WO2001066541A1

WO2001066541A1 - Process for the preparation of hydrazine derivatives

Info

Publication number: WO2001066541A1
Application number: PCT/JP2001/001750
Authority: WO
Inventors: Hideya Mizufune; Minoru Nakamura; Hiroaki Yamamoto; Shokyo Miki
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 2000-03-08
Filing date: 2001-03-07
Publication date: 2001-09-13
Also published as: AU2001241042A1

Abstract

A process for preparing a hydrazine derivative (II) by reducing a hydrazone derivative (I) with a solid amine-borane complex; [wherein R?1, R2, R3 and R4¿ are each hydrogen, an optionally substituted hydrocarbon group, or the like]. This process makes it possible to prepare hydrazine derivatives useful as drugs, agricultural chemicals, foods, cosmetics, or chemical products, or intermediates of them from easily available raw materials by a convergent route in a few steps under safe conditions through easy handling of reagents and wastes, thus being industrially advantageous.

Description

Manufacturing method of derivatives

The present invention relates to a method for producing a hydrazine derivative by reducing a hydrazone derivative; a method for alkylating a hydrazine derivative; a method for producing a hydrazine derivative by reducing and alkylating a hydrazone derivative; a method for reducing a hydrazine derivative with a carbonyl compound And a method of subjecting a hydrazine derivative to reductive alkylation and a reductive alkylation reaction with a carbonyl compound. Background art

Japanese Patent Application No. 2000-17956 (WO00 / 78747) discloses various novel anticoagulant FXa inhibitors that are effective for the prevention and treatment of myocardial infarction, cerebral thrombosis, etc .:

A conductor is disclosed. -One of the methods for producing this acyl hydrazine derivative is described in Japanese Patent Application No. 2000-17956 (W 000/78747), which is a method for producing the acyl hydrazine derivative by reducing the imine moiety. Production methods for alkylating moieties are disclosed.

In general, as a method for synthesizing a hydrazine derivative, a method for reducing a corresponding hydrazone derivative is disclosed in Synth. Commun., 1979, 49, 1979 (reference (a)).

As a general alkylation reaction of amines, a method of alkylating with a combination of sodium borohydride and potassium sulfonic acid or sodium trisiloxyborohydride is described in Chemical Society Review (Chem. Soc. Rev.), 27 Volume, p. 395, 1998 (reference (b)), Chemtech, 1996 (12), p. 26, 1996 (reference (c)), and Encyclopedia Obeliergenfo ゥ Organic Synthesis ( Encyc lopedia of Reagents for Organic Synthes is), Vol. 7, p. 4649, 1995, published by John Willie and Sons. (d)).

Also, a method of alkylating nitrogen substituted with a phenyl group of a phenylhydrazine derivative by a combination of sodium borohydride and a carboxylic acid is described in Canadian Journal of Chemistry (Can. J. 0 ^ 111.). , Vol. 76, pp. 118, 1989 (literature)).

Also, a method for reductive alkylation of a hydrazine derivative with a carbonyl compound is described in Tetrahedron LeU., Vol. 26, pp. 232, pp. 1973 (literature (f)) and Journal of Medicinal. Chemistry (L Med. Chem.), 36, pp. 169, 1993 (reference (g)). According to the method for producing an acylhydrazine derivative described in Japanese Patent Application No. 2000-17956 (WO0O / 78747), the corresponding acylhydrazone derivative is reduced, but the highly toxic hydrogenated cyanoboron sodium as a reducing agent is corrosive. However, it uses a system of triethylsilane and trifluoroacetic acid, which are not suitable for industrial production, and has a problem that a satisfactory yield cannot be obtained with other reducing agents described in the specification.

In addition, in the production method by N-alkylation of an acylhydrazine derivative, a protective group is required when the reaction is carried out with various alkyl halides, and when there is another reactive group, there is a problem that the production process becomes long. On the other hand, in the production method by reductive alkylation using a combination of an aliphatic aldehyde and formic acid, only methylation with formaldehyde is disclosed, and there is a problem that aldehydes that can be used are limited. Further, there is a problem that the 1-amino-2-piperazinone derivative, which is one of the starting compounds in the above-mentioned production method, is produced from 2-piperazinone, which is hardly industrially available. On the other hand, the above-mentioned known literature, which describes a method for producing another hydrazine derivative, also reduces the corresponding hydrazone derivative.However, in the literature ω, a borane-pyridine complex is used as a reducing agent, and Pyridine complexes are liquid at room temperature and unstable in the air, so they must be transported and stored under an inert gas atmosphere, which is industrially disadvantageous.

References (b), (c) and (d) describe that various amines are alkylated by a combination of sodium borohydride and a carboxylic acid or by sodium triacyloxyborohydride. Is the alkylation of hydrazine derivatives. No reductive alkylation of the drazone derivative is described.

Reference (e) describes a method of alkylating nitrogen substituted with a phenyl group of a phenylhydrazine derivative with a combination of sodium borohydride and a carboxylic acid. It is not described that the nitrogen substituted with the alkylidene group of the obtained nitrogen-hydrazone derivative is reductively alkylated.

References ω and (g) describe a method for reductive alkylation of a hydrazine derivative with a carbonyl compound, but the method uses highly toxic sodium cyanoborohydride as a reducing agent. During post-processing, toxic cyan gas is generated, and there is a problem that post-processing waste liquid processing is required.

Therefore, as a method for producing an acylhydrazine derivative useful as an FXa inhibitor, using readily available raw materials, using short-term, convergent production routes, and carrying out safe and easy handling of reagents and waste There was a need for an industrially advantageous manufacturing method that could be used. In addition, a new synthesis method capable of synthesizing various hydrazine derivatives has been demanded. Disclosure of the invention

Under these circumstances, the present inventors have conducted intensive studies and unexpectedly found that 1) .The hydrazine derivative can be safely derived into a hydrazine derivative by using a solid, easy-to-handle amineporan complex as a reducing agent. 2) The hydrazine derivative can be alkylated with a combination of a borohydride complex compound and sulfonic acid or a triacyloxyborohydride complex compound.3) The hydrazone derivative can be hydrogenated with a hydrogen hydride complex. The nitrogen of the hydrazone can be alkylated simultaneously with the reduction by the combination of the compound and the sulfonic acid or the triacyloxyborohydride complex compound.4) The hydrazine derivative having a substituted 2-substituted nitrogen atom is converted to a carbonyl compound in the presence of a reducing agent. Reacts with to form a 3-substituted hydrazine derivative, 5). Starting from 2-oxo-1, 2,3,4-tetrahydropyrazine, in which the nitrogen atom at the 4-position that can be derived is protected, and starting from a derivative of a compound or an alkylamino compound at the 1-position, the above 1) 2). 3) or 4). After reduction and deprotection, aryl (, heteroaryl or alkane) sulfonylchlora It has been found that sulfonamidation with an amide leads to an acylhydrazine derivative useful as an FXa inhibitor, thereby completing the present invention.

That is, the present invention

[In the formula, R ¹ R ² , R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group. , RR ² , R ^3, and R ⁴ may combine with each other to form a ring] or a salt thereof with a polanamine complex having a melting point of 25 ° C or higher (solid state at room temperature). Using a polamine amine complex of the formula)

Wherein each symbol is as defined above, a method for producing a hydrazine derivative or a salt thereof;

(2) Equation (II)

[In the formula, RR ² , R ³ and R ⁴ are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group (preferably, One of R ¹ and R ² is not a hydrogen atom, more preferably neither R ¹ nor R ² is a hydrogen atom), and R ¹ R ² , R ³ and R ⁴ are each other A hydrazone derivative represented by the formula: or a salt thereof, with a trioxyloxyborohydride complex compound, a borohydride complex compound and a compound represented by the formula R ⁵ '_COOH , R ⁵ ′ represents a hydrogen atom or a hydrocarbon group which may be substituted], and a carboxylic acid represented by the formula (IIΓ):

Four

[Wherein each symbol has the same meaning as described above], a method for producing a hydrazine derivative or a salt thereof;

(3) Equation (I)

[In the formula, R ¹ , R ² , R ³ and R ⁴ are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group ( Preferably, ^one of R ¹ and R ² is not a hydrogen atom, and more preferably, neither R ¹ nor R ² is a hydronizing atom), and RR ² , R ³ and R ⁴ are bonded to each other the to hydrazone derivative or a salt thereof may also be 'to form a ring, is reacted with bets Riashirokishi borohydride complex compounds, beauty formula R ⁵ Oyo borohydride complex compounds' - COOH [wherein , R ⁵ ′ represents a hydrogen atom or a hydrocarbon group which may be substituted], and a carboxylic acid represented by the formula (IIΓ):

(4) Equation (IV)

[Wherein, R ¹ and R ² each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group,

¹ and R ² may combine with each other to form a ring, and R ⁵ represents an optionally substituted hydrocarbon group], or a hydrazine derivative thereof or a salt thereof with a reducing agent (preferably , A polyanamine complex having a melting point of 25 ° C. or higher, a triacyloxyborohydride complex compound, or a borohydride complex compound, and a compound represented by the formula R ⁵ ′ —COOH wherein R ⁵ ′ may be a hydrogen atom or may be substituted A carboxylic acid of the formula:

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R ³ and R ⁴ May combine with each other to form a ring]. Or a salt of the formula (III)

(5) Equation (IV)

1

R

N-MH 2

¹ and R ² may combine with each other to form a ring], or a salt thereof, with a triacyloxyborohydride complex compound and a compound of formula (V)

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R ³ and R ⁴ May combine with each other to form a ring], or a borohydride complex compound represented by the formula: R ⁵ ′ —COOH [where 5 ′ is a hydrogen atom or substituted A hydrocarbon group which may be represented by the formula: 6

ヽ,

S

One o

Wherein each symbol is as defined above, or a salt thereof.

(6) An expression that is used as the starting compound (I), Formula (II), in the compound represented by formula (IV) or formula (IV), R ¹ has the formula

D

R ■ N——X

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and ⁷ represents R ² And X ¹ may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably a bond or an optionally substituted alkylene group) A group, more preferably, an alkylene group which may be substituted), and D represents an oxygen atom or a sulfur atom.] The method according to any one of (1) to (5) above,

(7) In a compound represented by the formula (I), (II), (IV) or (IV) or a salt thereof used as a starting compound,

Is a group represented by the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and D represents an oxygen atom or a sulfur atom]. 1) to (5).

(8) In the compound represented by the formula (I), (II), (IV) or (IV) or a salt thereof used as a starting compound,

Is a group represented by the formula

[Wherein, R ⁸ represents a nitrogen-protecting group, and D represents an oxygen atom or a sulfur atom.] The production method according to any one of (1) to (5) above,

(9) Equation (VI)-

[Wherein, R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom] and a hydrazine derivative or a salt thereof represented by the formula (V)

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R ³ and R ⁴ May combine with each other to form a ring] with a carbonyl compound represented by the formula (VI I)

R

[Wherein each symbol is as defined above], to produce a hydrazone derivative or a salt thereof, followed by reacting with a poraneamine complex having a melting point of 25 or more to obtain a compound of the formula (VI II)

Wherein each symbol is as defined above, to produce a hydrazine derivative or a salt thereof, and further, after reduction and deprotection, a compound of the formula (IX)

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof. Characteristic expression (X)

(Wherein each symbol is as defined above), a method for producing a hydrazine derivative or a salt thereof; (10) Formula (VI)

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R ³ and R ⁴ May be bonded to each other to form a ring], in contrast to the carbonyl compound represented by the formula (VII)

[Where the symbols are as defined above] or a hydrazone derivative represented by the formula: And reacting with a trisiloxyborohydride complex or with a borohydride complex and the formula R ⁵ ′ —COOH, where R ⁵ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group. Reacting with the carboxylic acid represented by the formula (Χ Γ)

Wherein each symbol is as defined above) to produce a hydrazine derivative represented by the formula (IX)

R6_0 ^ _s ^

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof. Special formula (XI)

[Wherein each symbol is as defined above], a method for producing a hydrazine derivative or a salt thereof;

(11) Equation (X I I I)

[In the formula, R ⁵ represents an optionally substituted hydrocarbon group, and R ⁸ is a protecting group for a nitrogen atom. And D represents an oxygen atom or a sulfur atom.] In the presence of a reducing agent, a hydrazine derivative represented by the formula (V)

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted T group, and R ³ and R ⁴ May be bonded to each other to form a ring] with a carbonyl compound represented by the formula (XI)

[Wherein each symbol is as defined above] to produce a hydrazone derivative or a salt thereof, and after deprotection and reduction, obtain a compound of the formula (IX).

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof. Characteristic expression (XII)

Wherein each symbol is as defined above], a method for producing a hydrazine derivative or a salt thereof;

(12) Equation (VI)

Wherein R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom. After reducing and deprotecting the hydrazine derivative represented by the formula (IX),

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof, Formula (XIV)

[Wherein the symbols are as defined above]

To produce a hydrazine derivative or salt represented by the formula:

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and R ³ and R ⁴ May combine with each other to form a ring], or a borohydride complex compound and a compound represented by the formula R ⁵ ′ —COOH wherein R ⁵ ′ is a hydrogen atom or A hydrocarbon group which may be substituted] and a carboxylic acid represented by the formula (V) R,

Wherein each symbol is as defined above], or a salt thereof.

(13)

Wherein n represents 1 or 2, m represents 2 or 3, and D represents an oxygen atom or a sulfur atom.

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom] or a salt thereof. Expression to feature

Wherein each symbol is as defined above, or a salt thereof. (14) The method according to (13), wherein the reaction is carried out in the presence of a base;

(15) The method according to (13), wherein n is 1 and m is 2.

The compound represented by the formula (II) or a salt thereof and the compound represented by the formula (III) or (IIΓ) or a salt thereof obtained by the above-mentioned production method are useful as a drug such as an FXa inhibitor, It is also useful as other pharmaceuticals, pesticides, foods, cosmetics and chemicals or intermediates thereof.

In the above formula, R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, among which an optionally substituted acyl group Is preferred. '

Examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹ include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, and the like. Formula hydrocarbon groups are preferred.

Examples of the “aliphatic chain hydrocarbon group” as an example of the hydrocarbon group include a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.

Here, as the alkyl group, for example, methyl, ethyl, n-propyl, isopyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-methylpropyl —Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n —Octyl, 1-methylheptyl, nonyl, etc.

Examples include an alkyl group (preferably (^ alkyl or the like)).

Examples of the alkenyl group include bier, aryl, isoprobenyl, 2-methylaryl, 1-propenyl, 2-methyl_1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- Ethyl 1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2 - to hexenyl Le, the 3-hexenyl, 4 one hexenyl, etc. C ₂ _ ₆ alkenyl group cyclohexenyl, etc., to 5 and the like. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- to hexynyl, the 3-key Shin Il, 4 one to Kisheru include C ₂ _ ₆ alkynyl group hexynyl, etc., to 5. The “alicyclic hydrocarbon group” as an example of the hydrocarbon group includes, for example, a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.

Here, the "cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, c ₃ such Shikurono nil - ₉ cycloalkyl, and the like.

Examples of the “cycloalkenyl group” include 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-11-yl, 3-cyclohexene-11-yl, 1- cyclobutene one 1 one I le, 1 over sheet Kuropenten -. 1 one I le, 1 Shikuro hexene one 1 one I le, etc. C ₃ _ ₉ consequent Roarukeniru group such as 1-cycloheptene one 1 Iru the like.

Examples of the “cycloalkadienyl group” include C _4, such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, and 2,5-cyclohexadiene-1-yl — ₆ cycloalkajenyl group and the like.

The "Ariru group" as examples of the hydrocarbon group, a monocyclic or condensed polycyclic aromatic hydrocarbon group, for example phenyl, naphthyl, anthryl, Fuenanto Lil, such Asenafuchireniru C ₆ - _{1 4} Ariru Groups and the like are preferable, and phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.

Examples of the hydrocarbon group include the above-mentioned alicyclic hydrocarbons such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, and fluorenyl. Examples thereof include a bi- or tricyclic hydrocarbon group derived from the condensation of two or three identical or different groups (preferably two or more groups) selected from a hydrogen group and an aromatic hydrocarbon group.

The heterocyclic group of the “optionally substituted heterocyclic group” represented by R ¹ includes, for example, an oxygen atom, a sulfur atom, a nitrogen atom, or the like as an atom (ring atom) constituting a ring system. An aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from saturated or unsaturated And a non-aromatic heterocyclic group (aliphatic heterocyclic group).

As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 2,4-oxadiazolyl, 1,3,4-oxadazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 5- or 6-membered aromatic monocyclic heterocyclic and fused aromatic heterocyclic groups such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. Benzoflael, benzo [b] chenyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, Benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2_benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalaragel , Naphthyridinyl, purinyl, buteridinyl, kyrvazolyl, Q! -Kyrupolinil, β-carbolinyl, ercarborinyl, acridinil, phenoxazinyl, phenothiazinyl, fenazinyl, fenoxathiinyl, thianthrenyl, fenatrilinyl, indone [L, 2-b] pyridazinyl, pyrazo opening [l, 5-a] pyridyl, imidazo. [1,

2—a] pyridyl, imidazo [1, 5—a] pyridyl, imidazo [1, 2—b] pyridazinyl, imidazo [1, 2—a] pyrimidinyl, 1, 2, 4-triazolo [4,

3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc.) and an 8- to 12-membered fused aromatic heterocyclic group (preferably, the 5- or 6-membered aromatic unit represented by A heterocyclic ring in which a cyclic heterocyclic group is condensed with a benzene ring, or a heterocyclic ring in which two identical or different heterocyclic rings of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are condensed, more preferably Examples of the above-mentioned heterocyclic ring in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo [b] thienyl, and the like are mentioned. Examples of the "non-aromatic heterocyclic group" include 3- to 8-membered groups such as oxilanyl, azetidinyl, oxeynyl, ceynyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydrovinylanyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. (Preferably 5 to 6 members) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydroxylyl, 1,2,3 And non-aromatic heterocyclic groups in which some or all of the above-mentioned aromatic monocyclic heterocyclic groups or aromatic condensed heterocyclic groups are saturated, such as 1,4-tetrahydroisoquinolyl. It is.

Examples of the substituent of the `` optionally substituted hydrocarbon group '' and the `` optionally substituted heterocyclic group '' represented by R ¹ include an optionally substituted alkyl group and an optionally substituted Alkenyl group, alkynyl group which may be substituted, aryl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, A good heterocyclic group, an optionally substituted amino group, an optionally substituted imidoyl group (for example, in the formula, c (u ′) = N—U, wherein U and U ′ are each a hydrogen atom or a substituted An amidino group which may be substituted (for example, a group represented by a group represented by a group (U preferably represents a hydrogen atom)]), for example, a group represented by the formula —C (NT′T ”) = N-T , T, T 'and T "each represent a hydrogen atom or a substituent ( T preferably represents a hydrogen atom))), an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified propyloxyl group, an optionally substituted Carbamoyl group, thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, halogen atom (for example, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), cyano Group, nitro group, (^ -6 alkyleneoxy group (eg, ethyleneoxy, propyleneoxy, etc.), (^ -6 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, etc.), sulfonic acid-derived acyl group And a carboxylic acid-derived acyl group. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions. May be in conversion. Further, "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ¹ may have a O Kiso group, For example, if the R ¹ Gabe Nzopiraniru, R ¹ Habe Benzo-α-pyronyl, benzo-T-pyronyl and the like may be formed.

It is a Ariru group in the "optionally substituted Ariru group" as the substituent, for example phenyl, naphthyl, anthryl, Fuenantoriru, such Asenafuchire sulfonyl (:. ₆ - _{1 4} Ariru group, etc. Here, Examples of the substituent of the aryl group include a lower alkoxy group (eg, ₆ alkoxy groups such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and a lower alkyl group (eg, methyl, ethyl). , propyl, etc. (^ - ₆ alkyl group, etc.), lower alkenyl groups (e.g. Biel, C etc. Ariru ₂ - ₆ alkenyl group), if example a lower alkynyl group (e.g. Echiniru, C ₂ _ ₆ alkynyl group propargyl Etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a cyano group, Amidino groups and the like may be mentioned, and these optional substituents may be substituted at 1 to 3 substitutable positions.

"Optionally substituted amino group", "optionally substituted hydroxyl group", and "optionally substituted amidino group" as substituents of "optionally substituted aryl group"'' May be `` optionally substituted '' as a substituent which the `` optionally substituted hydrocarbon group '' and `` optionally substituted heterocyclic group '' represented by R ¹ may have And the same as the “good amino group”, “optionally substituted hydroxyl group”, and “optionally substituted amidino group”.

The Shikuroa alkyl group in the "optionally substituted cycloalkyl group" as a substituent, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cyclo, 〇 ₃ of heptyl and the like cyclohexane - mentioned such _cycloalkyl groups are Can be Here, examples of the substituent of the cycloalkyl group include the same number of the same substituents as those in the above-mentioned “optionally substituted aryl group”.

The cyclo alkenyl group in the "optionally substituted cycloalkenyl group" as the substituent, for example Shikuropuro Bae sulfonyl, cyclobutenyl, Shikuropen thenyl, C ₃ of cyclohexenyl etc. cyclohexane - like ₆ cycloalkenyl group. Here, examples of the substituent of the optionally substituted cycloalkenyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”. Examples of the alkyl group in the “optionally substituted alkyl group” as a substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , Isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc.

(3 ^ 6 alkyl and the like. Here, examples of the substituent of the alkyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”. Can be

Examples of the alkenyl group in the “optionally substituted alkenyl group” as the substituent include, for example, vinyl, aryl, isoprobenyl, 2-methylaryl, 1-propyl, 2-methyl-1-propenyl, -Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4 one methyl - 3 _ pentenyl, cyclohexenyl 1, cyclohexenyl 2, to 3-hexenyl, 4 one hexenyl, C ₂ _ ₆ alkenyl groups such as cyclohexenyl can be mentioned, et al are to 5 scratch. Here, examples of the substituent of the alkenyl group include the same number of the same substituents as in the above-mentioned “optionally substituted aryl group”.

Examples of the alkynyl group in the “optionally substituted alkynyl group” as a substituent include, for example, ethynyl, 1-propenyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentyl two Le, 4 _ pentynyl, 1 one to Kisheru, 2 into single Kisheru, three to the hexynyl, 4 one to hexynyl include C ₂ _ ₆ alkynyl group hexynyl, etc., to 5. Here, examples of the substituent of the alkynyl group include the same number of the same substituents as those in the above-mentioned “optionally substituted aryl group”.

As the heterocyclic group in the “optionally substituted heterocyclic group” as a substituent, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like as an atom (ring atom) constituting a ring system 1 An aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2), a saturated or unsaturated non-aromatic heterocyclic group ( Aliphatic heterocyclic group) and the like. As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 2,4-year-old oxadiazolyl, 1,3,4-monoxaziazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-tria 5- to 6-membered aromatic monocyclic heterocyclic groups and fused aromatic heterocyclic groups such as zolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. Benzofuranyl, benzo [b] chenyl, indolyl, isoindolyl, 1H-indazolyl, benzoindazolyl , Benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H_benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, Phthalazinyl, naphthyridinyl, prenyl, buteridinyl, carbazolyl, α-carbolinyl, / 3-carbolinyl, τ-carbolinyl, acridinil, phenoxazinyl, phenothiazinyl, fenazinyl, fenoxathiinyl, thianthrenyl, ind. Pyro mouth [1, 2-b] pyridazinyl, pyrazo mouth [1, 5-a] Pyridyl, imidazo [1, 2-a] Pyridyl, imidazo [1, 5-a] Pyridyl, imidazo [1, 2- b] Pyridazinyl, imidazo [1, 2-a] pyrimidiny 8-, 12-membered aromatic condensed heterocyclic groups such as 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc. Preferably, the heterocyclic ring in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring or the same or different heterocyclic ring of the 5- or 6-membered aromatic monocyclic heterocyclic group described above. Heterocyclic ring in which two are fused).

As the “non-aromatic heterocyclic group”, for example, 3- to 8-membered groups such as oxilael, azetidinyl, oxeynyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholinel, piperazinyl and the like ( (Preferably 5 to 6 members) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydridoquinolyl, 1,2,3 Fragrance such as 4,4-tetrahydroisoquinolyl Non-aromatic heterocyclic groups in which double bonds of part or all of the aromatic monocyclic heterocyclic group or the aromatic condensed heterocyclic group are saturated are exemplified.

As the "optionally substituted heterocyclic group optionally" is the substituent that may have as a substituent, a lower alkyl group (e.g. methyl, Echiru, propyl, etc. (^ _-6 alkyl Le group), lower alkenyl groups (e.g. vinyl, C ₂ etc. Ariru - like ₆ alkenyl group), a lower alkynyl group (e.g. Echiniru, C ₂ of propargyl - like ₆ alkynyl group), Ashiru groups (e.g. formyl, Asechiru, propionyl, etc. Pibaroiru C ₆ -alkanol, benzoyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), And an optionally substituted amidino group, etc .: As the substituent, "optionally substituted `` Optionally substituted amino group '', `` optionally substituted hydroxyl group '', `` optionally substituted imidoyl group '', and `` optionally substituted Examples of the `` good amidino group '' include `` substituted hydrocarbon '' which is represented by R ¹ and `` substituted And an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted imidoyl group, and an optionally substituted amidino group.

"Optionally substituted amino group" as a substituent which the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ¹ may have The `` optionally substituted imidoyl group '', `` optionally substituted amidino group '', `` optionally substituted hydroxyl group '' and `` optionally substituted thiol group '' For example, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) and optionally halogenated alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trimethoxy) , 2,2,2-trichloromouth ethoxy, etc.) which may be substituted with a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl) Pill, heptyl, Isopuchiru, t one heptyl, such as 0 ^ _ ₆ § alkyl group of hexyl such as pentyl, to), Ashiru based on (C ^ Arukanoiru (for example, formyl, Asechiru, professional Pionyl, bivaloyl, etc.), benzoyl, etc.), optionally halogenated alkoxy monopropyl (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxy) Carbonyl, 2,2,2-tricyclomouth ethoxycarbonyl, etc.), and a heterocyclic group (the same as the “cyclic ring group” in the “optionally substituted heterocyclic group” for R ¹ ); Preferably pyridyl, more preferably 4-pyridyl, etc., etc., and the “amino group” in the “optionally substituted amino group” as the substituent is an optionally substituted imidoyl group (e.g., ₆ Al Kiruimidoiru (eg, formyl imidoyl, § cetyl imidoyl etc.), ₆ § Rukokishiimi Yl, (^ - 6 alkylthio imidoyl, amidino, etc.), 1-2 c _x _ ₆ alkyl may be substituted by such amino group which may be substituted, also the two substituents A cyclic amino group may be formed together with a nitrogen atom. Examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl and position a lower alkyl group (e.g. methyl, Echiru, propyl, isopropyl, heptyl, t one heptyl, pentyl, a hexyl, etc., to C -! ₆ alkyl group), Ararukiru group (for example benzyl, c ₇ _ ₁ such phenethyl ₀ Ararukiru group), Ariru group (e.g. Hue sulfonyl, 1 one naphthyl, C ₆ _ ₁ such as 2 _ naphthyl ₀ Ariru group) 1 may have such Piperajie And a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino such as 1-pyrrolyl, 1-imidazolyl and the like.

The “optionally substituted rubamoyl group” includes unsubstituted rubamoyl groups, N-monosubstituted rubamoyl groups and N, N-disubstituted rubamoyl groups.

"N-monosubstituted rubamoyl group" means a disubstituted group having one substituent on a nitrogen atom, such as a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl). , isobutyl, t-butyl, etc. C WINCH ₆ alkyl group hexyl etc. pentyl,), lower alkenyl groups (e.g. vinyl, Ariru, isopropenyl, propenyl, C ₂ etc. hexenyl butenyl, pentenyl, to - ₆ § alkenyl group), a cycloalkyl group (e.g. cyclopropyl, cyclobutyl, consequent opening pentyl, C ₃ of cyclohexyl etc. cyclohexane - ₆ cycloalkyl group), § Li Ichiru group (eg If phenyl, 1 _ naphthyl, 2-C ₆ of naphthyl - _{1 0} Ariru group), Araruki Le group (e.g. benzyl, C y- i Ararukiru group such as phenethyl, preferably phenylene Le -. C _i-4 alkyl group, etc.), § reel alkenyl group (e.g., C ₈ of cinnamyl etc. - _{1 0} § reel alkenyl group, preferably represented phenylene Lou C ₂ _ ₄ alkenyl group), in the heterocyclic group (e.g., the above-described R ¹ And the like as the “heterocyclic group” as the substituent in the “optionally substituted hydrocarbon group”). The lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, aralkyl group, aryl alkenyl group, and heterocyclic group may have a substituent. Examples of the substituent include a hydroxyl group and a substituted an amino group [the amino group optionally has, for example, a lower alkyl group (for instance methyl, Echiru, propyl, isopropyl, heptyl, isobutanol chill, t one heptyl, etc. C WINCH ₆ alkyl group hexyl etc. pentyl,), One or more of an acyl group (eg, formyl, acetyl, propionyl, pivaloyl, etc., 6-alkanoyl, benzoyl, etc.), a lipoxyl group, a 6-alkoxy monopropylonyl group, etc.

It may have two substituents. ], Halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, lower optionally substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) Examples thereof include an alkyl group and a lower alkoxy group which may be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Examples of the lower alkyl group include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, and particularly, methyl, ethyl and the like. Is preferred. Examples of the lower alkoxy group include C alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, and particularly methoxy, ethoxy and the like. Are preferred. Further, it is preferable that one or two to three (preferably one or two) of these substituents are the same or different.

“N, N-disubstituted rubamoyl group” means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is an “N-monosubstituted carbamoyl group” described above. And the other are, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t- heptyl, pentyl, C _i-6 alkyl groups hexyl, etc., to such), C ₃ - ₆ Shikuroaruki Le group (e.g. cyclopropyl, cyclobutyl, cyclohexyl, etc. cyclopentyl, cyclohexylene), c ₇ _ _{1 0} Ararukiru group (e.g. Benzyl, phenethyl and the like, preferably a phenyl _4- alkyl group and the like. In addition, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl and 1-pyrrolidinylcaprolyl. Ruponiru, piperidinocarbonyl, morpholinocarbonyl, 1 Piperajiniruka Ruponiru and 4-position a lower alkyl group (e.g. methyl, Echiru, propyl, isopropoxy port pills, heptyl, t one heptyl, C j _ ₆ alkyl groups hexyl etc. pentyl, etc.), § aralkyl group (e.g. benzyl, c such phenethyl ₇ - i _Q Ararukiru group), Ari Le group (e.g. phenyl, 1 one-naphthyl, have a 2-C 6 ^ 0 Ariru group naphthyl, etc.), etc. 3 to 8-membered (preferably 5 to 6-membered) cyclic amino-carbonyl such as 1-piperazinylcarbonyl .

Examples of the substituents of the “optionally substituted thiocarbamoyl group” and the “optionally substituted sulfamoyl group” include the same substituents as those of the above-mentioned “optionally substituted carbamoyl group”. No.

Examples of the carboxyl group which may be esterified include, in addition to a free carboxyl group, a lower alkoxycarbonyl group, a 7-reoxycarbonyl group, an aralkyloxycarbonyl group and the like.

Examples of the "lower alkoxycarbonyl group" include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycapillonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyl And the like. Examples thereof include _6- alkoxy mono-propyl groups such as oxycarbonyl and neopentyloxy carbonyl, among which C 3 alkoxy-propyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are preferable.

The "§ reel O carboxymethyl Cal Poni Le group", for example, phenoxy force Ruponiru, 1 one naphthoxycarbonyl, 2 one naphthoquinone C ₆ _ _{1 Q} Ariruokishi such deer Lupo sulfonyl - force Ruponiru group and the like. The "§ Lal Kill O alkoxycarbonyl group" such as benzyl O carboxymethyl Cal Po two Le, Hue phenethyl Ruo carboxymethyl cull Poni Le etc. (3 ₇ _ _{1 4} Ararukiruokishi one carboxymethyl sulfonyl group

(Preferably C 6 ^ 0 aryl-4 alkoxycarbonyl) and the like. The “aryloxycarbonyl group” and the “aralkyloxycarbonyl group” may have a substituent. Examples of the substituent include the above-mentioned N-monosubstituents such as lubamoyl group. The same numbers as those described as the substituents of the aryl group and the aralkyl group as examples of the substituent are used.

Examples of the `` sulfonic group derived from sulfonic acid '' as a substituent include those in which the above-mentioned `` N-monosubstituent rubamoyl group '' has one substituent on a nitrogen atom and a sulfonyl bond, and the like. Preferably, acyl such as C ₆ alkylsulfonyl such as methanesulfonyl and ethanesulfonyl is exemplified.

Examples of the `` carboxylic acid-derived acyl group '' as a substituent include those in which a hydrogen atom or a substituent having one of the above-mentioned `` N-monosubstituent rubamoyl groups '' on a nitrogen atom is bonded to carbonyl. Preferred examples include ^ -ealkanols such as formyl, acetyl, propionyl, and vivaloyl, and acyls such as benzoyl.

As "optionally substituted Ashiru group" represented by R ^1, "replacement is hydrocarbon group which may be substituted" represented by R ^1, "heterocyclic ring which may be substituted represented by R ¹ A "optionally substituted amino group" or an "optionally substituted amino group" (optionally possessed by an "optionally substituted hydrocarbon group" for R ¹⁾ formyl group; "and the like as similar) is a sulfonyl group, Karuponiru group, Chio carbonyl group, a group formed by combining with such Okishikaruponiru group the like Karupokishi Le group. Among them, R ¹ described above As the substituents of the "optionally substituted hydrocarbons" represented by the formulas, there may be mentioned a "sulfonic group derived from a sulfonic acid", a "carboxylic group derived from a carboxylic acid", a "carboxyl group which may be esterified" and the like. Or properly, "Ashiru group derived from a carboxylic acid" is more preferable.

The “optionally substituted acyl group” represented by R ¹ includes a group represented by the formula

Wherein, R ⁶ represents a optionally substituted hydrocarbon group or an optionally substituted double heterocyclic group, R ⁷ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ⁷ And R ² or the substituent of X ¹ and R ⁷ may be bonded to each other to form a ring, and X ¹ is a bond, an optionally substituted alkylene group or an optionally substituted imino group ( Preferably an alkylene group which may be substituted), and D represents an oxygen atom or a sulfur atom. An acyl group represented by the formula:

(In the formula, R ⁸ represents a protecting group for an amino group, R ⁷ represents a hydrogen atom or a hydrocarbon group which may be substituted, and the substituents of R ⁷ and R ² or X ¹ and R ⁷ are mutually bonded. X ¹ may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably an optionally substituted alkylene group). And D represents an oxygen atom or a sulfur atom. ], Etc. are also preferably used.

In the above formula, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, among which a hydrogen atom or a substituted Hydrocarbon groups which may be present are preferred.

Examples of the `` optionally substituted hydrocarbon group '' represented by R ² include the same as the aforementioned `` optionally substituted hydrocarbon group '' represented by R ¹ , An optionally substituted C ^ ₄ lower alkyl group is preferred.

As the “optionally substituted heterocyclic group” for R ² , the same as the aforementioned “optionally substituted heterocyclic group” for R ¹ can be mentioned.

As the “optionally substituted acyl group” for R ² , the aforementioned R ¹ The same as the optionally substituted acyl group j can be mentioned, and among them, the `` optionally substituted hydrocarbon group '' represented by R ¹ described above Preferred are an sulfonic acid-derived acyl group, a carboxylic acid-derived acyl group, and an optionally esterified hydroxyl group.

R ² is preferably bonded to R ¹ to form a ring, and R ¹ has the formula

(In the formula, R ⁸ represents a protecting group for an amino group, R ⁷ represents a hydrogen atom or a hydrocarbon group which may be substituted, and the substituents of R ⁷ and R ² or X ¹ and R ⁷ are mutually bonded. X ¹ may be a bond, an optionally substituted alkylene group or an optionally substituted imino group (preferably an optionally substituted alkylene group). And D represents an oxygen atom or a sulfur atom. R ² is preferably bonded to a substituent of R ⁷ or X ¹ to form a ring.

In the above formula, when R ² and R ¹ are combined to form a ring together, that form a "optionally substituted nitrogen-containing heterocyclic group" together with the nitrogen atom to which Oyobi ¹ are adjacent. Such nitrogen-containing heterocyclic groups include, as atoms (ring atoms) constituting a ring system, one to three (preferably one to two) hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. 5 to 7-membered aromatic heterocyclic group containing at least one (preferably 1 to 3, more preferably 1 to 2), or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic) Group heterocyclic group).

Examples of the “nitrogen-containing aromatic heterocyclic group” include, for example, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxazinediazole, 1,2,4-oxaziazole. 1,2,5-thoxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3 5-membered aromatic heterocycles such as 1,4-thiadiazole, 1,2,3_triazole, 1,2,4-triazole, and, for example, pyridine, pyridazine, pyrimidine, 1,2,4-triazine, 1 And 6-membered aromatic heterocycles such as 3,3,5-triazine and the like.

Examples of the “non-aromatic heterocyclic group” include, for example, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopidazine, 2,4-thiazolidinedione, 2,4-oxazolidinedione, hydantoin, Examples thereof include 5- to 7-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups) such as rhodanine, succinimide, maleimide, thiomaleimide and phthalimide.

Such a nitrogen-containing heterocyclic group is referred to as a “bivalent nitrogen-containing heterocyclic group which may be substituted” (a divalent group formed by the bonding of R ² and R ⁷ ). It may have the same substituent as the substituent which the “heterocyclic group” may have, and a substituent selected from an oxo group and a thioxo group.

When R ² and R ⁷ combine to form a ring, they form an “optionally substituted divalent nitrogen-containing heterocyclic group” with one N—X ¹ —CD—N—.

As the “divalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom is used as an atom (ring atom) constituting a ring system. Divalent 5- to 8-membered nitrogen-containing heterocyclic group containing 2 or 3 (preferably a divalent 5- to 8-membered nitrogen-containing heterocyclic group composed of a carbon atom and two nitrogen atoms) Is mentioned. These “divalent nitrogen-containing heterocyclic groups” have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R ² is bonded, and have a “divalent 5 to 8 A specific example of such a divalent 5- to 8-membered nitrogen-containing cyclic amide group is, for example, 2-oxoimidazolidin-1,1,3-diyl, 2 —Oxoimidazolone-1, 3-diyl, 2-year-old oxopiperazine-1, 4, diyl, 2-oxo-1, 2,3,4, tetrahydropyrazine-1,4, diyl, 2-oxohomopyrazine-1 1 , 4 gil, 5-oxo homopyrazine 1, 4 gil, 2 oxo 1, 4 diazacyclooctane 1, 4 dimethyl, 5 oxo 1, 4-diazacyclooctane 1 1 , 4 gil, 2 oxo 1, 5-diazacyclooctane 1, 5-di Yl, 5-oxo-1,2,3-dehydrohomopirazine-1,4-diyl, 3-oxo-1,2,4-triazacyclohexane-1,4-diyl, 3-oxo-1,2,3 , 4-tetrahydro-1,2,4-triadiyne-1,4 diyl and 6-oxo-1,2,4-triazacyclohexane-11,4-diyl.

The substituent of the “divalent nitrogen-containing heterocyclic group” in the above-mentioned “optionally substituted divalent nitrogen-containing heterocyclic group” is, for example, a substituent other than one oxo group or thioxo group. An optionally substituted hydroxyl group, an optionally substituted mercapto group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, an oxo group, an optionally substituted amino group, Optionally substituted lower alkyl group, optionally substituted lower alkylidene group, optionally substituted lower aralkylidene group, and 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) Optionally substituted lower alkoxy group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted thiocal Examples include a bamoyl group and an optionally substituted sulfamoyl group. These optional substituents may be substituted at 1 to 3 (preferably 1 or 2) at substitutable positions.

Here, `` substituents of the optionally substituted amino group J include one to two optionally substituted alkyl groups, optionally substituted rubamoyl groups, and optionally substituted A carbamoyl group, an optionally substituted sulfamoyl group, Examples include a carboxyl group which may be steered, an acyl group derived from a sulfonic acid, an acyl group derived from a carboxylic acid, and the like; "optionally substituted alkyl group";"optionally substituted rubamoyl" A thiocarbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a carboxyl group which may be esterified, an acyl group derived from sulfonic acid, and As the `` carboxylic acid-derived acyl group '', the `` optionally substituted alkyl group '' as a substituent of the `` optionally substituted hydrocarbon group '' represented by R ¹ described above and `` optionally substituted Good carbamoyl group, "optionally substituted thiocarbamoyl group", "optionally substituted sulfamoyl group", "optionally substituted carboyl group" The same groups as those described above for the "sil group", "sulfonic acid-derived acyl group" and "carboxylic acid-derived acyl group" are preferable. Preferred examples of the "optionally substituted amino group" include (1) methylation, Echiru, n- propyl, isopropyl, n one-butyl, isobutyl, sec- butyl Le, lower (C ^ ₆₎ alkyl group such as tert- butyl, (2) mono- or di-lower (C preparative ₆₎ alkyl force A substituent selected from (^ -6 alkanol and (5) benzoyl such as (3) C j- ₆ alkylsulfonyl such as (3) methanesulfonyl and ethanesulfonyl, (4) formyl, acetyl, propionyl, and vivaloil; And amino which may have 2 to 2.

Examples of the lower alkyl group in the “optionally substituted lower alkyl group” include C alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particularly preferred are methyl, X tyl and the like. Examples of the substituent include a halogen atom (e.g. fluorine, chlorine, bromine, iodine), amino group, forces Rupokishiru group, hydroxyl group, C ₆ - _{1 ()} Ariru, C ₆ _ _{1 0} § Li one Ruokishi, C ₆ - _{1 0} Ariru one - ₄ alkoxy and the like, these optional substituents ranges from 1 to substitutable positions to 5 (preferably 1 or 2) may be in substitution.

Examples of the “optionally substituted lower alkylidene group” include alkylidene such as methylidene and ethylidene. Examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an amino group, And any of these substituents may be substituted with 1 to 5 at a substitutable position. (Preferably 1 or 2) may be substituted.

Examples of the “optionally substituted lower aralkylidene group” include C 6 ^ such as benzylidene. § Li one Roux (^ - ₄ alkylidene, and the like, examples of the substituent, for example, eight androgenic atom (e.g. fluorine, chlorine, bromine, iodine), amino group, carboxyl group, hydroxyl group, and the like. These May have 1 to 5 (preferably 1 or 2) substituents at substitutable positions.

The lower alkoxy group in the "optionally substituted lower alkoxy group optionally substituted with a halogen atom", for example methoxy, ethoxy, n- Purobokishi, Isopuropoki shea, n- butoxy, isobutoxy, sec- butoxy, etc. tert- butoxy ₆ Alkoxy groups and the like are mentioned, and methoxy, ethoxy and the like are particularly preferable.

The `` carboxyl group which may be esterified '' is the same as the carboxyl group which may be esterified as a substituent of the `` optionally substituted hydrocarbon group '' represented by R ¹ described above. Things.

"Optionally substituted force Rubamoiru group", the "optionally substituted Chiokaruba carbamoyl group" and "sulfamoyl group which may be substituted", "substituted represented by the R ¹ And optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, and optionally substituted sulfamoyl groups as substituents of .

In the aforementioned “divalent nitrogen-containing heterocyclic group”, the “optionally substituted hydroxyl group” and the “optionally substituted mercapto group” as the substituents that the “divalent nitrogen-containing heterocyclic group” may have, “hydroxyl group” and “mercapto group” The substituent which the group may have is, for example, a lower alkyl group which may be substituted, an olepoxyl group which may be esterified, an rubamoyl group which may be substituted, and a substituted A thiocarbamoyl group, an optionally substituted sulfamoyl group, a sulfonic acid-derived acyl group, and a carboxylic acid-derived acyl group. Examples of the lower alkyl group include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. Examples of the substituent which may have a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), an aryl group which may be substituted [for example, Rogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl C i _ ₆ alkyl group), a lower alkoxy group (e.g. an equal, methoxy, ethoxy, n- Purobokishi, Isopurobokishi, n- butoxy, isobutoxy, sec- butoxy, etc. tert- butoxy - 6 alkoxy group), etc. Phenyl or naphthyl, each of which may be substituted], a hydroxyl group which may be substituted (eg, a substituted or unsubstituted hydrocarbon group represented by R ¹⁾ Thiol group (e.g., the same as the above-mentioned hydroxyl group), or a thiol group (e.g., the above-mentioned optionally substituted hydrocarbon represented by R ¹⁾ Those similar to the optionally substituted thiol group as the substituent of the original "), replacement is an amino group which may be (for example," optionally substituted represented by the R ¹ carbide The same as the optionally substituted amino group as a substituent of the `` hydrogen group ''), the carboxyl group which may be esterified (eg, the `` optionally substituted '' represented by R ¹ described above) And the like as the substituent of the "hydrocarbon group" which may be esterified). In the “optionally substituted mercapto group”, the sulfur atom may be oxidized, and has, for example, a structure represented by S (O) k [k is an integer of 0 to 2]. May be. In the aforementioned “divalent nitrogen-containing heterocyclic group”, the “optionally substituted hydroxyl group” and the “optionally substituted mercapto group” as the substituents which the “divalent nitrogen-containing heterocyclic group” may have, “hydroxyl group” and "Optionally esterified olepoxyl group", "optionally substituted olevamoyl group", "optionally substituted thiocarbamoyl" as a substituent which the "mercapto group" may have group "," optionally substituted sul Famoiru also be group ", as" sulfonic acid-derived Ashiru group "and" carboxylic acid-derived Ashiru group "is represented by the R ¹ 'may be substituted hydrocarbon "Hydroxyl group which may be esterified", "Lubamoyl group which may be substituted", "Ciocarbamo which may be substituted" Le group "," optionally substituted sulfamoyl group ", and the like as similar to the" Ashiru group derived from a sulfonic acid "and" Ashiru group derived from force Rupon acid ".

As the above-mentioned “divalent nitrogen-containing heterocyclic group”, for example, Z CH) H ₂ / _m

[In the formula, D represents an oxygen atom or a sulfur atom, n represents 1 or 2, and m represents 2 or 3. And the like.

In the above formula, m is preferably 2 and n is preferably 1.

Also, for example, the expression

CH ■ 2 _? ) ^D

No

[In the formula, D represents an oxygen atom or a sulfur atom, and η represents 1 or 2 (preferably 1). And the like.

Examples of the above-mentioned "divalent nitrogen-containing heterocyclic group" include 2-oxopiperazine-1,4-diyl and 2-oxo-1,2,3,4-tetrahydropyrazine-1,4-diyl. Is most preferred.

Further, the substituent of X ¹ and R ² may be bonded to each other to form a ring, and a divalent group represented by X ¹ —CD—N (R ² ) — A divalent nitrogen-containing heterocyclic group ".

As the “divalent nitrogen-containing heterocyclic group” in the “optionally substituted divalent nitrogen-containing heterocyclic group”, a nitrogen atom other than a carbon atom is used as an atom (ring atom) constituting a ring system. 5- to 8-membered nitrogen-containing heterocyclic group containing 1 to 3 (preferably a divalent 5- to 7-membered nitrogen-containing heterocyclic group composed of a carbon atom and one nitrogen atom) Is mentioned.

These “divalent nitrogen-containing heterocyclic groups” have an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which the substituent represented by R ² is bonded, and to form a 8-membered nitrogen-containing cyclic amide group "but as the substituent of the" divalent nitrogen-containing heterocyclic group "in such" two optionally substituted divalent nitrogen-containing heterocyclic group ", R ⁷ and R ² is bonded to each other to form an “optionally substituted divalent nitrogen-containing complex” And the same substituents as the “divalent nitrogen-containing heterocyclic group” in the “ring group” may have.

The “divalent nitrogen-containing heterocyclic group” formed by the substituent of X ¹ and R ² bonded to each other is, for example, a group represented by the formula

[In the formula, D represents an oxygen atom or a sulfur atom, n ′ represents 0 or 1, and m ′ represents 2 or 3. And the like.

In the above formula, m ′ is preferably 2 and n ′ is preferably 0.

As the above-mentioned "divalent nitrogen-containing heterocyclic group", 2-pyrrolidone-1,3-diyl is most preferred.

In the above formula, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group; An optionally substituted hydrocarbon group is preferred.

Examples of the “optionally substituted hydrocarbon group” represented by R ³ and R ⁴ include the same as the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ . Among them, optionally substituted — 4 lower alkyl groups and optionally substituted phenyl groups are preferred.

Examples of the “optionally substituted heterocyclic group” represented by R ³ and R ⁴ include the same as the aforementioned “optionally substituted heterocyclic group” represented by R ¹ .

Examples of the `` optionally substituted acyl group '' represented by R ³ and R ⁴ include the same as the above-mentioned `` optionally substituted acyl group '' represented by R ¹ above. A `` sulfonic acid-derived acyl group '', a `` carboxylic acid-derived acyl group '' as a substituent of the `` optionally substituted hydrocarbon group '' represented by R ¹ , or `` esterified And a good hydroxyl group.

The substituents that the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ³ and R ⁴ may have are, for example, (1) an optionally substituted amino group, (2) It may be an imidoyl group which may be substituted or (3) a nitrogen-containing bicyclic group which may be substituted.

Here, they are in as a substituent in the "optionally substituted amino group optionally substituted", "optionally substituted hydrocarbon group" represented by the R ¹ and "substitution as (1) And a substituent may be combined with a nitrogen atom to form a cyclic amino group.In such a case, the cyclic amino group includes For example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and a lower alkyl group at the 4-position (for example, C6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.) ), Ararukiru groups (e.g. benzyl, etc. C 7 ^ ₀ § aralkyl groups such as phenethyl), § Li Ichiru group (e.g. phenyl, 1_ naphthyl, 2-naphthyl C ₆ - _{1 ()} § Li Lumpur group) 3-8 membered or 1 Piperajiniru like have a like (good Mashiku are cited and cyclic Amino 5-6 membered), such cyclic amino group, the above was R ¹ It may have the same number of the same substituents as those in the “optionally substituted hydrocarbon group” shown.

Further, the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted hydrocarbon group-substituted amino group” may be replaced with an “optionally substituted diamino group” at the α-position. In the case of containing, the "optionally substituted amino group" as (1) forms an amino group substituted with the "optionally substituted imidoyl group" as (2) described later. Formula 1 N (R ") 1 C (R ') = NR"' [wherein, R "represents a hydrogen atom or an optionally substituted hydrocarbon group, and R"'represents a hydrogen atom, And R ′ represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group derived from sulfonic acid, a substituted or unsubstituted hydrocarbon group, or an optionally substituted hydrocarbon group. Optionally substituted amino group, optionally substituted mercapto group or substituted Or an optionally substituted hydroxyl group] are also included in the “optionally substituted amino group”. In the `` optionally substituted imidoyl group '', when R ′ represents a mercapto group or a hydroxyl group and R ″ ′ represents a hydrogen atom, the `` optionally substituted imidoyl group '' is It may represent a group represented by the formula: 1 C (-0) 1 NH ₂ or 1 C (= S) 1 NH ₂ . In the above formula, the “optionally substituted hydrocarbon group” represented by R ′ ″, R ′ and R ″ includes the “optionally substituted hydrocarbon group” represented by R ¹ described above. Examples of the “carboxylic acid-derived acyl group” represented by R ″ ′ and R ′ include the “optionally substituted hydrogen urine group” represented by R ¹ described above. Examples of the substituent that may be possessed include the same as the `` carboxylic acid-derived acyl group '', and the `` optionally substituted hydroxyl group '' represented by R ′ is represented by R ¹ described above. Examples of the substituent which the "optionally substituted hydrocarbon group" may have include the same as the "optionally substituted hydroxyl group", and the "substituted or substituted" represented by R ' as also an amino group ", the be" replacement represented by the R ¹ The same as the `` optionally substituted amino group '' as the substituent which the `` optional hydrocarbon group '' may have or the `` optionally substituted hydrocarbon group '' represented by R ¹ described above. Examples thereof include an amino group which may have 1 to 2 amino groups.

Examples of the “carboxylic acid-derived acyl group” represented by R ′ ″ include, for example, “carboxy” as a substituent which the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ may have The same as the “acid-derived acyl group” can be mentioned, but the “carboxylic acid-derived acyl group” represented by R ¹ is, for example, a group represented by the formula —COOR ′ ″ ″, wherein R ′ ′ ″ ′ is substituted Or a hydrocarbon group which may be esterified, such as a group represented by the following formula:

Examples of the “optionally substituted hydrocarbon group” represented by R ″ ′ include, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ described above.

Preferable examples of the "hydrocarbon group" in R '"'" optionally substituted hydrocarbon group "represented by, for example, ₆ alkyl, C ₂ _ ₆ alkenyl, C ₃ - ₆ consequent opening alkyl, C ₆ - ₁₀ Ariru, C ₆ - i. Aryl- _1-4 alkyl and the like. Examples of the substituent that the “hydrocarbon group” may have include, for example, the same as the substituents that the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ may have Similar numbers are included.

Examples of the group represented by the formula (1) COOR '"' include, among others, an alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycal 6) alkanoyloxy C- ₆ alkoxy-carbonyl group (eg, pivaloyloxymethoxycarponyl, 1- (acetoxy) ethoxycarbonyl, acetoxy tert-butoxycarpoel, etc.) _ ₆ Alkoxy mono-lponyloxy-Alkoxy mono-lponyl group (eg, ethoxycarponyloxy methoxycarbonyl, etc.), 5-^- ₄ Alkyl-2-oxo-l-oxo-l-oxylene-14-yl-Alkoxy mono-lponyl group (eg, 5-methyl-2-oxodoxolen-4-ylmethoxycarbonyl). '

As "is an amino group optionally substituted", more specifically, for example amino group (preferably, phenyl) C ₆ _ ₁₀ § Li Ichiru group further optionally substituted mode no or G. In such lower (C Medicine ₆₎ alkylamino group (e.g. Mechiruamino, Echirua amino, benzyl methyl § amino, Jimechiruamino, Jechiruamino, diisobutyl amino, diisopropyl amine. Roh, N- Echiru t- Puchiruamino, Benjirumechi Ruamino etc.), formula _N (R " 1) C (R ') = NR "' [wherein, R" represents a hydrogen atom or a hydrocarbon group which may be substituted (preferably, a hydrogen atom or a lower (C ^) alkyl group); '' Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, or an carboxylic acid-derived acyl group (preferably, a hydrogen atom or a carboxylic acid-derived acyl group) R ′ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxyl group (preferably, hydrogen atom, a lower ((^ _ ₆₎ alkyl group, an amino group or a mono- or di- lower (C ^) alkyl amino group),] a group represented by (e.g., Guanijino group, formimidoyl group, § Se And a 5- to 6-membered cyclic amino group (eg, piperidino group).

Examples of the “optionally substituted imidoyl group” as (2) include, for example, a group represented by the formula: C (R ′) = NR ″ ′ [wherein the symbols have the same meanings as described above], and the like. Are listed.

Here, R ′ represents an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino, ethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.) In this case, the “optionally substituted imidoyl group” as (2) forms an optionally substituted amidino group. The tool body Examples of such optionally substituted amidino group, one or two lower ((: ^ alkyl group, a lower ((^ _ ₆₎ Arukanoi group, optionally substituted with like Benzoiru group Good amidino groups (eg, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-jetylamidino, N-methyl-N'-getylamidino, N —Formylamidino, N-acetylamidino, etc.).

In the above formula, as Konomarei examples of R '''is hydrogen, lower alkyl (e.g. methylation, Echiru, propyl, isopropyl, heptyl, C WINCH ₆ alkyl group isobutyl), Ashiru groups (e.g. formyl, Acetyl, propionyl, pivaloyl, etc.

- ₆ Arukanoiru; Benzoiru; for example, methoxycarbonyl, ethoxycarbonyl Cal Poni Le, propoxycarbonyl, iso Boki deer Lupo sulfonyl, butoxide deer Lupo sulfonyl, isobutoxide such deer Lupo sulfonyl _<8 alkoxycarbonyl and the like; for example, Benjiruoki aryloxycarbonyl, c ₇ such as Hue phenethyl Ruo alkoxycarbonyl _. Ararukiruokishi force Lupo sulfonyl, etc.), a hydroxyl group can be mentioned, as preferable examples of R 'are hydrogen, lower alkyl groups (e.g. methyl, Echiru, propyl, isopropyl, heptyl, isobutyl, etc. (: Preparative ₆ alkyl group), An optionally substituted amino group (eg, one or two identical or different lower alkyl groups (eg, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (eg, formyl, Amino group, hydrazino group, 5- or 6-membered cyclic amino group which may be substituted with C ₆ alkanol such as acetyl, propionyl, pivaloyl, benzoyl, etc.

(E.g., piperidino, thiomorpholino, morpholino, piperazino, etc.), etc.), a hydroxyl group, a lower alkoxy group (e.g. methoxy, ethoxy, Purobokishi, isoproterenol epoxy, butoxy, isobutoxy, etc. (^ _ ₆ alkoxy group), a mercapto group, lower alkylthio group (e.g., methylthio, Echiruchio, propylthio, isopropylthio Chio, Puchiruchio, C _ _e alkylthio group such Isopuchiruchio) and the like. in the above formulas, is preferably hydrogen.

In the above formula, R ′ is preferably hydrogen, a lower alkyl group or an optionally substituted amino group, and particularly preferably a lower alkyl group or an optionally substituted amino group. An amino group is preferable, and an amino group which may be substituted (preferably, an amino group which may be substituted with C ₄ alkyl) is particularly preferable.

As the “nitrogen-containing heterocyclic group” in the “optionally substituted nitrogen-containing heterocyclic group” as (3), at least a nitrogen atom other than a carbon atom as an atom (ring atom) constituting a ring system is used. An aromatic nitrogen-containing heterocyclic group which may contain 1 (preferably 1 to 3) and may further contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom; And an aromatic nitrogen-containing heterocyclic group (aliphatic heterocyclic group).

Examples of the “aromatic nitrogen-containing heterocyclic group” include, for example, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazolyl, 1H-imidazolyl-4-yl, etc.) , Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3 , 4-Asiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-1, liazolyl 1-yl, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl And aromatic monocyclic nitrogen-containing heterocyclic groups such as pyridyl (2-, 3- or 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and N-oxides thereof. 6 member An aromatic monocyclic nitrogen-containing heterocyclic group is preferable, and imidazolyl and pyridyl are particularly preferable.

Examples of the “non-aromatic nitrogen-containing heterocyclic group” include partially reduced forms of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidel, etc.), as well as azetidinyl, pyrrolidinyl, piperidyl ( 2-, 3- or 4-pibelidyl), morpholinyl, thiomorpholinyl, piperazinyl (such as 1-piperazinyl), homopiperazinyl, and the like. Among them, a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group is preferable.

As the substituent for the “nitrogen-containing heterocyclic group”, the same substituents as those described above for the “heterocyclic group” for R ¹ can be used. Further, the nitrogen atom constituting the nitrogen-containing heterocyclic group may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” may be bonded to each other to form a ring (eg, a benzene ring or the like). As the “optionally substituted nitrogen-containing heterocyclic group” as (3), an optionally substituted nitrogen-containing heterocyclic group and the like are preferable, and especially an optionally substituted aromatic nitrogen-containing heterocyclic group. Are preferred.

In the above formula, R ³ and R ⁴ are preferably bonded to each other to form a ring together with adjacent carbon atoms, and such a cyclic group may be substituted, and is preferably a cyclic group having a substituent. . As the substituent, those similar to the aforementioned substituents of R ³ and R ⁴ are used.

Examples of such a “cyclic group” include a monovalent or divalent cyclic hydrocarbon group or a heterocyclic group (preferably a heterocyclic group).

The “hydrocarbon group” as the “cyclic group” includes a saturated or unsaturated cyclic monovalent or divalent hydrocarbon group.

Examples of the cyclic saturated hydrocarbon group, a cycloalkyl group (e.g., consequent opening, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, Shikurookuchiru, C ₃ _ ₉ cycloalkyl such cyclononyl, preferably, C ₅ - ₇ cycloalkyl, more preferably a hexyl etc.) and the like cyclohexane.

Here, unsaturated cyclic hydrocarbon groups include cycloalkenyl groups (for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-1-ynole, 3- cyclohexene - 1 one I le, 1-cyclobutene one 1-I le, -1-cyclopentene one 1-I le, etc. C ₃ - ₆ cycloalkenyl group, etc.), Shikuroa Rukajieniru group (e.g., 2, 4-Shikuropen evening Jen one 1-I le, 2, 4 Shiku port to Kisajen 1 I le, 2, 5-C ₄ such Kisajen _ 1 Iru cyclohexane - ₆ cyclo alkadienyl group), Ariru group (e.g., phenyl And aryl groups such as naphthyl, and preferably phenyl).

Here, as the “saturated or unsaturated cyclic divalent hydrocarbon group”, the aforementioned “saturated or unsaturated cyclic hydrocarbon group” is converted from any carbon atom having a bond to water. A group formed by removing one elementary atom.

The “heterocyclic group” as the “cyclic group” includes, as atoms (ring atoms) constituting a ring system, one to three heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. (Preferably 1 or 2) at least 1 (preferably not 1) And more preferably 1 or 2) and a 5- or 6-membered divalent saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).

As the “non-aromatic heterocyclic group”, for example, a 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, etc. And a heterocyclic group (aliphatic heterocyclic group).

Examples of the “divalent heterocyclic group” as the “cyclic group” include a group formed by adding one bond to any atom having the above-mentioned “non-aromatic heterocyclic group”. Is mentioned.

As the “cyclic group”, piperidine which may be substituted is preferable.

In the above formula,

R ^{3 3}

—— CH = C

\ Four \. Four

R and ^κ

The groups represented by are each represented by the formula

— Υ— X— Ζ and = Υ—

[In the formula, X ² represents a bond, an optionally substituted alkylene group or an optionally substituted diamino group (preferably a bond), and γ represents an optionally substituted chain hydrocarbon. And Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a nitrogen-containing heterocyclic group which may be substituted. Or a group represented by the formula:

[In the formula, X ² represents a bond, an optionally substituted alkylene group or an optionally substituted diamino group (preferably a bond), A represents a cyclic group which may be substituted, Z represents (1) an amino group which may be substituted, (2) an imidoyl group which may be substituted, or (3) a nitrogen-containing heterocyclic group which may be substituted. ] May form a group represented by

In the above formula, as the “chain hydrocarbon group” in the “optionally substituted chain hydrocarbon group” represented by Y, the “optionally substituted hydrocarbon group” represented by R ¹ Or a divalent or branched chain formed by removing one or two hydrogen atoms from one carbon atom in the "linear or branched (preferably linear) aliphatic hydrocarbon group" And more specifically, an optionally substituted alkylene group (e.g., the same as the “optionally substituted alkylene group” represented by X ¹ and X ² described below) ), which may have a substituent on any carbon atom, the formula _{_{= CH - (CH 2) k}} -. wherein, k, is an integer of 0-5] a group represented by the Is mentioned.

As the substituent which the “chain hydrocarbon group” as the “optionally substituted chain hydrocarbon group” represented by Y may have, an optionally substituted lower alkyl group A lower alkyl group such as the same as the above-mentioned “optionally substituted lower alkyl group” as a substituent of the “optionally substituted divalent nitrogen-containing heterocyclic group” For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, alkyl such as tert-butyl, etc.)]), an optionally substituted rubamoyl group, [the above-mentioned “substituted And the like as the “optionally substituted carbamoyl group” as a substituent of the “optionally divalent nitrogen-containing heterocyclic group”, preferably a carbamoyl group, N-mono-lower ((^ _ ₆₎ alkyl force Luba Yl group, N, N-di-lower (C Preparative ₆₎ alkyl force Rubamoiru group], Shiano group, a halogen atom (e.g. fluorine, chlorine, bromine, iodine), a hydroxyl group, a carboxyl group which may be esterified ( Examples of the substituent of the “optionally substituted hydrocarbon group” represented by R ¹ include the same as the “optionally esterified carboxy group”). May have 1 to 3 substituents at substitutable positions.

Further, the “chain hydrocarbon group” in the “optionally substituted chain hydrocarbon group” (preferably an optionally substituted C 6 alkylene group) represented by Y is any methylene group is replaced by Okiso group, carbonylation Le group may form a, specific examples thereof, one CH _₂ - CH ₂ - wherein the methylene group is substituted with Okiso group A group represented by one (C = 0) one CH ₂ — and the like.

In the above formula, as the substituent for the “optionally substituted cyclic group” represented by A, the same substituents as those for the aforementioned “divalent nitrogen-containing heterocyclic group” can be used.

Examples of the “cyclic group” of the “optionally substituted cyclic group” represented by A include a divalent or trivalent cyclic hydrocarbon group or a heterocyclic group (preferably a heterocyclic group).

Examples of the “hydrocarbon group” as the “cyclic group” of the “optionally substituted cyclic group” represented by A include a saturated or unsaturated cyclic divalent or trivalent hydrocarbon group. Examples of the cyclic divalent saturated hydrocarbon group, a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Shikurohepu chill, Shikurookuchiru, C _3, such as cyclononyl - ₉ cycloalkyl, preferably ,

C ₅ - ₇ cycloalkyl, more preferably any position hexyl etc.) and the like cyclohexane (good Mashiku is different carbon atoms, more preferably, to remove one of the most distant position hydrogen atom of the carbon atoms) of group (e.g., c ₅ _ ₇ cycloalkylene, preferably 1, such as xylene to 4-cyclopropyl) may be mentioned.

Here, the unsaturated cyclic divalent hydrocarbon group is a cycloalkenyl group (for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-1). one I le, 3-cyclopropyl hexene one 1-I le, 1 Shikurobuten one 1-I le, etc. C ₃ _ ₆ cycloalkenyl groups such as 1-cyclopentene one 1-I le), cycloalkadienyl groups (e.g. C4-16 cycloalkadienyl groups such as, 2,4-cyclohexene. 1-yl, 2,4-cyclohexadiene 1-yl, 2,5-cyclohexadiene-1-yl etc.), § Li Ichiru group (e.g., phenyl, C _6, such as naphthyl Le - like _{1 0} Ariru group, preferably, any position (preferably such as phenyl), different carbon atoms, more preferably, farthest Removed one hydrogen atom Among them, phenylene are preferred, especially, 1, 4-phenylene is preferred.

As the "divalent hydrocarbon group", C ₅ _ ₇ cycloalkylene (preferably xylene to 1, 4 Shikuro), phenylene '(preferably, 1, 4 one phenylene, etc.), etc. Is preferred.

Here, the “saturated or unsaturated cyclic trivalent hydrocarbon group” is as described above. Examples of the group include a “saturated or unsaturated cyclic divalent hydrocarbon group” formed by removing one hydrogen atom from any carbon atom having a bond.

As the “divalent heterocyclic group” as the “cyclic group” of the “optionally substituted cyclic group” represented by A, as the atoms (ring atoms) constituting the ring system, in addition to carbon atoms, oxygen 5 to 6 members containing at least 1 (preferably 1 to 3, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms, sulfur atoms and nitrogen atoms And a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).

Examples of the “divalent aromatic heterocyclic group” include, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3 5-membered aromatic heterocycles such as, 4-thiadiazole, 1,2,3-triazol, 1,2,4-triazol, and, for example, pyridine, pyridazine, pyrimidine, 1,2 ,,, It is obtained by removing two hydrogen atoms from two different ring atoms (at least one of which is a carbon atom) such as a 6-membered aromatic heterocycle such as 4-triazine and 1,3,5-triazine. And other divalent groups. '

Examples of the “divalent non-aromatic heterocyclic group” include 5- to 6-membered saturated or unsaturated (preferably saturated) groups such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholine, thiomorpholine, and piperazin. Divalent groups obtained by removing two hydrogen atoms from two different ring atoms (at least one of which is a carbon atom) such as a non-aromatic heterocyclic group (aliphatic heterocyclic group) And the like.

As the “trivalent heterocyclic group” as the “cyclic group” of the “optionally substituted cyclic group” represented by A, the above “divalent non-aromatic heterocyclic group” has a bond Examples include a group formed by adding one bond to a carbon atom.

A is preferably phenylene which may be substituted, piperidine which may be substituted and the like.

In the above formula, Z is (1) an optionally substituted amino group, (2) And (3) a nitrogen-containing heterocyclic group which may be substituted.

Examples of the substituent in the “optionally substituted amino group” represented by Z include the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ¹ described above. But the two substituents may combine with the nitrogen atom to form a cyclic amino group. In such a case, examples of the cyclic amino group include 1-azetidinyl, Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and a lower alkyl group at the 4-position (eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc. (: to ₆ alkyl group, etc.), aralkyl group (e.g. benzyl, C ₇ such as phenethyl - like _{1 D} Ararukiru group), Ariru group (e.g. phenyl, 1 one naphthyl, C ₆ 2-naphthyl and the like -. E § Lumpur group) 3-8 membered or 1 Piperajiniru like have a like (rather preferably is mentioned and cyclic Amino the 5-6 membered), such cyclic amino group, the above was R ¹ It may have the same number of the same substituents as those in the “optionally substituted hydrocarbon group” shown.

In addition, the `` optionally substituted hydrocarbon group '' as a substituent in the `` amino group substituted by an optionally substituted hydrocarbon group '' represented by Z is `` When it contains a `` imino group '', the `` optionally substituted amino group '' represented by Z forms an amino group substituted by the `` optionally substituted imidoyl group '' represented by Z described below. Is, for example, a compound represented by the formula: N (R '') — C (R ') = N-R''' wherein R '' represents a hydrogen atom or an optionally substituted hydrocarbon group; '' Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group, or an acyl group derived from a carboxylic acid, and R '' represents a hydrogen atom, an optionally substituted hydrocarbon group. An carboxylic acid-derived acyl group, an optionally substituted amino group, an optionally substituted mel group A capto group or an optionally substituted hydroxyl group] are also included in the “optionally substituted amino group” represented by Z. Further, in the “optionally substituted imidoyl group”, when R ′ represents a mercapto group or a hydroxyl group and R ′ ″ ′ represents a hydrogen, the “optionally substituted imidoyl group” is Each may represent a group represented by the formula —C (= 0) —NH ₂ or —C (= S) —NH ₂ . In the above formula, as the “optionally substituted hydrocarbon group” represented by R ′ ″ ′ R ′ and R ′ ″, the “optionally substituted hydrocarbon group” represented by the aforementioned R ¹ and the like can be mentioned, R ',' and as a 'Ashiru group derived from a carboxylic acid "represented by R' is represented by R ¹ described above" optionally substituted hydrocarbon group "is Yes like it can be mentioned as "Ashiru group derived from a carboxylic acid" as the substituent which may have been, as the "optionally substituted hydroxy group" represented by R 'is represented by the R ¹ " As the substituent which the (optionally substituted hydrocarbon group) may have, the same as the `` optionally substituted hydroxyl group '' may be mentioned, and the `` optionally substituted hydroxyl group '' represented by R ′ the amino group ", Ru is represented by the R ¹ 'substituted Good carbide "replacement is a well an amino group" optionally may be "replacement indicated by like or R ¹ mentioned above hydrocarbon group as a hydrogen group" optionally has substituent And an amino group which may have 12 or more.

As the `` carboxylic acid-derived acyl group '' represented by R ′ ″ ′, for example, as the substituent which the aforementioned `` optionally substituted hydrocarbon group '' represented by R ¹ may have The same ones as the “carboxylic acid-derived acyl group” can be mentioned, but the “carboxylic acid-derived acyl group” represented by R ¹ is, for example, a group represented by the formula COOR ′ ″ ″ wherein R ′ ″ ″ is substituted And a carboxyl group which may be esterified, such as a group represented by the following formula:

As the “optionally substituted hydrocarbon group” represented by R ′ ″ ′, for example, the same as the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ can be mentioned.

Preferable examples of the "hydrocarbon group" in R '"'" optionally substituted hydrocarbon group "represented by, for example, alkyl, C ₂ _ ₆ alkenyl, C _{3 6} consequent opening alkyl, C 6 ^ . Ariru, C _{6 1Q} Ariru - Ji such as E alkyl Ru mentioned. Examples of the substituent that the “hydrocarbon group” may have include, for example, the same as the substituents that the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ may have Similar numbers are included. '

As the group represented by the formula-<〇0 '''', Poniru group (e.g., methoxycarbonyl, ethoxycarbonyl Cal Poni le, etc. isopropoxyphenyl Cal Poniru), ^ - ₆ alk Noi Ruo Kishi alkoxy Ichiriki Ruponiru group (e.g., pivaloyl I Ruo carboxymethyl methoxy Cal Poni le, 1 i (Asetokishi) ethoxycarbonyl, Asetokishi tert-butoxycarbonyl, etc.), alkoxy-carbonyl- _1-6- alkoxycarbonyl group (eg, ethoxycarbonyloxymethoxycarbonyl, etc.), 5-alkyl-1-oxo-dioxolene-4-yl-6-alkoxy —Capillonyl groups (eg, 5-methyl-2-oxo-dioxo-l-41-methoxycarbonyl) and the like.

More specifically, the “optionally substituted amino group” represented by Z may be, for example, an amino group, a C 6 ^ 0 aryl group (preferably phenyl), etc. Good mono- or di-lower (peto ₆ ) alkylamino groups (eg methylamino, ethylamino, benzylmethylamino, dimethylamino, getylamino, diisobutylamino, diisopropylamino, N-ethyl-1-butylamino, benzylmethylamino) Mino, etc.), the formula: N (R, ')-C (R,) = N-R'", wherein R"'is a hydrogen atom or a hydrocarbon group which may be substituted (preferably, hydrogen Represents an atom or a lower (C ^ e) alkyl group), and R '"" represents a hydrogen atom, an optionally substituted hydroxyl group, and an optionally substituted hydrocarbon group represents an carboxylic acid-derived acyl group ( Preferably, hydrogen And R ′ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted mercapto group. An optionally substituted hydroxyl group (preferably a hydrogen atom, lower ((: alkyl group, amino group or mono- or di-lower (C ^

₆ ) alkylamino group] (for example, guanidino group, formimidoylamino group, acetimidoylamino group, etc.), 5- to 6-membered cyclic amino group (for example, piperidino group, etc.) Are used.

Examples of the “optionally substituted imidoyl group” represented by Z include, for example, a compound represented by the formula: C (R ′) = N—R ′, “wherein the symbols have the same meanings as described above. And the like.

Here, R ′ may be an optionally substituted amino group (preferably amino, methylamino, ethylamino, propylamino, dimethylamino, acetylamino, In the case of hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.), the “optionally substituted imidoyl group” represented by Z forms an optionally substituted amidino group. Specific examples of such an amidino group which may be substituted include one or two lower (C- ₆ ) alkyl groups, lower (C- ₆ ) alkanol groups, and benzoyl groups. Good amidino groups' (eg, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-getylamidino, N-methyl-N'-getylamidino, N_ Formylamidino, N-acetylamidino, etc.).

In the above formula, preferred examples of R '''is hydrogen, lower alkyl (e.g. methylation, Echiru, propyl, isopropyl, butyl, C physician ₆ alkyl le groups isobutyl), Ashiru groups (e.g. formyl, Asechiru , Propionyl, vivaloyl, etc.

- 6 Arukanoiru; Benzoiru; e.g. methoxy Cal Poni Le, ethoxycarbonyl, cycloalkenyl, propoxy force Ruponiru, isopropoxy force Ruponiru, butoxycarbonyl, C _2-8 alkoxycarbonyl, such as I Su Wu Toki deer Lupo sulfonyl and the like; for example, benzyl O alkoxycarbonyl, Fuenechiruo C ₇ _ _{1 Q} aralkyloxyl such as xycarponyl, etc.), a hydroxyl group and the like. Preferred examples of R ′ are hydrogen, lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.). ₆ alkyl groups), an optionally substituted amino group (eg, 1 to 2 identical or different lower alkyl groups (eg, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or an acyl group (For example, formyl , Acetyl, propionyl, pivaloyl, etc. (^ -6 alkanol, benzoyl, etc.) optionally substituted amino group, hydrazino group, 5- to 6-membered cyclic amino group (for example, piperidino, thiomorpholino, morpholino, piperazino) etc.), etc.), a hydroxyl group, a lower alkoxy group (e.g. methoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, C ^ isobutoxy, etc. - ₆ alkoxy group), mercapto bets, lower alkylthio (e.g. methylthio, Echiruchio, propylthio, I Sopuropiruchio , Puchiruchio, (^ _ ₆ alkylthio group) such as Isopuchiruchio and the like.

In the above formula, as R ′ ″ ′, hydrogen is preferable. ' In the above formula, R ′ is preferably hydrogen, a lower alkyl group or an amino group which may be substituted, and among them, a lower alkyl group or an amino group which may be substituted is preferable. An amino group (preferably an amino optionally substituted with C ₄ alkyl) is preferred.

As the “nitrogen-containing heterocyclic group” in the “optionally substituted nitrogen-containing heterocyclic group” represented by Z, at least one nitrogen atom other than a carbon atom as an atom (ring atom) constituting a ring system is used. (Preferably 1 to 3) aromatic nitrogen-containing cyclic groups which may further contain 1 to 3 heteroatoms selected from oxygen atoms and sulfur atoms, and saturated or unsaturated non-aromatics Group-containing nitrogen-containing heterocyclic group (aliphatic heterocyclic group).

Examples of the “aromatic nitrogen-containing heterocyclic group” include, for example, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazole 111-yl, 1H-imidazo-l 4-yl, etc.), pyrazolyl, 1 , 2,3-oxosaziazolyl, 1,2,4-oxodiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-111, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl), pyridazinyl, pyri.midinyl, pyragel, triazinyl, and other aromatic monocyclic nitrogen-containing heterocyclic groups and N-oxo derivatives thereof, among which 5 to 6 members are preferred. Lay preferred aromatic monocyclic nitrogen-containing heterocyclic group, among others, imidazolyl, etc. pyridyl are preferred.

Examples of the “non-aromatic nitrogen-containing heterocyclic group” include partially reduced forms of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidel, etc.), as well as, for example, azetidinyl, Mouth V-dinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl, etc.), homopiperazinyl, etc., among which 5- to 6-membered non-aromatics Monocyclic nitrogen-containing heterocyclic groups are preferred.

As the substituent for the “nitrogen-containing heterocyclic group” represented by Z, those similar to the substituents for the “heterocyclic group” represented by R ¹ described above are used. Also forms a nitrogen-containing heterocyclic group Nitrogen atoms may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” represented by Z may combine with each other to form a ring (eg, a benzene ring or the like).

Z is preferably a nitrogen-containing heterocyclic group which may be substituted, and particularly preferably an aromatic nitrogen-containing heterocyclic group which may be substituted.

In the above formula, the `` optionally substituted hydrocarbon group '' represented by R ⁵ or R ⁵ ′ is the same as the `` optionally substituted hydrocarbon group '' represented by R ¹ described above. R ⁵ is preferably unsubstituted at the α-position, and a group represented by R ⁵ ′ —CH ² — [R ⁵ ′ is a hydrogen atom or an optionally substituted hydrocarbon group That is, it is preferably a group formed by adding a methylene group to R ⁵ ′. The R ^5, optionally substituted lower (Ji alkyl group, an optionally substituted lower (c ₂ - ₄₎ an alkenyl group is preferable, also optionally substituted lower (C 4) alkyl group such as There further preferred R ⁵ 'is a hydrogen atom, substituted There may lower even.. (^ - ₄₎ alkyl group, an optionally substituted lower (C ₂ - ₄₎ such as an alkenyl group are preferable ,, More preferred are a hydrogen atom and an optionally substituted lower (C ^ ₄ ) alkyl group.

“Optionally substituted hydrocarbon group”, “optionally substituted lower ((: ₄ ) alkyl group”) and “optionally substituted lower (C ₂ _) represented by R ⁵ or R ⁵ ′ ₄ ) The substituent which the “alkenyl group” may have is a substituent which may be possessed by the “hydrocarbon group” in the “optionally substituted hydrocarbon group” for R ¹ described above. The same groups as the above groups can be mentioned, and among them, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally esterified carboxyl group and the like are preferably used.

In the above formula, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and among them, an optionally substituted hydrocarbon group is preferable.

As the “optionally substituted hydrocarbon group” for R ⁶ , the same as the aforementioned “optionally substituted hydrocarbon group” for R ¹ can be mentioned. atom or C ₂ - ₄ alkenyl which may be Ariru substituted with (. good Mashiku is phenyl, 1 one-naphthyl, 2-naphthyl and the like ₆ _ ₁₄ Ariru group) are preferable. · The `` optionally substituted heterocyclic group '' represented by R ^{6 includes the same} as the `` optionally substituted heterocyclic group '' represented by R ¹ described above. And a heterocyclic group which may be substituted with a halogen atom (preferably a benzofuranyl group, a benzopyranyl group or the like, and more preferably a benzopyranyl group). In the above formula, the `` optionally substituted hydrocarbon group '' represented by R ^{7 includes the same} as the `` optionally substituted hydrocarbon group '' represented by R ¹ described above. , which may be inter alia substituted (^ _ ₄ lower alkyl group is preferred in the formula, the "protecting group of the Amino group" represented by R ^8, for example, formyl group, C u alkyl -. power Ruponiru group (e.g. Asechiru, Echirukaruponiru etc.), C u alkyl chromatography alkylsulfonyl group, C ^ 6 alkoxy -. group (e.g., methoxycarbonyl, butoxycarbonyl, tert- butyl O butoxycarbonyl group, etc.), 0 ₆ _ Ararukiruokishi carbonyl group (e.g., base Nji Ruo alkoxycarbonyl group), C ₂ _ 6 alkenyl over carbonitrile el groups (e.g. § Lil O alkoxycarbonyl, etc.), C ₆ - _{1 0} § Li one Rukaruponiru group ( In example phenylene Rukaruponiru, naphthylcarbonyl), C ₆ _ _{1 0} § reel sulfonyl group (e.g., phenylalanine sulfonyl, naphthylsulfonyl, etc.), C

₇ - _{1 Q} Ararukiru Ichiriki Ruponiru group (e.g. downy Njirukaruponiru etc.), C bets ₆ alkyl Le group (e.g. methyl, etc.), C ₇ _ _{1 8} 7 aralkyl group (e.g. benzyl, Jifuenirume -. Chill, trityl, full Orenylmethyloxycarbonyl) and the like. These groups may have one to three substituents such as a halogen atom (eg, fluorine, chlorine, bromine, etc.) and a nitro group at a substitutable position.

The “protecting group for an amino group” represented by R ⁸ is preferably a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an aryloxycarbonyl group, a fluorenylmethyloxycarbonyl group, a C ₆ alkyloxy group. A carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.) or an aralkyl group (eg, benzyl, diphenylmethyl, trityl group, etc.), more preferably a benzyloxycarbonyl group, an aryloxycarbyl group, Aralkyl tombs (eg, benzyl, diphenylmethyl, trityl, etc.), among which benzyloxycarbonyl and benzyl groups are preferred.

In the above formula, `` optionally substituted alkylene group '' represented by X ¹ and X ² Definitive as the "alkylene group", for example, methylene, ethylene, propylene, blanking styrene, straight-chain lower (C ^ ₆₎ alkylene and the like, such as pentylene, among which methylene, ethylene, etc. (^ _ ₄ alkylene or the like are preferable Examples of the substituent of the “alkylene group” include an optionally substituted lower alkyl group [optionally substituted as a substituent of the “optionally substituted divalent nitrogen-containing heterocyclic group”. Preferred are lower alkyl groups (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.). ₆ alkyl, etc.)], substituted optionally may force be Rubamoiru group, as a substituent of the [pre-marked with "two optionally substituted divalent nitrogen-containing heterocyclic group", " Such conversion is good force Rubamoiru group optionally "and the like, preferably, the force Rubamoi Le group, N- mono-lower (() alkyl force Rubamoiru group, N, N- di-lower (Ji DOO ₆₎ alkyl force Rubamoiru Group, etc.), a cyano group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, a carboxyl group which may be esterified (the above-mentioned optionally substituted hydrocarbon represented by R ¹ And the like. As the substituent for the group, the same as the “optionally esterified alkoxyl group” can be mentioned), and one or three of these optional substituents are substituted at substitutable positions. It may be.

The “optionally substituted imino group” represented by X ¹ and X ² is represented, for example, by the formula —N (R ⁹ ) —wherein R ⁹ represents a hydrogen atom or a substituent. R ⁹ is preferably a hydrogen atom, a hydrocarbon group which may be substituted, or the like.

In the above formula, as the “optionally substituted hydrocarbon group” represented by R ⁹ , the same as the “optionally substituted hydrocarbon group” represented by R ¹ can be mentioned. In the above formula, X ¹ is preferably methylene, and X ² is preferably a bond. In the above formula, D represents an oxygen atom or a sulfur atom (preferably, an oxygen atom). Each of the above-mentioned production methods and the starting materials used in each of the production methods are described below.For example, the compound represented by the formula (I) or a salt thereof may be referred to as “compound I”. The compound represented by the formula (II) or a salt thereof and the compound represented by the formula (IV) or a salt thereof may be referred to as “compounds II and IV”. The durazone derivative (compound I, VI I) is reacted with a polanamine complex, In the method for producing a derivative (compound I, VI II), the “poranamine complex having a melting point of 25 ° C. or more” used has a melting point of 25 ° C. or more (preferably, a melting point of 30 ° C. or more) Polamine complex in the solid state at room temperature (15 to 25 ° C), such as porane · ( _4- alkylamine complex, porane · dimethylamine complex such as porane · tributylamine complex, etc. Polan di C _w alkylamine complexes etc., Pollan 'trimethylamine Pollen tri alkylamine emissions complexes such as complexes, Pollan-Echirenjiamin complex, borane-dimethyl § amino pyridine complex, Pollan-4 one-methylmorpholine complex, Pollan-4 monounsaturated Enyl morpholine complexes, porane 2,6-lutidine complexes, among which porane dimethylamine complex, porane '' A trimethylamine complex and a porane tributylamine complex are preferably used, and these polamine amine complexes may be dispersed or dissolved in the reaction solvent.

The hydrazine derivative (compound I, VI I) or the hydrazine derivative (compound Π) is reacted with a “combination of a borohydride complex compound and a carboxylic acid” or a “triacyloxyborohydride complex compound” to form a hydrazine derivative (compound Γ Γ). , ΧΙ ') include borohydride complex compounds used in the method for producing borohydride, metal borohydride, alkali metal borohydride, alkaline earth metal borohydride, quaternary ammonium borohydride For example, sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, barium borohydride, etc., as well as sodium borohydride and alkali (earth) metal salts

(For example, lithium chloride and calcium chloride). As the "acid", for example, Compound I or a substituent II R ⁵ '-C Η ₂ - are those capable of producing the compound [pi gamma by introducing and intended reaction can proceed Any one may be used as long as it is present, for example, a carboxylic acid represented by the formula R ⁵ ′ —CO OH (where R ⁵ ′ represents a hydrogen atom or a hydrocarbon group which may be substituted) However, a preferable example is an aliphatic carboxylic acid which may be substituted.

(For example, alkyl-carboxylic acids such as formic acid, acetic acid, and propionic acid, C ₆ ^. Halogenated C. alkyl alkyl carboxylic acids such as cycloalkyl monoacetic acid, chloroacetic acid, bromoacetic acid, and trifluoroacetic acid. , Halogenated C . Cycloalkyl Ichiriki carboxylic acid, wherein single amino acid wherein the nitrogen atom is protected, such as benzyl O alkoxycarbonyl Dali Singh [, as the protective group for the nitrogen atom, the "protecting group for the nitrogen atom" represented by R ⁸ will be described later And the like)), and optionally substituted aromatic carboxylic acids (eg, benzoic acid, picolinic acid, furan carboxylic acid, etc.). Among them, aliphatic carboxylic acids which may be substituted Is preferably used. Here, for example, when formic acid and acetic acid are used as the carboxylic acid, the substituent R ⁵ ′ in the resulting compound represents methyl and ethyl, respectively.

As the “triacyloxyborohydride complex compound”, a compound obtained by reacting the above borohydride complex compound with 3 equivalents of a carboxylic acid (for example, the same as the above carboxylic acid, preferably an aliphatic carboxylic acid, etc.) Examples thereof include sodium triformyloxyborohydride, sodium triacetoxyborohydride, sodium tribenzoyloxyborohydride, and the like. Here, for example, when sodium triformyloxyborohydride and sodium triacetoxyborohydride are used, in the resulting compound は ′, the substituent R ⁵ ′ represents methyl and ethyl, respectively.

When a “combination of a borohydride complex compound and a carboxylic acid” is used as a reducing agent, the borohydride complex compound used and the carboxylic acid react in the reaction system, and a part or all of them react. A “triacyloxyborohydride complex compound” may be formed.

A hydrazine derivative (compounds IV, IV ', XI II, XIV) and a carbonyl compound (compound V) are reacted in the presence of a "reducing agent" to form a hydrazine derivative (compounds III, Ι Ι', XI, XI ', XI I , XI I '), the "reducing agent" used is the above-mentioned "poranamine complex having a melting point of 25 ° C or more", "combination of borohydride complex compound and carboxylic acid" or "triacyroxy acid". Preferably used are "borohydride complex compounds", such as lithium aluminum hydride, trimethoxylithium aluminum hydride, tree tert-butoxylithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, hydrogen Sodium borohydride, sodium trimethoxyborohydride, triacetoxyborohydride Metal hydride compounds such as lithium, lithium borohydride and lithium triethylborohydride are also preferably used. Further, a catalytic reduction method using a catalyst may be used. Examples of such a catalyst include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, and palladium barium sulfate; platinum catalysts such as platinum oxide, platinum carbon, and platinum black; rhodium catalysts such as rhodium carbon and rhodium alumina; ruthenium oxide The reaction is carried out in a hydrogen atmosphere using a ruthenium catalyst such as ruthenium carbon or Raney nickel.

The method for deprotection of the `` protecting group for an amino group '' represented by R ⁸ is a method known per se or a method analogous thereto, for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate or the like Are used.

A preferred method of “deprotection” is a reduction method which can be performed simultaneously with the reduction of the double bond in the ring of compound VI, VIII, XI, ΧΓ. A preferable reduction method is a method of reacting hydrogen or a hydrogen donor (formic acid and a salt thereof, cyclohexene, sodium hypophosphite, saturated hydrazine, etc.) in the presence of a catalyst. The aforementioned “reducing agent” catalyst is used. Particularly preferred is a method in which formic acid or a salt thereof is used as a hydrogen donor. This method does not require a special reactor, and is industrially advantageous.

Each of the above manufacturing methods will be described below.

[Production method 1]

In a method for producing a hydrazine derivative (compounds II and VI II) by reacting a hydrazone derivative (a compound I, VI I) with a polanamine complex, a solvent used is not particularly limited as long as the reaction is not affected. No restrictions.

For example, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, pentane and heptane, esters such as ethyl acetate and butyl acetate, getyl ether, diisopropyl ether and tributyl methyl ester Ethers such as ter, tetrahydrofuran, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol Alcohol, such as phenol, 2-methyl-1-propanol, 类, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν- Examples include amides such as methylpiperidone, dimethylsulfoxide, hexamethylphosphoric amide, dimethylimidazolidinone, water and the like. , 2-propanol, ethyl acetate and toluene are preferred.

The amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, particularly preferably 5 to 20 times the weight of the hydrazone derivative (compounds I, IV, VII). .

In this case, the amount of the polanamine complex used is 0.34 to 10 times, preferably 0.5 to 7 times, particularly preferably 0.1 to 10 times the mol of the hydrazone derivative (compound 1, 1 V, VII). It is 5 to 3 times the mole.

The reaction with the polanamine complex is preferably performed in the presence of an acid. Such an acid is not particularly limited as long as the reaction proceeds, but hydrochloric acid, hydrobromic acid, oxalic acid, sulfuric acid, nitric acid, phosphoric acid, etc. And inorganic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, and trifluoroacetic acid. The amount of these acids to be used is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 2 to 4 moles, per mole of the hydrazone derivative (compounds I, IV, VII).

The reaction temperature with the polanamine complex is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 100 hours, preferably 1 to 100 hours. 550 hours, particularly preferably 1-25 hours.

[Production method 2]

A hydrazine derivative (compound I, VI I) or a hydrazine derivative (compound II) is reacted with a combination of a borohydride complex and a carboxylic acid or a triacyloxyborohydride complex to form a hydrazine derivative (compounds Π,, ΧΙ '). In the production method, the solvent used may be carboxylic acid itself as a raw material, and is not particularly limited as long as it does not affect the reaction, and may be mixed with the same solvent as in Production method 1. .

The amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, more preferably 5 to 50 times the weight of the hydrazone derivative (compounds I and VII) or the hydrazine derivative (compound II). 20 times the weight. In this case, the amount of the borohydride complex compound or triacyloxyborohydride complex compound used is 1 to 20 times that of the hydrazone derivative (compound I, VII) or the hydrazine derivative (compound Π). The molar amount is preferably 1 to 15 times, particularly preferably 1 to 10 times.

In this case, the amount of the carboxylic acid used is 3 to 200 times, preferably 3 to 150 times, the molar amount of the hydrazone derivative (the compound I or VI I) or the hydrazine derivative (the compound II). The molar amount is twice, particularly preferably 3 to 30 times.

The reaction temperature of the borohydride complex compound with the combination of the fatty acid or the triacyloxyborohydride complex compound is usually 0 to 150 ° C, preferably 10 to 100 ° C, and particularly preferably 10 to 50 ° C. The reaction time is generally 1 to 50 hours, preferably 1 to 25 hours, particularly preferably 1 to 10 hours.

[Production method 3]

A hydrazine derivative (compounds IV, IV ', XI II, XIV) is reacted with a carbonyl compound (compound V) in the presence of a reducing agent to give a hydrazine derivative (compounds III, III', XI, ΧΙ ', XI I, ΧΙ Γ) The solvent used in the method for producing is not particularly limited, as long as it does not affect the reaction, and the same solvent as used in the above-mentioned production method 1 or 2 is used. The amount of the solvent used in this reaction is 5 to 50 times by weight, preferably 5 to 30 times by weight, particularly preferably 5 to 20 times by weight, relative to the hydrazine derivative (compounds IV, IV ', XIII, XIV). It is twice.

In this case, the amount of the carbonyl compound (compound V) used is 0.34 to 10 times, preferably 0.5 to 7 times the amount of the hydrazine derivative (compounds IV, IV ′, XIII, XIV). And particularly preferably 0.5 to 3 moles.

In this case, the amount of the reducing agent such as a polanamine complex used is 0.34 to 10 times, preferably 0.5 to 7 times the amount of the hydrazine derivative (compounds IV, IV ', XIII, XIV). And particularly preferably 0.5 to 3 moles.

This reaction is preferably carried out in the presence of an acid. Such an acid is not particularly limited as long as the reaction proceeds, and examples thereof include hydrochloric acid, hydrobromic acid, oxalic acid, sulfuric acid, nitric acid, and phosphoric acid. Inorganic acids and organic acids such as methanesulfonic acid, P-toluenesulfonic acid, acetic acid, propionic acid and trifluoroacetic acid are used. The use of these acids The amount is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 1 to 4 moles relative to the hydrazine derivative (compounds IV, IV ', XIII, XIV).

The reaction temperature is generally 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is generally 1 to 100 hours, preferably 1 to 50 hours. Particularly preferred is 1 to 25 hours.

[Production method 4]

In the process of reacting a hydrazine derivative (compound VI) with a carbonyl compound (compound V) to produce a hydrazone derivative (compound VII), the solvent used is not particularly limited as long as the reaction is not affected. In addition to the same as in the above-mentioned Production method 1, nitriles such as acetonitrile and propionitrile are used.

The amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, particularly preferably 5 to 20 times the weight of the hydrazine derivative (compound VI). In this case, the amount of the carbonyl compound (compound V) used is 1 to 10 moles, preferably 1 to 7 moles, and particularly preferably 1 to 3 moles relative to the hydrazine derivative (compound VI).

This reaction is preferably performed in the presence of an acid. Such an acid is not particularly limited as long as the reaction proceeds, and examples thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Inorganic acids and organic acids such as methanesulfonic acid, p'-toluenesulfonic acid, acids, propionic acid and trifluoroacetic acid are used. The amount of these acids to be used is 1 to 0 mol, preferably 1 to 5 mol, particularly preferably 1 to 4 mol, per mol of the hydrazone derivative (compound IV).

The reaction temperature is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 100 hours, preferably 1 to 40 hours, particularly preferably. 'Is 1-30 hours.

[Production method 5]

The hydrazine derivative (compounds VI, VI II, XI, ΧΓ) is reduced and deprotected with formic acid or a salt thereof, and then a halide such as sulfonyl chloride (compound I »[in the compound of formula IX, Examples of the halogen atom represented include fluorine, chlorine, and bromine, and chlorine is preferably used.) In the process for producing the hydrazine derivative (compounds X, XI I, XI ,, XIV), the solvent used is not particularly limited as long as it does not affect the reaction. Besides the same, nitriles such as acetonitrile and propionitrile, and ketones such as acetone and 2-butaneone are used.

The amount of the solvent used in the reduction and deprotection and the subsequent reaction with a halide such as a sulfonyl chloride (Compound IX) is 5 to 50 times the weight of the hydrazine derivative (Compound VI, VI II, XI, XI '). It is preferably 5 to 30 times by weight, particularly preferably 5 to 20 times by weight.

The amount of formic acid or a salt thereof used in the reduction and deprotection reactions is 1 to 10 times, preferably 1 to 7 times, the mol of the hydrazine derivative (compounds VI, VIΠ, XI, ΧΓ), particularly 1 to 7 times. Preferably it is 1 to 3 moles.

The reduction and deprotection reactions are preferably performed in the presence of a catalyst. Examples of such a catalyst include palladium catalysts such as palladium black, palladium carbon, palladium-silica gel, and barium palladium monosulfate; platinum oxide; platinum carbon; For example, a platinum catalyst such as Rhodium catalyst such as rhodium carbon and rhodium alumina, a ruthenium catalyst such as ruthenium oxide and ruthenium carbon, and Raney nickel are used. The amount of these catalysts used is about 0.0001 to about 2 mol, preferably about 0.001 to about 1 mol, based on the hydrazine derivative (compounds VI, VIII, XI, Χ). Is a mole.

The temperature in the reduction and deprotection reactions is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 50 hours, preferably 1 to 25 hours. Hours, particularly preferably 1 to 10 hours.

The reaction with a halide such as sulfonyl chloride (compound IX) may be performed in the presence of a base. Examples of such a base include alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxy. Metal alkoxides having 1 to 6 carbon atoms, such as lithium, tert-butoxide, sodium methoxide, sodium methoxide, sodium ethoxide, carboxyl-iert-butoxide, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, Inorganic bases such as potassium carbonate and sodium bicarbonate, such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, Tertiary amines such as cyclohexyldimethylamine, pyridine, lutidine, τ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used.

The amount of the base to be used is 1 to 100 times, preferably 1 to 50 times, more preferably 1 to 100 times the mol of the hydrazine derivative (the hydrazine compound νι, νπι, χι, χι '). It is 10-fold molar.

The temperature in the reaction with an octogenide such as sulfonyl chloride (compound IX) is usually 0 to 150 ° C, preferably 10 to 100 ° C, particularly preferably 0 to 50 ° C, and the reaction time is usually It is 1 to 50 hours, preferably 1 to 25 hours, particularly preferably 1 to 10 hours.

The starting compounds I, IV, IV, V, VI, IX, and XI II used in the above Production Methods 1 to 5 can be produced by a method known per se or a method analogous thereto. For example, for compound (vr), the formula

Can be produced by aminating the amide nitrogen atom of the compound represented by the formula or a salt thereof with, for example, o-diphenylphosphinylhydroxylamine. Also the formula.

Wherein n represents 1 or 2, m represents 2 or 3, and D represents an oxygen atom or a sulfur atom, and a salt thereof and a halide (compound IX) such as sulfonyl chloride. Can be carried out under the same conditions as in the reaction described in the above-mentioned Production Method 5, but in this reaction, the unsubstituted amino group (primary amino group) present on the nitrogen-containing heterocyclic ring is not used. A nitrogen atom present on the nitrogen-containing heterocycle and having a hydrogen atom A selective sulfonylamidation reaction proceeds to the atom (secondary amino group). Compound (XIII) can be produced, for example, by subjecting to alkylamination with 0-diphenylphosphinyl N-alkylhydridoxylamine in the same manner as compound (VI).

Such O-diphenylphosphinyl N-alkylhydroxylamine can be produced by reacting 0-diphenylphosphinic chloride or the like with N-alkylhydroxylamine.

When the compound is obtained in a free state by each of the above-mentioned reactions of the present invention, it may be converted to a salt according to a conventional method, and when the compound is obtained as a salt, a free form or another salt is obtained according to a conventional method. Can also be converted to

Compounds II, III, ΙΙΓ, Χ, ΧΠ, and られる thus obtained can be obtained from the reaction mixture by a method known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, and the like. Isolation and purification can be performed by using means such as chromatography.

The salts of compounds II, III, ΙΠ ′, Χ, ΧΠ, ΧΠ ′ may be prepared by adding a mineral acid or an organic acid to the compounds Π, III, III ′, X, XII, XII ′ according to a method known per se. It can be manufactured by such means.

When compounds II, III, ΠΓ, Χ, ΧΠ, and 立体 may have stereoisomers, each of these respective isomers and mixtures thereof is, of course, included in the scope of the present invention. Can also be produced individually.

Compounds II, III, ΙΠ ′, Χ, ΧΙΙ, ΧΙΓ and salts thereof may be hydrates, and both hydrates and non-hydrates are included in the scope of the present invention. It is.

The compounds II, III, ΠΓ, Χ, XII, 得 obtained by the production method of the present invention are useful, for example, as pharmaceuticals, agricultural chemicals, foods, cosmetics, chemicals or intermediates thereof. In particular, in compounds Χ, ΧΠ, ΧΙΓ, the formula CH

R

Is a group represented by the formula

— Y— x— z

Wherein each symbol is as defined above; or a group represented by the formula:

[Wherein each symbol has the same meaning as described above], the compound having the group represented by is safe, low-toxic, inhibits FXa, and has an anticoagulant effect.

(For example, humans, monkeys, cats, cats, horses, pests, mice, rats, guinea pigs, dogs, puppies, etc.), for example, it is useful for the prevention or treatment of the following diseases, It is preferably used for prevention or treatment of cerebral infarction due to fibrillation, deep vein thrombosis and the like.

Brain:

Cerebral infarction due to atrial fibrillation, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Allahimaima disease, transient ischemic attack (TIA), mixed dementia, cerebrovascular heart :

Acute myocardial infarction, sequelae of myocardial infarction, unstable angina pectoris, angina pectoris, stent placement or PTCA (percutaneous intracoronary angioplasty) and revascularization and stenosis after atherectomy primary coronary intervention,

Peripheral:

Deep vein thrombosis, peripheral vascular disease, adult respiratory distress syndrome, chronic kidney disease (eg, dysuria nephropathy, chronic glomerulonephritis, Ig A nephropathy, etc.), diabetic circulatory disorders, pain, nerves, etc. : Thrombocytopenia due to dialysis, thrombocytopenia during major surgery, arteriosclerosis, cancer metastasis, systemic inflammatory response syndrome (SIRS) or pancreatic intravascular coagulation syndrome (DIC) occurring in patients with inflammation and cancer, transplant rejection Various organ failures caused by reaction, organ protection or functional improvement at the time of transplantation, shock or progression of DIC (for example, lung failure, liver failure, renal failure, heart failure)

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described more specifically with reference to Examples, Reference Examples, and Experimental Examples, but the present invention is not limited to these. Example

Reference example 1

Synthesis of 0-diphenylphosphinylhydroxylamine

NH20H. HC1 _n ,

Ph2P (0) Cl P 2P (0) ONH2

NaOHaq./THF

Sodium hydroxide (39.2 g, 0.98 mol) and water (200 ml) were charged into a 2 L four-necked flask with stirring under ice cooling. Subsequently, hydroxylamine hydrochloride (80.5 g, 1.16 mol), city water (110 ml), tetrahydrafuran (900 ml) and diphenylphosphinic chloride (100 g, 0.42 mol) were added. After stirring for 5 minutes, the precipitated solid was collected by filtration. The solid was stirred with 0.25N sodium hydroxide (1 L) under ice-cooling for 30 minutes, and the solid was collected by filtration, washed with city water (300 ml), dried under reduced pressure at room temperature for 10 hours, and dried under reduced pressure. Nylphosphinylhydroxyamine (57.2 g) was obtained (58% yield).

Reference example 2

4-benzyloxycarbonyl-2-oxo-1, 2, 3, 4- 1) .2,2-diethoxyshetilamine,

0 Tolethyl -3--(3-dimethylamino

_Λ ΝΗ propyl) Karupojiimido hydrochloride,

L ² , NH

Ethyl acetate

P-toluenesulfonic acid-.

N-benzyloxycarbonyldaricin (100 g, 478 g 1) Add 2,2-diethoxyshetilamine (76.4 g, 574 ol) and ethyl acetate (800 mL), and add 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride under ice-cooling. Salt (110 g, 574 mmol) and ethyl acetate (200 mL) were added. After stirring at room temperature for about 3 hours, 1N-hydrochloric acid (500 mL) was added to separate the layers, and the aqueous layer was further extracted with ethyl acetate (500 mL × 2). The organic layers were combined, washed with a saturated saline solution (400 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to about 1 L. To the concentrated solution, p-toluenesulfonic acid monohydrate (9.09 g, 48 t ol) was added and reacted at 70 ° C for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (300 mL) was added to the reaction solution, and the mixture was separated, and extracted with ethyl acetate (300 mL × 2). The organic layers were combined, washed with a saturated saline solution (300 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to about 230 mL. The concentrated solution was stirred for 1 hour under ice-cooling, and the precipitated crystals were collected by filtration, washed with a mixture of ethyl acetate-diisopropyl ether (1: 4) (washed with 100111) and dried under reduced pressure (about 40 ° C) to give 4-benzyloxy. Carbonyl-2-oxo-1,3,4-tetrahydropyrazine (57.6 g) was obtained (52% yield).

Synthesis of 1-Amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine

n 1) .Sodium hydride, _n

η Ν, Ν-dimethylformamide

"H 2). 0—Diphenylphosphinyl (^ NNH.

Hydroxylamine

Cbz 'one _ one _ _ Cbz

4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (5.67 & 24.4 ol), N, N-dimethylformamide (300 ml four-necked flask) under a nitrogen stream Sodium hydride (60% in oil, 976 mg, 24.4 mmol) was added slowly with stirring under ice-cooling, and the mixture was stirred at the same temperature for 25 minutes and reacted at room temperature for 1.5 hours. Was. Add 0-diphenylphosphinylhydroxylamine (5.68 g, 24.4 l 01) and N, N-dimethylformamide (5.7 ml) and heat to 60-. The reaction was performed at C for 11 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, city water (30 ml) and saturated aqueous sodium hydrogen carbonate (130 ml) were added to the residue, and the mixture was extracted with ethyl acetate (130 ml × 2 + 65 ml × 2). The organic layers were combined, washed with water (390 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (7 ml) was added to the residue and recrystallized to obtain first crystals of 1-amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine. The mother liquor concentrated residue was recrystallized by adding ethanol (lml) and Two crystals (201 mg) were obtained. (Total yield 66%)

_{(Check) 'Η- NMR (CDC1 3,} TMS, 300MHz)

δ (ppm): 4.40 (2H, s), 4.41 (2H, br), 5.21 (2H, s), 5.78 (1H, dd, J = 26 and 6Hz), 6.33 (1H, dd, J-26 and 6Hz) ), 7.34 (2H, s)

Reference example 4

Synthesis of 1-amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine

1) .t Butoxy sodium,

N, N-dimethylformamide

2) .0—Diphenylphosphinyl (^ NNH.

Hydroxylamine

_J Cbz ^

4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (54.lg, 233iol), Ν, Ν-dimethylformamide (351 m) in a 2 L four-necked flask in a nitrogen stream. L) was added, and while stirring under ice cooling, tobutoxy sodium (23.5 g, 244 mmol) and N-dimethylformamide (233 mL) were added, and the mixture was stirred at room temperature for 50 minutes. The mixture was cooled again with water, and 0-diphenylphosphinylhydroxylamine (57. Og, 244 tmol) and N, N-dimethylformamide (351 mL) were added, followed by stirring at room temperature for 15 minutes. Water (2 L) was added to the reaction solution, and extracted with ethyl acetate (2 L + 1.5 L + 1.2 LX2). The organic layers were combined, washed with a saturated saline solution (1.2 LX2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated solution was stirred for about 1 hour under ice cooling, and the precipitated crystals were collected by filtration, sprinkled with cold ethanol (5 mL), and washed. The crystals were dried under reduced pressure (about 40 ° C) to obtain 1-amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (44.8 g). (78% yield)

(Verification)

E -丽_{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with the spectrum of the compound of Reference Example 3. Reference example 5

Synthesis of 0-diphenylphosphinyl-N-methyl-hydroxylamine

41.7 g (1.OOmol) of sodium hydroxide and 300 ml of water are charged into a 1 L four-necked flask, and 50.0 g (0.58 1) of N-methylhydroxylammonium chloride powder is stirred for 5 to 5 under ice-cooling. Added at 10 ° C. 100 ml of city water and 40 Oml of tetrahydrofuran were added. At the same temperature, 101.2 g (0.419 mol) of diphenylphosphonyl chloride was added dropwise over 15 minutes. After stirring at the same temperature for 30 minutes, the reaction was terminated. 400 ml of tetrahydrofuran was added. Ethyl acetate extraction (2 L, 1 LX 3 times) was performed. The organic layer was washed with a cooled aqueous solution of 0.25 N-sodium hydroxide (1 L × 2 times). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to about 400 ml. The mixture was stirred for 30 minutes under ice cooling to age a white precipitate, which was collected by filtration and washed with a small amount of ethyl acetate. After air-drying overnight, it was dried under vacuum at room temperature for 24 hours to obtain 84.2 g of white crystals of N-methyl-0 diphenylphosphiel-hydroxylamine. (Yield 81.0%)

NMR confirmed the structure.

_{'HN R (CDC1 3, TMS} , 300MHz)

6 (ppm): 2.90 (s, 3H), 6.24 (br-s, 1Η), 7.46 to 7.77 (m, 6H), 7.81 to 7.89 (5H, m) Reference example 6

Preparation of 4-benzyloxycarbonyl-1-methylamino-2-oxo-1,2,3,4-tetrahydropyrazine α |

^—One

In a 500 ml four-neck flask, 11.75 g (48.76 mmol) of 4-benzyloxycarbonyl-2-oxo-1,4,4-tetrahydrovirazine and 3.72 g of N, N-dimethylformamide (51.20 mmoK 1.05 eq) Was added to 150 ml of toluene, and 2.05 g (51.20 liters, 1.05 eq) of 60% sodium hydride (oil) was added while stirring at 1 to 4 ° C. 40-45. C For 1.5 hours. 13.30 g (53.63 ol, 1. leq) of 0-diphenylphosphinylmethylhydroxylamine was added, and 200 ml of toluene was added, followed by a reaction at 90 ° C for 40 minutes. After returning to room temperature, 250 ml of a saturated saline solution was added, and the mixture was extracted with ethyl acetate (250 ml × 1 times, 150 ml × 2 times). After the extract was washed with saturated brine (100 ml x 2 times), and MgSO ₄ dried. The filtrate was concentrated under reduced pressure. The residue was subjected to phlegm lysyl (Φ5.75 × 9 cm) treatment, and eluted with N-hexane: ethyl acetate = 2: 1 to 1: 2. An eluate of two fractions containing mainly trimethylamino-2-oxo-4-benzyloxycarbonyl-1,2,3,4-tetrahydrovirazine was obtained. Each was concentrated to dryness and the resulting white crystals were dried to give four fractions of 4-benzyloxycarbonyl-1-methylamino-2-oxo-1,2,3,4-te Trahydropyrazine was obtained. First fraction 3.85 g (HPLC area percentage 93.83%). Second fraction 8.35 g (HPLC area percentage 67.05) ₀ Total yield 72.3¾ (HPLC area percentage correction).

(HPLC conditions: column YMC ODS A 302, 150X4.6 Awake ID, s-5, 120 people, eluent acetonitrile: 0.05M potassium dihydrogen phosphate = 35:65, flow rate lml / min, uv wavelength 246 nm.)

(Check) - negation _{R (CDC1 3, TMS, 300MHs} )

δ (ppm): 2.66 (3H, s), 4.40 (2H, s), 5.23 (2H,), 5.75 (1H, m), 6.37 (1H, m), 7.39 (5H, m).

Reference Example 7

Synthesis of 4- (6-chloronaphthalene-2-sulfonyl) -1- [tri (4-pyridyl) -4-piperidinylideneamino]-2-piperazinone

1-Amino-4- (6-clonal naphthalene-2-sulfonyl) -2-piperazinone (859mg, 2.53mmol), 1- (4-pyridyl) -4-piperidone (490mg, 2.78 t 1) and ethanol (8.6 ml) were added, and the mixture was reacted under reflux for 21.5 hours and concentrated under reduced pressure. The residue was washed with ethanol (5 ml) while heating under reflux, cooled slowly and cooled with ice, and the crystals were collected by filtration. Dry at 40 ° C under reduced pressure to give 4- (6-chloronaphthalene-2-sulfonyl) -1- (1- (4-pyridyl) -4-pi [Ridinylideneamino] -2-piperazinone (1.07 g) was obtained (yield 85%).

(Check) E- field _{R (CDC1 3, TMS, 300MHz} ) d (ppm): 2.13 (2H, t, J = 5.8Hz), 2.53 (2H, t, J = 5.8Hz), 3.3 (2H, t, J = 5.9Hz), 3.4-3.7 (6H, m), 3.80 (2H, s), 6.55 (2H, d, J = 6.5 Hz), 7.54 (2H, dd, J = 8.8 and 1.9Hz), 7.7 ( 1H, dd, J = 8.7 and 1.7Hz), 7.80-7.90 (3H, m), 8.21 (2H, d, J = 6.3Hz), 8.30 (1H, s),

Reference Example 8

Production of 4- (6-chloronaphthalene-2-sulfonyl) -trimethylamino-2-piperazinone

1) Ammonium formate 10% palladium-carbon / ethanol

, So ₂ ci 10 sodium carbonate aqueous solution / ethyl acetate

1-methylamino-2-oxo-4-benzyloxycarbonyl-1,2,3,4-tetrahydropyrazine 2.64 g (Daros weight, equivalent to 10.0 mmol ol) in ethanol (50 ml), ammonium formate 1.26 g (20. Ommol) and 0.66 g of 10% palladium-carbon (containing 50% water) were added, and the mixture was heated and refluxed for 1 hour under a nitrogen stream. After returning to room temperature, the catalyst was removed by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure.

To the residue were added 36 inl of ethyl acetate, 1.03 g (10. Ommol) of triethylamine and 2.61 g (10.0 mol) of 6-chloronaphthalene-2-sulfonyl chloride, and the mixture was reacted at room temperature for 4.5 hours. After adding 200 ml of water to the reaction solution and cooling with ice, a white solid was collected by filtration. After washing with methanol (20 ml), the crystals were dried under vacuum at 40 ° C. to obtain 2.42 g of crystals of 4- (6-chloronaphthalene-2-sulfonyl) -1-methylamino-2-piperazinone. (Yield 72%).

(Check) '.eta. Awakening: _{R (CDC1 3, TMS, 300MHz} )

6 (ppm): 2.45 (3H, s), 3.40 (2H), 3.54 (2H, m), 3.76 (2H, s), 7.54 (1H, dd, J = 2.0 and 8.72Hz), 7.73 (1H, dd, J = l.8 and 8.7Hz), 7.8-7.9 (3H, m), 8.30 (1H, s) Reference example 9

Synthesis of 3- (3,4-dimethoxybenzylideneamino) 2-thioxo-1,3-thiazolidine-4-one

3-Amino r2-thioxo-1,3-thiazolidine-4-one (892 mg, 6.02 mmol), 3,4-dimethoxybenzaldehyde (1.OOg, 6.02 mmol) and ethanol After the addition of ethanol (10 ml) and the reaction at room temperature for 5 hours, the mixture was cooled on ice and the crystals were collected by filtration. Drying under reduced pressure at room temperature gave 3- (3,4-dimethoxybenzylideneamino) -2-thioxo-1,3-thiazolidin-4-one (L 07 g) (94% yield).

(Confirmation) ^ -NMR CDC TMS, 300MHz)

δ (ppm): 3.94 (6H, s), 4.06 (2H, s), 6.91 (1H, d, J = 8.3Hz), 7.29 (1H, dd, J = 8. 3 and 1.9H z), 7.57 (1H, d, J = l.9Hz)

Reference example 10

3- (triphenyl-1,3-propagenylideneamino)-2-thioxo-1,3-thiazolidine-

4-on production

ethanol

Similarly to Reference Example 9, 1-amino 2-thioxo-1,3-thiazolidine-4-one (892 mg, 6.

From 2-transyl) and trans-cinnamaldehyde (796 mg, 6.02IMO I) from 3-[(3-phenyl-2-propenylidene) amino] -2-thioxo-1,3-thiazolidine-4 -On (1.45 g) was obtained (yield 9).

(Check) - negation _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 4.32 (2H, s), 7.2-7.3 (2 (, m), 7.4-7.5 (4Η, m), 7.7-7.8 (2Η, m), 8.43 (1 Η, d, J = 9.4 Hz), '

Reference example 1 1

5-{[5- (4-c-mouth phenyl) -2-furyl] methyleneto 3- [ethyl (3-7enyl-2-provenyl) amino] -2-thioxo-1,3-thiazolidine-4- On manufacture

In a 35 ml eggplant-shaped flask, 3- [ethyl (3-phenyl-2-propenyl) amino] -2-thioxo-1,3-thiazolidine-4-one (the compound of Example 23) (1. ol), 5- (4-chlorophenyl) furfural (240 mg, 1.16 mmol), sodium acetate (3.8 mg, 0.0464 thigh mo 1) And ethanol (3.4 ml) were charged and reacted under reflux for 1.5 hours. After completion of the reaction, the reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure at room temperature to obtain the title compound (435 mg) (yield 78%).

(Confirmation) 'Η-Awake R (CDCi ₃ , TMS, 300MHz)

δ (ppni): 1.13 (2H, t, J = 7.2 Hz), 3.4-3.7 (2H, m), 4.1-4.2 (2H, m), 6.2-6.4 (2H, m), 6.56 (2H, d, J = 15.8Hz), 6.81 (1H, d, J = 3.7Hz), 6.90 (1H, d, J = 3.7Hz), 7.2-7.5 (8H, m), 7.66 (2H, d, J = 8.6Hz)

MS (EI): (M ⁺ ) 480

Elemental analysis _{_{_{(C 25 H 21 N 2 0}}} 2 SC1) '

Theoretical C: 62.42, H: 4.40, N: 5.82

Measured value: C: 62.06, H: 4.36, N: 5.67

Reference Example 12

Production of 1- (3,4-methylenedioxybenzylideneamino) homopiperidine

Tamino homopiperidine (1.78 g, 15.6 mmol), piperonal (2.34 g, 15.6 mol) and ethanol (23 ml) were added to a 100 ml eggplant-shaped flask, and the mixture was reacted under reflux for 7.5 hours. After the completion of the reaction, the precipitated crystals were collected by filtration to obtain 1- (3,4-methylenedioxybenzylidamino) homopiperidine (2.87 g). The mother liquor was similarly filtered to obtain a second crystal (149 mg).

_{(Check) NMR (CDC1 3, TMS,} 300MHz)

δ (pm): 1.6-1.9 (8H, m), 3.59 (4H, t, J = 5.7Hz), 6.02 (2H, s), 6.8 (1H, d, J = 8.OH z), 6.96 (1H , dd, J = 8.0 and 1.5Hz), 7.14 (1H, s), 7.28 (1H, d, J = l.4Hz)

Reference Example 13

Production of l- (3,4-methylenedioxybenzylideneamino) piperidine

As in Reference Example 12, 1- (3,4-methylenedioxybenzylideneamino) piperidine (1. Olg) was prepared from triaminopiperidine (603 mg, 6.02 minol) and piperonal (904 mg, 6.02 mmol). Was obtained (yield 72%).

_{(Check) NMR (CDC1 3, TMS,} 300MHz)

δ (ppm): 1.5-1.8 (6H, m), 3.1 (4H, t, J = 5.6Hz), 5.97 (2H, s), 6.79 (1H, d, J = 8.OHz), 6.95 (1H , dd, J = 8.0 and 1.6Hz), 7.27 (1H, d, J = l.5Hz), 7.50 (1H, s) Reference example 14

Production of tri (3,4-methylenedioxybenzylideneamino) pyrrolidine

As in Reference Example 12, triaminopyrrolidine hydrochloride (738 mg, 6.02 mmol) was reacted with piperonal (904 mg, 6.02 mmol), neutralized, and recrystallized with ethanol to give tri (3,4). -Methylenedioxybenzylideneamino) pyrrolidine (1.01 g) was obtained (78% yield).

(Check) - Awakening: _{R (CDC1 3, TMS, 300MHz} ).

δ (ppm): 1.9-2.0 (4H, m), 3.33 (4H, t, J = 6.6Hz), 5.96 (2H, s), 6.77 (1H, d, J = 8.OHz), 6.91 (1H , dd, J = 8.0 and 1.5Hz), 7.14 (1H, s), 7.20 (1H, d, J = l.5Hz) Reference example 15

Production of 1- (3,4-methylenediolin

In the same manner as in Reference Example 12, triaminomorpholine (615 mg, 6.02 ol) and piperonal (904 mg, 6.02 ol) were reacted to give 1- (3,4-methylenedioxybenzylideneamino). ) Morpholine (1.04 g) was obtained (74% yield).

(Check) '.eta.丽_{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 3.15 (4H, t, J-4.8Hz), 3.90 (4H, t, J = 4.8Hz), 5.98 (2H, s), 6.80 (1H, d, J = 8.0Hz), 6.97 ( 1H, dd, J-8.0 and 1.5Hz), 7.27 (1H, d, J = l.5Hz), 7.54 (1H, s) Reference example 16 Production of l- (3,4-mino) -4-methylpiperazine

In the same manner as in Reference Example 12, triamino-4-methylbiperazine (693 mg, 6.02 thigh ol) was reacted with piperonal (904Π1 & 6.02 thigh ol) to give 1- (3,4-methylenedioxybenzylideneamide). (No) -4-methylpiperazi (1.19 g) was obtained (80% yield).

(Check) - Awakening: _{R (CDC1 3, TMS, 300MHz} ) '

δ (ppm): 2.44 (3H, s), 2.70 (4H, t, J = 5.0Hz), 3.27 (4H, t, J = 5.2Hz), 6.0 (2H, s), 6.86 (1H, d, J = 8.0Hz), 7.04 (1H, dd, J = 8.0 and 1.5Hz), 7.3 (1H, d, J = l.5Hz), 7.57 (1H, s)

Reference Example 17

Of 2- (3-hydroxy-3-amino) homopiperidine

In the same manner as in Reference Example 12, 6.02 mmol of thiol was reacted with o-vanillin (916 mg, 6.02 mmol) to obtain 1- (3,4-; morpholine (1.15 g) (yield 77%). .

(Check) E- noodles _{R (CDC1 3, TMS, 300MHz} )

δ (pm): 1.6-1.9 (8H, m), 3.58 (4H, t, 7Hz), 3.99 (3H, s), 6.7-6.9 (3H, m), 7.31 (1H, s), 12.0 ( 1H, s)

Example 1

Preparation of 4- (6-chloronaphthalene-2-sulfonyl) -1- {ethyl (1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone

4- (6-chloronaphthalene-2-sulfonyl) -1-[1-(4-pyri Jill) -4-piberdinylamino] -2-piperazinone (1.45 g, 2.90 mmol) and acetic acid (14.5 ml), and stirring at room temperature in a nitrogen stream at room temperature, while stirring sodium triacetoxyborohydride ( 6. 15 g, 29 ol ol) was slowly added (9 hours at room temperature, stirred overnight, 12 hours and 20 minutes), and further stirred at room temperature for 7 hours and 20 minutes (total 28 hours and 40 minutes at room temperature) After completion of the reaction, the reaction solution was transferred to a 200-ml eggplant-shaped flask, and city water (29 ml) was added. A 1N aqueous solution of sodium hydroxide (200 ml) and sodium hydroxide (3.OOg) were added to precipitate a solid. After stirring under ice-cooling, the crystals were collected by filtration and sprinkled and washed with city water (25 ml) to obtain a crude product.

The crude product was washed with methanol (7.25 ml) under reflux with heating, stirred slowly and cooled with ice, and the crystals were collected by filtration, sprinkled and washed with methanol, and dried under reduced pressure at 40 ° C to give 4- (6- Chloronaphthalene-2-sulfonyl) -1- {ethyl [1- (4-pyridyl) -4-piperidinyl] amino} _2-piperazinone (1.29 g) was obtained. (Yield 84%)

(Hydrochlorination process)

4- (6-Chloronaphthalene-2-sulfonyl) -triethyl [1- (4-pyridyl) -4-piberidinyl] aminotri 2-piperazinone (1.20 g, 2.27 t ol), ethanol (12 ml) and 4N-hydrochloric acid / ethyl acetate (1.14 ml, .54 liter) were reacted at room temperature for 1 hour and 20 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and acetone (12 ml) and ethanol (1.0 ml) were added to the concentrated residue to dissolve almost completely. After heating and refluxing for 40 minutes, the mixture was allowed to cool at room temperature to confirm the precipitation of crystals. After stirring under ice cooling, the crystals were collected by filtration, sprinkled with acetone and washed. After drying under reduced pressure at 40 ° C for 20 hours, 4- (6 chloronaphthalene-2-sulfonyl) -1- (ethyl [tri (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone monohydrochloride (1. 07g) was obtained. (Yield 92%)

(Confirmation) Marauder R (DMS0-d ₆ , TMS, 300MHz)

δ (ppm): 0.83 (3H, t, J = 7.1 Hz), 1.1-1.3 (2H, m), 1.5-2.0 (2H, m), 2. 8- 2.9 (1H, m), 3.0-3.3 (3H, m), 3.84 (2H, s), 3.4-3.6 (4H, m), 4.05 (2H, m q, J = 34Hz and 14Hz), 7.15 (2H, d, J = 7.5Hz), 7.80 (1H, dd, J = 8.8 and 1.9Hz), 7.96 (1H, dd) , J = 8.8 and 1.9Hz), 8.2.8.3 (3H, m), 8.35 (2H, d, J = 7.5 Hz), 8.66 (1H, s), 13.7 (1H, br)

Elemental analysis _{_{_{(C 26 H 31 N 5 0}}} 3 SC1 2 · 0. 5¾0)

C: 54.45, H: 5.62, N: 12.21, S: 5.59, CI: 12.36 Found: C: 54.77, H: 5.54, N: ll.75, S: 5.48, CI: 12.22

C: 54.62, H: 5.84, N: ll.79, S: 5.49, Cl: 12.19

Example 2

4- (6-chloronaphthalene-2-sulfonyl) -1-{ethyl [1- (4-pyridyl) -4-piperidinyl] amino}

-Synthesis of 2-piperazinone

4- (6-chloronaphthalene-2-sulfonyl)-1-[1- (4-pyridyl) -4- piperidinylamino]-2-piperazinone (2.00 g, 4.00) in a nitrogen stream in a 200 ml four-necked flask Oral ol), toluene (10 ml) and sodium borohydride (1.51 g, 40 mmol) were charged, and acetic acid (20 ml) was added dropwise with stirring under ice-water cooling over 22 minutes. After stirring for 30 minutes as it was, the mixture was stirred for 5 hours and 30 minutes at room temperature, left overnight (14 hours), and then stirred for 11 hours and 30 minutes at room temperature (total reaction at room temperature for 31 hours). After the completion of the reaction, the reaction solution was transferred to a 300 ml eggplant-shaped flask, and separated by adding water (40 ml), a 2N-sodium hydroxide aqueous solution (200 ml) and tetrahydrofuran (40 ml). The aqueous layer was extracted with tetrahydrofuran / ethyl acetate (1: 1, 40 ml + 20 ml), and the organic layers were combined, washed with city water (100 ml × 2), and then concentrated under reduced pressure. The residue is washed with methanol (5m1) while heating under reflux, stirred under ice-cooling, and the crystals are collected by filtration, sprinkled and washed with methanol, dried at 40 ° C under reduced pressure, and dried with 4- (6-clomouth naphthalene-2 sulfonyl) -1- {Ethyl [tri (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (1.64g) was obtained. (78% _{yield) Ή- NMR (CDC1 3, TMS} , 300MHz)

δ (ppm): 0.97 (3H, t, J = 7.1Hz), 1.-1.5 (2H, m), 1.6-2.0 (2H, m), 2.7-3.0 (2H, m), 3.2-3.5 (4H , m), 3.46 (2H, s), 3.6-3.8 (2H, m), 3.81 (2H, q, J = 28Hz and 17Hz), 6.59 (2H, d, J = 6.4Hz), 7.63 (1H , dd, J = 8.9 and 1.7Hz), 7.81 (1H, dd, J = 8.9 and 1.7Hz), 7.90-8.10 (3H, m), 8.24 (2H, d, J = 6.4Hz), 8.36 (1H , s)

Example 3

Production of 4- (6-cyclonaphthalene-2-sulfonyl) -1- (methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone

4- (6-Chloronaphthalene-2-sulfonyl) -1- (tri (4-pyridyl) -4-piperidinylamino) -2-piperazinone (l.OOg, 2.00) mmol), toluene (20 ml) and sodium borohydride (756 mg, 20 mmol), and formic acid (10 ml) was added dropwise over 15 minutes while stirring under ice-water cooling (internal temperature was dropped from 10 ° C to 29 ° C). . After stirring for 8 minutes, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 4N-sodium hydroxide (40 ml) and tetrahydrofuran (40 ml) were added to the reaction solution to carry out liquid separation. The aqueous layer was extracted with tetrahydrofuran / ethyl acetate (1: 1, 20 ml × 2), and the combined organic layers were washed with city water (100 × 1 × 2) and concentrated under reduced pressure. The residue was washed with methanol (7 ml) while heating under reflux, stirred under ice-cooling, and the crystals were collected by filtration, sprinkled and washed with methanol (5 ml), dried at 40 ° C under reduced pressure, and dried under reduced pressure at 4- ° C. -2-sulfonyl) -1- {methyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (850 mg) was obtained. (Yield 83)

(Check) Awakening: _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 1.2-1.4 (2H, m), 1.6-1.9 (2H, m), 2.71 (3H, s), 2.7-3.0 (2H, m), 3.3-3.

9 (9H, HI), 6.58 (2H, d, J = 5.5Hz), 7.62 (1H, d, J = 9.0Hz), 7.81 (1H, d, J = 9.0Hz), 7.9

0-8.10 (3H, Hi), 8.24 (2H, d, J = 5.4Hz), 8.36 (1H, s),

Elemental analysis _{_{_{(C 25 H 28 N 5 0}}} 3 SCI)

Theoretical C: 58.41, H: 5.49, N: 13.62

Found C: 58.22, H: 5.52, N: 13.46

Example 4

Preparation of 4- (6-chloronaphthalene-2-sulfonyl) -triethyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone

In a 35 ml eggplant-shaped flask in a nitrogen stream, 4- (6-clonal naphthylene-2-sulfonyl) -1- [1- (4-pyridyl) -4-pyridinylideneamino] -2-piperazinone (500 mg, 1.000 mmol), acetic acid (5.Oml) and sodium triacetoxyborohydride (2.12 g, 10.0 t ol). After stirring at room temperature for 9 hours, the mixture was allowed to stand overnight (13 hours and 20 minutes), and stirred at room temperature for 1 hour and 40 minutes (total reaction at room temperature for 24 hours). After the completion of the reaction, the reaction solution was transferred to a 100-ml eggplant-type corben, and city water (10 ml) and 2N-sodium hydroxide (75 ml) were added to precipitate a solid. After stirring under ice cooling, the crystals were collected by filtration and sprinkled and washed with city water. The crude product was washed with methanol (2.75 ml) under heating and reflux, and the crystals were cooled on ice and collected by filtration, dried at 40 ° C under reduced pressure, and dried under reduced pressure at 40 ° C. Thus, ethyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (400 mg) was obtained. (76% yield)

(Verification)

'H-NMR (CDC13 ₎ TMS, 300 MHz) was completely consistent with the spectrum of the compound of Example 2. Elemental analysis _{_{_{(C 26 H 3 .N 5 0}}} 3 SC1 · 0. 5H 2 0)

Theoretical value C: 58.14, H: 5.81,: 13.04

Found: C: 58.36, H: 5.86, N: 13.15

Example 5

Production of 4- (6-chloronaphthalene-2-sulfonyl) -tri {methyl [tri (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone

In a 100 ml four-necked flask in a nitrogen stream, 4- (6-chloronaphthyl-2-ene-2-sulfonyl) -tri [1- (4-pyridyl) -4-piperidinylideneamino] -2-piperazinone (1. OOg, 2.01 thigh 01), toluene (20 ml) and sodium borohydride (757 mg, 20 thol) were charged, and formic acid (1 Oml) was added dropwise over 25 minutes while stirring under ice-water cooling (inner temperature). Drops at 5 ° C to 11 ° C). After stirring for 20 minutes as it was, the mixture was stirred at room temperature for 2 hours and 40 minutes. After completion of the reaction, the 4N- layer was extracted with tetrahydrofuran / ethyl acetate (1: 1, 40 ml × 2), and the organic layers were combined, washed with city water (100 ml × 2), and concentrated under reduced pressure. The residue is washed with methanol (7 ml) while heating under reflux, stirred under ice-cooling, and the crystals are collected by filtration, sprinkled and washed with methanol, and dried under reduced pressure at 40 ° C to give 4- (6-chloronaphthalene-2-sulfonyl). ) -Trimethyl [1-(4-pyridyl) -4-piridinyl] amino 2-piperazinone (820 mg) was obtained. (Yield 80) Thigh _{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with scan Bae spectrum of the compound of Example 3. Elemental analysis _{_{_{(C 25 H 28 N 5 0}}} 3 SC1 · 0.5¾0)

Theoretical C: 57.41, H: 5.59, N: 13.39 '

Obtained C: 57.55, H: 5.33, N: 13.56

Example 6

Synthesis of 4-benzyloxycarbonyl-2-oxo-1- [1- (4-pyridyl) -4-pyridinylamino] -1,2,3,4-tetrahydropyrazine

C

Ethanol

1-Amino-4-benzyloxycarbon-2-oxo-1,2,3,4-tetrahydropyrazine (1.00 g, 4.04 mmol), 1- (4-pyridyl) -4- Piperidone (713 mg, 4.04 mol), acetic acid (243 mg, 4.04 mol) and ethanol (20 ml) were charged and reacted at room temperature for 24 hours.

Subsequently, a polan-dimethylamine complex (298 mg, 5.06 t ol) was added with stirring under ice-cooling, followed by a 4N hydrochloric acid / ethyl acetate solution (3.50 ml, 14.2 nether ol). After stirring at the same temperature for 1 hour, the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the mixture was extracted with city water (20 ml) and 0.25 N hydrochloric acid (20 ml). The aqueous layers were combined, 2N-aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate (40 ml × 2). The organic layers were combined, washed with a saturated saline solution (80 ml × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 4-benzyloxycarbonyl-2-oxo- [tri (4-pyridyl) + piridinylamino] -1,2,3,4-tetrahydropyrazine (1.16 g) was obtained. (70% yield)

(Confirmation) iH-NMR CDClg, TMS, 300MHz)

δ (ppm): 1.3-1.6 (2H, m), 1.8-2.0 (2H, m), 2.8-3.1 (2H, m), 3.1-3.3 (1H, m), 3.7 -4.0 (2H,] n) , 4.40 (2H, s), 5.12 (1H, br), 5.22 (2H, s), 5.72 (1H, dd, 1 = 29 and 5.1 Hz), 6.30 (1H, dd, J = 29 and 5.1Hz), 6.65 (2H, dd, J = 5.1 and 1.Hz), 7.38 (2H, s), 8.26 (2H, dd, J = 5.1 and 1.4Hz)

Example 7

Synthesis of 4- (6-chloronaphthalene-2-sulfonyl) -1-[[(4-pyridyl) -4-piperidinylamino] -2-piperazinone

4-Benzyloxycarbonyl-1- [1- (4-pyridyl) -4-piperidinylamino] -2-oxo-1,2,3,4-tetrahydropyrazine in a 200 ml eggplant-shaped flask 1. Palladium carbon (50% water content, 580 mg, 0.272 mmol), ethanol (23.2 ml), and ammonium formate (539 mg, 8.54 mmol) were produced under the nitrogen flow to the product produced in Example 6, 1.16 & 2.85 The resulting mixture was stirred for 1 hour while heating under reflux. After the completion of the reaction, the catalyst was removed by filtration and washed with ethanol. The filtrate was concentrated under reduced pressure.

A 10% aqueous solution of sodium carbonate (11.4 ml) and dimethyl chloride (11.m1) were added to the above concentrated residue, and 6-chloronaphthalene-2-sulfonyl chloride (740 mg, 2.83 MIO1) was added thereto with stirring at room temperature. The reaction was performed for 2 hours. After completion of the reaction, the reaction solution was separated, and the aqueous layer was extracted with methylene chloride.

The organic layers were combined, washed with city water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanol (5 ml) was added to the oily concentrated residue for crystallization, followed by repulp washing under reflux, followed by slow cooling and ice cooling, and the crystals were collected by filtration. Dry under reduced pressure at 40 ° C to give 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piiperidinylamino] -2-piperazinone (854mg). Obtained. (60% yield)

_{(Check) - NMR (CDC1 3, TMS} , 300MHz)

δ (pm): 1.3-1.5 (2H, m), 1.6-1.9 (2H, m), 2.7-3.0 (2H, m), 3.1-3.3 (1H, m), 3.4 5 (2H, t, J = 4.9Hz), 3.60 (2H, t, J = 4.9Hz), 3.7-3.8 (2H, m), 3.86 (2H, s), 5.07 (1H, d, J = 4.8Hz), 6.61 (2H, dd, J = 5.1 and 1.4Hz), 7.61 (1H, dd, J = 8.9 and 2.0Hz), 7.80 (1H, dd, J = 8.9 and 2.0Hz), 7.90-8.00 (3H, m), 8.23 (2H , dd, J = 5.1 and 1.4Hz), 8.37 (1H, s) Example 8

Preparation of 4- (6-chloronaphthylene-2-sulfonyl) -tri [1- (4-pyridyl) -4-piperidinyl] amino-2-piperazinone

°. [I> Acetic acid, methanol-denatured ethanol

1-Amino-4-benzyloxycarbonyl-2-oxo- 1,2,3,4-tetrahydropyrazine (44. Og, 178 mmol), 1_ (4-pyridyl) _4 piperidone ( 31. 36 g, 178 ol), methanol-denatured ethanol (880 mL) and acetic acid (10.7 g, 178 ul) were added and stirred at room temperature for 16 hours.

In a stream of nitrogen, while stirring under ice-cooling, a polan-dimethylamine complex (5.24 g, 89 mL) was added, and a solution of concentrated hydrochloric acid in methanol-denatured ethanol (1Z3 dilution, lllml, 445 m fflol) was added in 10 minutes. The mixture was stirred for 1 hour. After stirring at room temperature for about 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (800 mL) was extracted with concentrated water (800 mL × 2). The aqueous layers were combined, a 2N aqueous sodium hydroxide solution (220 mL) was added, and the mixture was extracted with ethyl acetate (1.6 LX2). The organic layers were combined and washed with saturated saline (1.6 LX2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Under a nitrogen stream, 10 palladium carbon (50% water content, 17.7 g, 8.32 t ol), ammonium formate (24. Og, 381 t ol), methanol-modified ethanol (1.4 L) were added to the above concentrated residue under a nitrogen stream. Was. The reaction was performed under reflux for 1 hour. After completion of the reaction, the catalyst was removed by filtration, washed with the reaction solvent, and the filtrate was concentrated under reduced pressure.

Ethyl acetate (697 mL), 10% aqueous sodium carbonate solution (697 mL), and 6-chloronaphthalene sulfo-ercide (45.2 g, 173 mmol) were added to the above concentrated residue, and the mixture was stirred at room temperature for about 2 hours. City water (697 mL) was added, and the mixture was stirred for about 1 hour under ice-cooling. The crystals were collected by filtration and washed with city water (697 mL). The crude crystals were washed with methanol (573 mL) under reflux, cooled slowly and cooled on ice, and the crystals were collected by filtration. The crystals were dried under reduced pressure at 40 ° C. to obtain 4- (6-chloronaphthalene-2-sulfonyl) -1- (1- (4-pyridyl) _4-piperidinylamino) -2-piperazinone (54.3 g). (Yield 6 l%) _a

_{(Check) Ή- NMR (CDC1 3, TMS} , 300MHz) was completely match the spectrum of the compound of Example 7.

Example 9

Production of 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinyl] amino-2-piperazinone

1).

, Acetic acid, methanol denatured ethanol

In a 2-L four-necked flask, triamino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (5. Og, 20.2 ol), 1- (4-pyridyl) ) -4 Piperidone (3.56 g, 20.2 mmol), methanol-denatured ethanol (100 mL), acetic acid 21 g, 20.2 alcohol) were added, and the mixture was stirred at room temperature for 16 hours.

In a nitrogen stream, while stirring under ice-cooling, add a polan-t-butylamine complex (1.76 g, 20.2 ol) and dilute a concentrated methanol solution of concentrated hydrochloric acid in methanol-denatured ethanol (1/3 dilution, 12.6 ml, 50 .5 mmol) was added in 10 minutes, and the mixture was stirred as it was for 1 hour. After stirring at room temperature for about 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (100 mL) was extracted with concentrated water (100 mL × 2). The aqueous layers were combined, a 2N aqueous solution of sodium hydroxide (25 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layers were combined, and washed with saturated saline (400 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Under a nitrogen stream, add 10 palladium carbon (50% water content, 1.68 g, 0.789 ol), ammonium formate (2.28 g, 36.2 ol), methanol-modified ethanol ( 134 ml) was added. The reaction was performed under reflux for 1 hour. After completion of the reaction, the catalyst was removed by filtration, washed with a reaction solvent, and the filtrate was concentrated under reduced pressure.

To the above concentrated residue was added ethyl acetate (66.mL), 10% aqueous sodium carbonate solution (66.mL), and 6-cloth naphthyl lensulfonyl chloride (4.30 g, 16.5 mmol), and the mixture was added at room temperature for about 2 hours. While stirring. City water (66.mL) was added, and the mixture was stirred for about 1 hour under ice cooling, and the crystals were collected by filtration. 6. lmL). The crude crystals were washed with methanol (58.8 mL) under reflux, cooled slowly and cooled on ice, and the crystals were collected by filtration. The crystals were dried under reduced pressure at 40 ° C, and 4_ (6_chloronaphthylene-2-sulfonyl) -1- [1- (4-pyridyl) -4-pyridinylamino] -2 piperazinone (4.48 g) ) (4% yield)

(Check) the solid _{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with the spectrum of the compound of Example 7.

Example 10

Preparation of 4- (6-chloronaphthalene-2-sulfonyl) -1- (methyl [1- (4-pyridyl) -4-piperidinyl] amino} _2-piperazinone

1).

Man

, Formic acid, ethanol

:. N

1 amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (1.00 g, 4.004 mmol), 1- (4-pyridyl) -4 -Piperidone (78 2 mg, 4.44 t ol), formic acid (186 mg, 4.04 t ol) and ethanol (10 ml) were charged, reacted at room temperature for 24 hours, and concentrated under reduced pressure.

Tetrahydrofuran (iOml) was added to the concentrated residue, and sodium borohydride (1.53 g, 40.4 mol) was added thereto under ice-cooling in a nitrogen stream, and formic acid (10 ml) was further added dropwise. After reacting at room temperature for 14 hours, 1N-hydrochloric acid (40 ml) and ethyl acetate (20 ml) were added to the reaction solution, the layers were separated, and further extracted with 1N-hydrochloric acid (10 ml × 4). The aqueous layers were combined, a 4N-7K aqueous sodium oxide solution (120 ml) was added, and the mixture was extracted with ethyl acetate (40 ml × 4). The organic layers were combined, washed with city water (100 ml × 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and dried to give an oil (1.43 g).

(The above oil is an intermediate, 4-benzyloxycarbonyl-1- {methyl [1- (4-pyridyl) -4-piberidinylamino]}-2-oxo-1,2,3,4 -Tetrahydrovirazine was confirmed by R-paint R.

_{'H-NMR (CDC1 3,} TMS, 300ΜΗζ) δ (ppjn):... 1. 2-1 5 (2H, ffl), 1. 7-2 0 (2H, ffl), 2. 8-3 l (2H, m), 2.86 (3H, s), 3.4-3.6 (1H, m), 3.7-3.9 (2H, i), .2-4.4 (2H, m), 5.20 (2 H, s), 5.59 (1H, dd, J = 33 and 5.9Hz), 6.27 (1H, dd, J = 38 and 6.1 Hz), 6.62 (2H, dd, J = 5.0 and 1.5Hz), 8.23 (2H, dd, J = 5.0 and 1.5Hz), 7.37 (2H, s)

Ethanol (34 ml), 10% palladium carbon (50% water content, 850 mg, 0.395 mL), and ammonium formate (561 mg, 8.89 t ) And stirred under heating and refluxing for 1 hour and 30 minutes. After completion of the reaction, the catalyst was removed by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure.

A 10% aqueous solution of sodium carbonate (Π., Ϊ́πιΐ) and ethyl acetate (17.lml) were charged to the above concentrated residue, and 6-chloronaphthalene-2-sulfonyl chloride (1.05 g, 4.04 mmol) was added with stirring at room temperature. In addition, the reaction was carried out for 15 hours at room temperature for 1 hour, and left overnight. After the reaction was completed, city water (34 ml) was added to the reaction solution, and the mixture was cooled on ice and the crystals were collected by filtration. The crude crystals were washed with methanol (12 ml) while heating under reflux, gradually cooled, and cooled with ice, and the crystals were collected by filtration. Dry at 40 ° C under reduced pressure to obtain 4- (6-chloronaphthalene-2-sulfonyl) -1- {methyl [tri (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (i. 37 g). Was. (Yield 66%)

_{(Check) - NMR (CDC1 3, TMS} , 300MHz) is in complete agreement with the spectrum of the compound of Example 3.

Elemental analysis (C ₂₅ H ₂₈ N SC1)

Theoretical C: 58.41, H: 5.49, N: 13.62

Found 58.11, H: 5.51, N: 13.46

Example 1 1

Production of 4- (6-chloronaphthylene-2-sulfonyl) -1- {ethyl (tri (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone

Cbz

1-Amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (1. OOg, 4.04 t), 1- (4-pyridyl)- 4-piperidone _{(78 2mg f 4 · 44mmol)} , acetic acid (243mg, 4. 04mmol), were charged ethanol (10 ml), at room temperature for 2 The mixture was reacted for 1.5 hours, and concentrated under reduced pressure.

Ethyl acetate (10.5 ml) was added to the concentrated residue, and sodium triacetoxyborohydride (8.0 OOg, 37.7 mmol) was added in a nitrogen stream at room temperature, followed by a reaction at room temperature for 3 days. After completion of the reaction, water was added to the reaction solution to carry out liquid separation and further extracted with 1N-hydrochloric acid (20 ml × 3). The aqueous layers were combined, sodium hydroxide (8.0 g) was added, and the mixture was extracted with ethyl acetate (20D11X3). The organic layers were combined, washed with city water (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

10% palladium carbon (50% water-containing, 880 mg, 0414 mmol), ethanol (35 ml), and ammonium formate (561 mg, 8.89 tmol) were charged to the concentrated residue in a 100-ml eggplant-type corben under a nitrogen stream. The mixture was stirred under reflux for 1 minute. After completion of the reaction, the catalyst was removed by filtration, sprinkled and washed with ethanol, and the filtrate was concentrated under reduced pressure.

A 10% aqueous solution of sodium carbonate (18 ml) and ethyl acetate (18 ml) are charged to the above concentrated residue, and 6-CNS [6-chloronaphthalene-2-sulfonyl chloride] (1.05 g, 4.04 mmol) is stirred at room temperature while stirring. ) And reacted at room temperature for 2.5 hours and left overnight. After completion of the reaction, water (36 ml) was added to the reaction solution, and the mixture was cooled on ice and the crystals were collected by filtration. Dry at 40 ° C under reduced pressure to obtain 4- (6_ chloro mouth naphthalene-2-sulfonyl) -triethyl [tri (4-pyridyl) -4-pyridinyl] amino} -2-piperazinone (1.36 g). Was. (64% yield)

_{(Check) NMR (CDC1 3, TMS,} 300MHz) is in complete agreement with the spectrum of the compound of Example 2.

Elemental analysis _{_{_{(C 26 H 3 .N 5 0}}} 3 SC1) '

Theoretical value C: 59.14, H: 5.73, N: 13.26

Measured value: C: 58.92, H: 5.70, N: 13.10

Example 1 2

Production of amino-4_ (6-chloro-naphthylene-2-sulfonyl) -2-piperazinone

9

cbz ^{ΝΗ ΝΗ2}

1-Amino-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (2.00 g, 8.00 tI) in a 100 ml eggplant-shaped flask under a nitrogen stream, methanol-modified ethanol Toluene (30 ml), tetrahydrofuran (20 ml), 10% palladium hydroxide (50 hydrate, 190 mg, 0.47 t) and ammonium formate (190 mg, 3.01 t) were heated and refluxed for 1 hour and 20 minutes. It was stirred under. After completion of the reaction, the catalyst was removed by filtration, sprinkled and washed with ethanol, and the filtrate was concentrated in vacuo by dividing into two portions.

To a half-minute (equivalent to 4.04 mmol) of the above concentrated residue, 10% aqueous sodium carbonate solution (6.lml) and ethyl acetate (6.lml) were charged, and the mixture was stirred at room temperature with stirring. -2-Suljoelk mouth ride (1.05 g, 4.04 olol) was added, and the mixture was allowed to react at room temperature for 2.5 hours and left overnight. After completion of the reaction, city water (13 ml) was added to the reaction solution, the mixture was cooled on ice, and the crystals were collected by filtration. Drying under reduced pressure at 40 ° C gave triamino-4- (6-chloronaphthylene-2-sulfonyl) -2-piperazinone (859 mg). (63% yield)

Water (6. lml), triethylamine (409 mg, 4.04 mmol) and tetrahydrofuran (6.1 ml) were charged into 1/2 minute (equivalent to 4.04 tmol) of the above concentrated residue, and stirred at room temperature while stirring. 6-Chloronaphthalene-2-sulfonyl chloride (1.05 g, 4. (Mmiiiol)) was added, the reaction was allowed to stand at room temperature for 1.5 hours, and the mixture was allowed to stand overnight After completion of the reaction, city water (13 ml) was added to the reaction mixture. After cooling on ice, the crystals were collected by filtration and dried under reduced pressure at 40 ° C. to give triamino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (1.13 g) (yield). (82%)

_{(Check) ¾ - NMR (CDC1 3,} TMS, 300MHz)

δ (ppm): 3.50 (2H, t, J = 4.5Hz), 3.66 (2H, t, J = 4.5Hz), 3.88 (2H, s), 4.41 (2H, s), 7.65 (1H, dd, J = 8.8 and 1.9 Hz), 7.84 (1H, dd, J = 8.8 and 1.9 Hz), 7: 90-8.10 (3H , m),

8.41 (1H, s),

Elemental analysis _{_{_{(C M H I4 N 3 0}}} 3 SC1)

Theoretical C: 49.49, H: 4.15, N: 12.37

Obtained C: 49.72, H: 4.06, N: 12.09

Example 13

Preparation of 4- (6-chloronaphthalene-2-sulfonyl) -1- (ethyl) [1- (4-pyridyl) -4-piperidinyl] amino 2-piperazinone

Sodium triacetoxyborohydride

1-Amino-4- (6-chloronaphthalene-2-sulfonyl) -2-piperazinone (800 mg, 2.35 mmol), acetic acid (8.Oml) and 1- (4- Pyridyl)-4-pyridone (435 mg, 2.47 bandol) was stirred at room temperature for 4 hours, and sodium triacetoxyborohydride (4.98 g, 23.5 mmol) was added for 1 hour 20 Minutes. The mixture was left overnight (15 hours and 30 minutes) and further stirred at room temperature for 8 hours and 10 minutes (total reaction at room temperature for 24 hours). A 4N aqueous solution of sodium hydroxide (40 ml) was added to the reaction solution, and the mixture was extracted with tetrahydrofuran / ethyl acetate (1: 1, 40 ml + 20 inlX2). The organic layers were combined, washed with water (100 mlX2), and concentrated under reduced pressure. . The residue was washed with methanol (4.5 ml) under reflux while heating, stirred under slow cooling and ice cooling, and the crystals were collected by filtration and sprinkled and washed with methanol (2.5 ml). Dry at 40 ° C under reduced pressure to give 4- (6-chloronaphthalene-2-sulfonyl)-1- {ethyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (835mg). Obtained. (67% yield)

-顧_{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with scan Bae spectrum of the compound of Example 1. Example 14 '

4- (6-chloronaphthalene-2-sulfonyl) -trimethyl (1- (4-pyridyl) -4-piberidi

-I-

1) 1 ^

, Borane dimethylamine complex

In a 200 ml four-necked flask, 3.85 g of 1-methylamino-2-oxo-4 -benzyloxycarbonyl-1,2,3,4-tetrahydropyrazine of the first fraction of Reference Example 6 (Daros weight, 13 Dissolve 2.50 g (13.82 mmol) of 1- (4-pyridyl) -4-piperidone in 70 ml of dehydrated ethanol, and add 4 N-hydrochloric acid / ethyl acetate 12. 10 ml (48.37 ol) were added dropwise at 22-24 ° C. After returning to room temperature and stirring for 15 minutes, 276 mg (4.61 hall) of polan 'dimethylamine complex was added, and the reaction was started at room temperature. Track reactions with HPLC While taking 7 hours and 45 minutes, the polan * dimethylamine complex 1.66 g (27.6 mol), 1- (4-pyridyl) -4-piperidone 6.25 g (34.55 t) and 4N-hydrochloric acid / ethyl acetate 26. 22 g (104.76 t) were added in small portions (Table 1). The reaction was performed for a total of 22 hours. The reaction solution was concentrated under reduced pressure, 50 ml of 1N-hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate (50 ml, 20 ml). The acidic aqueous layer was adjusted to pH 7.0 with a 5N aqueous sodium hydroxide solution, and extracted with ethyl acetate (200 ml × 1 time, 250 ml × 2 times). The aqueous layer was adjusted to pH 8.7 with a 5N aqueous sodium hydroxide solution, and further extracted with ethyl acetate (150 ml). The ethyl acetate extract layers were combined and washed with water (70 ml × 3 times). After drying over anhydrous magnesium sulfate and concentration under reduced pressure, 5.22 g of a pale yellow oily residue was obtained. This oil was analyzed by 'H-NMR for 4-benzyloxycarbonyl-1- [tri (4-pyridyl) -4-piberidinylmethylamino] -2-oxo- 1,2,3,4-tetrahydrido Lopyrazine was confirmed.

'H-NMR (CDC13 _> TMS, 300MHz)

δ (ppm): 1.44 to 1.82 (4H,), 2.82 (3H, s), 2.88 and 3.37 (4H, m), 3.78 (1H, br,), 4.28 (2H, q), 5.18 (2H, s) , 5.52 (1H, m), 6.19 (1H, m), 6.62 and 8.21 (4H, m), 7.35 (5H, s).

Reaction time and additional raw materials (Table 1)

Reaction time Additive Additive amount mg or ml (thigh ol)

0:00, piperidone body 2500mg (13.82 删 ol)

4N-HCl / AcOEt 12.10ml (48.37mmol)

276mg (4.61 ol)

0:30 'BH ₃ -Me ₂ NH 276ing (4.61 marauder.1)

1:00, BH ₃ -Me ₂ NH 276mg (4.61 thighs)

2:15 'piperidone 1250mg (6.91 brain ol)

4N-HCl / AcOEt 6.05ml (24.19 thigh.1)

3:00 'B¾-Me ₂ NH, 276ing (4.61 brain.1)

4:00 'Piperidone 1250mg (6.91mmol) 5:20 'piperidone 1250mg (6.91 strokes 1)

4N-HCl / AcOEt 6.05ml (24.19

5:50 'BH ₃ -Me ₂ NH 276mg (4.61 ol)

7:10 'BH ₃ -Me ₂ NH 276mg (4.61mmol)

7:45 '4N-HCI / AcOEt 2.02ml (8.02 thighs.1)

22:00 'End of reaction

Piperidone form: 1_ (4_pyridyl) -4- -piperidone 5.22 g of the above oily residue in 93 ml of dehydrated ethanol in 54 g of ammonium formate L (24.43 awake 01) and 2.33 g of 10% palladium on carbon (containing 50% water) Was added thereto, and the mixture was refluxed for 1 hour under a nitrogen stream. The mixture was returned to room temperature and concentrated under reduced pressure.

To the residue were added 79 ml of ethyl acetate and 79 ml of a 10% aqueous sodium carbonate solution, and 2.90 g (11.OO mmol) of 6-chloronaphthalene-2-sulfonyl chloride was added. The mixture was reacted at room temperature for 1.5 hours. After 100 ml of water was added to the reaction solution and ice-cooled, a white solid was collected by filtration. After washing with cold water (50 ml X 2 times), it is dried under vacuum at 40 ° C, and 4_ (6-chloro-naphthylene-2_sulfonyl) -trimethyl [1- (4-pyridyl) -4-piberidinyl] 3.49 g of crystals of amino} -2-piperazinone were obtained. (Yield 49%).

(Verification)

'H-NMR (CDCl ₃₁ TMS, 300 MHz) was completely consistent with the spectrum of the compound of Example 3. Elemental analysis _{_{_{(C 25 H 28 N 5 0}}} 3 SC1'0.5 0)

Theory C; 57.41, H; 5.59, N; 13.39.

Found C; 57.98, H; 5.52, N; 13.26.

Example 15

Production of 4- (6-chloronaphthalene-2-sulfonyl) methyl [1- (4-pyridyl) -4-piberidinyl] amino} -2-piperazinone

In a 200 ml four-necked flask, 3.90 g of trimethylamino-2-oxo-4-benzyloxycarbonyl-1,2,3,4-tetrahydropyrazine of the second fraction of Reference Example 6 (Daros weight, lO Oimol) and 1.81 g (10. Oinniol) of tri (4-pyridyl) -4-pyridone were dissolved in 50 ml of dehydrated ethanol. Under water cooling, 8.75 ml (35.0 tmol) of 4N-hydrochloric acid / ethyl acetate was added dropwise at 25 to 27 ° C. The water bath was removed, and PORAN 'dimethylamine complex (00 mg, 3.3 ol) was added, and the reaction was started at room temperature. While monitoring the reaction by HPLC, 1.20 g (20.0 olol) of polan 'dimethylamine complex, 3.62 g (30.0 mmol) of 1- (4-pyridyl) -4-piperidone, and 17.55 ml of 4N-hydrochloric acid / ethyl acetate (75.8 mmol) was slowly added over 9 hours and 10 minutes (Table 2). The reaction was completed in 23.5 hours. The mixture was concentrated under reduced pressure, 50 ml of 1N hydrochloric acid was added, and the mixture was washed with ethyl acetate (50 ml × 2 times). The acidic aqueous layer was adjusted to pH 8.0 with 1N-sodium hydroxide. Ethyl acetate extraction was performed (100 ml × 3 times). The aqueous layer was adjusted to pH 10 with 1H-sodium hydroxide, and further extracted with ethyl acetate (120 ml × 1). The extracted layers were combined, washed with water (50 ml × 3 times), and then dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure to obtain 3.50 g of a pale yellow oil. The oily substance is 4-benziloxycarponyl [1-(4-pyridyl) -4-piberidinylmethylamino] -2, -oxo- 1,2,3,4-tetrahydrovira Jin was confirmed. Table 2 Reaction time and additional raw materials (Table 2)

Reaction time Additives Caloric content mg or ml (miol)

0:00 'piperidone 1810mg (10.0 rol ol)

4N-HCl / AcOEt 8.75ml (17.5 ol)

BH ₃ -Me ₂ NH 200mg (3.33 ol) 0 40 'B¾ -Me ₂ NH 200fflg (3.33 腳 .1)

1 00 'BH ₃ -Me ₂ NH 200mg (3.33 thighs. 1)

1 15, 4N-HCl / AcOEt 4.40ml (17.5 麵 ol)

1 55 'BH ₃ -Me ₂ NH 200mg (3.33 ol)

3 45 'piperidone 905mg (5.00 bandol ol)

3 50, 4N-HCl / AcOEt 4.40ml (17.5mmol)

3 55 'BH ₃ -Me ₂ NH 200mg (3.33 strokes 1)

5 15 'piperidone 905mg (5.00 bun ol)

5 35 'BH ₃ -Me ₂ NH 200mg (3.31)

9 10 'BH ₃ -Me ₂ NH 200mg (3.

23 30 'Reaction completed

Piperidone: 1_ (4-pyridyl) -4-piperidone 3.50 g (7.64 mmol) of the above oil and 93 ml of absolute ethanol were charged, and ammonium formate 1.01 g (16.02 mol) and 10 % Pd-C (50 wet) 1.53g, in a nitrogen stream

The mixture was heated under reflux for 1 hour. After cooling to room temperature and removing the catalyst by filtration, the mixture was concentrated under reduced pressure.

To the above oily residue were added 50ffll of ethyl acetate and 50ffll of 10% aqueous sodium carbonate solution, followed by 1.90 g (7.64 bandol) of 6-chloronaphthalenesulfonyl chloride, and the mixture was vigorously stirred at room temperature for 1.5 hours. 100 ml of water was added to the reaction solution having a white precipitate, and the mixture was stirred under ice cooling, and the white precipitate was collected by filtration. After washing with cold water (30 Π 11 回 3 times), drying under vacuum at 40 ° C., 4- (6-chloronaphthalene-2-sulfonyl) -1--1- {methyl [1- (4-pyridyl) 2.61 g of 4--4-piperidinyl] amino} -2-piperazinone crystals were obtained (yield 51%).

(Verification)

E - field _{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with scan Bae spectrum of the compound of Example 3. Elemental analysis (C ₂₅ ¾ ₈ N ₅ 0 ₃ SC1)

Theory C; 58. 41, H; 5.49, N; 13. 62.

Found C; 58. 20, H; 5.44, N; 13. 41.

Example 16 Synthesis of 4- (6-chloronaphthalene-2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinyla: no] -2-piperazinone

In a 100 ml eggplant-shaped flask, 4- (6-chloro-naphthylene-2-sulfonyl)-1- [1- (4-pyridyl)-4-piperidinylideneamino piperazinone (959 mg, 1.91 mg ol) and ethanol (19 ml), and add a polan-dimethylamine complex (113 mg, 1.91 liters) under ice-cooling and stirring in a nitrogen stream, followed by a 4N hydrochloric acid / ethyl acetate solution (1. 3 ml, 5.73 thigh) was added. After stirring at the same temperature for 30 minutes, the reaction was carried out at room temperature for 3 hours. Further, a 4N-hydrochloric acid / ethyl acetate solution (0.25 ml, 1. (kmol)) was added and reacted for 3.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate (10 ml) was added to the residue. In addition, the mixture was extracted with city water (101111X2), the aqueous layers were combined, a 2N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml X3). The residue was washed with methanol (4 ml) while heating under reflux, cooled slowly, cooled on ice, and the crystals were collected by filtration. 2-sulfonyl) -1- [1- (4-pyridyl) -4-piperidinylamino] -2 piperazinone (789 mg) was obtained (yield 8 «).

Elemental analysis _{_{_{(C 24 H 26 N 5 0}}} 3 SC1)

Theoretical C: 57.65, H: 5.24, N: 14.01

Found: C: 57.49, H: 5.24, N: 13.94

Example 17

Preparation of 4- (6-chloro-naphthalene-2-sulfonyl) '-methyl {1 [4- (pyridyl) -4-piperidinyl] amino} -2-piperazinone

1).

Ethanol

; N

2〉 .Sodium borohydride, formic acid

, Tetrahydrofuran

1-Amino _4- (6-chloronaphthalene-2-sulfonyl) -2-pi Pelazinone (800 mg, 2.35 mmol), 1 (4-pyridyl) -4-piperidone (456 mg, 2.59 benzyl) and ethanol (8 ml) were charged, and the mixture was reacted under reflux for 14.5 hours and concentrated under reduced pressure.

Tetrahydrofuran (U. 8 ml) was added to the concentrated residue, and sodium borohydride (889 mg, 23.5 t ol) was added while stirring under ice-water cooling in a nitrogen stream, followed by formic acid (11.8 ml). It was dropped in 30 minutes. After stirring for 30 minutes as it was, the mixture was stirred at room temperature for 4 hours and left overnight. After completion of the reaction, the reaction solution was added to city water (10 ml) and 4N-sodium hydroxide aqueous solution (60 ml).

After washing with 0 mlX2), the mixture was concentrated under reduced pressure. The residue is washed with methanol (20 ml) while heating under reflux, stirred under ice-cooling, and the crystals are collected by filtration, sprinkled and washed with methanol, and dried under reduced pressure at 40 ° C to give 4- (6-chloronaphthalene-2-sulfonyl). ) -1- {Methyl [1- (4-pyridyl) -4-piperidinyl] amino} 2-piperazinone (884 mg) was obtained. (73% yield)

E -顧_{R (CDC1 3, TMS, 300MHz} ) is in complete agreement with scan Bae spectrum of the compound of Example 3. Elemental analysis value (C ₂₅ ¾ ₈ N ₅ 0 ₃ SC1)

Theoretical value C: 58.41, H: 5.49, N: 13.62

Measured value C: 58.33, H: 5.43, N: 13.60

Example 18

4- (6-chloronaphthalene-2-sulfonyl) -trimethyl (1- (4-pyridyl) -4-piberidi

In a 200 ml four-necked flask, 4- (6-chloronaphthalene-2-sulfonyl) -trimethylamino-2-piperazinone 2.27 g (6.42 t) and tri (4-pyridyl) -4-piperidone 1 Dissolve 71 g (9.70 ol) in 30 nil acetic acid and add a suspension of sodium triacetoxyborohydride (2.12 g, 10.0 mol ol) in 5 ml of acetic acid a at room temperature in a nitrogen stream. The mixture was stirred for 70 minutes, and then sodium triacetoxyborohydride (0.21 g, 0.99 toluene) was added, followed by stirring for 70 minutes. After completion of the reaction, city water (120 ml) and a 5N-hydric sodium hydroxide aqueous solution were added to the reaction solution to precipitate crystals. After stirring under ice-cooling, the crystals were collected by filtration, washed with city water, and further washed with methanol (lOffll). Dry at 50 ° C under reduced pressure to obtain 4- (6-chloronaphthalene-2-sulfonyl) -1_ {methyl [1- (4-pyridyl) -4-pyridinyl] amino} -2-piperazinone (3.04 g). Obtained.

(Yield 92%)

(Confirmation) iH-NMlUCDCls, TMS, 300 MHz) completely matched the spectrum of the compound of Example 3.

Elemental analysis value (C ₂₅ H ₂₈ N ₅ 0 ₃ SC1)

Theoretical C: 58.41, H: 5.49, N: 13.62

Measured value C: 58.27, H: 5.54, N: 13.60

Example 19

Production of 4- (6_chloronaphthalene-2-sulfonyl) -1- {methyl [1-1 (4-pyridyl) -4-piberidinyl] amino} -2-piperazinone

3) Triethylamine / ethyl acetate-water

, S0 ₂ C1

In a 200 ml four-neck flask, 13.96 g of 1-methylamino-2-oxo-4-benzyloxycarponyl-1,2,3,4-tetrahydropyrazine (weight of Daros, equivalent to 50.46 tmol) 1- (4-Pyridyl) -4-piperidone 18. lg (102.7 marl) was dissolved in 300 ml of acetic acid, and sodium triacetoxyborohydride (22.52 g, 106.3 tol) was dissolved in a nitrogen stream at room temperature. Of acetic acid (200 ml) was added, and the mixture was stirred as it was for 35 minutes. After completion of the reaction, city water (2 L) and ethyl acetate (2 L) were added to the reaction solution, and the mixture was separated. The organic layer was extracted with IN-hydrochloric acid (300Π11Π2). The aqueous layers were combined, adjusted to pH 8.0 with a 5N-sodium hydroxide aqueous solution, and extracted with ethyl acetate (2 L). The organic layer was washed with saturated saline (200nii), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a pale yellow oily residue (18.64 g). This oil is ¹ H-band R with 4-benzyloxycarbonyl-1- (1- (4-pyridyl) -4-piperidinylmethylamino) -2-oxo--1,2,3,4- It was confirmed to be tetrahydropyrazine.

_{. Ή - NMR (CDC1 3,} TMS, 300ΜΗζ) δ (pm): 1. 44~1 82 (4H,), 2. 82 (3H, s), 2. 88 a nd 3. 37 (4H, m) , 3.78 (1H, br,), 4.28 (2H, q), 5.18 (2H, s), 5.52 (1H, m), 6. 19 (1H, m), 6.62 and 8.21 (4H, m), 7.35 (5H, s).

Ethanol, ammonium formate 1.39 g (22.Ommol) and 10% palladium-carbon (containing 50 water) 1.05 g were added to 4.38 g of the above oily residue, and heated under a nitrogen stream for 1 hour and 20 minutes. Refluxed. After returning to room temperature, the catalyst was removed by filtration, washed with ethanol, and the filtrate was concentrated under reduced pressure.

To the residue were added 50 ml of tetrahydrofuran, 1.03 g (10.0 s) of triethylamine and 2.61 g (10.0 s) of 6-chloronaphthylene-2-sulfonyl chloride, and the mixture was reacted at room temperature for 4.5 hours. After adding 200 ml of water to the reaction solution and cooling with ice, a white solid was collected by filtration. After washing with methanol (20 ml), it was dried under vacuum at 40 ° C to give 4- (6-chloronaphthalene-2-sulfonyl) -1- (methyl [1- (4-pyridyl) -4- 3.71 g of crystals of [piberidinyl] amino} -2-piperazinone were obtained. (Yield 72%).

(Check) '.eta. Awakening: R (CDC1 _3, TMS, 300 MHz) was in complete agreement with the spectrum of the compound of Example 3.

Example 20

Production of 4- (6-chloronaphthalene-2-sulfonyl) -1- (propyl [1- (4-pyridyl) -4-piridinyl] amino} -2-piperazinone

4- (6-chloronaphthalene-2-sulfonyl) -tri [4- (pyridyl) -4-piberidinylamino] -2-piperazinone (300mg, 0.60mmol) Toluene (3 ml) and sodium borohydride (227 mg, 6.00 mol) were charged, and propionic acid (3 ml) was added dropwise with stirring under ice-water cooling. The mixture was stirred for 1 hour and reacted at room temperature for 4 days. After completion of the reaction, a 4N-sodium hydroxide aqueous solution (15 ml) and city water (15 ml) were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with city water (100 ml X2), and then concentrated under reduced pressure. The residue is washed with ethyl acetate / n-hexane under heating and reflux, stirred under ice-cooling, and the crystals are collected by filtration, dried at 40 ° C under reduced pressure, and dried with 4- (6-chloronaphthalene-2-sulfonyl) -triol. {Propyl [1- (4-pyridyl) -4-piridinyl] amino} -2-piperazinone (268 mg) was obtained. (82% yield) (Confirmation) 'H-NMR (CDCl _3l TMS, 300MHz) δ (ppm):-0.8-0.9 (3H, m), 1.2-2.1 (6H, m), 2.6-2.8 (4H, m), 3.1- 3.5 (5H, m), 3.5-3.9 (2H, m), 6.58 (2H, d, J = 6.4Hz), 7.6-7.7 (m, m), 7.7-7.8 (m, ra), 7.8-8.0 ( 3H, m), 8.1-8.3 (2H, m), 8.36 (1H, s) Example 21

4- (6-chloronaphthalene-2-sulfonyl) -tri (2-methoxyethyl [tri (4-pyridyl) -4

-Piperidinyl] amino} -Production of 2-piperazinone

4- (6-chloronaphthalene-2-sulfonyl) -nitro in a 100 ml eggplant-shaped flask

[4- (Pyridyl) -4-piperidinylamino]-2-piperazinone (300 mg, 0.60 ol), toluene (3 ml) and sodium borohydride (227 mg, 6.00 ol) were charged under ice-water cooling. With stirring, methoxyacetic acid (3 ml) was added. After stirring for 1 hour as is, at room temperature

The reaction was performed for 6 days. After completion of the reaction, water (15 ml) and 4N-sodium hydroxide aqueous solution a5 ml) were added to the reaction solution, and the mixture was extracted four times with ethyl acetate. The organic layers were combined, washed once with city water, and then concentrated under reduced pressure. The residue was washed with ethanol (3 ml) while heating under reflux, stirred under ice-cooling, and the crystals were collected by filtration, dried at 40 ° C under reduced pressure, and dried under 4- (6-chloronaphthalene-2-sulfonyl) -1-(2

-Methoxyethyl [1- (4-pyridyl) -4-piperidinyl] amino} -2-piperazinone (188 mg) was obtained. (56% yield)

(Check) - thigh _{(CDC1 3, TMS, 300MHz)} δ (ppm): 1.2-1.5 (2H, m), 1.5-1.7 (1H, m),

1.7-2.0 (1H, m), 2.7-2.9 (2H, m), 3.0-3.2 (1H, m), 3.2-4.0 (15H, m), 6.57 (2H, d, J = 5.2Hz), 7.62 ( 1H, dd, J = 8.7 and 1.7Hz), 7.80 (1H, dd, J = 8.7 and 1.7Hz), 7.8-

8.0 (3H, m), 8.24 (2H, d, J = 5.4Hz), 8.36 (1H, s)

MS (EI): (M ⁺ ) 557

Elemental analysis value (C _{27 2} N ₅ 0 ₄ SC1)

Theoretical C: 58.11, H: 5.78, N: 12.55

Found C: 57.91, H: 5.88, N: 12.33

Example 22

3-[Ethyl (3,4-dimethoxybenzyl) amino] -2- 2-oxo-1,3-thiazolidine-4- On manufacture

A 100 ml eggplant-shaped flask is charged with 3- (3,4-dimethoxybenzylideneamino) -2-thioxo-1,3-thiazolidine-4-one (634 mg, 2.14 mmol'l) and acetic acid (8 ml), and a nitrogen gas stream is supplied. With stirring at room temperature at room temperature, sodium triacetoxyborohydride (4.54 g, 21.4 mmol) was slowly added. After reacting for 10 days, sodium triacetoxyborohydride (10.2 g, 48.1 ol) and acetic acid (7 ml) were added. After the reaction was completed, water (15 ml) was added to the reaction solution, and a 4N-sodium hydroxide aqueous solution (50 ml), a 2N-sodium hydroxide aqueous solution (100 ml) and sodium hydroxide (3.00 g) were added, and the solid was added. Was deposited. After stirring under ice-cooling, the crystals are collected by filtration, sprinkled and washed with city water, and dried under reduced pressure at room temperature to give 3- [ethyl (3,4-dimethoxybenzyl) amino] -2-thioxo-1,3-thiazolidine. -4-one (456 mg) was obtained. (64% yield)

(Confirmation) -NMR (CDCl ₃ , TMS, 300MHz)

δ (ppm): 1.07 (3H, t, J = 7.2Hz), 3.2-3.4 (2H, m), 3.74 (1H, dd, J = 32 and 18Hz), 3. 84 (2H, s), 3.86 (2H, s), 4.38 (1H, dd, J = 54 and 12Hz), 6.74 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 8.1 and 1.6Hz), 7.16 (1H, d, J = l.7Hz)

Example 2 3

Preparation of 3- [ethyl (3-phenyl-2-probenyl) amino] -2-thioxo-1,3-thiazolidine-4-one

In a 100 ml eggplant-shaped flask, 3-[(3-phenyl-2-propenylidene) amino] -2-thioxo-1,3-thiazolidine-4-one (500 mg, 1.91 t ol) and acetic acid (10 ml) , Sodium triacetoxyborohydride (4.05 g, 19.1 mmol) was slowly added thereto while stirring at room temperature in a nitrogen stream, and the mixture was reacted for 39.5 hours. After completion of the reaction, city water (70 ml) and sodium hydroxide (10 g) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 m 2). Combine organic layers After washing with city water (lOOral), the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was further dried under reduced pressure to give 3- [ethyl (3-phenyl-2-butenyl) amino] -2-thioxo-1,3-thiazolidine-4-one (400 mg). (Yield 72)

_{(Check) - NMR (CDC1 3, TMS} , 300MHz)

δ (pm): 1.10 (3H, t,] = 7.23Hz), 3.45 (2H, t, J-7.2Hz), 3.77 (2H, dd, J = 26.9 and 1 8.1Hz), 4.0-4.2 (2H, m), 6.1-6.3 (1H, m), 6.56 (1H, d, J = 15.8Hz), 7.2-7.4 (5H, m) MS (FAB) :( MH ⁺ ) 293

Elemental analysis _{_{_{(C 14 H 16 N 2 0S}}} )

Theoretical C: 57.50, H: 5.52, N: 9.58

Obtained C: 57.65, H: 5.42, N: 9.51

Example 24

Preparation of 1- [methyl (3,4-methylenedioxybenzyl) amino] homopiperidine hydrochloride

A 100 ml eggplant-shaped flask is charged with nitrogen (3,4-methylenedioxybenzylideneamino) homopiperidine (500 mg, 2.03 IMO1), toluene (5 ml) and sodium borohydride (768 mg, 20.3 mmol) in a nitrogen stream. Formic acid (3 ml) was added dropwise while stirring under ice-water cooling. After stirring for 1 hour as it was, the reaction was allowed to proceed at room temperature for 3 days, and sodium borohydride (386 mg, 10.2 rinse) and formic acid (2.5 ml) were added during the reaction. After the reaction was completed, a 4N-sodium hydroxide aqueous solution (35 ml) and water (20 ml) were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with city water (15 (kl), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The ethyl acetate (7.5ral) and 4N-hydrochloric acid / ethyl acetate (1.02 ml,

4. O61M10I) was added to precipitate crystals. After stirring under ice-cooling, the crystals are collected by filtration, sprinkled and washed with ethyl acetate, dried under reduced pressure at room temperature, and dried with 1- [methyl (3,4-methylenedioxybenzyl) amino] homopiperidine hydrochloride (496 mg). ). (82% yield)

(Check) E- Ran _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 1.6-1. cold, m), 2.3-2.4 (2H, br), 2.56 (3H, s), 3.2-3.3 (2H, m), 3.7-3.9 (2H, m), 4.14 (2H, s), 5.95 (2H, s), 6.7-6.9 (3H, m), 13.6 (1H, br) MS (EI): (M ⁺ ) 262

Elemental analysis _{_{_{(C 16 H 25 N 2 0}}} 2 C1)

Theoretical value: C: 60.29, H: 7.76, N: 9.38

Found C: 60.19, H: 7.82, N: 9.36

Example 25

Preparation of 1- [1-methoxyethyl (3,4-methylenedioxybenzyl) amino] homopiperidine hydrochloride

1- (3,4-Methylenedioxybenzylideneamino) homopiperidine (500 mg, 2.03 mmol), toluene (5 ml) and sodium borohydride (768 mg, 20.3 mmol) were placed in a 100 ml eggplant-shaped flask in a nitrogen stream. While charging and stirring under ice-water cooling, methoxyacetic acid (5 ml) was added dropwise. The mixture was stirred for 1 hour and reacted at room temperature for 4 days. Toluene (2.

5 ml). After completion of the reaction, a 4N aqueous solution of sodium hydroxide (75 ml) and city water (20 ml) were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with city water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (4.5 ml) and 4N-hydrochloric acid / ethyl acetate (1.02 ml, 4.06 mmol) were added to the concentrated residue to precipitate crystals. After stirring under ice-cooling, the crystals are collected by filtration, sprinkled and washed with ethyl acetate, dried under reduced pressure at room temperature, and dried.

[Trimethoxyethyl (3,4-methylenedioxybenzyl) amino] homopiperidine hydrochloride (541 mg) was obtained. (78% yield)

(Check) '.eta. anonymous _{R (CDC1 3, TMS, 300MHz} )

δ (Sir): 1.6-221 (6Η, in), 2.3-2-24 (2H, br), 3.0-3.4 (9H, m), 3.6-3.9 (2H, m), 4.

29 (2H, s), 5.95 (2H, s), 6.7-6.9 (3H, m), 13.3 (1H, br)

MS (EI): (M ⁺ ) 306

Elemental analysis _{_{_{(C 16 H 25 N 2 0}}} 2 C1)

Theoretical C: 59.55, H: 7.94, N: 8.17

Measured value: C: 59.33, H: 7.81, N: 8.04

Example 26 1-[Ethyl (3, 4-, 'Hydrochloride production

A 1- (3,4-; no) homopiperidine (500 mg, 2.03 bandol) and acetic acid (10 ml) are charged into a 100-ml eggplant-shaped flask, and sodium triacetoxyborohydride (4.30 g) is stirred in a nitrogen stream at room temperature at room temperature. , 20.3 bandits) and reacted for 33.5 hours. After completion of the reaction, city water (20 ml) and 4N-sodium hydroxide aqueous solution (75 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layers were combined, washed with city water (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the concentrated residue, ethyl acetate (3 ml) and 4N-hydrochloric acid / ethyl acetate (1.02 ml, .06 marl) were added to precipitate crystals. After stirring under ice-cooling, the crystals were collected by filtration, sprinkled and washed with ethyl acetate, and dried under reduced pressure at room temperature to give 1- [ethyl (3,4-methylenedioxybenzyl) amino] homopiberidine hydrochloride (534 mg). Obtained. (Yield 84%)

(Check) Ή -丽_{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 0.99 (3H, t, J = 6.3Hz), 1.4-1.9 (7H, m), 2.2-2.4 (1H, br), 2.9-3.4 (5H, m), 3.7-3.9 (1H, br), 4.1-4.3 (2H, m), 5.95 (2H, s), 6.7-7.0 (2H, m), 7.1-7.4 (1H, m), 13.3 (1H, br)

MS (EI): (M ⁺ ) 276

Elemental analysis _{_{_{(C 16 H 25 N 2 0}}} 2 C1)

Theoretical value C: 61.43, H: 8.05, N: 8.95

Obtained C: 61.15, H: 7.91,: 8.74

Example 27

Preparation of [Edyl (3,4-methylenedioxybenzyl) amino] piperidine hydrochloride

1). Triacetoxyborohydride

Sodium, acetic acidn I

2) Hydrochloric acid / ethyl acetate

In the same manner as in Example 26, 1- (3,4-one (500 mg, 2.15 tmol) was converted to 1- [ethyl (3,4-methylenediol). Peridine hydrochloride (583 mg) was obtained (yield 91%).

_{(Check) Ή- NMR (CDC1 3, TMS} , 300MHz)

δ (ρριη): 1.0-2.1 (8Η, br), 2.60 (1H, br), 2.8-3.2 (5H, br), 3.58 (1H, br), 4.18 (2H, br), 5.95 (2H, s) , 6.79 (1H, d, J = 7.5Hz), 6.7-7.4 (2H, m), 13.4 (1H, br) MS (EI): (M ⁺ ) 262

Elemental analysis value (C ₁₅ H ₂₃ N ₂ 0 ₂ CI)

C: 60.29, H: 7.76, N: 9.38

As in Example 26, 1- (3,4-methylenedioxybenzylideneamino) pyrrolidine> (450 mg, 2.06 ol) to 1- [ethyl (3,4-methylenedioxybenzyl) amino] pirate Lysine hydrochloride (453 mg) was obtained (yield 77%).

(Check) '.eta. negation _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 1.13 (3H, i, J = 6.8Hz), 1.8-2.2 (4H, m), 3.10 (3H, i, J = 6.9Hz), 3.0-3.5 (2H, br), 3.7-3.9 (1H, br), 4.1 (2H, br), 5.95 (2H, s), 6.7-7.0 (3H, m), 13.6 (1H, br)

MS (EI): (M ⁺ ) 248

Elemental analysis _{_{_{(C 14 H 21 N 2 0}}} 2 C1)

Theoretical C: 59.05, H: 7.43, N: 9.84

Obtained C: 59.03, H: 7.28, N: 9.79

Example 29

Production of 1- [ethyl (3,4-methylenedioxybenzyl) amino] morpholine hydrochloride

In the same manner as in Example 26, tri [ethyl (3,4-methylenedioxybenzyl) amino] morpholine hydrochloride was obtained from tri (3,4-methylenedioxybenzylideneamino) morpholine (500 mg, 2.13 marl ol). (583 mg) was obtained (80% yield).

(Check) '.eta. negation _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 1.48 (3H, br), 3.0-3.4 (2H, br), 3.76 (4H, br), 4.1-4.4 (2H, br), 5.98

(2H, s), 6.79 (1H, d, J = 8.0Hz) '7.0-7.3 (2H, m), 13.7 (1H, br)

MS (EI): (M ⁺ ) 264

Elemental analysis _{_{_{(C 16 H 27 N 2 0}}} 2 C1)

Theoretical C: 55.91, H: 7.04, N: 9.31

Found: C: 55.45, H: 7.04, N: 9.14

Example 30

Preparation of 1- [ethyl (3,4-methylenedioxybenzyl) amino] -4-methylpiperazine hydrochloride

[Mino] -4-methylpiperazine hydrochloride (435 mg) was obtained (yield 67%).

_{(Check) 'Η- NMR (CDC1 3,} TMS; 300MHz)

δ (ppm): 1.24 (3H, br), 2.7-3.0 (7H, m), 3.1-3.7 (6H, m), 3.9 (2H, br), 5.97 (2H, s), 6.7-7.1 (3H, br) m), 13.0 (1H, br)

MS (EI): (M ⁺ ) 277

Elemental analysis _{_{_{(C 15 H 24 N 3 0}}} 2 Cl-2.5H 2 0)

Theoretical value C: 50.20, H: 8.15, N: ll.71

Obtained C: 50.49, H: 8.09, N: ll.68

Example 31

[Ethyl (2-hydroxy-3-methoxybenzyl) amino] homopiperidine hydrochloride

In the same manner as in Example 26, the compound (2-hydroxy-3-meth-

1- [Ethyl (2-hydroxy-3-methoxybenzyl) amino] homopiperidine hydrochloride (420 mg) was obtained from peridine (500 mg, 2.01 liter) (67% yield).

(Check) E- Awakening: _{R (CDC1 3, TMS, 300MHz} )

δ (ppm): 0.6-2. 1 (9H, br), 3.0-3.6 (6H, br), 3.89 (3H, s), 4.3 (2H, br), 6 . 0-7. 8

(4H 'br), 12.9 (1H, br)

MS (EI): (M ⁺ ) 258

Elemental analysis _{_{_{(C 16 H 27 N 2 0}}} 2 C1)

Theoretical value C: 61.04, H: 8.64, N: 8.90

Measured value: C: 60.72, H: 8.30, N: 8.79

Example 3 2

Preparation of 1- [Ethyl (3-phenyl-2-probenyl) amino] homopiperidine hydrochloride

1). Sodium triacetoxyborohydride, acetic acid

2) Hydrochloric acid / ethyl acetate

• HC1

1-Aminohomopiperidine (687 mg, 6.02 mmol), trans-cinnamaldehyde (796 mg, 6.02 mmol) and ethanol (8 ml) were added to a 100 ml eggplant-shaped flask, and the mixture was reacted under reflux for 8 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Acetic acid (28 ml) was added to the residue, and sodium triacetoxyborohydride (12.8 g, 60.2 mmol) was slowly added thereto with stirring in a nitrogen stream at room temperature, followed by a reaction for 38.5 hours. After completion of the reaction, city water (56 ml) and a 4N aqueous solution of sodium hydroxide (160 ml) were added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with city water (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (1 Omi) and 4N-hydrochloric acid / ethyl acetate (3 ml) were added to the concentrated residue. The mixture was concentrated under reduced pressure, and the residue was crystallized by adding ethyl acetate and n −. Ice cold After stirring under reduced pressure, the crystals are collected by filtration, sprinkled and washed with ethyl acetate, and dried under reduced pressure at room temperature to give 1- [ethyl (3-phenyl-2-probenyl) amino] homopiperidine hydrochloride (1.16 g). Obtained. (65% yield)

(Confirmation) 'H-NMR CDCls, TMS, 300MHz)

δ (ppm): 1.1-2, 5 (11H, m), 3.0-3.5 (4H, m), 3.6-4.2 (2H, m), 6.1-6.8 (2H, m), 7.2-7.6 (5H , m), 13.1-13.6 (1H, br)

MS (EI): (M ⁺ ) 258

Elemental analysis _{_{_{(C 17 H 27 N 2 C1}}} )

Theoretical C: 69.25, H: 9.23, N: 9.50

Found C: 69.06, H: 9.18, N: 9.42 Industrial applicability

According to the present invention, easily available raw materials can be used, and short-term and convergent production routes can be carried out under easy and safe conditions such as handling of reagents and wastes. A hydrazine derivative by reduction with an amine polan complex at 25 ° C or higher; (2) a method of alkylating a hydrazine derivative with a combination of a borohydride complex compound and a carboxylic acid or a trisiloxyborohydride complex compound; (3) A method for producing a hydrazine derivative by reducing and alkylating a hydrazone derivative with a combination of a borohydride complex compound and carboxylic acid or a trisiloxyborohydride complex compound; (4) Two replacement of the reacting nitrogen atom Hydrazine derivative is converted to hydrazine derivative in the presence of an amamine porane complex with a melting point of 25 ° C or higher. (5) Reduction of primary amino group of hydrazine derivative by combination of borohydride complex compound and sulfonic acid or trisyloxyborohydride complex compound · Alkylation reaction and reductive reaction by carbonyl compound A method for producing a 3-substituted hydrazine derivative by subjecting it to an alkylation reaction; (6) having a nitrogen-containing heterocycle, and (i) an unsubstituted amino group (primary amino group) And (ii) a method for selectively sulfonylamidating a secondary amino group of a hydrazine derivative having a nitrogen atom having a hydrogen atom (secondary amino group).

Claims

Claims Formula (I)

[Wherein, R ¹ , R ² ,: ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group; And R ¹ R ² , R ³ and R ⁴ may combine with each other to form a ring.] The hydrazone derivative represented by the formula or a salt thereof is reduced with a polanamine complex having a melting point of 25 ° C or more. Characteristic formula (II)

[Wherein the symbols are as defined above], or a method for producing a hydrazine derivative or a salt thereof.

2. R ¹ is the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and R ⁷ represents R ² And X ¹ represents a bond, an optionally substituted alkylene group or an optionally substituted imino group, and D represents an oxygen atom or a sulfur atom.) The production method according to claim 1, which is a group represented by the formula.

3. Expression

Is a group represented by the formula

(Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and D represents an oxygen atom or a sulfur atom). Production method as described.

4. Expression

Is a group represented by the formula

2. The method according to claim 1, wherein R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom.

5. Equation (II)

[In the formula, R ¹ R ² , R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group. , RR ² , R ³ and R ⁴ may be bonded to each other to form a ring], or a triacyloxyborohydride complex compound, or a borohydride complex compound; Formula (IIII) characterized by reacting with a carboxylic acid represented by the formula R ⁵ ′ —COOH, wherein R ⁵ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group.

[Wherein the symbols have the same meanings as described above].

6. R ¹ is the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and R ⁷ represents R ² And X ¹ represents a bond, an optionally substituted alkylene group or an optionally substituted imino group, and D represents an oxygen atom or a sulfur atom.) 6. The production method according to claim 5, which is a group represented. '

7. Expression

Is a group represented by the formula

8. Expression

Is a group represented by the formula

Wherein, R ^s represents a protecting group for the nitrogen atom, D is an oxygen atom or a sulfur atom] The process according to claim 5, wherein a group represented by.

9.

Expression (.1)

[In the formula, R ¹ R ² , R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group. , RR ² , R ³ and R ⁴ may be bonded to each other to form a ring], or a trisiloxyborohydride complex compound, or Reacting with a carboxylic acid represented by the formula R ⁵ ′ —COOH, wherein R ⁵ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group.

[Wherein the symbols have the same meanings as described above], a method for producing a hydrazine derivative or a salt thereof. '

10. R ¹ is the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and R ⁷ represents R ² And X ¹ represents a bond, an optionally substituted alkylene group or an optionally substituted imino group, and D represents an oxygen atom or a sulfur atom.) 10. The production method according to claim 9, which is a group represented.

11 expressions

Is a group represented by the formula

D

N-

(Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and D represents an oxygen atom or a sulfur atom).

9. The production method according to 9.

12. Expression

Is a group represented by the formula

10. The method according to claim 9, wherein R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom.

13. Equation (IV)

¹ and R ² may combine with each other to form a ring, and R ⁵ represents an optionally substituted hydrocarbon group.]

(1) Formula (V) in the presence of a polanamine complex having a melting point of 25 or more

[Wherein, R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group,

^And R ⁴ may combine with each other to form a ring] or a salt thereof;

(2) Trisiloxyborohydride complex compound and formula (V)

Wherein each symbol is as defined above, or with a carbonyl compound represented by the formula:

(3) a borohydride complex compound, a carboxylic acid represented by the formula R ⁵ ′ —COOH, wherein R ⁵ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group, and a compound represented by the formula (V)

Wherein each symbol is as defined above, or a salt thereof.

14. R ¹ is the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and R ⁷ represents R ² And X ¹ represents a bond, an optionally substituted alkylene group or an optionally substituted imino group, and D represents an oxygen atom or a sulfur atom.) 14. The production method according to claim 13, which is a group represented.

15. Expression

Is a group represented by the formula WO 01/66541 _ PCT / JPOl / 01750

113

(Wherein, R ^s represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and D represents an oxygen atom or a sulfur atom). Production method as described.

16. Expression

Is a group represented by the formula

14. The production method according to claim 13, wherein R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom.

17.

Formula (IV ')

Wherein R ¹ and R ² represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group optionally, substituted heterocyclic group or an optionally substituted Ashiru group, R ¹ and R ² May combine with each other to form a ring.

^And R ⁴ may combine with each other to form a ring] or a borohydride complex compound represented by the formula: R ⁵ '-COO

A carboxylic acid represented by H [wherein R ⁵ ′ represents a hydrogen atom or an optionally substituted hydrocarbon group], and a compound represented by the formula (V)

Wherein each symbol is as defined above, or a salt thereof.

18. R ¹ is the formula

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, R ⁷ represents an optionally substituted hydrocarbon group, and R ⁷ represents R ² And X ¹ represents a bond, an optionally substituted alkylene group or an optionally substituted imino group, and D represents an oxygen atom or a sulfur atom.) 18. The production method according to claim 17, which is a group represented.

1 9 Expression

Is a group represented by the formula

17. The production method according to 17.

2 0. Expression

1

R

Is a group represented by the formula

18. The method according to claim 17, wherein R ⁸ represents a protecting group for a nitrogen atom, and D represents an oxygen atom or a sulfur atom.

2 1.

Wherein η represents 1 or 2, m represents 2 or 3, and D represents an oxygen atom or a sulfur atom.

s

[Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an optionally substituted complex ring group, and W represents a halogen atom.] Or a salt thereof. An expression characterized by

[Wherein the symbols are as defined above] or a method for producing a salt thereof.

22. The method according to claim 21, wherein the reaction is carried out in the presence of a base.

23. The production method according to claim 21, wherein n is 1 and 2 is 2.