JPH0631230B2 - Saturated heterocyclic carboxylic acid amide derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel saturated heterocyclic carboxylic acid amide derivative having a dish-platelet activating factor (PAF) antagonism and salts thereof.

(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, 1 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,
It is considered to be a factor that causes various symptoms such as thrombosis and shock. Therefore, studies on substances that antagonize the physiological activity of PAF have been conducted, and some anti-PAF drugs have been reported (for example, JP-A-61-93191 and JP-A-60-116).
679, JP-A-60-142932, JP-A-59-134798, JP-A-61-87684, JP-A-61-37726).

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

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

(The symbols in the formula have the following meanings.

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 ¹ : an oxygen atom, Sulfur atom, or methylene group optionally substituted by lower alkyl group, Y ¹ : oxygen atom, or group represented by formula> N—R ⁴ , A ¹ : methylene optionally substituted by lower alkyl group Group or ethylene group, R ³ : Formula A group represented by A group represented by Or a group represented by A group represented by, R ^4: a hydrogen atom, a lower alkyl group, a carboxy group, lower alkoxycarbonyl group, or an acyl group, A ² and A ^3: What identical 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, lower alkoxycarbonyl group, an acyl group,
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. ) A feature of the chemical structure of the compound of the present invention is that it is a saturated heterocyclic carboxylic acid amide derivative in which a specific position of a specific saturated heterocycle is necessarily substituted with a specific heterocycle and a specific carboxamide. That is, the formula (I) The compound of the present invention represented by A saturated heterocycle represented by, that is, a 5- or 6-membered saturated heterocycle at a specific position may be fused with a specific heterocycle, that is, a benzene ring represented by R ^1; It has a chemical structural feature in that a specific amino group represented by COR ³ is always substituted with a substituted carboxamide.

Conventionally, various compounds have been known as saturated heterocyclic carboxylic acid amide derivatives such as the compound (I) of the present invention.
For example, West German Patent 2729414 R ₁ : a alkanoyl group having _{2 to} 17 carbon atoms R ₂ : a carboxyl group or a compound represented by an ester or an amide thereof has a calculus-removing action, according to US Pat. No. 3,592,905. 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 was not specifically known. Of.

The compound of the present invention is described in more detail below.

In the definition of the general formulas 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, methyl group, ethyl group, propyl group, isopropyl 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 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-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like can be mentioned.

Further, the “mono- or di-lower alkylaminocarbonyl group” means a group in which the amino group of a carbamoyl group is mono- or di-substituted with the above “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 hydrocarbon molecule, which is a general term for compounds consisting only of carbon and hydrogen, and particularly an acyclic hydrocarbon. Is an alkyl group which is a saturated hydrocarbon monovalent group, a cyclic alkyl group is a cycloalkyl group which is a monocyclic saturated hydrocarbon monovalent group, an aromatic monocyclic and 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, 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, 10-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-methylhexadecyl group, octadecyl group, 16-methylheptadecyl group, nonadecyl group, 17- Examples thereof include a methyloctadecyl group, an eicosyl group and an 18-methylnonadecyl group.

The "cycloalkyl group" is preferably one having a carbon number of 3 to 7, 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 ones.

The "aralkyl group" is preferably a group in which any hydrogen atom of the "lower alkyl group" is substituted with the "aryl group", and specifically, a benzyl group, a phenethyl group, 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 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-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) pentyl group, 4-methyl-5- (2-naphthyl)
Examples include a pentyl group, a diphenylmethyl group (benzhydryl group), a trityl group and the like.

The “aralkenyl group” is the above “aryl group” 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
A hexenyl group and the like.

The "non-aromatic condensed polycyclic hydrocarbon group" is specifically an indanyl 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.), Indenyl group Etc.), tetrahydronaphthyl group Dihydronaphthyl group Etc.), 1,2-benzo-1-cycloheptenyl group Fluorenyl group 2,3-dihydro-1H-benz [f] indenyl group 1H-benz [f] indenyl group Etc.) and the like, and condensed polycyclic hydrocarbon groups that are not included in aromatic hydrocarbon groups.

In the compound of the present invention, "benzene ring may be condensed 5 represented by R ¹ or R ² when it is the same group as R ¹ 5
As a "to 6-membered heterocyclic group", 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, Imidazolyl group, imidazolinyl group, imidazolidinyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, triazolyl group, tetrazolyl group, indolyl group, benzimidazolyl group, imidazolyl group, pyridyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, pyrimidinyl group , Pyridazinyl group, pyrazinyl group, piperazinyl group, quinolyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, cinnolinyl group, monocyclic or bicyclic saturated or unsaturated heterocyclic group containing only nitrogen atom, thiazolyl group, Thiazolinyl group, thi Zolidinyl group, isothiazolyl group, thiadiazolyl group, benzothiazolyl group, monocyclic or bicyclic saturated or unsaturated heterocyclic group containing nitrogen atom and sulfur atom such as benzoisothiazolyl group, oxazolyl group, oxazolinyl group, oxazolidinyl group, Other nitrogen-containing heterocyclic groups such as isoxazolyl group, oxadiazolyl group, benzoxazolyl group, benzisoxazolyl group, and other monocyclic or bicyclic saturated or unsaturated heterocyclic groups containing nitrogen atom and oxygen atom , Thienyl group, sulfur-containing heterocyclic group such as tetrahydrothienyl group and furyl group, tetrahydrofuryl group, pyranyl group, tetrahydropyranyl group,
Dioxolyl group, benzofuryl group, benzopyranyl group,
Examples thereof include oxygen-containing heterocyclic groups such as benzodioxolyl group.

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 is preferably a linear alkylene group having 1 to 3 carbon atoms, and specific examples thereof include a methylene group, an ethylene group and a trimethylene group.

Further, the "acyl group" is, in particular, 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-phenylpentanoyl group, 3-phenylpentanoyl group, 2-phenylpentanoyl group, 1-phenylpentanoyl group, 3-methyl-4-phenylbutane group Noyl group, 3-methyl-2-phenylbutanoyl group, 6-phenylhexanoyl group, 5-phenylhexanoyl group,
4-phenylhexanoyl group, 3-phenylhexanoyl group, 2-phenylhexanoyl group, 1-phenylhexanoyl group, 4-methyl-5-phenylpentanoyl group, 4-methyl-3-phenylhexanoyl group, Aralkanoyl group such as 4-methyl-2-phenylhexanoyl group, benzoyl group, 1-naphthoyl group, 2-naphthoyl group, (o, m, or p) toluoyl group, (o, m, or p) -fluorobenzoyl group Group, (o, m, or p) -chlorobenzoyl group, (o, m, or p) -bromobenzoyl group, various fluoronaphthoyl groups, various chloronaphthoyl groups, various bromonaphthoyl groups, etc. Aryl carbonyl group etc. are mentioned as a suitable thing.

Further, as "lower alkoxycarbonyl group", 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 the “5- or 6-membered heterocyclic group which may be condensed with a benzene ring” are R ⁷ , R ¹ and R.
² may further have a substituent, and these substituents include a halogen atom, a lower alkyl group, a hydroxyl group (a hydroxyl group, a mercapto group, an alkoxy group, a lower alkylthio group, a cycloalkyl lower alkoxy group, a cycloalkyl lower group). Alkylthio group, aralkyloxy group, aralkylthio group, aryloxy group, silylthio group, aryloxy lower alkoxy group, aryloxy lower alkylthio group, arylthio lower alkoxy group, arylthio lower alkylthio group, oxo group group (oxo group, thioxo group) ), Carboxy group group (carboxy group, lower alkoxycarbonyl group, acyl group), cyano group, carbamoyl group group (carbamoyl group, mono- or di-lower alkylaminocarbonyl group), nitro group, amino group group (amino group, mono or The Grade alkylamino group, a mono- or di-aralkylamino groups, selected from among N- aralkyl -N- lower alkylamino group).

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 linear or branched one having 1 to 10 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a 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,
An 8-methylnonyloxy group and the like can be mentioned.

In addition, "lower alkoxy group" means the above "alkoxy group"
Among them, those having 1 to 6 carbon atoms can be mentioned.

As the “lower alkylthio group”, the oxygen atom of the above “lower alkoxy group” is a sulfur atom, and specifically, a methylthio group, an ethylthio group, a 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, a cyclopropyl-methoxy (or methylthio) group (meaning a cyclopropylmethoxy group or a cyclopropylmethylthio 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-cyclo Propyl - butoxy (or-butylthio) group, 5-cyclopropylpentyl - oxy (or thio) groups, 6-cyclopropyl-hexyl - oxy (or thio) groups, 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-cyclopentyl- Ethoxy (or ethylthio) group, 3-cyclopentyl-propoxy (or propylthio) group, 2-cyclopentyl-propoxy (or propylthio) group, 1-cyclopentyl-propoxy (or propylthio) group, 2-cyclopentyl-1
-Methyl-ethoxy (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, cyclo Heptyl-methoxy (or methylthio) group, 2-cycloheptyl-ethoxy (or ethylthio) group, 1-cycloheptyl-ethoxy (or ethylthio) group, 3-cycloheptyl-propoxy (or propylthio) group, 2-cycloheptylpropoxy (Or propylthio) group, 1-cycloheptyl-propoxy (or propylthio) group, 2-cycloheptyl-1-methyl-
Ethoxy (or ethylthio) group, 4-cycloheptyl-
Examples thereof include butoxy (or butylthio) group, 5-cycloheptylpentyl-oxy (or thio) group, 6-cycloheptylhexyl-oxy (or thio) group and the like.

The "aralkyloxy group" and "aralkylthio group" mean a group in which any hydrogen atom of the "lower alkoxy group" or "lower alkylthio group" is substituted with the "aryl group", and specifically, For example, when only a phenyl group is used as the “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 ethylthio) group, 4-phenyl-butoxy (or butylthio) group, 5-phenylpentyl-oxy (or thio) group, 6-phenylhexyl-oxy ( Or a thio) group and the like.

The "aryloxy group" and "arylthio" group are specifically derived from aromatic monocyclic or polycyclic hydrocarbon hydroxy or mercapto compounds such as phenoxy (or phenylthio) group and 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 the "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) pentyl-oxy (or thio) group, 6-
And a 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, the number of carbon atoms such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, and isohexylamino group is 1 A monoalkylamino group which is linear with 6 linear or branched alkyl groups,
Dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, dihexylamino group and the like, which are di-substituted by a linear or branched alkyl group having 1 to 6 carbon atoms Type dialkylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropylamino group such as straight or branched chain having 1 to 6 carbon atoms Among the alkyl groups, an asymmetric dialkylamino group disubstituted with different alkyl groups can be mentioned.

The "mono or diaralkylamino group" is benzylamino group, phenethylamino group, 3-phenylpropylamino group, 4-phenylbutylamino group, 5-phenylpentylamino group, 6-phenylhexylamino group, 1-naphthyl. 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 , A monoaralkylamino group such as a triphenylmethylamino group, a dibenzylamino group, a diphenethylamino group,
Symmetrical diaralkylamino groups such as bis (3-phenylpropyl) amino group, bis (4-phenylbutyl) amino group, bis (5-phenylpentyl) amino group, 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- (4-phenylbutyl) -5-phenylpentylamino group, N- (4-phenylbutyl) -6-phenylhexylamino group, N- (5 -Phenylpentyl)
Asymmetrical diaralkylamino groups such as -6-phenylhexylamino group can be mentioned.

The “N-aralkyl-N-lower alkyl group” means an amino group which is tertiaryized by substituting the “lower alkyl group” with the amino group of the “monoaralkylamino group”, and is an N-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-phenylpropyl Amino group, N-methyl-4-phenylbutylamino group, N-ethyl-4-phenylbutylamino group, N-propyl-4-phenylbutylamino group, N-butyl-4
-Phenylbutylamino group, N-pentyl-4-phenylbutylamino group, N-hexyl-4-phenylbutylamino group and the like are mentioned as typical specific groups.

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

The compound (I) of the present invention forms a salt. The present invention includes a salt of compound (I). Specific examples of such a salt 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.

In addition, 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.

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

First production method (amidation A) Second production method (amidation B) Third production method (N-acylated A) Fourth production method (N-sialylation B) Fifth production method (N-acylated C) Process 6 (ether or thioetherification A) 7th production method (ether or thioetherification B) Eighth manufacturing method (cyclization) Ninth production method (N-alkylated A) Tenth production method (N-alkylated B) Eleventh production method (N-alkylated C) 12th production method (N-alkylated D) 13th manufacturing method 14th manufacturing method (reduction) (In the reaction formula, R ¹ , R ² , R ³ , R ⁴ , X ¹ , A ¹ , Y
¹ and Z have the above meanings, and other symbols have the following meanings.

R ¹² : the same group as R ¹ which may have a protecting group, R ¹³ : the same group as R ² which may have a protecting group, Y ² : which may have a protecting group The same group as Y ¹ , R ¹⁴ : the same group as R ³ which may have a protecting group, R ¹⁸ : a residue obtained by removing a carbonyl group from an acyl group, : 5- to 6-membered nitrogen-containing heterocyclic group which may be condensed with a non-tertiaryized benzene ring, R ¹⁹ : hydrogen atom, lower alkyl group or formula R ²⁰ : the same group as R ¹ which may have a protecting group, R ²¹ : the same group as R ² which may have a protecting group, Y ³ : which has a protecting group Optionally the same group as Y ¹ , A ⁵ : a hydrocarbon divalent group or a divalent group represented by the formula —A ⁴ —X ² —A ⁶ —, A ⁴ : a hydrocarbon divalent group X ² : Oxygen atom or sulfur atom, A ⁶ : lower alkylene group, D ¹ and D ² : one is a hydroxyl group, a mercapto group, or an alkali metal substitution product thereof, the other is a halogen atom or an organic sulfonic acid residue, R ²³ : carbon number There 1-10 alkyl group, a cycloalkyl-lower alkyl group, an aralkyl group, an aryl group or an aryloxy-lower alkyl group, arylthio-lower alkyl group, X ^3: an oxygen atom or a sulfur atom a ^7: benzene ring condensed Good 5 to 6 membered hetero Ring divalent group, or the formula ^-A 6 ^-X 2 -A ⁸ - group represented by, ^{A 8:} a benzene ring or a heterocyclic divalent group fused 5 or may be 6-membered, R ^24: a protecting group The same group as R ³ which may have: X ⁴ : an oxygen atom or a sulfur atom, Y ⁴ : an oxygen atom, or an imino group (—NH—), D ³ : a halogen atom or an organic sulfonic acid residue, R ²⁵ : lower alkyl group, lower alkoxycarbonyl group,
Or an acyl group, D ⁴ and D ⁵ : an amino group, one of which may have a protecting group, the other of which is a halogen atom or an organic sulfonic acid residue, and R ²⁶ : D ⁵ may have a protecting group. When it is an amino group, a hydrogen atom, a lower alkyl group, or an aralkyl group,
When D ⁵ is a halogen atom or an organic sulfonic acid residue, a lower alkyl group or an aralkyl group, or D ⁵ -R ^{26 is} combined with potassium phthalate (provided that D ⁴ is a halogen atom or an organic sulfonic acid residue), R ²⁷ : a lower alkyl group or an aralkyl group which is the same as or different from R ²⁶ , R ²⁸ : a hydrogen atom, the same group as R ²⁶ or the same group as R ²⁷ , R ²⁹ : a hydrogen atom, a lower alkyl group, or formula D ⁴ -A ⁸ -
A group represented by, R ^30: a hydrogen atom, a lower alkyl group, or an aralkyl group, R ^31: a hydrogen atom, a lower alkyl group, an aralkyl group, or aryl group, X ^5: an oxygen atom, a lower as sulfur atom, or a substituent A methylene group which may have an alkyl group, or a methine group which may have a lower alkyl group as a substituent, ...: Either bond is a double bond. 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. Examples of the amino group protecting group include a benzyloxycarbonyl group and p-methoxy group. Benzyloxycarbonyl group, p-methylbenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3, Urethane type such as 5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, tert-butoxycarbonyl group, tert-butoxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group Protecting group Acyl-type protecting groups such as formyl group, acetyl group, trifluoroacetyl group, phthalyl group, tosyl group, o-nitrophenylsulfenyl group, p-methoxy-o-nitrophenylsulfenyl group-benzoyl group and chloroacetyl group. , A trityl group, a benzyl group, a 2-benzoyl-1-methylvinyl group, an alkyl type protecting group such as a trimethylsilyl group, a benzylidene group,
Examples include an arylidene-type protecting group such as a 2-hydroxyallylidene group.

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

Examples of the protecting group for the mercapto group 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 or the like, and as a hydroxyl group-protecting group, benzyl group, tert-butyl group,
Examples thereof include an acetyl group, a trifluoroacetyl group and a benzyloxycarbonyl group.

The “hydrocarbon divalent group” corresponds to the hydrocarbon group substituted in R ⁷ , and includes an alkylene group, a cycloalkanediyl group, an arylene group, a non-aromatic condensed polycyclic hydrocarbon divalent group, and aralkylene. A group and an arkenylene group are preferred.

The "alkylene group" is preferably a linear or branched group having 1 to 20 carbon atoms, and specifically, methylene group, methylmethylene group, ethylene group, trimethylene group, propylene group, tetramethylene group, 1 -Methyltrimethylene group, 2
-Methyltrimethylene group, 3-methyltrimethylene group,
Pentamethylene group, 1-methyltetramethylene group, 4-
Methyltetramethylene group, hexamethylene group, 5-methylpentamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene group, tridecamethylene group, tetradecamethylene group, penta Examples thereof include a decamethylene group, a hexadecamethylene group, a heptadecamethylene group, an octadecamethylene group, a nonadecamethylene group, and an aicosamethylene group.

The "cycloalkanediyl group" includes various cyclopropanediyl groups, various cyclobutanediyl groups, various cyclopentanediyl groups, various cyclohexanediyl groups and various cycloheptanediyl groups, and "nonaromatic condensed polycyclic hydrocarbon divalent groups". The "group" is specifically various indandiyl groups, various indendiyl groups, various tetrahydronaphthalenediyl groups, various dihydronaphthalenediyl groups, various 1,
Preferred examples include 2-benzo-1-cycloheptenediyl group, various fluorenediyl groups, various 2,3-dihydro-1H-benz [f] indenediyl groups, and various 1H-benz [f] indenediyl groups. It In addition,
The "arylene group" is a phenylene group (o, m,
p), various naphthalenediyl groups and the like. The "aralkylene group" means a divalent group of an arylalkane in which a lower alkylene group having 1 to 6 carbon atoms and the above "arylene group" are bonded, a phenylene group as the arylene group, and a methylene group as the lower alkylene group. For example Becomes

Examples of the alkali metal atom forming an alcoholate (phenolate) or thiolate (thiophenolate) include potassium and sodium.

As the "residue obtained by removing a carbonyl group from an acyl group", a lower alkyl group, an aralkyl group, a halogen-substituted or unsubstituted aryl group and a lower alkoxy group are particularly preferable, and specific examples thereof are the same as those described above. Groups.

The "5- or 6-membered nitrogen-containing heterocyclic group which may be condensed with a non-tertiaryized benzene ring" is "the benzene ring represented by R ² when R ¹ and R ¹ are the same groups. 5 to 6-membered heterocyclic group which may be condensed ”, means a group containing at least one nitrogen atom and at least one of the nitrogen atoms not being tertiaryized, and a 1H-pyrrolyl group , Δ ¹ or Δ ³ -pyrrolinyl group, pyrrolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, pyrazolyl group, pyrazolinyl group, pithizolidinyl group, 1H-1,2,3-triazolyl group, 2H-1,2,3- Triazolyl group, 1H-1,2,4-triazolyl group, 4H-1,
2,4-triazolyl group, 1H-1,2,3,4, -tetrazolyl group, indolyl group, benzimidazolyl group, 1H-indazolyl group, 2H-indazolyl group, 1,4, -dihydropyridyl group, tetrahydropyridyl group , A piperidinyl group,
Piperazinyl group, Δ ⁴ -thiazolinyl group, thiazolidinyl group, Δ ⁴ -oxazolinyl group, oxazolidinyl group,
Examples include Δ ⁴ -isoxazolyl group and isoxazolidinyl group.

The "halogen atom" represented by D ¹ , D ² , D ³ , D ⁴ and D ⁵ is an iodine atom, a bromine atom, a chlorine atom or the like, and the organic sulfonic acid residue is a methanesulfonyloxy group,
Examples thereof include alkylsulfonyloxy groups such as ethanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy group and toluene (particularly p-toluene) sulfonyloxy group.

The “cycloalkyl lower alkyl group” represented by R ²⁵ represents a group in which any hydrogen atom of the “lower alkyl group” is substituted with the “cycloalkyl group”, and the lower alkyl group may be a methyl group or a cycloalkyl group. An example of a cyclohexyl group is a cyclohexylmethyl group.

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

“A ⁷ or A ⁸ represents“ may be condensed with a benzene ring 5
To 6-membered heterocyclic divalent group "is a" 5- to 6-membered heterocyclic group which may be condensed with a substituted benzene ring "represented by R ² when it is the same group as R ¹ and R ^1. Corresponding to, specifically, a pyridine ring, for example, pyridine-
2,3-diyl group Pyridine-2,4-diyl group Pyridine-2,5-diyl group Pyridine-2,6-diyl group Pyridine-3,4-diyl group Pyridine-3,5-diyl group To become various pyridinediyl groups.

Other groups are the same as above.

Each manufacturing method will be described in detail below.

First Production Method The compound (I) of the present invention comprises a heterocyclic carboxylic acid which may have a protecting group represented by the general formula (II) or a reactive derivative thereof and a protecting group represented by the general formula (III). It can be produced by reacting with an amine which may have and then removing a protecting group if necessary.

Examples of the reactive derivative of the compound (II) include acid chloride,
Acid halides such as acid bromides; acid azides; active esters with N-hydroxybenzotriazole, N-hydroxysuccinimide and the like; symmetrical acid anhydrides; alkyl carbonates, mixed acid anhydrides with p-toluenesulfonic acid and the like. To be

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 raw material compound, particularly the reactive derivative of compound (II), but include pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform. ,Ethyl acetate,
It is advantageous to react the starting compounds (II) and (III) in an equimolar amount or an excessive molar amount of one of them in an organic solvent inert to the reaction such as acetonitrile.

Depending on the type of reactive derivative, or the starting compound (II
When the salt of I) is used in the reaction, organic bases such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, 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) in an excess mole. Pyridine can also serve as a solvent.

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

In this reaction, it is preferable that no other mercapto group, reactive amino group, carboxy group, or hydroxy group is present. However, after the protective group is introduced and reacted, the target group is obtained by removing the protective group. be able to.

Removal of the protecting group depends on the type of the protecting group.

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

Further, when the protecting group of the carboxy group is a methyl group or an ethyl group, by saponification, the benzyl group and various substituted benzyl groups are subjected to catalytic reduction or saponification, and the tert-butyl group is treated with the same acid as above. The trimethylsilyl group is easily removed by bringing it into 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 (for example, O-benzyl,
O-benzyloxycarbonyl, S-p-nitrobenzyl) catalytic reduction can be applied, and when it is an acyl-based protecting group, it can be removed by hydrolysis in the presence of acid or alkali.

These treatments can be performed by a conventional method.

Second Production Method The compound represented by the general formula (Ia) in which Y ¹ is an imino group may be produced by reacting the oxazolidinedione ring-fused heterocyclic compound represented by the general formula (IV) with the compound (III). it can.

Compound (IV) is a compound in which the C-terminal of compound (II) is activated and the amino group is simultaneously protected, and this method is included in the category of amidation method.

Reactivity, protecting group and removal thereof are almost the same as those in the first production method.

Third Production Method The compound of the present invention represented by the general formula (Ic) is prepared by reacting the corresponding cyclic secondary amine (VII) with a carboxylic acid represented by the general formula (VIII) or a reactive derivative thereof, and then, if necessary, a protecting group. It can be manufactured by removing.

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

Fourth Production Method The compound of the present invention represented by the general formula (Id) is reacted with the corresponding heterocyclic secondary amine (IX) with the carboxylic acid of the general formula (X) or a reactive derivative thereof, and then, if necessary, a protecting group is added. It is possible to manufacture by removing.

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

During the fifth production method the present compound also includes compounds that cyclic secondary amine-containing heterocyclic acyl group is bonded as R ² when it is the same group as R ¹ and R ¹ (Ie), Compound ( It can be produced by reacting XI) with (XII) or a reactive derivative thereof in the same manner as in the first production method.

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

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

The ether or thioether compound represented by the general formula (Ig) is a hydroxy or mercapto compound represented by the general formula (XVI) or an alkali metal substitution product thereof,
Alternatively, it is produced by reacting a halide or sulfonate compound with a halide or sulfonate compound represented by the general formula (XVII), a hydroxy or mercapto compound, or an alkali metal substitution product thereof.

In the reaction, the compound (XVI) and the compound (XVII) are almost equimolar, or one of them is in a slight excess mol, and N, N-dimethylformamide, dimethylsulfoxide, acetone, methylethylketone (2-butanone), methanol, ethanol, ethylene are used. Chloride, chloroform, ether,
It is carried out in an organic solvent such as tetrahydrofuran or dioxane or water, or a mixed solvent of water and an organic solvent.

As the starting compound (XVI) or (XVII), when an alkali metal substitution product is not used, it is carried out in the presence of a base, and examples of such a base include sodium hydroxide, potassium hydroxide, sodium hydride and sodium carbonate. , Bases such as potassium carbonate and Triton B are preferably used.

Although the reaction temperature is not particularly limited, it is usually set at room temperature or under heating.

When a free mercapto group or its substituted alkali metal compound is present in the starting compound (XVI), it is usually also thioetherified at that portion at the same time.

In addition, depending on the kind of the substituent, it is preferable to introduce a protective group for the reaction in order to suppress a side reaction, and the removal of the protective group after the reaction is performed in the same manner as described in the first production method. It is done by

Seventh Production Method Also, the ether or thioether compound represented by the general formula (Ih) is produced by treating the compound (XVIII) and the compound (XIX) as starting compounds in the same manner as in the sixth production method.

Eighth Production Method In the compound of the present invention, the compound (Ii) in which X ¹ is an oxygen atom or a sulfur atom is a ketone (or aldehyde) represented by the general formula (XX) and a diol or dithiol represented by the general formula (XXI). , Hydroxy mercaptan or amino alcohol, or an amino mercaptan compound can be used for the cyclization reaction.

The reaction is usually carried out at room temperature using approximately equimolar amounts of compound (XX) and compound (XXI) in a solvent such as alcohols such as methanol, ethanol, isopropanol or hydrous alcohol, or a slight excess of one of the starting compounds. Be done. Further, it can be carried out by using an azeotropic dehydration solvent such as benzene and toluene while applying a dehydration means such as a Dean-Stark apparatus. , In this reaction,
In addition, a raw material having no mercapto group, amino group, carboxy group, or the like is advantageous, but these groups can be protected before implementation.

Removal of those protecting groups is the same as in the first production method.

Ninth Process The N-substituted compound represented by the general formula (Ij) has the general formula (XX
II) corresponding cyclic secondary amine and general formula (XXII
It is prepared by reacting with a halide or sulfonate compound represented by I), and then removing a protecting group if necessary.

The reaction using the halide compound as the starting compound (XXIII) is carried out in the same solvent as in the sixth production method, using the compound (XXIII) in an approximately equimolar amount to the compound (XXII) or using a slight excess of one of the compound (XXIII), from room temperature to heating. It is advantageous to carry out the heating under heating or under heating.

In this reaction, pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, trimethylamine,
Secondary and tertiary bases such as triethylamine and dimethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate,
It may be advantageous to add an inorganic base such as sodium hydroxide or potassium hydroxide in order to allow the reaction to proceed smoothly.

The reaction using a compound substituted with an organic sulfonic acid residue as the raw material compound (XXIII) is carried out in the same solvent as in the sixth production method, in which the compound (XXII) and the compound (XXIII) are almost equimolar or one is slightly in excess. It is advantageous to carry out under cooling or at room temperature. The reaction time is appropriately set in consideration of various reaction conditions.

Also in this reaction, it is preferable that no other mercapto group, reactive carboxy group, hydroxyl group or the like is present, but it is also possible to introduce a protective group and react to give the desired product. In addition, when another reactive amino group is present, the amino group may also undergo N-alkylation at the same time depending on the reaction conditions. It can also be removed and used as a target.

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

Tenth Production Method The compound (II) in the compound of the present invention can be produced by reacting the corresponding cyclic secondary amine (XXVII) with the compound (XXVIII). The reaction conditions and the like are almost the same as in the ninth production method.

Eleventh Production Method Compound (Im) can also be derived from starting compounds (XXIX) and (XXX) by treating in the same manner as in Production Method 9.

Twelfth production method R ¹ and an amino group for R ² when the same group as R ¹ .
The compound of the present invention having a mono- or di-substituted amino group (I
n) can be produced by applying a method of reacting the amine or halide or sulfonate represented by the general formula (XXXI) with the halide or sulfonate or amine represented by the general formula (XXVII).

Regarding the reaction conditions, the solvent, temperature conditions, addition of a base, elimination of the protecting group, etc. are almost the same as those in the ninth production method, but the amount of the raw material compound used is such that when a symmetrical di-substituted amino compound is produced as a target product. Compound (XXXI) or compound (XXVII)
One is approximately twice the molar amount of the other, preferably an amine is used as the compound (XXXI), a halide or the like is used as the compound (XXVII), and the compound (XXVII) such as the halide is approximately 2 times as much as the amine compound (XXXI). Use twice the molar amount. Further, when a mono-substituted amine or a di-substituted amine is produced from a mono-substituted amine as a raw material as a target product, it is suitable that the respective raw material compounds have approximately equimolar amounts.

When producing a mono-substituted amine as the target product, in order to suppress the tertiary amination and to manufacture the target product in good yield, a protecting group for suppressing the tertiary conversion is added to the amino group of D ⁴ or D ⁵ , For example, toluenesulfonyloxy group, acetyl group, phenacylsulfonyl group, trifluoromethanesulfonyl group,
It is preferable to introduce a bisbenzenesulfonyl group or the like for secondary amination.

Further, when a primary amine is produced from a halide or sulfonate compound (XXXI) in which D ⁴ represents a halogen or an organic sulfonic acid residue as a raw material, ammonia can be used as the compound (XXVII), but potassium phthalate imide After reacting with, it is advantageous to apply the method of removing the protecting groups.

Thirteenth Production Method In the compound of the present invention, a group In the case of producing an imidazolidine compound in which is a 5-membered ring, various 1,3-diazole synthesis methods may be applied, but in the case of producing compound (Io), the compound of general formula (XXXIV) is used. A method in which a compound having an amide bond with one nitrogen atom of the corresponding ethylenediamine shown is used as a starting compound and the compound is cyclized is advantageous. Although various carbonyl compounds can be used as the reaction reagent, the aldehydes represented by the general formula (XXXV) are preferable in consideration of introduction of a hydrocarbon-based substituent.

The reaction is carried out by reacting the compound (XXXIV) in an organic solvent (eg, toluene) inert to the reaction with the addition of molecular sieves.
And (XXXV) can be performed by heating.

Also in this reaction, a compound having no other mercapto group, amino group, carboxy group or the like is advantageous, but it may be carried out by introducing a protecting group in some cases.
In that case, the removal of the protecting group is carried out in the same manner as in the first production method.

Fourteenth Production Method The compound of the present invention contains various compounds that can be obtained by applying a reducing means (for example, C = C → C-C, Or, NO ₂ → NH ₂ , S−S → SH, etc.).

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

The reduction is advantageously carried out by catalytic reduction in the presence of a reducing catalyst such as platinum black, platinum oxide, palladium carbon, Raney nickel.

Other production methods The above is the amidation method, ether or thioetherification method,
Although the cyclization reaction, N-alkylation reaction and the like have been described in detail, the compound of the present invention contains various functional groups, and it can be produced by applying various methods depending on the characteristics of the groups.

For example, in the compound (I) of the present invention, a compound having a free carboxy group as a substituent can be obtained by removing an ester residue from a corresponding ester by a conventional method, or conversely, an ester-formed lower alkoxycarbonyl as a substituent. The compound which is a group can be produced by reacting the corresponding carboxylic acid or its reactive derivative with a reactive derivative of an alcohol component such as a lower alcohol or a lower alkyl halide and subjecting it to a conventional ester forming reaction.

The compound (I) of the present invention thus produced is isolated and purified as a free salt or a salt thereof. The salt can be produced by subjecting it to a commonly used salt-forming reaction.

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

As described above, the compounds of the present invention include racemic isomers, optically active isomers, optical isomers such as diastereomers, geometric isomers of cis isomers, trans isomers, keto-type and enol-type tautomers. Present in or as a mixture. The racemic compound can be obtained by using an appropriate starting material compound or by a general racemic resolution method [for example, a method of leading to a diastereomeric salt with a general optically active acid (tartaric acid, etc. to perform optical resolution)] stereochemistry Can lead to a pure isomer. Further, the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.

Geometric isomers can be separated by utilizing the difference in physicochemical properties between isomers.

(Effects of the Invention) The compound (I) of the present invention and a salt thereof have a PAF antagonistic action and are useful for treating and preventing various diseases caused by PAF. In particular, it can be used as an anti-asthma agent, an anti-inflammatory agent, an anti-ulcer agent, a shock symptom relieving agent, a therapeutic agent for ischemic heart / brain disease, liver disease, thrombosis and nephritis, a rejection inhibitor for organ transplantation and the like.

In addition, the compound of the present invention includes a compound that also has a vasodilatory action, and such a compound is also useful as a vasodilator.

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

Effect on PAF-induced platelet aggregation Method: 3.8 from the ear artery of a male Japanese white rabbit weighing about 3 kg
9 volumes of blood were collected in a plastic syringe containing 1 volume of an aqueous sodium citrate solution. Blood at 270 xg 1
Centrifuge for 0 minutes at room temperature and the supernatant is platelet rich plasma (hereinafter,
PRP) and the rest was further centrifuged at 1100 × g for 15 minutes to obtain platelet poor plasma (hereinafter, PPP). PRP to PP
After diluting with P to adjust the platelet count to 500,000 / μ1,
Bone and Cross on Platelet Aggregation by PAF (Journal of Physiology, 168, 178-195 (1963)) [G. V. R. Born and M.D. J. Cr
oss, Journal of Physiology, 168 , 178-19.
5, (1963)]. That is,
The change in the light transmittance of PRP by PAF (10 ^-8 M) was measured using NBS Hematracer (Nikko Bioscience). The compound was added 2 minutes before the addition of PAF, and the IC ₅₀ value (50% inhibitory concentration) was determined from the inhibition rate of the maximum light transmittance by PAF in the control.

Results: As shown in Table 1, a large number of the compounds of the present invention showed anti-PAF action (IC ₅₀ value of 19 ⁻⁶ M or more) in rabbit platelets, and in particular, Examples 6, 13, 19, 23, 3
It was strong at 3,35,37,40,41,59,79, and its IC ₅₀ was 2.8 × 10 ^{−8 to} 8.5 × 10 ⁻⁸ M.

These compounds are ADP (3 μM), arachidonic acid (1
(00 μM) and collagen (10 μg / m) have no inhibitory effect on platelet aggregation (data not shown), so it seems to be a PAF-specific antagonist.

(Examples) The present invention will be described in more detail with reference to the following examples.

In addition, a novel compound is contained in the above-mentioned raw material compounds, and the production method thereof will be shown in Reference Example.

In the text, NMR is a nuclear magnetic resonance spectrum using 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
Represents N, N-dimethylformamide.

Reference example 1 Di-tert-butyl-di-carbonate 2. was added to a mixture of 2.1 g of 2- (3-pyridyl) thiazolidine-4-carboxylic acid prepared from L-cysteine and pyridine-3-aldehyde, 20 m of water and 40 m of dioxane. 4g and 10m 1N sodium hydroxide aqueous solution were added at 4 ° C or lower,
Stir for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure and water 30
m, and a 0.5 M aqueous citric acid solution was added to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give N-tert-butoxycarbonyl-2-
1 g of (3-pyridyl) thiazolidine-4-carboxylic acid was obtained. Melting point 167-169 [deg.] C.

Reference example 2 Pyridine-4-aldehyde 1.07 g and L-cysteine 1.
21 g was heated in 60% ethanol to reflux temperature for 4 hours. 100 mg of activated carbon was added while warm and filtered. The crystals precipitated when cold were collected by filtration and washed with ethanol to obtain 1.2 g of 2- (4-pyridyl) thiazolidine-4-carboxylic acid. Melting point 171-173 [deg.] 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
1.21 g was dissolved in 50% ethanol 50 m and stirred at room temperature for 1 hour. The precipitated crystals were collected by suction, washed with 50% ethanol and dried to obtain 1.95 g of 2- (3-quinolyl) thiazolidine-4-carboxylic acid. Melting point 173 ~
175 ° C (decomposition) Reference Example 4 1-ethoxycarbonylpiperazine 1.93 g, potassium carbonate 1.76 g, 2-butanone 15 m at room temperature 1
A solution of 2.47 g of bromo-4-phenylbutane and 5 m 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 subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 4 :).
Purification in 1) gave 1-ethoxycarbonyl-4- (4-phenylbutyl) piperazine. The obtained compound was treated with 20 m of ethanol and 20% of 10% aqueous sodium hydroxide solution.
It was dissolved in m and 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 give an oily 1- (4-
1.5 g of (phenylbutyl) piperazine was obtained.

NMR (CDCl ₃ ) δ: 1.34 to 1.85 (4H, m), 2.20 to 3.04 (12H, m), 7.04 to 7.4
0 (5H, m) MS: m / z 217 (M ⁺ ) Reference example 5 1-ethoxycarbonylpiperazine and 1-bromo-3-
Using phenylpropane as a starting material, the same treatment as in Reference Example 4 was carried out to obtain 1- (3-phenylpropyl) piperazine.

NMR (CDCl ₃ ) δ: 1.63 to 1.97 (2H, m), 2.44 to 3.00 (12H, m), 7.04 to 7.4
4 (5H, m) MS: m / z 203 (M ⁺ ) Reference Example 6 A mixture of 20 g of 5-phenylpentan-1-ol and 30 m of 47% hydrobromic acid is heated under reflux for 6 hours. The reaction solution is cooled and extracted with n-hexane. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 100: 1), and 1-bromo-
16.87 g of 5-phenylpentane was obtained.

NMR (CDCl ₃ ) δ: 1.28 to 2.03 (6H, m), 2.63 (2H, t), 3.42 (2H, t), 7.08
~ 7.40 (5H, m) MS: m / z 228 (M ⁺ +1) Reference Example 7 To a solution of ethyl 4-carboxypiperidine-1-carboxylate (1.01 g) and triethylamine (0.72 g) in tetrahydrofuran (20 m) was added a solution of ethyl chloroformate (0.67 g) and tetrahydrofuran (2 m) at -10 to -5 ° C, and the mixture was stirred for 30 minutes. The precipitated crystals are filtered off, the filtrate is added to a solution of sodium borohydride (0.57 g) and water (10 m) over 30 minutes under ice cooling, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is acidified with 1N hydrochloric acid under ice cooling and extracted with ether. The ether layer is water, saturated aqueous sodium hydrogen carbonate solution,
The extract is washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography. Hexane-ethyl acetate (1: 1 v /
Elution with a mixed solution of 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 to
2.00 (5H, m), 2.77 (2H, dt, J = 12.0,3.0Hz), 3.52 (2H, d,
J = 6.0Hz), 4.15 (2H, q, J = 7.0Hz), 4.00-4.36 (2H, m) MS: m / z187 (M ⁺ ) (2) Oxalyl chloride 1.59g dichloromethane 30m
Dimethyl sulfoxide was added to the solution in the range of -60 to -50 ° C.
A solution of 1.97 g of dichloromethane in 5 m was added, and after 5 minutes, a solution of ethyl 4-hydroxymethylpiperidine-1-carboxylate in an amount of 2.11 g of 10 m in dichloromethane was added dropwise, and the mixture was stirred for 15 minutes. Triethylamine in the reaction mixture
Add 5.73 g and stir for 5 minutes, then stir 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 to 3.24 (2H, m), 3.82 to 4.41 (4H, m), 9.
68 (1H, s), MS: m / z 185 (M ⁺ ) (3) 0.24 g of sodium hydride was added to 6 m of dimethyl sulfoxide.
Was stirred for 30 minutes at 75 ° C, then the temperature was returned to room temperature, and 2.1 g of benzyltriphenylphosphonium chloride was added at room temperature.
5m suspension of dimethylsulfoxide in 1 is added and stirred for 15 minutes. A solution of 0.93 g of ethyl 4-formylpiperidine-1-carboxylate in 5 m of dimethyl sulfoxide was added to this mixture, 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), eluted with a mixed solution of hexane: ethyl acetate (3: 1), and eluted with ethyl acetate.
4-styrylpiperidine-1-carboxylate 1.13
g was obtained.

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 = 1)
2.0Hz), 6.43 (6 / 7H, d, J = 16.0Hz), 7.08-7.45 (5H, m) MS: m / z 259 (M ⁺ ) (4) A mixture of 0.80 g of ethyl 4-styrylpiperidine-1-carboxylate and 80 mg of 10% palladium-carbon in ethyl acetate (40 m) is catalytically reduced at room temperature until absorption of hydrogen stops. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 4- (2-phenylethyl) piperidine-1-carboxylate 0.80 g.

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 to 7.54 (5H, m) MS: m / z 261 (M ⁺ ) (5) Ethyl 4- (2-phenylethyl) piperidine-1-
A solution of 0.70 g of carboxylate and 6 m of 47% hydrobromic acid is heated to reflux at 100 ° C. for 6 hours. A small amount of water is added, the crystals are dissolved and washed with ether, and the water bath is made 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 (CDCl ₃ ) δ: 0.78 to 2.06 (8H, m), 2.30 to 2.86 (4H, m), 2.86 to 3.32.
(2H, m), 6.95 to 7.50 (5H, m) MS: m / z 189 (M ⁺ ) Reference Examples 8 to 10 Ethyl 1- (4-formyl) piperidinecarboxylate of Reference Example 7 (2), (U: 2 to 4) and treated in the same manner as in Reference Example 7 (3) to (5) to obtain the following compound.

Reference Example 11 (1) To a solution of 1.10 g of homopiperazine in 15 m of water, 2N hydrochloric acid at room temperature is added until pH 2 is reached. Next, a 40% aqueous solution of sodium acetate and 1.28 g of ethyl chloroformate were added thereto to adjust the pH to 2.0.
Add alternately in the range of 3.5 and stir at room temperature for 2 hours. The reaction solution is washed with ethyl acetate and the aqueous layer is saturated with potassium carbonate. After extraction with ethyl acetate and washing the organic layer with saturated saline,
Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate with ethyl 1-
1.27 g of homopiperazinecarboxylate was obtained.

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 / z 172 (M ⁺ ) (2) Ethyl 1-homopiperazinecarboxylate 0.86g
And benzol bromide 0.90 g of tetrahydrafuran 5
To the m solution, 0.80 g of kalim carbonate is added and 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. Elute with a mixed solution of hexane-ethyl acetate (2: 1) to obtain ethyl 4-benzylhomopiperazine-1.
-1.06 g of carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7Hz), 1.62 to 2.05 (2H, m), 2.50 to 2.8
1 (4H, m), 3.32 to 3.75 (4H, m), 3.61 (2H, s), 4.14 (2H, q, J
= 7Hz), 7.29 (5H, s) MS: m / z 262 (M ⁺ ) (3) A mixture of 0.85 g of ethyl 4-benzylhomopiperazine-1-carboxylate and 5 m of 47% hydrobromic acid solution is heated at 100 ° C. for 10 hours. A small amount of water is added to the reaction solution, which is washed with ethyl acetate. The aqueous layer is made alkaline with 30% aqueous sodium hydroxide solution, 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 to 1,96 (2H, m), 1.91 (1H, s), 2.52 to 2.80 (4H,
m), 2.80 to 3.07 (4H, m), 3.68 (2H, s), 7.12 to 7.45 (5H, m) MS: m / z 190 Reference Examples 12 to 15 (2) to (3) of Reference Example 11 The same treatment was performed to obtain the following compound.

Reference Example 16 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 m of 2-butanone was stirred overnight at 80 ° C. 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. 20m of ethanol in the residue, 20m of 10% caustic soda solution
And stir overnight at 100 ° C. Cool the reaction,
Extract 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 to 1.74 (19H, m), 2.16 to 2.52 (6H, m), 2.84 to 2.98 (4H, m) MS: m / z 226 (M ⁺ ) Reference Example 17 to 28 Reference Example The following compound was obtained in the same manner as in 16.

Reference Example 29 Ethyl 1-piperazinecarboxylate 1.6 g, p-
To a mixed solution of 1.3 g of tolualdehyde and 30 m of ethanol,
Add 500 mg of sodium borohydride and stir overnight at room temperature. The reaction mixture is concentrated under reduced pressure, 50 m 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-
0.8 g of 1-carboxylate was obtained. According to the method of Reference Example 16, the carboethoxy group was removed from this product 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 30 Ethyl 1-piperazinecarbochelate and cinnamaldehyde were used as raw materials and treated in the same manner as in Reference Example 29 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 ~ 7.5
(5H, m) Reference example 31 A mixture of 1.72 g of N-methyl-L-cysteine hydrochloride, 1.07 g of nicotinaldehyde and 2 m of water is stirred at room temperature for 24 hours. 0.8m pyridine and 1m ethanol in the reaction solution
The precipitated crystals were collected by filtration, washed with ethanol and dried to obtain 0.74 g of 3-methyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid.

_{NMR (DMSO-d 6) δ} : 2.24,2.32 (3H / 2 × 2, s, N-CH 3), 3.00~3.64 (5/2
H, m), 4.16 to 4.32 (H / 2, m), 4.92,5.36 (H / 2 × 2, s),
7.10 ~ 7.32 (1H, m), 7.80 ~ 8.00 (1H, m), 8.44 ~ 8.72 (2H, m)
m) MS (FAB): m / z 225 (M + H) ⁺ Reference Example 32 3-acetylpyridine 3.63 g, L-cysteine 3.63
A mixture of g, 25 m of water and 25 m 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 by filtration. Ethanol is added to the powder, the insoluble matter is filtered off, and the mixture is concentrated to dryness.
The residue is dissolved in water, diluted hydrochloric acid is added to the solution with stirring under ice-cooling to adjust the pH to 6, and the resulting powder is collected by filtration, washed with ethanol, and dried to give 2-methyl-2- (3-pyridyl) thiazolidine-.
2.54 g of 5-carboxylic acid was obtained.

NMR (DMSO-d ₆ ) δ: 1.78, 1.88 (total 3 H, each s), 2.92 to 3.56 (2 H,
m), 3.56 to 4.38 (1H, m), 7.20 to 7.44 (1H, m), 7.80 to 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 33 Di-2-pyridyl ketone 3.68 g, L-cysteine 2.4
A mixture of 2 g, 25 m of water and 25 m of ethanol is heated under reflux for 3.5 hours. After cooling, the insoluble material is filtered off, and the mixture is concentrated to dryness under reduced pressure. The residue was washed successively with ethyl acetate and ether to obtain 0.63 g of 2,2-di- (2-pyridyl) thiazolidine-4-carboxylic acid.

_{NMR (DMSO-d 6) δ} : 2.85~4.15 (3H, m), 7.20~8.90 (8H, m) Reference Example 34 3-piperidine methanol 4.00 g dioxane 50 m
In a solution of water (30 m) at 0 ° C, 7.58 g of di-tert-butyl-dicarbonate and 1N sodium hydroxide (3)
5m was added. The reaction mixture was brought to room temperature and stirred for 1.5 hours, 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 1-tert-butoxycarbonylpiperidine-3-methanol 7.20 g. 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 35 Oxalyl chloride 0.50 m dichloromethane 10 m
Dimethyl sulfoxide 0.85m at -60 ℃
Was added 3 minutes later, 1-tert-butoxycarbonylpiperidine-3-methanol 1.08 g of dichloromethane 10 m
The medium solution was added dropwise over 5 minutes. After stirring for 15 minutes, 3.0 m of triethylamine was added to the reaction mixture. After stirring for 5 minutes, 20 m 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. 0.98 g was obtained.

NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.4-2.0 (4H), 2.4 (1H, m, w / 2 = 21H
z), 3.10 (1H, dd, J = 8.5 and 14Hz), 3.65 (1H, ddd, J = 4,
5 and 12.5Hz), 3.94 (1H, dd, J = 4 and 14Hz), 9.68 (1
H, s) MS: m / z 213 (M ⁺ ) In the same manner as in Reference Example 2, the following compound was obtained.

Reference Example 46 3-tert-butoxycarbonyl-2- (3-pyridyl)
A solution of 3.10 g of thiazolidine-4-carboxylic acid in 30 m of dichloromethane at -78 ° C oxalyl chloride 1.3.
1 m and 50 mg of N, N-dimethylformamide were added. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The resulting precipitate was filtered and dried to give 1,3-dioxo-5-
1.90 g of (3-pyridyl) thiazolidino [3,4-c] oxazolidine hydrochloride was obtained.

Melting point 170 ° C (decomposition) Elemental analysis value (as C ₁₀ H ₉ ClN ₃ O ₃ S) Reference Example 47 5.34 g of p-methoxycinnamic acid in methanol solution
% Palladium-carbon (200 mg) was used as a catalyst and stirred until absorption of hydrogen gas stopped. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 3- (p-methoxyphenyl) propionic acid (5.43 g).
Got

NMR (CDCl ₃ ) δ: 2.34 to 3.15 (4H), 3.76 (3H, s), 6.64 to 7.30 (4H), 1
1.00 (1H, s) Reference Example 48 Lithium aluminum hydride 1.10 g anhydrous ether 5
100 m of anhydrous 3- (p-methoxyphenyl) propionic acid ether while stirring in a 0 m suspension at room temperature.
The medium solution was added dropwise over 20 minutes. 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 solution under ice cooling, and a 10% hydrochloric acid aqueous solution was added to acidify the reaction solution, which was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to 3- (p
5.06 g of -methoxyphenyl) 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 47 and 48, the following compounds were obtained.

Reference Example 53 5.80 g of p-nitrocinnamic acid and 10.4 of methyl iodide
g, 10.4 g of anhydrous potassium carbonate and 200 m of acetone were stirred at room temperature for 2 days. After removing the precipitate by filtration, the filtrate 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 to 7.95 (3
H), 8.21 (2H, d, J = 9Hz) Reference example 54 A solution of 1.20 g of o-tolualdehyde and 20 m of anhydrous tetrahydrofuran was added to a suspension of 3.67 g of methyl (triphenylphosphoranylidene) acetate in 20 m of anhydrous tetrahydrofuran at room temperature, and the mixture was heated under 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 mixed solution 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 to 7.66 (4H), 7.97 (1H, d, J = 16Hz), cis body 2.29 (s), 3.63 (s), 6.03 (d, J = 12Hz) In the same manner as in Reference Examples 47 and 48. The following compounds were synthesized.

Reference Example 57 A 1M super hydride / tetrahydrofuran solution (3.3 m) and anhydrous tetrahydrofuran (5 m) solution were cooled to −50 to −60 ° C. under an argon gas stream. To this, a tetrahydrofuran 2m solution of 210 mg of 3- (p-cyanophenyl) propionic acid methyl ester obtained according to Reference Examples 54 and 47 using p-cyanobenzaldehyde and methyl (triphenylphosphoranylidene) acetate as raw materials was added dropwise. The mixture was stirred at the same temperature for 10 minutes. At the same temperature, water and 1N hydrochloric acid were sequentially added to the reaction solution to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 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 = 6Hz), 7.10 to 7.75 (4H) Reference Example 58 47 g of 2.13 g of 3- (p-methylphenyl) propanol
The mixture was heated under reflux with a 7% 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 is distilled under reduced pressure to 3-
1.75 g of (p-methylphenyl) propyl bromide was obtained.

Boiling point 65 ° C / 0.7 mm 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 59 3.8 g of methanesulfonyl chloride was slowly added dropwise to a solution of 5 g of 3- (p-methoxyphenyl) propanol in 50 m of anhydrous pyridine under ice cooling, and the mixture was stirred at the same temperature for 3 hours.
The solvent was concentrated under reduced pressure, water was added to the residue, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was 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 3- (p.
-Methoxyphenyl) propyl methanesulfonate 6.3
2 g was obtained.

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 60 Acetone 1 of 6.30 g of 3- (p-methoxyphenyl) propyl methanesulfonate and 1.11 g of sodium iodide
The 00m mixed solution 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 give 3- (p-methoxyphenyl) propyliodide (6.62 g).

NMR (CDCl ₃ ) δ: 1.81−2.35 (2H), 2.18 (2H, br, t, J = 7Hz), 3.16 (2H,
t, J = 6 Hz), 3.80 (3H, s), 6.71-7.30 (4H) In the same manner as in Reference Example 60, the following compound was obtained.

Reference Example 62 To a solution of 1.55 g of 3- (p-chlorophenyl) propanol and 2.51 g of triphenylphosphine in 10 m of N, N-dimethylformamide was added 2.42 g of N, N-dimethylformamide at room temperature.
The N-dimethylformamide 8m solution was slowly added dropwise while confirming the disappearance of the color. After the disappearance of the color of the reaction solution stopped, water was added to the reaction solution and a 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 was obtained.

NMR (CDCl ₃ ) δ: 1.92-2.40 (2H), 2.71 (2H, br, t, J = 7Hz), 3.13 (2H,
t, J = 6 Hz), 6.91-7.40 (4H) In the same manner as in Reference Example 62, the following compound was obtained.

Reference Example 66 Phenylpropyl bromide (5.01 g) was added dropwise to a mixed solution of concentrated nitric acid (65%) 10 m and concentrated sulfuric acid 10 m under ice cooling over 5 minutes, and the mixture was stirred at the same temperature for 1 hour and 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-
Elution with ethyl acetate (10: 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 = 3)
Hz, J = 9Hz), 8.79 (1H, d, J = 3Hz) Reference Example 67 3- (p-aminophenyl) propanol (0.51 g)
47% aqueous hydrobromic acid solution (5 m) was heated under reflux for 6 hours, and the solvent was concentrated under reduced pressure. Methanol and toluene were added, the solvent was concentrated under reduced pressure, and the reaction was repeated again to give 3- (p-aminophenyl) propyl bromide hydrobromide (1.04
g) was obtained.

_{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, br, s), 7.40 (4H, s) The following compounds were obtained in the same manner as in Reference Example 11 (2) to (3).

The following compounds were obtained as in Reference Example 16.

Reference Example 79 3- (p-cyanophenyl) propyl iodide 250
A mixed solution of mg and anhydrous piperazine 0.85 g potassium carbonate 0.5 g tetrahydrofuran 10 m was heated under reflux for 2 hours. The mixture was concentrated 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)
Got

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 = 9 Hz), 7.56 (2H, d, J = 9 Hz) MS: m / z 229 (M ⁺ ) Reference Example 80 To a solution of 1-benzylpiperazine (1.76 g) and tetrahydrofuran (20 m) was added a solution of n-butylisocyanate (1.0 g) and tetrahydrofuran (5 m) 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 purification.

NMR (CDCl ₃ ) δ: 0.90 (3H, t), 1.1-1.7 (4H, m), 2.2-2.6 (4H, m), 3.
0-3.6 (6H, m), 3.50 (2H, s), 4.5 (1H, br, s), 7.0-7.5 (5
H, m) Reference example 81 To a mixed solution of 3.52 g of 1-benzylpiperazine, 3.5 g of 3-phenylpropionic acid and 20 m of tetrahydrofuran was added 4.5 g of dicyclohexylcarbodiimide, and the mixture was stirred overnight at room temperature. The resulting dicyclohexylurea is filtered off and the mother liquor is concentrated under reduced pressure. Ethyl acetate (100 m) and water (50 m) were added to the residue, and the mixture was made alkaline with potassium carbonate and then separated. Wash the ethyl acetate layer sequentially with water and saturated saline,
It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily 1-
6 g of benzyl-4- (3-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 82 1-benzyl-4-butylaminocarbonylpiperazine
To a solution of 2.8 g and 15 m of ethanol, 250 mg of 10% palladium-carbon is added, and catalytic reduction is performed until absorption of hydrogen stops. The catalyst was filtered off, and the filtrate 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 83 1-Benzyl-4- (3-phenylpropionyl) piperazine was used as a starting material in the same manner as in Reference Example 82.
(3-Phenylpropionyl) piperazine was obtained.

MS: m / z 218 (M ⁺ ) Reference Example 84 N-carbobenzyloxy-serine 2.0 g, 1- (3-
To a solution of 1.57 g of (phenylpropyl) piperazine and 1.04 g of 1-hydroxybenzodriazole in 30 m of N, N-dimethylformamide was added 1.58 g of dicyclohexylcarbodiimide under ice cooling. The reaction mixture at room temperature for 24
The mixture was stirred for an hour, 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- [2- (benzyloxylcarbonylamino).
2.39 g of -3-hydroxypropionyl] -4- (3-phenylpropyl) piperazine was obtained.

Melting point 95-97 ° C Elemental analysis value (as C ₂₄ H ₃₁ N ₃ O ₄ ) Reference Example 85 1- [2- (benzyloxycarbonylamino) -3-
To a solution of 1.12 g of hydroxypropionyl] -4- (3-phenylpropyl) piperazine in 30 m of ethanol was added 100 mg of 10% palladium-carbon, and the mixture was stirred under a hydrogen stream until absorption of hydrogen stopped. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 1- (2-amino-3-hydroxypropionyl) -4- (3-phenylpropyl) piperazine.
I got 800mg.

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 / z 291 (M ⁺ ) Reference Example 86 2- (3-pyridyl) -1-pyrroline-5-carboxylic acid / hydrobromide 1.15 g, 1-heptylpiperazine 77
0 mg, dicyclohexylcarbodiimide 860 mg and 1
A mixture of 560 mg of hydroxybenzotriazole in 15 m of N, N-disimerformamide was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off,
The filtrate 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-[[ 2-
1.01 g of (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 ~ 3.26 (2H, m), 3.37 ~ 4.30 (3H, m), 5.04
~ 5.30 (1H, m), 7.26 ~ 7.46 (1H, ddd, J = 1Hz, J = 5Hz),
J = 8Hz), 8.18 (1H, dt, J = 2Hz, J = 8Hz), 8.68 (1H, 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.

Example 1 2- (3-pyridyl) thiazolidine-4-carboxylic acid 5
A mixture of 20 mg, pyrrolidine 180 mg, dicyclohexylcarbodiimide 510 mg and 1-hydroxybenzotriazole 500 mg in tetrahydrofuran 15 m was stirred at room temperature overnight. Dilute the reaction mixture with ethyl acetate,
The insoluble material was filtered off. The filtrate is sodium hydrogencarbonate water, water,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate: methanol = 1).
Purification with 0: 1) gave 1- [2- (3-pyridylthiazolidin-4-ylcarbonyl] pyrrolidine.This compound was dissolved in 10m ethyl acetate and 2N hydrogen chloride-
2 m of dioxane solution was added. The resulting solid was collected by filtration,
After washing with ethyl acetate and drying, 80 mg of 1- [2- (3-pyridylthiazolidin-4-ylcarbonyl] pyrrolidine dihydrochloride was obtained, 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 4.71
(1H, m), 6.09, 6.26 (1H for each, each s), 8.08 (1H, d
d), 8.72 to 9.20 (3H, m) Example 2 2- [3- (Pyridyl) thiazolidine-4-carboxylic acid and morpholine acid were used as starting materials and treated in the same manner as in Example 1 to give 4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] morpholine dihydrochloride. I got salt. Melting point 14
_{3 ℃ NMR (DMSO-d 6} ) δ: 2.97~3.78 (10H, m), 4.62~4.78 (1H, m), 6.00,6.2
3 (1H in total, each s), 8.05 (1H, dd), 8.71 to 9.10 (3H, m) Example 3 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 1-phenylpiperazine were used as starting materials and treated in the same manner as in Example 1 to give 1-phenyl-4- [2- (3-pyridyl) thiazolidine-4-. Ilcarbonyl] piperazine
The trihydrochloride was obtained.

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 in total, each s), 7.047.64 (5H, m), 7.99 to 8.14 (1H,
m), 8.70 to 9.16 (3H, m) Example 4 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and piperidine were used as starting materials and treated in the same manner as in Example 1 to give 1- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine.2. The hydrochloride salt was obtained. Melting point 1
72 ℃ Elemental analysis value (as C ₁₄ H ₂₁ N ₃ OSCl ₂ · 0.3H ₂ O) Example 5 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 4-benzylperidine were used as starting materials and treated in the same manner as in Example 1 to give 4-benzyl-1- [2- (3-pyridyl) thiazolidine-4. -Ylcarbonyl] piperidine
The dihydrochloride was obtained.

Mp _{135 ℃ NMR (DMSO-d 6} ) δ: 0.76~2.06 (5H, m), 2.35~4.52 (8H, m), 4.68~5.08
(1H, m), 6.08, 6.28 (1H for each, each s), 7.06 to 7.28 (5H,
m), 8.07 (1H, dd), 8.71-9.30 (3H, m) Example 6 2- (3-Pyridyl) thiazolidine-4-carboxylic acid and 1- (3-phenylpyropyr) piperazine as starting materials were treated in the same manner as in Example 1 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 of 1H, each.
s), 7.10 to 7.48 (5H, m), 8.06 (1H, dd), 8.65 to 9.12 (3H,
m) Example 7 2- (3-pyridyl) thiazolidine-4-carboxylic acid 5
00 mg, O-benzylhydroxylamine hydrochloride 38
0 mg, 1-hydroxybenzotriazole 480 mg, N
-Methylmorpholine 240 mg, tetrahydrofuran 15
A solution of 490 mg of dicyclohexylcarbodiimide and 5 m of tetrahydrofuran was added dropwise to the mixture of m under ice-cooling, 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 m of ethyl acetate, and the insoluble material was filtered off. The filtrate 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) and N-benzyloxy-2- (3-pyridyl) thiazolidine-4-
260 mg of carboxamide was obtained. This compound was dissolved in ethyl acetate and a 2N hydrogen chloride-dioxane solution was added to 1.5 m.
added. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give N-benzyloxy-2- (pyridin-3-yl) thiazolidine-4-carboxamide dihydrochloride 24
0 mg was obtained.

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 to 7.53 (5H, m),
8.07 (1H, dd), 8.64-9.26 (3H, m) Example 8 3-tert-butoxycarbonyl-2- (3-pyridyl)
A solution of 540 mg of dicyclohexylcarbodiimide and 5 m of tetrahydrofuran was added dropwise to a mixture of 810 mg of thiazolidine-4-carboxylic acid, 260 mg of 4-methylpiperidine, 530 mg of 1-hydroxybenzotriazole and 10 m of tetrahydrofuran, 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 m of ethyl acetate, and the insoluble material was filtered off. The filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 4-methyl-1- [3-tert-butoxycarbonyl-2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine was obtained. 5 m 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 is purified by silica gel column chromatography (eluent: ethyl acetate) to give 4-methyl-1- [2-3-pyridyl) thiazolidin-4-ylcarbonyl] piperidine. It was This compound was dissolved in ethyl acetate, and 3N of 2N hydrogen chloride-dioxane solution was added. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give 4-methyl-1- [2- (3
530 mg of -pyridyl) thiazolidin-4-ylcarbonyl] piperidine dihydrochloride were obtained.

Melting point 130 ° C Elemental analysis value (as C ₁₅ H ₂₃ N ₃ OSCl ₂ ) Example 9 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 Example 8 to give N'-methyl-N'-phenyl-2-(-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
(1H for each, each s), 6.70 to 7.32 (5H, m), 8.07 (1H, dd),
8.69 to 9.17 (3H, m) Example 10 3-tert-butoxycarbonyl-2- (3-pyridyl)
Thiazolidine-4-carboxylic acid and 4-phenylpiperidine were used as starting materials and treated in the same manner as in Example 8 to give 4-phenyl-1- [2- (3-pyridyl) thiazolidine-4.
-Ylcarbonyl] piperidine dihydrochloride was obtained.

Mp _{115 ℃ NMR (DMSO-d 6} ) δ: 1.32~2.08 (4H, m), 2.58~3.82 (6H, m), 3.96~5.00
(2H, m), 6.04, 6.28 (1H in total, each s), 7.08 to 7.
44 (5H, m), 8.06 (1H, dd), 8.68-9.16 (3H, m) Example 11 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 Example 8 to give 1-methyl-4- [2- (3-pyridyl) thiazolidine-4-
Ilcarbonyl] piperidine trihydrochloride was obtained.

Melting point 182 ° C NMR (DMSO-d ₆ ) δ: 2.62 to 5.00 (14H, m), 6.03 to 6.22 (total 1H, each s),
8.09 (1H, dd), 8.70-9.20 (3H, m) Example 12 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 Example 8 to give 1-
Benzyl-4- [2- (3-pyridyl) thiazolidine-
4-ylcarbonyl] 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 to 7.80 (5H, m), 8.03 (1H, dd), 8.62 ~
9.10 (3H, m) Example 13 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 Example 8 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
~ 3.78 (6H, m), 3.99 ~ 4.30 (1H, m), 5.96, 6.17
(1H for each, each s), 7.12 to 7.44 (6H, m), 8.12 (1
H, dd), 8.72 to 9.17 (2H, m) Example 14 3-tert-butoxycarbonyl-2- (3-pyridyl)
Thiazolidine-4-carboxylic acid 680 mg, phenylhydrazine 240 mg, 1-hydroxybenzotriazole 4
A solution of dicyclohexylcarbodiimide (450 mg) and tetrahydrofuran (5 m) was added dropwise to a mixture of 50 mg and tetrahydrofuran (20 m) under ice cooling, and the mixture was stirred under ice cooling for 1 hour.
The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 30 m of ethyl acetate, and the insoluble material was filtered off. The filtrate 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. 5m of trifluoroacetic acid was added to the obtained compound,
It was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with saturated saline 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.

Mp _{155 ℃ NMR (CDCl 3 + DMSO} -d 6) δ: 3.22~3.56 (2H, m), 4.22~4.36 (1H, m), 5.6
0, 5.72 (1H for each, each s), 6.72 to 7.44 (6H, m), 7.
81 to 7.95 (1H, m), 8.56 (1H, dd), 8.79 (1H, d) Example 15 360 mg of 4- (p-methylbenzyl) piperazine, 2-
(3-Pyridyl) thiazolidine-4-carboxylic acid 470
mg, dicyclohexylcarbodiimide 450 mg, and 1
A mixture of 250 mg of hydroxybenzotriazole in 10 m of N, N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was diluted with 50 m of ethyl acetate and the insoluble material was filtered off. The filtrate is a saturated aqueous sodium hydrogen carbonate solution,
The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol = 9: 1), and 1- (p-methylbenzyl) -4- [2- (3-pyridyl) thiazolidine-4-
Ilcarbonyl] piperazine was obtained. To a solution of this compound in 20 m of ethyl acetate was added 4 m of 4N hydrogen chloride-dioxane solution. The separated solid was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 1- (p-methylbenzyl)-.
730 mg of 4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine-3-hydrochloride were obtained.

Melting point 168 ° C NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 2.5 to 3.5 (8H, m), 4.0 to 4.6 (4
H, m), 4.4 to 4.9 (1H, m), 5.96, 6.18 (total 1H,
S), 7.26, 7.56 (4H, dd, AB _q ), 6.9 to 7.2 (1H,
m), 7.6 to 8.2 (3H, m) Examples 16 to 32 In the same manner as in Example 15, the following compounds were obtained.

Example 33 2- (3-pyridyl) thiazolidine-4-carboxylic acid 0.34 g, 1-decylpiperazine 0.37 g, 1-hydroxybenzotriazole 0.33 g, and N, N-dimethylformamide 10 m were mixed with dicyclohexyl under ice cooling. 0.34 g of carbodiimide was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and the insoluble material was filtered off. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 5 m of ethyl acetate was added to the residue, and the insoluble material was filtered off. A 2N hydrogen chloride-dioxane solution was added to the filtrate. The generated crystals were collected by filtration, washed with ethyl acetate and dried to obtain 0.63 g of 1-decyl-4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine.3 hydrochloride.

Melting point 170 ° C Elemental analysis value (as C ₂₃ H ₄₁ N ₄ OSCl ₃ · H ₂ O) Examples 34 to 37 The following compounds were obtained in the same manner as in Example 33.

Example 38 A solution of 40 mg of 1- (3-phenylpropyl) -4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine and 5 m of dichloromethane was mixed with a mixed solution of formic acid-acetic anhydride (5: 3 v / v). 5 m was added, and the mixture was stirred overnight at room temperature. Add 20m of ethyl acetate to the reaction mixture and add 5%.
It was washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oily 1- [3-formyl-2- (3-pyridyl) thiazolidin-4-ylcarbonyl] -4- (3-phenylpropyiene. 30 ml of 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), 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 ⁺ ) Example 39 3-tert-butoxycarbonyl-2- (3-pyridyl)
Thiazolidine-4-carboxylic acid 650 mg and 1- (3-
The same treatment as in Example 15 was carried out using 400 mg of phenylpropyl) piperazine as a starting material. Purification by silica gel column chromatography (eluent: ethyl acetate) without converting into hydrochloride, and oily 1- [3- (tert-butoxycarbonyl) -2- (3-pyridyl) thiazolidine-4-
560 mg of ylcarbonyl] -4- (3-phenylpropyl) piperazine was obtained.

NMR (CDCl ₃ ) δ: 1.40 (9H, s), 1.6 to 2.1 (2H, m), 2.2 to 2.8 (8
H, m), 3.0 to 3.4 (2H, m), 3.4 to 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 ⁺ ) Example 40 2- (3-pyridyl) thiazolidine-4-carboxylic acid 0.84 g, 1-octylpiperazine 0.79 g, 1-
To a mixed solution of 0.54 g of hydroxybenzotriazole and 20 m of N, N-dimethylformamide, 0.82 g of dicyclohexylcarbodiimide was added under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and the insoluble material was filtered off. The filtrate 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, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: 10% methanol-ethyl acetate], the obtained oily substance is dissolved in 25 m of ethanol, and 0.32 g of fumaric acid is added.
After standing for 2 days, the resulting crystals were collected by filtration, washed with cold ethanol and dried to give 1-octyl-4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine fumarate 0.72 g. Got

Melting point 135 ° C Elemental analysis value (as C ₂₅ H ₃₈ N ₄ O ₅ S) Examples 41 to 44 The following compounds were obtained by treating in the same manner as in Example 40.

The following compounds were obtained as in Example 39.

The following compounds were obtained as in Example 39.

Example 72 1-heptyl-4- [2- (3-pyridyl) -2-pyrrolin-5-ylcarbonyl] piperazine (570 mg) in water (2)
Platinum oxide was used as a catalyst in a 0 m-ethanol 20 m solution to carry out catalytic reduction until absorption of hydrogen stopped. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (5 g). Elution with a mixed solution of methanol-ethyl acetate (1:10) gave 250 mg of 1-heptyl-4- [5- (3-pyridyl) pyrrolidin-2-ylcarbonyl] piperazine. According to Example 15, 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) The following compounds were obtained as in Example 72.

(However, hydrogen chloride treatment is not performed.) Example 74 To a solution of 50 mg of 1,3-dioxo-5- (3-pyridyl) thiazolidino [3,4-c] oxazolidine hydrochloride in 1 m of dimethyl sulfoxide was added at room temperature 40 mg of 1- (3-phenylpropyl) piperazine dimethyl sulfoxide. The solution in 5 m 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 give 1- (3 70 mg of -phenylpropyl) -4- [2- (3-pyridyl) thiazolidin-4-ylcarbonyl] piperazine were obtained.
The physicochemical properties of this product were in agreement with those of Example 53.

Example 75 1- [2- (1-tert-butoxycarbonyl-3-piperidinyl) thiazolidin-4-ylcarbonyl] -4-
430 mg of (3-phenylpropyl) piperazine was dissolved in 3 m of dichloromethane, 2 m of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 m of saturated aqueous sodium hydrogen carbonate solution, and the product was extracted with ethyl acetate. Wash the ethyl acetate layer with saturated saline,
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give 280 mg of 1- (3-phenylpropyl) -4- [2- (3-piperidinyl) thiazolidin-4-ylcarbonyl] piperazine. This compound was dissolved in 8 m of ethyl acetate, and 1 m of a 4N hydrogen chloride dioxane solution was added. After stirring for 30 minutes, the resulting solid was collected by filtration and dried to obtain 200 mg of 1- (3-phenylpropyl) -4- [2- (3-piperidinyl) thiazolidin-4-ylcarbonyl] piperazine trihydrochloride. It was

Mp one hundred seventy-four to one hundred and seventy-eight ° C. Elemental analysis (as _{C 22 H 37 N 4 OSCl 3} · 1.5H 2 O) Example 76 1- (2-amino-3-hydroxypropionyl) -4
-(3-phenylpropyl) piperazine 800 mg, pyridine-3-aldehyde 340 mg, benzene 35 m,
10 mg of p-toluenesulfonic acid in a solution of 2 m of pyridine
Was added and refluxed for 8 hours for azeotropic dehydration. After cooling, the reaction mixture was treated twice with saturated aqueous sodium hydrogen carbonate solution, three times with water,
The extract was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1- (3-phenylpropyl) -4- [2- (3-pyridyl) oxazolidin-4-ylcarbonyl] piperazine (500 mg).

Elemental analysis value (as C ₂₂ H ₂₈ N ₄ O ₂ ) MS: m / z 380 (M ⁺ ) In the same manner as in Example 39, the compound of Reference Example 88 was obtained.

Example 77 N- (3-phenylpropylaminoethyl) -2- (3
-Pyridyl) thiazolidine-4-carboxamide 50 m
g, p-trialdehyde 17 mg, molecular sieve (4A) 100 mg toluene 2 m mixed solution at 120 ° C.
And heated in a sealed tube for 8 hours. After filtering the reaction solution, the filtrate is concentrated under reduced pressure and the residue is subjected to thin layer preparative chromatography (2%
(Development twice with methanol-ethyl acetate, Rf value 0.15)
1- (3-phenylpropyl) -3- [2-
(3-Pyridyl) thiazolidin-4-ylcarbonyl]
There was obtained 3.3 mg of 2- (p-tolyl) imidazolidine.

NMR (CDCl ₃ ) δ: 1.55 to 1.93 (3H, m), 2.39 (3H, s), 2.42 to 2.87 (8
H, 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 (1H, dd, J = 2Hz, J = 5Hz), 8.63 (1H,
d, J = 2 Hz) MS: m / z 472 (M ⁺ ) Example 78 730 mg of 1- [2- (5,6-dimethoxy-3-pyridyl) thiazolidin-4-ylcarbonyl] -4- (3-phenylpropyl) piperazine was dissolved in 25 m of ethyl acetate, and 2N hydrogen chloride was stirred at room temperature. -Add dioxane solution. The powder formed is filtered off 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 is separated and purified by silica gel column chromatography (silica gel 5
0 m, 10% methanol-ethyl acetate), 1- [2-
(5-Methoxy-6-oxo-5,6-dihydro-3-pyridyl) thiazolidin-4-ylcarbonyl] -4-
210 mg of (3-phenylpropyl) piperazine was obtained.

_{NMR (DMSO-d 6) δ} : 1.56~1.94 (2H, m), 2.20~2.80 (8H, m), 2.90~
4.40 (10H, m), 5.28 ~ 5.66 (1H, m), 6.80 ~ 7.44 (7H,
m) MS: m / z 442 (M ⁺ ) Reference Example 89 (1) In the same manner as in Reference Example 58, the following compound was 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) (2) Ethyl 1-piperazinecarboxylate 0.78 g,
A mixed solution of 1.08 g of 3-phenylbutyl bromide and 1.4 g of anhydrous potassium carbonate in 10 m of tetrahydrofuran was heated under reflux overnight. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to alumina column chromatography (2
5 g). Elution with hexane-ethyl acetate (3: 1) gave 0.70 g of ethyl 1- [4- (3-phenylbutyl)] piperazinecarboxylate.

NMR (CDCl ₃ ) δ: 1.11 to 1.50 (6H, m), 1.56 to 3.05 (9H, m), 3.50 (4
H, t, J = 6Hz), 4.19 (2H, q, J = 7Hz), 7.24 (5H, s) Reference example 90 A solution of 0.64 g of ethyl 1- [4- (3-phenylbutyl)] piperazinecarboxylate in 8 m of concentrated hydrochloric acid was heated in a sealed tube at 120 ° C. overnight. After concentrating the solvent under reduced pressure, 1
The mixture was made alkaline with 0% sodium hydroxide, salted out with sodium chloride, and 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 0.38 g of 1- (3-phenylbutyl) piperazine.

NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7Hz), 1.76 (2H, q, J = 7Hz), 1.
93 (1H, s), 2.10 to 2.46 (6H, m), 2.51 to 2.97 (5H,
m), 7.00 to 7.38 (5H, m) MS: (m / z) 218 (M ⁺ ) Example 79 Treated in the same manner as in Example 40, 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) MS: (m / z) 410 (M + -C 4 H 4 O 4) afforded Reference Example 91 Reference Example 48,58,89 (2) and the compound of the following in the same manner as 90.

(1) 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) (2) 1-Bromo-3-methyl-3-phenylbutane NMR (CDCl ₃ ) δ: 1.33 (6H, s), 2.04 to 2.33 (2H, m), 2.95 to 3.21 (2H,
m), 7.02 to 7.43 (5H, m) (3) 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 (2
H, m), 2.15 to 2.46 (6H, m), 3.43 (4H, t, J = 6Hz),
4.13 (2H, q, J = 7Hz), 7.03 to 7.50 (5H, m) (4) 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 ~ 2.20 (2H, m), 2.30 (4H, t, J = 6Hz), 2.85 (4H,
t, J = 6 Hz), 7.03 to 7.46 (5H, m) MS: (m / z) 232 (M ⁺ ). Example 80 Treated in the same manner as in Example 39, the following compound was obtained.

1- (3-methyl-3-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 to 2.48 (7H,
m), 2.78 to 3.73 (6H, m), 3.78 to 4.30 (1H, m), 5.57
(0.5H, br d, J = 12Hz), 5.95 (0.5H, br d, J = 5H
z), 7.05 to 7.43 (6H, m), 7.71 to 7.96 (1H, m), 8.43
~ 8.63 (1H, m) 8.69 ~ 8.81 (1H, m) MS: m / z 424 (M ⁺ ) Example 81 The compound of Example 80 was used as a starting material and treated in the same manner as in the salt formation reaction of Example 40 to give Was obtained.

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) Reference example 92 (1) A solution of phenylacetic acid methyl ester (7.50 g) and 60% sodium hydride (2.1 g) in N, N-dimethylformamide (70 m) was stirred at room temperature for 1 hour. Methyl iodide (10 g) was added dropwise to this mixed solution under ice cooling, the mixture was stirred at 50 ° C. for 3 hours, and the crystals formed after cooling were filtered off. 60% Sodium hydride (2.1 g) was added to the filtrate, and the same treatment was performed thereafter. To the filtrate obtained again, 60% sodium hydride (0.4 g) was added, and the mixture was heated at 50 ° C. for 1 hour, and methyl iodide (2.0 g) was added thereto under ice cooling, and the mixture was 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). Hexane-
Elute with a mixture of ethyl acetate (10: 1), 2-methyl-
8.04 g of 2-phenylpropionic acid methyl ester was obtained.

NMR (CDCl ₃ ) δ: 1.60 (6H, s), 3.68 (3H, s), 7.36 (5H, br s) (2) A solution of 2-methyl-2-phenylpropionic acid methyl ester (7.97 g) in tetrahydrofuran (20 m) was added dropwise to a suspension of lithium aluminum hydride (1.71 g) in tetrahydrofuran (50 m) under ice cooling, and the mixture was stirred at room temperature. Stir for 30 minutes. 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-
Elute with a mixture of ethyl acetate (2: 1), 2-methyl-2
-6.32 g of phenylpropanol was obtained.

NMR (CDCl ₃ ) δ: 1.32 (6H, s), 1.72 (1H, s), 3.61 (2H, s), 7.10-7.
61 (5H, m) (3) A solution of oxalyl chloride (4.1 m) in dichloromethane (100 m) was added with dimethyl sulfoxide (7.14 m).
A solution of g) in dichloromethane (10m) is added dropwise at -60 ° C and stirred for 10 minutes. 2-Methyl-2- in the mixture
A solution of phenylpropanol (6.16 g) in dichloromethane (15 m) was added, and the mixture was stirred for 1 hr, triethylamine (20.7 g) was added, and the mixture was further stirred for 30 min. 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) (4) 2-Methyl-2-phenylpropanal (0.30 g)
A solution of triphenylphosphylidene acetic acid methyl ester (0.74 g) in tetrahydrofuran (7 m) was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (25 g),
Elute with a mixture of hexane-ethyl acetate (2: 1) to give 4-
0.37 g of methyl-4-phenyl-2-pentenoic acid methyl ester was obtained.

NMR (CDCl ₃ ) δ: 1.46 (6H, s), 3.75 (3H, s), 5.82 (1H, d, J = 17H
z), 7.19 (1H, d, J = 17Hz), 7.30 (5H, s) (5) Ribbon-shaped metal 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 m), and the mixture was stirred at room temperature for 2 hours. 10% Hydrochloric acid was added to the reaction mixture, which was 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.
0.30 g of -phenyl-pentanoic acid methyl ester was obtained.

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 93 The following compounds were obtained in the same manner as in Reference Examples 92 (2), 58, 89 (2) and 90.

(1) 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) (2) 1-bromo-4-methyl-4-phenyl-pentane _{NMR (CDCl 3) δ: 1.32} (6H, s), 1.40~1.91 (4H, m), 3.29 (2H, t, J = 6
Hz), 7.11 to 7.48 (5H, m) (3) 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 to 1.93 (4
H, m), 2.08 to 2.53 (6H, m), 3.48 (4H, t, J = 6Hz),
4.29 (2H, q, J = 7Hz), 7.09 to 7.52 (5H, m) (4) 1- (4-methyl-4-phenylpentyl) piperazine NMR (CDCl ₃ ) δ: 1.07 to 1.45 (2H, m), 1.32 (6H, s), 1.45 to 1.77 (2H,
m), 1.70 (1H, s), 2.08-2.45 (6H, m), 2.87 (4H,
t, J = 6 Hz), 7.01 to 7.43 (5H, m) Example 82 Treated in the same manner as in Example 40, the following compound was obtained.

1- (4-methyl-4-phenylpentyl) -4- [2
-(3-Pyridyl) thiazolidin-4-ylcarbonyl] piperazine fumarate NMR (CDCl ₃ ) δ: 1.05 to 1.47 (2H, m), 1.35 (6H, s), 1.47 to 1.86 (2H,
m), 2.09 to 2.63 (6H, m), 2.73 to 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 to 7.53 (6H, m), 7.75 to 8.05 (1H,
m), 8.38 to 8.75 (2H, m) MS: m / z 438 (M ⁺ -C ₄ H ₄ O ₄ ). Safely orally or parenterally as a pharmaceutical composition (eg, tablets, capsules, powders, granules, pills, ointments, syrups, injections, inhalants, suppositories) mixed with a form, etc. It can be administered. Although the dose varies depending on the administration subject, administration route, symptoms, etc., it is usually 0.1 to 500 mg per adult per day, preferably 1
˜200 mg, which is orally or parenterally administered in 2 to 3 divided doses per day.

Formulation Example 1 Tablets Compound of Example 41 20 mg Lactose 57 mg Corn starch 38 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1 mg Total amount 120 mg 20 g of the compound of Example 41, 57 g of lactose and 38 g of corn starch are uniformly mixed. Next, 40 g of a 10% hydroxypropyl cellulose solution is added and wet granulation is performed. After sieving, it is dried. 1 g of magnesium stearate is added to the obtained granulated product and mixed. Tablets are tableted using a 7 m / m 5.6 R pestle.

Formulation Example 2 Capsule Compound of Example 41 15 mg Crystalline cellulose 40 mg Crystalline lactose 144 mg Magnesium stearate 1 mg Total amount 200 mg Compound 41 of Example 41, 40 g of crystalline cellulose, 144 g of crystalline lactose, and 1 g of magnesium stearate are uniformly mixed and filled in a capsule. Fill No. 3 capsules with a machine to make capsules.

Formulation Example 3 Freeze-dried formulation 1 vial Compound of Example 41 1 mg D-mannitol 50 mg Total amount 51 mg Take 800m of water, and compound 1g of Example 41 and D-
Add 50 g of mannitol sequentially to dissolve and add water to add 1
And Aseptically filter this solution and add 1 to the vial.
Fill each m and lyophilize to make a soluble injection before use.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 413/04 213 8829-4C 417/04 211 9051-4C 417/14 209 9051-4C 211 9051- 4C 213 9051-4C 513/04 301 8415-4C // C07D 211/12 9165-4C 211/16 9165-4C 211/22 9165-4C 211/30 9165-4C 211/62 9165-4C 243/08 295 / 02 A 295/06 A 295/08 A 295/10 A 295/18 A 295/20 A (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 (56) References Japanese Patent Publication No. 45-31186 (JP, B1) US Patent 3592905 ( US, A) Tetrahedron vol. 31 No. 24 (1975) P. 3049-3054 Bull Chem Soc. Jpn. vol. 58 No. 8 (1985) P. 2304-2306

Claims (2)

[Claims] 1. A general formula (The symbols in the formulas have the following meanings: R ¹ : a substituted or unsubstituted 5- or 6-membered heterocyclic group optionally condensed with a benzene ring, R ² : a hydrogen atom, a lower alkyl group, or R ^The same group as ¹ , X ¹ : an oxygen atom, a sulfur atom, or a methylene group which may be substituted with a lower alkyl group, Y ¹ : an oxygen 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 ³ : A group represented by A group represented by Or a group represented by A group represented by, R ^4: a hydrogen atom, a lower alkyl group, a carboxy group, lower alkoxycarbonyl group, or an acyl group, A ² and A ^3: What identical 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, lower alkoxycarbonyl group, an acyl group,
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. ) A saturated heterocyclic carboxylic acid amide derivative represented by or a salt thereof. 2. A group represented by the formula: X ¹ is a sulfur atom, Y ¹ is a formula> N—R ⁴ (wherein R ⁴ has the meaning described in claim 1), and A ¹ is a lower alkyl group. The compound according to claim 1, which is a methylene group which may be substituted.