JPH0696532B2 - Platelet activating factor antagonist - Google Patents

Description

The present invention relates to a platelet activating factor (PAF) containing a saturated heterocyclic carboxylic acid amide derivative represented by the following general formula (I) or a non-toxic salt thereof as an active ingredient. ) Regarding antagonists.

(The symbols in the formula have the following meanings.

R ¹ : a substituted or unsubstituted 5- or 6-membered heterocyclic group which may be condensed with a benzene ring, R ² : a hydrogen atom, a lower alkyl group, or the same group as R ¹ , X: an oxygen atom, sulfur Atom, or a methylene group which may be substituted with a lower alkyl group, Y: an oxygen atom, a sulfur atom, or a group represented by the formula> N—R ⁴ , A ¹ : which may be substituted with a lower alkyl group Methylene group or ethylene group, 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 carbonized group Hydrogen group, or 5- to 6-membered heterocyclic group which may be condensed with benzene ring, A ² and A ³ : same or different, substituted or unsubstituted lower alkylene group, Z: methine group (> CH- ), Or a nitrogen atom R ⁷ : a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a carboxy group, a lower alkoxycarbonyl group, an acyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group, R ⁸ , R ⁹ , R ¹⁰ and R ^11: What the same or different, a hydrogen atom, a lower alkyl group, an aralkyl group, or an aryl group. (Prior Art) PAF is a chemical substance released from human and animal cells and is an acetylglyceryl ether of phosphorylcholine represented by the following formula.

(In the formula, ι means 15 or 17.) PAF has physiological activities such as airway smooth muscle contraction, vascular permeability enhancement, platelet aggregation, and blood pressure reduction, and asthma, inflammation, thrombosis, shock. It is considered to be a factor that causes various symptoms such as. Therefore, research on substances that antagonize the physiological activity of PAF has been advanced, and several anti-PAF drugs have been reported (for example, JP-A-61-93191 and JP-A-60-116679,
JP-A-60-142932, JP-A-59-134798, JP-A-61-876
84, JP-A-61-37726).

On the other hand, conventionally, various compounds have been known as the saturated heterocyclic carboxylic acid amide derivative such as the compound (I) which is the active ingredient of the present invention. For example, West German Patent 2729414
Is an expression R _{1 is} an alkanoyl group having 2 to 17 carbon atoms, and R ₂ is a compound represented by a carboxyl group or its ester or amide, which has a stone removing effect. It has been disclosed that the compound represented by (R: OH, alkoxy, amino) has an anti-inflammatory action, but the compound having the above-mentioned chemical structural characteristics is not specifically known.

(Problems to be Solved by the Invention) However, the activity of conventionally known anti-PAF drugs is low, and they are still insufficient for clinical use, and improvements thereof have been desired.

(Means for Solving the Problem) Then, the inventors of the present invention have conducted extensive studies for the purpose of solving the above-mentioned problems, and as a result, the novel saturated heterocyclic carboxylic acid amide derivative represented by the above general formula (I) and a salt thereof have strong antibacterial activity. PA
They found that they have F activity, and completed the present invention.

(Compound) The compound represented by the above general formula (I), which is an active ingredient of the medicament of the present invention, is a saturated heterocycle in which a specific position of a specific saturated heterocycle is necessarily substituted with a specific heterocycle and a specific carboxamide. It is characterized by a chemical structure in that it is a carboxamide derivative. Specifically, the compound is At a specific position of the saturated heterocycle represented by, that is, a 5- or 6-membered saturated heterocycle, that is, R ¹
5 or 6 in which the benzene ring represented by may be condensed
It is a compound that is always substituted with a carboxamide substituted with a member heterocycle and a specific carboxamide group, that is, a specific amino group represented by -COR ³ .

The compound (I) is described in detail below.

In the general formulas used herein, unless otherwise specified, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, as the "lower alkyl group", specifically, for example, a methyl group, an ethyl group, a propyl group, an isopyropyr group,
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl 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-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-
Examples thereof include an ethyl-1-methylpropyl group and a 1-ethyl-2-methylpropyl group.

The "mono- or di-lower alkylaminocarbonyl group" means a group obtained by mono- or di-substituted the amino group of a carbamoyl group with the "lower alkyl group". Therefore, specifically, for example, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, isobutylaminocarbonyl group, pentylaminocarbonyl group, isopentylaminocarbonyl group, hexyl Aminocarbonyl group, isohexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, dibutylaminocarbonyl group, dipentylaminocarbonyl group, dihexylaminocarbonyl group, ethylmethylaminocarbonyl group , Methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, ethylisopropylaminocarbonyl group, butyl Chill aminocarbonyl group, a butyl propylamino carbonyl group.

In the present invention, the “hydrocarbon group” means a monovalent group obtained by removing one hydrogen atom from a molecule of hydrocarbon, which is a generic term for a compound consisting only of carbon and hydrogen, and particularly an acyclic hydrocarbon. Is a saturated hydrocarbon monovalent group as an alkyl group, and a cyclic hydrocarbon group is a monocyclic saturated hydrocarbon monovalent group as a cycloalkyl group, an aromatic monocyclic or polycyclic hydrocarbon monovalent group. An aryl group, a non-aromatic condensed polycyclic hydrocarbon group, and an aralkyl group or an aralkenyl group which is a monovalent group in the side chain portion of an aromatic monocyclic or polycyclic hydrocarbon having a side chain are preferable.

Here, the “alkyl group” is preferably a linear or branched one having 1 to 20 carbon atoms, and specifically, in addition to the specific examples of the above “lower alkyl group”, 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, 1
0-methylundecyl group, tridecyl group, 11-methyldodecyl group, tetradecyl group, 12-methyltridecyl group, pentadecyl group, 13-methyltetradecyl group, hexadecyl group, 14-methylpentadecyl group, heptadecyl group, 15 −
Examples thereof include a methylhexadecyl group, an octadecyl group, a 16-methylheptadecyl group, a nonadecyl group, a 17-methyloctadecyl group, an eicosyl group, and an 18-methylnonadecyl group.

The "cycloalkyl group" preferably has 3 to 7 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

As the "aryl group", specifically, a phenyl group, a naphthyl group and the like can be exemplified as preferable examples.

The “aralkyl group” is preferably a group in which any hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”, specifically, benzyl group, phenethyl group, 1-phenylethyl group, 3- Phenylpropyl group, 2-phenylpropyl group, 1-phenylpropyl group, 1-methyl-2-phenylethyl group, 4-phenylbutyl group, 3-phenylbutyl group, 2-phenylbutyl group, 1-phenylbutyl group, 2-methyl-3-phenylpropyl group, 2-methyl-2-phenylpropyl group, 2-methyl-1-phenylpropyl group, 1-methyl-3-phenylpropyl group, 1-methyl-2-phenylpropyl group, 1-methyl-1-phenylpropyl group, 1-
Ethyl-2-phenylethyl group, 1,1-dimethyl-2-phenylethyl group, 5-phenylpentyl group, 4-phenylpentyl group, 3-phenylpentyl group, 2-phenylpentyl group, 1-phenylpentyl group, 3-methyl-4-phenylbutyl group, 3-methyl-3-phenylbutyl group, 3-methyl-
2-phenylbutyl group, 3-methyl-1-phenylbutyl group, 6-phenylhexyl group, 5-phenylhexyl group, 4-
Phenylhexyl group, 3-phenylhexyl group, 2-phenylhexyl group, 1-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 group, 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, 2-2-methyl-2- (1
-Naphthyl) propyl group, 2-methyl-2- (2-naphthyl) propyl group, 2-methyl-1- (1-naphthyl) 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) hexyl group, 6- (2-naphthyl) hexyl group, 5- (1-naphthyl) hexyl group, 5- (2-naphthyl) hexyl group, 4-methyl-5- (1-naphthyl)
Examples thereof include a pentyl group, 4-methyl-5- (2-naphthyl) pentyl group, diphenylmethyl group (benzhydryl group) and trityl group.

The “aralkenyl group” is a group in which the above “aryl group” is bonded to a lower alkenyl group, and specifically, for example, 2
-Phenylethenyl group, 3-phenyl-1-propenyl group, 3-phenyl-2-propenyl group, 1-methyl-2-phenyl-1-butenyl group, 4-phenyl-2-butenyl group, 4-phenyl- 3-butenyl group, 5-phenyl-1-pentenyl group, 5-phenyl-2-pentenyl group, 5-phenyl-3-pentenyl group, 5-phenyl-4-pentenyl group, 6-phenyl-1-hexenyl group, 6-phenyl-2-
Hexenyl group, 6-phenyl-3-hexenyl group, 6-phenyl-4-hexenyl group, 6-phenyl-5-hexenyl group, 2- (1-naphthyl) ethenyl group, 2- (2-naphthyl) ethenyl group, 3- (1-naphthyl) -2-propenyl group, 3- (2-naphthyl) -2-propenyl group, 4- (1-
Naphthyl) -3-butenyl group, 4- (2-naphthyl) -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.

Specific examples of the "non-aromatic condensed polycyclic hydrocarbon group" (However, it indicates that the bond may be bonded to either a benzene ring or a saturated ring. Hereinafter, the same bond has the same meaning), an indenyl group, Examples thereof include condensed polycyclic hydrocarbon groups that are not included in the aromatic hydrocarbon group.

In the compound of the present invention, R ¹ and the “5- or 6-membered heterocyclic group to which a benzene ring may be condensed” represented by R ² , R ⁵ or R ⁶ when it is the same group as R ¹ are A saturated or unsaturated heterocyclic group containing an oxygen atom, a sulfur atom, and / or a nitrogen atom is preferable, and specifically, a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolyl group. Group, pyrazolinyl group, pyrazolidinyl group, triazolyl group, tetrazolyl group, indolyl group, benzimidazolyl group, indazolyl group, pyridyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, pyrimidinyl group, pyridazini group, pyrazinyl group, piperazinyl group, Quinolyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, cinnolinyl , Etc. Nitrogen atoms such as monocyclic or bicyclic saturated or unsaturated heterocyclic groups containing only nitrogen atoms, thiazolyl groups, thiazolinyl groups, thiazolidinyl groups, isothiazolyl groups, thiadiazolyl groups, benzothiazolyl groups, benzisothiazolyl groups, etc. Nitrogen such as monocyclic or bicyclic saturated or unsaturated heterocyclic group containing sulfur atom and sulfur atom, oxazolyl group, oxazolinyl group, oxazolidinyl group, isoxazolyl group, oxadiazolyl group, benzoxazolyl group, benzisoxazolyl group Atoms and oxygen-containing monocyclic or bicyclic saturated or unsaturated heterocyclic groups such as nitrogen-containing heterocyclic groups, thienyl groups, tetrahydrothienyl groups such as sulfur-containing heterocyclic groups, furyl groups, tetrahydrofuryl groups , Pyranyl group, tetradropyranyl group, dioxolyl group, benzofuryl group, benzene Pyranyl group, and oxygen-containing heterocyclic groups such as benzodioxolyl phosphorus groups.

These heterocyclic groups may have a bond at any of a ring carbon atom or a ring nitrogen atom, or at any of a heterocycle or a benzene ring.

The "lower alkylene group" represented by A ² or A ³ has 1 to 3 carbon atoms.
A straight-chain alkylene group is preferable, and specific examples thereof include a methylene group, an ethylene group, and a trimethylene group.

Further, the "acyl group" is particularly a lower alkanoyl group such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, benzylcarbonyl group, 3
-Phenylpropanoyl group, 2-phenylpropanoyl group, 1-phenylpropanoyl group, 4-phenylbutanoyl group, 3-phenylbutanoyl group, 2-phenylbutanoyl group, 1-phenylbutanoyl group, 2- Methyl-3-phenylpropanoyl group, 5-phenylpentanoyl group, 4-felpentanoyl group, 3-phenylpentanoyl group, 2-phenylpentanoyl group, 1-phenylpentanoyl group, 3-methyl-4- Phenylbutanoyl group, 3-methyl-2-phenylbutanoyl group, 6-phenylhexanoyl group, 5phenylhexanoyl group, 4-phenylhexanoyl group, 3-phenylhexanoyl group, 2-phenylhexanoyl group, 1-phenylhexanoyl group, 4-methyl-5-phenylpentanoyl group, 4-methyl-3-phenylhexanoyl group, 4-methyl-2-phenylhexanoyl group, etc. Aralkanoyl group, benzoyl group, 1-naphthoyl group, 2-naphthoyl group, (o, m, or p) toluoyl group, (o, m or p) -fluorobenzoyl group, (o, m or p) -chlorobenzoyl group , (O, m or p) -bromobenzoyl group, (o, m, p)-
Substituted or unsubstituted arylcarbonyl groups such as phenylbenzoyl groups, various fluoronaphthoyl groups, various chloronaphthoyl groups, various bromonaphthoyl groups, methoxalyl groups (CH ₃ OOC-CO-), ethoxalyl groups (C ₂ H ₅ OOC- Preferred examples include lower alkoxyoxalyl groups such as CO-).

The "lower alkoxycarbonyl group" includes methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group. Group, 3-methylbutoxycarbonyl group, hexyloxycarbonyl group, 4-methylpentyloxycarbonyl group and the like.

The “aralkyl group” and “aryl group” of R ^{8 to} R ¹¹ are preferably the groups exemplified as the aralkyl group and aryl group shown in the above hydrocarbon group.

The "hydrocarbon group" and "5- or 6-membered heterocyclic group which may be condensed with a benzene ring" are R ⁵ , R ⁶ and R ⁷ and R ¹
And R ² may further have 1 to 3 substituents, and these substituents include halogen 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 groups and monooxides (sulfinyl groups) or dioxides (sulfonyl groups) of the thio groups, oxo groups (oxo groups, thioxo groups), carboxy groups (carboxy groups, lower alkoxycarbonyl groups, acyl groups), cyano Group, carbamoyl group (carbamoyl group, mono- or di-lower alkylaminocarbonyl group), nitro group, amino group (amino group, mono- or di-lower alkylamino group, mono- or diaralkylamino group, (N-aralkyl-N-lower alkylamino group, pyrrolidino group, piperidino group, piperazino group) and R ⁵ and R ⁶ are selected from those to which a nitrogen-containing heterocyclic group is further added.

Here, as the "halogen atom", a fluorine atom, a chlorine atom and a bromine atom are preferable. The "lower alkyl group" means the above.

The "alkoxy group" is preferably a straight-chain or branched one having 1 to 10 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group,
Isobutoxy group, sec-butoxy group, tert-butoxy group,
Pentyloxy (amyloxy) group, isopentyloxy 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
-Methylheptyloxy group, nonyloxy group, 7-methyloctyloxy group, decyloxy group, 8-methylnonyloxy group and the like.

“Lower alkoxy group” means the above “alkoxy group”
Among them, those having 1 to 6 carbon atoms can be mentioned.

The "lower alkylthio group" is a compound in which the oxygen atom of the above "lower alkoxy group" has become a sulfur atom, and specifically, methylthio group, ethylthio group, propylthio group,
Isopropylthio group, butylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethylpropylthio group, hexylthio group Etc.

The "cycloalkyl lower alkoxy group" and "cycloalkyl lower alkylthio group" mean a group in which any hydrogen atom of the "lower alkoxy group" or "lower alkylthio group" is substituted with the "cycloalkyl group". , Specifically, for example, cyclopropyl-methoxy (or methylthio) group (meaning cyclopropyl-methoxy group or cyclopropyl-methylthio group; the same applies hereinafter), 2-cyclopropyl-ethoxy (or ethylthio) group, 1-cyclopropyl -Ethoxy (or ethylthio) group, 3-cyclopropyl-
Propoxy (or propylthio) group, 2-cyclopropyl-propoxy (or propylthio) group, 1-cyclopropyl-propoxy (or propylthio) group, 2-cyclopropyl-1-methyl-ethoxy (or ethylthio) group, 4-
Cyclopropyl-butoxy (or butylthio) group, 5-cyclopropylpentyl-oxy (or thio) group, 6-cyclopropylhexyl-oxy (or thio) group, cyclobutyl-methoxy (or methylthio) group, 2-cyclobutyl-ethoxy (Or ethylthio) group, 1-cyclobutyl-ethoxy (or ethylthio) group, 3-cyclobutyl-propoxy (or propylthio) group, 2-cyclobutyl-propoxy (or propylthio) group, 1-cyclobutyl-1-methyl-ethoxy (or Ethylthio) group, 4-cyclobutyl-butoxy (or butylthio) group, 5-cyclobutylpentyl-oxy (or thio) group, 6-cyclobutylhexyl-oxy (or thio) group, cyclopentyl-methoxy (or methylthio) group, 2-cyclopentyl-ethoxy (or ethylthio) group, 1-cyclo Pentyl - ethoxy (or ethylthio), 3-cyclopentyl - propoxy (or propylthio) group, 2-cyclopentyl - propoxy (or propylthio) group, 1-cyclopentyl - propoxy (or propylthio) group, 2-cyclopentyl-1
Methyl-ethoxy (or ethylthio) group, 4-cyclopentyl-butoxy (or butylthio) group, 5-cyclopentylpentyl-oxy (or thio) group, 6-cyclopentylhexyl-oxy (or thio) group, cyclohexyl-methoxy (or methylthio ) Group, 2-cyclohexyl-ethoxy (or ethylthio) group, 1-cyclohexyl-ethoxy (or 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-cyclohexylpentyl-oxy (or thio) group, 6-cyclohexylhexyl-oxy (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-cycloheptyl-propoxy ( Or propylthio) group, 1-cycloheptyl-propoxy (or propylthio) group, 2-cycloheptyl-
1-methyl-ethoxy (or ethylthio) group, 4-cycloheptyl-butoxy (or butylthio) group, 5-cycloheptylpentyl-oxy (or thio) group, 6-cycloheptylhexyl-oxy (or thio) group, etc. Can be mentioned.

The "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 "aryl group", and specifically, If only a phenyl group is shown as an "aryl group", for example, benzyl-oxy (or thio)
Group, phenethyl-oxy (or thio) group, 1-phenyl-
Ethoxy (or ethylthio) group, 3-phenyl-propoxy (or propylthio) group, 2-phenyl-propoxy (or propylthio) group, 1-phenyl-propoxy (or propylthio) group, 2-phenyl-1-methyl-ethoxy ( Or an ethylthio) group, a 4-phenyl-butoxy (or butylthio) group, a 5-phenylpentyl-oxy (or thio) group, a 6-phenylhexyl-oxy (or thio) group and the like.

The "aryloxy group" or "arylthio" group is specifically derived from an aromatic monocyclic or polycyclic hydrocarbon hydroxy or mercapto compound such as a phenoxy (or phenylthio) group or a naphthyl-oxy (or thio) group. And ether or thioether residues.

The “aryloxy lower alkoxy group”, “aryloxy lower alkylthio group”, “arylthio lower alkoxy group” and “arylthio lower alkylthio group” are the same as those described above for any hydrogen atom of the above “lower alkoxy group” or “lower alkylthio group”. "Aryloxy group" or "arylthio group" means a substituted group, and if "phenoxy (or phenylthio) group" alone is used as "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 phenylthio) -1-methyl- Ethoxy (or ethylthio)
Group, 4-phenoxy (or phenylthio) -butoxy (or butylthio) group, 5-phenoxy (or phenylthio)
Examples thereof include a pentyl-oxy (or thio) group and a 6-phenoxy (or phenylthio) hexyl-oxy (or thio) group.

As the “acyl group” and the “mono- or di-lower alkylaminocarbonyl group”, the same groups as described above can be mentioned as specific substituents.

The “mono- or di-lower alkylamino group” means a group in which one or two hydrogen atoms of an amino group are substituted with the above “lower alkyl group”. Specifically, a methylamino group,
Ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group,
A monoalkylamino group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms such as isohexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, Symmetrical dialkylamino group, dimethylamino group, methylpropylamino group, ethylpropylamino group, which is di-substituted by a linear or branched alkyl group having 1 to 6 carbon atoms such as dipentylamino group and dihexylamino group. , A butylmethylamino group, a butylethylamino group, a butylpropylamino group, etc., and an asymmetric dialkylamino group which is di-substituted by different alkyl groups among linear or branched alkyl groups having 1 to 6 carbon atoms, Can be mentioned.

"Mono- or diaralkylamino group" includes benzylamino group, phenethylamino group, 3-phenylpropylamino group, 4-phenylbutylamino group, 5-phenylpentylamino group, 6-phenylhexylamino group, 1-naphthyl group. Methylamino group, 2-naphthylmethylamino group, 1-naphthylethylamino group, 2-naphthylethylamino group, 1-
Naphthylpropylamino group, 2-naphthylpropylamino group, 1-naphthylbutylamino group, 2-naphthylbutylamino group, diphenylmethylamino group, 2,2-diphenylethylamino group, 3,3-diphenylpropylamino group, 4 , 4-diphenylbutylamino group, monophenylalkylamino group such as triphenylmethylamino group, dibenzylamino group, diphenethylamino group, bis (3-phenylpropyl) amino group, bis (4-phenylbutyl) amino group, Symmetrical diaralkylamino groups such as bis (5-phenylpentyl) amino group and bis (6-phenylhexyl) amino group, N-benzylphenethylamino group, N-benzyl-3-
Phenylpropylamino group, N-benzyl-4-phenylbutylamino group, N-benzyl-5-phenylpentylamino group, N-benzyl-6-phenylhexylamino group, N
-Phenethyl-3-phenylpropylamino group, N-phenethyl-4-phenylbutylamino group, N-phenethyl-
5-phenylpentylamino group, N-phenethyl-6-phenylhexylamino group, N- (3-phenylpropyl)
-4-phenylbutylamino group, N- (3-phenylpropyl) -5-phenylpentylamino group, N- (3-phenylpropyl) -6-phenylhexylamino group, N-
Asymmetric di-group such as (4-phenylbutyl) -5-phenylpentylamino group, N- (4-phenylbutyl) -6-phenylhexylamino group, N- (5-phenylpentyl) -6-phenylhexylamino group An aralkylamino group may be mentioned.

The “N-aralkyl-N-lower alkylamino group” means an amino group which is tertiaryized by substituting the “lower alkyl group” with the amino group of the “monoaralkylamino group”,
-Methylbenzylamino group, N-ethylbenzylamino group, N-propylbenzylamino 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
-Phenylpropylamino group, N-ethyl-3-phenylpropylamino group, N-propyl-3-phenylpropylamino group, N-butyl-3-phenylpropylamino group, N
-Pentyl-3-phenylpropylamino group, N-hexyl-3-phenylpropylamino group, N-methyl-4-phenylbutylamino group, N-ethyl-4-phenylbutylamino group, N-propyl-4-phenyl Butylamino group, N
-Butyl-4-phenylbutylamino group, N-pentyl-
A 4-phenylbutylamino group, an N-hexyl-4-phenylbutylamino group and the like are mentioned as typical specific groups.

The "nitrogen-containing heterocyclic group" as a substituent of R ⁵ and R ⁶ contains a nitrogen atom as a hetero atom, and may further contain a sulfur atom or an oxygen atom, and may be condensed with a benzene ring. Means a saturated or unsaturated 5- to 6-membered heterocyclic group, specifically, having at least one nitrogen atom in the "5- to 6-membered heterocyclic group optionally condensed with benzene ring" Heterocyclic groups are mentioned.

The bonds of these heterocycles may be bonded to any of ring carbon atoms or ring nitrogen atoms, or to any of heterocycles or benzene rings, as described above.

Further, as the substituent which A ² or A ³ may have, a lower alkyl group, an aralkyl group or an aryl group is preferable,
Specifically, the groups exemplified in the above "lower alkyl group",
Among the “hydrocarbon groups”, the groups exemplified as the aralkyl group and the aryl group are preferable.

The pharmacologically acceptable non-toxic salt of compound (I) is also included as an active ingredient of the medicament of the present invention. Specific examples of such salts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, and acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apple. Acids, fumaric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, etc., acid addition salts, salts with acidic amino acids such as glutamic acid, aspartic acid, methyl chloride, methyl bromide, methyl iodide, etc. And a quaternary ammonium salt formed by bonding with an alkyl halide.

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

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

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

Compound (I), which is an active ingredient of the present invention, is a novel substance, but Japanese Patent Application No. 63-37224 filed by the present applicant
It can be easily obtained by the method described in the specification.

Typically, compound (I) has the general formula (II) (In the formula, X and A ¹ have the above-mentioned meanings, R ¹² is the same group as R ¹ which may have a protecting group, and R ¹³ is R ² which may have a protecting group. The same group, Y ² means the same group as Y ¹ which may have a protecting group), and a heterocyclic carboxylic acid which may have a protecting group or a reactive derivative thereof in general. H-R ¹⁴ (III) (wherein R ¹⁴ represents the same group as R ³ which may have a protecting group) is reacted with an amine represented by the formula (III) All can then be prepared by the method of removing the protecting groups.

Here, examples of the protecting group include an amino group-protecting group, a carboxy group-protecting group, a mercapto group-protecting group, and a hydroxyl group-protecting group. Benzyloxycarbonyl group, p-methylbenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3, 5-dimethoxybenzyloxycarbonyl group, 3,4,5
-Trimethoxybenzyloxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group,
Urethane type protecting groups such as p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, formyl group, trifluoroacetyl group, phthalyl group, tosyl group, o-nitrophenylsulfenyl group, p
An acyl type protecting group such as -methoxy-o-nitrophenylsulfenyl group, benzoyl group, chloroacetyl group,
Examples thereof include alkyl type protecting groups such as trityl group, benzyl group, 2-benzoyl-1-methylvinyl group and trimethylsilyl group, and allylidene type protecting groups such as benzylidene group and 2-hydroxyallylidene group.

Further, as a protecting group for the carboxy group, a benzyl group, p-
Nitrobenzyl group, p-methoxybenzyl group, 2,4,6-trimethylbenzyl group, pentamethylbenzyl group, methyl group, ethyl group, tert-butyl group, benzhydryl group, trityl group, phthalimidomethyl group, cyclopentyl group, 2
Examples include ester residues such as -methylthioethyl group, phenacyl group and 4-picolyl group.

Protecting groups for mercapto groups include benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, benzyloxycarbonyl group, benzoyl group, ethylcarbamoyl group, acetamidomethyl group, ethylthio group, benzylthio group. Methyl group, etc., and as a protective group for hydroxyl group, benzyl group, tert-butyl group,
Examples thereof include an acetyl group, a trifluorocetyl group and a benzyloxycarbonyl group.

As the reactive derivative of the compound (II), acid chloride,
Acid halides such as acid bromides; acid azides; active esters with N-hydroxybenzotriazole, N-hydroxysuccinimide, etc .; symmetrical acid anhydrides; alkyl carbonates, p
-Mixed acid anhydrides with toluene sulfonic acid and the like can be mentioned.

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

The reaction conditions vary slightly depending on the type of the starting compound, especially the reactive derivative of compound (II), but include pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform. It is advantageous to react the starting compounds (II) and (III) in an equimolar amount or an excess of one of them in an organic solvent inert to the reaction, such as ethyl acetate and acetonitrile.

Depending on the type of reactive derivative, or the starting compound (II
When using the salt of I) in the reaction, organic bases such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, and N-methylmorpholine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and hydroxide. It may be advantageous to carry out in the presence of a base such as an inorganic base such as potassium. The reaction can be promoted by using the starting compound (III) as an excess mole. Pyridine can also serve as a solvent.

The reaction temperature varies depending on the type of reactive derivative and is set appropriately.

In this reaction, it is preferable that no other mercapto group, reactive amino group, carboxy group, or hydroxy group is present, but the target product is obtained by introducing a protecting group and reacting it, and then removing the protecting group. be able to.

Removal of the protecting group depends on the type of protecting group. For example, when the amino-protecting group is a substituted or unsubstituted benzyloxycarbonyl group, catalytic reduction is preferable,
Depending on the case, acid treatment with hydrobromic acid / acetic acid, hydrobromic acid / trifluoroacetic acid, hydrofluoric acid, or the like is used. Other urethane type protecting groups such as tert-butoxycarbonyl group are hydrobromic acid / acetic acid, trifluoroacetic acid, hydrochloric acid,
Acid treatment with hydrochloric acid / acetic acid, hydrochloric acid / dioxane, etc. is advantageous.

When the protecting group of the carboxy group is a methyl group or an ethyl group, the benzyl group and various substituted benzyl groups are subjected to catalytic reduction or saponification by saponification, and the tert-butyl group is treated with the same acid as above. The trimethylsilyl groups are easily removed by contact with water.

Most of the mercapto groups and hydroxyl protecting groups are sodium /
It can be removed by liquid ammonia treatment or hydrofluoric acid treatment, and depending on the type of protecting group (eg O-benzyl, O
-Benzyloxycarbonyl, Sp-nitrobenzyl)
It can be removed by applying catalytic reduction or, when it is an acyl-based protecting group, by hydrolysis in the presence of an acid or an alkali.

These treatments can be performed by a conventional method.

(Use) On the other hand, the “platelet activating factor antagonist” according to the present invention, for various pathological conditions caused by PAF, suppresses the onset of the pathological condition based on the antagonistic action or brings about the remission of the pathological condition Means preventive / therapeutic agents, especially asthma agents, anti-inflammatory agents, anti-ulcer agents, relievers of shock symptoms, therapeutic agents for ischemic brain and heart diseases, liver diseases, thrombosis and nephritis,
Examples include anti-rejection agents for organ transplantation. The compound (I) or a non-toxic salt thereof includes a compound having not only the above-mentioned action but also a vasodilator action, and is a therapeutic agent for a disease in which the above-mentioned pathological condition is accompanied by vasoconstriction or a pathological condition caused thereby. Can also be mentioned.

(Pharmacological effect, administration method and dose) The pharmacological activity exhibited by compound (I) and its non-toxic salts was confirmed by the following test methods.

Effect of PAF on platelet aggregation Method: 3.8% from ear artery of male Japanese white rabbit weighing about 3 kg
9 volumes of blood were collected in a plastic syringe containing 1 volume of sodium citrate aqueous solution. Blood was centrifuged at 270 xg for 10 minutes at room temperature, and the supernatant was used for platelet-rich plasma (hereinafter, PRP).
The rest was further centrifuged at 1100 × g for 15 minutes to obtain platelet poor plasma (hereinafter, PPP). Dilute PRP with PPP to remove platelets
After adjusting to 500,000 cells / μl, platelet aggregation by PAF was made into bone and cross (Journal of Physiology, 168, 178
-195 (1963)) [GVRBorn and MjCross, Journ
al of Physiology, 168 , 178-195, (1963)]. That is, the change in light transmittance of PRP by PAF (10 ^-8 M) was measured using NBS Hemattracer (Nikko Bioscience). The compound was added 2 minutes before the addition of PAF, and the IC ₅₀ value (50% inhibitory concentration) was calculated from the inhibition rate of the maximum light transmittance by PAF in the control.

Results: As shown in Table 1, many of the compounds of the present invention showed anti-PAF action (IC ₅₀ value of 10 ⁻⁶ M or more) in rabbit platelets, and particularly, Production Examples 37,49,67,71,81,83. , 85,90,91,119,14
Strong with 2,144 compounds, with an IC ₅₀ value of 2.8 × 10 ^{-8 to} 8.5
It was × 10 ^-8 M.

These compounds are ADP (3 μM), arachidonic acid (100 μM
M) and collagen (10 μg / ml) have no inhibitory effect on platelet aggregation (data not shown), which suggests that it is a PAF-specific antagonist.

The pharmaceutical preparation of the present invention comprises compound (I) or a non-toxic salt thereof as it is or a pharmaceutically acceptable carrier known per se,
Orally or parenterally safe as a pharmaceutical composition mixed with excipients [eg, tablets, capsules, powders, granules, pills, ointments, syrups, injections, inhalants, suppositories] Can be administered to. The dose varies depending on the administration subject, administration route, symptoms, etc., but is usually per adult per day
0.1 to 500 mg, preferably 1 to 200 mg, which is 2
Oral or parenteral administration in 3 divided doses.

(Effects of the invention) As is clear from the results of the above-mentioned drug efficacy test, the present invention can solve the above-mentioned problems by using a compound (I) showing excellent anti-PAF activity or a non-toxic salt thereof as an active ingredient.
The fact that we have been able to provide an antagonist will have a significant industrial effect.

(Formulation Example) Formulation Example 1. Tablet Compound of Production Example 91 20 mg Lactose 57 mg Corn starch 38 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1 mg Total amount 120 mg The compound of Production Example 91 20 g, lactose 57 g, and corn starch 38 g are uniformly mixed. Next, 40 g of a 10% hydroxypropyl cellulose solution is added and wet granulation is performed. After sieving, dry. 1 g of magnesium stearate is added to the obtained granulated product and mixed. Tablets are made using a 7m / m5.6R Usuki.

Formulation Example 2 Capsule Compound of Production Example 91 15 mg Crystalline cellulose 40 mg Crystalline lactose 144 mg Magnesium stearate 1 mg Total amount 200 mg Production Example 91 compound 15 g, Crystalline cellulose 40 g, Crystalline lactose 144
g and 1 g of magnesium stearate are mixed uniformly, and the capsule filling machine receives No. 3 capsules to form capsules.

Formulation Example 3 Lyophilized formulation 1 vial Compound 1 mg of Preparation Example 50 mg D-mannitol 50 mg Total amount 51 mg Take 800 ml of water, dissolve 1 g of the compound of Preparation Example 91 and 50 g of D-mannitol sequentially and dissolve, and add 1 liter of water. And After aseptically passing this solution, fill 1 ml each into a vial, freeze-dry and prepare a dissolution-type injection at the time of use.

(Manufacturing Example) The present invention will be described in more detail by posting a manufacturing example below.

The raw material compound contains a new compound, and its production method will be described in Reference Example.

In the text, NMR is a nuclear magnetic resonance spectrum with TMS as an internal standard, MS is a mass spectrum, LAH is lithium aluminum hydride, HOBT is 1-hydroxybenzotriazole, DCC is dicyclohexylcarbodiimide, and THF is tetrahydrofuran. , DMF stands for N, N-dimethylformamide.

Reference example 1. 2- (3-Pyridyl) thiazolidine-4-carboxylic acid prepared from L-cysteine and pyridine-3-aldehyde 2.
To a mixed solution of 1 g, 20 ml of water and 40 ml of dioxane, di-tert-butyl-
Add 2.4 g of di-carbonate and 10 ml of 1N aqueous sodium hydroxide solution at 4 ° C or lower, and stir at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, 30 ml of water is added, 0.5 M aqueous citric acid solution is added to adjust the pH to 2-3, and the mixture is 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.

Reference example 2. Pyridine-4-aldehyde 1.07g and L-cysteine 1.21g
Was heated to reflux temperature in 60% ethanol for 4 hours. Activated carbon
100 mg was added while warm. The crystals precipitated in the cold were collected and washed with ethanol to obtain 1.2 g of 2- (4-pyridyl) thiazolidine-4-carboxylic acid. Melting point 171-173 ° C.

NMR (DMSO-d ₆ ) δ: 3.0 to 3.5 (2H), 3.9 to 4.2 (1H), 5.56, 5.78 (each s, 1H in total), 7.4 to 7.6 (2H), 8.5 to 8.6 (2H) Reference example 3. Quinoline-3-aldehyde 1.57 g and L-cysteine 1.2
1 g was dissolved in 50 ml of 50% ethanol and stirred at room temperature for 1 hour. The precipitated crystals were collected by suction, washed with 50% ethanol and dried to give 2- (3-quinolyl) thiazolidine-4-
1.95 g of carboxylic acid was obtained. Melting point 173-175 ° C (decomposition) Reference example 4. p-chloromethyl- (4-phenylbutoxy) benzene
A solution of 1.20 g and 1.15 g of phthalimido potassium in 20 ml of N, N-dimethylformamide was stirred at 100 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water three times and saturated brine successively, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was recrystallized from ethyl acetate to give N-
1.85 g of [p- (4-phenylbutoxy) benzyl] phthalimide was obtained. Melting point 106-107.5 ° C N- [p- (4-phenylbutoxy) obtained in (1)
Benzyl] phthalimide 920mg and hydrazine hydrate 200mg
Was heated to reflux for 3 hours in 10 ml of ethanol. After cooling,
The separated solid was filtered off and the liquid was concentrated. Chloroform was added to the residue and the insoluble material was separated. This solution was concentrated to give p- (4-phenylbutoxy) benzylamine 19
0 mg was obtained.

NMR (CDCl ₃ ) δ: 1.6 to 1.9 (4H), 2,5 to 2.8 (2H), 3.75 (2H, br), 3.8
~ 4.0 (2H), 6.7 ~ 6.9 (2H), 7.1 ~ 7.3 (7H) Reference example 5. 900 mg of p-chloromethyl (heptyloxy) benzene
A solution of 1.25 g of sodium azide in 2.5 ml of water was added to a solution of 25 ml of N, N-dimethylformamide, and the mixture was stirred at 100 ° C for 6 hours. After cooling, the reaction mixture was 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
A suspension of 200 mg of lithium aluminum hydride in 15 ml of tetrahydrofuran was added dropwise at 0 ° C over 5 minutes. After stirring at the same temperature for 1 hour and at room temperature for 1 hour, sodium sulfate was added.
Decahydrate was added to decompose excess lithium aluminum hydride. The insoluble matter is filtered off, the liquid is concentrated under reduced pressure, and
-860 mg of heptyloxybenzylamine was obtained.

MS: m / z 221 (M ⁺ ) NMR (CDCl ₃ ) δ: 0.8 to 1.0 (3H), 1.2 to 1.5 (10H), 1.6 to 1.9 (2H),
3.80 (2H, s), 3.94 (2H, t), 6.87 (2H, d), 7.22 (2H,
d) Reference example 6. 380 mg of m-hydroxybenzaldehyde, 1-bromo-4
-Phenylbutane 600 mg and potassium carbonate 580 mg N, N-
The mixture in 3 ml of dimethylformamide was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N sodium hydroxide, water and saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure to give 660 mg of m- (4-phenylbutoxy) benzaldehyde.
Got

MS: m / z 254 (M ⁺ ) NMR (CDCl ₃ ) δ: 1.6 to 1.9 (4H), 2.6 to 2.8 (2H), 4.06 (2H, t), 7.2
~ 7.4 (9H), 9.96 (1H, s) 660 mg of m- (4-phenylbutoxy) benzaldehyde
Sodium borohydride 200m in a solution of methanol in 10ml
g was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 5% hydrochloric acid was added to the obtained 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 give 510 mg of m- (4-phenylbutoxy) benzyl alcohol.

_{NMR (CDCl 3) 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) m- (4-phenylbutoxy) benzyl alcohol 510m
g was dissolved in 5 ml of benzene, 1.4 g of thionyl chloride was added, 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-phenylbutoxy) benzene. This compound was subsequently treated by the method of Reference Example 4 to give 470 mg of m- (4-phenylbutoxy) benzylamine.
Got

MS: m / z 255 (M ⁺ ) NMR (CDCL ₃ ) δ: 1.6-1.9 (4H), 2.6-2.8 (2H), 3.6-3.9 (2H), 3.
9 to 4.1 (2H), 6.7 to 6.9 (3H), 7.2 to 7.4 (6H) Reference example 7. 2-amino-5-mercapto-1,3,4-thiadiazole 3
A mixture of 20 mg, 1-bromo-4-phenylbutane 430 mg and potassium carbonate 350 mg in 5 ml N, N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed successively with water, 1N sodium hydroxide, water and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to obtain 300 mg of 2-amino-5-[(4-phenylbutyl) thio] -1,3,4-thiadiazole. Melting point 111 ° C Elemental analysis value (as C ₁₂ H ₁₅ N ₃ S ₂ ) C (%) H (%) N (%) S
(%) Theoretical value 54.31 5.70 15.83 24.16 Experimental value 54.29 5.69 15.88 23.90 Reference example 8. 5.0 g of 2,4-dihydroxy-3-propylacetophenone,
1,3-dibromobutane 11.1 g, potassium carbonate 6.0 g and tetra-n-butylammonium bromide 50 mg acetone 130 m
The mixture in 1 was heated to reflux overnight. After cooling, the insoluble material was removed and the liquid was concentrated. Silica gel column chromatography of the residue (eluent; hexane: ethyl acetate = 8: 1)
And purified to give 1- [4- (3-bromobutoxy) -2-hydroxy-3-propylphenyl] ethanone (2.47 g). Melting point 53-55 ° C Elemental analysis value (as C ₁₅ H ₂₁ O ₃ Br) C (%) H (%) Br (%) Theoretical value 54.72 6.43 24.27 Experimental value 54.98 6.40 23.91 Reference example 9. 1-ethoxycarbonylpiperazine1.93g, potassium carbonate
1-brom-4 in a mixture of 1.76 g and 2-butanone 15 ml at room temperature
A solution of 2.47 g of phenylbutane and 5 ml of 2-butanone 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) to obtain 1-ethoxycarbonyl-4- (4-phenylbutyl) piperazine. The obtained compound was dissolved in 20 ml of ethanol and 20 ml of a 10% aqueous sodium hydroxide solution, and the mixture was stirred at 100 ° C for 12 hours.
After cooling, the reaction solution was extracted with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent; chloroform: methanol: 25% aqueous ammonia = 100: 10: 1) to obtain 1.59 g of oily 1- (4-phenylbutyl) piperazine. Obtained.

NMR (CDCl ₃ ) δ: 1.34 to 1.85 (4H, m), 2.20 to 3.04 (12H, m), 7.04 to 7.
40 (5H, m) MS: m / z 217 (M ⁺ ) Reference example 10. 1-ethoxycarbonylpiperazine and 1-bromo-3-
Using phenylpropane as a starting material, the same treatment as in Reference Example 9 was performed to obtain 1- (3-phenylpropyl) piperazine.

_{NMR (CDCl 3) δ: 1.63~1.97} (2H, m), 2.44~3.00 (12H, m), 7.04~7.
44 (5H, m) MS: m / z203 (M ⁺ ) Reference example 11. A solution of 6.43 g of di-tert-butyl-di-carbonate and 5 ml of THF was added to a mixture of 30 ml of 3.06 g of p-aminophenol and 10% aqueous sodium hydroxide solution at room temperature. After stirring at 80 ° C. for 12 hours and cooling, the reaction solution was extracted with ethyl acetate, and the extract 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 = 4: 1) and p- (tert
4.35 g of -butoxycarbonylamino) phenol were obtained. A mixture of the obtained compound (300 mg), potassium carbonate (210 mg) and 2-butanone (10 ml) was stirred at room temperature for 30 minutes, and then 1-
A solution of brom-4-phenylbutane (310 mg) and 2-butanone (5 ml) was added, and the mixture was stirred at 80 ° C for 12 hr. After cooling, water was added to the reaction solution and the organic matter was extracted with ethyl acetate. Extract the water,
The organic layer was washed successively with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 1).
Purification by 0: 1) gave 0.2 g of 1- (tert-butoxycarbonylamino) -4- (4-phenylbutoxy) benzene. 5 ml of trifluoroacetic acid was added to the obtained compound under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine,
It was dried over anhydrous sodium sulfate. Concentrate under reduced pressure and p-
0.13 g of (4-phenylbutoxy) aniline was obtained.

NMR (CDCl ₃ ) δ: 1.66 to 1.90 (4H, m), 2.67 (2H, t), 3.90 (2H, t), 6.
56 to 6.82 (4H, m), 7.13 to 7.33 (5H, m) MS: m / z241 (M ⁺ ) Reference example 12. 5-phenylpentan-1-ol 20 g, 47% hydrobromic acid
The 30 ml mixture is heated to reflux for 6 hours. The reaction solution is cooled to n-
Extract with 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 = 100: 1) to obtain 16.87 g of 1-bromo-5-phenylpentane.

NMR (CDCl ₃ ) δ: 1.28 to 2.03 (6H, m), 2.63 (2H, t), 3.42 (2H, t), 7.
08 to 7.40 (5H, m) MS: m / z 228 (M ⁺ +1) Reference example 13. Cyclopentanemethanol 1.11g, triethylamine 1.50
To a solution of g in 30 ml of dichloromethane, 1.52 g of methanesulfonyl chloride was added dropwise over 5 minutes while cooling on an ice bath. The reaction mixture was stirred at room temperature for 30 minutes and washed successively with water 3 times and saturated brine once. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.06 g of cyclopentane methyl methanesulfonate.

_{NMR (CDCl 3) δ: 1.1~1.9} (8H), 2.1~2.5 (1H, m), 2.02 (3H, s), 4.
13 (2H, d, J = 7Hz), MS: m / z178 (M ⁺ ) Cyclopentanemethyl methanesulfonate (0.80 g) obtained in (1), p-hydroxybenzaldehyde (0.60 g) and anhydrous potassium carbonate (0.93 g), N, N-dimethylformamide (6 ml)
The medium mixture was stirred at 70 ° 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, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 460 mg of p-cyclopentanemethoxybenzaldehyde.

NMR (CDCl ₃ ) δ: 1.2-2.0 (8H), 2.40 (1H, quintet, J = 7Hz), 3.92
(2H, d, J = 7Hz), 6.99 (2H, d, J = 10Hz), 7.86 (2H, d, J
= 10Hz), 9.88 (1H, s) MS: m / z204 (M ⁺ ) Reference example 14 A mixture of 1.00 g p-hydroxybenzaldehyde, 1.46 g isoamyl iodide and 1.80 g potassium carbonate in 15 ml N, N-dimethylformamide was stirred for 2 days at room temperature. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 1N sodium hydroxide, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give p- (3-methylbutoxy) benzaldehyde.
Obtained 1.34 g.

NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 7Hz), 1.6 to 1.9 (3H), 4.08 (2H, t, J
= 7Hz), 6.99 (2H, d, J = 8Hz), 7.87 (2H, d, J = 8Hz), 9.
90 (1H, 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 A mixture of 770 mg of p-isopropoxybenzaldehyde and 4.0 g of ammonium acetate in 330 ml of methanol and 330 mg of sodium cyanoborohydride was stirred at room temperature for 40 hours. Concentrated hydrochloric acid was added to the reaction mixture to adjust 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 pH to 11
That's it. 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 give p-isopropoxybenzylamine (110 mg).

NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6Hz), 1.50 (disappeared at 2H, D ₂ O), 3.71
(2H, s), 4.46 (1H, hep ・, J = 6Hz), 6.75 (2H, d, J = 8H
z), 7.14 (2H, d, J = 8Hz) MS: m / z 165 (M ⁺ ) Reference Examples 19 to 21 The following compounds were obtained in the same manner as in Reference Example 18.

Reference example 22 p- (3-phenylpropoxy) benzaldehyde 750m
g and hydroxylamine hydrochloride 2.3 g methanol 20 ml
Under ice cooling, 10% sodium hydroxide was added to the medium solution to adjust the pH to 8
Adjusted to. The reaction mixture was stirred for 1 hour, water was added to the residue obtained by evaporating 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, concentrated, and p- (3
750 mg of -phenylpropoxy) benzoxime were obtained.
A solution of this compound in 10 ml of tetrahydrofuran was added dropwise to a suspension of 300 mg of lithium aluminum hydride in 6 ml of tetrahydrofuran at -30 ° C. After stirring at -30 ° C for 20 minutes, the mixture was stirred at room temperature for 2 hours. After decomposing excess lithium aluminum hydride with sodium sulfate decahydrate, the reaction mixture was passed through. The solution was diluted with ethyl acetate and washed with 10% hydrochloric acid. The hydrochloric acid layer was made alkaline with solid potassium hydroxide, and 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 give 260 mg of p- (3-phenylpropoxy) benzylamine.

NMR (CDCl ₃ ) δ: 1.6 (2H, disappeared with D ₂ O), 2.00 to 2.35 (2H, m), 2.70 to 3.
00 (2H, m), 3.81 (2H, s), 3.97 (2H, t, J = 6Hz), 6.87
(2H, d, J = 9Hz), 7.24 (2H, d, J = 9Hz), 7.25 (5H, s) MS: m / z241 (M ⁺ ) Reference Examples 23 to 27 The compound was obtained.

Reference example 28 To a solution of 1.35 g of p- (3-methylbutoxy) benzaldehyde in 50 ml of tetrahydrofuran, 350 mg of lithium aluminum hydride was gradually added at -10 ° C. After stirring at room temperature for 1 hour, excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate. The liquid obtained by separating the insoluble matter from this mixture was concentrated to obtain 1.33 g of p- (3-methylbutoxy) benzyl alcohol. To a solution of this compound in 25 ml of benzene was added 3 g of thionyl chloride, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and p- (3-
1.45 g of methylbutoxy) benzyl chloride was obtained. To a solution of this compound in 50 ml of N, N-dimethylformamide was added a solution of 3.3 g of sodium azide in 14 ml of water under ice cooling. The reaction mixture was stirred overnight at room temperature, 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, concentrated under reduced pressure and p- (3-methylbutoxy) benzylazide 1.48.
got g. To a solution of this compound in 30 ml of tetrahydrofuran was added 500 mg of lithium aluminum hydride under ice cooling.
The reaction mixture was gradually brought to room temperature and stirred for 2 hours. Excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate. The solution from which the insoluble matter was removed was concentrated under reduced pressure to obtain 1.13 g of p- (3-methylbutoxy) benzylamine.

NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 7Hz), 1.5 (disappeared at 2H, D ₂ O), 1.6-1.
9 (3H), 3.80 (2H, s), 3.98 (2H, t, J = 7Hz), 6.87 (2H,
d, J = 9Hz), 7.24 (2H, d, J = 9Hz) MS: m / z193 (M ⁺ ) Reference example 29 A solution of 1.01 g of ethyl 4-carboxypiperidine-1-carboxylate and 0.72 g of triethylamine in 20 ml of tetrahydrofuran was added at 0.60 g of ethyl chloroformate at -10 to -5 ° C.
Add a solution of 2 ml of tetrahydrofuran and stir for 30 minutes.
The precipitated crystals are removed and the solution is sodium borohydride.
Add to a solution of 0.57 g and 10 ml of water over 30 minutes under ice-cooling, and add at room temperature for 30 minutes.
Stir for minutes. The reaction mixture is acidified with 1N hydrochloric acid under ice cooling and extracted with ether. The ether layer is washed successively with water, saturated aqueous sodium hydrogen carbonate 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 mixed solution of hexane-ethyl acetate (1: 1 v / v) gave 0.69 g of ethyl 4-hydroxymethylpiperidine-1-carboxylate.

NMR (CDCl ₃ ) δ: 0.88 to 1.42 (1H, br), 1.30 (3H, t, J = 7.0Hz), 1.42
~ 2.00 (5H, m), 2.77 (2H, dt, J = 12.0,3.0Hz), 3.52 (2
H, d, J = 6.0Hz), 4.15 (2H, q, J = 7.0Hz), 4.00 to 4.36 (2
H, m) MS: m / z187 (M ⁺ ) To a solution of 1.59 g of oxalyl chloride in 30 ml of dichloromethane was added a solution of 1.97 g of dimethylsulfoxide in 5 ml of dichloromethane at -60 to -50 ° C, and 5 minutes later, ethyl 1- (4-
Hydroxymethyl) piperidinecarboxylate 2.11g
10 ml of dichloromethane solution is added dropwise and stirred for 15 minutes.
Triethylamine (5.73 g) was added to the reaction mixture, and the mixture was stirred for 5 minutes and at room temperature for 15 minutes. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 4-formylpiperidine-1-carboxylate (1.97 g).

NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0Hz), 1.42 to 2.10 (4H, m), 2.24 to
2.65 (1H, m), 2.65 ~ 3.24 (2H, m), 3.82 ~ 4.41 (4H,
m), 9.68 (1H, s) MS: m / z185 (M ⁺ ) Sodium hydride (0.24 g) is added to dimethyl sulfoxide (6 ml) and the mixture is stirred at 75 ° C for 30 minutes and then returned to room temperature. At room temperature, 2.1 g of benzyltriphenylphosphonium chloride (5 g) in dimethyl sulfoxide is added and the mixture is stirred for 15 minutes. To this mixture was added a solution of ethyl 1- (4-formyl) piperidinecarboxylate 0.93 g in dimethylsulfoxide 5 ml and the mixture was stirred for 1 hour. Water was added 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 subjected to silica gel column chromatography (35 g) and eluted with a mixed solution of hexane: ethyl acetate (3: 1) to obtain ethyl 4-styrylpiperidine-1-carboxylate (1.13 g).

NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.0Hz), 1.10 to 1.95 (4H, m), 2.03 to
2.58 (1H, m), 2.58 to 3.05 (2H, m), 4.16 (2H, q, J = 7.0H
z), 3.88-4.40 (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 to 7.45 (5H,
m) MS: m / z259 (M ⁺ ) Ethyl 4-styrylpiperidine-1-carboxylate
0.80 g and 10% palladium-carbon 80 mg ethyl acetate (40 m
l) Catalytic reduction of the medium mixture at room temperature until absorption of hydrogen ceases. The catalyst was removed, the liquid was concentrated under reduced pressure, and ethyl 1-
0.80 g of [4- (2-phenylethyl)] piperidinecarboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 8.0Hz), 0.72 to 2.01 (7H, m), 2.50 to
2.98 (4H, m), 3.89 to 4.42 (2H, m), 4.14 (2H, q, J = 8.0H
z), 7.02-7.54 (5H, m) MS: m / z261 (M ⁺ ) A solution of 0.70 g of ethyl 1- [4- (2-phenylethyl)] piperidinecarboxylate and 6 ml of 47% hydrobromic acid was added to 1
Heat at reflux for 6 hours at 00 ° C. Add a small amount of water, dissolve the crystals, wash with ether, and make the aqueous layer alkaline with 20% sodium hydroxide. After salting out with sodium chloride, extraction with ether is performed.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.42 g of 4- (2-phenylethyl) piperidine.

NMR (CDCl₃) Δ: 0.78 ~ 2.06 (8H, m), 2.30 ~ 2.86 (4H, m), 2.86 ~ 3.3
2 (2H, m), 6.95 to 7.50 (5H, m) MS: m / z189 (M⁺) Reference Examples 30 to 32 Ethyl 1- (4-formyl) piperidi of Reference Example 29 (2)
Carboxylate and Ph (CH₂)_uP Ph₃Br (U: 2〜
4) and the same treatment as in Reference Examples (3) to (5)
The following compound was obtained.

Reference example 33 To a solution of 1.10 g of homopiperazine in 15 ml of water, add 2N hydrochloric acid at room temperature to pH 2
Add until. Next, a 40% aqueous solution of sodium acetate and 1.28 g of ethyl chloroformate were alternately added in the range of pH 2.0 to 3.5, and the mixture was stirred at room temperature for 2 hours. The reaction solution is washed with ethyl acetate and the aqueous layer is saturated with potassium carbonate. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.27 g of ethyl 1-homopiperazinecarboxylate.

NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7Hz), 1.60 to 1.99 (3H, m), 2.75 to 3.
04 (4H, m), 3.30 to 3.65 (4H, m), 4.15 (2H, q, J = 7Hz) MS: m / z172 (M ⁺ ) 0.80 g of potassium carbonate is added to a solution of 0.86 g of ethyl 1-homopiperazinecarboxylate and 0.90 g of benzyl bromide in 5 ml of tetrahydrofuran, and the mixture is heated under reflux for 4 hours. After the reaction, water is added to this and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography. It was eluted with a mixed solution of hexane-ethyl acetate (2: 1) to obtain 1.06 g of ethyl 4-benzylhomopiperazine-1-carboxylate.

_{NMR (CDCl 3) δ: 1.25} (3H, t, J = 7Hz), 1.62~2.05 (2H, m), 2.50~2.
81 (4H, m), 3.32 to 3.75 (4H, m), 3.61 (2H, s), 4.14 (2
H, q, J = 7Hz), 7.29 (5H, s) MS: m / z262 (M ⁺ ) A mixture of 0.85 g of ethyl 4-benzylhomopiperazine-1-carboxylate and 5 ml of 47% hydrobromic acid solution was added for 100 hours for 100 hours.
Heat at ℃. Add a small amount of water to the reaction mixture and wash with ethyl acetate. The aqueous layer is made alkaline with 30% aqueous sodium hydroxide solution, salted out with sodium chloride, a large excess of sodium chloride is added, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-benzylhomopiperazine (0.55 g).

_{NMR (CDCl 3) δ: 1.60~1.96} (2H, m), 1.91 (1H, s), 2.52~2.80 (4H,
m), 2.80 to 3.07 (4H, m), 3.68 (2H, s), 7.12 to 7.45 (5
H, m) MS: m / z 190 Reference Examples 34 to 37 The following compounds were obtained by treating in the same manner as in Reference Example 33 (2) to (3).

Reference Example 38 A mixture of 2.02 g of ethyl 1-piperazinecarboxylate, 1.92 g of anhydrous potassium carbonate, 3.08 g of decyl bromide and 20 ml of 2-butanone is stirred at 80 ° C. overnight. Water is added to the reaction solution and extracted 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. 20 ml of ethanol to the residue, 10
Add 20 ml of an aqueous solution of caustic soda and stir at 100 ° C overnight.
The reaction solution is cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.38 g of oily 1-decylpiperazine.

_{NMR (CDCl 3) 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 Examples 39 to 50 In the same manner as in Reference Example 38, the following compounds were obtained.

Reference example 51 To a mixture of 1.6 g of ethyl 1-piperazinecarboxylate, 1.3 g of p-tolualdehyde and 30 ml of ethanol, add 500 mg of sodium borohydride and stir at room temperature overnight. The reaction mixture is concentrated under reduced pressure, 50 ml of water is added, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is extracted with dilute hydrochloric acid. The diluted hydrochloric acid extract is washed with ethyl acetate, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous potassium carbonate and concentrated under reduced pressure to give oily ethyl 4- (p
-Methylbenzyl) piperazine-1-carboxylate
0.8g was obtained. The carboethoxy group was removed from this product according to the method of Reference Example 38 to obtain 0.36 g of oily 1- (p-methylbenzyl) piperazine.

NMR (CDCl ₃ ) δ: 2.42 (3H, s, CH ₃ ), 2.3 to 2.6 (4H, m), 2.7 to 3.1 (4H,
m), 3.43 (2H, s, CH ₂ ), 7.14 (4H, s) Reference example 52 Ethyl 1-piperazinecarboxylate and cinnamaldehyde were used as raw materials and treated in the same manner as in Reference Example 51 to obtain oily 1-cinnamylpiperazine.

NMR (CDCl ₃ ) δ: 2.2 to 2.6 (4H, m), 2.8 to 3.0 (4H, m), 3.16 (2H, d, CH
₂ ), 6.28 (1H, dt), 6.56 (1H, d), 7.0 to 7.5 (5H, m) Reference example 53 A mixture of 1.72 g of N-methyl-L-cysteine hydrochloride, 1.07 g of nicotinaldehyde and 2 ml of water is stirred at room temperature for 24 hours.
0.8 ml of pyridine and 1 ml of ethanol were added to the reaction solution, and the precipitated crystals were washed with ethanol and dried to give 3-methyl-
2- (3-pyridyl) thiazolidine-4-carboxylic acid 0.
I got 74g.

NMR (DMSO-d ₆ ) δ: 2.24,2.32 (3H / 2 × 2, s, N-CH ₃ ), 3.00 to 3.64 (5 / 2H,
m), 4.16 to 4.32 (H / 2, m), 4.92,5.36 (H / 2 x 2, s), 7.10
~ 7.32 (1H, m), 7.80 ~ 8.00 (1H, m), 8.44 ~ 8.72 (2H,
m) MS (FAB): m / Z225 (M + H) ⁺ Reference example 54 3-Acetylpyridine 3.63g, L-cysteine 3.63g, water 25m
A mixture of l and 25 ml of ethanol is 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. Ethanol is added to the powder to remove insoluble matter, and then the mixture is concentrated to dryness. Dissolve the residue in water, add dilute hydrochloric acid to pH 6 while stirring with ice cooling, and remove the resulting powder.
After washing with ethanol and drying, 2-methyl-2- (3
2.54 g of -pyridyl) thiazolidine-5-carboxylic acid was obtained.

NMR (DMSO-d ₆ ) δ: 1.78, 1.88 (total 3H, each s), 2.92 to 3.56 (2H, m),
3.56 ~ 4.38 (1H, m), 7.20 ~ 7.44 (1H, m), 7.80 ~ 9.08
(1H, m), 9.32 to 9.52 (1H, m), 9.68 to 9.86 (1H, m) MS (FAB): m / z 225 (M + H) ⁺ Reference example 55 Di-2-pyridyl ketone 3.68 g, L-cysteine 2.42 g, water 2
A mixture of 5 ml and 25 ml of ethanol is heated under reflux for 3.5 hours. After cooling, the insoluble material is removed, and the mixture is concentrated to dryness under reduced pressure. The residue was washed successively with ethyl acetate and ether to obtain 0.62 g of 2,2-di- (2-pyridyl) thiazolidine-4-carboxylic acid.

NMR (DMSO-d ₆ ) δ: 2.85 to 4.15 (3H, m), 7.20 to 8.90 (8H, m) Reference Example 56. 3-piperidine methanol 4.00 g of dioxane 50 ml, water 30
di-tert-butyl-di-carbonate at 0 ° C in a solution in ml.
7.58 g and 1N sodium hydroxide 35 ml were added. The reaction mixture was brought to room temperature and stirred for 1.5 hours, and then 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 7.20 g of 1-tert-butoxycarbonylpiperidine-3-methanol. Melting point 77-79 ° C NMR (CDCl ₃ ) 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 ⁺ ) Reference example 57. 0.85 ml of dimethylsulfoxide was added to a solution of 0.50 ml of oxalyl chloride in 10 ml of dichloromethane at -60 ° C, and after 3 minutes.
A solution of 1.08 g of 1-tert-butoxycarbonylpiperidine-3-methanol in 10 ml of dichloromethane was added dropwise over 5 minutes. After stirring for 15 minutes, 3.0m of triethylamine was added to the reaction mixture.
l was added. After stirring for 5 minutes, 20 ml of water was added to the reaction mixture and the mixture was shaken, and then the dichloromethane layer was separated. The dichloromethane layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-tert-butoxycarbonylpiperidine-3-aldehyde. Obtained 0.98 g.

NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.4 to 2.0 (4H), 2.4 (1H, m, w / 2 = 21H
z), 3.10 (1H, dd, J = 8.5 and 14Hz), 3.6.5 (1H, ddd, J =
4,5 and 12.5Hz), 3.94 (1H, dd, J = 4 and 14Hz), 9.68
(1H, s) MS: m / z 213 (M ⁺ ) In the same manner as in Reference Example 2, the following compound was obtained.

Reference example 68. 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 3.10 g of dichloromethane 30 m
The solution in l at -78 ℃ 1.31 ml of oxalyl chloride and N, N-
50 mg of dimethylformamide was added. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The resulting precipitate was collected and dried to obtain 1.3-dioxo-5- (3-pyridyl) thiazolidino [3,4-c] oxazolidine hydrochloride (1.90 g).

Melting point 170 ° C (decomposition) Elemental analysis value (as C ₁₀ H ₉ Cl N ₃ O ₃ S) C (%) H (%) N (%) S (%) Cl (%) Calculated value 44.04 3.33 10.27 11.76 13.00 Experiment Value 43.94 3.37 10.24 11.76 13.30 Reference example 69. 5.34 g of p-methoxycinnamic acid was stirred using 200 mg of 10% palladium-carbon in a methanol solution as a catalyst until stirring of hydrogen gas stopped. The catalyst was removed and the solution was concentrated under reduced pressure to give 3-
5.43 g of (p-methoxyphenyl) propionic acid was obtained.

NMR (CDCl ₃ ) δ: 2.34 to 3.15 (4H), 3.76 (3H, s) 6.64 to 7.30 (4.H),
11.00 (1H, s) Reference example 70. Lithium aluminum hydride 1.10 g anhydrous ether 50 ml
A solution of 3- (p-methoxyphenyl) propionic acid in 100 ml of anhydrous ether was added dropwise to the suspension solution at room temperature over 20 minutes while stirring. After stirring for 30 minutes at room temperature, the mixture was heated under reflux for 1 hour. After cooling, water was added to the reaction mixture under ice cooling, and 10% hydrochloric acid aqueous solution was further added to acidify the reaction mixture, which was extracted with ether,
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3- (p-methoxyphenyl).
5.06 g of propanol was obtained.

NMR (CDCl ₃ ) δ: 1.60 to 2.16 (2H), 2.38 to 2.95 (3H), 3.69 (2H, t, J
= 6 Hz), 3.80 (3H, s), 6.71 to 7.30 (4H) In the same manner as in Reference Examples 69 and 70, the following compounds were obtained.

However, in Reference Examples 73 and 74, platinum oxide was used as the catalyst for catalytic reduction.

Reference example 75. 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 ml of acetone at room temperature 2
It was stirred for a day. After removing the precipitate, the 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 hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give p-nitrocinnamic acid methyl ester (3.30 g).

NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.52 (1H, d, J = 16Hz), 7.50-7.95 (3
H), 8.21 (2H, d, J = 9Hz) Reference example 76. 1.20 g of o-tolualdehyde and 20 m of anhydrous tetrahydrofuran
At room temperature, the solution of l is methyl (triphenylphosphoranylidene) acetate 3.67 g of anhydrous tetrahydrofuran 20 m
It was added to the suspension and heated to reflux for 15 hours. The solvent was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (40
g). Elution with a mixture of hexane-ethyl acetate (2: 1) gave 1.65 g of o-methylcinnamic acid methyl ester.

NMR (CDCl ₃ ) δ: trans isomer 2.45 (3H, s), 3.80 (3H, s), 6.34 (1H,
d, J = 16Hz), 6.99-7.66 (4H), 7.97 (1H, d, J = 16Hz), cis-body 2.29 (s), 3.63 (s), 6.03 (d, J = 12Hz) Reference Examples 69 and 70 The following compounds were synthesized in the same manner as in.

Reference Example 79. 1M super hydride / tetrahydrofuran solution (3.
A solution of 3 ml) and anhydrous tetrahydrofuran (5 ml) was cooled to −50 to −60 ° C. under a stream of argon gas. To this was added dropwise a solution of 3- (p-cyanophenyl) propionic acid methyl ester (210 mg) obtained in accordance with Reference Examples 76 and 69 by using p-cyanobenzaldehyde and methyl (triphenylphosphoranylidene) acetate as starting materials in 2 ml of tetrahydrofuran, The mixture was stirred at the same temperature for 10 minutes. Water and 1N hydrochloric acid were sequentially added to the reaction solution at the same temperature to make the solution 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 120 mg of 3- (p-cyanophenyl) propanol.

NMR (CDCl ₃ ) δ: 1.61-2.20 (3H), 2.60-3.06 (2H), 3.68 (2H, t, J = 6
Hz), 7.10-7.75 (4H) Reference example 80. 47% of 2.13 g of 3- (p-methylphenyl) propanol
The mixture was heated under reflux in 7 ml of an aqueous solution of hydrobromic acid for 5 hours. 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 to give 3- (p
1.75 g of -methylphenyl) propyl bromide was obtained.

Boiling point 65 ° C / 0.7mm Hg NMR (CDCl ₃ ) 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) propanol in 50 ml of anhydrous pyridine was added methanesulfonyl chloride under ice cooling.
8 g was slowly added dropwise, 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 methyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6.32 g of 3- (p-methoxyphenyl) propyl methanesulfonate.

_{NMR (CDCl 3) δ: 1.75-2.36} (2H), 2.55-2.93 (2H), 3.00 (3H, s), 3.
80 (3H, s), 4.24 (2H, t, J = 6Hz), 6.70-7.30 (4H) Reference example 82 A mixed solution of 6.30 g of 3- (p-methoxyphenyl) propyl methanesulfonate and 1.11 g of sodium iodide in 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 3
-(P-Methoxyphenyl) propyl iodide 6.62g
Got

NMR (CDCl ₃ ) δ: 1.81-2.35 (2H), 2.18 (2H, br, t, J = 7Hz), 3.16 (2
H, t, J = 6 Hz), 3.80 (3H, s), 6.71-7.30 (4H) In the same manner as in Reference Example 82, the following compound was obtained.

Reference example 84. A solution of 1.55 g of 3- (p-chlorophenyl) propanol and 2.51 g of triphenylphosphine in 10 ml of N, N-dimethylformamide was added with 8 ml of N, N-dimethylformamide containing 2.42 g of iodine at room temperature to confirm the disappearance of color. While dripping slowly. After the disappearance of the color of the reaction solution was stopped, water was added to the reaction solution and 5% sodium thiosulfate aqueous solution was added to reduce excess iodine, followed by extraction 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 to give 3- (p-chlorophenyl) propyl iodide 1.82 g.

NMR (CDCl ₃ ) δ: 1.92-2.40 (2H), 2.71 (2H, brt, J = 7Hz), 3.13 (2
H, t, J = 6 Hz), 6.91-7.40 (4H) In the same manner as in Reference Example 84, the following compound was obtained.

Reference example 88. 5.01 g of phenylpropyl bromide was added to concentrated nitric acid (6
(5%) 10 ml and concentrated sulfuric acid 10 ml were added dropwise over 5 minutes, the mixture was stirred at the same temperature for 1 hour and then left at room temperature for 1 week. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (150 g). Hexane-ethyl acetate (10:
Elution with 1) gave 5.50 g of 2,3-dinitrophenylpropyl bromide.

NMR (CDCl ₃ ) δ: 2.08-2.51 (2H), 3.20 (2H, dd, J = 7Hz, J = 9Hz), 3.5
0 (2H, t, J = 6Hz), 7.68 (1H, d, J = 9Hz), 8.42 (1H, dd, J
= 3Hz, J = 9Hz), 8.79 (1H, d, J = 3Hz) Reference example 89. 4-of 3- (p-aminophenyl) propanol (0.51g)
A 7% aqueous hydrobromic acid solution (5 ml) was heated under reflux for 6 hours, and the solvent was concentrated under reduced pressure. Methanol and toluene were added and the solvent was concentrated under reduced pressure and repeated again to give 3- (p-aminophenyl) propyl bromide hydrobromide (1.04 g).

NMR (DMSO-d ₆ + CDCl ₃ (3: 1)) δ: 1.91-2.47 (2H), 2.64-3.03 (2H), 3.43 (2H, t, J = 6
Hz), 4.85 (3H, brs), 7.40 (4H, s) In the same manner as in Reference Example 33 (2) to (3), the following compound was obtained.

Reference example 101.Carboethoxyethylenediamine 0.88g, 3-phenyl ether
1.33 g of ropirobromide and 1.0 g of anhydrous potassium carbonate
A mixed solution of 10 ml of lahydrofuran was heated to reflux overnight. Not
After the melt was removed, the solution was concentrated under reduced pressure and the residue was washed with alumina.
Subjected to ram chromatography (25g). Hexane-
N-carbethoxy-eluting with ethyl acetate (3: 1)
N ', N'-bis (3-phenylpropyl) ethylenedia
Min 0.54g And N-carbethoxy-N '-(3-phen
Nylpropyl) ethylenediamine 0.60 g Got

NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7Hz), 1.56-2.02 (4
H, m), 2.20-2.87 (10H, m), 3.00-3.45 (2H, m), 4.12 (2
H, t, J = 7Hz), 5.13 (1H, br), 7.21 (10H, s) NMR (CDCl ₃ ) δ: 1.21 (1H, s), 1.25 (3H, t, J = 7Hz),
1.61-2.10 (2H, m), 2.45-2.93 (6H, m), 3.29 (2H, q, J =
6Hz), 4.15 (2H, t, J = 7Hz), 5.15 (1H, br), 7.21 (5H,
s) Reference example 102 A solution of 580 mg of N-carbethoxy-N- (3-phenylpropyl) ethylenediamine in 10 ml of concentrated hydrochloric acid was heated in a sealed tube at 120 ° C overnight. The solvent was concentrated under reduced pressure, toluene was added and the mixture was concentrated again, and this operation was repeated twice to obtain 630 mg of N-3-phenylpropylethylenediamine dihydrochloride, which was used for the next reaction without purification.

NMR (DMSO-d ₆ ) 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 (5H, br) MS: m / z 179 (M ⁺ +1) In the same manner as in Reference Example 102, the following compound was obtained.

Reference example 104. 250 mg of 3- (p-cyanophenyl) propyl iodide
A mixed solution of 0.85 g of anhydrous piperazine and 0.5 g of potassium carbonate in 10 ml of tetrahydrofuran was heated under reflux for 2 hours. After concentration under reduced pressure, saturated brine was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 1- [3- (p- Cyanophenyl) propyl] piperazine (140 mg) was obtained.

NMR (CDCl ₃ ) δ: 1.60-2.10 (2H, m), 2.04 (1H, s), 2.19-2.54 (6H,
m), 2.69 (2H, t, J = 8Hz), 2.89 (4H, t, J = 5Hz), 7.27
(2H, d, J = 9Hz), 7.56 (2H, d, J = 9Hz) MS: m / z229 (M ⁺ ) Reference example 105. 1-benzylpiperazine 1.76 g, tetrahydrofuran 20 ml
A solution of 1.0 g of n-butylisocyanate and 5 ml of tetrahydrofuran is added to the above solution under ice 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 was used for the next reaction without being crude.

NMR (CDCl ₃ ) δ: 0.90 (3H, t), 1.1 to 1.7 (4H, m), 2.2 to 2.6 (4H, m),
3.0 ~ 3.6 (6H, m), 3.50 (2H, s), 4.5 (1H, br s), 7.0 ~
7.5 (5H, m) Reference example 106. 4.5 g of dicyclohexylcarbodiimide was added to a mixed solution of 3.52 g of 1-benzylpiperazine, 3.5 g of 3-phenylpropionic acid and 20 ml of tetrahydrofuran, and the mixture was stirred at room temperature overnight.
The resulting dicyclohexylurea is separated and the mother liquor is concentrated under reduced pressure. 100 ml of ethyl acetate and 50 ml of water are added to the residue, and the mixture is made alkaline with potassium carbonate and then separated. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give oily 1-benzyl-4- (3-
6 g of phenylpropionyl) piperazine was obtained.

NMR (CDCl ₃ ) δ: 2.1 to 2.5 (4H, m), 2.4 to 3.2 (4H, m), 3.3 to 3.8 (4H,
m), 3.45 (2H, s), 7.1 to 7.4 (10H, m) Reference example 107. 1-benzyl-4-butylaminocarbonylpiperazine
To a solution of 2.8 g and ethanol 15 ml, 10% palladium-carbon 250
Add mg and catalytically reduce until absorption of hydrogen stops. The catalyst was removed, and the solution was concentrated under reduced pressure to obtain 2.2 g of 1-butylaminocarbonylpiperazine. This product was used in the next reaction without purification.

NMR (CDCl ₃ ) δ: 0.92 (3H, t), 1.1 to 1.7 (4H, m), 2.7 to 3.0 (4H, m)
3.0 to 3.5 (6H, m) Reference example 108. 1-Benzyl-4- (3-phenylpropionyl) piperazine was used as a starting material in the same manner as in Reference Example 107.
(3-Phenylpropionyl) piperazine was obtained.

MS: m / z 218 (M ⁺ ) Reference example 109. N-carbobenzyloxy-serine 2.0 g, 1- (3-phenylpropyl) piperazine 1.57 g, 1-hydroxybenzotriazole 1.04 g in a solution of N, N-dimethylformamide 30 ml, dicyclohexylcarbodiimide 1.58 g under ice cooling.
Was added. The reaction mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate, washed successively with 4% aqueous sodium hydrogen carbonate solution twice, once with water, and once with saturated brine, dried over anhydrous sodium sulfate, and depressurized. It was concentrated under. The residue was purified by silica gel column chromatography and 1- [2- (benzyloxycarbonylamino) -3-hydroxypropionyl] -4- (3-phenylpropyl) piperazine 2.39 g.
Got

Melting point 95-97 ° C Elemental analysis value (as C ₂₄ H ₃₁ N ₃ O ₄ ) C (%) H (%) N (%) Calculated value 67.74 7.34 9.87 Experimental value 67.74 7.26 9.88 Reference example 110. 1- [2- (benzyloxycarbonylamino) -3-
To a solution of 1.12 g of hydroxypropionyl] -4- (3-phenylpropyl) piperazine in 30 ml of ethanol was added 100 mg of 10% palladium-carbon, and the mixture was stirred under a hydrogen stream until absorption of hydrogen stopped. After removing the catalyst, the solution was concentrated under reduced pressure and 1- (2-amino-3-hydroxypropionyl) -4- (3-phenylpropl) piperazine 800 mg.
Got

NMR (CDCl ₃ ) δ: 1.7 to 2.0 (2H), 1.8 to 2.6 (3H, disappeared at D ₂ O), 2.3 to 2.
8 (8H), 3.4 to 3.8 (7H), 7.1 to 7.3 (5H) MS: m / z291 (M ⁺ ) Reference example 111. To a solution of 200 mg p-heptyloxybenzylamine, 150 mg glycerol acid (65% aqueous solution) and 110 mg 1-hydroxybenztriazole in 2 ml N, N-dimethylformamide was added 160 mg dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography to give N- (p-heptyloxybenzyl)-.
80 mg of glyceramide was obtained.

NMR (CDCl ₃ ) δ: 0.90 (3H, br t), 1.2 to 1.5 (8H), 1.7 to 1.9 (2H),
3.0 (disappeared at 1H, D ₂ O), 3.8 to 4.0 (2H), 3.9 (disappeared at 1H, D ₂ O), 4.1 to 4.3 (1H), 4.38 (2H, d, J = 6Hz), 6.88 (2H ,
d, J = 8Hz), 7.18 (2H, d, J = 8Hz), 7.0 to 7.3 (disappeared at 1H, D ₂ O) MS: m / z 309 (M ⁺ ) Reference Example 112. 2- (3-pyridyl) -1-pyrroline-4-carboxylic acid hydrobromide 1.15 g, 1-heptylpiperazine 770 mg, dicyclohexylcarbodiimide 860 mg and 1-hydroxybenzotriazole 560 mg in N, N-dimethylformamide 15 ml The mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate to remove the insoluble matter, the solution was concentrated under reduced pressure, 0.5N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was extracted with 1N 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.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (15 g) and eluted with ethyl acetate to give 1-heptyl-4- [ 1.01 g of 2- (3-pyridyl) -2-pyrrolin-5-ylcarbonyl] piperazine was obtained.

1) NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 6Hz), 1.12 to 1.72 (10H, m), 1.92 to
2.93 (9H, m), 2.95 to 3.26 (2H, m), 3.37 to 4.30 (3H,
m), 5.04 to 5.30 (1H, m), 7.26 to 7.46 (1H, ddd, J = 1Hz, J
= 5Hz, J = 8Hz), 8.18 (1H, dt, J = 2Hz, J = 8Hz), 8.68 (1
H, dd, J = 2Hz, J = 5Hz), 9.05 (1H, dd, J = 1Hz, J = 2Hz) 2) MS: m / z 356 (M ⁺ ) In the same manner, the following compound was obtained.

Production example 1 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 600 mg, tetrahydrofuran
In a 10 ml solution, at 4 ° C or lower, L-methionine methyl ester / hydrochloride 390 mg, 1-hydroxybenzotriazole 390
mg, N-methylmorpholine 190 mg, and dicyclohexylcarbodiimide 440 mg were added sequentially, and the temperature was kept below 4 ° C for 1 hour and at room temperature for 1 hour.
Stir for hours. The formed precipitate was removed, and the solution was concentrated under reduced pressure. 50 ml of ethyl acetate was added, the insoluble matter was removed, and the solution was adjusted to 0.
It was washed successively with 5M aqueous citric acid solution, water, 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure to give oily N- [3-butoxycarbonyl-2- (3
440 mg of -pyridylthiazolidine-4-carbonyl] -L-methionine methyl ester was obtained.

NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.8 to 2.2 (3H, m), 2.2 to 2.6 (2H, m),
3.26 (1H, dd), 3.6 (1H, dd), 3.78 (3H, s), 4.6 ~ 4.8
(1H, m), 4.86 (1H, dd), 6.02 (1H, s), 7.3 (1H, dd),
7.8 to 8.0 (1H, m), 8.52 (1H, dd), 8.65 (1H, dd) Production Example 2 N-formyl-2- (3-pyridyl) thiazolidine-4
-L-methionine methyl ester / hydrochloride 1.16 g, 1-hydroxybenzotriazole 1.17 g, N-methylmorpholine 560 mg, dicyclohexyl in a mixed solution of -carboxylic acid 1.3 g, tetrahydrofuran 50 ml, N, N-dimethylformamide 10 ml at 4 ° C or less. Add carbodiimide (1.32 g) successively and stir at 4 ° C or lower for 1 hour and at room temperature for 1 hour. Thereafter, the same treatment as in Production Example 1 was carried out, followed by purification by silica gel column chromatography [eluent: chloroform-methanol (9: 1) mixture] to obtain oily N- [3-formyl-2- (3-pyridyl) thiazolidine. 820 mg of -4-ylcarbonyl] -L-methionine methyl ester was obtained.

Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₄ S ₂ ) N (%) Theoretical value 10.96 Experimental value 10.62 NMR (CDCl ₃ ) δ: 2.08 (3H, s), 1.8 to 2.6 (4H, m), 3.2 ~ 3.5 (1H, m),
3.8 (3H, s), 3.5 to 3.8 (1H, m), 4.5 to 4.8 (1H, m), 4.8
~ 5.1 (1H, m), 6.1, 6.41 (1H for each, each s), 7.2 ~ 7.5
(1H, m), 7.8 to 8.0 (1H, m), 8.34 (1H, s), 8.4 to 8.9 (2
H, m) Production example 3 N- [3-butoxycarbonyl-2- (3-pyridyl)
Thiazolidin-4-ylcarbonyl] -L-methionine methyl ester 430 mg under ice-cooling trifluoroacetic acid 5 ml.
Is added, the mixture is stirred at room temperature for 2 hours, and the reaction mixture is concentrated under reduced pressure.
Ethyl acetate is added to the residue and concentrated again under reduced pressure. The residue is dissolved in 5 ml of ethyl acetate, and 1 ml of 4N-hydrogen chloride-dioxane solution is added under ice cooling. The precipitated crystals were collected, washed with ethyl acetate and dried to obtain 300 mg of N- [2- (3-pyridyl) thiazolidine-4-carbonyl] -L-methionine methyl ester dihydrochloride. Melting point 110
℃ Elemental analysis value (as C ₁₅ H ₂₅ N ₃ O ₄ S ₂ Cl ₂ ) C (%) H (%) N (%) Theoretical value 40.36 5.64 9.41 Experimental value 40.00 5.35 9.24 Production example 4 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 600 mg, tetrahydrofuran
In a 5 ml solution, at 4 ° C or lower, L-leucine methyl ester / hydrochloride 350 mg, 1-hydroxybenzotriazole 390
mg, N-methylmorpholine 190 mg, and dicyclohexylcarbodiimide 440 mg are added sequentially, and the mixture is stirred overnight in an ice room. The resulting precipitate was removed, the solution was concentrated under reduced pressure, and ethyl acetate was added to 50 ml.
Was added to remove insoluble matter, and the solution was added with 0.5 M citric acid aqueous solution,
Wash sequentially with water, saturated aqueous sodium hydrogen carbonate solution and water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give an oily N-
830 mg of [3-butoxycarbonyl-2- (3-pyridyl) thiazolidin-4-ylcarbonyl] -L-leucine methyl ester was obtained. 3 ml of trifluoroacetic acid was added to 800 mg of the obtained compound under ice cooling, and the mixture was stirred at room temperature for 3 hours.
The reaction mixture is concentrated under reduced pressure, 10 ml of ethyl acetate is added, and the mixture is concentrated again under reduced pressure. Dissolve the residue in 10 ml of ethyl acetate, and under ice cooling, 2.2
Add 3 ml of normal-hydrogen chloride-dioxane solution and let stand overnight in an ice room. The crystals were collected, washed with ethyl acetate and dried to obtain 510 mg of N- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] -L-leucine methyl ester dihydrochloride. Melting point 97-100 ° C Elemental analysis value (as C ₁₆ H ₂₃ N ₃ O ₃ S ・ 2HCl ・ 4 / 5H ₂ O) C (%) H (%) N (%) S (%) Theoretical value 45.24 6.31 9.89 7.55 Experimental value 45.21 5.98 9.85 7.55 Production Example 5 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and D, L-α-aminobutyric acid
Production Example 4 using methyl ester / hydrochloride as a starting material
The same procedure was followed to obtain 2-[[2- (3-pyridyl) thiazolidin-4-ylcarbonyl] amino] butyric acid methyl ester dihydrochloride. Melting point 98 to 100 ° C. Elemental analysis value (as C ₁₄ H ₁₉ N ₃ O ₃ S.2HCl.H ₂ O) C (%) Theoretical value 42.00 Experimental value 42.08 Production Example 6 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and D-methionine ethyl ester / hydrochloride were used as starting materials, treated in the same manner as in Production Example 4, and treated with N- [2- ( 3-pyridyl) thiazolidine-
4-ylcarbonyl] -D-methionine ethyl ester dihydrochloride was obtained.

Mp 94 to 96 ° C. Elemental analysis _{(C 16 H 23 N 3 O} 3 S 2 · 2HCl · 4 / 5H 2 as O) C (%) H ( %) N (%) S (%) Cl (%) Theoretical Value 42.07 5.87 9.20 14.04 15.52 Experimental value 42.17 5.89 8.89 13.77 15.68 Production Example 7 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and L-methioninamide
Hydrochloric acid salt was used as a starting material and treated in the same manner as in Production Example 4 to obtain N
-[2- (3-Pyridyl) thiazolidin-4-ylcarbonyl] -L-methioninamide dihydrochloride was obtained. Melting point 131 ° C MS: m / z 340 (M ⁺ -2HCl) Production Example 8 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and glycine methyl ester / hydrochloride were used as starting materials, and treated in the same manner as in Production Example 4, to give N- [2- (3- Pyridyl) thiazolidin-4-ylcarbonyl] glycine methyl ester dihydrochloride was obtained. Melting point 116-118 ° C Elemental analysis value (as C ₁₂ H ₁₅ N ₃ O ₃ S ・ 2HCl ・ H ₂ O) C (%) H (%) N (%) Theoretical value 38.72 5.14 11.29 Experimental value 38.99 4.62 10.99 Manufacturing example 9 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 600 mg, tetrahydrofuran
3-methylthiopropylamine was added to 10 ml of the solution at 4 ℃ or less.
200 mg, 1-hydroxybenzotriazole 390 mg, and dicyclohexylcarbodiimide 440 mg were sequentially added, and the mixture was stirred at room temperature for 3
Stir for hours. The formed precipitate is removed, the solution is concentrated under reduced pressure, and the residue is dissolved in 50 ml of ethyl acetate. The ethyl acetate solution was washed successively with 0.5 M aqueous citric acid solution, water, saturated aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to N- (3-methylthiopropyl) -3-tert-.
250 mg of butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide were obtained. Compound 2 obtained
2 ml of trifluoroacetic acid was added to 50 mg under ice cooling and treated in the same manner as in Production Example 4 to give oily N- (3-methylthiopropyl)
130 mg of 2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained.

_{NMR (DMSO-d 6) δ} : 1.6~1.9 (2H), 2.08 (3H), 2.4~2.6 (2H), 3.0~
3.7 (4H), 4.05 to 4.50 (1H), 5.9 to 6.1 (1H), 7.4 to 9.2
(4H) Production example 10 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and n-heptylamine were used as starting materials and treated in the same manner as in Production Example 9 to obtain N-n-heptyl-2- ( 3-Pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained.

_{NMR (DMSO-d 6) δ} : 0.6~1.1 (3H), 1.1~1.8 (10H), 2.9~3.9 (4H),
4.4 to 4.7 (1H), 6.20 (1H), 8.0 to 8.3 (1H), 8.6 to 9.3
(3H) Production example 11 N- (2-pyridyl) -2 was prepared by treating with 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and 2-aminopyridine in the same manner as in Production Example 9.
-(3-Pyridyl) thiazolidine-4-carboxamide trihydrochloride was obtained. Mp 145 ° C. Elemental analysis (C ₁₄ H ₁₇ N ₄ as _{OSCl 3) C (%) H} (%) S (%) Theoretical values 42.49 4.33 8.10 Found 42.83 4.58 8.03 Preparation Example 12 N- (2-methoxyphenyl) was treated by using 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and o-anisidine in the same manner as in Production Example 9.
2- (3-Pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained. Melting point 129 ° C Elemental analysis value (as C ₁₆ H ₁₉ N ₃ O ₂ SCl ₂ ) C (%) H (%) N (%) Theoretical value 49.49 4.93 10.82 Experimental value 49.29 5.18 10.38 Production example 13 2- (3-pyridyl) thiazolidine-4-carboxylic acid 63
0 mg, m-anisidine 350 mg, dicyclohexylcarbodiimide 650 mg and 1-hydroxybenzotriazole 430 mg
The mixture in 8 ml of dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate to remove insoluble matter. Liquid is twice water, sodium hydrogen carbonate aqueous solution,
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 preparative thin layer chromatography to give N- (3-methoxyphenyl).
230 mg of 2- (3-pyridyl) thiazolidine-4-carboxamide was obtained. Dissolve this compound in ethyl acetate 2
1 ml of a normal hydrogen chloride-dioxane solution was added. The resulting solid was taken, washed with ethyl acetate and dried to give N- (3-methoxyphenyl) -2- (3-pyridyl) thiazolidine-
250 mg of 4-carboxamide dihydrochloride was obtained.

Melting point 129 ° C Elemental analysis value (as C ₁₆ H ₁₉ N ₃ O ₂ SCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 49.49 4.93 10.82 8.26 Experimental value 49.49 5.08 10.56 8.24 Production Example 14 N- (2-phenylethyl) -2- (3-pyridyl) was prepared from 2- (3-pyridyl) thiazolidine-4-carboxylic acid and 2-phenylethylamine according to the method of Production Example 13.
Thiazolidine-4-carboxamide dihydrochloride was obtained.
Mp 115 ° C. Elemental analysis (C ₁₇ H ₂₁ N ₃ as _{OSCl 2) C (%) H} (%) N (%) S (%) Theoretical values 52.85 5.48 10.88 8.30 Found 52.25 5.74 10.77 8.16 Production Example 15 According to the method of Production Example 13, N- (3-methylthiopropyl) -2- (4-pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained from the compound obtained in Reference Example 2 and 3-methylthiopropylamine. Melting point 70 ° C. Elemental analysis value (as C ₁₃ H ₂₁ N ₃ OS ₂ Cl ₂ ) C (%) H (%) N (%) Theoretical value 42.16 5.72 11.35 Experimental value 41.65 5.83 10.87 Production example 16 Pyridine-2-aldehyde 1.50g and L-cysteine 1.70g
Of 50% ethanol in 50% ethanol was stirred at room temperature for 4 hours. The reaction mixture from which insoluble matter was removed was concentrated under reduced pressure to obtain a syrup-like substance. This was dissolved in 35 ml of tetrahydrofuran, 2.89 g of dicyclohexylcarbodiimide, 1.89 g of 1-hydroxybenzotriazole and 1.62 g of 3-methylthiopropylamine were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and the insoluble matter was removed by filtration. The solution was washed with water twice, an aqueous solution of sodium hydrogencarbonate, water twice, and saturated saline in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent toluene: ethyl acetate = 1: 1) to obtain 1.50 g of N- (3-methylthiopropyl) -2- (2-pyridyl) thiazolidine-4-carboxamide. It was 800 mg of this compound
Was dissolved in ethyl acetate, and 2N hydrogen chloride-dioxane solution was added. The residue obtained by distilling off the solvent is dried, and N-
830 mg of (3-methylthiopropyl) -2- (2-pyridyl) thiazolidine-4-carboxamide hydrochloride was obtained. Melting point 65 ° C Elemental analysis value (as C ₁₃ H ₂₂ N ₃ O ₂ S ₂ Cl) C (%) H (%) N (%) S (%) Theoretical value 44.37 6.30 11.94 18.22 Experimental value 44.59 6.09 11.79 18.38 Production example 17 2- (3-pyridyl) thiazolidine-4-carboxylic acid 63
A mixture of 0 mg, 3,4,5-trimethoxyaniline 520 mg, dicyclohexylcarbodiimide 650 mg and 1-hydroxybenzotriazole 430 mg in N, N-dimethylformamide 8 ml was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and the insoluble material was removed. The solution was washed successively with aqueous sodium hydrogen carbonate solution, 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) and N- (3,4,5-trimethoxyphenyl) -2- (3-
370 mg of pyridyl) thiazolidine-4-carboxamide was obtained. This compound was dissolved in 10 ml of ethyl acetate, and 2 ml of 2N hydrogen chloride-dioxane solution was added. The resulting solid was taken, washed with ethyl acetate and dried to obtain 200 mg of N- (3,4,5-trimethoxyphenyl) -2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Melting point 130
〜132 ℃ Elemental analysis value (as C ₁₈ H ₂₃ N ₃ O ₄ SCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 48.22 5.17 9.37 7.15 Experimental value 48.23 5.35 9.02 7.12 Production example 18 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and aniline, N-phenyl-
2- (3-Pyridine) thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 145 to 148 ° C NMR (DMSO-d ₆ ) δ: 3.4 to 4.2 (2H), 4.96 (1H, t), 6.31,6.35 (total 1
H), 7.0 to 7.4 (3H), 7.6 to 7.8 (2H), 8.10 (1H, dd), 8.
9 ~ 9.0 (2H), 9.3 (1H) Manufacturing Example 19 N-benzyl-2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained according to the method of Production example 17 from 2- (3-pyridyl) thiazolidine-4-carboxylic acid and benzylamine. Melting point 126-130 ° C NMR (DMSO-d ₆ ) δ: 3.2-3.7 (2H), 4.3-4.6 (3H), 6.08, 6.14 (combined
1H), 7.3 (5H), 8.06 (1H, dd), 8.7 ~ 9.0 (2H), 9.1 ~
9.2 (1H) Manufacturing Example 20 N- (p-methylbenzyl) -2- (3-pyridyl) was prepared from 2- (3-pyridyl) thiazolidine-4-carboxylic acid and p-methylbenzylamine according to the method of Production example 17.
Thiazolidine-4-carboxamide dihydrochloride was obtained.
Melting point 130-136 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ OSCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 52.85 5.48 10.88 8.30 Experimental value 52.64 5.56 10.81 8.38 Production Example 21 N- (4-phenylbutyl) -2- (3-pyridyl) was prepared from 2- (3-pyridyl) thiazolidine-4-carboxylic acid and 4-phenylbutylamine according to the method of Production Example 17.
Thiazolidine-4-carboxamide dihydrochloride was obtained.
Melting point 100-104 ° C Elemental analysis value (as C ₁₉ H ₂₅ N ₃ OSCl ₂ · 0.2H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 54.36 6.15 10.01 7.64 16.84 Experimental value 54.44 6.16 10.08 7.68 16.59 Production example 22 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and N-methylbenzylamine, according to the method of Production Example 17, N-benzyl-N-methyl-2- (3-pyridyl) thiazolidine-4-carboxamide. The dihydrochloride was obtained. Melting point 105-110 ° C Elemental analysis value (as C ₁₇ H ₂₁ N ₃ OSCl ₂ · H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 50.50 5.73 10.39 7.93 17.54 Experimental value 50.63 5.60 10.43 7.98 17.26 Production example 23 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and p- (4-phenylbutoxy) benzylamine,
According to the method of Production Example 17, N- [p- (4-phenylbutoxy) benzyl] -2- (3-pyridyl) thiazolidine-
4-Carboxamide dihydrochloride was obtained. Melting point 133-135 ° C Elemental analysis value (as C ₂₆ H ₃₁ N ₃ O ₂ SCl ₂ · 0.2H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 59.58 6.04 8.02 6.12 13.53 Experimental value 59.58 6.02 7.96 6.23 13.58 Production example 24 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and p-heptyloxybenzylamine, according to the method of Production example 17, N- (p-heptyloxybenzyl) -2-
(3-pyridyl) thiazolidine-4-carboxamide
The dihydrochloride was obtained.

Melting point 155 to 160 ° C Elemental analysis value (as C ₂₃ H ₃₃ N ₃ O ₂ SCl ₂ · 0.3H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 56.16 6.88 8.54 6.52 14.41 Experimental value 56.11 6.84 8.47 6.53 14.50 Production example 25 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and m- (4-phenylbutoxy) benzylamine,
According to the method of Production Example 17, N- [m- (4-phenylbutoxy) benzyl] -2- (3-pyridyl) thiazolidine-
4-Carboxamide dihydrochloride was obtained. Melting point 88 to 93 ° C. Elemental analysis value (as C ₂₆ H ₃₁ N ₃ O ₂ SCl ₂ .0.5H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 58.97 6.09 7.94 6.06 13.39 Experimental value 58.96 6.07 7.96 6.11 13.36 Production example 26 From 2- (3-pyridyl) thiazolidine-4-carboxylic acid and m-heptyloxybenzylamine, according to the method of Production example 17, N- (m-heptyloxybenzyl) -2-
(3-pyridyl) thiazolidine-4-carboxamide
The dihydrochloride was obtained. Melting point 135-140 ° C Elemental analysis value (as C ₂₃ H ₃₃ N ₃ O ₂ SCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 56.76 6.84 8.64 6.59 Experimental value 56.68 6.85 8.69 6.62 Manufacturing Example 27 2- (3-pyridyl) thiazolidine-4-carboxylic acid and 2-amino-5-[(4-phenylbutyl) thio] -1,
From 3,4-thiadiazole, according to the method of Production Example 17, N
There was obtained-[5-[(4-phenylbutyl) thio] -1,3,4-thiadiazol-2-yl] -2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride.

Melting point 99-105 ° C Elemental analysis value (as C ₂₁ H ₂₅ OS ₃ Cl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 47.54 4.75 13.20 18.13 Experimental value 47.58 4.84 13.09 18.28 Production Example 28 According to the method of Production Example 17, from 2- (3-quinolyl) thiazolidine-4-carboxylic acid and 3-methylthiopropylamine, N- (3-methylthiopropyl) -2- (3-quinolyl) thiazolidine-4-carboxamide. The dihydrochloride was obtained. Mp 122-126 ° C. Elemental analysis _{(C 17 H 23 N 3 OS} 2 Cl as _{2 · 0.5H 2 O) C (} %) H (%) N (%) S (%) Cl (%) Theoretical values 47.55 5.63 9.78 14.93 16.51 Experimental value 47.57 5.72 9.75 15.02 16.47 Production example 29 N- (4-phenylbutyl) -2- (3-quinolyl) was prepared from 2- (3-quinolyl) thiazolidine-4-carboxylic acid and 4-phenylbutylamine according to the method of Production Example 17.
Thiazolidine-4-carboxamide dihydrochloride was obtained.
Mp 116-122 ° C. Elemental analysis (C ₂₃ H ₂₇ N ₃ as _{OSCl 2) C (%) H} (%) N (%) S (%) Theoretical values 59.48 5.86 9.05 6.90 Found 59.13 5.84 8.99 7.14 Production Example 30 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and pyrrolidine as starting materials were treated in the same manner as in Production Example 17 to give 1- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] pyrrolidine dihydrochloride. I got salt. Melting point 136 ° C NMR (DMSO-d ₆ ) δ: 1.60 to 2.13 (4H, m), 3.06 to 3.90 (6H, m), 4.55 to 4.7
1 (1H, m), 6.09,6.26 (1H for each, each s), 8.08 (1H, d
d), 8.72 to 9.20 (3H, m) Production example 31 Production Example 34 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and cyclohexylamine were used as starting materials and treated in the same manner as in Production Example 17 to obtain N-cyclohexyl-2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Got Melting point 139 ° C NMR (DMSO-d ₆ ) δ: 0.90 to 1.95 (11H, m), 3.06 to 3.69 (3H, m), 4.39 (1
H, dd), 6.07, 6.14 (1H for each, each s), 8.03 (1H, dd), 8.
46~9.13 (3H, m) mp _{169 ℃ NMR (DMSO-d 6} ) δ: 3.04~4.20 (10H, m), 4.64~4.84 (1H, m), 6.00,6.2
3 (1H for each, each s), 7.04 to 7.64 (5H, m), 7.99 to 8.14
(1H, m), 8.70-9.16 (3H, m) Manufacturing Example 33 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and piperidine were used as starting materials and treated in the same manner as in Production Example 17 to give 1- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine.2. The hydrochloride salt was obtained. Melting point 172 ° C Elemental analysis value (as C ₁₄ H ₂₁ N ₃ OSCl ₂ · 0.3H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 47.27 6.12 11.81 9.01 19.93 Experiment Value 47.36 6.03 11.75 9.01 19.71 2- (3-pyridyl) thiazolidine-4-carboxylic acid and morpholine were used as starting materials and treated in the same manner as in Production Example 17 to give 4- [2- (3-pyridyl) thiazolidin-4-yl. Carbonyl] morpholine dihydrochloride was obtained. Melting point 143 ° C NMR (DMSO-d ₆ ) δ: 2.97 to 3.78 (10H, m), 4.62 to 4.78 (1H, m), 6.00,6.2
3 (1H for each, each s), 8.05 (1H, dd) 8.71 to 9.10 (3H, m) Production Example 32 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 1-phenylpiperazine were used as starting materials and treated in the same manner as in Production Example 17 to give 1-phenyl-4- [2- (3-pyridyl) thiazolidine-4- Ilcarbonyl] piperazine
The trihydrochloride was obtained.

Production Example 35 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and isoamylamine were used as starting materials and treated in the same manner as in Production Example 17 to give N- (3-methylbutyl) -2- (3-pyridyl) thiazolidine-4-carboxamide. -Dihydrochloride was obtained. Melting point 115 ° C Elemental analysis value (as C ₁₄ H ₂₂ N ₃ OSCl ₂ · 0.3H ₂ O) C (%) H (%) N (%) S (%) Theoretical value 47.14 6.39 11.78 8.99 Experimental value 47.24 6.59 11.56 9.10 Production Example 36 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 4-benzylpiperidine were used as starting materials and treated in the same manner as in Production Example 17 to give 4-benzyl-1- [2- (3-pyridyl) thiazolidine-4-. Ilcarbonyl] piperidine
The dihydrochloride was obtained.

Melting point 135 ° C NMR (DMSO-d ₆ ) δ: 0.76 to 2.06 (5H, m), 2.35 to 4.54 (8H, m), 4.68 to 5.0
8 (1H, m), 6.08, 6.28 (1H for each, each s), 7.06 to 7.28 (5
H, m), 8.07 (1H, dd), 8.71 to 9.30 (3H, m) Production Example 37 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 1- (3-phenylpropyl) piperazine were used as starting materials and treated in the same manner as in Production Example 17 to give 1- (3-phenylpropyl) -4- [2- (3-Pyridyl) thiazolidin-4-ylcarbonyl] piperazine trihydrochloride was obtained.

Melting point 144 ° C NMR (DMSO-d ₆ ) δ: 1.85 to 4.86 (17H, m), 5.97, 6.18 (total 1H, each s),
7.10 ~ 7.48 (5H, m), 8.06 (1H, dd), 8.65 ~ 9.12 (3H,
m) Production example 38 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and p- (4-phenylbutoxy) aniline were used as starting materials and treated in the same manner as in Production Example 17 to obtain N- [p- (4-phenylbutoxy) phenyl]. 2- (3-Pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained.

Melting point 117 ° C Elemental analysis value (as C ₂₅ H ₂₉ N ₃ O ₂ SCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 59.28 5.77 8.30 6.33 Experimental value 59.65 5.76 8.40 6.39 Production example 39 2- (3-pyridyl) thiazolidine-4-carboxylic acid 51
To a mixture of 0 mg, 1-hydroxybenzotriazole 490 mg, nonadecylamine 680 mg, and tetrahydrofuran 12 ml, a solution of dicyclohexylcarbodiimide 500 mg and tetrahydrofuran 3 ml was added dropwise under ice cooling, and the mixture was stirred for 1 hour under ice cooling.
The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the insoluble material was removed. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, 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) and recrystallized from ethyl acetate to give 250 mg of N-nonadecyl-2- (3-pyridyl) thiazolidine-4-carboxamide. Obtained.

Melting point 108-110 ° C Elemental analysis value (as C ₂₈ H ₄₈ N ₃ OS-1 / 5H ₂ O) C (%) H (%) N (%) S (%) Theoretical value 70.30 10.20 8.78 6.70 Experimental value 70.37 10.34 8.83 6.80 Production Example 40. 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and decylamine were used as starting materials and treated in the same manner as in Production Example 39 to give N-decyl-2- (3-pyridyl) thiazolidine-
4-carboxamide was obtained.

Melting point 88 ° C Elemental analysis value (as C ₁₉ H ₃₀ N ₃ OS) C (%) H (%) N (%) S (%) Theoretical value 65.48 8.68 12.06 9.20 Experimental value 65.16 8.80 11.91 9.04 Production example 41. N-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and tyramine were used as starting materials and treated in the same manner as in Production Example 39 to give N- [2- (p-hydroxyphenyl) ethyl]. -3-tert-Putoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide was obtained.

Melting point 76 ° C NMR (CDCl ₃ ) δ: 1.34 (9H, s), 2.72 (2H, t), 3.22 (1H, dd), 3.43〜
3.70 (3H, m), 4.80 (1H, dd), 5.99 (1H, s), 6.70 ~ 7.03
(4H, m), 7.19 ~ 7.32 (1H, m), 7.75 ~ 7.84 (1H, m), 8.5
1 (1H, dd), 8.63 (1H, d) Manufacturing Example 42. 2- (3-pyridyl) thiazolidine-4-carboxylic acid 50
0 mg, O-benzylhydroxylamine hydrochloride 380 mg, 1-
Hydroxybenzotriazole (480 mg), N-methylmorpholine (240 mg), tetrahydrofuran (15 ml) under ice cooling,
A solution of 490 mg of dicyclohexylcarbodiimide and 5 ml of tetrahydrofuran was added dropwise, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the insoluble material was removed. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution 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 260 mg of N-benzyloxy-2- (3-pyridyl) thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1.5 ml of 2N hydrogen chloride-dioxane solution was added. The resulting solid was collected, washed with ethyl acetate and dried to obtain 240 mg of N-benzyloxy-2- (pyridin-3-yl) thiazolidine-4-carboxamide dihydrochloride.

Melting point 115 ° C NMR (DMSO-d ₆ ) δ: 3.02 to 3.52 (2H, m), 4.07 to 4.20 (1H, m), 4.90 (2H, m)
s), 6.00, 6.08 (total 1H, each s), 7.28 ~ 7.53 (5H, m),
8.07 (1H, dd), 8.64 to 9.26 (3H, m) Production Example 43. 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 810 mg, 4-methylpiperidine 260 mg, 1-hydroxybenzotriazole 530 mg, tetrahydrofuran 10 ml In a mixture of ice-cooled dicyclohexylcarbodiimide 540 mg and tetrahydrofuran 5 ml The solution was added dropwise, and the mixture was stirred for 1 hour under ice cooling, and then stirred at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the insoluble material was removed. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 4-methyl-1- [3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine. 5 ml of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent:
Purified with ethyl acetate), 4-methyl-1- [2- (3
-Pyridyl) thiazolidin-4-ylcarbonyl] piperidine was obtained. This compound was dissolved in ethyl acetate, and 3 ml of 2N hydrogen chloride-dioxane solution was added. The resulting solid was taken, washed with ethyl acetate, dried and treated with 4-methyl-1-
530 mg of [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine dihydrochloride were obtained.

Mp 130 ° C. Elemental analysis _{(C 15 H 23 N 3 OSCl} 2 as) C (%) H (% ) N (%) S (%) Theoretical values 49.45 6.39 11.53 8.80 Found 49.59 6.60 11.47 8.63 Production Example 44. 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and N, N-dimethylethylenediamine were used as starting materials and treated in the same manner as in Production Example 43 to produce N.
-[2- (N ', N'-dimethylamino) ethyl] -2-
(3-pyridyl) thiazolidine-4-carboxamide
The trihydrochloride was obtained.

Melting point 150 ° C NMR (DMSO-d ₆ ) δ: 2.63 to 3.80 (12H, m), 4.26 to 4.50 (1H, m), 6.01,6.0
8 (1H for each, each s), 8.06 (1H, dd), 8.70 to 9.18 (3H,
m) Production example 45. 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and N-methyl-N-phenylhydrazine were used as starting materials and treated in the same manner as in Production Example 43 to give N′-methyl-N. ′ -Phenyl-2- (3-pyridyl) thiazolidine-4-carbohydrazide dihydrochloride was obtained.

Melting point 145 ° C NMR (DMSO-d ₆ ) δ: 3.04 to 3.72 (5H, m), 4.28 to 4.50 (1H, m), 6.03,6.12
(Total 1H, each s), 6.70 to 7.32 (5H, m), 8.07 (1H, d
d), 8.69 to 9.17 (3H, m) Production example 46. 4-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 Production Example 43 to give 4-phenyl-1- [2- ( 3-Pyridyl) thiazolidin-4-ylcarbonyl] piperidine dihydrochloride was obtained.

Melting point 115 ° C NMR (DMSO-d ₆ ) δ: 1.32 to 2.08 (4H, m), 2.58 to 3.82 (6H, m), 3.96 to 5.0
0 (2H, m), 6.04, 6.28 (1H for each, each s), 7.08 to 7.44 (5
H, m), 8.06 (1H, dd), 8.68 to 9.16 (3H, m) Production Example 47. 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and 1-methylpiperazine were used as starting materials and treated in the same manner as in Production Example 43 to give 1-methyl-4- [2- (3 -Pyridyl) thiazolidin-4-ylcarbonyl] piperazine trihydrochloride was obtained.

Melting point 182 ° C NMR (DMSO-d ₆ ) δ: 2.62 to 5.00 (14H, m), 6.03,6.22 (total 1H, each s),
8.09 (1H, dd), 8.70-9.20 (3H, m) Manufacturing Example 48. 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and 1-benzylpiperazine were used as starting materials and treated in the same manner as in Production Example 43 to give 1-benzyl-4- [2- ( 3-pyridyl) thiazolidine-4-
Ilcarbonyl] piperazine trihydrochloride was obtained.

Melting point 165 ° C NMR (DMSO-d ₆ ) δ: 2.76 to 4.80 (13H, m), 5.93, 6.15 (total 1H, each s),
7.36 ~ 7.80 (5H, m), 8.03 (1H, dd), 8.62 ~ 9.10 (3H,
m) Production example 49. 3-tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and 1- (4-phenylbutyl) piperazine were used as starting materials and treated in the same manner as in Production Example 43 to give 1- (4- Phenylbutyl) -4- [2- (3-
Pyridyl) thiazolidin-4-ylcarbonyl] piperazine trihydrochloride was obtained.

Melting point 157 ° C NMR (DMSO-d ₆ ) δ: 1.33 to 1.85 (4H, m), 2.30 to 2.76 (8H, m), 2,86 to 3.7
8 (6H, m), 3.99 to 4.30 (1H, m), 5.96, 6.17 (total 1H,
Each s), 7.12 ~ 7.44 (6H, m), 8.12 (1H, dd), 8.72 ~ 9.17
(2H, m) Manufacturing example 50. 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid 680 mg, phenylhydrazine
A solution of dicyclohexylcarbodiimide (450 mg) and tetrahydrofuran (5 ml) was added dropwise to a mixture of 240 mg, 1-hydroxybenzotriazole (450 mg) and tetrahydrofuran (20 ml), and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the insoluble material was removed. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 840 mg of N'-phenyl-3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carbohydrazide. 5 ml of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The crystals obtained by concentration under reduced pressure were recrystallized from ethyl acetate to obtain 180 mg of N'-phenyl-2- (3-pyridyl) thiazolidine-4-carbohydrazide.

Melting point 155 ° C NMR (CDCl ₃ + DMSO-d ₆ ) δ: 3.22 to 3.56 (2H, m), 4.22 to 4.36 (1H, m), 5.60,5.72
(Total 1H, each s), 6.72 to 7.44 (6H, m), 7.81 to 7.95 (1
H, m), 8.56 (1H, dd), 8.79 (1H, d) Production Example 51. N- [2- (p-hydroxyphenyl) ethyl] -3-te
rt-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide 540 mg, potassium carbonate 180 mg,
To a mixed solution of 10 ml of N, N-dimethylformamide, 280 mg of 1-bromo-4-phenylbutane and a 5 ml solution of N, N-dimethylformamide were added at room temperature. After stirring at 80 ° C. for 3 days, 20 ml of water was added to the reaction solution after cooling, and the organic matter was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 3), and N- [2- [p- (4-phenylbutoxy) phenyl] ethyl] -3- 360 mg of tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide were obtained. 5 ml of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution 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), and N- [2- [p- (4-phenylbutoxy) phenyl] ethyl] -2- (3- 230 mg of pyridyl) thiazolidine-4-carboxamide was obtained. This compound was dissolved in ethyl acetate, and 1 ml of 2N hydrogen chloride-dioxane solution was added. The resulting solid was collected, washed with ethyl acetate, dried and N- [2- [p- (4-phenylbutoxy) phenyl] ethyl] -2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Obtained 130 mg.

Melting point 102 ° C Elemental analysis value (as C ₂₇ H ₃₃ N ₃ O ₂ SCl ₂ ) C (%) H (%) N (%) S (%) Theoretical value 60.67 6.22 7.86 6.00 Experimental value 60.51 6.15 7.94 5.97 Production example 52 . N- [2- (p-hydroxyphenyl) ethyl] -3-
tert-Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide and 1-bromo-3-phenylpropane were used as starting materials and treated in the same manner as in Production Example 51 to give N- [2- [p- ( 3-Phenylpropoxy) phenyl] ethyl] -2- (3-pyridyl) thiazolidine-
4-Carboxamide dihydrochloride was obtained.

Melting point 98 ° C Elemental analysis value (as C ₂₆ H ₃₁ N ₃ O ₂ SCl ₂ · 0.3H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 59.38 6.06 7.99 6.10 13.48 Experimental value 59.37 6.05 8.01 6.09 13.31 Production example 53. N- [2- (p-hydroxyphenyl) ethyl] -3-te
rt Butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxamide and 1-bromo-2-phenylethane were used as starting materials, treated in the same manner as in Production Example 51, and treated with N
-[2- [p- (2-phenylethoxy) phenyl] ethyl] -2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride was obtained.

NMR (DMSO-d ₆ ) δ: 2.58 to 3.64 (8H, m), 4.11 to 4.40 (3H, m), 6.03 (1H,
s), 6.83 to 7.35 (5H, m), 8.02 (1H, dd), 8.66 to 8.85 (1
H, m), 8.88 to 9.01 (1H, m), 9.07 (1H, dd) MS: m / z 433 (M ⁺ -2 x HCl) Production Example 54 p- (3-methylbutoxy) benzylamine 1.13 g, 2-
(3-pyridyl) thiazolidine-4-carboxylic acid 1.29 g,
A mixture of 1.25 g dicyclohexylcarbodiimide and 0.82 g 1-hydroxybenzotriazole in 20 ml N, N-dimethylformamide was stirred overnight at room temperature. Ethyl acetate 10
The reaction mixture was diluted with 0 ml and insoluble material was separated. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, 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), and N- [p- (3-
2.20 g of methylbutoxy) benzyl] -2- (3-pyridyl) thiazolidine-4-carboxamide was obtained. To a solution of this compound in 60 ml of ethyl acetate was added 4 ml of 4N hydrogen chloride-dioxane solution. The separated solid was taken, washed with ethyl acetate and dried under reduced pressure to obtain 2.30 g of N- [p- (3-methylbutoxy) benzyl] -2- (3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Obtained.

Melting point 120-128 ° C Elemental analysis value (as C ₂₁ H ₂₉ N ₃ O ₂ SCl ₂ · 0.4H ₂ O) C (%) H (%) N (%) S (%) Cl (%) Theoretical value 54.17 6.45 9.02 6.89 15.23 Found 54.23 6.37 8.96 7.00 15.16 Production Examples 55 to 80 The following compounds were obtained in the same manner as in Production Example 54.

Production Example 81. 2- (3-pyridyl) thiazolidine-4-carboxylic acid 0.
34 g, 1-decylpiperazine 0.37 g, 1-hydroxybenzotriazole 0.33 g, N, N-dimethylformamide 10 ml, mixed with ice-cooled dicyclohexylcarbodiimide 0.34 g
Was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and the insoluble material was removed. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 5m ethyl acetate in the residue
l was added and the insoluble material was removed. 2N hydrogen chloride in liquid
Dioxane solution was added. The resulting crystals were collected, washed with ethyl acetate and dried to give 1-decyl-4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine trihydrochloride (0.63 g).

Mp 170 ° C. Elemental analysis _{(C 23 H 41 N 4 OSCl} 3 · H 2 O as) C (%) H (% ) N (%) S (%) Cl (%) Theoretical values 50.59 7.94 10.26 5.87 19.48 Found 50.50 7.81 10.22 6.07 19.47 Production Examples 82 to 85 The following compounds were obtained in the same manner as in Production Example 81.

Production Example 86. 1- (3-phenylpropyl) -4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine
To a solution of 40 mg and 5 ml of dichloromethane, formic acid-acetic anhydride (5:
0.5 ml of a mixed solution of 3 v / v) was added, and the mixture was stirred at room temperature overnight. 20 ml of ethyl acetate was added to the reaction solution, washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give oily 1- [3-formyl-2- (3-pyridyl) thiazolidine-4. -Ylcarbonyl] -4- (3-
30 mg of (phenylpropyl) piperazine was obtained.

NMR (CDCl ₃ ) δ: 1.6 to 2.0 (2H, m), 2.2 to 2.8 (8H, m), 3.0 to 3.4 (2H, m)
m), 3.6 to 3.9 (4H, m), 5.0 to 5.7 (1H, m), 6.14,6.4 (1H for each, each s), 7.0 to 7.5 (5H, m), 7.6 to 7.9 (1H, m) , 8.
24 (1H, s), 8.4 to 8.8 (3H, m) MS: m / z 424 (M ⁺ ) Production Example 87. It was treated in the same manner as in Production Example 54 by using 650 mg of 3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid and 400 mg of 1- (3-phenylpropyl) piperazine as starting materials. Purification by silica gel column chromatography (eluent: ethyl acetate) without converting to hydrochloride, oily 1- [3- (tert-butoxycarbonyl) -2- (3-pyridyl) thiazolidin-4-ylcarbonyl ] -4- (3-phenylpropyl) piperazine
560 mg was obtained.

NMR (CDCl ₃ ) δ: 1.40 (9H, s), 1.6 to 2.1 (2H, m), 2.2 to 2.8 (8H, m),
3.0 ~ 3.4 (2H, m), 3.4 ~ 4.0 (6H, m), 5.08 (1H, br t),
6.16 (1H, br s), 7.0 to 7.5 (5H, m), 8.4 to 8.8 (4H, m) MS: z / m 496 (M ⁺ ) Production Examples 88 to 89 In the same manner as in Production Example 87, the following compounds were prepared. Obtained.

Production Example 90 2- (3-pyridyl) thiazolidine-4-carboxylic acid 0.
A mixture of 84 g, 1-octylpiperazine 0.79 g, 1-hydroxybenzotriazole 0.54 g, and N, N-dimethylformamide 20 ml was added with dicyclohexylcarbodiimide 0.82 under water cooling.
g was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and the insoluble material was removed. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue to remove insoluble matter, and the solution was concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: 10% methanol-ethyl acetate], the oil obtained is dissolved in 25 ml of ethanol, and 0.32 g of fumaric acid is added. After standing for 2 days, the crystals formed were washed with cold ethanol and dried to give 1-octyl-4- [2- (3
0.72 g of -pyridyl) thiazolidin-4-ylcarbonyl] piperazine fumarate was obtained.

Melting point 135 ° C Elemental analysis value (as C ₂₅ H ₃₈ N ₄ O ₅ S) C (%) H (%) N (%) S (%) Theoretical value 59.27 7.56 11.06 6.33 Experimental value 59.01 7.66 10.95 6.27 Production example 91- 94 By treating in the same manner as in Production Example 90, the following compounds were obtained.

The following compound was obtained in the same manner as in Production Example 54.

The following compounds were obtained in the same manner as in Production Example 87.

The following compounds were obtained in the same manner as in Production Example 90.

Production Example 132 570 mg of 1-heptyl-4- [2- (3-pyridyl) -2-pyrrolin-5-ylcarbonyl] piperazine in 20 ml of water
− Using platinum oxide as a catalyst in 20 ml of ethanol,
Catalytic reduction was performed until the absorption of hydrogen stopped. After leaving the catalyst,
The liquid was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (5 g). Methanol-ethyl acetate (1:
Elute with a mixture of 10) to give 1-heptyl-4- [5- (3-
Pyridyl) pyrrolidin-2-ylcarbonyl] piperazine 250 mg was obtained. According to Production Example 54, 180 mg of this trihydrochloride was obtained.

Melting point 138-143 ° C Elemental analysis value (as C ₂₁ H ₃₇ N ₄ OCl ₃ · 1.8H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 50.41 8.18 11.20 21.26 Experimental value 50.49 7.83 11.09 21.10 The following compounds were obtained in the same manner as in Production Example 132. (However, hydrogen chloride treatment is not performed.) Production Example 134 120 mg of 1-hydroxybenzotriazole, 180 mg of dicyclohexylcarbodiimide and 170 mg of 2- (3-pyridyl) thiazolidine-4-carboxylic acid were sequentially added to a mixed solution of 200 ml of 3-phenylpropylethylenediamine and 81 mg of N-methylmorpholine in 5 ml of dimethylformamide,
Stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the insoluble material was removed, and the solution was concentrated under reduced pressure. 0.5N to residue
Aqueous sodium hydroxide solution was added, extracted with ethyl acetate,
After the organic layer was extracted with 1N hydrochloric acid, 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) and eluted with a mixed solution of methanol-ethyl acetate (1:10). N- (3-phenylpropylaminoethyl) -2-
(3-Pyridyl) thiazolidine-4-carboxamide 16
0 mg was obtained. The NMR and MS data of this compound are shown in Production Example 115.
It was in agreement with that of the compound of.

Production Example 135 1,3-dioxo-5- (3-pyridyl) thiazolidino [3,4-c] oxazolidine hydrochloride 50 mg solution in 1 ml dimethylsulfoxide, at room temperature 1- (3-phenylpropyl) piperazine 40 mg dimethylsulfoxide 0.5 ml Medium solution was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 1- (3 -Phenylpropyl) -4- [2- (3-pyridyl) thiazolidine-4-
Ilcarbonyl] piperazine 70 mg was obtained. The physicochemical properties of this product were in agreement with those of Preparation Example 108.

The following compound was obtained in the same manner as in Production Example 135.

Production Example 137 1- [2- (1-tert-butoxycarbonyl-3-piperidinyl) thiazolidin-4-ylcarbonyl] -4-
430 mg of (3-phenylpropyl) piperazine was dissolved in 3 ml of dichloromethane, 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 ml of saturated aqueous sodium hydrogen carbonate 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 taken and dried to give 1- (3-phenylpropyl) -4- [2- (3-piperidinyl) thiazolidine-
4-ylcarbonyl] piperazine trihydrochloride 200 mg was obtained.

Mp one hundred seventy-four to one hundred seventy-eight ° C. Elemental analysis _{(C 22 H 37 N 4 OSCl} 3 · 1.5H 2 O as a) C (%) H (% ) N (%) S (%) Theoretical values 49.02 7.48 10.39 5.95 Found 49.02 7.40 10.29 6.00 Production Example 138 N- (p-heptyloxybenzyl) -glyceramide
To a solution of 70 mg of pyridine-3-aldehyde 50 mg in benzene 10 ml and pyridine 2.5 ml was added p-toluenesulfonic acid 5 mg, and the mixture was refluxed for 12 hours for azeotropic dehydration. After cooling, the reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution twice, water three times and saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography to obtain 60 mg of N- (p-heptyloxybenzyl) -2- (3-pyridyl) -1,3-dioxolane-4-carboxamide.

NMR (CDCl ₃ ) δ: 0.90 (3H, br t), 1.2 to 1.5 (8H), 1.6 to 2.0 (2H),
3.95 (2H, t, J = 7Hz), 4.1 to 4.8 (5H), 5.89,5.99 (1H in total), 6.6 to 7.2 (1H, disappears at D ₂ O), 6.8 to 7.4 (5H), 7.6
~ 7.8 (1H), 8.6 ~ 8.7 (2H) MS: m / z398 (M ⁺ ) Production Example 139 1- (2-amino-3-hydroxypropionyl) -4
-(3-phenylpropyl) piperazine and pyridine-3
-From aldehyde according to the method of Production Example 138, 1- (3
-Phenylpropyl) -4- [2- (3-pyridyl) oxazolidin-4-ylcarbonyl] piperazine was obtained.

Elemental analysis (C ₂₂ H ₂₈ N ₄ O as _{2) C (%) H (} %) N (%) Theoretical values 69.45 7.42 14.72 Found 69.16 7.38 14.58 MS: m / z380 (M +) Production Example 140 N- (3-phenylpropylaminoethyl) -2- (3
-Pyridyl) thiazolidine-4-carboxamide 50 mg, p
-Tolualdehyde 17mg, Molecular sieve (4A) 100mg
2 ml of a toluene mixed solution of was heated at 120 ° C. for 8 hours in a sealed tube. After passing the reaction solution, the 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) to give 1- (3-phenylpropyl) -3. -[2- (3-pyridyl) thiazolidine-4
-Ylcarbonyl] -2- (p-tolyl) imidazolidine (3.3 mg) was obtained.

NMR (CDCl ₃ ) δ: 1.55 to 1.93 (3H, m), 2.39 (3H, s), 2.42 to 2.87 (8H,
m), 3.09 (1H, dd, J = 8Hz, 12Hz), 3.41 (1H, dd, J = 4Hz, J
= 12Hz), 4.07 to 4.30 (1H, m), 5.16 (1H, s), 5.52 (1H,
s), 7.03 to 7.42 (10H, m), 7.60 to 7.81 (1H, m), 8.44 (1
H, dd, J = 2Hz, J = 5Hz), 8.63 (1H, d, J = 2Hz) MS: m / z472 (M ⁺ ) Production Example 141 730 mg of 1- [2- (5,6-dimethoxy-3-pyridyl) thiazolidin-4-ylcarbonyl] -4- (3-phenylpropyl) piperazine was dissolved in 25 ml of ethyl acetate,
A 2N hydrogen chloride-dioxane solution is added with stirring at room temperature. The resulting powder is taken and dissolved in saturated sodium carbonate solution. Ethyl acetate is added, the organic layer is separated, washed with water and dried, and then the solvent is distilled off under reduced pressure. The residue was decomposed and purified by silica gel column chromatography (silica gel 50 m
1, 10% methanol-ethyl acetate), 1- [2- (5-methoxy-6-oxo-5,6-dihydro-3-pyridyl) thiazolidin-4-ylcarbonyl] -4- (3-phenylpropyl) 210 mg of piperazine was obtained.

NMR (DMSO-d ₆ ) δ: 1.56 to 1.94 (2H, m), 2.20 to 2.80 (8H, m), 2.90 to 4.4
0 (10H, m), 5.28 to 5.66 (1H, m), 6.80 to 7.44 (7H, m) MS: m / z 442 (M ⁺ ) Reference Example 114 In the same manner as in Reference Example 80, the following compounds were obtained.

1-Bromo-3-phenylbutane NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7Hz), 2.11 (2H, q, J = 7Hz), 2.64 ~
3.50 (3H, m), 7.24 (5H, s) Reference Example 114 In the same manner as in Reference Example 101, the following compound was obtained.

Ethyl 1- [4- (3-phenylbutyl)] piperazinecarboxylate NMR (CDCl ₃ ) δ: 1.11-1.50 (6H, m), 1.56-3.05 (9H, m), 3.50 (4H,
t, J = 6 Hz), 4.19 (2H, q, J = 7Hz), 7.24 (5H, s) Reference Example 115 In the same manner as in Reference Example 102, the following compound was obtained.

1- (3-phenylbutyl) piperazine _{NMR (CDCl 3) δ: 1.24} (3H, d, J = 7Hz), 1.76 (2H, q, J = 7Hz), 1.93 (1
H, s), 2.10 ~ 2.46 (6H, m), 2.51 ~ 2.97 (5H, m), 7.00 ~
7.38 (5H, m) MS: (m / z) 218 (M ⁺ ) Preparation Example 142 Treated in the same manner as in Preparation Example 90, the following compound was obtained.

1- (3-phenylbutyl) -4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine
Fumarate Melting point 166-168 ° C Elemental analysis value (as C ₂₇ H ₃₄ N ₄ O ₅ S) C (%) H (%) N (%) S (%) Calculated value 61.58 6.51 10.64 6.09 Experimental value 61.21 6.45 1.58 6.42 MS: (m / z) 410 (M ⁺ -C ₄ H ₄ O ₄ ) Reference Example 116 The following compounds were obtained in the same manner as in Reference Examples 70, 80, 102 and 103.

3-Methyl-3-phenylbutanol NMR (CDCl ₃ ) δ: 1.10 (1H, s), 1.34 (6H, s) 1.92 (2H, t, J
= 7Hz), 4.48 (2H, t, J = 7Hz), 7.03 to 7.53 (5H, m) 1-Bromo-3-methyl-3-phenylbutane NMR (CDCl ₃ ) δ: 1.33 (6H, s), 2.04 to 2.33 (2H, m), 2.95
~ 3.21 (2H, m), 7.02 ~ 7.43 (5H, m) Ethyl 4- (3-methyl-3-phenylbutyl) piperazine-1-carboxylate NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7Hz), 1.32 (6H, s), 1.60
~ 2.15 (2H, m), 2.15 ~ 2.46 (6H, m), 3.43 (4H, t, J = 6H
z), 4.13 (2H, q, J = 7Hz), 7.03 to 7.50 (5H, m) 1- (3-Methyl-3-phenylbutyl) piperazine NMR (CDCl ₃ ) δ: 1.31 (6H, s), 1.60 (1H, s), 1.65 to 1.96
(2H, m), 1.96 to 2.20 (2H, m), 2.30 (4H, t, J = 6Hz), 2.
85 (4H, t, J = 6Hz), 7.03 to 7.46 (5H, m) MS: m / z 232 (M ⁺ ) Production Example 143 The following compounds were obtained by treating in the same manner as in Production Example 87.

1- (4-methyl-4-phenylbutyl) -4- [2-
(3-Pyridyl) thiazolidin-4-ylcarbonyl]
Piperazine NMR (CDCl ₃ ) δ: 1.35 (6H, s), 1.65 to 1.97 (2H, m), 1.97
~ 2.48 (7H, m), 2.78 ~ 3.73 (6H, m), 3.78 ~ 4.30 (1H,
m), 5.57 (0.5H, br d, J = 12Hz), 5.95 (0.5H, br d, J = 5)
Hz), 7.05 ~ 7.43 (6H, m), 7.71 ~ 7.96 (1H, m), 8.43 ~
8.63 (1H, m) 8.69 to 8.81 (1H, m) MS: m / z 434 (M ⁺ ) Production Example 144 Using the compound of Production Example 143 as a starting material, the following compound was treated in the same manner as in the salt formation reaction of Production Example 90. Got

1- (3-methyl-3-phenylbutyl-4- [2-
(3-Pyridyl) thiazolidin-4-ylcarbonyl]
Piperazine / fumarate Melting point 172-173 ° C Elemental analysis value (as C ₂₈ H ₃₆ N ₄ O ₅ S) C (%) H (%) N (%) S (%) Calculated value 62.20 6.71 10.36 5.93 Measured value 61.92 6.67 10.17 6.09 Reference example 117. N, N-dimethylformamide (70m) of phenylacetic acid methyl ester (7.50g) and 60% sodium hydride (2.1g)
l) The solution was stirred at room temperature for 1 hour. Methyl iodide (10 g) was added dropwise to this mixed solution under ice-cooling, and this was stirred at 50 ° C. for 3 hours, and crystals formed after cooling were removed. 60% Sodium hydride (2.1 g) was added to the solution, and the same treatment was performed thereafter. To the solution obtained again, add 60% sodium hydride (0.4g) and 50
Warm for 1 hour at ℃, and add methyl iodide (2.0g) to the mixture while cooling with ice.
Was added and stirred for 15 hours. Water was added dropwise to the reaction solution under ice cooling, and the solvent was concentrated under reduced pressure. Water was added to the residue and extracted with ether. The ether layer was washed twice with water, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (200 g). Elute with a mixture of hexane-ethyl acetate (10: 1),
-Methyl-2-phenylpropionic acid methyl ester 8.
I got 04g.

NMR (CDCl ₃ ) δ: 1.60 (6H, s), 3.68 (3H, s), 7.36 (5H, br
s) To a suspension of lithium aluminum hydride (1.71g) in tetrahydrofuran (50ml), a solution of 2-methyl-2-phenylpropionic acid methyl ester (7.97g) in tetrahydrofuran (20ml) was added dropwise under ice-cooling, and at room temperature for 30 minutes. It was stirred. Water was added dropwise to the reaction mixture under ice cooling, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g). Hexane-ethyl acetate (2: 1)
Eluted with a mixture of 2-methyl-2-phenylpropanol
Obtained 6.32 g.

NMR (CDCl ₃ ) δ: 1.32 (6H, s), 1.72 (1H, s), 3.61 (2H,
s), 7.10 to 7.61 (5H, m) Oxalyl chloride (4.1ml) in dichloromethane (100m
l) A solution of dimethyl sulfoxide (7.14 g) in dichloromethane (10 ml) was added dropwise at -60 ° C, and the mixture was stirred for 10 minutes.
2-Methyl-2-phenylpropanol (6.16
g) solution of dichlorotan (15 ml) was added and after stirring for 1 hour,
Triethylamine (20.7 g) was added and the mixture was further stirred for 30 minutes. The mixture was returned to room temperature, water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (400 g) and eluted with 2% ethyl acetate-hexane solution to give 2-methyl. 2-phenylpropanal (4.93 g) was obtained.

NMR (CDCl ₃ ) δ: 1.46 (6H, s), 7.32 (5H, s), 9.51 (1H,
s) 2-Methyl-2-phenylpropanal (0.30g) and triphenylphosphylidene acetic acid methyl ester (0.74g)
A solution of g) in tetrahydrofuran (7 ml) was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (25 g) and eluted with a mixed solution of hexane-ethyl acetate (2: 1) to give 4-methyl-4-phenyl-2-pentenoic acid methyl ester. 0.37 g was obtained.

NMR (CDCl ₃ ) δ: 1.46 (6H, s), 3.75 (3H, s), 5.82 (1H, d,
J = 17Hz), 7.19 (1H, d, J = 17Hz), 7.30 (5H, s) Ribbon-shaped metallic magnesium (0.36 g) was added to a solution of 4-methyl-4-phenyl-2-pentenoic acid methyl ester (0.3 g) in anhydrous methanol (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-methyl-4-phenyl-pentanoic acid methyl ester (0.30). g got.

NMR (CDCl ₃ ) δ: 1.35 (6H, s), 2.05 (4H, s), 3.63 (3H,
s), 7.01 to 7.52 (5H, m) Reference Example 118. The following compounds were obtained in the same manner as in Reference Example 117 (2), 80, 102 and 103.

4-Methyl-4-phenylpentanol NMR (CDCl ₃ ) δ: 1.32 (6H, s), 1.10 to 1.92 (4H, m), 1.56
(1H, s), 3.51 (2H, t, J = 7Hz), 7.05 to 7.50 (5H, m) 1-Promo-4-methyl-4-phenylpentane NMR (CDCl ₃ ) δ: 1.32 (6H, s), 1.40 to 1.91 (4H, m), 3.29
(2H, t, J = 6Hz), 7.11 to 7.48 (5H, m) Ethyl 4- (4-methyl-4-phenylpentyl) piperazine-1-carboxylate NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7Hz), 1.32 (6H, s), 1.08
~ 1.93 (4H, m), 2.08 ~ 2.53 (6H, m), 3.48 (4H, t, J = 6H
z), 4.29 (2H, q, J = 7Hz), 7.09 to 7.52 (5H, m) 1- (4-methyl-4-phenylpentyl) piperazine NMR (CDCl ₃ ) δ: 1.07 to 1.45 (2H, m), 1.32 (6H, s), 1.45
~ 1.77 (2H, m), 1.70 (1H, s), 2.08 ~ 2.45 (6H, m), 2.8
7 (4H, t, J = 6Hz), 7.01 to 7.43 (5H, m) Production Example 145. The following compounds were obtained by treating in the same manner as in Production Example 90.

1- (4-methyl-4-phenylpentyl) -4- [2
- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine fumarate _{NMR (CDCl 3) δ: 1.05~1.47} (2H, m), 1.35 (6H, s), 1.47
~ 1.86 (2H, m), 2.09 ~ 2.63 (6H, m), 2.73 ~ 3.76 (6H,
m), 4.27 (1H, q, J = 6Hz), 5.58 (0.5H, s), 5.89 (0.5H,
s), 6.65 (2H, s), 7.05 ~ 7.53 (6H, m), 7.75 ~ 8.05 (1
H, m), 8.38 to 8.75 (2H, m) MS: m / z 438 (M ⁺ -C ₄ H ₄ O ₄ ) Production Examples 146 to 173 The following compounds were obtained in the same manner as in Production Example 54.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 405/04 213 7602-4C 413/04 213 7602-4C 417/04 205 9051-4C 211 9051-4C 213 9051 -4C 215 9051-4C 417/14 207 9051-4C 209 9051-4C 211 9051-4C 213 9051-4C C07K 5/06 8318-4H (72) Inventor Takahashi Engineering 3-16-1, Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. Hasune Dormitory (72) Inventor Kenichi Tomioka 1214-76 Sakata, Okegawa City, Saitama Prefecture (72) Inventor Toshimitsu Yamada 2-24-12-412 Maenocho, Itabashi-ku, Tokyo

Claims (1)

[Claims] 1. A platelet activating factor antagonist comprising a saturated heterocyclic carboxylic acid amide derivative represented by the following general formula or a non-toxic salt thereof as an active ingredient. (The symbols in the formula have the following meanings: R ¹ : a substituted or unsubstituted 5- or 6-membered heterocyclic group which may be condensed with a benzene ring, R ² : a hydrogen atom, a lower alkyl group, or R ^The same group as ¹ , X: an oxygen atom, a sulfur atom, or a methylene group which may be substituted with a lower alkyl group, Y ¹ : an oxygen atom, a sulfur atom, or a group represented by the formula> N-R ⁴ , A ¹ : a methylene group or an ethylene group, each of which may be substituted with a lower alkyl group, 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 carbonized group Hydrogen group, or 5- to 6-membered heterocyclic group which may be condensed with benzene ring, A ² and A ³ : same or different, substituted or unsubstituted lower alkylene group, Z: methine group (> CH- ), Or a nitrogen atom, R ⁷ : a hydrogen atom, a substituted or unsubstituted hydrocarbon group, a carboxy group, a lower alkoxycarbonyl group, an acyl group, a carbamoyl group, or a mono- or di-lower alkylaminocarbonyl group, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ : the same or different, a hydrogen atom, a lower alkyl group, an aralkyl group, or an aryl group. )