.

The "r cycloalkyl lower alkyl group" represented by R25 indicates a group in which any hydrogen atom of the "lower alkyl group" is substituted with the "cycloalkyl group", and the lower alkyl group is a methyl group, and the cycloalkyl group is cyclohexyl. An example of a group is a cyclohexylmethyl group.

Similarly, "aryloxy lower alkyl group" and "arylthio lower alkyl group" mean a group in which any hydrogen atom of the "lower alkyl group" is substituted with the "aryloxy group" or "arylthio group", An example of a lower alkyl group is a propyl group, and an aryloxy group or an arylthio group is a phenoxy (or phenylthio) group, which is a phenoxy (or phenylthio)propyl group.

A7 and Aa indicate "5 which may be fused with a benzene ring"
``a 6-membered heterocyclic divalent group'' corresponds to ``a 5- to 6-membered heterocyclic group which may be fused with a substituted benzene ring represented by R2 when R1 and R1 are the same group'' A specific example of a pyridine ring is pyridine-2.
, 3-diyl group ('Q') and various pyridinediyl groups.

The other groups are the same as above.

Each manufacturing method will be explained in detail below.

First production method The compound (I) of the present invention comprises a peterocyclic carboxylic acid which may have a protecting group represented by the general formula (n) or a reactive derivative thereof, and a protecting group represented by the general formula (m). It can be produced by reacting with an amine which may have the following, and then removing the protecting group if necessary.

Reactive derivatives of compound (■) include acid chloride,
Examples include acid halides such as acid bromides; acid azides; active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonates, p-toluenesulfonic acid, etc. It will be done.

When compound (II) is reacted with a free carboxylic acid, it is advantageous to carry out the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimitazole.

The reaction conditions differ slightly depending on the raw material compound, especially the type of reactive derivative of compound (II), but pyridine.

Tetrahydrofuran, dioxane, ether.

N,N-dimethylformamide, benzene, toluene,
Raw material compound (■) in an organic solvent inert to the reaction, such as xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile, etc.

It is advantageous to react using equimolar amounts of ([) or an excess molar amount of one of them.

Depending on the type of reactive derivative or the raw material compound (I
In the case of using the salt of II), trimethylamine, triethylamine, pyridine.

It is advantageously carried out in the presence of a base, such as an organic base such as picoline, lutidine, dimethylaniline, N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide. There are cases. In addition.

The reaction can also be accelerated by using an excess molar amount of the starting compound ([[). Furthermore, pyridine can also serve as a solvent.

The reaction temperature varies depending on the type of reactive derivative.

Set as appropriate.

In this reaction, it is preferable that there are no other mercapto groups, reactive amine groups, carboxyne groups, or hydroxyl groups, but the target product can be obtained by introducing a protecting group and removing the protecting group after the reaction. be able to.

The removal of a protecting group differs depending on the type of protecting group.

For example, when the carrier group of the amine group is a substituted or unsubstituted benzyloxycarbonyl group, catalytic reduction is suitable, and depending on the case, hydrobromic acid/acetic acid, hydrobromic acid/
Acid treatment with trifluoroacetic acid, hydrofluoric acid, etc. is used. Other urethane-type protecting groups such as tert-phthoxycarbonyl groups are hydrobromic acid/acetic acid, trifluoroacetic acid, and hydrochloric acid.

Acid treatment with hydrochloric acid/acetic acid, hydrochloric acid/dioxane, etc. is advantageous.

In addition, when the protective group of Calhoki 7 group is a methyl group or an ethyl group, it can be treated by saponification, and when the benzyl group is substituted with various types of benzyl, it can be treated by catalytic reduction or saponification.

The tert-butyl group was treated with the same acid as above, and the trimethylsilyl group was treated with water.

Each is easily removed.

Protecting groups for mercapto and hydroxyl groups are Daio, sodium/
It can be removed by liquid ammonia treatment or hydrofluoric acid treatment, and depending on the type of protecting group (e.g. 0-benzyl,
When using an 0-benzyloxycarbonyl group, or when it is an acyl protecting group, it can be removed by hydrolysis in the presence of an acid or an alkali.

These treatments can be performed by conventional methods.

Second Production Method The compound represented by the general formula (Ia) consisting of Yf or an imino group can also be produced by the reaction of the oxazolidinedione ring-fused heterocyclic compound represented by the general formula (rV) and the compound (1). can.

The reaction method, protecting group and its removal are almost the same as in the first production method.

Third Production Method The compounds of the present invention also include amide compounds in which R3 is a hydrocarbon-substituted amine group having a carbamoyl group or a mono- or di-lower alkylaminocarbonyl group, and such compounds represented by the general formula (Ib) are can be produced by reacting a side chain carboxylic acid represented by the general formula (V) or a reactive derivative thereof with an amine structure represented by the general formula (''/I), and removing the protective group if necessary.

The reaction conditions and the like are the same as in the first production method.

Fourth Production Method The compound of the present invention represented by the general formula (1c) can be prepared by reacting the corresponding cyclic secondary amine (■) with a carboxylic acid represented by the general formula (VIIl) or a reactive derivative thereof, and then optionally a protective group. It can be manufactured by removing.

This N-unionization reaction can be carried out in the same manner as in the first production method.

The compound of the present invention represented by the general formula (d) of the fifth production process is produced by reacting the corresponding heterocyclic secondary amine (IX) with the carboxylic acid of the general formula (X) or a reactive derivative thereof, and then optionally with a protective group. It can be manufactured by removing .

The reaction conditions and the like are almost the same as in the first production method.

Sixth Production Method The compounds of the present invention also include a compound (Ie) in which an acyl group is bonded to a cyclic secondary amine-containing heterocycle as R2 when R1 and R1 are the same group, and the compound (XI
) and (X[I) or a reactive derivative thereof in the same manner as in the first production method.

Seventh Production Method The compound of the present invention contains an ether or thioether compound, and such a compound can be produced by applying a conventional etherification method or thioetherification method.

Among the conventional methods, the most common method, the method of reacting an alcohol or mercaptan or its alkali metal substituted product with a halide or sulfonate, is most advantageously used.

The ether or thioether compound represented by the general formula (If) includes - a hydroxy or mercapto compound represented by the formula (XIV) or an alkali metal substitute thereof, or a halide or sulfonate compound, and - a halide represented by the formula (XV). Alternatively, it is produced by reacting a sulfonate compound, a hydroxy or mercapto compound, or an alkali metal substituted product thereof.

The reaction is carried out using approximately equal moles of Compound (XIV) and Compound (XV), or slightly excess mole of one of them, with N,N-dimethylformamide and dimethylsulfoxide.

Acetone, methyl ethyl ketone (2-butanone).

It is carried out in an organic solvent such as methanol, ethanol, ethylene chloride, chloroform, ether, tetrahydrofuran, dioxane, etc., water, or a mixed solvent of water and an organic solvent.

When an alkali metal substitute is not used as the starting compound (XIV) or (XV), the reaction is carried out in the presence of a base,
Such bases include sodium hydroxide.

Potassium hydroxide, sodium hydride, sodium carbonate,
Bases such as potassium carbonate and Triton B are preferably used.

The reaction temperature is not particularly limited, but is usually set at room temperature or under heating.

When a free mercapto group or an alkali metal substituted product thereof is present in the starting compound (xrv), that portion is usually also thioetherified at the same time.

In addition, depending on the type of substituent, it is preferable to introduce a protecting group and carry out the reaction in order to suppress side reactions, and removal of the protecting group after the second reaction is the first step! This is carried out by processing in the same manner as described in Method A.

The ether or thioether compound represented by the general formula ○g) of the 8th production process can be produced by the reaction of compound (XVI) and compound (XS'll). be.

Ninth production method In addition, the ether or thioether compound represented by formula (Ih) can also be used to prepare compound (X1711) and compound (XI
It is produced by using X) as a raw material compound and treating it in the same manner as in the seventh production method.

10th Production Process Among the compounds of the present invention, the compound (Ii) in which Xl is an oxygen atom or a sulfur atom is a ketone (or aldehyde) represented by the formula (XX), a diol or dithiol represented by the formula (XXI), It can be produced by applying a cyclization reaction using hydroquine mercaptan, an amino alcohol, or an amino mercaptan compound as a raw material compound.

The reaction is carried out using compounds (
XX) and compound (XXI) in approximately equal moles, or using one of the raw material compounds in a slightly excessive amount.

It is usually carried out at room temperature. Furthermore, it can also be carried out using an azeotropic dehydration solvent such as benzene or toluene while applying a dehydration means such as a Dean-Stark apparatus. Note 9
In this reaction, it is advantageous to use a raw material that does not contain other mercapto groups, amine groups, carboxy groups, etc., but the reaction can be carried out with these groups protected.

Elimination of these protecting groups is the same as in the first production method.

The N-substituted compound represented by the general formula Crj) of the 11th production method is expressed by the formula (
X) It is produced by reacting the corresponding cyclic secondary amine represented by GII) with a halide or sulfonate compound represented by the general formula (XXI[I), and then removing the protecting group if necessary.

The reaction using a halide compound as the raw material compound (■) is carried out at room temperature or by adding approximately equal moles of compound (XX111) to compound (XXII) or a slight excess mole of one of the two in the same solvent as in the seventh production method. It is advantageous to carry out the reaction at room temperature or under heating under reflux.

For this reaction, secondary and tertiary bases such as pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, dimethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium hydroxide are used.

Adding an inorganic base such as potassium hydroxide may be advantageous in making the reaction proceed smoothly.

In the reaction using a compound substituted with an organic sulfonic acid residue as the starting compound (xxm), compound (XXII)
It is advantageous to carry out the reaction in the same solvent as in the seventh production process, using approximately equimolar amounts of and compound (XXIII), or a slightly excess molar amount of one of the two, under cooling or at room temperature. The reaction time is appropriately set in consideration of various reaction conditions.

In this reaction as well, it is preferable that there are no other mercapto group-reactive carboxy groups, hydroxyl groups, etc., but it is also possible to introduce a protecting group and react to obtain the desired product. Furthermore, when other reactive amino groups are present, those amino groups may also undergo N-alkylation at the same time depending on the two reaction conditions.

The desired product can also be obtained by introducing a protecting group that is easily removed and removing the protecting group.

The removal of the protecting group and the like are as described in the first production method.

12th Production Method The compound of the present invention in which R3 is a diamine type substituent is a compound in which R3 is a diamine type substituent, and an amine, halide, or sulfonate represented by the general formula (XXIV) and a halide, sulfonate, or amine represented by the general formula (XXV). It can be manufactured by applying a reaction method.

The reaction conditions, such as the solvent, temperature conditions, addition of a base, and removal of protecting groups, are almost the same as those in the 11th production process, but the amount of raw material compound used is when producing a symmetrical di-substituted amine compound as the target product. is the compound (XX[V) or the compound (
One of the compounds (XXV) is approximately twice the mole of the other, preferably an amine is used as the compound (XXIV), and the compound (XX
Using a halide etc. as V), a compound such as the halide (
XXV) is used in an amount approximately twice the mole of the amine compound (XX[V). Further, when producing a di-substituted amine using a mono-substituted amine or a mono-substituted amine as a raw material, it is appropriate that the moles of each raw material compound are approximately equal.

In addition, when producing a monosubstituted amine as a target product, in order to suppress tertiary amination and produce the target product in good yield, a protecting group 9 for suppressing tertiaryization is added to the amino group of D4 or DS, such as toluene. Sulfonyloxy group.

It is preferable to introduce an acetyl group, a phenacylsulfonyl group, a trifluoromethanesulfonyl group, a bisbenzenesulfonyl group, or the like to form a secondary amine.

In addition, when producing a primary amine using a halide or sulfonate compound (XX[V) in which p4 represents a halogen or an organic sulfonic acid residue as a raw material, ammonias can be used as the compound (XXV), but potassium phthalic acid imide It is advantageous to apply a method in which the protecting group is removed after the reaction using

Thirteenth Production Method The compound (II) among the compounds of the present invention can be produced by reacting the corresponding cyclic secondary amine (Wl) with the compound (XEGII). The reaction conditions and the like are almost the same as in the 11th production method.

14th Production Method Compound (1m) can also be derived from the raw material compounds (XXIx) and (XXX) by the same treatment as in the 11th Production Method.

15th manufacturing method An amino group in Rt when R1 and RI are the same group.

Compounds of the present invention having a mono- or di-substituted amine group (I
n) can be manufactured by processing in the same manner as in the twelfth manufacturing method.

When trying to produce an imidazolidine compound according to the 16th production method, 1
Application of the 1,3-diazole synthesis method of species 6 can be considered, but when producing compound (10), the general formula (xxxr
Using a compound shown in v) which has an amide bond with one nitrogen atom of the corresponding ethylenediamine as a raw material compound,
A method of cyclizing this is advantageous. Various carbonyl compounds can be used as reaction reagents, but if the introduction of hydrocarbon substituents is also considered, the general formula (xxxv
) are preferred.

The reaction is carried out by adding compound CXXXI in an organic solvent inert to the reaction (such as toluene) with the addition of regular sieves.
This can be done by heating V) and (XXXV).

In this reaction as well, it is advantageous to use a compound that does not have a mercapto group, an amine group, a carboxy group, etc., but it is also possible to carry out the reaction by introducing a protecting group depending on the case.

Removal of the protecting group in that case is number 11! It is done in the same way as the law.

The first production method The compound of the present invention contains various compounds that can be obtained by applying reduction means (for example, C=C-c-c).

C=C C=C-c c or No, -NH,, S-8-3
H etc.).

The method shown in the formula is particularly a method for producing a saturated heterocyclic compound, which is a basic skeleton, by reduction of the corresponding incompletely hydrogenated heterocycle.

Reduction is platinum black, platinum oxide, palladium carbon.

Catalytic reduction in the presence of a reduction catalyst such as Raney nickel is advantageous.

Other manufacturing methods include amidation method, ether or thioetherification method,
The cyclization reaction, N-alkylation reaction, etc. were detailed in 10.
The compounds of the present invention contain various functional groups, and can be produced by applying various methods depending on the characteristics of the groups.

For example, in the compound (I) of the present invention, a compound having a free carboxyl group as a substituent can be prepared by removing the ester residue from the corresponding ester by a conventional method. A compound having a chrysanthemum carbonyl group can be produced by reacting the corresponding carboxylic acid or its reactive derivative with a lower alcohol or a reactive derivative of an alcohol component such as a lower alkyl halide, and performing an ester-forming reaction in a conventional manner. .

The compound CI) of the present invention thus produced is:

Free mar-1 is isolated and purified as its salt. Salts can be produced by subjecting them to commonly used salt-forming reactions.

Isolation and purification is carried out by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.

As mentioned above, the compound of the present invention is a racemate.

Optical isomers such as optically active forms and diastereomers.

Geometric isomers of cis and trans forms and tautomers of keto and synthetic forms exist singly or as a mixture.

Racemic compounds can be produced by using appropriate raw material compounds.
Alternatively, stereochemically pure isomers can be obtained by a numerical racemic resolution method [for example, a method of forming diastereomeric salts with numerically optically active acids (tartaric acid, etc.) and optically resolving them]. can. Also, mixtures of diastereomers can be separated by conventional methods such as fractional crystallization or chromatography.

Geometric isomers can be separated using differences in physicochemical properties between the isomers.

(Effects of the Invention) The compound CI) of the present invention and its salts have PAF antagonistic activity and are useful for the treatment and prevention of various diseases caused by PAF. Especially anti-asthmatic and anti-inflammatory drugs.

Anti-ulcer agent, shock symptom reliever, ischemic heart/brain disease,
It can be used as a therapeutic agent for liver diseases, thrombosis and nephritis, and as a rejection inhibitor for FA organ transplantation.

Furthermore, one of the compounds of the present invention includes a compound that also has a vasodilatory effect, and such a compound is also useful as a vasodilator.

The anti-PAF effect of the compound of the present invention was confirmed by the following method.

Method of action of PAF on platelet aggregation Nine volumes of blood were collected from the ear artery of a male Japanese white rabbit weighing approximately 3 kg into a plastisocrine ring containing 1 volume of 3.8% sodium citrate aqueous solution. 270 blood
Centrifuge at room temperature for 10 minutes at
Centrifuge for 5 minutes and collect platelet-poor plasma (below).

PPP) was obtained. After diluting PRP with PPP and adjusting the platelet count to 500,000/μl, platelet aggregation by PAF was performed using bones and crosses (Journal Op Physiology, Vol. 168, pp. 178-195 (1963)).
) [G.V., R., Born and M. J., Cross
, Journal of Physiology,
168°178-195. (1963)]. That is, using NBS hematotracer (binary bioscience), PAF (10-8M)
The change in light transmittance of PRP was measured. In addition, IC from the inhibition rate of maximum light transmittance by PAF in the control in addition to 2 minutes before addition of compound UPAF. value (50
% inhibitory concentration) was determined.

Results As shown in Table 1, many of the compounds of the present invention exhibited anti-PAF activity (IC, value 10-6M) in rabbit platelets.
above), especially Example 37.49.67゜71,
Strongly in 81.83.85.90.91.119.142.

The IC. The value is 2.8 x 10-8 ~ 8.5 x 10
-8M.

These compounds include ADP (3 μM), arachidonic acid (
(100 μM) and collagen (to μg/ml), as it does not show any inhibitory effect on platelet aggregation (to μg/ml).
(data not shown) and appears to be a PAF-specific antagonist.

(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.

Note that the raw material compounds include novel compounds, and the manufacturing method thereof is shown in Reference Examples.

Note that in text 9, NMR refers to nuclear magnetic resonance spectra using TMS as an internal standard, MS refers to mass spectra, and LAH refers to lithium aluminum hydride.

HOBT is 1-hydroxybenzotriazole, D
CC is dicyclohexylcarbodiimide, THF is tetrahydrofuran, and DMF is N.

Represents N-dimethylformamide.

Reference example 1゜2-(3-pyridyl)thiazolidine-4-carboxylic acid 2 produced from L-cysteine and pyridine-3 aldehyde
．． 1g, water 20ml1. 2.4 g of di-tert-butyl-di-carbonate in a mixture of 740 ml of dioxa
, and ] Add 10 ml of a normal aqueous sodium hydroxide solution at 4°C or below, and stir at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, 30 ml of water was added, 05M citric acid aqueous solution was added to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4.
- 1 g of carboxylic acid was obtained. Melting point: 167-169°C.

Heated. 100 μm of activated carbon was added while still warm and filtered.

The crystals precipitated when cold were collected, washed with ethanol, and 2-(4
1.2 g of -pyridyl)thiazolidine-4-carboxylic acid was obtained. Melting point 171-173℃ONMR (DMSO-
d, ) δ: 3.0 to 3.5 (2H), 3.9 to 4.2 (IH
), 5.56.5.78 (39 each total IH), 7
．． 4-7.6 (2H), 8.5-8.6 (2H) Reference Example 3 Reference Example 2゜H2SH 1.07 g of pyridine-4-aldehyde and 1.2 g of L-cysteine were refluxed in 60% ethanol. 1.57 g of quinoline-3-aldehyde and 1.21 g of L-cysteine were dissolved in 50 ml of 50% ethanol at temperature for 4 hours.

Stirred at room temperature for 1 hour. The precipitated crystals were collected by suction, and
Wash with 0% ethanol and dry to obtain 2-(3-quinolyl)
1.95 g of thiazolidine-4-carboxylic acid was obtained. Melting point 173-175°C (decomposition) Reference example 4°N, N- of 1.20 g of p-chloromethyl-(4-phenylbutoxy)benzene and 1.15 g of potash phthalimide
solution in 20 ml of dimethylformamide at 100°C.
Stir for hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solid obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate to obtain 1.85 g of N-[p-(4-phenyldi-1-xy)benzyl phthalimide. melting point
106-1075°C (2) (I) - (CHt% oQ
A solution of 920 μl of N-[p-(4-phenylbutoxy)benzyl phthalimide obtained with 4° fl. cu. and 200 μl of hydrazine hydrate in 10 ml of ethanol was heated under reflux for 3 hours. From now on, the solid that has been released will be passed away.

The P solution was concentrated. Add chloroporum to the residue.

Insoluble matter was separated by f. This P solution was concentrated to obtain 1g of p-(4-7enylptoxy)benzylamine (19oIT).

NMR (CDCl, ) δ: 1.6-1.9 (4H), 2.5-2.8 (2H
), 3.75 (2H.

br), 3.8-4.0 (2H), 6.7-6.9
(2H), 7.1 to 7.3 (7H) Reference example 5°CH3(CHI)a-o+cH2NH! p-10 lomethyl(heptyloxy)benzene 900 ff1g N
, add a solution of 1.25 g of sodium azide in 2.5 ml of water to a solution of 25 ml of N-dimethylformamide,
The mixture was stirred at 100°C for 6 hours. After cooling, the two reaction mixtures were diluted with water and the product was extracted with ether.

The ether layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the resulting residual oil in 10 ml of tetrahydrofuran was added to 200 mg of lithium aluminum hydride in 1 ml of tetrahydrofuran.
It was added dropwise to the suspension in 5mt at 0°C over 5 minutes. After stirring at the same temperature for 1 hour and at room temperature for 1 hour, sulfuric acid was added)
Add IJum decahydrate.

Excess lithium aluminum hydride was decomposed.

Insoluble matter was filtered off, and the P solution was concentrated under reduced pressure to obtain 860 mg of p-hebutyloxybenzylamine.

MS: m/z 221 (M”) NMR (C
DCl3) δ: 0.8-1.0(3T(), 1.2-1.5(I
OH), 1.6-19 (2H), 3.80 (2H,
s), 3.94 (2H, t), 6.87 (2H, d
), 7.22 (2H, d) Promo 600 mg of 4-phenylbutane and 580 ml of potassium carbonate in 3 mZ of N,N-dimethylformamide were stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and diluted with water, 1N hydroxide).

The mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure to obtain 660 μm of m-(4-phenylbutoxy)benzaldehyde.

MS: m/z 254 (M+)NMR
(CDCl,) δ: 1,6-1.9 (4H), 2.6-2.8 (2H
), 4.06 (2H, t).

7.2-7.4 (9H), 9.96 (IH, s) Reference Example 6 m-Hydroxybenzaldehyde 3801'l! , 1-
m-(4-phenylbutoxy)benzaldehyde 660
200 ff1 g of sodium borohydride was added to a solution of (1) in 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 5% hydrochloric acid was added to the resulting residue, and the product was extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1 g of m-(4-phenylbutoxy)benzyl alcohol 5101T.

NMR (CDCl3) δ: 1.6-1.9 (4H), 2.6-2.8 (2H
), 3.9-4.1 (2H), 4.60 (2H,s
), 7.2-7.5 (9H) δ: 1.6-1.9 (
4H), 2.6-2.8 (2H), 3.6-3
, 9(2H), 3.9-4. D2)T), 6.7-6.
9(3T().

7.2-7.4 (6H) Reference example 7゜m-(4-phenylbutoxy)benzyl alcohol 5+
omg4 benzene 5mZ dissolved in thionyl chloride 1.4
g was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 520 mg of m-chloromethyl(4-72-2-butoxy)benzene. Continuing this compound, Reference Example 4
470 mg of m-(4-7enylbutoxy)benzylamine was obtained.

MS: m/z 255 (M+) NMR (CD
Cl, ) 2-amino-5-mercapto-1,3,4-thiadiazole 320 mg. 1-promo 4-phenylbuta 743
A warm mixture of 0111 g and 350 mg of potassium carbonate in 5 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed successively with water, 1N hydroxide, water, and saturated brine. The ethyl acetate layer was dried over 17 ml of anhydrous sulfuric acid and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 2-
Amino-5-[(4-phenylbutyl)thioko 1.3
．． 300 mg of 4-thiadiazole-# was obtained. melting point
]]]'C Elemental analysis value (as CHHI5N3S2) C H (c! Experimental value C (h) 54.72 54.98 H (@Brl@ 6.43 24.27 6.40 23.91 Reference example 8゜2.4-dihydroxy-3-propylacetophenone 5
．． A mixture of 0 g, 11.1 g of 1,3-dibromobutane, 60 g of potassium carbonate and 50 IT of tetra n-butylammonium bromide in 130 mt of acetone was heated to reflux overnight. From now on, the insoluble matter was removed from house to house and the P solution was concentrated.

The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 8: ]) to give 1-
[4-(3-bromobutoxy)-2-hydroxy-3-
247 g of propylphenyl]ethanone was obtained. melting point
53~55°C Elemental analysis value (as C5H7+ 03 Br) Reference example
9゜<1)s(CH,), -Br + l0IE-COOC
HtCI (, 4214G (CHt) 4-0H 1.93 g of 1-ethoxycarbonylpiperazine, 1.76 g of potassium carbonate, 15 mZ of 2-butanone and 2.47 g of 1-bromo, -4-phenylbutane at room temperature.
A solution of 7 and 5 ml of 2-buta was added. After stirring at 80°C for 12 hours, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 4:]).

1-ethoxycarbonyl-4-(4-7znilphthyl)
Piperazine was obtained. The obtained compound was added to 20 m of ethanol.
1. It was dissolved in 20mZ of 10% aqueous sodium hydroxide solution and stirred at 100°C for 12 hours. After cooling.

The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sulfuric acid.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent; chloroform: methanol: 25
% aqueous ammonia = 100:10:1) to obtain oily 1-(4-phenylbutyl)piperazine.

NMR (CDCl,) δ: 1.34-1.85 (4H, m), 2.20
-3.04 (12H, m).

7.04-7.40 (5H, m) MS: m/z 217 (M+) Reference example
10°C>-(CH2)3-QH 1-ethoxycarbonylpiperazine and 1-bromo3-
Using phenylpropane as a starting material, it was treated in the same manner as in Reference Example 9 to obtain 1-(3-phenylpropyl)piperazine.

NMR (CDCl3’) δ: 1.63 to 1.97 (2H, m).

7.04-7.44 (5H, m) MS: m/z 203 (M) 2.44-3
．． 00 (12H, m).

Reference example 11゜HtNoo (CHz)n'4fJ)) 3.06g of p-amine phenol and 10% aqueous sodium hydroxide solution
Add di-tert-butyl-di- to 0 ml of the mixture at room temperature.
Carbonate 6.43 g and T! A solution of 5'ml of F was added. After stirring at 80°C for 12 hours, the reaction solution was cooled and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 4:]1) + p-210, 2-butanone 1
After stirring 0 m7 of the mixture at room temperature for 30 minutes, 1-
Add a solution of 3101T1 g of bromo-4-phenylbutane and 5 ml of 2-butanone.

The mixture was stirred for 2 hours at 80°C. After cooling, add water to the reaction solution,
Organics were extracted with ethyl acetate. Add the extract to water.

After sequentially washing with saturated brine, it was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10:1), 5 ml of trifluoroacetic acid was added to l-(tert under water cooling, and the mixture was stirred for 30 minutes under water cooling. The reaction solution was concentrated under reduced pressure and washed successively with an aqueous solution of IJ and saturated brine.

NMR (CDC1,) δ: 1.66-1.90 (4H, m), 2.
67 (2H, t), 3.90 (2H, t), 6.5
6-6.82 (4H, m), 7.13-7.33 (5H
, m) MS: m/z 241 (M+) Reference example
12゜G(CI(,)s -OHG(CHt)s -Br5
A mixture of 20 g of -phenylpentan-1-ol and 30 ml of 47% hydrobromic acid is heated under reflux for 6 hours. The reaction solution was cooled and extracted with n-hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=-+00:]).
1687 g of 1-promo-5-7enylbentane was obtained.

NMR (CDCl, ') δ: 1.28-2.03 (6H, m), 2.63
(2H, t), 3.42 (2H, t), 7.013
-7.40 (5H, m) MS: m/z 228
(M”+1) Reference Example 1.52 g of methanesulfonyl chloride was added dropwise over 5 minutes to a solution of 1.11 g of 13° cyclopentane methanol and 1.50 g of ethylamine in 30 mt of dichloromethane while cooling on a water bath. The reaction mixture was heated at room temperature for 3
The mixture was stirred for 0 minutes and washed three times with water and once with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give cyclopentane methyl methanesulfonate 2.0
6g was obtained.

NMR (CDCl3) δ: 1.1-1.9 (8T(), 2.1-2.5(
IH, m), 2.02 (3H, s), 4.13 (2
H, d, J=7Hz).

MS: m/z 178 (M”) (cyclopentane methyl methanesulfone obtained in (1)) 0.80
The mixture was stirred at 0°C overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed successively with 1N sodium hydroxide, water, and saturated brine, and dried over anhydrous magnesium sulfate.

It was concentrated under reduced pressure to obtain 460 mg of p-cyclopentanemethoxybenzaldehyde.

NMR (CDCl, ) δ: 1.2-2.0 (8H), 2.40 (IH,
quintet, J=7Hz).

3.92 (2H, d, J-”7Hz), 6.99 (
2H, d, J = 10Hz), 7.86 (2H, d
, J=10Hz), 9.88 (IH.

S) MS: m/z 204 (M+) Reference example 14 p-hydroxybenzaldehyde 1.0Og, inamyl iodide 1.46g and potassium carbonate 1.80g
A mixture of 15 ml of N,N-dimethylformamide was stirred at room temperature for 2 days. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydroxide), water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give p-(3
-Methylbutoxy)benzaldehyde (1.34 g) was obtained.

NMR (CDCl!) δ: 0.97 (6H, d, J=7Hz), 1.
6-1.9 (3H).

4.08 (2H, t, J-7Hz), 6.99 (2
H, d, J=8Hz).

7.87 (2H, d, J=8Hz), 9.90
(L H,s)MS: m/z 192 (M”
) Reference Examples 15 to 17 The following compounds were obtained in the same manner as in Reference Example 14.

Reference example 18 H2N-cH, Qo-cH<:7 p-Impropoxybenzaldehyde 7701T1g.

A mixture of 4.0 g of ammonium acetate in 20 ml of methanol and 330 ml of sodium cyanopolhydride was stirred at room temperature for 40 hours. Concentrated hydrochloric acid was added to the reaction mixture to bring the pH to 2 or less. After concentration, the residue was dissolved in water and washed with ethyl acetate. Solid potassium hydroxide was added to the aqueous layer to adjust the pI to 11 or more. The product was extracted with ethyl acetate.

The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 110 mg of p-impropoxybenzylamine.

NMR (CDCI, ) δ: 1.28 (6H, d, J=6Hz), 1.5
0 (disappeared with 2H, D, O), 3.71 (2H, s
), 4.46 (IH, hep,.

J=6Hz), 6.75 (2H,d, J=8H
z), 7.14 (2H, d, J=8Hz) MS: m/z 165 (M'') Reference Examples 19-21 The following compounds were obtained in the same manner as Reference Example 18.

Reference example 22 T(2N-CH2eO-(CHz)s<I)p-(3-
Phenylpropoxy)benzaldehyde 750111g
and hydroxylamine hydrochloride 2.3 g methanol 2
0 ml bath solution, water cooling, 10% hydroxide) IJ
The pH was adjusted to 8. After stirring the reaction mixture for 1 hour, water was added to the residue obtained by evaporating the methanol and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated.

p-(3-phenylpropoxy)benzoxime 750
mg was obtained. 10 mt of this compound, tetrahydrofuran
The medium solution was added dropwise to 6 ml of lithium aluminum hydride (tetrahydro7) at 30°C.

After stirring at -30°C for 20 minutes, the mixture was brought to room temperature and stirred for 2 hours. After decomposing excess lithium aluminum hydride with sodium sulfate decahydrate, the reaction mixture was filtered. Solution F was diluted with ethyl acetate and washed with 10% hydrochloric acid. The hydrochloric acid layer is made alkaline with solid potassium hydroxide,
The product was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.

Concentration was performed under reduced pressure to obtain p-(3-phenylpropoxy)benzylamine 2601TIg.

NMR (CDCI, ) δ: 1.6 (2H, disappears at D20), 2.00-2
．． 35 (2H, m).

2.70-3. OO(21(,m), 3.81(2
H,s), 3.97 (2H,t, J=6Hz),
6.87 (2H, d, J=9Hz).

7.24 (2H, d, J=9Hz), 7.25 (5
1(,s)MS: m/z 241 (M'') Reference Examples 23-27 The following compounds were obtained in the same manner as in Reference Example 22.

Reference example 28 p-(3-methylbutoxy)benzaldehyde 1.35
g in solution in 50 ml of tetrahydrofuran.

Hydrogenated lithium aluminum 350rl1 at -10℃
g was gradually added. After stirring at room temperature for 1 hour, excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate. The P solution obtained by removing insoluble matter from this mixture was concentrated to obtain 1.33 g of p-(3-methylbutoxy)benzyl alcohol/I/.

A solution of this compound in 25 mt of ben-9 was added with thionyl chloride 3
g was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.45 g of p-(3-methylbutoxy)benzyl chloride. To a solution of this compound in 50 mt of N,N-dimethylformamide was added a solution of 3.3 g of sodium azide in 14 mt of water under water cooling.

After stirring the reaction mixture overnight at room temperature, it was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.48 g of p-(3-methylbutoxy)benzyl azide. A 30 ml bath solution of this compound in tetrahydrofuran 500 ml of lithium aluminum hydride
mg was added under water cooling.

The reaction mixture was gradually brought to room temperature and stirred for 2 hours.

Excess hydrogen ipylithium aluminum was decomposed with sodium sulfate decahydrate. The solution after removing insoluble matter was concentrated under reduced pressure to obtain 1.13 g of p-(3-methylbutoxy)benzylamine.

NMR (CDCI, ) δ: 0.95 (6) (, d, J=7Hz),
1.5 (disappeared at 2H, D20).

1.6-1.9 (3H), 3.80 (2H, s),
3.98 (2H, t.

J=7Hz), 6.87(2H,d, J=97(z
), 7.24 (2H.

d, J=9Hz) Ms: m/z 193 (M'') Reference Example 29 1.01 g of ethyl 1-(4-carboxy)piperidine carboxylate and 0.72 g of triethylamine.

-10 to 20 LIll of tetrahydrofuran solution
At -5°C, a solution of 0.67 g of ethyl chloroformate and 2 mZ of tetrahydrofuran was added and stirred for 30 minutes. Remove the precipitated crystals and remove the solution with sodium borohydride.
g, to a solution of 10 ml of water over 30 minutes under water cooling, and stirred at room temperature for 30 minutes. The reaction mixture was acidified with IN hydrochloric acid under water cooling and extracted with ether. The ether layer is washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (1:1 v/v) yielded 0.69 g of ethyl 1-(4-hydroxymethyl)piperidine carboxylate.

NMFt(CDC1,”) δ: 0.88 to 1.42 (IH, br), 1.3
0 (3H, t, J=7.0Hz).

1.42-2. OO (5H, m), 2.77 (2H
, dt, J=12.0°3.0Hz), 3.52(
2H, d, J=6.0Hz), 4.15 (2H, q
.

J=7.0Hz), 4.00~4.36(2)! ,
m) MS: m/z 187 (M”)H2C4 oxalyl chloride 1.59g dichloromethane 30m
1 solution, add 1.97 g of dimethyl sulfoxide in dichloromethane 5 [Ilt solution in the range of -60 to -50 °C, and after 5 minutes add 2.11 g of ethyl 1-(4-hydroxymethyl)piperidinecarboxylate in dichloromethane 10.
Add m1 solution dropwise and stir for 15 minutes.

Add 5.73 g of triethylamine to the reaction mixture, stir for 5 minutes, and stir at room temperature for 15 minutes. Add water to the reaction solution and extract with dichloromethane. The organic layer was sequentially washed with IN hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate,
Concentration under reduced pressure gave 1.97 g of ethyl 1-(4-formyl)piperidine carboxylate.

NMR (CDCI, ) δ: 1.25 (3H, t, J = 7.0Hz),
1.42-2.10 (4H, m).

2.24-2.65 (IH, m), 2.65-3.
24 (2H, m).

3.82-4.41 (4H, m), 9.68 (I
H,s) MS: m/z 185 (M”) Sodium hydride O,: 1g was dimethylsulfoxytromZ
After adding K and stirring at 75°C for 30 minutes, the temperature was returned to room temperature, and 2.1 g of benzyltriphenylphosphonium chloride was added at room temperature.
Add 5 ml of dimethyl sulfoxide suspension and stir for 15 minutes. A solution of 0.93 g of ethyl 1-(4-formyl)biveridine carboxylate in 5 ml of dimethyl sulfoxide was added to this mixture and stirred for 1 hour. Water was added and extracted with ether, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (35 g).

Elute with a mixture of hexane:ethyl acetate (3:1) and ethyl (4-styryl)piperidine carboxylate 1.
．． 13g was obtained.

NMR (CDCl!) δ: 1.29 (3H, t, J=7.0Hz) + 1
．． 10-1.95 (4H, m).

2.0:3-2.58 (IH, m), 2.58-3.
05 (2H, m).

4.16 (2H, q, J=7.0Hz), 3.8
8-4.40 (2H, m).

5.46 (1/7H, dd, J=12.0, 10.0H
z), 6.13 (6/7H, dd, J=16.0
．． 6.0Hz), 6.42 (1/7H, d.

J=12.0Hz), 6.43 (6/7H, d,
J=16.0Hz).

7.08-7.45 (5H, m) MS: mA 259 (M”) Warm mixture of 0.80 g of ethyl 1-(4-styryl)piperidine carboxylate and 80 μ of 10% palladium-carbon in ethyl acetate (40 ml) The product was catalytically reduced at room temperature until absorption in the sewage bed ceased. The catalyst was removed, and the solution F was concentrated under reduced pressure to give 0.80 g of ethyl 1-[4-(2-]enyl ethyl)cohyperidine carpoxylate. I got it.

NMR (CDCl, ) δ: 1.28 (3H, t, J=8.0Hz), 0
．． 72-2.01 (7H, m).

2.50-2.98 (4H, m), 3.89-4.4
2 (2H, m).

4.14 (2H, q, J=8.0Hz), 7.02
~7.54 (5H, m) MS: m/z 261
(M”) Ethyl 1-[4-(2-phenylethyl)]
A solution of 0170 g of piperidine carboxylate and 6 ml of 47% hydrobromic acid is heated under reflux at 100° C. for 6 hours. Add a small amount of water to dissolve the crystals, wash with ether, and hydroxylate the aqueous layer to 20%) Make alkaline with IJium. After salting out with common salt, extract with ether.

The organic layer was washed with saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain 0.42 g of 4-(2-phenylethyl)piperidine.

NMR (CDCI,) δ: 0.78-2.06 (8H, m), 2.30
~2.86 (4H, m).

2.86-3.32 (2H, m), 6.95-7.50
(5H, m)MS: m/z 189 (M”
) Reference Examples 30 to 32 were treated in the same manner as in Reference Examples (3) to (5) to obtain the following compounds.

Reference example 33 1.10g of homopiperazine in 15m of water? Solution at room temperature 2
Add N-hydrochloric acid until the pH reaches 2. Next, 40% aqueous sodium acetate solution and 1.28 g of ethyl chloroformate were added alternately to the mixture at a pH in the range of 2.0 to 3.5, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with ethyl acetate, and the aqueous layer was saturated with potassium carbonate. Extract with ethyl acetate, wash the organic layer with saturated brine, and remove anhydrous sulfuric acid.) Concentrate over IJum under pressure in a dry range to obtain ethyl 1-homopiperazinecarboxylate 1.
．． 27g was obtained.

NMR (CDCI,) δ: 4.2B (3H, t, J=7Hz), 1.60
~1.99(3)t, m).

2.75-3.04 (4) (, m), 3.30-3
．． 65 (4H, m).

4.15 (2H, q, J=7Hz) M S : m/z 172 (M”) Ethyl 1
- 0.86 g of homopiperazine carboxylate and 0.90 g of benzyl bromide in 5 ml of tetrahydrofuran
Add 0.80 g of potassium carbonate to the solution and heat under reflux for 4 hours. After the reaction, water was added thereto, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sulfuric acid, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.

Elute with a mixture of hexane-ethyl acetate (2:1).

1.06 g of ethyl 1-(4-benzyl) homopiperazine carboxylate was obtained.

NMR (CDCI,) δ: 1.25 (3H, t, J=71(z), 1
．． 62-2.05 (2H, m).

2.50-2.81 (4H, m), 3.32-3.
75 (4H, m).

3.61 (2H, s), 4.14 (2) (, q, J
=7Hz), 7.29 (5H, s) MS: A mixture of 0.85 g of m/z 252 (M+) and 5 ml of 47% hydrobromic acid solution is heated at 100°C for 10 hours. Add a small amount of water to the reaction solution.

Wash with ethyl acetate. 30% hydroxide in the aqueous layer) IJ
The mixture is made alkaline with an aqueous solution of aluminum, salted out with common salt, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain 0.55 g of 1-benzylhomopiperazine.

NMR (CDC5) δ: 1.60-1.96 (2H, m), 1.91 (
IH, s), 2.52-2.80 (4H, m), 2
．． 80-3.07 (4H, m), 3.68 (2H, s
), 7.12-7.45 (5H, m) MS:
m/z 190 Reference Examples 94-3□ The following compounds were obtained by treating in the same manner as (2) to (3) of Reference Example 33.

Reference example ethyl 1-hyperazine carpoxylate) 2.02 g,
Anhydrous potassium carbonate 1.92 g, decyl bromide 3
．． A mixture of 08 g of 2-butanone and 20 mZ of 2-butanone is stirred at 80° C. overnight. Add water to the reaction solution and extract with ethyl acetate. The ethyl acetate layer is extracted with 3N hydrochloric acid. The extract is made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add 20 mA of ethanol and 20 mA of 10% aqueous sodium hydroxide solution to the residue, and stir at 100°C overnight. The reaction solution was cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.38 g of oily 1-decylpiperazine.

NMR (CDCI!) δ: 0.73-1.74 (19H, m), 2.16
~2.52 (6H, m).

2.84-2.98 (4H, m) MS: m, /z 226 (M”) Reference example 51 CH3CH,0CO-UH + CH, -C)-CI-t.

Ethyl 1-piperazinecarboxylate) 1.6g.

p-tolualdehyde 1.3g, ethanol 30mZ
Add 500 μ of sodium borohydride to the mixture and stir overnight at room temperature. The reaction solution was concentrated under reduced pressure, 50 mZ of water was added, and the mixture was extracted with ethyl acetate. Extract the ethyl acetate extract with dilute hydrochloric acid. Wash the dilute hydrochloric acid extract with ethyl acetate and make alkaline with sodium bicarbonate.

Extract with ethyl acetate. The extract was washed with water, dried over anhydrous potassium carbonate, and concentrated under reduced pressure to obtain 0.8 g of oily ethyl 4-p-1 lylu-l-piperazinecarboxylate. From this product, 7 carboethyl groups were removed according to the method of Reference Example 38, and 0.3
6g was obtained.

NMR(CDCI,) δ: 2.42 (3H,s, CHl), 2. ．． 3-
2.6 (4H, m), 2.7~3.1 (4H, m)
, 3.43 (2H,s, CH2), 7.14 (4
1(.

S) Reference Example 52 Using ethyl 1-piperazine carboxylate and cinnamaldehyde as raw materials, the same treatment as in Reference Example 51 was carried out,
Oily 1-cinnamylpiperazine was obtained.

NMR(CDCI3) δ: 2.2-2.6 (4H, m), 2.8-3.0
(4H, m), 3.16 (2H, d, CH2),
6.28 (LH, dt), 6.56 (1) 1°d)
, 7.0 to 7.5 (5H, m) Reference Example 53 A mixture of 1.72 g of L-N-methylcystine [acid acid, 1.07 g of nicotinaldehyde, and 2 QIZ of water was mixed with 2 QIZ at room temperature.
Stir for 4 hours. 0.8 ml of pyridine and 1 rnl of ethanol were added to the reaction solution, and the precipitated crystals were washed several times with ethanol and dried to obtain 0.74 g of 3-methyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid. Ta.

NMR(DMSO-da)δ: 2.24. '2.32 (3H/2X2.a,
N-CH3), 3.00-3.64 (5/2 H,
m), 4.16-4.32 (H//2.m), 4
．． 92°5.36 ('/2X2.s), 7.10
~7.32 (IH, m), 7.80 ~ 8.00 (IH
, m), 8.44-8.72 (2H, m) M S (
FAB): m/z 225 (M+'f()''Reference example 54 Reference example 55 H2SH 3-acetylpyridine 3.63g, L-cysteine 3
．． A mixed solution of 63 g, 25 ml of water, and 25 ml of ethanol was heated under reflux for 24 hours. The reaction solution is concentrated under reduced pressure, isopropanol is added to the residue, and the resulting powder is collected. After adding ethanol to the powder and removing insoluble matter,
Concentrate to dryness. Dissolve the residue in water, add dilute hydrochloric acid under stirring under water cooling, adjust the pH to 6, and wash the resulting powder with ethanol, drying, and prepare 1-methyl-1-(3-pyridyl)thiazolidine-4-carboxylic acid 2. .54g was obtained.

NMR(DMSO-d6) δ: 1.78.1.88 (3H in total, each s), 2.
92-3.56(2)(.

m), 3.56-4.38 (IH, m), 7.20
~7.44 (IH, m).

7.8 (1-9,08 (IH, m), 9.32-9.
52 (IH, m).

9.68-9.86 (L H, m) M S (FA
B): m/z 225 (M+H)” Di-2-pyridylketone 3.68g, L-cysteine 2.42g+
A mixture of 25 ml of water and 25 ml of ethanol is heated under reflux for 3.5 hours. After cooling, remove the insoluble matter.

Concentrate to dryness under reduced pressure. The residue was washed successively with ethyl acetate and ether to obtain 63 g of 2,2-di(2-pyridyl)thiazolidine-4-carboxylic acid.

NMR (DMSOda) δ: 2.85-4.15 (3H, m), 7.20~
8.90 (8H, m) Reference Example 56 Reference Example 57° 3-Piperidine methanol 4. OOg dioxane 50
m1. 7.58 g of di-tert-butyl dicarbonate and 35 ml of 1N sodium hydroxide were added to the solution in 30 ml of water at 0°C. Bring the reaction mixture to room temperature; 1.
After stirring for 5 hours, the product was extracted with ethyl acetate.

The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give l-tert.
-butoxycarbonylpiperidine-3-methanol 72
Obtained 0g. Melting point 77-79°CNM R (CDC
l, ) δ: 1.48 (9H, s), 1.4-1.9 (4H
), 2.6-3.2 (4H).

3.6-3.9 (4H) MS: m/z 215 (M'') To a solution of 0.50 ml of oxalyl chloride in 10 ml of dichloromethane was added 085 mA of dimethyl sulfoxide at -60°C, and after 3 minutes l -tit-butoxy Carbonylpiperidine-3
- A solution of 1.08 g of methanol in 10 mZ of dichloromethane was added dropwise over 5 minutes. After stirring for 15 minutes, 3.0 rnl of triethylamine was added to the reaction mixture.

After stirring for 5 minutes, 20 ml of water was added to the reaction mixture and the mixture was shaken, followed by separating the dichloromethane layer. The dichloromethane layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give l -tert-
Butoxycarbonylpiperidine-3-aldehyde 0.9
8g was obtained.

NMR (CDCI,) δ: 1.46 (9H, s), 1.4-2.0 (4H
), 2.4 (LH, m.

XV/2=21 Hz), 3.10 (I H,d
d, J = 8.5 and 14Hy,).

3.6.5 (IH, ddd.

J-4゜ 5 and 12.5Hz), 3.94 (IH, dd, J=4 and 14Hz).

9.68 (IH.

S) MS: m/z 213 (M”) Reference example 68
゜Reference Example 69゜To a solution of 3.10 g of 3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 30 m4 of dichloromethane was added 1.31 ml of oxalyl chloride and N, N- at 78°C. 1 g of dimethylformamide 501'r was added. The reaction mixture is gradually warmed to room temperature.

Stirred for 12 hours. The resulting precipitate was collected and dried to 1°3
-dioxo-5-(3-pyridyl)thiasiridino[3,
4-c] 1.90 g of oxazolidine hydrochloride was obtained.

Melting point 170℃ (decomposition) Elemental analysis value (C+.H9CI N, O, S) #d
H (%l N1%l 3%) cIWd calculated value 44.04 3.33 10.27 11.76
13.00 Experimental value 43.94 3.37 10.2
4 11.76 13.30p-methoxyphenyl5.
34g of 10% palladium-carbon 20 in methanol solution
The mixture was stirred using 1 g of 0rl as a catalyst until absorption of hydrogen gas stopped. The catalyst was removed from the furnace and the F solution was concentrated under reduced pressure to obtain 5.43 g of 3-(p-methoxyphenyl)propionic acid.

NMR (CDCI,) δ: 2.34-3.15 (4H), 3.76 (3H,
s) 6.64-7.30 (4,, H), 11.00 (
IH,s) Reference Example 70 3-(p
-Anhydrous ether of (methoxyphenyl)propionic acid 10
The solution was added dropwise over 20 minutes. After stirring at room temperature for 30 minutes, the mixture was heated under reflux for 1 hour. After cooling, water was added to the reaction mixture under water cooling, and 10% aqueous hydrochloric acid was added to make the reaction mixture acidic. The reaction mixture was extracted with ether, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. Lower concentration 1-te
3-(p-methoxyphenyl)globanol 5.06g
Obtained ONMR (CDCI3) δ: 1.60-2.16 (2H), 2.38-2.9
5 (3H), 3.69 (2H, t, J=6Hz),
3.80 (3H, a).

671-7.30 (4H) Reference example 75゜o2NOcH=cH-cooH-1→O,N-1S)-
cH=CH-COOCH.

A mixed solution of 5.80 g of p-nitrocinnamic acid, 10.4 g of methyl iodide, 10.4 g of anhydrous potassium carbonate, and 200 mt of acetone was stirred at room temperature for 2 days. After removing the precipitate, the P solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.30 g of p-nitrocinnamic acid methyl ester.

NMR (CDCI,) δ: 3.83 (3H, a), 6.52 (IH, d
, J = 16Hz).

7.50-7.95 (3H), 8.21 (2H, d,
J = 9Hz) Reference Example 76゜A solution of 1.20 g of 0-tolualdehyde and 20 ml of anhydrous tetrahydrofuran was added to a 20 mt suspension of 3.67 g of methyl (triphenylphosphoranylidene) acetate) and anhydrous tetrahydrofuran at room temperature. , and heated under reflux for 15 hours. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ([)g).

Elute with a mixture of hexane-ethyl acetate (2:1) and
1.65 g of methylcinnamic acid methyl ester was obtained.

NMR (CDCI3) δ Nidorans form 2.45 (3H,s), 3.80 (
3H,s).

6.34 (IH, d, J = 16Hz), 6.9
9-7.66 (4H).

7.97 (IH, d, J=16Hz).

Cis body 2.29(a), 3.63(s), 6.03
(d, J = 12Hz) Reference example 79° Reference example 80° NC0CH, CH, C00CH, positive≠2NC-C>(C
I42) 3-OH 1M superhydride/tetrahydrofuran solution (3.3ml) and anhydrous tetrahydrofuran (5m#)? iG liquid under argon gas flow -50~-
Cooled to 60°C.

To this, 3-(p-cyanophenyl)propionic acid methyl ester 2101 [1 g
2 ml of tetrahydrofuran solution was added dropwise, and the mixture was heated for 10 minutes at the same temperature.
Stir for a minute. Water and IN hydrochloric acid were sequentially added to the reaction mixture at the same temperature to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-(p-cyanophenyl)propatoolx.
I got 20 mg.

NMR (CDCI,) δ: 1.61-2.20 (3H), 2.60-3.
06 (2H).

3.68 (2H, t, J=6Hz), 7.10-7
．． 75(4H)3-(p-)ril) Propertool 2.1
3 g was heated under reflux for 5 hours in 7 ml of a 47% aqueous hydrobromic acid solution.

The solvent was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure.
1.75 g of 3-(p-)lyl)propyl bromide was obtained.

Boiling point 65℃/Q, 7mm Hg NMR (CDCI,) δ: 1.85-2.43 (2H), 2.32 (3H
,s), 2.55-2.95(2H), 3.39
(2H, t, J = 6Hz), 7.04 (4H, s
) Reference Example 81 To a solution of 5 g of 3-(p-methoxyphenyl)pronoquinol in 50 tnl of anhydrous pyridine, 3.8 g of methanesulfonyl chloride was slowly added dropwise under water cooling, and the mixture was stirred at the same temperature for 3 hours. The solvent was concentrated under reduced pressure, water was added to the residue, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer was treated with IN hydrochloric acid and a saturated aqueous sodium bicarbonate solution.

After sequentially washing with saturated saline, drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 3-(p-methoxyphenyl).
6.32 g tz: Obtained.

NMR (CDCI,) a: 1.75-2.36 (2H), 2.55-2.
93 (2H), 3.00 (3H.

s ), 3.80 (3H, a ), 4.24 (2
H, t, J=6Hz).

6.70-7.30 (4H) A mixed solution of 100 ml of acetone was heated under reflux for 15 hours.

The mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.62 g of 3-(p-methoxyphenyl)furobylyotite.

NMR(CDCl,) δ: 1.81-2.35(2H), 2.18(2H
, br, t, J = 7Hz).

3.16 (2H, t, J = 6Hz), 3.80 (
3H,s), 6.71-7.30 (4H) Reference Example 82 Reference Example 84 of 6.30 g of 3-(p-methoxyphenyl)propyl methanesulfonate and 1.11 g of sodium iodide ) A solution of 2.42 g of iodine in 8 ml of N,N-dimethylformamide was added to a mixed solution of 1.55 g of furopanol and 2.51 g of triphenylphosphine in 10 mZ of N,N-dimethylformamide at room temperature, and the disappearance of one color was confirmed. It dripped slowly. After the color of the reaction solution stopped disappearing, water was added to the reaction solution, a 5% aqueous sodium thiosulfate solution was added to reduce excess iodine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (20 g) and eluted with hexane.

3-(p-chlorophenyl)furobylyotite 1.8
2 g was obtained.

NMR(CDCI,) δ: 1.922.40 (2H), 2.71 (2
H, br t, J=7Hz).

3.13 (2H, t, J = 6Hz), 6.91-
7.40 (4H) Reference Example 83 Reference Example 89 5.01 g of phenylpropyl bromide was added dropwise to a mixed solution of 10 mt of concentrated nitric acid (65%) and 10 mA of concentrated sulfuric acid under cooling with water for 5 minutes, and the solution was stirred at the same temperature for 1 After stirring for an hour, the mixture was left at room temperature for one week. Pour the reaction mixture into water.

Extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (150 g). Elution with hexane-ethyl acetate (10:1) yielded 5.5% of 2,3-dinitrophenylpropyl bromide.
0 g was obtained.

NMR (CDCI, ) δ: 2.08-2.51 (2H), 3.20 (2H
, dd, J = 7Hz.

J=9Hz), 3.50(2H,t, J=6Hz)
.

7.68 (IH, d, J=9Hz), 8.42 (I
H, dd, J=3Hz, J=9Hz), 8.79
(IH, d, J=3Hz)22N-C>(CH2),
-OHH,N-C> (CH2)3=Br -HB r
3-(p-aminophenyl)propatol (0.51g
) was heated under reflux for 6 hours, and the solvent was concentrated under reduced pressure. Add methanol and toluene, concentrate the solvent under reduced pressure, and repeat the process again.

3-(p-aminophenyl)propyl bromide hydrobromide (1.04 g) was obtained.

NMR (DMSO-d, +CDCl, (3:1)) δ
: 1.91-2.47 (2H), 2.64-3.0
3 (2H).

3.43 (2H, t, J=6Hz), 4.85 (3
H, br s).

7.40 (4H, a) Reference example 101゜ THE’ ■ 5.13 (IH.

NMR (CDCl!) J=7Hz).

(6Hs　m).

(2L tt (5H, 5) br), 7.21 (IOH, s) δ: 1.21 (IH, s), 1.25 (3H, t
.

1.61-2.10 (2H, m), 2.45-2.
933.29 (2H, q, J=6Hz), 4.15
J=7Hz), 5.15 (IJ br), 7.
21 carboethoxyethylenediamine 0.88g,
A mixed solution of 1.33 g of 3-phenylpropyrobromide and 1.0 g of anhydrous potassium carbonate in 10 ml of tetrahydrochloride was heated to reflux over a room. After removing insoluble matter from P.

The r liquid was concentrated under reduced pressure, and the residue was subjected to alumina column chromatography (25 g). Elute with hexane-ethyl acetate (3:]) to obtain N-carboethoxy-N,N-
C(3-7enylpropyl)ethylenediamine 0.5
4go and N-carboethoxy-N-(3-phenylpropyl)ethylenediamine 0.60go were obtained.

■ NMR (CDCl, ) δ: 1.23 (3H
, t, J=7Hz).

1.56-2.02 (4H, m), 2.20-2.
87・(IOH, m).

3.00-3.45 (2H, m), 4.12 (2H
, t, J=7Hz).

Reference example 102 Bleached 0 CONHCH Hatake NH-(CH,), () -→H,
NCH, CH, NH-(CH,), <>Fist 2HCI A solution of 1 g of N-carboethoxy-vJ-(3-phenylpropyl)ethylenediamine in 10 ml of concentrated hydrochloric acid was heated at 120° C. overnight in a sealed tube. Remove the solvent in NM under reduced pressure.
R(DMSOda) δ: 1.76-2.20 (2H, m), 2.48
-3.10 (4H, m), 3.22 (4H, s),
7.28 (5H, s), 8.0-10.0 (5
H, br) MS: m/z 179 (M”+1
) Reference example] 04゜NC-C) (CH2), CI-1 → HO-(CH,)3
<I) -CN5-(p-cyanophenyl)furobyluioditetom Q. A mixed solution of 5 g of tetrahydrofuran]Omt was heated under reflux for 2 hours. Concentrate under reduced pressure, add saturated brine to the residue, extract with ethyl acetate, wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate.

The solvent was concentrated under reduced pressure to give 1-[3-(p-Schiff/7
znyl) propylcopiperazine (140 mg) was obtained.

NMR (CDCl,) δ: 1.60°-2.10 (2H, m), 2.
04 (IH, s).

2, 19-2.54 (6H, m), 2.69 (2H
, t, J:=8Hz).

2, 89 (4H, t, , J=51(z), 7.2
7 (2H, d, J=9Hz).

7, 56 (2H, d, J=9Hz) MS:
m/z 229 (M”) Reference Example 105.

()-CH. N3JCONH(CH,)sCH.

To a solution of 1.76 g of 1-benzylpiperazine and 20 ml of tetrahydrofuran was added a solution of 1.0 g of n-butylisosilane and 5 rnl of tetrahydrofuran under water cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to obtain 2.8 g of crude 1-benzyl-4-butylaminocarbonylpiperazine. This product was used in the next reaction without purification.

NMR (CDCI, ) δ: 0.90 (3H, t), 1.1-1.7 (
4H, m), 2.2-2.6 (4H, m),
3.0-3.6 (6H, m), 3.50 (2H
, s).

4, 5 (IH, br s), 7.0-7.5 (5
H, m) Reference example 106.

3.52 g of 1-benzylpiperazine, 3.5 g of 3-7enylpropionic acid, 20 ml of tetrahydrofuran
4.5 g of dicyclohexylcarbodiimide was added to the mixed solution, and the mixture was stirred at room temperature overnight. The resulting dicyclohexylurea is separated from P, and the mother liquor is concentrated under reduced pressure. Add 1 part of ethyl acetate to the residue.
Add 00 ml and 50 ml of water, make alkaline with potassium carbonate, and separate the liquid. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain 6 g of oily 1-benzyl-4-(3-phenylpropionyl)piperazine.

NMR (CDCI, ) δ: 2.1-2.5 (4H, m), 2.4-3
．． 2(4H, m)+ 3.3~3,8(4H, m
), 3.45 (2H, s), 7.1-7.4
(IOH, m) Reference example 107 1-benzyl-4-butylaminocarbonyl biverage/
Add 250 mg of 10% palladium-carbon to a solution of 2.8 g + 15 ml of ethanol and perform catalytic reduction until hydrogen absorption stops. The catalyst was separated and the r liquid was concentrated under reduced pressure to obtain 2.2 g of 1-butylaminocarbonylpiperazine. This product was used in the next reaction without purification.

NMR (CDCl5) δ: 0.92 (3H, t), 1.1-1.7 (4H
, m), 2.7-3.0 (4H, m) 3.0-3
．． 5 (6H, m) Reference Example 10&.

Using 1-benzyl-4-(3-7enylpropionyl)piperazine as the starting material, prepare 1 in the same manner as Reference Example 07.
-(3-phenylpropionyl)piperazine was obtained.

MS: m/z 218 (M”) Reference example 109
゜N-carbobenzyloxy-serine 2.0g, ]
- To a solution in 30 ml of methylformamide was added 1.58 g of dicyclohexylcarbodiimide under water cooling. The reaction mixture was stirred at room temperature for 24 h, diluted with ethyl acetate, and diluted with 4
% hydrogen carbonate) twice with IJum aqueous solution.

The mixture was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-[2-(benzyloxycarbonylamino)=3-hydroxypropionyl]-4-(3-phenylpropyl)piperazine 2
．． 39g was obtained.

Melting point 95-97℃ Elemental analysis value (as CuHsrNsO*)
(c!AN(- Calculated value 67.74 7.34 9.87 Experimental value 67.74 7.26 9.88NMR(CD
Cl3) δ: 1.7-2.0 (2H), 1.8-2.6
(disappeared with 3H, nto).

2.3-2.8 (8H), 3.4-3.8 (7H)
, 7.1-7.3 (5H) MS: m/z
291 (M”) Reference example] 10° Reference example 11!.

]-[2-(benzyloxycarbonylamino)-3-
To a solution of 1.12 g of hydroxypropionyl]-4-(3-7enylpropyl)piperazine in 30 ml of ethanol was added 100 mg of 10% palladium-carbon.

The mixture was stirred under a hydrogen stream until hydrogen absorption stopped. The catalyst was removed, and the IP solution was concentrated under reduced pressure to obtain 1 g of 800 IT of]-(2-minor-3-hydroxyglopionyl)-4-(3-phenylpropyl)piperazine.

To a solution of 200 mg of p-hebutyloxybenzylamine, 1501q of glycerolic acid (65% aqueous solution) and 110ff1 of l-hydroxybenztriazole in 2 mZ of N,N-dimethylformamide was added 160 rl of dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 16 hours after dilution with 1-2 ethyl acetate.

It was washed successively with a saturated sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous magnesium sulfate.

It was concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography to obtain N-(p-heptyloxybenzyl)-glyceramide somg.

NMR (CDCl3) δ: 0.90 (3H, br t), 1.2-1
．． 5 (8H), 1.7-1.9 (2H), 3.
0 (disappeared with IH, D, O), 3.8-4.0 (2
H).

3.9 (disappeared with IH, D, O), 4.1-4.3 (
IH), 4.38 (2H, d, J=6Hz),
6.88 (2H, d, J=8Hz).

7.18 (2H, d, J”8Hz), 7.0-7.
3 (disappeared with IH, DzO) MS: m/z 309 (M”) Reference example 1
12゜MF 2-(3-pyridyl)-1-viroline-4-carboxylic acid (hydroxide salt 1.15 g, 1-hebutylpiperazine 770 mg, dicyclohexylcarbodiimide 86
0■ and ]-Hydroxybenzotriazole 560 f
A mixture of f1g of N,N-dimethylformamide in 1SmZ was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate and extracted with ethyl acetate. After the organic layer was extracted with IN hydrochloric acid, potassium carbonate was added to the aqueous layer to adjust the pH to 10, and the mixture was extracted again with ethyl acetate. After washing the organic layer with saturated brine, add anhydrous sulfuric acid)
The residue was subjected to silica gel column chromatography (15 g) and eluted with ethyl acetate to give 1-hebutyl-4-[2-(3-pyridyl)-2- 1.01 g of birolin-5-ylcarbonyl]hyperazine was obtained.

1) NMR (CDCl5) δ: 0.91 (3H, t, J=6H7,), 1.
12-1.72 (IOH, m).

1.92-2.93 (9H, m), 2.95-3.2
6 (2H, m).

3.37~4.30 (3H, m), 5.04~s, 3
o(tH, m).

Example 1 L-
Methionine methyl ester/hydrochloride 390rr1g,
1-Hydroxybenzotriazole 390 [rlg
, 190 ft1 g of N-methylmorpholine, and 440 μg of dicyclohexylcarbodiimide were added sequentially, and the mixture was heated at 4°C.
Stir for 1 hour below and 1 hour at room temperature. Remove the precipitate that has formed, concentrate solution F under reduced pressure, add 50 ml of ethyl acetate,
Take away unbathable items.

Solution F was washed successively with a 0.5 M citric acid aqueous solution, water, and 5% hydrogen carbonate solution, an IJium aqueous solution, and water, dried over sodium sulfate, and concentrated under reduced pressure to obtain an oily [N-tert-
440 mg of butoxycarbonyl-2-(3-pyridylthianlysine-4-carbonyl]-L-methionine methyl ester was obtained.

NMR (CDCI,) δ: 1.36 (9H,s), 1.8-2.2
(3H, m), 2.2-2.6 (2H.

m), 3.26 (IH, dd), 3.6 (IH, dd)
, 3.78 (3H.

s), 4.6-4.8 (IH, m), 4.86
(IH, dd), 6.02 (IH, s), 7.3
(IH, dd), 7.8-8.0 (IH, m).

8.52 (IH, dd), 8.65 (IH, dd
) Example 2 N-formyl-2-(3-pyridyl)thiacyly L-methionine methyl ester hydrochloride 1.16 at 4°C or below
g, 1-hydroxybenzotriazole 1.17
g, N-methy, 11/ 560 mg of morpholine and 1.32 g of dicyclohexylcarbodiimide were sequentially added, and 4
Stir for 1 hour below ℃ and 1 hour at room temperature. Example 1 below
and purified by silica gel column chromatography [eluent: chloroform-methanol (9:1) mixture] to obtain an oily [N-formyl-2-<3-pyridyl)thiazolidine-4-carbo-luco x,-methionine methyl ester 8201'9 was obtained.

Elemental analysis value (as C+a Ht+ NsO<St) N
(To) 10.96 10.62 Theoretical value Experimental value NMR (CDCI,) δ: 2.08 (3H,s), 1.8~2.6 (4
H, m), 3.2-3.5 (IH.

m), 3.8 (3H, s), 3.5-3.8 (L
H, m), 4.5~4.8 (IH, m), 4.8~
5.1 (IH, m), 6.1.6.41 (1 go in total, each s), 7.2 to 7.5 (IH, m),
7.8-8.0 (IH.

m), 8.34 (IH, a), 8.4"-8,
9(2H,m) Example 3 To 430 mg of pyridyl)thiazolidine-4-carbonyl]-L-methionine methyl ester was added 5 m7 of trifluoroacetic acid under water cooling, and the mixture was stirred at room temperature for 2 hours.

Concentrate the reaction solution under reduced pressure. Add ethyl acetate to the residue and concentrate again under reduced pressure. Dissolve the residue in 5 ml of ethyl acetate,
Add 1 ml of 4N hydrogen chloride-dioxane solution under ice cooling. The precipitated crystals were collected, washed with ethyl acetate, and dried to give [2-(3-pyridyl)thiazolidine-
1 g of 4-carbonyl]-L-methionine methyl ester dihydrochloride 300f was obtained. Melting point 110℃ Elemental analysis value (as C+5HzNsO*S2CIt)
C hook H (To) N (To) Theoretical value 40.36 5.64 9.41 Experimental value
40.00 5.35 9.24[N-tert
-Butoxycarbonyl-2-(3-Example 4) L-leucine methyl ester was added to a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 5 mA of tetrahydrofuran at 4°C or lower. - Hydrochloride 350ff1g, 1
-Hydroxybenzotriazole 390ff1g,
1 g of N-methylmorpholine and 440 r1 g of dicyclohexylcarbodiimide are added in sequence, and the mixture is stirred overnight in an ice chamber. The resulting precipitate was removed in an oven, the P solution was concentrated under reduced pressure, 50 ml of ethyl acetate was added, insoluble materials were removed, and the P solution was mixed with a 0.5 M citric acid aqueous solution, water, and saturated hydrogen carbonate).
IJium aqueous solution.

Washed sequentially with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily [N-tert-butoxycarbonyl-
2-(3-pyridyl)thiazolidine-4-carbonyl]
830 mg of -L-leucine methyl ester was obtained.

3 ml of trifluoroacetic acid was added to 800 rr@ of the obtained compound under ice cooling, and the mixture was stirred at room temperature for 3 hours.

The reaction solution was concentrated under reduced pressure, 10 ml of ethyl acetate was added, and the mixture was concentrated again under reduced pressure. The residue was dissolved in 10 m4 of ethyl acetate.

Under ice cooling, 3 ml of 2,2N-hydrogen chloride-dioxane solution
Add to the mixture and leave it in an ice room overnight. The crystals were separated, washed with ethyl acetate, and dried to obtain [2-(3-pyridyl)100'C elemental analysis value (C16H23N, O, S・C% H
Hook theoretical value 45.24 6.31 Experimental value 45.21 5.98 2HC1@415H,0) N ((to) S(to) 9.89 7.55 9.85 7.55 Example 5 N - tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid was treated in the same manner as in Example 4 using L-α-aminobutyric acid methyl ester hydrochloride as a starting material to obtain 2-[2 -(3-pyridyl)
Thiazolidin-4-yl]carbonylaminobutyric acid methyl ester dihydrochloride was obtained. Melting point 98~100℃ Elemental analysis value (C,, H,, N303S @ 2HC16
(as H2O) C (to) Theoretical value 42.00 Experimental value 42.08 Example 6 N-tart-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and D-methionine ethyl ester/hydrochloride As a starting material, it was treated in the same manner as in Example 4 to obtain [2-(3-pyridyl)thiazolidine-4-carbonyl]-D-methionine ethyl ester dihydrochloride.

Melting point 94-966C Elemental analysis value CC+5H2sNsOsSz・2HC1-/
As H2O) C open H open N hook S open C1 hook theoretical value 42.07 5.87 9.20 14.04
15.52 Experimental value 42.17 5.89 8.89
13.77 15.68 Example 7 N-tert-butoxycarbo=/Lz-2-(3-
[2-(3-pyridyl)thiazolidine-4-carboxylic acid and L-methionine amide hydrochloride were treated in the same manner as in Example 4, using as starting materials, [2-(3-pyridyl)thiazolidine-4
-carbonyl]-L-methioninamide dihydrochloride was obtained. Melting point 131℃MS: m/z 340 (M”
-2HC1) Example 8 N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and glycine methyl ester/hydrochloride were used as starting materials.

The same treatment as in Example 4 was carried out to obtain [2-(3-pyridyl)thiazolidine-4-carbonylcoglycine methyl ester dihydrochloride. Melting point 116-118℃ Elemental analysis value (C+tH+5NzOsS・2HC1-H
, O) C (to) H (to) N (to) Theoretical value 38.72 5.14 11.29 Experimental value 38.99 4.62 10.99 Example 9 N -tert-butoxycarbonyl-2- (3-Pyridyl)thiazolidine-4-carboxylic acid 600 ■.

In a solution of 10 ml of tetrahydrofuran, add 3-
200 rl 1 g of methylthiopropylamine, 390 rl 1 g of l-hydroxybenzotriazole, and 440 ff 1 g of dicyclohexylcarbodiimide are sequentially added and stirred at room temperature for 3 hours. The resulting precipitate was removed, and the P solution was concentrated under reduced pressure.

The residue is dissolved in 50 ml of ethyl acetate. The ethyl acetate bath solution was washed sequentially with 0.5 M citric acid aqueous solution, water, saturated sodium carbonate aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-(3-methylthiopropyl) -
250 mg of 3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide was obtained. 2 ml of trifluoroacetic acid was added to the obtained compound 2501TIg under ice cooling and treated in the same manner as in Example 4 to obtain an oily N-(3-methylthiopropyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. dihydrochloride 13
0 mg was obtained.

NMR (DMSO-d,) δ: 1.6-1.9 (2H), 2.08 (3H), 2
．． 4-2.6 (2H).

3.0-3.7 (4H), 4.05-4.50 (
IH), 5.9-6.1 (IH), 7.4-9.2 (
4H) Example 1O Using N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and n-heptylamine as starting materials, the same treatment as in Example 9 was performed to obtain N
-n-hebutyl-2-(3-pyridyl)thiazolidine-
4-carboxamide dihydrochloride was obtained.

NMR (DMSO-d6) δ: 0.6-1.1 (3H), 1.1-1.8 (l
0H), 2.9-3.9 (4H).

4.4-4.7 (IH), 6.20 (IH), 8.
0-8.3 (IH).

8.6-9.3 (3H) Example 11 N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 2-aminopyridine were treated in the same manner as in Example 9 -(2-pyridyl)-2-(3-pyridyl)thiazolidine-4-carboxamide trihydrochloride was obtained. Melting point 145℃ Elemental analysis value (C,, H, 7N40 S as Cl 3) C5%) HeF, I S (?n theoretical value
42.49 4.33 8.10 Experimental value 42.
83 4.58 8.03 Example 12 N-(2- Methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 129°C Elemental analysis value (as C+aH+oNiO□SCI)C
Hook H (to) N hook theoretical value 49.49 4.93 10.82 experimental value
49.29 5.18 10.38 Example 13 2-(3-pyridyl)thiazolidine-4-carboxylic acid 6
A mixture of 30 mg of m-aningine, 350 mg of m-aningine, 1 g of dicyclohexylcarbodiimide 650 ff and 4301 Qg of 1-hydroxybenzotriazole in 8 ml of dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, and insoluble materials were removed. P solution twice with water and sodium bicarbonate aqueous solution.

It was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by preparative thin layer chromatography to obtain N-(3-methoxyphenyl).
230 mg of -2-(3-pyridyl)thiazolidine-4-carboxamide was obtained. This compound was dissolved in ethyl acetate, and 1 mt of 2N hydrogen chloride-dioxane solution was added.

Count the solids produced.

After washing with ethyl acetate and drying, 250 ml of N-(3-methoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 129°C Elemental analysis value (as Cl6H19N302 S C'2) C hook H hook N opening 8%) Theoretical value 49.49 4.93 10.82 8.26
Experimental value 49.49 5.08 10.56 8.24
Example 14 N-(2-phenylethyl)-2-(3-pyridyl)thiazolidine-4 was prepared from 2-(3-pyridyl)thiazolidine-4-carboxylic acid and 2-phenylethylamine according to the method of Example 13. -Carboxamide dihydrochloride was obtained. Melting point: 115℃ Elemental analysis value (Cl7H21NsOS
As C12) C open H (to) N (to) S hook theoretical value 52.85 5.48 10.88 8.30
Experimental value 52.25 5.74 10.77 8.16
Example 15 According to the method of Example 13, the compound obtained in Reference Example 2 and 3-
N-(3-methylthiopropyl)-2-(4-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained from methylthiopropylamine. Melting point 70'C Original purple analytical value (as CuHz+N5O8, CI) C hook H open N (To) Theoretical value 42.16 5.72 11.35 Experimental value 4
1.65 5.83 IO, 87 Example 16 A solution of 1.50 g of pyridine-2-aldehyde and 1.70 g of L-cysteine in 50% ethanol was stirred at room temperature for 4 hours. The reaction mixture from which insoluble materials were removed was concentrated under reduced pressure to obtain a syrup-like substance. Add this to 3 parts of tetrahydrofuran
Dissolve in 5 ml of dicyclohexylcarbodiimide 2.
89g, 1-hydroxybenzotriazole 1.89g
and 1.62 g of 3-methylthiopropylamine were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate,
Insoluble matter was removed by filtration. (drink the solution twice with water and hydrogen carbonate)
IJum aqueous solution and water twice.

The mixture was washed successively with saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (eluent: toluene:ethyl acetate = 1:1).
) to give N-(3-methylthiopropyl)-2-
(2-pyridyl)thiazolidine-4-carboxamide 1
．． 50 g was obtained. 800 μm of this compound was dissolved in ethyl acetate, and a 2N aqueous chloride-dioxane solution was added. The residue obtained by distilling off the solvent was dried to obtain 830 mg of N-(3-methylthiopropyl)-2-(2-pyridyl)thiazolidine-4-carboxamide hydrochloride. Melting point 65°C Original cumulative digit value (CI3H2□N, 02S2C
1) C hook H (To) N hook S 5%) Theoretical value 44.37 6.30 11.94 18.2
2 Experimental value 44.59 6.09 11.79 L8
．． 38 Example 17 2-(3-pyridyl)thiazolidine-4-carboxylic acid 6
301T1g, 3.4.5-) dimethoxyaniline 520■, dicyclohexylcarbodiimide 650m
g and l-hydroxybenzotriazole 4301rg
A mixture of 8 ml of N,N-dimethylformamide was stirred at room temperature overnight. Dilute the reaction mixture with ethyl acetate.

Insoluble matter was removed by P. P solution with hydrogen carbonate) IJum water,
The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate),
N-(3,4,5-)rimethoxyphenyl)-2
370 mg of -(3-pyridyl)thiazolidine-4-carboxamide was obtained. Add this compound to 10 ml of ethyl acetate.
and 2 mZ of 2N aqueous chloride-dioxane solution was added. The resulting solid was separated, washed with ethyl acetate, and dried to give N-(3,4,5-trimethoxyphenyl)-2-(3
-Pyridyl)thiazolidine-4-carboxamide dihydrochloride (200 µm) was obtained. Melting point 130-132°C Elemental analysis value (as C+a H2sN304 S C1) C hook H open N hook S hook Theoretical value 48.22 5.17 9,37 7.15 Experimental value 48.23 5.35 9.02 7.12 Example 18 From 2-(3-pyridyl)thiazolidine-4-carboxylic acid and aniline according to the method of Example 17.

N-phenyl-2-(3-pyridyl)thiazolidine-4
-Carboxamide dihydrochloride was obtained.

Melting point 1.45-148°C NMR (DMSO-da) δ: 3.4-4.2 (2H), 4.96 (IH, t)
, 6.31.6.35 (total IH), 7.0-7.
4 (3H), 7.6-7.8 (2H).

8.10 (IH, dd), 8.9-9.0 (2H),
9.3 (IH) Example 19 N-benzyl-2-(3-pyridyl)thiasoridine-4-carboxamide dihydrochloride was obtained from ponic acid and benzylamine according to the method of Example 17. Melting point 12
6-130'C NMR (DMSO-d6) δ: 3.2-3.7 (2H), 4.3-4.6 (3
H), 6.08.6.14 (together IH), 7.3 (
5H), 8.06 (IH, dd).

8.7-9.0 (2H), 9.1-9.2 (IH
) Example 20 N-(p-methylpencyl)-2-(3-pyridyl)thiazolidine- 4-carboxamide dihydrochloride was obtained. Melting point 130-136℃ 2-(3-pyridyl)thiazolidine-4-cal elemental analysis value (C,, H,, N, OS
As CI2) C open H open N (marty S (to) Theoretical value 52.85 5.48 10.88 Experimental value 5
2.64 5.56 10.818.30 8.38 Example 21 N-(4- Phenylbutyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point: 100-104°C Elemental analysis value (C,, I2.
N3OS CI, ・0.2 as I20) C (capital)
H (to) N hook S hook C1 (to) Theoretical value 54.36
6.15 10.01 7.64 16.84 Experimental value 54.44 6.16 10.08 7.68 16
．． 59 Example 22 From 2-(3-pyridyl)thiazolidine-4-carboxylic acid and N-methylbenzylamine, according to the method of Example 17, N-benzyl-N-methyl-2-(3-pyridyl)thiazolidine- 4-carboxamide dihydrochloride was obtained. Melting point 105-110℃ Elemental analysis value (C,, I2.N
, OS CI, ・H, O) C hook H hook N (%!
S (To) C1 hook theoretical value 50.50 5.73 1
0.39 7.93 17.54 Experimental value 50.63
5.60 10.43 7.98 17.26 Example
23 From 2-(3-pyridyl)thiazolidine-4-carboxylic acid and p-(4-phenylbutoxy)benzylamine,
According to the method of Example 17, N-[p-(4-phenylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point 13
3~135°C elemental analysis value (CzaHs+N30□SC
I, 0.2 H, 0) C hook H hook N hook S hook C1 (To) Theoretical value 59.58 6.04 8.02 6.12
13.53 Experimental value 59.58 6.02 7.96
6.23 13.58 Example 24 From 2-(3-pyridyl)thiazolidine-4-carboxylic acid and p-hebutyloxybenzylamine, Example 17
N-(p-hebutyloxybenzyl)-
2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 155-160°C Elemental analysis value (Cts H>x N3O□SCI, ・0.
3 As I20) C hook H (To) N%) S hook C1 (To) Theoretical value 56.16 6.88 8.5
4 6.52 14.41 Experimental value 56.11 6.8
4 8.47 6.53 14.50 Example 25 2-(3-pyridyl)thiazolidine-4-carboxylic acid,
! -m-(4-7enylbutoxy)benzylamine and N-[m-(4-phenylbutoxy)benzyl]-2-(3-pyridyl)thiazolidine-4-carboxamide.2 The hydrochloride was obtained. melting point
88-93°C Elemental analysis value (C26I31 N, O□S CI2-0.
5 As I20) C hook H open N (to) S (to) C
I (To) Theoretical value 58.97 6.09 7.94 6
．． 06 13.39 Experimental value 58.96 6.07 7
．． 96 6.11 13.36 Example 26 From 2-(3-pyridyl)thiazolidine-4-carboxylic acid and m-hebutyloxybenzylamine, Example 17
N-(m-hebutyloxybenzyl)-
2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 135-140℃ Elemental analysis value (as C23HssNs 02 S CIt) CF4 HF4 N5%) SW4 theoretical value
56.76 6.84 8.64 6.59 Experimental value 5
6.68 6.85 8.69 6.62 Example 27 2-(3-pyridyl)thiazolidine-4-carboxylic acid and 2-amino-5-[(4-phenylbutyl)thio]-1
, 3,4-thiadiazole.

According to the method of Example 17, N-[5-[(4-phenylbutyl)thio]-1,3,4-thiadiazol-2-yl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloric acid Got salt.

Melting point 99-105℃ Elemental analysis value (Cz+) (as 2sO8xc1z)C(
g) H hook N (g) S hook theoretical value 47.54 4.75 13.20 18.1
3 Experimental value 47.58 4.84 13.09 18.
28 Example 28 N-(3-methylthiopropyl)-2-(3-
Quinolyl)thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point 122-126℃ Elemental analysis value (C, TH2, N30S2CJ2-0.5H
20) C open H□□□ N (to) S■)
C1 open theoretical value 47.55 5.63 9.78
14.93 16.51 Experimental value 47.57 5,72
9.75 15.02 16.47 Example 30 Example 29 From 2-(3-quinolyl)thiazolidine-4-carboxylic acid and 4-phenylbutylamine, N-(4-7enylbutyl )-2-(3-quinolyl)thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point: 116-122°C Elemental analysis value (CtsH2
? Ns OS C12) C (To) H (To) N
(Fly S (to) theoretical value 59.48 5.86 9.0
5 6.90 Experimental value 59.13 5.84 8.99
7.14 Using 2-(3-pyridyl)thiazolidin-4-carboxylic acid and pyrrolidine as starting materials, the same procedure as in Example 17 was carried out to obtain l-[2-(3-pyridyl)thiazolidin-4-ylcarponylcopyrrolidine. The dihydrochloride was obtained. Melting point 136°C NMR (DMSO-d6) δ: 1. ．． 60-2.13 (4H, m), 3.06
~3.90 (6H, m).

4.55-4.71 (IH, m), 6.09.6
．． 26 (In total, IH.

s), 8.08 (IH, dd), 8.72~
9.20 (3H, m) Example 31 4-[2-(3-pyridyl) Thiazolidin-4-ylcarbonylcomorpholine dihydrochloride was obtained. Melting point 1
43°C NMR (DMSO-d6) δ: 2.97-3.78 (IOH, m), 4.
62-4.78 (IH, m).

6.00.6.23 (total IH, each s), 8.0
5 (IH, aa) 8.71-9.10 (3H, m
) Example 32 Using 2-(3-pyridyl)thiazolidine-4-carbo, acid and 1-7 enylbiperazine as starting materials, Example 17
1-phenyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine trihydrochloride was obtained.

Melting point 169°C NMR (DMSO-d6) δ: 3.04-4.20 (10H, m), 4.64
~4.84 (IH, m).

6.00.6.23 (Total IH, 8 each), 7.04
~7.64 (5H.

m), 7.99-8.14 (LH, m), 8.70-9
．． 16(3H,m) Example 33 2-(3-pyridyl)thiazolidine-4-carboxylic acid and piperidine were treated in the same manner as in Example 17 to produce 1-[2-(3-pyridyl)thiazolidine. -4-
ylcarbonylcopiperidine dihydrochloride was obtained. melting point
1726C elemental analysis value (CI4 I21 NsOS CIt・0.
3 As I20) C hook H hook N (to) S hook C1
Hook theoretical value 47.27 6.12 11.81 9.01
19.93 Experimental value 47.36 6.03 11.7
5 9.01 19.71 Example 34 Example 35 2-(3-pyridyl)thiazolidine-4-carboxylic acid and cyclohexylamine as starting materials.

N-cyclohexyl-2 was treated in the same manner as in Example 17.
-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point 139°C NMR (DMSO
-d,) δ: 0.90 to 1.95 (11H, m), 3.06
~3.69 (3H, m).

4.39 (LH, dd), 6.07.6.14
(Total IH, each s).

8.03 (IH, dd), 8.46-9.13 (3
H, m) Example 1 using 2-(3-pyridyl)thiazolidine-4-carboxylic acid and isoamylamine as starting materials
Treated in the same manner as in 7 to obtain N-(3-methylbutyl)-2-
(3-pyridyl)thiazolidine-4-carboxamide.
The dihydrochloride was obtained. Melting point: 115℃ Elemental analysis value (Cl4H
, 2N3OS CI2・0.3 H, 0) C (to) H hook N hook S) Theoretical value 47.14 6.39 11.78 8.99
t/, t'6 Experimental value 47.24 6.59 ++-15-&9.
10 Example 36 Example 37 Using 2HC1 2-(3-pyridyl)thiazolidine-4-carboxylic acid and 4-benzylpiperidine as starting materials, Example 1
4-benzyl-1-(2-(3-
pyridyl)thiazolidin-4-ylcarbonylcopiperidine dihydrochloride was obtained.

Melting point 135°C NMR (DMSOds) δ: 0.76-2.06 (5H, m), 2.35-
4.54 (8H, m).

4.68-5.08 (IH, m), 6.0B, 6
．． 28 (Total IH1 each s), 7.06-7.2
8 (5H, m), 8.07 (LH.

dd )t 8.71-9.30 (3H,m)2-
(3-pyridyl)thiazolidine-4-carboxylic acid, and 1
Using 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine as a starting material, the same treatment as in Example 17 was carried out to obtain a Digin trihydrochloride was obtained.

Melting point 144°C NMR (DMSO-d, ) δ: 1.85-4.86 (17H, m), 5.97
, 6.18 (Total IH.

Each a), 7.10 to 7.48 (5H, m), 8.
06 (IH, dd).

8.65-9.12 (3H,m) Example 38 Example 39 Using 2-(3-pyridyl)thiazolidine-4-carboxylic acid and p-(4-phenylbutoxy)aniline as starting materials, Example 17 and The same treatment was performed to obtain N-[p-(4-phenylbutoxy)phenyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride.

Melting point 111℃ Elemental analysis value (C*sHt*NsO, as 5CIt)C
(%) H (%) N (%) S (%) Theoretical value 59.
28 5.77 8.30 6.33 Experimental value 59.
65 5.76 8.40 6.39 2-(3-pyridyl)thiazolidine-4-carboxylic acid 510 mg, 1-
490mg for hydroxybenzotriacy, /Nadeshi/
l/amine 680171g, 7″) Lahydrofuran 1
A solution of 500 tIlg of dicyclohexylcarbodiimide and 3 ml of tetrahydrofuran was added dropwise to the 2 mA mixture under water cooling, and the mixture was stirred for 1 hour under water cooling and then at room temperature for 12 hours. The reaction mixture was diluted with 30 m# of ethyl acetate, and the insoluble matter was removed in the oven. Solution F was washed successively with a saturated aqueous solution of hydrogen carbonate, water, and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate), recrystallized from ethyl acetate, and N-nonadecyl-2-
(3-pyridyl)thiazolidine-4-carboxamide.

Melting point 108-110℃ Elemental analysis value (CtaH+aN30S e 115 Hz
as O) C (%) H (%) N (%) s
(%) Theoretical value 70.30 10.20 8.78
6.70 Experimental value 70.37 10.34 8.83
6.80C (%) H (%) N (%) S (%) Theoretical value Experimental value 65.48 65.16 8.68 8.80 12.06 11.91 9.20 9.04 Example 41゜Example 40 Using 2-(3-pyridyl)thiazolidine-4-carboxylic acid and decylamine as starting materials, N-decyl-2-(3-pyridyl)thiazolidine-4-carboxamide was prepared in the same manner as in Example 39. Obtained.

Melting point 88℃ Elemental analysis value (CnHs.N, O3) N-tert
-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and tyramine were treated in the same manner as in Example 39, and N-[2-(p-hydroxyphenyl)ethyl] -3- Tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide was obtained.

Melting point 76°C NMR (CDCI, ) δ: 1.34 (9H, 3), 2.72 (2H, t
), 3.22 (IH, dd)t3.4:3”3.70
(3H, m), 4.80 (IH, dd), 5
．． 99 (IH, s) + 6.70-7.03 (4H, m
), 7.19-7.32 (IH, m), 7.75-7.
84 (IH, m), 8.51 (IH.

dd), 8.63 (IH, d) and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate), the product of Example 42 was dissolved in ethyl acetate, and 1.5 tnl of 2N hydrogen chloride-dioxane solution was added. Ta. Count the solids produced.

Wash with ethyl acetate, dry and give N-benzyl ox 2-(
3-pyridyl)thiazolidine-4-carboxylic acid soom
g, o-benzylhydroxylamine hydrochloride 380
mg, 1-hydroxybenzotriazole 480■,
A solution of 490 mg of dicyclohexylcarbodiimide and 5 ml of tetrahydrofuran was added dropwise to a mixture of 240 mg of N-methylmorpholine and 15 ml of tetrahydrofuran under water cooling, and the mixture was stirred for 1 hour under water cooling and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and insoluble materials were removed. Fluid F was washed with a saturated aqueous solution of hydrogen carbonate and a saturated saline solution. Melting point: 115°C NMR (DMSO-da) δ: 3.02-3.52 (2H, m).

4.90 (2H, s), 6.00°7.28~7.53 (5H, m)t9.26 (3
H,m) 4.07-4.20 (IH,m).

6.08 (total IH, each s).

8.07 (IH, dd), 8.64 ~ Example 4 81017 g of 3°N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid.

To a mixture of 2601 T1 g of 4-methylpiperidine, 530 ff1 g of 1-hydroxybenzotriazole, and 10 at of tetrahydrofuran, 540 ff1 g of dicyclohexylcarbodiimide and 5 ml of tetrahydrofuran were added under water cooling.
mL of the solution was added dropwise, and the mixture was stirred for 1 hour while cooling with water, and then stirred at room temperature for 12 hours. Dilute the reaction mixture with 30 ml of ethyl acetate.

Insoluble matter was removed in an oven. Solution F was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 4-methyl-1-[3-te
rt-Butoxycarbonyl-2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperidine was obtained. 5 rnl of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with a saturated aqueous solution of hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 4-
Methyl-1-[2-(3-pyridyl)thiazolidine-4
-ylcarbonylcopiperidine was obtained. This compound was dissolved in ethyl acetate, and 3 mL of 2N hydrogen chloride-dioxane solution was added. Separate the resulting solid, wash with ethyl acetate, and dry.

4-Methyl-1-[z=-(3-pyridyl)thiane Melting point 130°C Elemental analysis value (as C, 5H23NaO3C1!) C stem) H (%) N (%) Theoretical value 49.45 6.39 11. 53 experimental value
49.59 6.60 11.47S (%) 8.80 8.63 Example 44゜Example 45゜N -tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and N, N - Using dimethylethylenediamine as a starting material, the same treatment as in Example 43 was performed to obtain N-[2-(N',N'-dimethylamino)ethyl]-2-(3-pyridyl)thiazoridine-4-carboxamide trihydrochloric acid. Got salt.

Melting point 150°C NMR (DMSO-d,) δ: 2.63-3.80 (12H, m), 4.26-
4.50 (LH, m).

6.01.6.08 (Total IH9 each s) + 8.
06 (I Hldd)+8.70~9.18 (3
m) MCI N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and N-methyl-N
- Using phenylhydrazine as the starting material.

Treated in the same manner as in Example 43 to obtain N'-methyl-N/-7
Enyl-2-(3-pyridyl)thiasoricin-4-carbohydrazide dihydrochloride was obtained.

Melting point 145°C NMR (DMSOda) δ: 3.04-3.72 (5H, m), 4.28-
4.50 (IH, m).

6.03.6.12 (total IH, each s), 6
．． 70-7.32 (5H, m), 8.07 (LH, d
d), 8.6'J-9,17 (3H, m) Example 46
゜Example 47゜N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 4-phenylpiperidine were used as starting materials and treated in the same manner as in Example 43 to obtain 4-phenyl-1 -[2-(3-Biridyl)thiazolidin-4-ylcarbonylcopiperidine dihydrochloride was obtained.

Melting point 115°C NMR (DMSOda) δ: 1.32-2.08 (4H, m), 2.58-
3.82 (6H, m).

3.96-5. OO(2H,m)t 6.04.6.
28 (Total LH.

Each a), 7.08 to 7.44 (5H, m), 8.
06 (IH, dd).

8.68-9.16 (3H, m) MCI N Treated in the same manner as in Example 43 using tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 1-methylpiperazine as starting materials. 1-methyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine trihydrochloride was obtained.

Melting point 182°C NMR (DMSO-da) δ: 2.62-5. OO(14H,m), 6.03
．． 6.22 (Total IH.

each s), 8.09 (IH, dd), 8.70-9
．． 20 (3H, m) Example 48゜Example 49゜COOC(CH3)3 HC1 N -tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 1-benzylpiperazine as starting materials, The same treatment as in Example 43 was carried out to obtain 1-benzyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine.degree.3 hydrochloride.

Melting point 165°C NMR (DMSO-d, ) δ: 2.76-4.80 (13H, m), 5.9
3. ' 6.15 (total IH, each s), 7.3
6-7.80 (5H, m), 8.03 (IH.

dd), 8.6:2-9.10(3H,m)N-te
Using rt-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and 1-(4-phenylbutyl)piperazine as starting materials, the same procedure as in Example 43 was used to obtain the 1-(4-) dilbutyl)-4-[2-(3
-pyridyl)thiazolidin-4-ylcarbonylcopiperazine trihydrochloride was obtained.

Melting point 157°C NMR (DMSOda) δ: 1.33-1.85 (4H, m), 2.30
~2.76 (8H, m).

2.86-3.78 (6H, m), 3.99-4.
30 (IH, m).

5.96.6.17 (total IH, each s), 7
．． 12-7.44 (6H, m), 8.12 (IH,
dd), 8.72-9.17 (2H, m) Example 50° was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sulfuric acid. The crystals obtained by concentration under reduced pressure were recrystallized from ethyl acetate to give N'-phene N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-.
680 mg of carboxylic acid.

Phenylhydrazine 240■, 1-hydroxybenzotriazole 450 [[1g, tetrahydrofuran 20
A solution of 450 IQg of dicyclohexylcarbodiimide and 5 ml of tetrahydrofuran was added dropwise to the mixture under water cooling, and the mixture was stirred for 1 hour under water cooling and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and insoluble matter was removed. (p solution is saturated hydrogen carbonate) IJium aqueous solution,
It was washed successively with saturated brine and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain N'-phenyl melting point 155°C NMR (CDC13+DMSO-d,) δ: 3.2
2-3.56 (2H, m), 4.22-4.36 (IH
, m).

5.60.5.72 (Total IH, each s), 6.7
2-7.44 (6H.

m), 7.81~? , 9.5 (IH, m), 8.56 (
IH, dd).

8.79 (IH, d) Example 51° was obtained. 5 mZ of trifluoroacetic acid was added to the obtained compound with N
-[2-(p-hydroxyphenyl)ethyl]3t
ert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide 540 μ, potassium carbonate 180 mg, N,N-dimethylformamide 10
Add 1-promo-4-phenylbutane 2 to the mixture of m1 at room temperature.
801rll (and 5r of N,N-dimethylformamide
nt solution was added. The mixture was stirred at 80° C. for 3 days, and after cooling, 20 mZ of water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Wash the organic layer sequentially with water and saturated brine, and dilute with anhydrous sulfuric acid)
It was dried with IJum. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 1:3).

5 ml of N-[2-['p-(4-]dinylbutoxy)phenyl]ethyl]-3-tert-7'')oxyluponylloacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours.The reaction solution was vacuumed. Concentrate and dissolve the residue in ethyl acetate.

The mixture was washed successively with a saturated aqueous solution of hydrogen carbonate and saturated brine, and dried over anhydrous sulfuric acid. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate).

Dissolve N-[2-(p-(4-phenylbutoxy)phere) in ethyl acetate and add 2N hydrogen chloride-dioxane solution to 1
Added rnl. The resulting solid was separated, washed with ethyl acetate, and dried to give N-[2-[p-(4-phenylbutoxy)phenyl]ethyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. I started.

Melting point 102℃ Elemental analysis value (as CztHssN30zSC1t)C
(%) H (%) N (%) S (%) Theoretical value
60.67 6.22 7.86 6.00 Experimental value
60.51 6.15 7.94 5.97 Example 5
2゜Example 53゜HCl N-[2-(p-hydroxyphenyl)ethyl]-3-
tart-butoxycarbonyl-2-(3-pyridyl)
Thiazolidine-4-carboxamide and 1-bromo-3-
Using phenylpropane as a starting material, the same treatment as in Example 51 was performed to obtain N-[2-[p-(3-phenylpropoxy)phenyl]ethyl]-2-(3-pyridyl)thiazolidine-4-carboxamide-2. The hydrochloride was obtained.

Melting point 98℃ Elemental analysis value (CtaHsr Ns Ot S C1!・
As 0.3H, O) C (%) H ■) 8 flights) S (%
) C1 ■) Theoretical value 59.38 6.06 7.99
6.10 13.48 Experimental value 59.37 6.05
8.01 6.09 13.3121(CI N-C2-(p-hydroxyphenyl)ethyl]-3-
tertbutoxy7carbonyl-2-(3-pyridyl)thiazolidi/-4-carboxamide and 1-bromo-2-phenylethane as starting materials.

Treated in the same manner as in Example 51 to obtain N-[2-[p-(2-
7enylethoxy)phenyl]ethyl]-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

NMR (DMSO-ds) δ: 2.58-3.64 (8H1m), 4.11-4.
40 (3H1m).

6.03(1)(,s), 6.83~7.35(5H
,m)e 8.02(11(,dd), 8.66~
8.85 (IH, m), 8.88~9.01 (IH
, m), 9.07 (IH, dd) MS: m/
z 433 (M”-2XHCl) Example 54 p-(3-methylbutoxy)benzylamine 1.13 g
, 1.29 g of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 1 dicyclohexylcarbodiimide
．． A mixture of 25 g of N,N-dimethylformamide and 0.82 g of 1-hydroxybenzotriazole in 20 mZ was stirred at room temperature overnight. The reaction mixture was diluted with 100 mA of ethyl acetate, and insoluble matter was separated from P. (P solution is saturated hydrogen carbonate) IJum aqueous solution.

The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain N-[p-(3-methylbutoxy)benzyl]-
2.20 g of 2-(3-pyridyl)thiazolidine-4-carboxamide was obtained. Ethyl acetate of this compound 60mt
4 ml of 4N hydrogen chloride-dioxane solution was added to the medium solution. The separated solid was collected, washed with ethyl acetate, and dried under reduced pressure to give N-[P-(3-methylbutoxy)benzyl].
2.30 g of -2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 120-128℃ Elemental analysis value (C21H29N, 02SC12・0.4H
, O) C (%) H (%) N (%) S (%
) CI (%) Theoretical value 54.17 6.45 9.
02 6.89 15.23 Actual value 54.23 6.
37 8.96 7.00 15.16 Example 55~
80 The following compound was obtained in the same manner as in Example 54.

Example 81゜2-(3-pyridyl)thiazolidine-4-carboxylic acid 0
．． 34g, ]-Dedecylvi 99f 00.3f, ]-
Hydroxybenzotriazole 0.33g, N,N-
0.34 g of dicyclohexylcarbodiimide was added to a mixed solution of 10 ml of dimethylformamide under water cooling, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and insoluble materials were removed. Wash the f solution with saturated hydrogen carbonate solution), then wash with saturated saline solution, and add anhydrous sulfuric acid).
and concentrated under reduced pressure. Add 5 ml of ethyl acetate to the residue.
was added to remove insoluble matter. 2N hydrogen chloride-dioxane was added to the P solution. The resulting crystals were collected, washed with ethyl acetate, and dried to give 1-decyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine.
0.63 g of triphosphate was obtained.

Melting point 170℃ Elemental analysis values (as C2, H4, N40SCI, ・H, O)
Trout theoretical value 50.59 7.94 10.26 5.
87 19.48 Experimental value 50.50 7.81 1
0.22 6.07 19.47 Example 86° CHO 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine 40IT1g, dichloromethane 5rnl in a solution of, 0.5 m of a mixture of formic acid and acetic anhydride (5:3 v/v)
1 was added and stirred overnight at room temperature. Add 2 ethyl acetate to the reaction solution.
0IIIt was added, washed with a 5% aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate.

Concentrate under reduced pressure to obtain oily 1-[3-formyl-2-(3-
pyridyl)thiazolidin-4-ylcarbonyl]-4-
30 μl of (3-phenylpropyl)piperazine was obtained.

NMR (CDC15) δ: 1.6-2.0 (2H9m), 2.2-2.
8 (8H+m), 3.0-3.4 (2H, m),
3.6-3.9 (4H, m), 5.0-5.7 (I
H.

m) t 6.14, 6.4 (Total IH, 8 each
), 7.0-7.5 (5H.

m), 7.6-7.9 (IH, m), 8.24 (IH,
s), 8.4-8.8 (3H, m) MS: m/z 424 (M'') Example 87° NMR (CDCl3) δ: 1.40 (9H, s), 1.6-2. ] (
2H, m), 2.2-2.8 (8H, m), 3.0-3
．． 4 (2H, m), 3.4-4.0 (6H.

m), 5.08 (IH, br t), '6.16 (IH
, br s).

7.0~7.5 (5H, m), 8.4~8.8'
(4H, m) MS: z/m 496 (M
”)3-tert-butoxycarbonyl-2-(3-
pyridyl)thiazolidine-4-carboxylic acid 650111
g and 1-(3-7enylprobyl)piperazine 40
0 ITIg was used as the starting material and treated in the same manner as in Example 54. Purify by silica gel column chromatography (eluent: ethyl acetate) without converting it to the hydrochloride.

Oily 1-[3-(tert-butoxycarbonyl)
-2-(3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine 56
0 mg was obtained.

Examples 88-89 The following compound was obtained in the same manner as in Example 87.

Example 90゜2-(3-pyridyl)thiazolidine-4-carboxylic acid 0
．． 84g・l-octylpiperazine 0.79g,
1-hydroxypenzotriazole 0.54g, N,
Add 0.82 g of dicyclohexylcarbodiimide to a mixture of 20 ml of N-dimethylformamide under water cooling.
Stir overnight at room temperature. Dilute the reaction solution with ethyl acetate.

Insoluble matter was removed by P. The P solution was washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

Ethyl acetate was added to the residue to remove insoluble matter, and the P solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent = 1O% methanol-ethyl acetate]. The obtained oil was dissolved in 25 ml of ethanol, and 0.32 g of fumaric acid was added. After standing for 2 days, the resulting crystalline P was removed, washed with cold ethanol and dried to give 1-octyl-4-[2-(3-pyridyl)thiazolidine-4-
0.72 g of carbonylcopiperazine fumarate was obtained.

Melting point 135°C Elemental analysis value (as C25H38N405S) C(I
H(IN(15(cA theoretical value 59.27
7.56 11.06 6.33 Experimental value 59.0
1 7.66 10.95 6.27 Examples 91 to 94 The following compounds were obtained in the same manner as in Example 90.

Example 1 - Hebutyl-4-[2-(3-pyridyl)-2-pyrrolin-5-ylcarbonylcohyperazine 570[rlg
was subjected to catalytic reduction in a solution of 20 ml of water and 20 ml of ethanol using platinum oxide as a catalyst until hydrogen absorption stopped.

After removing the catalyst, the F solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (5 g). Elution with a mixture of methanol-ethyl acetate (1:10) yielded l-hebutyl-4-[5-(3-pyridyl)pyrrolidine-2-
250 μl of ylcarbonylcohyherazine were obtained. Example 5
4, this trihydrochloride was obtained.

Melting point 138-143℃ Elemental analysis value (C,, H17N, OCI, -1,8H2O
) C (%) H (%) N (%) cl (%)
Theoretical value 50.41 8.18 11.20 21.2
6 Experimental value 50.49 7.83 1109 21.1
0 Example 134 To a mixed solution of 200fng of 3-phenylpropylethylenediamine and 81mg of N-methylmorpholine in 5ml of dimethylformamide was added 120mL of 1-hydroxybenzotriazole and 180mL of dicyclohexylcarbodiimide.
g and 170 μg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid were sequentially added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, insoluble materials were removed, and the P solution was concentrated under reduced pressure. A 0.5 N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was extracted with IN hydrochloric acid, and the aqueous layer was adjusted to pH 10 with potassium carbonate and extracted again with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to alumina column chromatography (20 g), eluting with a mixture of methanol and ethyl acetate (1:10). teN-(3
-Phenylpropylaminoethyl) -2-(3-pyridyl)thiazolidine-4-carboxamide (160 µ) was obtained. NMR and MS data of this compound are Example 115
It was consistent with that of the compound.

Example 135 To a solution of 50 μl of 1,3-dioxo-5-(3-pyridyl)thiacyridino[3,4-c]oxazolidine hydrochloride in 1 mZ of dimethyl sulfoxide is added 1-(3-7z) at room temperature.
A solution of Nylpropyl)piperazine 40Q in 0.5 ml of dimethyl sulfoxide was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(3 -Phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine 70 mg was obtained. The physicochemical properties of this product were consistent with those of Example 108.

Example 137 1-[2(1-tert-butoxycarbonyl-3-piperidinyl)thiazolidin-4-ylcarbony#]-4
- Dissolve 430 mg of (3-phenylpropyl)piperazine in 3 ml of dichloromethane and add 2 ml of trifluoroacetic acid.
was added and stirred at room temperature for 6 hours.

The reaction mixture was poured into 60 ml of saturated aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate.

The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonyl] 280 mg of piperazine was obtained. This compound was dissolved in 8 ml of ethyl acetate, and 1 ml of 4N hydrogen chloride dioxane solution was added. After stirring for 30 minutes, the resulting solid was removed and dried to give 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonylcopiperazine trihydrochloride 20
I got 0 mg.

Melting point 174-178℃ Elemental analysis value (022H, 7N4O3CI, 1.5H2
0) C (%) H (%) N (%) s (%) Theoretical value 49.02 7.48 10.39 5.95 Experimental value 49.02 7.40 10.29 6.00 Example 138 N-(p-hebutyloxybenzyl)-glyceramide 70mg, pyridine-3-aldehyde 50rl1g
of benzene 10ml1. A solution of 5 mg of tc p-toluenesulfonic acid in 2.5 ml of pyridine was added and the mixture was refluxed for 12 hours for azeotropic dehydration. From now on, the 9 anti-core temperature mixture was added twice with saturated aqueous sodium bicarbonate solution, three times with water, and once with saturated saline.
After washing, dry with anhydrous sodium sulfate.

It was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography to obtain 0 mg of N-(p-hebutyloxybenzyl)-2-(3-pyridyl)-1,3-dioxolane-4-carboxamide.

NMR (CDCI,) δ: 0.90 (3H, br t), 1.2-1.5
(8H), 1.6-2.0 (2°H), 3.95 (
2H, t, J-7Hz), 4.1-4.8 (5H)
.

5.89.5.99 (total 1) (), 6.6-7.
2 (I H, disappeared at D20) t 6.8-7.4 (5
1(), 7.6-7.8 (IH), 8.6-8
．． 7 (2H) MS: mHz 398 (M”) Example 139 1-(2-amino-3-hydroxypropionyl) -
4-(3-phenylpropyl)piperazine and pyridine-
3-aldehyde, according to the method of Example 138, 1
-(3-phenylpropyl)-4-(2-(3-pyridyl)oxazolidin-4-ylcarbonylcopiperazine was obtained.

Elemental analysis value (as C22H2sN<Ot) C (%)
H (%) N (%) Theoretical value 69.45 7.42 14.72 Experimental value 6
9.16 7.38 14.58M5: mHz
380 (M+) CH.

N-(3~phenylglopylaminoethyl)-2-(
3-pyridyl)thiazolidine-4-carboxamide 50
A mixed solution of Toluev 2 Lot containing 1 g of Ruraldehyde 17r and 100 rng of Molecular Sheep (4A) was heated at 120° C. for 8 hours in a sealed tube. The reaction solution is f
After filtration, the F solution was concentrated under reduced pressure and the residue was subjected to thin layer preparative chromatography (developed twice with 2% methanol-ethyl acetate,
Rf value 0.15), 1-(3-7enylbrobyl)-3-[2-(3-hy+)yl)thiazolidine-4-
ylcarbonyl]-2-(p-tolyl)imidazolidine (3.3 mg) was obtained.

NMR(CDCl,) δ: 1.55-1.93(3H,m), 2.39(
3H,s).

2.4; l'-2,87 (8H, m), 3.09 (I
H, dd, J=8Hz.

12Hz), 3.41 (IH, dd, J=4Hz,
J=12Hz).

4.07-4.30 (I H, m), 5.16 (
IH,s), 5.52 (IH.

s), 7.03-7.42 (IOH, m), 7
．． 60-7.81 (Eng. H.

m), 8.44 (IH2dd, J=2H2, J=5H2
).

8.63 (IH, d, J=2Hz) MS: m
Hz 472 (M”) Example 141 730 mg of 1-[2-(5,6-simethoxy3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine was dissolved in 25 ml of ethyl acetate.
ml and add 2N hydrogen chloride-dioxane solution while stirring at room temperature. The resulting powdery P is removed and dissolved in saturated sodium carbonate solution. Ethyl acetate is added, the organic layer is separated, washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography using 50 rmt of silica gel.

10% methanol-ethyl acetate), 1-[2-(5-methoxy-6-oxo-5,6-cyhydro-3-pyridyl)thiazolidin-4-ylcarbonylco-4-(3-phenylpropyl)hiheracin 210■ I got it.

NMR (DMSO-d,) δ: I-56~L94 (2Hlrn)s 2-2
0~2-80 (8Hlm)-2,90-4,40(
IOH, m), 5.28-5.66 (IH, m).

6.8σ~7.44 (7H, m) M S: m/z 442 (M”) Reference example 11
4 The following compound was obtained in the same manner as in Reference Example 80.

1-Promo 3-phenylbutane NMR (CDCl, ) δ: 1.29 (3H, d, J=7Hz), 2.
11 (2H, q, J=7Hz), 2.64-3.5
0 (3H, m), 7.24 (5H, s) Reference example 11
4 The following compound was obtained in the same manner as in Reference Example 101.

Ethyl 1-[4-(3-phenylbutyl)copiperazine carboxylate NMR (Cf)CI,) δ: 1.11-1.50 (6H, m), 1.5
6-3.05 (9H, m).

3.50 (4) I, t, J==6Hz), 4.
19 (2H, q, J=7H2), 7.24 (5H, B
) Reference Example 115 The following compound was obtained in the same manner as Reference Example 102.

1-(3-phenylbutyl)hyberazine NMR (CDC
l,) δ: 1.24 (3H, d, J=7Hz), 1.7
6 (2H, q, J=7 Hz), 1.93 (I
H9s), 2-10~2.46 (6H-rn)*
2.51-2.97 (5H, m), 7.00-7.
38 (5H, m) MS: (m/z) 218 (M
”) Example 142゜The following compound was obtained by treating in the same manner as in Example 90.

1-(3-7enylbutyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonylcopiperazine.
7 Malate melting point 166-168℃ Elemental analysis value (as C2?H34N, O, S) C (%)
H (%) N (%) S (%) Calculated value 61.58
6.51 10.64 6.09 Experimental value 61.21
6.45 10.58 6.42M5: (m/z
) 410 (M''-C4H,O4) Compound of the present invention (
I) is a pharmaceutical composition as it is or mixed with known pharmaceutically acceptable carriers, excipients, etc. [Example 1 tablets, capsules, powders].

Granules, pills, ointments, syrups, injections, inhalants,
It can be safely administered orally or parenterally. Dosage is subject to administration.

Although it varies depending on the route of administration and symptoms, etc. 2 Usually for adults 1
041-500 mg per day preferably 1-200+r
! g and is administered orally or parenterally in 2 to 3 divided doses a day.

Prescription Example 1 Tablet Compound of Example 91 20mg Lactose
57 mg Corn starch 38 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1■ Total amount 120 mg 20 g of the compound of Example 91, 57 g of lactose, and 38 g of corn starch are mixed uniformly. Next, 40 g of 10% hydroxypropylcellulose solution is added and wet granulation is carried out. After sieving, dry. 1 g of magnesium stearate is added to the obtained granules and mixed.

7 rIV/m Compress into tablets using a 5.6 R mortar.

Formulation Example 2 Capsule Compound of Example 91 15rl 1g Crystalline cellulose 40■ Crystalline lactose 144 mg Magnesium stearate 1rr@Total amount 200ff1g 15g of the compound of Example 91, 40g of crystalline cellulose.

144 g of crystalline lactose and 1 g of magnesium stearate were mixed uniformly and filled into No. 3 capsules using a capsule filling machine to form capsules.

Formulation example 3 Freeze-dried preparation Compound D-mannitol 11 of Example 91 in 1 vial 0 mg Total amount 1 mg Take 800 m4 of water, add 1 g of compound 1rr of Example 91 and 5001 g of D-mannitol one after another, dissolve, and add water to make 11. do. After passing this solution aseptically.

Fill 1 mt each into vials and freeze-dry to make an injection that dissolves before use.

Patent applicant Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. 5- to 6-membered heterocyclic group, R^2: hydrogen atom, lower alkyl group, or the same group as R^1, X^1: optionally substituted with an oxygen atom, sulfur atom, or lower alkyl group Methylene group, Y^1: oxygen atom, sulfur atom, or group represented by the formula >N-R^4, A^1: methylene group or ethylene group, each optionally substituted with a lower alkyl group, R^3 : Groups and formulas shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups and formulas shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A group represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or a group represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^4: Hydrogen atom, lower alkyl group, carboxy group, lower alkoxycarbonyl group , or acyl group, R^5 and R^6: one is a hydrogen atom or a substituted or unsubstituted hydrocarbon group, the other is a substituted or unsubstituted hydrocarbon group, or 5 to 5 to which a benzene ring may be fused. 6-membered heterocyclic group, A^2 and A^3: the same or different, substituted or unsubstituted lower alkylene group, Z: methine group (>CH-), or nitrogen atom R^7: hydrogen atom, substituted or an unsubstituted hydrocarbon group,
Carboxy group, lower alkoxycarbonyl group, acyl group, carbamoyl group, or mono- or di-lower alkylaminocarbonyl group, R^8, R^9, R^1^0 and R^1^1: the same or different, A hydrogen atom, a lower alkyl group, an aralkyl group, or an aryl group. ) A saturated heterocyclic carboxylic acid amide derivative or a salt thereof.