HK1077066B - Novel piperidine compound - Google Patents

Description

Novel piperidine compounds

Technical Field

The present invention relates to novel piperidine compounds having an excellent tachykinin receptor antagonistic action.

Background

Tachykinins are common names for a group of neuropeptides, and substance P (hereinafter SP), neurokinin-a, and neurokinin-B have been known in mammals. These peptides are known to exhibit various types of biological activities by binding to their corresponding receptors (neurokinin-1, neurokinin-2, neurokinin-3) present in the body. Among them, SP is one of those having the longest history among neuropeptides, and has been studied in detail. Its presence was confirmed in 1931 in an extract of the equine intestinal tract, which is a peptide comprising 11 amino acids, the structure of which was determined in 1971.

SP is widely present in the peripheral nervous system, and has physiological activities such as vasodilation, vascular permeability-promoting action, smooth muscle contraction, hyperexcitability (neuronal excitation) action, salivation, diuretic action, immunological action, etc., and neurotransmitter function of primary sensory neurons. In particular, it is known that SP released from the posterior horn end of the spinal cord upon pain stimulation transfers pain information to secondary neurons, and SP released from the peripheral end induces inflammatory response of receptors. From these facts, SP is considered to be associated with various diseases (e.g., pain, inflammation, allergy, pollakiuria, urinary incontinence, respiratory diseases, mental diseases, depression, uneasiness, vomiting, etc.), and SP is considered to be associated with dementia of the alzheimer type [ review: physical Reviews, volume 73, pages 229-308 (1993), Journal of Automic Pharmacology, volume 13, pages 23-93 (1993).

At present, as a therapeutic agent for the above-mentioned various diseases (particularly for emesis, depression, urinary disturbance, etc.), any compound having an excellent tachykinin receptor antagonistic action (specifically, SP receptor antagonistic action) while having sufficiently satisfactory safety, sustainability (metabolism, in vivo kinetics, and absorption), etc. has not been found. Therefore, a compound having an excellent tachykinin receptor antagonistic action and having a sufficiently satisfactory clinical effect has been sought as a therapeutic agent.

Accordingly, it is an object of the present invention to provide a compound which has excellent tachykinin receptor antagonistic action and satisfactory clinical effects in terms of safety, sustainability (metabolism, in vivo kinetics and absorption), and the like.

Summary of The Invention

The present invention relates to a piperidine compound represented by the formula [ I ] or a pharmaceutically acceptable salt thereof:

wherein ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, R₁Represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group represented by the formula:

wherein R is¹¹And R¹²Are the same or different and are each a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, and the nitrogen atom contained in the heterocyclic group is optionally oxidized, or R ¹¹And R¹²Together with the adjacent nitrogen atom, form a heterocyclic ring selected from: piperidino, azepinyl, pyrrolidino, imidazolidinyl, hexahydropyrimidyl, thiazolidinyl, morpholino, triazolyl, tetrazolyl, and purinyl, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized, and R is₂Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by-N (R)³) A group represented by (a) wherein R is₃Represents a hydrogen atom or an optionally substituted alkyl group, R⁴Represents a hydrogen atom or an optionally substituted alkyl group.

In the present invention, ring a represents an optionally substituted benzene ring, and the benzene ring substituent is exemplified by an alkyl group, a halogen atom, a cyano group, an optionally protected hydroxyl group or an alkoxy group. Ring A may have 1 to 3 of these same or different substituents.

In the present invention, ring B represents an optionally substituted benzene ring, and the substituents of the benzene ring are exemplified by trihaloalkyl, a halogen atom, cyano, phenyl, a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, alkyl, optionally protected hydroxyl or alkoxy. The ring B may have 1 to 3 of these same or different substituents.

A preferred example of ring a and ring B in the compound of the present invention is exemplified by a compound wherein ring a is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹，A²And A³Identical or different and are each a hydrogen atom, a halogen atom, an alkyl group, an optionally protected hydroxyl or alkoxy group,

B¹，B²and B³Identical or different and are each a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, an alkyl group, an optionally protected hydroxyl group or an alkoxy group. The trihaloalkyl group is exemplified by trifluoromethyl, trichloromethyl and the like. The heterocyclic group is exemplified by tetrazolyl and the like.

In the present invention, the protecting group of the optionally protected hydroxyl group is exemplified by conventional protecting groups such as an optionally substituted aralkyl group, an optionally substituted silyl group and an acyl group. Among the above, preferred are aralkyl groups such as benzyl and phenethyl groups, substituted silyl groups such as t-butyldimethylsilyl and t-butyldiphenylsilyl groups, and acyl groups such as formyl, acetyl, propionyl, malonyl, acryloyl and benzoyl groups.

In the present invention, R¹Is an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group represented by the formula:

Wherein R is¹¹And R¹²Are the same or different and are each a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized, or R¹¹And R¹²Together with the adjacent nitrogen atom, form a heterocyclic ring selected from: piperidino, azepinyl, pyrrolidino, imidazolidino, hexahydropyrimidyl,thiazolidinyl, morpholino, triazolyl, tetrazolyl and purinyl groups, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized.

Among the above, R¹Preferably an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group represented by the formula:

wherein R is¹¹And R¹²Are the same or different and are each a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized,

More preferably an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group represented by the formula:

wherein R is¹¹Is a substituted carbonyl group, a substituted sulfonyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized, R is¹²Is a hydrogen atom, an optionally substituted alkyl group, a substituted carbonyl group, a substituted sulfonyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic groupThe metal ions are optionally oxidized by an oxidizing agent,

in the present invention, R¹The substituent for the optionally substituted alkyl group of (a) is exemplified by alkoxycarbonyl, morpholinocarbonyl, pyridylaminocarbonyl, morpholinoaminocarbonyl, alkoxyphenyl-substituted piperidinocarbonyl (piperidinocarbonyl), dialkylaminocarbonyl, hydroxy, hydroxyalkylaminocarbonyloxy or alkylpiperazinocarbonyl (alkylpiperazinocarbonyl).

In the present invention, R ¹The substituent for the optionally substituted hydroxyl group of (2) is exemplified by

(1) A substituted carbonyl group,

(2) a substituted sulfinyl group,

(3) substituted sulfonyl radicals or

(4) Optionally substituted alkyl.

The substituent of the substituted carbonyl group in the above (1) is exemplified by optionally substituted alkyl, optionally substituted alkoxy, substituted amino, a monocyclic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom and an oxygen atom as a hetero atom (the monocyclic heterocyclic group being optionally substituted). The substituent of the optionally substituted alkyl group is exemplified by a hydroxyl group. The substituent of the optionally substituted alkoxy group is exemplified by an alkoxy group, a hydroxyl group or a halogen atom. The substituent of the substituted amino group is exemplified by an alkyl group substituted with a group selected from: halogen atom, dialkylamino group, piperidyl group, morpholino group, carboxyl group, morpholinocarbonyl group, dialkylaminocarbonyl group, alkylaminocarbonyl group, alkanoylamino group, alkylthio group, alkoxy group, alkylsulfonyl group, alkanoyloxy group and hydroxyl group; a hydroxyalkanoyl or alkoxyalkanoyl substituted piperidinyl group; or a dialkylaminosulfonyl group. Monocyclic heterocyclic groups are exemplified by morpholino, piperazinyl, imidazolyl, thiomorpholino, piperidino, furyl, tetrahydrothiazolinyl or pyrrolidinyl (pirrolidinyl). The substituent for the monocyclic heterocyclic group is exemplified by alkyl which may be substituted by hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or morpholino, oxo or hydroxy.

The substituent for the sulfinyl group substituted in the above (2) is exemplified by an alkyl group or a thienyl group.

The substituent of the sulfonyl group substituted in the above (3) is exemplified by an alkyl group or a thienyl group.

The substituent for the optionally substituted alkyl group in the above (4) is exemplified by an optionally substituted hydroxyl group, a dialkylamino group or a monocyclic heterocyclic group (monocyclic heterocyclic group is optionally substituted) containing 1 to 4 atoms selected from the group consisting of a sulfur atom, a nitrogen atom and an oxygen atom as a hetero atom. The substituent for the optionally substituted hydroxyl group is exemplified by alkyl, alkylsulfonyl or tetrahydropyranyl. Monocyclic heterocyclic groups are exemplified by pyridyl, piperidyl, morpholino, isoxazolyl, triazolyl, tetrazolyl or pyrrolidinyl. The substituent of the monocyclic heterocyclic group is exemplified by alkyl or phenyl.

In the present invention, R¹The substituent of the substituted thiol group of (a) is exemplified by a substituted phenyl group, a substituted carbonyl group or an optionally substituted alkyl group. The substituent of the substituted phenyl group is exemplified by hydroxy. The substituent of the substituted carbonyl group is exemplified by alkyl. The substituent for the optionally substituted alkyl group is exemplified by alkylaminocarbonyl, dialkylaminocarbonylalkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino, alkanoyloxy or hydroxy.

In the present invention, R¹The substituent of the substituted carbonyl group of (a) is exemplified by a hydroxyl group, an alkoxy group, an optionally substituted amino group or a monocyclic heterocyclic group (monocyclic heterocyclic group being optionally substituted) containing 1 to 4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom as hetero atoms. The substituent of the optionally substituted amino group is exemplified by a group selected from: pyridyl optionally substituted with hydroxy, pyrimidinyl, alkylpyrido (pyrido), pyrazinyl, and alkyl optionally substituted with hydroxy or cyano. Monocyclic heterocyclic groups are exemplified by piperidino, piperazino, morpholino, thiomorpholino or pyrrolidino. Monocyclic heterocyclic radicalsThe substituent is exemplified by alkyl, hydroxy, oxo (oxo group), pyrimidinyl, pyrazinyl, alkylsulfonyl, alkanoyl or hydroxyalkyl.

In the present invention, R¹The substituent of the substituted sulfinyl group of (a) is exemplified by a hydroxyl group or an optionally substituted alkyl group. The substituent of the optionally substituted alkyl group is exemplified by a hydroxyl group.

In the present invention, R¹The substituent of the substituted sulfonyl group of (a) is exemplified by an optionally substituted alkyl group. The substituent of the optionally substituted alkyl group is exemplified by a hydroxyl group or an alkanoyloxy group.

In the present invention, when R is ¹Is a group of the formula:

(1)R¹¹and R¹²The substituent of the substituted carbonyl group of (a) is exemplified by an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, a substituted amino group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, and the nitrogen atom contained in the heterocyclic group is optionally oxidized. The substituent for the optionally substituted alkyl group is exemplified by alkylaminocarbonyl, dialkylaminocarbonyl in which the alkyl moiety thereof is optionally substituted by hydroxy, aminocarbonyl, alkoxycarbonylamino, alkanoylamino, amino substituted by alkoxycarbonyl and alkyl, amino substituted by alkanoyl and alkyl, alkoxy, halogen, tetrazolyl, pyridyl, furyl, hydroxy, alkylthio, 2-oxopyrrolidino, 2-aminothiazolyl, 2-thiol-4-alkylthiazolyl, 2, 2-dialkyl-1, 3-dioxolanyl, cycloalkyl, alkylsulfinyl, alkylsulfonyl, thienyl, 5-methyl-2, 4(1H, 3H) pyrimidinedione, amino or dialkylamino. The substituent of the optionally substituted aryl group is exemplified by nitro or amino, and the aryl group is exemplified by phenyl, naphthyl, phenanthryl or anthryl. Examples of substituents of substituted amino groups As the alkyl group optionally substituted with a group selected from a halogen atom, an alkoxy group and a hydroxyl group, an amino group is mono-or di-substituted. The heterocyclic group is exemplified by a saturated or unsaturated monocyclic or bicyclic aromatic heterocyclic group such as thienyl, furyl, tetrahydrofuryl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzopyranyl, indolyl, isoindolyl, indazolyl, purinyl, quinolizinyl, 1, 5-diazanaphthyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, benzothiazolyl, benzisothiazolyl, quinazolinyl, 2, 3-diazanaphthyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isobenzodihydrofuranyl, benzodihydrofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, dihydro-2, 3-naphthyridinyl, and the like. Among these heterocyclic groups, pyridyl, pyrrolidinyl, piperazinyl, quinolyl, piperidyl, pyrimidinyl, thiazolyl, pyrazinyl, morpholino, thiomorpholino, indolyl, cinnolinyl, furyl, tetrahydrofuranyl, thienyl, and the like are preferably used. The substituent for the heterocyclic group is exemplified by dialkylamino, alkoxycarbonyl, morpholinoalkyl, hydroxyalkyl, alkyl, benzyloxy, alkoxycarbonyl, alkanoyl, hydroxy, oxo or formyl.

(2)R¹¹And R¹²The substituent of the substituted sulfonyl group of (a) is exemplified by an optionally substituted alkyl group, a cyanophenyl group, a dialkylamino group, or an alkenyl group. The substituent for the optionally substituted alkyl group is exemplified by a halogen atom, a hydroxyl group, a dialkylamino group optionally substituted with a hydroxyl group, a morpholino group, a piperidino group or a 4-methylpiperazino group.

(3)R¹¹And R¹²The substituent for the optionally substituted alkyl group of (1) is exemplified by dialkylaminocarbonyl, alkoxy, dialkylamino, cyano, morpholineSubstituent, pyridyl group or halogen atom.

(4)R¹¹And R¹²The heterocyclic group containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom of (a) is exemplified by saturated or unsaturated monocyclic or bicyclic aromatic heterocyclic groups such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzopyranyl, indolyl, isoindolyl, indazolyl, purinyl, quinolizinyl, 1, 5-diazanaphthyl, quinoxalinyl, cinnolinyl, quinolyl, isoquinolyl, benzothiazolyl, benzisothiazolyl, quinazolinyl, 2, 3-diazanaphthyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isobenzodihydrofuranyl, benzodihydrofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, dihydro-2, 3-naphthyridinyl, and the like. Among these heterocyclic groups, pyridyl, pyrrolyl, piperazinyl, quinolyl, piperidyl, pyrimidinyl, thiazolyl, pyrazinyl, morpholino, indolyl, cinnolinyl, furyl, thienyl, and the like are preferably used. The substituent of the heterocyclic group is exemplified by dialkylamino, alkoxycarbonyl, alkyl, alkoxy, hydroxyl, a halogen atom and the like.

In addition, when R is¹¹And R¹²When a bond is formed at the terminal thereof to form a heterocycle selected from the group consisting of piperidino, azepinyl, pyrrolidino, imidazolidinyl, hexahydropyrimidyl, thiazolidinyl, morpholino, triazolyl, tetrazolyl and purinyl with an adjacent nitrogen atom, the substituent of the heterocycle is exemplified by alkyl substituted with alkoxy or hydroxy, piperidinyl, alkoxyphenyl, alkanoyl, hydroxy, oxo and amino.

When the nitrogen atom of the heterocyclic group is oxidized, the oxidized nitrogen atom refers to a state in which the nitrogen atom is cationized, and is exemplified by an N-oxomorpholino group or an N-alkylmorpholino group.

In the present invention, R²Represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom.

In the present invention, R²The substituent for the optionally substituted hydroxyl group of (2) is exemplified by an alkyl group.

In the present invention, R²The substituent of the optionally substituted amino group of (b) is exemplified by alkyl.

In the present invention, R²The substituent of the optionally substituted alkyl group of (2) is exemplified by an alkoxy group.

In the present invention, R²The substituent of the substituted carbonyl group of (a) is exemplified by a hydroxyl group, an alkoxy group or an alkylamino group.

In the present invention, Z is exemplified by an oxygen atom or-N (R) ³) -a group of (a).

In the present invention, R³Exemplified by a hydrogen atom or an optionally substituted alkyl group. R³The substituent for the optionally substituted alkyl group of (1) is exemplified by a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group.

In the present invention, R⁴Exemplified by a hydrogen atom or an optionally substituted alkyl group. R⁴The substituent of the optionally substituted alkyl group of (2) is exemplified by a halogen atom, an alkoxy group or an alkylamino group.

As preferred compounds of the invention, mention is made of those in which R¹A compound which is an optionally substituted alkyl group.

Preferred substituents of optionally substituted alkyl are dialkylaminocarbonyl, morpholinocarbonyl, hydroxy, alkoxycarbonyl or hydroxyalkylaminocarbonyloxy.

As preferred compounds of the invention, mention is made of those in which R¹Is an optionally substituted hydroxy compound. Of these, preferred is the one wherein R¹Is optionally substituted alkoxyThe compound of (1). Further preferred is where R is¹Is an optionally substituted carbonyloxy group.

Preferred substituents for optionally substituted alkoxy are hydroxy, alkylsulfonyloxy, tetrahydropyranyloxy, triazolyl, tetrazolyl, which are optionally substituted by alkyl, or alkoxy, more preferably hydroxy or tetrahydropyranyloxy. Preferred substituents of the optionally substituted carbonyloxy group are morpholino groups; an imidazolyl group; alkylamino wherein the alkyl moiety thereof is optionally substituted with: hydroxy, morpholinocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyl, alkanoylamino, alkylthio, alkoxy, alkylsulfonyl, alkanoyloxy or carboxy; substituted piperidino substituted with: hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or hydroxyalkyl; piperidinylamino substituted with hydroxyalkanoyl or alkoxyalkanoyl; thiomorpholino in which the sulfur atom is optionally substituted by oxo; an oxopyrrolidinyl group; oxotetrahydrothiazolinyl; or a dialkylaminosulfonylamino group, more preferably a morpholino group; alkylamino wherein the alkyl moiety thereof is optionally substituted with hydroxy; or a thiomorpholino group in which the sulfur atom is substituted by oxo.

As preferred compounds of the invention, mention is made of those in which R¹Are compounds which are substituted thiol groups.

Preferred substituents of the optionally substituted thiol group are alkanoyl; or alkyl optionally substituted with: hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino or alkanoyloxy.

As preferred compounds of the invention, mention is made of those in which R¹Is a substituted carbonyl compound.

Preferred substituents for the optionally substituted carbonyl group are alkoxy; amino optionally substituted with pyrimidinyl or alkylpyrido; alkylamino wherein the alkyl group thereof is optionally substituted by hydroxy or cyano; a di (hydroxyalkyl) amino group; pyridylamino wherein the pyridyl moiety thereof is optionally substituted with hydroxy; piperidino substituted with hydroxy or oxo; piperazino substituted with oxo, alkyl, alkylsulfonyl or alkanoyl; a morpholino group; a thiomorpholino group; or pyrrolidino substituted by hydroxyalkyl or hydroxy, more preferably pyrimidinylamino or hydroxypiperazino.

As preferred compounds of the invention, mention is made of those in which R¹Is a substituted sulfinyl group.

Preferred substituents of the optionally substituted sulfinyl group are alkyl optionally substituted with hydroxy, or hydroxy, more preferably alkyl optionally substituted with hydroxy.

As preferred compounds of the invention, mention is made of those in which R¹A compound which is a substituted sulfonyl group.

Preferred substituents of the optionally substituted sulfonyl group are alkyl or alkanoyloxy optionally substituted with hydroxy, more preferably alkyl optionally substituted with hydroxy.

As preferred compounds of the invention, mention is made of those in which R¹A compound which is a group of the formula:

wherein R is¹¹And R¹²Are the same or different and are each a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized, or R¹¹And R¹²Together with the adjacent nitrogen atom, form a heterocyclic ring selected from: piperidino, azepinyl, pyrrolesAn alkyl group, an imidazolidinyl group, a hexahydropyrimidyl group, a thiazolidinyl group, a morpholino group, a triazolyl group, a tetrazolyl group and a purinyl group, wherein the heterocyclic group is optionally substituted, and a nitrogen atom contained in the heterocyclic group is optionally oxidized.

Of these, preferred is the one wherein R¹¹Is a substituted carbonyl group and R¹²Is a hydrogen atom or an alkyl group. In addition, each of which R is preferred¹¹Various compounds which are respectively optionally substituted alkanoyl, optionally substituted aminocarbonyl, morpholinocarbonyl, and piperidinylcarbonyl substituted with alkanoyl. Another preferred example is where R is¹¹Is a substituted sulfonyl group and R¹²A hydrogen atom or an alkyl group.

Preferred substituents of optionally substituted alkanoyl are alkanoyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl, alkoxycarbonylamino, alkanoylamino, amino substituted by alkoxycarbonyl and alkyl, amino substituted by alkanoyl and alkyl, alkoxy optionally substituted by phenyl, furyl, tetrazolyl, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 2-aminothiazolyl, 2-oxopyrrolidino, 2-thiol-4-alkylthiazolidinyl or cycloalkyl, more preferably alkoxy, hydroxy or cycloalkyl. Preferred substituents of the optionally substituted aminocarbonyl group are a halogen atom, a hydroxyl group or an alkyl group optionally substituted with an alkoxy group, more preferably an alkyl group. Preferred substituents of the optionally substituted sulfonyl group are alkyl, alkenyl or dialkylamino groups, more preferably alkyl groups, optionally substituted with hydroxyl or halogen groups.

The compound of the present invention is exemplified by a compound of the formula [ I ], wherein ring A is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹Is an alkyl group, a hydrogen atom, a halogen atom or an alkoxy group, A²Is a hydrogen atom or a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl group, a halogen atom or an alkyl group, B²Is a trihaloalkyl group, a halogen atom or an alkyl group, B³Is a hydrogen atom, R¹Is a hydroxyl group; alkyl substituted with: dialkylaminocarbonyl, morpholinocarbonyl, hydroxy, alkoxycarbonyl, morpholinoaminocarbonyl, hydroxyalkylaminocarbonyloxy or alkylpiperazinocarbonyl; a dihydroxyphenylthio group; an alkanoylthio group; alkylthio optionally substituted with: hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino or alkanoyloxy; dialkylthionium (dialkylthionium); alkoxy optionally substituted with: hydroxy, alkylsulfonyloxy, tetrahydropyranyloxy, dialkylamino, pyridyl, triazolyl, tetrazolyl, optionally substituted with alkyl, piperidino, morpholino, pyrrolidino or alkoxy; a thienyl sulfonyloxy group; morpholinocarbonyloxy; an alkylpiperazinocarbonyloxy group; an imidazolyl carbonyl group; piperidinoalkylaminocarbonyloxy; morpholino alkylamino carbonyloxy; (ii) an alkylaminocarbonyloxy group wherein the alkyl moiety thereof is optionally substituted with: hydroxy, morpholinocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyl, alkanoylamino, alkylthio, alkoxy, alkylsulfonyl, alkanoyloxy or carboxy; a dialkylaminoalkylaminocarbonyloxy group; piperidino-carbonyloxy substituted with: hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or hydroxyalkyl; a dialkylaminocarbonyloxy group optionally substituted with a hydroxy group; substituted by hydroxyalkanoyl or alkoxyalkanoyl Piperidinylaminocarbonyloxy of (a); a thiomorpholinocarbonyloxy group in which the sulfur atom is optionally substituted by oxo; oxopyrrolidinylcarbonyloxy; oxotetrahydrothiazolinylcarbonyloxy; a dialkylaminosulfonylaminocarbonyloxy group; a carboxyl group; an alkoxycarbonyl group; aminocarbonyl optionally substituted with pyrimidinyl or pyrazinyl; alkylaminocarbonyl wherein the alkyl moiety is optionally substituted with hydroxy or cyano; di (hydroxyalkyl) aminocarbonyl; pyridylaminocarbonyl wherein the pyridyl moiety is optionally substituted with hydroxy; aminocarbonyl substituted with alkylpyrido; piperidinocarbonyl substituted with hydroxy or oxo; piperazinocarbonyl substituted with oxo, alkyl, pyrimidinyl, pyrazinyl, alkylsulfonyl or alkanoyl; morpholinocarbonyl; thiomorpholinocarbonyl; pyrrolidinocarbonyl substituted with hydroxyalkyl or hydroxy; alkylsulfinyl optionally substituted with hydroxy; a hydroxysulfinyl group; alkylsulfonyl optionally substituted with hydroxy or alkanoyloxy; or a group of the formula:

wherein R is¹¹Is a hydrogen atom; a pyridyl group; alkanoyl optionally substituted with a group selected from: alkanoyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl, amino, alkoxycarbonylamino, alkanoylamino, amino substituted with alkoxycarbonyl and alkyl, amino substituted with alkanoyl and alkyl, a halogen atom, dialkylamino, alkoxy optionally substituted with phenyl, furyl, tetrazolyl, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 2-aminothiazolyl, 2-oxopyrrolidino, 2, 2-dialkyl-1, 3-dioxolanyl, 2-thiol-4-alkylthiazolinyl, cycloalkyl and 5-alkyl-2, 4(1H, 3H) pyrimidinedione; phenylcarbonyl optionally substituted with amino or nitro; pyridylcarbonyl optionally substituted with alkyl or hydroxy; furyl carbonyl optionally substituted with formyl, morpholinoalkyl, or hydroxyalkyl; a thienyl carbonyl group; quinolylcarbonyls A group; indolylcarbonyl substituted with alkyl; pyrazinylcarbonyl optionally substituted with alkyl or alkanoyl; morpholinocarbonyl; pyrrolidinylcarbonyl optionally substituted with benzyloxy, alkoxycarbonyl, alkanoyl, hydroxy or oxo; tetrahydrofuranyl carbonyl; piperidinylcarbonyl substituted with alkoxycarbonyl or alkanoyl; thiomorpholinocarbonyl, wherein the sulfur atom is optionally substituted by oxo; 3-alkyl-2, 4(1H, 3H) pyrimidinedione carbonyl; alkylaminocarbonyl, wherein the alkyl moiety thereof is optionally substituted with a halogen atom, hydroxyl group or alkoxy group; a dialkylaminocarbonyl group; alkoxycarbonyl optionally substituted by alkoxy, hydroxyl or a halogen atom; alkylsulfonyl optionally substituted with a group selected from: hydroxy, morpholino, alkylpiperazino, dialkylamino optionally substituted with hydroxy and a halogen atom; an alkenylsulfonyl group; a dialkylaminosulfonyl group; or alkyl optionally substituted with: a morpholino group, a halogen atom, an alkoxy group, a cyano group, a pyridyl group, a dialkylaminocarbonyl group or a dialkylamino group, and

R¹²is a hydrogen atom; a pyridyl group; a pyrazinyl group; or alkyl, or

-N(R¹¹)(R¹²) Is triazolyl, tetrazolyl, aminopurinyl, morpholino in which the nitrogen atom is substituted by alkyl, N-oxomorpholino, piperidino optionally substituted by piperidino, pyrrolidino optionally substituted by hydroxy or alkoxyalkyl, imidazolidinyl substituted by hydroxyalkyl and oxo, hexahydropyrimidyl substituted by hydroxyalkyl and oxo, dioxopyrrolidino, thiazolidinyl or azepinyl,

R²Is a hydrogen atom, and is a hydrogen atom,

z is an oxygen atom or a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is alkyl optionally substituted with hydroxy or alkanoyl,

R⁴is a hydrogen atom or an alkyl group optionally substituted with a hydroxyl group.

Of these, preferred is the one wherein R¹A compound substituted with: a hydroxyl group; alkyl substituted with: dialkylaminocarbonyl, morpholinocarbonyl, morpholinoaminocarbonyl, or alkylpiperazinocarbonyl; a dihydroxyphenylthio group; an alkanoylthio group; alkylthio optionally substituted with hydroxy; alkoxy optionally substituted with: hydroxy, alkylsulfonyloxy, tetrahydropyranyloxy, dialkylamino, pyridyl, triazolyl, tetrazolyl optionally substituted with alkyl, piperidino, morpholino, pyrrolidino or alkoxy; morpholinocarbonyloxy; an alkylpiperazinocarbonyloxy group; an imidazolyl carbonyl group; piperidinoalkylaminocarbonyloxy; morpholino alkylamino carbonyloxy; (ii) an alkylaminocarbonyloxy group, wherein the alkyl moiety thereof is optionally substituted with hydroxy, morpholinocarbonyl or carboxy; a dialkylaminoalkylaminocarbonyloxy group; piperidinocarbonyloxy optionally substituted with hydroxy or hydroxyalkyl; a dialkylaminocarbonyloxy group optionally substituted with a hydroxy group; thiomorpholinocarbonyloxy, wherein the sulfur atom is optionally substituted by oxo; oxopyrrolidinylcarbonyloxy; oxotetrahydrothiazolinylcarbonyloxy; a dialkylaminosulfonylaminocarbonyloxy group; an alkoxycarbonyl group; aminocarbonyl optionally substituted with hydroxyalkyl; alkylsulfinyl optionally substituted with hydroxy; alkylsulfonyl optionally substituted with hydroxy; or a group of the formula:

Wherein R is¹¹Is a hydrogen atom; alkanoyl optionally substituted with a group selected from: amino group, halogen atom, dialkylamino group, alkoxy group, furyl group, tetrazolyl group, hydroxyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2, 2-dialkyl-1, 3-dioxolanyl group, 2-thiol-4-alkylthiazolinyl group, cycloalkyl group and 5-alkyl-2, 4(1H, 3H) pyrimidinedione group; phenylcarbonyl optionally substituted with amino or nitro;a pyridyl carbonyl group; furyl carbonyl optionally substituted with formyl, morpholinoalkyl, or hydroxyalkyl; a thienyl carbonyl group; a quinolylcarbonyl group; pyrazinylcarbonyl optionally substituted with alkyl; morpholinocarbonyl; pyrrolidinocarbonyl; tetrahydrofuranyl carbonyl; piperidinylcarbonyl substituted with alkoxycarbonyl; alkylaminocarbonyl optionally substituted with a halogen atom, hydroxyl group or alkoxy group; a dialkylaminocarbonyl group; alkoxycarbonyl optionally substituted by alkoxy, hydroxyl or a halogen atom; alkylsulfonyl optionally substituted with a group selected from: hydroxy, morpholino, alkylpiperazino, dialkylamino optionally substituted with hydroxy and a halogen atom; an alkenylsulfonyl group; a dialkylaminosulfonyl group; or alkyl optionally substituted with: a morpholino group, a halogen atom, an alkoxy group, a cyano group, a pyridyl group, a dialkylaminocarbonyl group or a dialkylamino group, and

R¹²Is a hydrogen atom; a pyridyl group; or an alkyl group.

More preferably a compound wherein R¹Is a hydroxyl group; alkyl substituted with: dialkylaminocarbonylmorpholinocarbonyl, morpholinoaminocarbonyl, or alkylpiperazinocarbonyl; a dihydroxyphenylthio group; an alkanoylthio group; alkylthio optionally substituted with hydroxy; alkoxy optionally substituted with: hydroxy, alkylsulfonyloxy, tetrahydropyranyloxy, pyridinyl, triazolyl, tetrazolyl, optionally substituted with alkyl or alkoxy; morpholinocarbonyloxy; an imidazolyl carbonyl group; piperidinoalkylaminocarbonyloxy; morpholino alkylamino carbonyloxy; (ii) alkylaminocarbonyloxy optionally substituted with hydroxy, morpholinocarbonyl or carboxy; a dialkylaminoalkylaminocarbonyloxy group; piperidinocarbonyloxy optionally substituted with hydroxy or hydroxyalkyl; a dialkylaminocarbonyloxy group optionally substituted with a hydroxy group; a halomorpholinocarbonyloxy wherein the sulfur atom is optionally substituted by oxo; oxopyrrolidinylcarbonyloxy; oxotetrahydrothiazolinylcarbonyloxy; a dialkylaminosulfonylaminocarbonyloxy group; an alkoxycarbonyl group; aminocarbonyl optionally substituted with hydroxyalkyl; optionally, the Alkylsulfinyl substituted with hydroxy; alkylsulfonyl optionally substituted with hydroxy; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with a group selected from: amino group, halogen atom, alkoxy group, furyl group, tetrazolyl group, hydroxyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, 2-aminothiazolyl group, 2, 2-dialkyl-1, 3-dioxolanyl group, 2-thiol-4-alkylthiazolinyl group, cycloalkyl group and 5-alkyl-2, 4(1H, 3H) pyrimidinedione group; phenylcarbonyl optionally substituted with amino or nitro; a pyridyl carbonyl group; furyl carbonyl optionally substituted with formyl or hydroxyalkyl; a quinolylcarbonyl group; morpholinocarbonyl; pyrrolidinocarbonyl; tetrahydrofuranyl carbonyl; piperidinylcarbonyl substituted with alkoxycarbonyl; alkylaminocarbonyl optionally substituted with a halogen atom, hydroxyl group or alkoxy group; a dialkylaminocarbonyl group; alkoxycarbonyl optionally substituted by alkoxy, hydroxyl or a halogen atom; alkylsulfonyl optionally substituted with hydroxyl or a halogen atom; an alkenylsulfonyl group; or thienylsulfonyl, and

R¹²is a hydrogen atom; a pyridyl group; or an alkyl group.

Among the compounds of the present invention, a compound in which ring a is a benzene ring of the formula:

Ring B is a benzene ring of the formula:

wherein A is¹Is an alkyl group, a hydrogen atom, a halogen atom or an alkoxy group, A²Is a hydrogen atom or a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl group, a hydrogen atom or an alkyl group, B²Is a trihaloalkyl group, a hydrogen atom or an alkyl group, B³Is a hydrogen atom, and is a hydrogen atom,

R¹is a hydroxyl group; alkyl substituted with: dialkylaminocarbonyl, morpholinocarbonyl, hydroxy, alkoxycarbonyl or hydroxyalkylaminocarbonyloxy; a dihydroxyphenyl sulfinyl group; an alkanoylthio group; alkylthio optionally substituted with: hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino or alkanoyloxy; dialkylsulfonium salts; alkoxy optionally substituted with: hydroxy, alkylsulfonyloxy, tetrahydropyranyloxy, triazolyl, tetrazolyl optionally substituted with alkyl, or alkoxy; a thienyl sulfonyloxy group; morpholinocarbonyloxy; an imidazolyl carbonyl group; (ii) an alkylaminocarbonyloxy group, wherein the alkyl portion thereof is optionally substituted with: hydroxy, morpholinocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyl, alkanoylamino, alkylthio, alkoxy, alkylsulfonyl, alkanoyloxy or carboxy; piperidinocarbonyloxy substituted with: hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or hydroxyalkyl; a dialkylaminocarbonyloxy group optionally substituted with a hydroxy group; piperidinylaminocarbonyloxy substituted with hydroxyalkanoyl or alkoxyalkanoyl; thiomorpholinocarbonyloxy, wherein the sulfur atom is optionally substituted by oxo; oxopyrrolidinylcarbonyloxy; oxotetrahydrothiazolinylcarbonyloxy; a dialkylaminosulfonylaminocarbonyloxy group; a carboxyl group; an alkoxycarbonyl group; aminocarbonyl optionally substituted with pyrimidinyl; alkyl in which the alkyl moiety is optionally substituted by hydroxy or cyano An aminocarbonyl group; di (hydroxyalkyl) aminocarbonyl; pyridylaminocarbonyl wherein the pyridyl moiety is optionally substituted with hydroxy; aminocarbonyl substituted with alkylpyrido; hydroxy or oxo substituted piperidinocarbonyl; piperazinocarbonyl substituted with: oxo, alkyl, alkylsulfonyl or alkanoyl; morpholinocarbonyl; thiomorpholinocarbonyl; pyrrolidinocarbonyl substituted with hydroxyalkyl or hydroxy; alkylsulfinyl optionally substituted with hydroxy; a hydroxysulfinyl group; alkylsulfonyl optionally substituted with hydroxy or alkanoyloxy; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with a group selected from: alkanoyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl, alkoxycarbonylamino, alkanoylamino, alkoxycarbonyl and alkyl substituted amino, alkanoyl and alkyl substituted amino, alkoxy optionally substituted with phenyl, furyl, tetrazolyl, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 2-aminothiazolyl, 2-oxopyrrolidino, 2, 2-dialkyl-1, 3-dioxolanyl, 2-thiol-4-alkylthiazolinyl and cycloalkyl; phenylcarbonyl optionally substituted with amino or nitro; pyridylcarbonyl optionally substituted with hydroxy; a furancarbonyl group optionally substituted with a formyl group or a hydroxy group; a thienyl carbonyl group; an alkyl-substituted indolylcarbonyl group; morpholinocarbonyl; pyrrolidinylcarbonyl optionally substituted with: benzyloxy, alkoxycarbonyl, alkanoyl, hydroxy or oxo; tetrahydrofuranyl carbonyl; alkoxycarbonyl or alkanoyl substituted piperidinylcarbonyl; thiomorpholinocarbonyl in which the sulfur atom is optionally substituted by oxo; 3-alkyl-2, 4(1H, 3H) pyrimidinedione carbonyl; alkylaminocarbonyl, wherein the alkyl moiety thereof is optionally substituted with a halogen atom, hydroxyl group or alkoxy group; a dialkylaminocarbonyl group; alkoxy optionally substituted by alkoxy, hydroxy or halogen atoms A carbonyl group; alkylsulfonyl optionally substituted with a group selected from: hydroxyl group, and halogen atom; an alkenylsulfonyl group; or a dialkylaminosulfonyl group; and

R¹²is a hydrogen atom; a pyrazinyl group; or alkyl, or

-N(R¹¹)(R¹²) Is triazolyl, tetrazolyl, aminopurine-yl, morpholino in which the nitrogen atom is substituted by alkyl, N-oxomorpholino, imidazolidinyl substituted by hydroxyalkyl and oxo, hexahydropyrimidyl substituted by hydroxyalkyl and oxo, or dioxopyrrolidino,

R²is a hydrogen atom, and is a hydrogen atom,

z is an oxygen atom or a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group optionally substituted with a hydroxyl group,

R⁴is a hydrogen atom or an alkyl group optionally substituted with a hydroxyl group.

Among these, a compound is preferred, wherein ring a is a benzene ring of the formula:

ring B is a benzene ring of the formula:

wherein A is¹Is alkyl, A²Is a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl radical, B²Is a trihaloalkyl radical, B³Is a hydrogen atom, and is a hydrogen atom,

R¹is hydroxy or tetrahydropyranyloxy substituted alkoxy(ii) a (ii) an alkylaminocarbonyloxy group, wherein the alkyl portion thereof is optionally substituted with hydroxy; thiomorpholinocarbonyloxy, wherein the sulfur atom is substituted by oxo; an alkylsulfinyl group; a hydroxy-substituted alkanoyl group; aminocarbonyl substituted with a group selected from alkyl, pyrazinyl and pyrimidinyl; alkanoyl substituted piperazinocarbonyl; hydroxy-substituted piperidinocarbonyl; alkylsulfinyl optionally substituted with hydroxy; alkylsulfonyl optionally substituted with hydroxy; or a group of the formula:

Wherein R is¹¹Is alkanoyl optionally substituted with a group selected from: alkoxy, hydroxy and cycloalkyl; an alkoxycarbonyl group; a hydroxy-substituted pyridylcarbonyl group; morpholinocarbonyl; an alkylaminocarbonyl group; or an alkylsulfonyl group; pyrazinyl, and

R¹²is a hydrogen atom, or an alkyl group,

-N(R¹¹)(R¹²) Is triazolyl, tetrazolyl or N-oxomorpholino,

R²is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

Even more preferred is a compound wherein R is¹Is an alkylaminocarbonyloxy group wherein the alkyl portion thereof is substituted with a hydroxy group; thiomorpholinocarbonyloxy in which the sulfur atom is replaced by oxo; alkanoyl substituted with hydroxy; alkanoyl-substituted piperazino (piperazino) carbonyl; hydroxy-substituted piperidinocarbonyl; alkylsulfinyl substituted with hydroxy; alkylsulfonyl optionally substituted with hydroxy; or a group of the formula:

wherein R is¹¹Is alkanoyl substituted by hydroxy, and

R¹²is a hydrogen atom.

In the present invention, particularly preferred compounds are compounds selected from the following (a) to (BK) or pharmaceutically acceptable salts thereof.

(A) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylpropanoylamino) piperidine,

(B) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholino-carbonylaminopiperidine,

(C) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) -piperidine,

(D) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (2-tetrahydropyranyloxy) ethoxy } piperidine,

(E) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxy-acetylaminopiperidine,

(F) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxy-carbonylaminopiperidine,

(G) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonylamino-2- (4-fluoro-2-methylphenyl) piperidine,

(H) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-metansulfonylaminopiperidine,

(I) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine,

(J) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxy-acetamidopiperidine,

(K) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxypropoxy) piperidine,

(L) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- (2-cyclopropyl-2-hydroxyacetamido) -2- (4-fluoro-2-methylphenyl) piperidine,

(M) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropionylamino) piperidine,

(N) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -3-hydroxybutyrylamino) piperidine,

(O) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl-aminocarbonyloxy) piperidine,

(P) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfinyl-piperidine,

(Q) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine,

(R) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] -aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine,

(S) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methoxypropionylamino) piperidine,

(T) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methanesulfonyl-N-methylamino) piperidine,

(U) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine,

(V) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxy-3-methylbutanamido) piperidine,

(W) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfinyl) piperidine,

(X) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxy-acetamidopiperidine,

(Y) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -2-hydroxypropionylamino) piperidine,

(Z) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -3-hydroxybutyrylamino) piperidine,

(AA) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylphenyl) -N-methyl ] -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl) piperidine,

(AB) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethanesulfinyl) piperidine,

(AC) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (S) - ((S) -2-hydroxypropane) sulfinyl } piperidine,

(AD) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (R) - ((S) -2-hydroxypropane) sulfinyl } piperidine,

(AE) (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl) piperidine,

(AF) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -2-hydroxypropanesulfonyl) piperidine,

(AG) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethylsulfonyl) piperidine,

(AH) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl) piperidine,

(AI) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (S) - ((S) -2-hydroxypropane) sulfinyl } piperidine,

(AJ) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (R) - ((S) -2-hydroxypropane) sulfinyl } piperidine,

(AK) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (R) - ((R) -2-hydroxypropane) sulfinyl } piperidine,

(AL) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- { (S) - ((R) -2-hydroxypropane) sulfinyl } piperidine,

(AM) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -2-hydroxypropanesulfonyl) piperidine,

(AN) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -3-hydroxy-butyrylamino) piperidine,

(AO) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -3-hydroxy-butyrylamino) piperidine,

(AP) (2R, 4S) -4- (4-acetylpiperazinocarbonyl) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine,

(AQ) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methyl-ethanesulfinyl) piperidine,

(AR) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothio-morpholinocarbonyloxy) piperidine,

(AS) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-ethanesulfonyl) piperidine,

(AT) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methyl-ethanesulfonyl) piperidine,

(AU) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-hydroxypiperidinocarbonyl) piperidine,

(AV) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonyl-piperidine,

(AW) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -2-hydroxy-propionyl) piperidine,

(AX) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-pyrazin-2-ylaminocarbonyl) piperidine,

(AY) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (pyrazin-2-yl-amino) piperidine,

(AZ) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-pyrazin-2-ylamino) piperidine,

(BA) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethylsulfinyl) piperidine,

(BB) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-triazolyl) piperidine,

(BC) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-tetrazolyl) piperidine,

(BD) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine,

(BE) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine,

(BF) (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) -piperidine,

(BG) (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxypyridin-5-yl-carbonylamino) piperidine,

(BH) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-pyrimidin-4-ylaminocarbonyl) piperidine,

(BI) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-pyrimidin-4-ylaminocarbonyl) piperidine,

(BJ) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyacetamido) piperidine, or

(BK) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethylthio) piperidine.

In the present invention, more particularly preferred compounds are compounds selected from the following (a) to(s) or pharmaceutically acceptable salts thereof.

(a) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanoylamino) piperidine,

(b) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -3-hydroxybutyrylamino) piperidine,

(c) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl-aminocarbonyloxy) piperidine,

(d) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxy-3-methylbutanamido) piperidine,

(e) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -3-hydroxybutyrylamino) piperidine,

(f) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl) piperidine,

(g) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl) piperidine,

(h) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -2-hydroxy-propanesulfonyl) piperidine,

(i) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -3-hydroxy-butyrylamino) piperidine,

(j) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -3-hydroxy-butyrylamino) piperidine,

(k) (2R, 4S) -4- (4-acetylpiperazinocarbonyl) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine,

(l) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothio-morpholinocarbonyloxy) piperidine,

(m) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-ethanesulfonyl) piperidine,

(N) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methyl-ethanesulfonyl) piperidine,

(o) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-hydroxypiperidinocarbonyl) piperidine.

(p) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonyl-piperidine,

(q) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((R) -2-hydroxy-propionyl) piperidine,

(R) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyacetamido) piperidine, or

(S) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethylthio) piperidine.

Among the compounds of the present invention, a compound in which ring a is a benzene ring of the formula:

ring B is a benzene ring of the formula:

wherein A is¹Is alkyl, A²Is a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl group or a halogen atom, B²Is a trihaloalkyl group or a halogen atom, B³Is a hydrogen atom, and is a hydrogen atom,

R¹is a hydroxyl group; alkyl substituted with: dialkylaminocarbonyl or morpholinocarbonyl, alkoxy optionally substituted with hydroxy, alkylsulfonyloxy, triazolyl, or tetrazolyl optionally substituted with alkyl; morpholinocarbonyloxy; a hydroxyalkylaminocarbonyloxy group; an imidazolyl carbonyl group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; alkylaminocarbonyl substituted by hydroxy A group; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with: hydroxy or 5-alkyl-2, 4(1H, 3H) pyrimidinedione; a pyridyl carbonyl group; a furanylcarbonyl group; a thienyl carbonyl group; morpholinocarbonyl; an alkoxycarbonyl group; or an alkylsulfonyl group;

R¹²is a hydrogen atom; or alkyl, or

-N(R¹¹)(R¹²) Is triazolyl, morpholino in which the nitrogen atom is substituted by alkyl, or N-oxomorpholino,

R²is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

Of these, preferred is a compound wherein R is¹Is a hydroxyl group; alkyl substituted with: a dialkylaminocarbonyl or morpholinocarbonyl group; alkoxy optionally substituted with: hydroxy, alkylsulfonyloxy, triazolyl, or tetrazolyl optionally substituted with alkyl; morpholinocarbonyloxy; a hydroxyalkylaminocarbonyloxy group; an imidazolyl carbonyl group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; alkylaminocarbonyl substituted with hydroxy; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with: hydroxy or 5-alkyl-2, 4(1H, 3H) pyrimidinedione; a pyridyl carbonyl group; a furanylcarbonyl group; a thienyl carbonyl group; morpholinocarbonyl; an alkoxycarbonyl group; an alkylsulfonyl group;

R¹²Is a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, more preferred is a compound wherein R is¹Is a hydroxyl group; hydroxy or triazolyl substituted alkoxy; a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with hydroxy; and

R¹²is a hydrogen atom; or alkyl, or

-N(R¹¹)(R¹²) Is a morpholino group in which the nitrogen atom is substituted with an alkyl group, an N-oxomorpholino group, an alkyl group or an alkanoyl group-substituted piperazinyl group,

R²is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

More preferably a compound wherein R¹Is a hydroxyl group; alkoxy substituted with hydroxy or triazolyl; a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy group is substitutedA substituted piperidinocarbonyl group; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with hydroxy;

R¹²is a hydrogen atom; or an alkyl group.

Among the compounds of the present invention, the other preferred compound is a compound wherein R is ¹Is a hydroxyl group; alkoxy optionally substituted with hydroxy, alkylsulfonyloxy or tetrazolyl; a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with hydroxy; a furanylcarbonyl group; morpholinocarbonyl; an alkoxycarbonyl group; or an alkylsulfonyl group; and

R¹²is a hydrogen atom; or alkyl, or

-N(R¹¹)(R¹²) Is a triazolyl group, or a tetrazolyl group,

R²is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

Another preferred compound is exemplified by a compound wherein ring a is a benzene ring of the formula:

ring B is a benzene ring of the formula:

wherein A is¹Is alkyl, A²Is a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl radical, B²Is a trihaloalkyl radical, B³Is a hydrogen atom, and is a hydrogen atom,

R¹is a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted with hydroxy; or an alkoxycarbonyl group; and

R¹²Is a hydrogen atom; or alkyl

R²Is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

Still another preferred compound is a compound wherein ring a is a benzene ring of the formula:

ring B is a benzene ring of the formula:

wherein A is¹Is alkyl, A²Is a halogen atom, A³Is a hydrogen atom, B¹Is a trihaloalkyl radical, B²Is a trihaloalkyl radical, B³Is a hydrogen atom, and is a hydrogen atom,

R¹is a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted by hydroxy, and

R¹²is a hydrogen atom; or alkyl, or

-N(R¹¹)(R¹²) Is a morpholino group in which the nitrogen atom is substituted with an alkyl group, or an N-oxomorpholino group,

R²is a hydrogen atom, and is a hydrogen atom,

z is a group consisting of-N (R)³) -a group represented by (a) or (b),

R³is an alkyl group, and the alkyl group,

R⁴is a hydrogen atom or an alkyl group.

More excellentSelecting a compound wherein R¹Is a hydroxyalkylaminocarbonyloxy group; alkylsulfinyl optionally substituted with hydroxy; an alkylsulfonyl group; hydroxy-substituted alkylaminocarbonyl; hydroxy-substituted piperidinocarbonyl; or a group of the formula:

wherein R is¹¹Is alkanoyl optionally substituted by hydroxy, and R ¹²Is a hydrogen atom; or an alkyl group.

The compound [ I ] of the present invention can be used for pharmaceutical applications in free form or in the form of a pharmaceutically acceptable salt.

As the pharmaceutically acceptable salts of the compound [ I ] of the present invention, there may be mentioned, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide; and organic acid salts and the like, such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, maleate, succinate and tartrate.

Further, the compound [ I ] of the present invention or a pharmaceutically acceptable salt thereof includes any of inner salts, solvates, hydrates, and the like thereof.

Although optical isomers based on asymmetric carbon may exist in the compound [ I ] of the present invention, the present invention includes any of these optical isomers and mixtures thereof. In the present invention, among these optical isomers, a compound having an R configuration at the 2-position of the piperidine ring (the linking site of ring A) is preferred, and a compound having an R configuration at the second position of the piperidine ring (the linking site of ring A) and an S configuration at the 4-position (the linking site of R1) is particularly preferred.

The compound [ I ] of the present invention or a pharmaceutically acceptable salt thereof has an excellent tachykinin receptor antagonistic action, particularly an SP receptor antagonistic action, and thus it is useful as a safe drug for the prophylaxis and treatment of the following diseases in mammals (e.g., mouse, mongolian gerbil, ferret, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.): inflammatory or allergic diseases (e.g., atopic dermatitis, herpes, psoriasis (prodiasis), asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, ophthalmia, cystitis, etc.), pain, migraine, neuralgia, itch (itchiness), cough, and additional central nervous system diseases (e.g., schizophrenia, parkinson's disease, depression, restlessness, psychosomatic disorders, morphine dependence, dementia (e.g., alzheimer's disease, etc.)), digestive organ diseases (e.g., irritable bowel disease, ulcerative colitis, crohn's disease, disorders associated with urease-positive spirochetes (e.g., helicobacter pylori, etc.) (e.g., gastritis, gastric ulcer, etc.)), nausea, emesis, urinary diseases (e.g., pollakiuria, urinary incontinence, etc.), circulatory diseases (e.g., angina pectoris, hypertension, heart failure, thrombosis, etc.) and immune disorders, etc. In particular, since the compound [ I ] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, is highly transportable in the brain while having low toxicity and showing little side effect, it is used as a therapeutic or prophylactic agent for central nervous system diseases such as emesis, depression, etc., or urinary diseases such as pollakiuria, etc.

The measurement of the compound of the present invention or a pharmaceutically acceptable salt thereof can be carried out according to the method described in European Journal of Pharmacology, Vol.254, pp.221-227 (1994) for neurokinin-1 receptor binding, according to the method described in European Journal of Pharmacology, Vol.265, pp.179-183 (1994) for neurokinin-1 receptor induction, and according to the method described in British Journal of Pharmacology 119, pp.931-936 (1996) for emesis, and according to the method described in Journal of Urology, Vol.155, No.1, pp.355-360 (1996) for pollakiuria inhibition.

The compound [ I ] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and it can be formulated into an appropriate preparation using a pharmaceutical carrier conventionally used for oral or parenteral administration. As the pharmaceutical carrier, there may be mentioned, for example, binders (syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone and the like), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbitol, glycine and the like), lubricants (magnesium stearate, talc, polyethylene glycol, silica and the like), disintegrants (potato starch and the like) and wetting agents (anhydrous sodium lauryl sulfate and the like) and the like.

Further, when these pharmaceutical preparations are orally administered, they may be solid preparations such as tablets, granules, capsules, powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, when they are administered parenterally, for example, they may be administered as an injection solution or an infusion solution using distilled water for injection, physiological saline, an aqueous glucose solution or the like, or they may be administered as a suppository or the like.

The dose of the compound [ I ] of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the administration method, the age, body weight or condition of a patient, etc., and for example, in the case of oral administration, it is usually administered at a dose of 0.1 to 20 mg/kg/day, particularly preferably 0.1 to 10 mg/kg/day, and in the case of parenteral administration, it is usually 0.01 to 10 mg/kg/day, particularly preferably 0.01 to 1 mg/kg/day.

[ method A ]

The target compound [ I ] of the present invention can be prepared by reacting a compound of the formula [ II ] with a compound of the formula [ III ] in the presence of urea:

wherein ring A represents an optionally substituted benzene ring, R¹Is optionally substituted alkyl, optionally substituted hydroxy, substituted thiol, substituted carbonyl, substituted sulfinyl, substituted sulfonyl or a group of the formula:

Wherein R is¹¹And R¹²Are the same or different and are each a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as hetero atoms, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized, or R¹¹And R¹²Together with the adjacent nitrogen atom, form a heterocyclic ring selected from: piperidino, azepinyl, pyrrolidino, thiazolidinyl, morpholino, triazolyl, tetrazolyl, and purinyl, wherein the heterocyclic group is optionally substituted, the nitrogen atom contained in the heterocyclic group is optionally oxidized,

R²represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom,

wherein ring B represents an optionally substituted benzene ring, R³Represents a hydrogen atom or an optionally substituted alkyl group, R⁴Represents a hydrogen atom or an optionally substituted alkyl group.

[ method B ]

In the object compound [ I ] of the present invention, a compound of the formula [ I-a ] can be produced, for example, by reducing a compound of the formula [ IV ]:

wherein Ring A, Ring B, R²，Z，R³And R⁴Have the same meaning as defined above,

wherein Ring A, Ring B, R ²，Z，R³And R⁴Have the same meaning as defined above.

[ method C ]

Among the compounds of the present invention, the compound of the formula [ I-b ] can be produced by reacting a compound of the formula [ IV ] with a compound of the formula [ V ]:

wherein Ring A, Ring B, R¹¹，R¹²，R²，Z，R³And R⁴Have the same meaning as defined above,

wherein Ring A, Ring B, R²，Z，R³And R⁴Have the same meaning as defined above,

wherein X¹Represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or a magnesium atom, R¹¹And R¹²Have the same meaning as defined above.

[ method D ]

Among the compounds of the present invention, the compound of the formula [ I-c ] can be produced by reacting the compound of the formula [ IV ] with the compound of the formula [ VI ], reducing the resulting compound of the formula [ VII ],

wherein Ring A, Ring B, R²，Z，R³And R⁴Has the same meaning as defined above, R¹³Represents an optionally substituted carboxyl group, wherein,

wherein Ring A, Ring B, R²，Z，R³And R⁴Have the same meaning as defined above,

X²CH₂R¹³ [VI]

wherein X²Represents a leaving group, R¹³Have the same meaning as defined above,

wherein Ring A, Ring B, R¹³，Z，R²，R³And R⁴Have the same meaning as defined above.

[ method E ]

Among the compounds of the present invention, the compound of the formula [ I "] can be prepared by reacting the compound of the formula [ II ] with the compound of the formula [ III' ] in the presence of a reagent forming a urea bond:

Wherein Ring A, Ring B, R¹，R²And R⁴Have the same meaning as defined above,

wherein ring A, R¹And R²Have the same meaning as defined above,

wherein B and R⁴Have the same meaning as defined above.

These [ method A ] to [ method E ] can be carried out as follows.

[ method A ]

The reaction of the compound [ II ] with the compound [ III ] may be carried out in an appropriate solvent in the presence of a urea bond-forming agent. The urea bond forming agent is exemplified by a compound represented by the following formula:

wherein W¹And W²The same or different and each represents a leaving group or the like.

W¹And W²The same or different and each is exemplified by an imidazolyl group, a halogen atom, a phenoxy group and the like. 1, 1 '-carbonyldiimidazole, phosgene, etc. are particularly preferred, and carbonyl dihalides such as 1, 1' -carbonyldiimidazole, triphosgene, phosgene, etc. can be used. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction,for example, acetonitrile, dichloromethane, tetrahydrofuran, and the like can be suitably used. The reaction can be carried out, for example, at from 0 ℃ to 80 ℃, preferably from 0 ℃ to 50 ℃.

In addition, in this reaction, the compound [ I ] can also be prepared as follows:

reacting the compound [ II ] with a urea bond-forming agent of the formula:

wherein W ¹And W²Identical or different and each represents a leaving group,

to provide a resulting compound of formula [ VIII-a ]:

wherein ring A, R¹，R²And W²Have the same meaning as defined above,

subsequently reacting the compound [ VIII-a ] as an active derivative thereof with a compound [ III ],

or alternatively, compound [ I ] can be prepared as follows:

reacting the compound [ III ] with a urea bond-forming agent of the formula:

wherein W¹And W²Have the same meaning as defined above,

to provide a resulting compound of formula [ VIII-b ]:

wherein ring B, R³，R⁴And W²Have the same meaning as defined above,

the compound [ VIII-b ] is subsequently brought into its reactive derivative and reacted with the compound [ II ].

As the active derivative, there are mentioned compounds in which the compound [ VIII-a]Or a compound [ VIII-b]Middle W²A group represented by the following formula, etc.,

the reaction of the compound [ II ] or the compound [ III ] with the urea bond-forming agent can be carried out, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran, or the like may be suitably used.

The reaction of the compound [ VIII-a ] or the compound [ VIII-b ] into its active derivative can be carried out using a derivatizing agent (e.g., a derivative-imparting agent) such as methyl iodide, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran, or the like may be suitably used.

The reaction of each reactive derivative with the compound [ III ] or the compound [ II ] may be carried out in the presence of a base, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, triethylamine and the like can be used as the base, and any solvent can be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be suitably used.

[ method B ]

The reduction of the compound [ IV ] may be carried out in an appropriate solvent in the presence of a reducing agent. As the reducing agent, sodium borohydride and the like are preferable, and for example, sodium borohydride, aluminum hydride such as diisobutylaluminum hydride and the like can be used. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, ethanol, tetrahydrofuran, dichloromethane, or the like may be suitably used. The reaction can be carried out, for example, at from-70 ℃ to reflux, preferably at from-70 ℃ to 20 ℃.

[ method C ]

Compound [ IV ] can be carried out in an appropriate solvent by subjecting the compound to a reductive amination reaction]And compound [ V]The reaction of (1). The reductive amination reaction can be carried out by hydrogenation under acidic conditions in the presence of a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or a reducing catalyst such as palladium. As compounds [ V ] ]Group [ X ] of (1)¹]Mention may be made, for example, of hydrogen atoms, hydroxyl groups, silicon atoms, lithium atoms or magnesium atoms, preferably hydrogen atoms and hydroxyl groups. Any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, dichloromethane, acetic acid, ethanol, methanol, or the like may be suitably used. As compounds [ V ]]As the salt, hydrochloride, acetate and the like can be suitably used. The reaction can be carried out, for example, at from-10 ℃ to 80 ℃, preferably from 0 ℃ to 30 ℃.

[ method D ]

The compound [ IV ] can be carried out in a suitable solvent optionally in the presence of a base]And compound [ VI]The reaction of (1). As compounds [ VI]Leaving group [ X ] of²]As the "alkyl" group, there are mentioned diethyl phosphonyl, triphenyl phosphinyl and the like. As the base, there are mentioned, for example, potassium tert-butoxide, triethylamine, sodium hydroxide and the like, preferably potassium tert-butoxide, triethylamine and the like. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, tetrahydrofuran, dichloromethane, or the like may be suitably used. The reaction may be carried out, for example, at-30 ℃ to 80 ℃, preferably-20 ℃ to 30 DEG CThe process is carried out as follows.

In addition, the reduction of the compound [ VII ] can be carried out by a conventional method by hydrogenation in the presence of a reducing catalyst such as palladium or the like. As the solvent, methanol, ethanol, or the like can be suitably used. The reaction can be carried out, for example, at from 0 ℃ to 50 ℃.

[ method E ]

The reaction of the compound [ II ] with the compound [ III' ] may be carried out in an appropriate solvent in the presence of a reagent forming a urea bond. As the urea bond forming agent, those represented by the following formula:

wherein W¹And W²Identical or different and each represents a leaving group.

As the same or different W¹And W²As the group, there may be mentioned an imidazolyl group, a halogen atom or a phenoxy group, etc. In particular, 1 '-carbonyldiimidazole and phosgene are preferred, and for example, carbonyl dihalide such as 1, 1' -carbonyldiimidazole, triphosgene, phosgene and the like can be used. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran, or the like may be suitably used. The reaction can be carried out, for example, at from 0 ℃ to 80 ℃, preferably from 0 ℃ to 50 ℃.

In addition, the compound [ I "] can also be prepared as follows:

reacting the compound [ II ] with a urea bond-forming agent of the formula:

wherein W¹And W²Are the same or different and each representsA leaving group which is a substituent of a carboxyl group,

to provide a resulting compound of formula [ VIII-a ]:

wherein ring A, R¹，R²And W²Have the same meaning as defined above,

subsequently, the compound [ VIII-a ] is made into an active derivative thereof, and is reacted with the compound [ III' ],

Or alternatively, compound [ I "] can be prepared as follows:

reacting the compound [ III' ] with a urea bond forming reagent of the formula:

wherein W¹And W²Have the same meaning as defined above,

to provide a compound of formula [ VIII' ]:

wherein ring B, R⁴And W²Have the same meaning as defined above,

the compound [ VIII' ] is subsequently made its reactive derivative, which is reacted with the compound [ II ].

As the active derivative, for example, a compound in which the compound [ VIII-a ] is mentioned]Or compound [ VIII']Middle W²To a group represented by the following formula:

the reaction of the compound [ II ] or the compound [ III' ] with the urea bond-forming agent can be carried out, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran, or the like may be suitably used.

The reaction of the compound [ VIII-a ] or the compound [ VIII' ] into its active derivative can be carried out using a derivatizing agent such as methyl iodide, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, any solvent may be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran, or the like may be suitably used.

The reaction of each reactive derivative with the compound [ III ] or the compound [ II ] may be carried out in the presence of a base, for example, at 0 ℃ to 80 ℃, preferably 0 ℃ to 50 ℃. In addition, triethylamine and the like can be used as the base, and any solvent can be used as long as it does not exert any adverse effect on the reaction, and for example, acetonitrile, dichloromethane, tetrahydrofuran and the like can be suitably used.

By reacting the radical R of the compound obtained in the above-mentioned process¹And a group R³Compounds of the invention [ I ] can also be prepared by conversion to the desired substituents]. The method of substituent conversion may be appropriately selected depending on the kind of desired substituent, and the following various methods (method a) to (method q) may be employed.

(method a)

By using the corresponding hydroxyl-containing radical as R¹The compound of formula (I) can be prepared by alkylation, acylation or sulfonylation by a conventional method, wherein]R in (1)¹Is a group containing a substituted hydroxyl group (e.g., optionally substituted alkoxy, substituted carbonyloxy or alkylsulfonyloxy, etc.)Compound [ I ] of]. For example, alkylation may be carried out at-10 ℃ to 80 ℃, acylation may be carried out at 5 ℃ to 80 ℃, and sulfonylation may be carried out at 5 ℃ to 80 ℃.

(method b)

By conventional methods, the corresponding amino-containing substituent is substituted as R ¹Can be prepared wherein the compound of formula (I)]R in (1)¹Is a compound [ I ] containing a substituted amino group](for example, an alkoxycarbonyl group such as a tert-butoxycarbonyl group, an arylalkoxycarbonyl group such as a benzyloxycarbonyl group and the like, an alkanoyl group such as a formyl group, an acetyl group, a propionyl group and the like, an alkyl group such as a methyl group, an ethyl group, a propyl group and the like, an alkylsulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group and the like, an alkenylsulfonyl group such as a vinylsulfonyl group and the like, a heterocyclic group such as a. Alternatively, it may be prepared by using a urethane synthesis reagent such as N, N' -succinimidyl carbonate with, for example, an alkoxyalkyl alcohol or the like. Depending on the kind of the substituent, the substitution may be appropriately carried out by an ordinary method by alkylation, acylation, sulfonylation, arylation, etc. Further, by substituting a hydrogen atom on an amino group, it can be made into a disubstituted compound. The reaction can be carried out at-20 ℃ to 50 ℃.

In addition, in R¹Is a compound [ I ] containing a substituted amino group]In the case of having a urea bond, according to [ method A ]]The same method or the method described in Japanese provisional patent publication No. 10-195037, which can be prepared by reacting the corresponding amine compound with a reagent for forming a urea bond.

In addition, wherein the formula [ I]In R¹Is a compound [ I ] containing a substituted amino group]Can be prepared by adding a compound containing an amino group to the corresponding compound at R¹A compound containing a carbon-carbon double bond. The reaction can be carried out by refluxing the solvent under heating or in the absence of a catalyst.

(method c)

Wherein the formula [ I]R in (1)¹Is a compound [ I ] containing an amino group]By reaction from the corresponding at R¹Is prepared fromRemoving the protecting group from the compound for protecting the amino group. The removal of the protecting group can be carried out by a conventional method (e.g., acid treatment, base treatment, catalytic reduction, etc.). In the reaction, the reaction of acid treatment can be carried out at 5-120 ℃, the reaction of alkali treatment can be carried out at 5-40 ℃, and the reaction of catalytic reduction can be carried out at 10-40 ℃.

In addition, wherein the formula [ I]R in (1)¹Is a compound [ I ] containing an amino group]Can be prepared by reducing the corresponding compound at R¹A compound having a nitro group. The reduction may be carried out by reaction with tin chloride, zinc, or the like in the presence of an acid. For example, the reaction may be carried out while refluxing the solvent under heating.

In addition, wherein the formula [ I]R in (1)¹Is a compound [ I ] containing an amino group ]Can be prepared by reacting¹And (b) a compound having a carboxyl group is subjected to Curtius rearrangement and the like. Curtius rearrangements can be carried out, for example, as described in Advanced Organic Chemistry, Vol.4, p.1054. That is, it can be performed as follows: the carboxyl group is converted into an acid chloride by thionyl chloride or the like, followed by azidation with sodium azide or the like, followed by hydrolysis.

(method d)

Wherein the formula [ I]R in (1)¹Is a compound [ I ] containing a hydroxyl group]Can be prepared by conventional methods by reacting the corresponding compound at R¹Removing the protecting group from the compound containing the protected hydroxyl group. Depending on the kind of the protecting group, the removal of the protecting group may be performed by acid treatment, base treatment, catalytic reduction, or the like. The reaction can be carried out, for example, at from 0 ℃ to 80 ℃ and particularly preferably from 5 ℃ to 50 ℃.

In addition, wherein the formula [ I]R in (1)¹Is a compound [ I ] containing a hydroxyl group]Can be prepared by reducing the corresponding compound at R¹A compound containing a formyl group. The reduction can be carried out by reacting the compounds in the presence of a reducing agent such as sodium borohydride and the like. The invention can be carried out, for example, at from-80 ℃ to 80 ℃, particularly preferably from-70 ℃ to 20 DEG CThe process is carried out as follows.

In addition, wherein the formula [ I ]R in (1)¹Is a compound [ I ] containing a hydroxyl group]Can be prepared by reducing the corresponding compound at R¹Or a compound containing an ester or carboxyl group. The reduction can be carried out by reacting the compounds in the presence of a reducing agent such as lithium aluminum hydride or the like. The invention can be carried out, for example, at from-50 ℃ to 200 ℃ and particularly preferably from-20 ℃ to 60 ℃.

(method e)

In the formula [ I]R in (1)¹In the case of a hydroxyl group and it has an asymmetric center at the bonded portion, the configuration of the compound can be converted to the opposite configuration, for example, according to the method described in Mitsunobu et al, Synthesis, pages 1-28, 1981. In particular, the conversion can be carried out by reacting the compounds in the presence of triphenylphosphine, benzoic acid and diethyl azodicarboxylate in a suitable solvent. The invention can be carried out, for example, at from 0 ℃ to 60 ℃, particularly preferably from 5 ℃ to 40 ℃.

(method f)

For example, according to the method described by Mitsunobu et al, Synthesis, pp.1-28, 1981, by reacting the corresponding compound at R¹Wherein a compound having a hydroxyl group is reacted with a corresponding thiol group-containing compound to prepare a compound having the formula [ I ]]R in (1)¹Is a compound [ I ] containing an optionally substituted thiol group]. In particular, the reaction can be carried out by reacting the compounds in the presence of triphenylphosphine, and diethyl azodicarboxylate in a suitable solvent. The reaction can be carried out, for example, while refluxing the solvent under heating.

By reacting at R¹Compounds containing halogen in position [ I ]]Can be prepared by reaction with the corresponding thiol group-containing compound, wherein the formula [ I]R in (1)¹Is a compound [ I ] containing an optionally substituted thiol group]. The invention can be carried out, for example, at from-50 ℃ to 150 ℃, particularly preferably from 10 ℃ to 100 ℃.

In addition, by adding the corresponding compounds in R¹Compounds containing thiol groups[I]Or corresponding compounds containing a protected thiol group (e.g. acetylated thiol groups), may be prepared wherein R is¹Is a compound [ I ] containing an alkylthio group]. The reaction can be carried out in the presence of a base, for example at-10 ℃ to 80 ℃, particularly preferably at 5 ℃ to 50 ℃.

(method g)

For example, according to the method described by Mitsunobu et al, Synthesis, pp.1-28, 1981, by reacting the corresponding compound at R¹Compounds containing hydroxy groups [ I ]]Can be subjected to amination to prepare the compound of the formula (I)]R in (1)¹Is a compound [ I ] containing a substituted amino group]。

(method h)

The corresponding compound at R is reduced according to a conventional method (for example, by hydrolysis with a base such as sodium hydroxide or the like, treatment with an acid such as hydrochloric acid, hydrobromic acid or the like, reduction using palladium (black), palladium on carbon or the like under a hydrogen atmosphere, depending on the kind of the ester residue)¹Compounds containing an esterified carboxyl group [ I ] ]By carrying out the deesterification, the compound of the formula [ I ] can be prepared]R of (A) to (B)¹Is a compound having a free carboxyl group [ I]. In the deesterification reaction, for example, the alkali hydrolysis may be carried out at 5 ℃ to 70 ℃, the acid treatment may be carried out at 5 ℃ to 80 ℃, or the reduction may be carried out at 10 ℃ to 40 ℃.

(method i)

In the presence or absence of a condensing agent by reacting the corresponding compound at R¹Compounds containing free carboxyl groups [ I ]]By reaction with the corresponding amine compound, or by reaction of the corresponding compound at R¹Compounds containing free amino groups [ I ]]Can be prepared by reaction with the corresponding carboxylic acid compound, wherein the formula [ I]R in (1)¹Is a compound [ I ] containing an amide bond]. As the condensing agent, 1' -carbonyldiimidazole, 1, 3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, isobutyl chloroformate, N-methylmorpholine or the like is used, which is generally used for the reaction of forming an amide bond from a carboxylic acid and an amine. The reaction can be carried out, for example, at-20 ℃ to 50 ℃.

(method j)

By treating the corresponding compound at R with an oxidizing agent (e.g., 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, etc.)¹A compound [ I ] containing a heterocyclic group]Can be prepared into the formula (I)]R in (1)¹Is a heterocyclic group-containing group [ I ]And the nitrogen atom in the heterocyclic group is substituted with oxo (nitrogen atom is oxidized) (e.g., N-oxomorpholino, etc.). The reaction can be carried out, for example, at 5 ℃ to 50 ℃.

(method k)

By reacting at R¹A compound [ I ] containing a heterocyclic group]By reaction with alkyl halides, the compounds [ I ] can be prepared]Wherein is represented by the formula [ I]R in (1)¹Is a group containing a heterocyclic group in which a nitrogen atom is oxidized, and other than the above-mentioned compounds (method j) (e.g., N-alkyl-4-morpholino group and the like). The reaction can be carried out, for example, at from 20 ℃ to 80 ℃.

(method l)

By reacting a corresponding compound of formula (I) wherein R³Compounds [ I ] which are hydrogen atoms]By alkylation in a conventional manner, a compound of the formula [ I ] can be prepared]R in (1)³Compounds which are alkyl [ I]. The alkyl group may be substituted. The reaction can be carried out, for example, at from 20 ℃ to 80 ℃.

(method m)

By treating the corresponding compound at R with an oxidizing agent (e.g., 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxone, etc.)¹Compounds containing thio groups [ I ]]Can be prepared into the formula (I)]R in (1)¹Is a compound [ I ] containing a group whose sulfur atom is monosubstituted by oxo (e.g., sulfinyl, etc.)]. The reaction can be carried out, for example, at from-80 ℃ to 150 ℃ and particularly preferably at from 0 ℃ to 40 ℃.

(method n)

By treating the corresponding compound at R with an oxidizing agent (e.g., 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxone, etc.)¹Compounds containing thio groups [ I ]]Can be prepared into the formula (I)]R in (1)¹Is a compound [ I ] containing a group whose sulfur atom is disubstituted with oxo (e.g., sulfonyl group, etc.)]. The reaction can be carried out, for example, at from-80 ℃ to 150 ℃ and particularly preferably at from 0 ℃ to 40 ℃.

(method o)

By reacting at R¹Compounds containing a carbonyl group [ I ]]By reductive amination to produce compounds of the formula]R in (1)¹Is a compound [ I ] containing an amino group]. Can be used in combination with [ method C ] described above]The reaction was carried out in the same manner.

(method p)

For example, by applying the corresponding primer at R according to the method described by Synlett, April, pp.375-377, 1997¹Compounds containing alkylsulfinyl groups [ I ]]The reaction can prepare the compound of the formula [ I]R in (1)¹Is a compound containing a sulfinic acid group [ I]。

(method q)

For example by reacting the corresponding compound at R in the presence of a condensing agent such as 1, 1' -carbonyldiimidazole or the like¹Compounds containing aminoalkylamino groups [ I)]By carrying out the cyclization, the compound of the formula [ I ] can be prepared]R in (1)¹Is a compound [ I ] containing an imidazolidinyl or hexahydropyrimidyl group ]. The reaction can be carried out, for example, at-20 ℃ to 50 ℃.

As the solvent used in the above-mentioned reactions (method a) to (method q), any solvent may be used as long as it does not affect the reaction, and for example, the following may be used by appropriately selecting: dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, ethanol, dichloromethane, carbon tetrachloride, 1, 3-dimethyl-2-imidazolidine, acetic acid, diethyl ether, methoxyethane, dimethyl sulfoxide, acetonitrile, water, and mixtures thereof.

Incidentally, the compound [ IV ] as a starting material in the present invention is a novel compound, which can be prepared, for example, as shown by the following chemical formula:

wherein R is⁵¹Represents an alkyl group, R⁶¹Represents a protecting group of an amino group, R⁵²Represents an alkyl group which may be bonded at the terminal thereof, X³Represents a leaving group, X⁴Represents a leaving group, ring A, ring B, R³And R⁴Have the same meaning as defined above.

Namely, a pyridine compound [ IX ] and a Grignard compound [ X ] are subjected to a condensation reaction, and in addition, an amino group is protected to provide a compound [ XI ]. Subsequently, it is subjected to reduction reaction to provide the compound [ XII ]. Next, the carbonyl group of the compound [ XII ] is protected with a ketal to prepare a compound [ XIII ], and the protecting group for the amino group is removed to provide a compound [ XIV ]. Subsequently subjecting the compound [ XIV ] and the compound [ XV ] to a condensation reaction to provide a compound [ XVI ], followed by reacting with the compound [ XVII ], or subjecting the compound [ XIV ] and the compound [ III ] to a condensation reaction to provide a compound [ XVIII ], and providing a compound [ IV ] by removing a protecting group thereof.

The compound [ IV ] has an asymmetric carbon, and thus optical isomers based on the asymmetric carbon exist. By using the optical isomer of the above-mentioned compound [ XIV ], the desired optical isomer of the compound [ IV ] can be produced.

The optical isomer of the compound [ XIV ] can be prepared by optically resolving a racemic mixture of the compound [ XIV ] by a conventional method. The optical resolution can be carried out, for example, by reacting the compound [ XIV ] with an N-acyl-optically active amino acid or an N-sulfonyl-optically active amino acid to provide two diastereomeric salts, and by separating and collecting one of the diastereomeric salts by utilizing the difference in solubility thereof.

The acyl group of the N-acyl-optically active amino acid is exemplified by acetyl, propionyl, tosyl or benzyloxycarbonyl, and the optically active amino acid is exemplified by L-phenylalanine, L-leucine, L-glutamine, L-methionine, L-valine, L-threonine, D-phenylalanine or D-phenylglycine.

Further, the compound [ II ] of the present invention as a starting material is a novel compound, which can be prepared, for example, as shown by the following chemical formula:

wherein, ring A, R¹¹，R¹²，R⁶¹And X¹Have the same meaning as defined above.

Namely, subjecting the compound [ XII ] and the compound [ V ] to reductive amination to provide a compound [ XIX ], and preparing the compound [ II-a ] by removing the protecting group of the amino group thereof. Reductive amination can be carried out in the same way as [ method C ].

In the preparation of the above-mentioned compound [ IV ], the intermediate compounds are each not limited to those shown in the reaction formula, and a salt thereof or a reduced derivative thereof may be suitably used as long as it does not affect the reaction.

Further, in the raw material [ II ] of the present invention, the compound [ II-b ] can be produced, for example, as shown by the following chemical formula:

wherein R is⁵³Represents an alkyl group, X³Represents a halogen atom, and ring A has the same meaning as defined above.

That is, the pyridine compound [ XX ] and the compound [ XXI ] are condensed, and the resulting compound [ XXII ] is reduced to provide the compound [ II-b ].

Further, in the starting material of the present invention, the compound of the formula [ II-c ] can be prepared as shown below:

wherein the symbols have the same meaning as defined above.

Wherein the symbols have the same meaning as defined above.

That is, the compound [ XII ] is reduced to provide the compound [ XXIII ], and the amino group of the obtained compound [ XXIII ] is deprotected to provide the compound [ II-c ].

Although an optical isomer of the compound [ II-c ] exists, it can be prepared by optical resolution from a racemic mixture in a similar manner to the above-mentioned optical resolution of the compound [ XIV ].

In addition, in the preparation of the raw material of the compound of the present invention, when the raw material or the intermediate contains a functional group, an appropriate protecting group may be introduced into each functional group by a conventional method other than the above-mentioned method, and if they are not necessary, these protecting groups may be appropriately removed.

In the present specification, alkyl means, for example, straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, isopentyl and the like, preferably those having 1 to 4 carbon atoms. Alkenyl means, for example, straight or branched chain alkenyl groups containing 2 to 7 carbon atoms, such as vinyl, aryl, propenyl, isopropenyl and the like, preferably those containing 1 to 4 carbon atoms. Alkoxy means straight or branched alkoxy groups containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, preferably those containing 1 to 4 carbon atoms. Alkanoyl means straight or branched alkanoyl containing 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, valeryl, tert-butylcarbonyl and the like, preferably those containing 1 to 4 carbon atoms. Cyclic lower alkyl means cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably those having 3 to 6 carbon atoms. Further, the halogen atom is exemplified by a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.

Examples

Hereinafter, the present invention will be explained in more detail by referring to examples and reference examples, but the present invention is not limited by these examples.

Example 1

(1) In 30ml of methanol was dissolved 1.43g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, to which 114mg of sodium borohydride was added. The mixture was stirred at room temperature for 3 hours. To the reaction mixture were added aqueous ammonium chloride solution and ethyl acetate, and after stirring the mixture, the layers were separated. The organic layer was washed with water and brine, dried, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 4: 1) to give 0.99g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine as shown in table 1 below.

(2) 200mg of the compound of (1) above was further purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give 18mg of (a) trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 125mg of (b) cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine as shown in Table 1 below.

Example 2

200mg of (2R) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 10ml of tetrahydrofuran, 60mg of sodium borohydride are added thereto, and the mixture is refluxed. While the mixture was continuously refluxed, a mixed solvent of 1ml of methanol and 5ml of tetrahydrofuran was added dropwise thereto. After 5 hours, the reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine and dried, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1 to 1: 2) to give 33mg of (a) (2R, 4R) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 160mg of (b) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 2 below.

Example 3

Using (2R) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, treated in the same manner as in example 2 to provide (a) (2R, 4R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and (b) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in table 2 below.

Example 4

150mg of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 5ml of dimethylformamide, to which 40mg of sodium hydride (60%) are added at 0 ℃. To this solution, 0.2ml of methyl iodide was added at 0 ℃ and the mixture was stirred at room temperature for 16 hours. After water and ethyl acetate were added to the solution, the mixture was stirred, and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 72mg of (a) cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxypiperidine and 36mg of (b) trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxypiperidine as shown in table 3 below.

Example 5

The same procedures used in example 4 above were repeated using 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 2-pyridylmethyl chloride hydrochloride to provide 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyridylmethoxy) piperidine as shown in Table 4 below.

Example 6

To a solution of 98mg of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine in 2ml of toluene were added 57.6mg of dimethylaminoethyl chloride hydrochloride, 12.5mg of tetrabutylammonium bromide and 1ml of a 10M aqueous solution of sodium hydroxide at room temperature. After stirring the mixture at room temperature for 2 hours, stirring was carried out at 60 ℃ for a further 16 hours. After completion of the reaction, ethyl acetate and aqueous sodium bicarbonate solution were added to the reaction mixture and the separation layer. The organic layer was further washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol 19: 1). The oily substance obtained was treated with a 4M hydrochloric acid-ethyl acetate solution. The precipitate formed was collected by filtration and dried to provide 53mg of 1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-4- (1-dimethylaminoethoxy) -2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 4 below.

Example 7

1- (2-chloroethyl) piperidine hydrochloride and 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine were treated in the same manner as in example 6 to give 1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-piperidinylethoxy) piperidine hydrochloride as shown in Table 4 below.

Example 8

100mg of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 3ml of dichloromethane, 0.03ml of piperidine and 0.018ml acetic acid are added thereto, and the mixture is stirred. 129.7mg of sodium triacetoxyborohydride was added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried and the solvent was removed by distillation under reduced pressure. Subsequently, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine and cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine. Each of the obtained compounds was dissolved in 1ml of chloroform, and 0.2ml of a 4M hydrochloric acid-ethyl acetate solution was added thereto. After stirring the mixture for a while, the mixture was concentrated under reduced pressure to give 58mg of (a) trans-1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine hydrochloride and 16mg of (b) cis-1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine hydrochloride as shown in Table 5 below.

Examples 9 to 44

Using the corresponding starting materials and treated in the same manner as in example 8, the compounds shown in tables 6 to 18 below were provided.

Example 45

In 20ml of acetic acid was dissolved 2.45g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, to which 3.85g of ammonium acetate and 5g of sodium sulfate were added. The mixture was stirred at room temperature for 1 hour. Subsequently, 1.18g of sodium triethoxyborohydride was added thereto, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 2M aqueous sodium bicarbonate solution, chloroform and water were added thereto. The mixture was stirred for 0.5 h and the layers were separated. The aqueous layer was extracted again with chloroform and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol 10: 1). The oily substance obtained was treated with a 4M hydrochloric acid-ethyl acetate solution and concentrated under reduced pressure. Subsequently, the concentrate was triturated with isopropyl ether to give 1.16g of 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 19 below.

Example 46

The same procedures used in example 45 were repeated except for using (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine to give (2R) -4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 19 below.

Example 47

To a solution of 1.06g of 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine in 20ml of methylene chloride were added 0.42ml of triethylamine and 660mg of dibutoxycarbonate, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give 130mg of (a) trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 120mg of (b) cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine as shown in Table 20 below.

Example 48

100mg of trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine are treated with 4M hydrochloric acid-ethyl acetate solution. To this was added diethyl ether and hexane, and the formed precipitate was collected by filtration, washed with hexane and dried in vacuo to provide 56mg of trans-4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride salt as shown in Table 21 below.

Example 49

The same procedures used in example 48 were repeated except for using cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine to give cis-4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 21 below.

Example 50

60mg of 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 1.2ml of dichloromethane, 0.02ml of triethylamine and 0.013ml of propionyl chloride were added thereto under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. The reaction mixture was poured into saturated brine and the layers were separated. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with brine, dried and the solvent was removed by distillation. The residue was purified by thin layer silica gel chromatography (chloroform: methanol ═ 9: 1) to give 40mg of (a) trans-1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine and 27mg of (b) cis-1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine, as shown in Table 22 below.

Examples 51 to 69

The same procedures as in example 50 were carried out using the corresponding starting materials to provide the compounds shown in tables 23 to 33 below.

Example 70

0.056ml of triethylamine and 0.028ml of acetyl chloride were added successively at 0 ℃ to a solution of 98mg of 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine in 4ml of dichloromethane and the mixture was stirred at 0 ℃ for 0.5 hour. After completion of the reaction, an aqueous sodium hydrogencarbonate solution and chloroform were added thereto, and the mixture was stirred and the layers were separated. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 4: 1) and dried in vacuo to give 86mg of 4-acetylamino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as a powder as shown in table 34 below.

Example 71

The same procedures used in example 70 were repeated except for using 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and nicotinoyl chloride hydrochloride to give 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-pyridylcarbonylamino) piperidine as shown in Table 34 below.

Example 72

To a solution of 124mg of 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine in 3ml of dimethylformamide were added 44mg of N-tert-butoxycarbonylglycine, 58mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 13.5mg of 1-hydroxy-1H-benzotriazole, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, an aqueous sodium hydrogencarbonate solution and chloroform were added thereto, and the mixture was stirred and the layers were separated. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol 19: 1) and treated with 4M hydrochloric acid-ethyl acetate solution. The mixture was concentrated under reduced pressure. The precipitate formed was washed with isopropyl ether, collected by filtration and dried in vacuo to provide 83mg of 4-aminoacetamido-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride salt, as shown in Table 35 below.

Example 73

The same procedures used in example 72 were repeated except for using 4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and N, N-dimethylglycine to give 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4-dimethylaminoacetamido-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride salt as shown in Table 35 below.

Example 74

To a solution of 320mg of cis-1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-nitrobenzoyl) aminopiperidine in 25ml of ethanol was added 480mg of tin dichloride, and the mixture was refluxed for 4 hours. After completion of the reaction, ethanol was removed by distillation under reduced pressure. Diethyl ether and 2M aqueous sodium hydroxide solution were added thereto, and the layers were separated. The organic layer was washed again with 2M aqueous sodium hydroxide solution and then with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1), and the obtained oily substance was treated with 4M hydrochloric acid-ethyl acetate solution. The reaction mixture was concentrated under reduced pressure and triturated with isopropyl ether to give 152mg of cis-4- (4-aminobenzoyl) amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 36 below.

Example 75

To 60ml of a tetrahydrofuran solution containing 3.91g N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methylamine was added 2.34g of 1, 1' -carbonyldiimidazole and the mixture was stirred at 40 ℃ overnight. After removal of the solvent by distillation, ethyl acetate was added. The whole organic layer was washed with water and saturated brine, and dried. White crystals obtained by removing the solvent by distillation under reduced pressure were collected by diisopropyl ether. The obtained white crystals were dissolved in 60ml of acetonitrile, and 3.5ml of methyl iodide was added thereto. After the reaction was carried out at 60 ℃ for 2 hours, the solvent was removed by distillation under reduced pressure. 224mg of the residue was dissolved in 2ml of dichloromethane, and 100mg of cis-2- (4-fluoro-2-methylphenyl) -4- (propionylamino) piperidine and 0.11ml of triethylamine were added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with water and saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 3) to give 83.5mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine as shown in table 37 below.

Examples 76 to 84

The same procedures as in example 75 were carried out using the corresponding starting materials to give the compounds shown in tables 37 to 39 below.

Example 85

To a solution of 212mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine in 1ml of ethyl acetate was added 2ml of a 4M hydrochloric acid-ethyl acetate solution under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. After the solvent was removed by distillation under reduced pressure, chloroform and a 2M aqueous solution of sodium hydroxide were added to the residue. The layers were separated and the aqueous layer was extracted with chloroform, the combined organic layers were dried and the solvent was removed by distillation under reduced pressure to give 177mg of (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 40 below.

Example 86

Using (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and treating in the same manner as in example 85, there was provided (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 40 below.

Example 87

To a solution of 253mg of (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 0.139ml of triethylamine in 2ml of dichloromethane was added 0.071ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with chloroform, the combined organic layers were washed and dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 243mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-methanesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 41 below.

Example 88

The same procedures used in example 87 were repeated except for using (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and ethanesulfonyl chloride to give (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethanesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 41 below.

Example 89

To a solution of 58.4mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-methanesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine in 1ml of dimethylformamide was added 4.6mg of sodium hydride under ice-cooling. The mixture was stirred for 30 minutes, 0.010ml of methyl iodide was added thereto, and the mixture was further stirred for 1 hour. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, and the solvent was removed by distillation under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 36.7mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- (N-methanesulfonyl-N-methyl) amino-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 41 below.

Example 90

The same procedures used in example 89 were repeated except for using (2R, 4S) -1- [ N- (1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethanesulfonylaminopiperidine to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-ethanesulfonyl) aminopiperidine, which is shown in Table 41 below.

Example 91

To 20ml of a toluene solution containing 985mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 129mg of tetrabutylammonium bromide and 10ml of a 10M aqueous sodium hydroxide solution containing 2- (2-bromoethoxy) tetrahydropyran were added at room temperature, the stability of the mixture was raised to 60 ℃ to 70 ℃ and the mixture was stirred overnight. To this was added 2.42ml of 2- (2-bromoethoxy) tetrahydropyran, and the mixture was stirred overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 3: 2) to give 1.12g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (tetrahydropyran-2-yloxy) ethoxy } piperidine as shown in table 42 below.

Example 92

To a solution of 1.04g of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (tetrahydropyran-2-yloxy) ethoxy } piperidine in 30ml of methanol was added 64mg of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 1: 1) to give 703mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine as shown in table 42 below.

Example 93

To a solution of 53.6mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine, 13.8mg of 4H- [1, 2, 4] -triazole and 24.4mg of triphenylphosphine in 2ml of tetrahydrofuran under ice-cooling was added 0.092ml of a 40% solution of azodicarboxylic acid diethyl ester in toluene. The temperature of the mixture was raised to room temperature and the mixture was stirred overnight. Subsequently, the temperature was raised to 50 ℃, 24.4mg of triphenylphosphine was added thereto, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 1: 1 and chloroform: methanol ═ 19: 1) to give 43.2mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (1, 2, 4) triazolylethoxy } piperidine as shown in table 42 below.

Examples 94 and 95

The corresponding starting materials were treated in the same manner as in example 93 to provide the compounds shown in Table 42 below.

Example 96

To a solution of 215mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine in 2ml of dichloromethane containing 0.084ml of triethylamine was added 0.037ml of methanesulfonyl chloride under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with brine, dried and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 2: 1) to give 189mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine as shown in table 42 below.

Example 97

(1) To a solution of 61.5mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine in 1ml of dichloromethane containing 0.028ml of triethylamine was added 0.013ml of morpholine under ice-cooling, and the mixture was refluxed overnight under heating. 1ml of morpholine was further added thereto, and the mixture was stirred for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) and NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 36.3mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethoxy) piperidine.

(2) 30.7mg of the compound of the above (1) was dissolved in 1.0ml of chloroform, and 0.02ml of a 4M hydrochloric acid-ethyl acetate solution was added thereto. The mixture was stirred for a while and concentrated under reduced pressure to give 35.3mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethoxy) piperidine hydrochloride salt as shown in Table 42 below.

Example 98

The same procedures used in example 97(1) were repeated except for using (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine and diethylamine to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (2-diethylaminoethoxy) -2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 42.

Example 99

200mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 2ml of methylene chloride, 0.1ml of ethyl isocyanate and 0.1ml of triethylamine are then added thereto, and the mixture is stirred at 60 ℃ for 3 days with heating. The reaction mixture was cooled to room temperature, water and chloroform were added thereto, and the layers were separated. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 78mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 42 below.

Example 100

200mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 2ml of methylene chloride, and then 0.1ml of morpholine-4-carboxychloride and 0.1ml of triethylamine are added thereto, and the mixture is stirred at 60 ℃ for 3 days with heating. After the reaction mixture was cooled to room temperature, water and chloroform were added thereto, and the layers were separated. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 68mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonyloxypiperidine as shown in table 42 below.

Example 101

248mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 5ml of tetrahydrofuran, 81mg of 1, 1' -carbonyldiimidazole are then added thereto, and the mixture is stirred at 60 ℃ for 16 hours with heating. The reaction mixture was cooled to room temperature, water and chloroform were added and the layers were separated. The aqueous layer was extracted again with chloroform and the combined organic layers were further washed with water. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrated residue obtained was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 135mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolyl) carbonyloxypiperidine as shown in table 42 below.

Example 102

(1) 298mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolyl) carbonyloxypiperidine are dissolved in 3ml of acetonitrile, and then 0.06ml of methyl iodide is added thereto, and the mixture is stirred with heating for 1 hour. The solution was cooled to room temperature and the solvent was removed by distillation under reduced pressure. To the residue were added 2.5ml of dichloromethane, 0.11ml of 4-methylpiperazine and 0.14ml of triethylamine, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added an aqueous sodium hydrogencarbonate solution and chloroform, and the mixture was stirred for 30 minutes. The layers were separated and the organic layer obtained was further washed with water and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-methylpiperazino) carbonyloxypiperidine.

(2) Treatment of the compound of the above (1) with 4M hydrochloric acid-ethyl acetate solution provided 78mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (4-methylpiperazino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 43 below.

Example 103-105

The same procedures as in examples 102(1) and (2) were carried out using the corresponding starting materials to give the compounds shown in Table 43 below.

Example 106

(1) 5g of cis-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 10.5g of triphenylphosphine and 4.88g of benzoic acid were dissolved in 100ml of tetrahydrofuran, and then 18.3ml of a 40% diethyl azodicarboxylate-toluene solution was added thereto under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water and ethyl acetate, and the mixture was stirred for 30 minutes. The solution was separated by layer, and the obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 4.36g of trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4-benzoyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) In 10ml of methanol was dissolved 1.4g of the above compound (1), followed by addition of 325mg of potassium carbonate thereto and stirring of the mixture at room temperature for 16 hours. After the solution was concentrated under reduced pressure to remove the solvent by distillation, water and ethyl acetate were added thereto, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 0.68g of trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine as shown in table 44 below.

Example 107

To 10ml of tetrahydrofuran were added 98mg of trans-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 70mg of [1, 2, 4] triazole and 262mg of triphenylphosphine, followed by addition of 0.48ml of a 40% solution of azodicarboxylic acid diethyl ester in toluene, and the mixture was stirred under reflux for 16 hours. After the completion of the reaction, an aqueous sodium hydrogencarbonate solution and ethyl acetate were added thereto, and the mixture was stirred for 30 minutes. The reaction mixture was separated by layer, and the obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 46mg of cis-1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1, 2, 4-triazolyl) piperidine as shown in table 44 below.

Example 108

The same procedures used in example 107 were repeated except for using cis-1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 4, 6-dihydroxy-2-mercaptopyrimidine to provide the compounds shown in table 45 below.

Example 109

The same procedures used in examples 106(1) and 2 (were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine to provide (2R, 4R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, as shown in Table 46 below.

Example 110-

The same procedures as in example 107 were carried out using the corresponding starting materials to give the compounds shown in Table 46 below.

Example 113

(1) A solution of 1.2ml of triethyl phosphonoacetate in 30ml of tetrahydrofuran was ice-cooled, and sodium hydride was slowly added thereto. While maintaining the same temperature, the mixture was stirred for 30 minutes, and 30ml of a tetrahydrofuran solution containing 3.02g of (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was added dropwise thereto. The mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonylmethine (methylidene) -2- (4-fluoro-2-methylphenyl) piperidine as a colorless liquid.

(2) The compound of the above (1) was dissolved in 50ml of methanol, 500mg of palladium on carbon was added thereto, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The catalyst was removed and methanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give 3.23g of (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonylmethyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 46 below.

Example 114

(1) 3.23g of (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonylmethyl-2- (4-fluoro-2-methylphenyl) piperidine were dissolved in 20ml of methanol, and 5.73ml of a 2M aqueous sodium hydroxide solution was added thereto. The mixture was stirred at room temperature overnight, and after neutralizing the mixture by 2M hydrochloric acid, methanol was removed by distillation under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and the solvent was removed by distillation under reduced pressure to give 2.97g of (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxymethyl-2- (4-fluoro-2-methylphenyl) piperidine as a yellow powder.

(2) 200mg of the compound of (1) above was dissolved in 2ml of dimethylformamide, 84mg of 1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimidazole hydrochloride, 65mg of 1-hydroxy-1H-benzotriazole and 0.037ml of morpholine were added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried, and the solvent was removed by distillation to obtain a residue, which was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 138mg of (2R) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylmethylpiperidine as shown in table 46 below.

Example 115-

The same procedures as in example 114(2) were carried out using the corresponding starting materials to provide the compounds shown in the following table 46.

Example 118

(1) In 10ml of ethanol was dissolved 1.49g of (2R) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, to which 226mg of hydroxylamine hydrochloride and 267mg of sodium acetate were added. The mixture was stirred overnight. Ethanol was removed by distillation under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was removed by distillation under reduced pressure to provide a compound in a resin state.

(2) The compound of the above (1) was dissolved in 50ml of methanol, and 844mg of nickel chloride was added thereto. The mixture was ice-cooled, and 224mg of sodium borohydride was slowly added thereto. After the mixture was stirred overnight, it was concentrated under reduced pressure, water and ethyl acetate were added thereto, and the layers were separated. The organic layer was washed with saturated brine and dried. The solvent was removed by distillation under reduced pressure to give 1.44g of (2R) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 47 below.

Example 119

The same procedures used in examples 119(1) and (2) were repeated except for using (2R) -1- { N- (3, 5-bistrifluoromethylphenyl) methyl-N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine to give (2R) -4-amino-1- { N- (3, 5-bistrifluoromethylphenyl) methyl-N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 47 below.

Example 120

The same procedures used in example 50 were repeated except for using (2R) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine to provide (a) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyrazinylcarbonylamino) piperidine and (b) (2R, 4R) -1- [ N- {1- (S) - (3, 5-bis-trifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyrazinylcarbonylamino) piperidine, as shown in Table 47 below.

Example 121

To a solution of 80mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine in 2ml of acetonitrile was added 0.034ml of methyl iodide, and the mixture was stirred at 60 ℃ overnight. The solvent was removed by distillation and the precipitated yellow powder was dried to give 98mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-4-morpholino) piperidine iodide as shown in Table 48 below.

Example 122

The same procedures used in example 121 were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-4-morpholino) piperidine iodide as shown in Table 48 below.

Example 123

To a solution of 80mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine in 2ml of dichloromethane was added 34mg of 3-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The precipitated white powder was dried to provide 79mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine as shown in Table 48 below.

Example 124

The same procedures used in example 123 were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinopiperidine to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxomorpholino) piperidine as shown in Table 48 below.

Example 125-

The same procedures as in example 8 were carried out using the corresponding starting materials to provide the compounds shown in Table 49 below.

Example 128-

The same procedures as in example 50 were carried out using the corresponding starting materials to give the compounds shown in tables 49 to 51 below.

Example 137

263mg of (2R) -4-amino-1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 2ml of dichloromethane, and 52. mu.l of 2-chloroethyl isocyanate and 167. mu.l of triethylamine were added thereto at room temperature, and the mixture was stirred for 2 hours. To the solution was added a saturated sodium bicarbonate solution, and the dichloromethane layer was separated, and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 109mg of (2R) -4- (2-chloroethyl) ureido-1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 51.

Example 138

In 20ml of dimethylformamide were dissolved 2.65g of (2R) -4-amino-1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride and 1g of 5-formylfuran-2-carboxylic acid, to which was added 1.92g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.6g of 1-hydroxy-1H-benzotriazole and 1.4ml of triethylamine. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, an aqueous citric acid solution and ethyl acetate were added thereto and the layers were separated. The organic layer was further washed with saturated brine, and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 289mg of (a) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine and 185mg of (b) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 52 below.

Example 140-

The same procedures used in example 138 were repeated except for using the corresponding starting materials to provide the compounds shown in tables 53 to 57 below.

Example 169

80mg of (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 1ml of tetrahydrofuran, 25.7mg of 1, 1-carbonyldiimidazole was added thereto under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the solution, 19. mu.l of 2-aminoethanol and 44. mu.l of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 22 hours. The solvent was removed by distillation, water and dichloromethane were added to the residue and the layers were separated. The organic layer was washed with saturated brine, dried and concentrated. To the residue was added isopropyl ether, and the precipitated white crystals were collected by filtration to give 74mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) ureidopiperidine as shown in Table 57 below.

Example 170-

Corresponding starting materials were used and treated in the same manner as in example 169 to provide the compounds shown in table 57 below.

Example 174-177

The corresponding starting materials were used and treated in the same manner as in example 87 to provide the compounds shown in table 58 below.

Example 178

In 10ml of methylene chloride were dissolved 1.01g of (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 0.558ml of triethylamine, to which was added 0.314ml of 2-chloroethanesulfonyl chloride under ice-cooling, and the mixture was stirred for 4 hours. The solution was poured into water, the layers were separated and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 725mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethylenesulfonamido-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 58 below.

Example 179

The same procedures used in example 178 were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine to give (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- (1-ethylidenesulfonyl-1-methylamino) -2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 58.

Example 180-

The same procedures as in example 87 were carried out using the corresponding starting materials to give the compounds shown in Table 59 below.

Example 183-

The same procedures as in example 89 were carried out using the corresponding starting materials to give the compounds shown in Table 59 below.

Example 185

The same procedures used in example 91 were repeated except for using (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and 2-methoxyethyl chloride to give (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methoxyethoxy) piperidine as shown in Table 59 below.

Example 186-

The same procedures as in example 91 and example 92 were carried out using the corresponding starting materials to provide the compounds shown in tables 59 to 60 below.

Example 190

The same procedures used in example 96 were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine and methanesulfonyl chloride to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) -piperidine as shown in Table 60 below.

Example 191-

The same procedures as in example 97 were carried out using the corresponding starting materials to provide the compounds shown in tables 60 to 61 below.

Example 197-

The same procedures as in example 101 were carried out using the corresponding starting materials to provide the compounds shown in table 62 below.

Example 199-

The same treatment as in example 102(1) or examples 102(1) and (2) was carried out using the corresponding starting materials, to provide the compounds shown in table 63 below.

Example 206

The same procedures used in example 123 were repeated except for using (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidinopiperidine to give (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-oxopiperidino) piperidine as shown in table 65 below.

Example 207

124mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine are dissolved in 4ml of ethanol, 3.8mg of sodium borohydride are added thereto, and the mixture is stirred at room temperature for 2 hours. To the solution was added an aqueous sodium bicarbonate solution, the mixture was stirred for 10 minutes and concentrated, and ethanol was removed by distillation. Ethyl acetate and water were added to the residue, and the layers were separated. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 68mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (5-hydroxymethylfuran-2-yl) carbamoylpiperidine as shown in table 65 below.

Example 208

124mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine, 44. mu.l of morpholine and 2.9. mu.l of acetic acid were dissolved in 4ml of dichloroethane, 106mg of sodium triethoxyborohydride were added thereto, and the mixture was stirred at room temperature for 3 hours. To the solution were added aqueous sodium carbonate solution and chloroform, the mixture was stirred for 10 minutes and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by NH silica gel column chromatography (n-hexane: ethyl acetate 1: 1). The oily substance obtained was treated with 4M hydrochloric acid-ethyl acetate solution to give 78mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (5-morpholinomethylfuran-2-yl) carbamoylpiperidine hydrochloride as shown in Table 65 below.

Example 209

197mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in a mixture of 3.3ml of toluene and 0.4ml of dichloromethane, to which 78mg of 1, 1' -carbonyldiimidazole are added. The mixture was stirred at 60 ℃ for 4 hours. Distilled water was added thereto, and the mixture was extracted with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 3.7ml of acetonitrile, 100. mu.l of methyl iodide was added thereto, and the mixture was stirred at 50 ℃ for 3 hours. The solution was concentrated under reduced pressure, 3.6ml of toluene and 156. mu.l of thiomorpholine were added to the residue, and the mixture was stirred at 70 ℃ for 16 hours. Distilled water was added thereto, and the mixture was extracted with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1 to 1: 2) to give 197mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine as shown in table 65 below.

Example 210-

The same procedures as in example 209 were carried out using the corresponding starting materials to give the compounds shown in Table 65 below.

Example 213

62mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine was dissolved in 1.9ml of methylene chloride, 22mg of 3-chloroperbenzoic acid was added thereto under ice cooling, and the mixture was stirred at 0 ℃ for 30 minutes. The solution was extracted by adding 0.1M aqueous sodium hydroxide and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: acetone ═ 4: 1) to give 63mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxythiomorpholino) carbonyloxypiperidine as shown in table 65 below.

Example 214

79mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine were dissolved in 2.4ml of methylene chloride, 68mg of 3-chloroperbenzoic acid was added thereto, and the mixture was stirred at room temperature for 4 hours. The solution was extracted by adding 0.1M aqueous sodium hydroxide and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: acetone ═ 4: 1) to give 76mg of (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- (1, 1-dioxothiomorpholino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 65 below.

Example 215

78mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2, 2, 5-trimethyl [1, 3] dioxolan-5-yl) carbamoylpiperidine was dissolved in 1ml of tetrahydrofuran, and 0.5ml of a 2M aqueous hydrochloric acid solution was added thereto under ice-cooling. After 15 minutes, the temperature was raised to room temperature and the mixture was stirred for a further 30 minutes. The mixture was poured into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 2: 1) to give 64mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {1, 1-bis (hydroxymethyl) ethyl } carbamoylpiperidine as shown in table 66 below.

Example 216

50.5mg of (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 1ml of dichloromethane, and 25.3mg of methyl isocyanate was added thereto under ice-cooling. After the temperature of the mixture was raised to room temperature, the mixture was stirred for 30 minutes. The solution was poured into water, the dichloromethane layer was separated, and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 47.9mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylureidopiperidine as shown in table 66 below.

Example 217

The same procedures used in example 216 were repeated except for using (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and tert-butyl isocyanate to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-tert-butylureido-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 66.

Example 218

50.5mg of (2R, 4S) -4-amino-1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 1ml of dichloromethane, and 42. mu.l of triethylamine and 18. mu.l of dimethylcarbamoyl chloride were added thereto under ice-cooling. After the mixture was allowed to warm to room temperature steadily, the mixture was stirred overnight. The solvent was poured into water, the dichloromethane layer was separated, and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 39: 1) to give 41.8mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- (3, 3-dimethylureido) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 66 below.

Example 219-

The same procedures as in example 216 were carried out using the corresponding starting materials to provide the compounds shown in Table 67 below.

Example 225

(1) The same procedures used in example 216 were repeated except for using 80mg of (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine to give (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-methylpiperazinecarboxyl) piperidine.

(2) The compound of the above (1) was dissolved in 1ml of ethyl acetate, 0.5ml of a 4M hydrochloric acid-ethyl acetate solution was added thereto under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. The solvent was removed by distillation under reduced pressure, and diethyl ether was added thereto. The precipitated white crystals were collected by filtration to provide 80mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-methylpiperazinecarbonyl) piperidine hydrochloride as shown in table 67 below.

Example 226

100mg of (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 2ml of dichloromethane, 33. mu.l of triethylamine and 19. mu.l of methyl chloroformate were added thereto under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The solution was poured into water and the dichloromethane layer was separated, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 80mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxycarbamoylpiperidine as shown in table 66 below.

Example 227-

The same procedures as in example 226 were carried out using the corresponding starting materials to give the compounds shown in Table 68 below.

Example 230

22mg of 2-ethoxy-ethanol was dissolved in 1.2ml of acetonitrile, 94mg of N, N' -disuccinimidyl carbonate and 0.1ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed by distillation, and a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the residue, and extracted. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in 0.8ml of methylene chloride, 80mg of (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 33. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and dichloromethane were added to the solution and extracted. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: methanol ═ 19: 1) to give 85mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- (2-ethoxyethoxy) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 68 below.

Example 231

Using 3-hydroxy-3-methylbutanol and (2R, 4S) -4-amino-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, treatment in the same manner as in example 230 provided (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxy-3-methylbutyloxy) carbamoylpiperidine, as shown in table 68 below.

Example 232

(1) 119mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-vinylsulphonylaminopiperidine are dissolved in 1ml of tetrahydrofuran. 26. mu.l of morpholine were added thereto at room temperature, and the mixture was refluxed under heating. After 5 hours, 26. mu.l of morpholine were added and the mixture was refluxed for a further 2.5 hours with heating. The solution was concentrated and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 129mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethyl) sulfonylaminopiperidine.

(2) 34.1mg of the above compound (1) was dissolved in 1ml of chloroform, and 25. mu.l of a 4M hydrochloric acid-ethyl acetate solution was added thereto. The mixture was concentrated to give 33.1mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinoethyl) sulfonylaminopiperidine hydrochloride as shown in Table 69 below.

Example 233-

The same procedures as in examples 232(1) and (2) were carried out using the corresponding starting materials to give the compounds shown in the following table 69.

Example 239

In a mixture of 1.6ml of dimethylformamide and 0.2ml of dichloromethane, 101mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved, to which 39mg of (S) - (-) -2-pyrrolidone-5-carboxylic acid, 58mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 12mg of 4- (dimethylamino) pyridine are added, and the mixture is stirred at room temperature for 6 hours, followed by stirring at 60 ℃ for 4 days. To the solution was added a 5% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydroxide solution and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone ═ 4: 1 to 2: 1) to give 64mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4- { (2S) -5-oxopyrrolidin-2-yl } carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 70 below.

Example 240

(1) In a mixture of 3.2ml of toluene and 0.4ml of methylene chloride 179mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved, to which 69mg of 1, 1' -carbonyldiimidazole are added, and the mixture is stirred at 60 ℃ for 3 hours. Distilled water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 3.2ml of acetonitrile, 88. mu.l of methyl iodide was added thereto, and the mixture was stirred at 50 ℃ for 3 hours. After concentrating the solution, 3.2ml of toluene and 114. mu.l of thiazolidine were added and the mixture was stirred at 70 ℃ for 16 hours. Distilled water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1 to 1: 2) to give 141mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1, 3-tetrahydrothiazol-3-yl) carbonyloxypiperidine.

(2) 62mg of the compound (1) above was dissolved in 2ml of dichloroethane, 22mg of 3-chloroperbenzoic acid was added thereto under ice cooling, and the mixture was stirred at 0 ℃ for 1 hour. Saturated aqueous sodium bicarbonate was added to the mixture and extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform: acetone ═ 4: 1) to give 42mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxo-1, 3-tetrahydrothiazol-3-yl) carbonyloxypiperidine, as shown in table 70 below.

Example 241

(1) 101mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 1.9ml of toluene, 46. mu.l of ethyl isocyanate and one drop of acetic acid are added thereto, and the mixture is stirred at 70 ℃ for 16 hours. The solution was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1 to 1: 1) to give 124mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonylmethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 106mg of the compound of the above (1) was dissolved in a mixture of 1.35ml of tetrahydrofuran and 0.15ml of methanol, 92. mu.l of a 2M sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 1 hour. After the solution was concentrated, a 10% citric acid aqueous solution was added thereto, and the precipitate was collected by filtration and washed with water to give 92mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 70 below.

Example 242

In 0.9ml of dimethylformamide were dissolved 61mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine, to which was added 9. mu.l of morpholine, 15mg of 1-hydroxybenzotriazole monohydrate and 19mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred at room temperature for 1 day. Distilled water was added to the solution, the mixture was extracted with chloroform, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 50mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylaminocarbonyloxypiperidine as shown in table 70 below.

Example 243

In 1.9ml of toluene was dissolved 101mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, 37. mu.l of chlorosulfonyl isocyanate was added thereto, and the mixture was stirred at room temperature for 10 minutes. 207. mu.l of diethylamine was added thereto, and the mixture was stirred at room temperature for 1 hour. Distilled water was added to the solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 116mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-diethylaminosulfonylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 70 below.

Example 244

The same procedures used in example 239 were repeated except for using (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and (S) - (-) -2-pyrrolidone-5-carboxylic acid to give (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-4- { (2S) -5-oxopyrrolidin-2-yl } carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 70 below.

Example 245

264mg of (2R) -4-amino-1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride, 80mg of 2-bromopyridine, 12mg of palladium acetate, 32mg of 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl and 48mg of sodium tert-butoxide are dissolved in 2ml of toluene, and the mixture is stirred at 80 ℃ for 16 hours. The solution was cooled to room temperature, ethyl acetate and an aqueous sodium hydrogencarbonate solution were added thereto, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 68mg of (a) (2R, 4S) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyridylamino) piperidine and 56mg of (b) (2R, 4R) -1- [ N- (3, 5-bistrifluoromethylbenzyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyridylamino) piperidine as shown in table 71 below.

Example 246-

Using the corresponding starting materials, the same procedures as in example 245 were repeated to give the compounds shown in the following tables 71 to 72.

Example 248-

Using the corresponding starting materials, the same procedures as in example 75 were carried out to obtain the compounds as shown in table 72 below.

Example 250

(1) 800mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine were dissolved in 5ml of tetrahydrofuran, 5ml of a 2M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added an aqueous citric acid solution to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solution was concentrated to give 700mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 110mg of the above compound (1) was dissolved in dimethylformamide, 96mg of 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride, 30mg of 1-hydroxybenzotriazole and 0.1ml of a 40% ammonium aqueous solution were added thereto, and the mixture was stirred at room temperature for 3 hours. To the solution was added aqueous citric acid solution and ethyl acetate, and the layers were separated. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 87mg of (2R, 4S) -4-aminocarbonyl-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 73 below.

Example 251-

The same procedures as in examples 250(1) and (2) or example 250(2) were carried out using the corresponding starting materials to provide the compounds shown in table 73 below.

Example 254

(1) In 40ml of tetrahydrofuran was dissolved 2g of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine, to which was added 1.59g of carbon tetrabromide and 1.26g of triphenylphosphine, and the mixture was stirred at room temperature for 2 hours. 80ml of diethyl ether was added to the solution, and after stirring the mixture, insoluble matter precipitated was removed by filtration. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (N-hexane: ethyl acetate ═ 10: 1) to give 1.26g of (2R, 4R) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-bromo-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 1.14g of the above compound (1) was dissolved in 20ml of dimethylformamide, 1.14g of potassium thioacetate was added thereto, and the mixture was stirred at 80 ℃ for 2 hours. After the solution was cooled to room temperature, an aqueous citric acid solution and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (N-hexane: ethyl acetate ═ 6: 1) to give 920mg of (2R, 4S) -4-acetylthio-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 74 below.

Example 255-

The same procedures as in examples 254(1) and (2) were carried out using the corresponding starting materials to give the compounds shown in Table 74 below.

Example 257

880mg of (2R, 4S) -4-acetylthio-1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 10ml of methanol, to which methyl iodide and 5ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 2 hours. An aqueous citric acid solution was added to the solution to neutralize it, and methanol was removed by distillation. To the residue were added ethyl acetate and saturated brine and the layers were separated. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (N-hexane: ethyl acetate ═ 6: 1) to give 560mg of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylthiopiperidine as shown in table 74 below.

Example 258-

The same procedures used in example 257 were repeated except for using corresponding starting materials to provide compounds shown in tables 74 to 75 below.

Example 264-

The same procedures as in example 213 were carried out using the corresponding starting materials to give the compounds shown in the following tables 76 to 77.

Example 271-

The same procedures as in example 214 were carried out using the corresponding starting materials to provide the compounds shown in the following tables 78 to 79.

Example 279-

The same procedures used in example 138 were repeated except for using the corresponding starting materials to provide the compounds shown in tables 80 to 87 below.

Example 313

To 4M hydrochloric acid in 4.2ml ethyl acetate was added 361mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } amino-carbonyl-4- [ { (2S, 4R) -4-benzyloxy-1-tert-butoxycarbonyl-pyrrolidin-2-ylcarbonyl } amino ] -2- (4-fluoro-2-methylphenyl) -piperidine, and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo the residue was triturated with hexane and the solvent was removed by decantation. The residue was dissolved in 4ml of dichloromethane, and 158ml of triethylamine and 36ml of acetyl chloride were added to the mixture under ice cooling. After stirring for 1 hour, water was added to the mixture under ice-cooling and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and dried in vacuo. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 49: 1 to 19: 1) to give 304mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-4- { [ (2S, 4R) -4-benzyloxy-1-acetylpyrrolidin-2-ylcarbonyl ] amino } -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 86.

Example 314-

The same procedures as in example 313 were carried out using the corresponding starting materials to provide compounds shown in tables 86 and 87 below.

Example 317-

The same procedures as in example 113(2) were carried out using the corresponding starting materials to give the compounds shown in the following table 87.

Example 319

98mg of (2R, 4S) -4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } amino-carbonyl-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 1.8ml of toluene, 24mg of succinic anhydride and 0.033ml of triethylamine were added thereto, and the mixture was refluxed for 18 hours. The mixture was cooled to room temperature, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 79mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (2, 5-dioxopyrrolidino) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 87 below.

Example 320-330

The same procedures used in example 209 were repeated except for using the corresponding starting materials to provide the compounds shown in tables 88 to 90 below.

Example 331

The same procedures used in example 113 were carried out using the corresponding starting materials to give (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (ethoxycarbonylmethyl) -piperidine as shown in table 91 below.

Example 332

In 20ml of tetrahydrofuran was dissolved 2.03g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethoxycarbonylmethylpiperidine, to which was added 450mg of lithium aluminum hydride under ice-cooling, and the mixture was stirred for 1 hour. 2ml of water was slowly added thereto, and after stirring the mixture for 10 minutes, 5ml of a 1M aqueous sodium hydroxide solution was added, and the mixture was further stirred for 10 minutes. The white precipitate formed was removed, diethyl ether and water were added to the filtrate, and the layers were separated. The organic layer was further washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 to 3: 2) to give 830mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) piperidine as shown in table 91 below.

Example 333

The corresponding starting material was used and treated in the same manner as in example 245 to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl-N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-pyrazin-2-ylamino) piperidine as shown in table 91 below.

Example 334

In 2ml of N, N-dimethylformamide were dissolved 114mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-pyrazin-2-ylamino) piperidine, to which 10mg of sodium hydride (40% oil mixture) was added under ice-cooling, and after stirring the mixture for 5 minutes, 0.013ml of methyl iodide was added, and the mixture was stirred at room temperature for 2 hours. To the solution were added water and ethyl acetate, and after stirring the mixture for 10 minutes, the layers were separated. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate 85: 15 to 1: 1) to give 98mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-pyrazin-2-yl-N-methylamino) piperidine as shown in table 91 below.

Example 335

In 40ml of methylene chloride was dissolved 8.0g of (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, to which was added 10ml of an ethanol solution of methylamine (35%, about 8M), 2ml of acetic acid and 4.24g of sodium triethoxyborohydride, and the mixture was stirred at room temperature for 16 hours. To the solution were added 2M aqueous sodium carbonate solution and chloroform, and after stirring the mixture for 30 minutes, the layers were separated. The aqueous layer was further extracted with chloroform, and the combined organic layers were dried and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give a mixture of (a) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine and (b) (2R, 4R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine.

(2) The mixture of the above (1) was dissolved in 40ml of methylene chloride, 4.4g of di-tert-butyl dicarbonate was added thereto, and the mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 10: 1) to give 4.2g of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (tert-butoxycarbonyl-N-methylamino) piperidine.

(3) The compound of (2) above was treated with 4M hydrochloric acid-ethyl acetate solution and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of hexane and ethyl acetate to give 3.6g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylaminopiperidine hydrochloride as shown in Table 91 below.

Example 336

(1) The same procedures used in example 248 were repeated except for using 2.12g of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine to give 3.8g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

(2) The compound of (1) above was treated in the same manner as in example 250(1) to give 2.3g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } amino-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 91 below.

Example 337-340

The same procedures as in example 250(2) were carried out using the corresponding starting materials to provide the compounds shown in the following table 91.

Example 341

(1) Using 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting material, the same procedure as in example 248 was followed and purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give (2R, 4S) -1- [ N- (1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl) -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethoxycarbonylpiperidine.

(2) Using the compound of the above (1), the same procedure as in example 250(1) was conducted to give (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in the following table 92.

Example 342-349

Using (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting material, the same procedure was followed as in example 250(2), to provide the compounds as shown in Table 92 below.

Example 350

In 12ml of tetrahydrofuran was dissolved 1.62g of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine, 2ml of borane in dimethyl sulfide complex (about 10M) was added dropwise thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 10ml of methanol and the mixture was stirred for 0.5 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 1.32g of (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine as shown in table 93 below.

Example 351-

The same procedures used in example 209 were repeated except for using (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine and the corresponding starting material to provide the compounds shown in Table 93 below.

Example 353

The compound (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine was provided by treating with 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting material in the same manner as in example 341, as shown in table 94 below.

Example 354-

Using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting material, the same procedure was followed as in example 250(2), to provide the compounds shown in tables 94 and 95 below.

Example 366

132mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine were dissolved in 2ml of dichloromethane, 0.027ml of oxalyl dichloride and one drop of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5ml of tetrahydrofuran and 0.12ml of 2-aminopyrazine were added to the residue, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 63mg of (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-pyrazinylaminocarbonyl) piperidine as shown in Table 96 below.

Example 367

The same procedures used in example 350 were repeated except for using (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine to provide (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine as shown in Table 96 below.

Example 368

In a mixture of 20ml of toluene and 20ml of acetic anhydride, 1.07g of the compound of example 268 was dissolved, 165mg of sodium acetate was added thereto, and the mixture was stirred while refluxing under heating for 16 hours. After the reaction mixture was cooled to room temperature, an aqueous sodium hydrogencarbonate solution was slowly added thereto until no foam was generated.

To the mixture were added water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give 980mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-acetoxymethylthiopiperidine as shown in table 97 below.

Example 369

The same procedures used in example 214 were repeated except for using (2R, 4S) -4-acetoxymethylsulfanyl-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine to give (2R, 4S) -4-acetoxymethylsulfonyl-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 97 below.

Example 370

In 10ml tetrahydrofuran and 5ml 2M sodium hydroxide aqueous solution dissolved 200mg (2R, 4S) -4-acetoxymethylsulfonyl-1- { N- (3, 5-bis trifluoromethyl benzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methyl phenyl) piperidine, at room temperature stirring mixture for 3 hours. The reaction mixture was neutralized with 2M hydrochloric acid, and the mixture was extracted 2 times with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to give 80mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxysulfinylpiperidine as shown in Table 97 below.

Example 371

130mg of the compound of example 261 was dissolved in 2.5ml of acetonitrile, 0.5ml of methyl iodide was added thereto, and the mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give 117mg of (2R, 4S) - [1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidin-4-yl ] dimethylsulfonium iodide as shown in Table 97 below.

Example 372

10.7g of (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-hydroxypropyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine are dissolved in 100ml of tetrahydrofuran, 20ml of pyridine and 20ml of acetic anhydride are added thereto, and the mixture is stirred at room temperature for 5 hours. To the reaction mixture were added aqueous sodium hydrogencarbonate and diethyl ether, and the mixture was stirred for 1 hour. The layers were separated, and after washing the organic layer 2 times with water, dried and concentrated under reduced pressure. The residue was dissolved in 100ml of ethanol, 1.5g of sodium borohydride was added thereto under ice-cooling, and the mixture was stirred for 0.5 hour. An aqueous ammonium chloride solution was added to the reaction mixture, and after stirring the mixture for 30 minutes, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the solution was extracted with chloroform 2 times. The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 9.6g of (2R, 4S) -1- { N- (3-acetoxypropyl) -N- (3, 5-bistrifluoromethylbenzyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine as shown in table 98 below.

Example 373-376

Using (2R, 4S) -1- { N- (3-acetoxypropyl) -N- (3, 5-bis-trifluoromethylbenzyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and a corresponding starting material, treatment was carried out in the same manner as in example 209 to provide the compounds shown in table 98 below.

Example 377

600mg of (2R, 4S) -1- { N- (3-acetoxypropyl) -N- (3, 5-bistrifluoromethylbenzyl) } aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was dissolved in 5ml of methanol, 5ml of a 2M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 2M aqueous hydrochloric acid solution to neutralize, and the mixture was extracted 2 times with chloroform. The combined organic layers were dried, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 550mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl) } aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 99 below.

Example 378-

The same procedures as in example 377 were carried out using the corresponding starting materials to provide the compounds shown in Table 99 below.

Example 382

The same procedures used in example 213 were repeated except for using (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl) } aminocarbonyl-4-thiomorpholinocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl) } aminocarbonyl-4- (1-oxothiomorpholino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 99 below.

Example 383

(1) The same procedures used in examples 254(1) and (2) were repeated except for using (2R, 4S) -1- { N-acetoxypropyl-N- (3, 5-bistrifluoromethylbenzyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine to provide (2R, 4S) -1- { N-acetoxypropyl-N- (3, 5-bistrifluoromethylbenzyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-acetylthiopiperidine.

(2) Using the compound of the above (1), the same procedure as in example 257 was conducted to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-hydroxypropyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-propylthio) piperidine.

(3) Using the compound of the above (2), the same procedures as in example 213 were carried out to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-hydroxypropyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (propane-2-sulfinyl) piperidine as shown in Table 99 below.

Example 384

The same procedures used in example 214 were repeated except for using (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-hydroxypropyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-propylthio) piperidine to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-hydroxypropyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (propane-2-sulfonyl) piperidine as shown in table 99 below.

Example 385

Using 148mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and the corresponding starting material, the same procedures as in reference example 6 were conducted to give 36mg of (2R, 4S) -1- { N- (3, 5-dimethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in Table 100 below.

Example 386

The same procedures used in example 385 were repeated except for using the corresponding starting materials to give (2R, 4S) -1- { N- (3, 5-dichlorobenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 100 below.

Example 387

676mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-acetoxyethylaminocarbonyloxy) piperidine hydrochloride was dissolved in 10ml of tetrahydrofuran, 0.28ml of triethylamine was added thereto, and the mixture was stirred for 30 minutes. To the reaction mixture was added 330mg of 1, 1' -carbonyldiimidazole, and the mixture was stirred at 65 ℃ for 2 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 5ml of dichloromethane. The mixture was washed with water and saturated brine and dried. The mixture was evaporated in vacuo and the residue was dissolved in 5ml of acetonitrile. 1ml of methyl iodide was added to the solution, and the mixture was stirred at 60 ℃ for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20ml of tetrahydrofuran, 600mg of N- {1- (3, 5-bistrifluoromethylphenyl) -2-hydroxyethyl } -N-methylamine and 0.5ml of triethylamine were added thereto, and the mixture was stirred at 70 ℃ for 3 hours. To the reaction mixture were added ethyl acetate and water, and the layers were separated. The organic layer was dried and concentrated under reduced pressure. Purification by silica gel column chromatography (chloroform: methanol ═ 19: 1) affords 780mg of a mixture of (a) (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) -2-hydroxyethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and (b) (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) -2-hydroxyethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, as shown in table 101 below.

Example 388

122mg of the compound according to example 387 were dissolved in 2ml of methanol, 1ml of 2M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 6M aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. Chloroform and water were added to the residue and the layers were separated. The aqueous layer was further extracted with chloroform, and the combined organic layers were dried and concentrated under reduced pressure. The residue was dried in vacuo to give a mixture of 88mg of (a) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) -2-hydroxyethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2R, 4S) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) -2-hydroxyethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine, as shown in table 101 below.

Example 389

(1) 4.92g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 50ml of dichloromethane, 2.43g of carbonyldiimidazole are added to the solution at room temperature, and the mixture is stirred for 1.5 hours. Water was added to the reaction mixture and the layers were separated with dichloromethane. The organic layer was washed with saturated brine, dried, and the solvent was removed by distillation under reduced pressure to give 5.99g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolylcarbonyloxy) piperidine.

(2) 1.17g of the compound of the above (1) was dissolved in a toluene solution (12ml) of N, N-dimethylformamide (5ml), 0.925ml of ethyl 3-piperidinecarboxylate was added thereto at room temperature, and the mixture was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 39: 1) to give 1.24g of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-4- (4-ethoxycarbonylpiperidinocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 102.

Example 390

1.08g of the compound of example 389 was dissolved in 15ml of ethanol, and 4.8ml of a 1M potassium hydroxide-ethanol solution was added thereto at room temperature. After the temperature of the mixture was raised to 50 ℃, the mixture was stirred for 3 hours. To the reaction mixture was added 2M aqueous hydrochloric acid, and ethanol was removed by distillation under reduced pressure. Water and chloroform were added thereto, and the layers were separated with chloroform. The organic layer was washed with saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 1.05g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (4-carboxypiperidinocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 102 below.

Example 391

64.8mg of the compound of example 390 and 18.6mg of ethanolamine were dissolved in 1ml of methylene chloride, 48.6mg of carbonyldiimidazole was added thereto at room temperature, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 17.8mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {4- (2-hydroxyethylaminocarbonyl) piperidinocarbonyloxy } piperidine as shown in table 102 below.

Example 392-

Using the compound of example 390 and the corresponding starting materials, the same procedure as in example 391 was conducted to provide the compounds shown in the following Table 102-103.

Example 399

(1) 1.17g of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolylcarbonyloxy) piperidine was dissolved in 12ml of toluene, 1.14g of 4-amino-1-benzylpiperidine was added thereto at room temperature, and the mixture was stirred for 3 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine and dried. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 0.89g of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (1-benzylpiperidin-4-yl) aminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine.

(2) 890mg of the above compound (1) was dissolved in 10ml of methanol, 400mg of palladium on carbon and one drop of concentrated hydrochloric acid were added thereto, and the mixture was stirred under a hydrogen atmosphere for 4.5 hours. After the reaction mixture was filtered and the filtrate was evaporated in vacuo, the residue was crystallized (ethyl acetate-hexane) to give 802mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-piperidinyl) aminocarbonyloxypiperidine.

(3) 14.2mg of 3-hydroxy-3-methylbutyric acid was dissolved in 2ml of methylene chloride, 21.1mg of carbonyldiimidazole was added thereto at room temperature, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 61.9mg of the compound of (2) above, and the mixture was further stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 57.5mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl } aminocarbonyloxypiperidine as shown in table 104 below.

Example 400-402

The compound of example 399(2) and the corresponding starting material were treated in the same manner as in example 399(3) to provide the compounds shown in table 104 below.

Example 403

(2R, 4S) -1- { N- (3, 5-Bistrifluoromethylbenzyl) -N-ethyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine obtained by treating the compound of reference example 11(2) in the same manner as in example 2 in the same manner as in example 209, affording the compounds shown in Table 105 below.

Example 404

The corresponding starting materials were treated in the same manner as in example 209 to give the compounds shown in Table 105 below.

Example 405

The compound of example 404 was treated in the same manner as in example 213 to provide the compounds shown in table 105 below.

Example 406

The compound of example 404 was treated in the same manner as in example 214 to provide the compounds shown in table 105 below.

Example 407-

The corresponding starting materials were treated in the same manner as in example 257 to provide the compounds shown in the following Table 106-107.

Example 414

In 50ml of methanol was dissolved 1.17g of (2R, 4S) -4-acetylthio-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine, to which was added 1.17g of tert-butyl 2-bromoethylcarbamate at room temperature. Subsequently, 25ml of a 1M aqueous solution of sodium hydroxide was added dropwise thereto. The reaction mixture was stirred for 5 minutes, the solvent was removed by distillation under the reduced pressure, and the mixture was extracted with dichloromethane, washed with saturated brine and dried. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 710mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-4- (2-tert-butoxycarbonylaminoethylthio) -2- (4-fluoro-2-methylphenyl) piperidine as shown in table 107 below.

Example 415

(1) To 681mg of the compound of example 414 was added 2ml of a 4M hydrochloric acid-ethyl acetate solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried and the solvent was removed by distillation under reduced pressure to give 612mg of (2R, 4S) -4- (2-aminoethylthio) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride as shown in Table 107 below.

(2) 55.2mg of the above compound (1) and 9.1mg of glycolic acid were dissolved in 1ml of N, N-dimethylformamide, and 24.9mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 19.9ml of N-hydroxybenzotriazole monohydrate were added thereto, and the mixture was stirred at room temperature overnight. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, dried and the solvent was removed by distillation under the reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 28.8mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (1-hydroxyacetamido) ethylthio } piperidine as shown in table 107 below.

Example 416-

The compound of example 415(1) and the corresponding starting material were treated in the same manner as in example 415(2) to provide the compounds shown in table 108 below.

Example 420

55.2mg of the compound of example 415(1) was dissolved in 1ml of N, N-dimethylformamide, 9.1mg of carbonyldiimidazole was added thereto, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and brine and dried. The solvent was removed by distillation, the residue was dissolved in 1ml of acetonitrile, and 0.025ml of methyl iodide was added thereto. The mixture was stirred at 50 ℃ overnight. Subsequently, 0.025ml of methyl iodide was further added, and the mixture was stirred at the same temperature overnight. After N, N-dimethylformamide and methyl iodide were removed by distillation under reduced pressure, 1ml of toluene and 0.040ml of morpholine were added, and the mixture was stirred at room temperature for 5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 38.0mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinocarbonylaminoethylthio) piperidine as shown in table 108 below.

Example 421

The compound of example 415(1) and the corresponding starting material were treated in the same manner as in example 420 to give (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (2-hydroxymethylamino) carbonylaminoethylthio } piperidine as shown in table 108 below.

Example 422

The corresponding starting material was treated in the same manner as in example 213 to give (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {4- (2-methylsulfinylethylaminocarbonyl) piperidinocarbonyloxy } -piperidine as shown in Table 108 below.

Example 423

The corresponding starting material was used and treated in the same manner as in example 214 to give (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {4- (3-methylsulfonylpropylaminocarbonyl) piperidinocarbonyloxy } -piperidine as shown in table 108 below.

Example 424-

The same procedures as in example 209 were carried out using the corresponding starting materials to give the compounds shown in Table 109 below.

Example 426

82.0mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylthioethylaminocarbonyloxy) piperidine was dissolved in 1.5ml of methylene chloride, 99.5mg of m-chloroperbenzoic acid was added thereto at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was partitioned with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was removed by distillation under the reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 48.6mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylsulfonylethylaminocarbonyloxy) piperidine as shown in table 109 below.

Example 427

(2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-methylthiopropylaminocarbonyloxy) piperidine was treated in the same manner as in example 426 to give (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-methylsulfonylpropylaminocarbonyloxy) piperidine as shown in Table 109 below.

Example 428-

The corresponding starting materials were treated in the same manner as in example 169 to provide the compounds shown in table 110 below.

Example 432-

The corresponding starting materials were treated in the same manner as in example 213 to provide the compounds shown in the following table 111.

Example 434-

The corresponding starting materials were treated in the same manner as in example 214 to provide the compounds shown in table 111 below.

Example 436

130mg of imidazole-1-carboxylic acid N- (3, 5-bistrifluoromethylbenzyl) -N- (2-methoxyethyl) amide was dissolved in 2.8ml of acetonitrile, 411. mu.l of methyl iodide was added thereto, and the mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in 2.7ml of methylene chloride, 89mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and 50. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a 5% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform: methanol ═ 19: 1) to give 63mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (2-methoxyethyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 112 below.

Example 437

94mg of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was dissolved in 2.7ml of methylene chloride, 163mg of 3- [ (3, 5-bistrifluoromethylbenzyl) -methylcarbamoyl ] -1-methyl-3H-imidazol-1-ium iodide and 50. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature for 18 hours. Distilled water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform: methanol ═ 19: 1) to give 84mg of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in Table 112 below.

Example 438

In 5.2ml of acetonitrile, 201mg of imidazole-1-carboxylic acid N- [ (1S) -1- (3, 5-bistrifluoromethylphenyl) ethyl ] -N-carboxamide was dissolved, to which 137. mu.l of methyl iodide was added. After stirring the mixture at 50 ℃ for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 4.5ml of methylene chloride, 132mg of 4- (2-hydroxyethylcarbamoyloxy) -2-phenylpiperidine and 84. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 5% aqueous citric acid solution, the mixture was extracted with chloroform, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform: acetone ═ 4: 1) to give 75mg of (2R, 4R) -1- [ N- ((S) -1- (3, 5-bistrifluoromethylphenyl) ethyl) -N-methyl ] aminocarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine as shown in table 112 below.

Example 439

(1) 127mg of 1- (3, 5-bistrifluoromethylphenyl) ethylimidazole-1-carboxylate was dissolved in 3ml of acetonitrile, to which 448. mu.l of methyl iodide was added. The mixture was stirred at 50 ℃ for 3 hours, and the reaction mixture was concentrated. The residue was suspended in 2.7ml of methylene chloride, 102mg of 2- [ (2R, 4S) -2- (4-fluoro-2-methylphenyl) piperidin-4-yloxycarbonylamino ] acetic acid ethyl ester and 50. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature for 18 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by thin layer silica gel chromatography (hexane: ethyl acetate ═ 1: 1) to give 43mg of (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- { (S) -1- (3, 5-bistrifluoromethylphenyl) ethyl } oxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

MS(m/z)：623[M⁺+1]

(2) 43mg of the compound of the above (1) was dissolved in a mixture of 0.9ml of tetrahydrofuran and 0.1ml of methanol, 103. mu.l of a 1M aqueous solution of sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 1 hour. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: methanol ═ 19: 1) to give 37mg of (2R, 4S) -1- { (S) -1- (3, 5-bistrifluoromethylphenyl) ethyl } oxycarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 112 below.

Example 440

50mg of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine are dissolved in 2.4ml of N, N-dimethylformamide, and 0.044ml of triethylamine and 99.3mg of N- (3, 5-bistrifluoromethylbenzyl) -N-methylaminocarbonyl chloride are added thereto under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was poured into water, and the mixture was extracted 2 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1 to 1: 2) to give 128mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine as shown in table 113 below.

Example 441

560mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine are dissolved in 2.0ml of dichloromethane, and a solution of 0.22ml of pyridine and 0.314ml of phenyl chloroformate in 1.5ml of dichloromethane are added thereto under a nitrogen atmosphere under ice-cooling. The reaction mixture was stirred at a temperature of 0 ℃ to 5 ℃ for 3.5 hours, and further stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted 2 times by adding dichloromethane. The organic layers were combined and washed 2 times with 1M aqueous hydrochloric acid and further with saturated brine. The organic layer was dried and concentrated. The residue was dissolved in 11ml of N, N-dimethylformamide, 0.274ml of ethanolamine was added thereto under a nitrogen atmosphere at room temperature, and the mixture was stirred at 60 ℃ for 26 hours. The reaction mixture was poured into water and extracted 2 times by adding ethyl acetate. The organic layers were combined and washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 39: 1) to give 493mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 113 below.

Example 442

In 8ml of methylene chloride dissolved 1.0g (2R) -4-amino-1- { N- (3, 5-two three methyl benzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methyl phenyl) piperidine, to which was added 0.31ml three and 466mg two tert butyl carbonate, at room temperature stirring mixture for 16 hours. Water was added to the reaction mixture and the mixture was extracted 2 times with dichloromethane. The organic layers were combined and washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 1) to give 481mg of (a) (2R, 4R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 516mg of (b) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, as shown in table 113 below.

Example 443

In 3.5ml of ethyl acetate were dissolved 700mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine, to which was added 3.5ml of a 4M hydrochloric acid-ethyl acetate solution under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The solvent was removed by distillation, and ethyl acetate was added to the residue and filtered. Chloroform and a 2M aqueous solution of sodium hydroxide were added to the collected substance and the layers were separated. The aqueous layer was extracted with chloroform. The combined organic layers were dried and concentrated to provide 489mg of (2R, 4S) -4-amino-1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in table 113 below.

Example 444-

Using the corresponding starting materials and treated in the same manner as in example 138, the compounds shown in table 114 below were provided.

Example 450-

Using the corresponding starting materials and treated in the same manner as in example 102(1), the compounds shown in table 114 below were provided.

Example 452-

Using the corresponding starting materials and treated in the same manner as in example 250(2), the compounds shown in the following Table 115-117 were provided.

Example 470

52.8mg of (2R, 4S) -4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } amino-carbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride was dissolved in 1ml of dichloromethane, 0.017ml of triethylamine and 24.3mg of 1, 1-carbonyldiimidazole were added thereto at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in 1ml of acetonitrile, 0.025ml of methyl iodide was added, and the mixture was stirred at 60 ℃ overnight. The reaction mixture was concentrated, the residue was dissolved in 1ml of a toluene-acetonitrile (7: 3) solution, 24.4mg of ethanolamine was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 53.1mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylamino) piperidine as shown in table 118 below.

Example 471-

Using the corresponding starting materials and treated in the same manner as in example 470, the compounds shown in the following Table 118-119 were provided.

Example 481

490mg of (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } amino-carbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and 312mg of 2- (2-aminoethylamino) ethanol are dissolved in 10ml of dichloromethane, 0.086ml of acetic acid and 669mg of sodium triacetoxyborohydride are added thereto at room temperature, and the mixture is stirred overnight. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried and concentrated to provide 581mg of (2R, 4RS) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methyl-phenyl) -4- {2- (2-hydroxyethylamino) ethylamino } piperidine [ (2R, 4S): 2R, 4R) ═ 74: 26 ]. In 2ml of methylene chloride was dissolved 116mg of (2R, 4RS) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (2-hydroxyethylamino) ethylamino } piperidine, to which was added 39mg of 1, 1-carbonyldiimidazole at room temperature, and the mixture was stirred for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give (a)75.5mg of (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- [3- (2-hydroxyethyl) -2-oxoimidazolidin-1-yl ] piperidine and (b)22.6mg of (2R, 4R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- [3- (2-hydroxyethyl) -2-oxoimidazolidin-1-yl ] piperidine, as shown in table 120 below.

Example 482-

Using the corresponding starting materials and treated in the same manner as in example 481, the compounds shown in the following Table 120-122 were provided.

Example 487

12.4ml of ethylene glycol was dissolved in 1ml of methylene chloride, and 32.4mg of ethylene glycol was added thereto at room temperature

1, 1-carbonyldiimidazole. The mixture was stirred at room temperature for 7.5 hours, and 52.8mg of (2R, 4S) -4-amino-1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride and 0.021ml of triethylamine were added to the mixture. The mixture was stirred for 4 days and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to give 16.4mg of (2R, 4S) -1- (N- (3, 5-bistrifluoromethylbenzyl) -N-methyl) -amino-carbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyloxycarbonylamino) -piperidine as shown in table 123 below.

Example 488

(1) 58mg of triphosgene are dissolved in 3ml of dichloromethane, 2ml of dichloromethane solution containing 138mg of N- { 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl } -N-methylamine and 0.201ml of triethylamine are added dropwise thereto at-60 ℃ and the mixture is then warmed to 0 ℃. The mixture was concentrated and the residue was dissolved in 2ml of dichloromethane. To the mixture was added dropwise a dichloromethane solution containing 135mg of (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -2- (4-fluoro-2-methylphenyl) -piperidine in an amount of 2ml and triethylamine in an amount of 0.084ml, and the mixture was stirred at room temperature for 1 day. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: acetone ═ 10: 1) to give 44mg of (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- [ N- { 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl } -N-methyl ]Aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine. MS (m/z): 652[ M⁺+1]

(2) 44mg of (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1- [ N- { 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine were dissolved in 0.9ml of a mixture solution (tetrahydrofuran: methanol ═ 8: 1), 0.101ml of a 1M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 36mg of (2R, 4S) -1- [ N- { 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in table 124 below.

Reference example 1

To a Grignard reagent prepared from 14.2g magnesium, 93.1g 2-bromo-5-fluorotoluene and 500ml tetrahydrofuran was added dropwise 50ml 4-methoxypyridine at-20 ℃ under nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred at the same temperature for 20 minutes. Next, the reaction mixture was cooled to-50 ℃ and 85ml of benzyl chloroformate was added dropwise while maintaining the temperature at-40 ℃ or below. After completion of the dropwise addition, the temperature of the reaction mixture was slowly raised, 200g of ice was added at-15 ℃ and the mixture was stirred for 30 minutes. Then, 200ml of a 5M aqueous citric acid solution was added thereto, and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. To the residue was added 200ml of ethyl acetate and the mixture was extracted 2 times. The organic layers were combined, washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was collected by filtration and washed with isopropyl ether to give 146.5g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine as shown in Table 125 below.

Reference example 2

190g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine was dissolved in 4600ml of acetic acid, 91g of zinc powder was added thereto, and the mixture was stirred at room temperature for 24 hours. Insoluble matter was removed from the reaction mixture by filtration, and the solvent was removed by distillation under the reduced pressure. To the residue was added 400ml of ethyl acetate, and the mixture was washed with aqueous sodium hydrogencarbonate solution and saturated brine and dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give 166g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine as shown in table 125 below.

Reference example 3

To 132g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine were added 650ml of methanol, 84ml of trimethoxymethane and 2g of a strongly acidic resin IR-120 (prepared by Japan organic Co., Ltd.), and the mixture was stirred at room temperature for 3 days. Insoluble matter was removed from the reaction mixture by filtration, and the solvent was removed by distillation under the reduced pressure, to give 146g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine as shown in Table 125 below.

Reference example 4

To 300ml of ethanol were added 30g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine and 3.0g of 10% palladium on carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Insoluble matter was removed from the reaction mixture by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 300ml of ethyl acetate. 20ml of a 4M hydrochloric acid-ethyl acetate solution was slowly added dropwise under ice-cooling. The crystals were collected by filtration and washed with ethyl acetate. After drying, the crystals were added to a mixture of dichloromethane-sodium carbonate aqueous solution, and the mixture was stirred. After separation of the organic layer, the aqueous layer was further extracted with dichloromethane. The organic layers were combined and dried over magnesium sulfate, and the solvent was removed by distillation under the reduced pressure to give 16.7g of 2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine as shown in Table 125 below.

Reference example 5

To a suspension of 10.1g of 2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine and 3.18g L-N-acetylvaline in 130ml of ethyl acetate were added 35ml of methanol, the mixture was dissolved by heating, and then cooled at room temperature. After 3.5 hours, the precipitated crystals were collected by filtration and washed with 20ml of ethyl acetate. The obtained crystals were dried under reduced pressure. Subsequently, 50ml of chloroform was added thereto, and the mixture was washed with 30ml of a 2M aqueous solution of sodium hydroxide and 30ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the obtained residue was added diethyl ether, and the precipitated crystals were further concentrated under reduced pressure to give 2.94g of (2R) -2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine (optical purity: 97.0% ee) as shown in Table 125 below.

Reference example 6

To a solution of 5.0g N- (3, 5-bistrifluoromethylbenzyl) -N-methylamine in 36ml of tetrahydrofuran was added 3.47g of 1, 1' -carbonyldiimidazole, and the mixture was stirred at 65 ℃ for 20 minutes. The solvent was removed by distillation under the reduced pressure, and methylene chloride was added thereto. The whole organic layer was washed with saturated brine and dried, and the solvent was removed by distillation. The residue was dissolved in 26ml of acetonitrile, 4.84ml of methyl iodide was added thereto, and the mixture was stirred at 60 ℃ for 2 hours. The solvent was removed by distillation under the reduced pressure, and the residue was dissolved in 80ml of dichloromethane. Under ice-cooling, 5.17g of 2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine and 3ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 4: 3) to give 9.7g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine as shown in table 126 below.

Reference example 7

9.7g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine was dissolved in 180ml of tetrahydrofuran, and 70ml of a 1M aqueous sulfuric acid solution was added thereto under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the mixture was adjusted to pH 8-9 with 1M aqueous sodium hydroxide solution, tetrahydrofuran was removed by distillation. To the residue were added water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried. The solvent was removed by distillation. To the obtained residue was added diisopropyl ether, and white crystals were collected by filtration to give 7.86g of 1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine as shown in Table 126 below.

Reference example 8

To a solution of 3.91g N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methylamine in 60ml of tetrahydrofuran was added 2.34g of 1, 1' -carbonyldiimidazole and the mixture was stirred at 40 ℃ overnight. The solvent was removed from the reaction mixture by distillation, ethyl acetate was added thereto, and the organic layer was washed with water and saturated brine and dried. The solvent was removed by distillation and the white crystals obtained were collected by filtration through diisopropyl ether. The obtained white crystals were dissolved in 60ml of acetonitrile, 3.4ml of methyl iodide was added, and the mixture was stirred at 60 ℃ for 2 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 40ml of dichloromethane. To this were added 3.47g of 2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine and 3.82ml of triethylamine under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and saturated brine and dried, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in 90ml of tetrahydrofuran, and 30ml of an aqueous 1M sulfuric acid solution was added thereto under ice cooling, and the mixture was stirred at room temperature for 5 hours. After the pH of the mixture was adjusted to 8-9 with 1M aqueous sodium hydroxide solution, tetrahydrofuran was removed by distillation. To the residue were added water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried, and the solvent was removed by distillation under the reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 2.12g of (2R) -1- [ N- {1- (S) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine as shown in table 126 below.

Reference examples 9 to 11

Using the corresponding starting materials, the same procedures as in reference example 8 were conducted to provide the compounds as shown in the following Table 126-127.

Reference example 12

16.7g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine were dissolved in 140ml of ethanol, 3.74g of hydroxylamine hydrochloride and 4.41g of sodium acetate were added thereto, and the mixture was stirred at room temperature for 2 hours. Ethanol was removed under reduced pressure. To the residue were added water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried, and the solvent was removed under reduced pressure. The residue was dissolved in 500ml of methanol, and after stirring the mixture, 23.2g of nickel chloride hexahydrate was added thereto, 3.7g of sodium borohydride was slowly added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. Methanol was removed by distillation under reduced pressure, ammonia water and methylene chloride were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried, and the solvent was removed by distillation. The residue was dissolved in 480ml of dichloromethane, 8.2ml of triethylamine and 5.1ml of propionyl chloride were added thereto under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into saturated brine and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine and dried, and the solvent was removed by distillation under the reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give 6.43g of (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine and 5.65g of (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine, as shown in table 127 below.

Reference example 13

The same procedures used in reference example 12 were repeated except for using 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and isobutyryl chloride to give (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-isobutyrylaminopiperidine and (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-isobutyrylaminopiperidine, which are shown in Table 128 below.

Reference example 14

In 17ml of ethanol was dissolved 1.73g of trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine, to which 280mg of palladium on carbon (50.9% moisture content) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and the ethanol was removed by distillation. The residue was purified by NH silica gel column chromatography (chloroform: hexane: ethyl acetate 5: 2) to give 772mg of trans-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine as shown in Table 129 below.

Reference examples 15 to 17

Using the corresponding starting materials, the same procedures as in reference example 14 were conducted to provide the compounds as shown in the following Table 129-130.

Reference example 18

110g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine were dissolved in 900ml of ethanol, 24.8g of hydroxylamine hydrochloride and 29.3g of sodium acetate were added thereto, and the mixture was stirred at room temperature for 5 hours. Ethanol was removed by distillation, and water and ethyl acetate were added to the residue. The layers were separated and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 2.4 liters of methanol, and 92.5g of nickel chloride hexahydrate was added thereto. After the mixture was stirred, 18.4g of sodium borohydride was slowly added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. Methanol was removed by distillation, ammonia water and methylene chloride were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried, and the solvent was removed by distillation. The residue was dissolved in 1.21 dichloromethane, 45.2ml of triethylamine and 74.5ml of di-tert-butyl dicarbonate were added thereto under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated brine, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine and dried, and the solvent was removed by distillation under the reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 36.7g of (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and 37.9g of (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine as shown in table 131 below.

Reference example 19

37.0g of cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine was dissolved in 350ml of ethanol, 5.5g of palladium on carbon (moisture content: 50.9%) was added thereto, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and the ethanol was removed by distillation to provide 25.8g of cis-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine as shown in table 132 below.

Reference example 20

To 1.34g of 3-hydroxy-2-hydroxymethyl-2-methylpropionic acid and 13ml of acetonedimethyl acetal at room temperature were added 95mg of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 6 hours. Further, 95mg of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred overnight. The solution was concentrated and poured into water and extracted. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 19: 1) to give 333mg of 2, 2, 5-trimethyl- [1, 3] dioxane-5-carboxylic acid as shown in table 132 below.

Reference example 21

31.5g of 2-chloroisonicotinic acid was dissolved in 400ml of tetrahydrofuran, to which 32.5g of 1, 1' -carbonyldiimidazole was added. The mixture was stirred under ice-cooling for 1 hour. 50ml of ethanol was added to the solution, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated and extracted by adding ethyl acetate and water. The organic layer was dried over magnesium sulfate and the residue was dried under vacuum to give 35.6g of ethyl 2-chloroisonicotinate as shown in Table 132 below.

Reference example 22

In a mixture of 250ml of toluene and 50ml of ethanol were dissolved 20g of ethyl 2-chloroisonicotinate and 20g of 2-methyl-4-fluorophenylboronic acid, and 5.8g of tetrakis (triphenylphosphine) palladium and 250ml of 2M aqueous sodium carbonate solution, and the mixture was stirred at 50-70 ℃ for 2 hours. The solution was cooled to room temperature and extracted by adding ethyl acetate and water. The organic layer was further washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 6: 1) to give 24.8g of 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) pyridine as shown in table 132 below.

Reference example 23

5.2g of 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) pyridine and 1.5g of platinum oxide were dissolved in 200ml of ethanol, and 15ml of concentrated hydrochloric acid was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. 200ml of water was added thereto, the mixture was stirred for 30 minutes, and then, insoluble matter was removed by filtration through celite. The insoluble material was washed with ethanol, and the filtrate and the liquid used for washing were combined and concentrated. To the residue were added ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution. After the aqueous solution proved sufficiently basic, extraction was then carried out. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and concentrated to provide 3.6g of 2, 4-cis-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine as shown in Table 132 below.

Example 24

(1) 7.4g2, 4-cis-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and 4.0-4.0 g N-p-toluenesulfonyl-D-phenylalanine were dissolved under heating in a mixture of 50ml ethyl acetate and 50ml diethyl ether. The solvent was concentrated by heating, 30ml of diisopropyl ether was added thereto, and the mixture was stirred. The precipitated crystals were removed, the mother liquor was washed with concentrated aqueous ammonia, dried and concentrated under reduced pressure. To the residue was added 4.0g N-p-toluenesulfonyl-L-phenylalanine, 50ml of ethyl acetate and 30ml of diisopropyl ether were added thereto, dissolved by heating, and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to give 4.0g of N-p-toluenesulfonyl-L-phenylalanine salt of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine.

(2) The compound of the above (1) was dissolved in an aqueous ammonia solution, and after confirming that the solution was sufficiently basic, it was extracted 2 times with chloroform. The combined organic layers were dried and concentrated under reduced pressure to give 2.6g of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine (optical purity: 96% ee) as shown in Table 133 below.

Reference example 25

(1) 7.5g of 3-aminopropanol was dissolved in 50ml of N, N-dimethylformamide, 16g of t-butyldimethylsilyl chloride and 6.8g of imidazole were added thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 11g of citric acid, and after stirring the mixture at room temperature for 1 hour, the mixture was concentrated under reduced pressure. To the residue were added 2M aqueous sodium hydroxide solution and diethyl ether, and the layers were separated. The organic layer was dried and concentrated under reduced pressure. The residue and 12.1g of 3, 5-bistrifluoromethylbenzaldehyde were dissolved in 300ml of dichloromethane, 21.2g of sodium triethoxyborohydride and 2.9ml of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 2M aqueous sodium carbonate solution. The mixture was stirred for 30 minutes and extracted 2 times with chloroform. The combined organic layers were dried, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 20g of 3-tert-butyldimethylsilyloxypropyl-3, 5-bistrifluoromethylbenzylamine.

(2) Using 12.5g of the compound of (1) above and the compound of reference example 5, the same procedures used in reference example 6 were conducted to give 19g of (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (3-tert-butyldimethylsilyloxypropyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4, 4-dimethoxypiperidine.

(3) Using 19.0g of the compound of (2) above, the same procedures as in reference example 7 were conducted to give 19g of (2R) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl) } aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine as shown in Table 133 below.

Reference example 26

(1) 4.8g of the compound of reference example 5 was dissolved in 40ml of methylene chloride, 4.4g of di-tert-butyl dicarbonate was added thereto, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100ml of acetone, 200mg of an acidic resin (IR-120) was added thereto, and the mixture was stirred at room temperature for 3 days. After removing the resin from the reaction mixture, the mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate 4: 1) afforded 3.9g of (r) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine.

(2) 3.9g of the above compound (1) was dissolved in 20ml of ethanol, 400mg of sodium borohydride was added thereto at-20 ℃ and the mixture was stirred for 1 hour. To the reaction mixture was added an aqueous ammonium chloride solution, and ethanol was removed by distillation. To the residue were added ethyl acetate and water, the layers were separated, and the mixture was further washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 3.1g of (2R, 4S) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine.

(3) The same procedures used in example 209 were repeated except for using 3.1g of the compound of (2) above and the corresponding starting material to give 2.3g of (2R, 4S) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine.

(4) 2.3g of the above compound (3) was dissolved in 20ml of a 4M hydrochloric acid-ethyl acetate solution, and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dried to give 1.5g of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-acetoxyethylaminocarbonyloxy) piperidine hydrochloride.

(5) 1.5g of the above compound (4) was dissolved in 25ml of a 1M aqueous solution of sodium hydroxide, and the solution was extracted 2 times with chloroform. The combined organic layers were dried and concentrated under reduced pressure. The residue was dried to give 1.5g of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in Table 133 below.

Reference example 27

4.8g of 3, 5-bistrifluoromethyl group is dissolved in 250ml of acetonitrile, 6.6g of trimethylsulfonium iodide, 3.2g of crushed potassium hydroxide and 0.5ml of water are added thereto, and the mixture is stirred in the presence of alumina balls at a temperature of 65 ℃ to 70 ℃ for 16 hours. After completion of the reaction, insoluble matter was removed, ethyl acetate and water were added to the filtrate, and the layers were separated. The organic layer was washed, dried and concentrated under reduced pressure. To the residue was added 50ml of a 40% methylamine-methanol solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate 1: 2) to give 1.23g of 1- (3, 5-bistrifluoromethylphenyl) -2-hydroxyethylamine as shown in table 133 below.

Reference example 28

(1) In 43ml of methylene chloride were dissolved 2.45g of 3, 5-bistrifluoromethylbenzaldehyde, 835mg of 2-methoxyethylamine and 687. mu.l of acetic acid, to which was added 3.12g of sodium triethoxyborohydride, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was washed with 0.5M aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate 19: 1 to 9: 1) to give 2.76g of 3, 5-bistrifluoromethylbenzyl-2-methoxyethylamine. MS (m/z): 302[ M ] ⁺+1]⁺

(2) In a mixed solution of 37ml of toluene and 4ml of methylene chloride, 2.76g of 3, 5-bistrifluoromethylbenzyl-2-methoxyethylamine was dissolved, 1.78g of 1, 1' -carbonyldiimidazole was added thereto, and the mixture was stirred at 60 ℃ for 3 hours. The organic layer was dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone ═ 9: 1 to 2: 1) to give 3.45g of imidazole-1-carboxylic acid 3, 5-bistrifluoromethylbenzyl-2-methoxyacetamide as shown in table 133 below.

Reference example 29

(1) In 15ml of N, N-dimethylformamide were dissolved 3.94g of 2-bromo-5-fluorophenol and 1.62ml of methyl iodide, and thereto were slowly added 5.08g of potassium carbonate under ice-cooling. The mixture was stirred at room temperature for 3 hours. After removing insoluble matter by filtration, distilled water was added to the filtrate, and the mixture was extracted with diethyl ether and washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 19: 1 to 9: 1) to give 4.10g of 1-bromo-4-fluoro-2-methoxybenzene. MS (m/z): 204/206 (M)⁺+1)

(2) To 7ml of tetrahydrofuran were added 486mg of magnesium and a trace of iodine, and to this were added 4.10g of a solution of the compound of the above (1) in 16ml of tetrahydrofuran to prepare a Grignard reagent. Under nitrogen atmosphere at-60 deg.C or below To the solution was added dropwise a solution of 1.96g of 4-methoxypyridine in 7ml of tetrahydrofuran. Subsequently, a solution of 3.75g of benzyl chloroformate in 18ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 40ml of 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1 to 1: 2) to give 3.15g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-oxo-3, 4-dihydro-2H-pyridine. MS (m/z): 356[ M ]⁺+1]

(3) In a mixed solution of 79ml of ethanol and 6ml of tetrahydrofuran, 3.15g of the above compound (2) was dissolved, 706mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, and distilled water was added to the residue. The mixture was extracted with chloroform, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone ═ 19: 1 to 9: 1) to give 1.62g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-hydroxypiperidine. MS (m/z): 360[ M ]⁺+1]

(4) 1.62g of the above compound (3) was dissolved in 20ml of toluene, 876mg of 1, 1' -carbonyldiimidazole was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. 1.09ml of ethanolamine was added thereto, and the mixture was stirred at 60 ℃ for 6 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone 4: 1 to 1: 1) to give 1.81g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine. MS (m/z): 447[ M ] M ⁺+1]

(5) 1.81g of the above compound (4) was dissolved in 20ml of methanol, 90mg of 10% palladium on carbon was added thereto, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After insoluble matter was removed by filtration, the filtrate was concentrated. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give 1.30g of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in Table 134 below.

Reference example 30

(1) 5.46g of 4-methoxypyridine was dissolved in 40ml of tetrahydrofuran, and 55ml of a 1M phenylmagnesium bromide-tetrahydrofuran solution was added dropwise thereto at-60 ℃ or below under a nitrogen atmosphere. Subsequently, a solution of 10.24g of benzyl chloroformate in 50ml of tetrahydrofuran was added dropwise thereto, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 120ml of a 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration to give 8.51g of 1-benzyloxycarbonyl-4-oxo-2-phenyl-3, 4-dihydro-2H-pyridine. MS (m/z): 308[ M ]⁺+1]

(2) 8.48g of the above compound (1) was dissolved in 260ml of acetic acid, 3.61g of zinc powder was added thereto, and the mixture was stirred at room temperature for 18 hours. Subsequently, 1.8g of zinc powder was added, and after stirring the mixture at room temperature for 6 hours, 1.8g of zinc powder was additionally added thereto, and the mixture was stirred at 50 ℃ for 3 days. After removing insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried and concentrated to give 8.54g of 1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine. MS (m/z): 310[ M ] ⁺+1]

(3) 619mg of the above compound (2) was dissolved in 15ml of tetrahydrofuran, and 4ml of a 1M toluene solution of diisobutylaluminum hydride was added thereto at-60 ℃ or below under a nitrogen atmosphere. The mixture was stirred for 10 minutes. To the reaction mixture was added 667. mu.l of a 6M aqueous hydrochloric acid solution, and the mixture was concentrated. Distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1 to 1: 1) to give 553mg of 1-benzyloxycarbonyl-4-hydroxy-2-phenylpiperidine. MS (m/z): 312[ M ]⁺+1]

(4) 511mg of the above compound (3) was added to a mixed solution of 14ml of toluene and 1.6ml of methylene chloride, 319mg of 1, 1' -carbonyldiimidazole was added thereto, and they were mixed with stirring at 60 ℃The reaction mixture was stirred for 2 hours. To this was added 396. mu.l of ethanolamine, and the mixture was stirred at 60 ℃ for 3 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone ═ 9: 1 to 2: 1) to give 462mg of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine. MS (m/z): 399[ M ]⁺+1]

(5) 430mg of the above compound (4) was dissolved in 10ml of methanol, 30mg of 10% palladium on carbon was added thereto, and the mixture was stirred at room temperature for 5 days under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated to give 348mg of 4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine as shown in Table 134 below.

Reference example 31

(1) 2.61g of 3, 5-bistrifluoromethylacetophenone was dissolved in 47ml of ethanol, 478mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was concentrated. The residue was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 9: 1 to 4: 1) to give 2.51g of 1- (3, 5-bistrifluoromethylphenyl) -ethanol. MS (m/z): 258[ M ]⁺+1]

(2) In a mixed solution of 40ml of toluene and 4ml of acetonitrile, 2.49g of the above compound (1) was dissolved, 1.72g of 1, 1' -carbonyldiimidazole was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried and concentrated under reduced pressure to give 3.40g of 1- (3, 5-bistrifluoromethylphenyl) ethylimidazole-1-carboxylate as shown in Table 134 below.

Reference example 32

To 1.74g of magnesium and 40ml of tetrahydrofuran was added a trace amount of iodine, and 10.4g of 2-bromo-5-fluorotoluene was added dropwise under a nitrogen atmosphere at room temperature for 40 minutes. The reaction mixture was refluxed under heating for 1 hour to prepare a grignard reagent solution. 5.46g of 4-methoxypyridine are added dropwise to the prepared Grignard reagent solution under nitrogen at-40 ℃ over 20 minutes. After completion of the dropwise addition, the mixture was stirred at a temperature of-40 ℃ to-30 ℃ for 30 minutes. Subsequently, the reaction mixture was cooled to-40 ℃ and a solution of 12g of di-tert-butyl dicarbonate in 20ml of tetrahydrofuran was added dropwise thereto while keeping the temperature at-40 ℃ or lower. After the completion of the dropwise addition, the temperature of the reaction mixture was slowly raised. At-15 ℃, ice was added thereto and the mixture was stirred for 20 minutes. An aqueous citric acid solution was further added thereto, and the mixture was stirred at room temperature for 40 minutes. Tetrahydrofuran was removed by distillation, and ethyl acetate was added to the resulting residue to extract 2 times. The combined organic layers were washed with saturated brine, dried and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the obtained crystals were collected by filtration with diisopropyl ether to give 11.9g of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine as shown in Table 134 below.

Reference example 33

To 6.0ml of ethanol were added 916mg of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine and 110mg of 10% palladium on carbon (50.5% moisture content), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. After removing insoluble matter by filtration, the solvent was removed by filtration. The residue was dissolved in 15ml of toluene and the solution was cooled to-78 ℃. To the solution was slowly added dropwise 1.8ml of lithium butylaluminum hydride (65% by weight of the toluene solution) under a nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred at a temperature of-78 ℃ to-60 ℃ for 1 hour. To the reaction mixture was added 1M aqueous sodium hydroxide solution, and the mixture was stirred for 10 minutes. The precipitate formed was separated by filtration through celite and extracted 2 times with ethyl acetate. The organic layers were combined and washed with saturated aqueous ammonia and saturated brine. The organic layer was dried and concentrated under reduced pressure. After 7.5ml of ethyl acetate was added to the residue, 7.5ml of a 4M hydrochloric acid-ethyl acetate solution was slowly dropped thereinto under ice-cooling. The crystals were collected by filtration and washed with ethyl acetate. After drying, the crystals were added to a mixture of ethyl acetate-1M aqueous sodium hydroxide solution and stirred. The organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to give 471mg of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine as shown in the following Table 134.

Reference example 34

831ml of triphosgene was dissolved in 3.0ml of dichloromethane, and a solution of 1.08g N- (3, 5-bistrifluoromethylbenzyl) -N-methylamine and 1.76ml of triethylamine in 5.0ml of dichloromethane was added dropwise thereto under a nitrogen atmosphere over 10 minutes under ice-cooling. The reaction mixture was stirred at 0 ℃ to 5 ℃ for 30 minutes. The solvent was removed by evaporation and the residue was dried. To the residue were added water and dichloromethane, and the mixture was extracted 2 times with dichloromethane. The organic layers were combined and washed with saturated brine and dried. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane-hexane: ethyl acetate 10: 1) to give 760mg of N- (3, 5-bistrifluoromethylbenzyl) -N-methylaminocarbonyl chloride as shown in table 134 below.

Reference example 35

24.5g of 3, 5-bistrifluoromethylbenzaldehyde was dissolved in 20ml of methanol, and 60ml of ethylamine (2M tetrahydrofuran solution) was added thereto under ice cooling. Subsequently, 4.38g of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture and concentrated under reduced pressure. The residue was extracted with dichloromethane, the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 to chloroform: methanol 9: 1) to give 6.35g N- (3, 5-bistrifluoromethylbenzyl) -N-ethylamine as shown in table 135 below.

Reference example 36

(1) To 20ml of tetrahydrofuran were added 1.34g of magnesium and a trace of iodine, and thereto was added dropwise a solution of 9.50g of 2-bromotoluene in 45ml of tetrahydrofuran to prepare a Grignard reagent. A solution of 5.46g of 4-methoxypyridine in 20ml of tetrahydrofuran is added dropwise to the Grignard reagent under a nitrogen atmosphere at-60 ℃ or below. Subsequently, a solution of 10.24g of benzyl chloroformate in 50ml of tetrahydrofuran was added dropwise thereto at-40 ℃The mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 120ml of a 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether, and the crystals were collected by filtration to give 11.15g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine. MS (m/z): 322[ M ]⁺+1]

(2) 11.15g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-3, 4-dihydro-2H-pyridine was dissolved in a mixed solution of 125ml of ethanol and 35ml of tetrahydrofuran, 2.76g of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 1 day. 1.38g of sodium borohydride was further added thereto, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and distilled water was added to the residue. The mixture was extracted with chloroform, and the organic layer was dried and distilled under reduced pressure. The residue was purified by silica gel chromatography (chloroform: acetone 49: 1 to 9: 1) to give 6.18g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine. MS (m/z): 326[ M ] ⁺+1]

(3) 1.63g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine was dissolved in 21ml of toluene, 973mg of 1, 1' -carbonyldiimidazole was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. To the solution was added 1.21ml of ethanolamine, and the mixture was stirred at 60 ℃ for 6 hours. Distilled water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone 9: 1 to chloroform: methanol 19: 1) to give 1.34g of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine. MS (m/z): 413[ M ]⁺+1]

(4) 1.33g of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine was dissolved in 30ml of methanol, 70mg of 10% palladium on carbon was added thereto, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. After removing insoluble matter by filtration, the filtrate was concentrated to give 880mg of 4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine as shown in Table 135 below.

Reference example 37

(1) The same procedures used in reference example 1 were repeated except for using 25g of 4-fluoro-1-bromobenzene to give 22.3g of 1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-oxo-3, 4-dihydro-2H-pyridine.

(2) 20g of the above compound (1) was dissolved in 400ml of ethanol, 7.6g of sodium borohydride was added thereto, and the mixture was stirred at-20 ℃ for 2 hours. After the reaction was completed, an aqueous citric acid solution was slowly added thereto until no foam was generated. The solvent was removed by distillation under the reduced pressure, and water and chloroform were added to separate layers. The aqueous layer was further extracted with chloroform, and the combined organic layers were dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate ═ 10: 1), to give 6.3g of a mixture of (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine and (b) (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine.

(3) The same procedures used in example 209 were repeated except for using 6.2g of the compound of (2) above to give 7.3g of a mixture of (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine.

(4) Using 6.3g of the compound of (3) above, the same procedures as in reference example 4 were conducted to give 2.6g of a mixture of (a) (2R, 4S) -2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2S, 4R) -2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine as shown in Table 135 below.

Reference example 38

0.639g N-tosyl-D-phenylalanine was dissolved in 5ml of methanol, the solution was warmed to 59 ℃ and then 1.3ml of a methanol solution containing 0.418g of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine was added dropwise thereto. After crystals formed within 20 minutes from the start of crystallization, a solution of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine in another methanol was added dropwise to the mixture over a period of 5 minutes. The mixture was cooled from 59 ℃ to 30 ℃ over 1 hour, and then crystals were formed for 1.5 hours. The resulting crystals were isolated by filtration, washed with cooled methanol and air-dried at 60 ℃ for 1 night to give 0.325g of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine N-toluenesulfonyl-D-phenylalanine salt. To the obtained salt was added 0.62ml of 2M aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. To the aqueous layer was added 0.3ml of 5M aqueous sodium hydroxide solution, followed by extraction with ethyl acetate 4 times. The organic layer was dried and concentrated under reduced pressure to give 0.129g of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine, as shown in Table 136 below.

Reference example 39

2.72g of 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde were dissolved in 40ml of methylene chloride, 2.5ml of an 8M ethanol solution of methylamine, 0.572ml of acetic acid and 3.12g of sodium triethoxyborohydride were added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, dried and the organic layer was concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol ═ 49: 1 to 4: 1) to give 2.2g N- { 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl } -N-methylamine as shown in Table 136 below.

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INDUSTRIAL APPLICABILITY

The compound of the present invention or a salt thereof has an excellent tachykinin receptor antagonistic action. In addition, the compound of the present invention or a salt thereof is excellent in safety, absorption, transportability to the brain, metabolic stability, blood concentration and sustainability, and thus it has an excellent pharmaceutical effect.

Claims (12)

1. A piperidine compound represented by the formula [ I ]:

wherein ring A is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹，A²And A³The same or different and each is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

B¹，B²and B³Identical or different and are each a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a tetrazolyl group, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

R¹represents:

a hydroxyl group or a hydroxyl group substituted with:

(1) a substituted carbonyl group, said substituent selected from the group consisting of:

alkyl, alkyl substituted with hydroxy;

alkoxy, alkoxy substituted by alkoxy, hydroxy or halogen atoms;

amino substituted with: an alkyl group substituted by a group selected from a halogen atom, a dialkylamino group, a piperidyl group, a morpholino group, a carboxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group and a hydroxyl group; a hydroxyalkanoyl or alkoxyalkanoyl substituted piperidinyl group; or a dialkylaminosulfonyl group; and

An unsubstituted or substituted monocyclic heterocyclic group selected from morpholino, piperazinyl, imidazolyl, thiomorpholino, piperidino, furanyl, tetrahydrothiazolinyl or pyrrolidinyl, said monocyclic heterocyclic group having as a substituent alkyl, alkyl substituted with hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or morpholino, oxo or hydroxy;

(2) a substituted sulfinyl group, said substituent selected from:

alkyl, and

a thienyl group,

(3) a substituted sulfonyl group, said substituent selected from the group consisting of:

alkyl, and

a thienyl group,

(4) a substituted alkyl group, said substituent selected from the group consisting of:

hydroxy substituted by alkyl, alkylsulfonyl or tetrahydropyranyl,

a dialkylamino group, and

an unsubstituted or substituted monocyclic heterocyclic group selected from: pyridyl, piperidyl, morpholino, isoxazolyl, triazolyl, tetrazolyl and pyrrolidinyl, the substituents of the monocyclic heterocyclic group being alkyl or phenyl,

a thiol group substituted with:

a phenyl group substituted by a hydroxyl group, a phenyl group,

A carbonyl group substituted with an alkyl group,

alkyl, or

Alkyl substituted with: alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino, alkanoyloxy or hydroxy;

sulfinyl substituted with:

a hydroxyl group(s),

alkyl, or

Alkyl substituted with hydroxy;

a sulfonyl group substituted with:

alkyl, or

Alkyl substituted with hydroxy or alkanoyloxy; r²Represents a hydrogen atom, a hydroxyl group or a hydroxyl group substituted by an alkyl group, an amino group or an amino group substituted by an alkyl group, an alkyl group or an alkyl group substituted by an alkoxy group, a hydroxyl groupAn alkoxy or alkylamino group, Z represents an oxygen atom or a group represented by the formula-N (R)³) A group represented by (a) wherein R is³Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group, R⁴Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, an alkoxy group, or an alkylamino group.

2. A compound according to claim 1, wherein R is¹Is hydroxy or hydroxy substituted by:

(1) a substituted carbonyl group, said substituent selected from the group consisting of:

alkyl, or alkyl substituted with hydroxy;

Alkoxy, or alkoxy substituted with alkoxy, hydroxyl, or a halogen atom;

amino substituted with: an alkyl group substituted with a group selected from a halogen atom, a dialkylamino group, a piperidyl group, a morpholino group, a carboxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group and a hydroxyl group; a hydroxyalkanoyl or alkoxyalkanoyl substituted piperidinyl group; or a dialkylaminosulfonyl group; and

an unsubstituted or substituted monocyclic heterocyclic group selected from morpholino, piperazinyl, imidazolyl, thiomorpholino, piperidino, furanyl, tetrahydrothiazolinyl or pyrrolidinyl, said monocyclic heterocyclic group having as a substituent alkyl, alkyl substituted with hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or morpholino, oxo or hydroxy;

(2) a substituted sulfinyl group, said substituent selected from:

alkyl, and

a thienyl group,

(3) a substituted sulfonyl group, said substituent selected from the group consisting of:

Alkyl, and

a thienyl group,

(4) a substituted alkyl group, said substituent selected from the group consisting of:

hydroxy, or hydroxy substituted with alkyl, alkylsulfonyl or tetrahydropyranyl,

a dialkylamino group, and

an unsubstituted or substituted monocyclic heterocyclic group selected from: pyridyl, piperidyl, morpholino, isoxazolyl, triazolyl, tetrazolyl and pyrrolidinyl, wherein the substituent of the monocyclic heterocyclic group is alkyl or phenyl.

3. A compound according to claim 1, wherein R is¹Is a thiol group substituted with:

a phenyl group substituted by a hydroxyl group, a phenyl group,

a carbonyl group substituted with an alkyl group,

alkyl, or

Alkyl substituted with: alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino, alkanoyloxy or hydroxy.

4. A compound according to claim 1, wherein R is¹Is sulfinyl substituted with:

a hydroxyl group(s),

alkyl, or

Alkyl substituted by hydroxy.

5. A compound according to claim 1, wherein R is¹Is a sulfonyl group substituted with:

alkyl, or

Alkyl substituted with hydroxy or alkanoyloxy.

6. A compound selected from the group consisting of:

(c) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl-aminocarbonyloxy) piperidine,

(f) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfonyl) piperidine,

(g) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-2-methylpropanesulfinyl) piperidine,

(h) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- ((S) -2-hydroxy-propanesulfonyl) piperidine,

(l) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothio-morpholinocarbonyloxy) piperidine,

(m) (2R, 4S) -1- { N- (3, 5-bis-trifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxy-ethanesulfonyl) piperidine,

(N) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methyl-ethanesulfonyl) piperidine,

(p) (2R, 4S) -1- { N- (3, 5-bistrifluoromethylbenzyl) -N-methyl } -aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonyl-piperidine, and

(S) (2R, 4S) -1- [ N- {1- (R) - (3, 5-bistrifluoromethylphenyl) ethyl } -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-methylethylthio) piperidine.

7. A process for preparing a piperidine compound of formula [ I' ] or a pharmaceutically acceptable salt thereof,

wherein ring A is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹，A²And A³The same or different and each is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

B¹，B²and B³Identical or different and are each a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a tetrazolyl group, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

R¹represents a hydroxyl group or a hydroxyl group substituted with:

(1) a substituted carbonyl group, said substituent selected from the group consisting of:

alkyl, alkyl substituted with hydroxy;

alkoxy, alkoxy substituted by alkoxy, hydroxy or halogen atoms;

Amino substituted with: an alkyl group substituted by a group selected from a halogen atom, a dialkylamino group, a piperidyl group, a morpholino group, a carboxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group and a hydroxyl group; a hydroxyalkanoyl or alkoxyalkanoyl substituted piperidinyl group; or a dialkylaminosulfonyl group; and

an unsubstituted or substituted monocyclic heterocyclic group selected from morpholino, piperazinyl, imidazolyl, thiomorpholino, piperidino, furanyl, tetrahydrothiazolinyl or pyrrolidinyl, said monocyclic heterocyclic group having as a substituent alkyl, alkyl substituted with hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or morpholino, oxo or hydroxy;

(2) a substituted sulfinyl group, said substituent selected from:

alkyl, and

a thienyl group,

(3) a substituted sulfonyl group, said substituent selected from the group consisting of:

alkyl, and

a thienyl group,

(4) a substituted alkyl group, said substituent selected from the group consisting of:

Hydroxy substituted by alkyl, alkylsulfonyl or tetrahydropyranyl,

a dialkylamino group, and

an unsubstituted or substituted monocyclic heterocyclic group selected from: pyridyl, piperidyl, morpholino, isoxazolyl, triazolyl, tetrazolyl and pyrrolidinyl, the substituents of the monocyclic heterocyclic group being alkyl or phenyl,

a thiol group substituted with:

a phenyl group substituted by a hydroxyl group, a phenyl group,

a carbonyl group substituted with an alkyl group,

alkyl, or

Alkyl substituted with: alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino, alkanoyloxy or hydroxy;

sulfinyl substituted with:

a hydroxyl group(s),

alkyl, or

Alkyl substituted with hydroxy;

a sulfonyl group substituted with:

alkyl, or

Alkyl substituted with hydroxy or alkanoyloxy;

R²represents a hydrogen atom, a hydroxyl group or a hydroxyl group substituted by an alkyl group, an amino group or an amino group substituted by an alkyl group, an alkyl group or an alkyl group substituted by an alkoxy group, a carbonyl group substituted by a hydroxyl group, an alkoxy group or an alkylamino group, R³Represents a hydrogen atom, an alkyl group, or a substituted hydroxyl group, an alkyl group Acyl, halogen, alkoxy or alkylamino substituted alkyl, R⁴Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, an alkoxy group or an alkylamino group,

the process comprises reacting a compound of the formula [ II ] with a compound of the formula [ III ] in the presence of a urea bond forming agent and, if necessary, converting into a pharmaceutically acceptable salt thereof:

wherein ring A, R¹And R²Have the same meaning as defined above,

wherein ring B, R³And R⁴Have the same meaning as defined above.

8. A process for producing a piperidine compound of the formula [ I-a ] or a pharmaceutically acceptable salt thereof,

wherein ring A is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹，A²And A³Identical or different and are each a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group, a benzyl group, a benzene groupEthyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, propionyl, malonyl, acryloyl or benzoyl-substituted hydroxyl, or alkoxy,

B¹，B²and B³Identical or different and are each a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a tetrazolyl group, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

R²Represents a hydrogen atom, a hydroxyl group or a hydroxyl group substituted by an alkyl group, an amino group or an amino group substituted by an alkyl group, an alkyl group or an alkyl group substituted by an alkoxy group, a carbonyl group substituted by a hydroxyl group, an alkoxy group or an alkylamino group, Z represents an oxygen atom or a group represented by the formula-N (R)³) A group represented by (a) wherein R is³Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group, R⁴Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, an alkoxy group or an alkylamino group,

the process comprises reducing a compound of formula [ IV ] and, if desired, converting to a pharmaceutically acceptable salt thereof:

wherein Ring A, Ring B, R²Z and R⁴Have the same meaning as defined above.

9. A process for producing a piperidine compound of the formula [ I "], or a pharmaceutically acceptable salt thereof,

wherein ring A is a benzene ring of the formula:

and ring B is a benzene ring of the formula:

wherein A is¹，A²And A³The same or different and each is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

B¹，B²and B³Identical or different and are each a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a tetrazolyl group, an alkyl group, a hydroxyl group substituted with a benzyl group, a phenethyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group, or an alkoxy group,

R¹Represents a hydroxyl group or a hydroxyl group substituted with:

(1) a substituted carbonyl group, said substituent selected from the group consisting of:

alkyl, alkyl substituted with hydroxy;

alkoxy, alkoxy substituted by alkoxy, hydroxy or halogen atoms;

amino substituted with: an alkyl group substituted by a group selected from a halogen atom, a dialkylamino group, a piperidyl group, a morpholino group, a carboxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkanoylamino group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group and a hydroxyl group; a hydroxyalkanoyl or alkoxyalkanoyl substituted piperidinyl group; or a dialkylaminosulfonyl group; and

an unsubstituted or substituted monocyclic heterocyclic group selected from morpholino, piperazinyl, imidazolyl, thiomorpholino, piperidino, furanyl, tetrahydrothiazolinyl or pyrrolidinyl, said monocyclic heterocyclic group having as a substituent alkyl, alkyl substituted with hydroxy, alkoxycarbonyl, carboxy, hydroxyalkylaminocarbonyl, alkoxyalkylaminocarbonyl, alkylthioalkylaminocarbonyl, alkylsulfinylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl or morpholino, oxo or hydroxy;

(2) A substituted sulfinyl group, said substituent selected from:

alkyl, and

a thienyl group,

(3) a substituted sulfonyl group, said substituent selected from the group consisting of:

alkyl, and

a thienyl group,

(4) a substituted alkyl group, said substituent selected from the group consisting of:

hydroxy substituted by alkyl, alkylsulfonyl or tetrahydropyranyl,

a dialkylamino group, and

an unsubstituted or substituted monocyclic heterocyclic group selected from: pyridyl, piperidyl, morpholino, isoxazolyl, triazolyl, tetrazolyl and pyrrolidinyl, the substituents of the monocyclic heterocyclic group being alkyl or phenyl,

a thiol group substituted with:

a phenyl group substituted by a hydroxyl group, a phenyl group,

a carbonyl group substituted with an alkyl group,

alkyl, or

Alkyl substituted with: alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, hydroxyalkanoylamino, morpholinocarbonylamino, hydroxyalkylaminocarbonylamino, alkanoyloxy or hydroxy;

sulfinyl substituted with:

a hydroxyl group(s),

alkyl, or

Alkyl substituted with hydroxy;

a sulfonyl group substituted with:

alkyl, or

Alkyl substituted with hydroxy or alkanoyloxy;

R²represents a hydrogen atom, a hydroxyl group or Hydroxy substituted by alkyl, amino or amino substituted by alkyl, alkyl or alkyl substituted by alkoxy, carbonyl substituted by hydroxy, alkoxy or alkylamino, R⁴Represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, an alkoxy group or an alkylamino group,

the process comprises reacting a compound of formula [ II ] with a compound of formula [ III' ] in the presence of a urea bond forming agent and, if necessary, converting to a pharmaceutically acceptable salt thereof:

wherein ring A, R¹And R²Have the same meaning as defined above,

wherein rings B and R⁴Have the same meaning as defined above.

10. A pharmaceutical composition comprising a clinically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

11. The use of compounds according to any of claims 1 to 6 for the preparation of medicaments for the treatment and prophylaxis of diseases selected from the group consisting of: inflammation, allergic diseases, pain, migraine, neuralgia, itching, cough, central nervous system diseases, digestive organ diseases, nausea, vomiting, urinary diseases, circulatory diseases and immune diseases.

12. Use according to claim 11, wherein the disorder is a urinary disorder.