JP4380508B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition comprising a piperidine derivative having excellent tachykinin receptor antagonistic activity as an active ingredient.

  Tachykinin is a general term for a group of neuropeptides. Substance P (hereinafter referred to as SP), neurokinin A, and neurokinin B are known in mammals, and these peptides are the receptors ( It is known to exhibit various biological activities by binding to neurokinin 1, neurokinin 2, and neurokinin 3). Among them, SP is one of the longest and most extensively studied neuropeptides among which 11 amino acids were found in horse intestinal intestinal extracts in 1931 and the structure was determined in 1971. Is a peptide consisting of

  SP is widely distributed in the central and peripheral nervous systems, and functions as a transmitter of primary sensory neurons, as well as vasodilatory action, vascular permeability enhancing action, smooth muscle contraction action, nerve cell excitatory action, salivary secretion action. Physiological activities such as diuretic enhancement and immunity. In particular, it is known that SP released from the terminal of the dorsal horn of the spinal cord by pain impulses conveys pain information to secondary neurons, and SP released from the peripheral terminal induces an inflammatory reaction at its receptor. Therefore, it is considered that SP is involved in various pathological conditions (for example, pain, inflammation, allergy, frequent urination, urinary incontinence, respiratory tract disease, psychosis, depression, anxiety, vomiting, etc.) SP is also considered to be involved in Alzheimer-type dementia [Review: Physiological Reviews 73, 229-308 (1993) (Non-Patent Document 1), Journal Of Autonomic Pharmacology, Vol. 13, pp. 23-93 (1993) (Non-patent Document 2)].

  In addition, piperidine compounds are described in WO2002 / 032867 (Patent Document 1) and WO2003 / 0665889 (Patent Document 2).

WO2002 / 032867

WO2003 / 065589 Physiological Reviews, 73, 229-308 (1993).

Journal of Autonomic Pharmacology, 13: 23-93 (1993).

  Currently, it has excellent tachykinin receptor antagonism (especially SP receptor antagonism) as a therapeutic agent for the various pathological conditions (especially vomiting, depression or dysuria), and is safe and durable (metabolism, in vivo A pharmaceutical composition comprising a compound that is sufficiently satisfactory in terms of kinetics and absorbability) as an active ingredient has not yet been found. Therefore, it is desired to develop a pharmaceutical composition comprising as an active ingredient a compound that has an excellent tachykinin receptor antagonism and can sufficiently satisfy clinical effects as a therapeutic agent for the disease state.

  The present invention relates to general formula [I]

(In the formula, ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, and R ¹ represents an optionally substituted alkyl. Group, a hydroxyl group which may have a substituent, a thiol group having a substituent, a carbonyl group having a substituent, a sulfinyl group having a substituent, and a substituent Sulfonyl group or formula:

A group represented by
R ¹¹ represents a carbonyl group having a substituent or a sulfonyl group having a substituent, R ¹² represents a hydrogen atom or an alkyl group which may have a substituent, and R ² represents a hydrogen atom. Represents a hydroxyl group which may have a substituent, an amino group which may have a substituent, an alkyl group which may have a substituent, a carbonyl group which has a substituent, or a halogen atom. , Z represents an oxygen atom or a group represented by —N (R ³ ) —, R ³ represents a hydrogen atom or an alkyl group which may have a substituent, and R ⁴ has a hydrogen atom or a substituent. Represents an optionally substituted alkyl group. )
And a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention relates to a pharmaceutical composition comprising as an active ingredient a compound having excellent tachykinin receptor antagonistic activity and clinically satisfactory from the viewpoint of safety and sustainability (metabolism, pharmacokinetics, absorbability), etc. It is to provide.

  In the present invention, ring A of compound [I], which is an active ingredient, represents a benzene ring which may have a substituent. Examples of the substituent on the benzene ring include an alkyl group, a halogen atom, a cyano group, and a protected group. Examples thereof may include a hydroxyl group or an alkoxy group. Ring A may have 1 to 3 of these substituents which may be the same or different.

  In the present invention, ring B of compound [I], which is an active ingredient, represents a benzene ring which may have a substituent. Examples of the substituent on the benzene ring include a trihalogenoalkyl group, a halogen atom, a cyano group, phenyl Examples thereof include a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group. Ring B may have 1 to 3 of the same or different substituents.

  Preferred examples of ring A and ring B in compound [I] which is an active ingredient of the present invention include, for example, ring A represented by the formula:

And ring B is represented by the formula:

And A ¹ , A ² and A ³ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group, and B ¹ , B ² And B ³ are the same or different and each represents a hydrogen atom, a trihalogenoalkyl group, a halogen atom, a cyano group, a phenyl group, a hetero atom containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. The compound which is a cyclic group, an alkyl group, a hydroxyl group which may be protected, or an alkoxy group is mentioned. Examples of the trihalogenoalkyl group include a trifluoromethyl group and a trichloromethyl group. Examples of the heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a hetero atom include a tetrazolyl group.

  In the present invention, the protective group for the hydroxyl group which may be protected includes an arylalkyl group which may have a substituent, a silyl group which may have a substituent, an acyl group and other conventional protective groups. Is mentioned. Among these, preferred are, for example, arylalkyl groups such as benzyl group and phenethyl group, silyl groups having a substituent such as tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, formyl group, and acetyl group. And acyl groups such as propionyl group, malonyl group, acryloyl group and benzoyl group.

In the compound [I] which is an active ingredient of the present invention, R ¹ is an alkyl group which may have a substituent, a hydroxyl group which may have a substituent, a thiol group which has a substituent, a substituent. A carbonyl group having a substituent, a sulfinyl group having a substituent, a sulfonyl group having a substituent, or the formula:

R ¹¹ represents a carbonyl group having a substituent or a sulfonyl group having a substituent, and R ¹² represents a hydrogen atom or an alkyl group which may have a substituent. To express.

In the compound [I] which is an active ingredient of the present invention, the substituent of the alkyl group which may have a substituent of R ¹ includes an alkoxycarbonyl group, a morpholinocarbonyl group, a pyridylaminocarbonyl group, a morpholinoaminocarbonyl group, Examples include a piperidinocarbonyl group, a dialkylaminocarbonyl group, a hydroxyl group, a hydroxyalkylaminocarbonyloxy group, or an alkylpiperazinocarbonyl group substituted with an alkoxyphenyl group.

In the compound [I] which is an active ingredient of the present invention, the substituent of the hydroxyl group which may have a substituent of R ¹ is
(1) a carbonyl group having a substituent,
(2) a sulfinyl group having a substituent,
(3) The sulfonyl group which has a substituent, or (4) the alkyl group which may have a substituent is mentioned.

  As the substituent of the carbonyl group having the substituent of (1) above, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, and a substituent 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 may have a substituent). Can be mentioned. Examples of the substituent of the alkyl group that may have the substituent include a hydroxyl group. Examples of the substituent of the alkoxy group that may have a substituent include an alkoxy group, a hydroxyl group, and a halogen atom. Examples of the substituent of the amino group having the substituent include a halogen atom, 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 alkyl group substituted with a group selected from an alkanoyloxy group and a hydroxyl group; a piperidinyl group substituted with a hydroxyalkanoyl group or an alkoxyalkanoyl group; or a dialkylaminosulfonyl group. Examples of the monocyclic heterocyclic group include a morpholino group, an imidazolyl group, a thiomorpholino group, a piperidino group, a furyl group, and a tetrahydrothiazolinyl group. Examples of the substituent of the monocyclic heterocyclic group include a hydroxyl group, a hydroxyalkyl group, an alkoxycarbonyl group, a carboxyl group, a hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl group, an alkylthioalkylaminocarbonyl group, and an alkylsulfinylalkylaminocarbonyl group. And an alkyl group, an oxo group or a hydroxyl group which may be substituted with an alkylsulfonylalkylaminocarbonyl group.

  Examples of the substituent of the sulfinyl group having the substituent (2) include an alkyl group and a thienyl group.

  Examples of the substituent of the sulfonyl group having the substituent (3) include an alkyl group and a thienyl group.

  As the substituent of the alkyl group which may have a substituent of the above (4), a hydroxyl group which may have a substituent or an atom selected from a sulfur atom, a nitrogen atom and an oxygen atom as a hetero atom is 1 Or a monocyclic heterocyclic group containing 4 or more (the monocyclic heterocyclic group may have a substituent). Examples of the substituent of the hydroxyl group that may have the substituent include an alkyl group, an alkylsulfonyl group, and a tetrahydropyranyl group. Examples of the monocyclic heterocyclic group include a piperidinyl group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, and a pyrrolidinyl group. Examples of the substituent of the monocyclic heterocyclic group include an alkyl group and a phenyl group.

In the compound [I] which is an active ingredient of the present invention, the substituent of the thiol group having the substituent of R ¹ includes a pyrimidinyl group having a substituent and a carbonyl group having a substituent. Or the alkyl group which may have a substituent is mentioned. Examples of the substituent of the pyrimidinyl group having a substituent include a hydroxyl group. Examples of the substituent of the carbonyl group having a substituent include an alkyl group. Examples of the substituent of the alkyl group which may have a substituent include alkylaminocarbonyl group, dialkylaminocarbonyl group, alkoxycarbonylamino group, hydroxyalkanoylamino group, morpholinocarbonylamino group, hydroxyalkylaminocarbonylamino group, alkanoyl An oxy group or a hydroxyl group is mentioned.

In the compound [I] which is an active ingredient of the present invention, the substituent of the carbonyl group having the substituent of R ¹ includes a hydroxyl group, an alkoxy group, an amino group which may have a substituent, or a hetero atom As a monocyclic heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom (the monocyclic heterocyclic group may have a substituent). Examples of the substituent of the amino group which may have a substituent include a group selected from a pyridyl group substituted with a hydroxyl group, a pyrimidinyl group, an alkylpyrido group, and an alkyl group optionally substituted with a hydroxyl group or a cyano group. Can be mentioned. One or two amino group substituents may be substituted on the amino group. Examples of the monocyclic heterocyclic group include a piperidino group, a piperazino group, a morpholino group, a thiomorpholino group, and a pyrrolidino group. Examples of the substituent of the monocyclic heterocyclic group include an alkyl group, a hydroxyl group, an oxo group, a pyrimidinyl group, an alkylsulfonyl group, an alkanoyl group, and a hydroxyalkyl group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the sulfinyl group having a substituent of R ¹ include a hydroxyl group or an alkyl group which may have a substituent. Examples of the substituent of the alkyl group that may have a substituent include a hydroxyl group.

In the compound [I] which is the active ingredient of the present invention, examples of the substituent of the sulfonyl group having the substituent of R ¹ include an alkyl group which may have a substituent. Examples of the substituent of the alkyl group which may have a substituent include a hydroxyl group or an alkanoyloxy group.

In the compound [I] which is an active ingredient of the present invention, R ¹ is represented by the formula:

In the case of R ¹¹ (1) the substituent of the carbonyl group having a substituent may have an alkyl group which may have a substituent or a substituent. Heterocyclic group containing 1 to 4 atoms selected from an alkoxy group, an optionally substituted allyl group, a substituted amino group or a hetero atom as a nitrogen atom, an oxygen atom and a sulfur atom And a group in which the heterocyclic group may have a substituent, and a nitrogen atom or a sulfur atom contained in the heterocyclic group may be oxidized. Examples of the substituent of the alkyl group which may have the substituent include an alkanoyl group, a benzyloxy group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group in which the alkyl group moiety may be substituted with a hydroxyl group, and an aminocarbonyl group. , Alkoxycarbonylamino group, alkanoylamino group, amino group substituted by alkoxycarbonyl group and alkyl group, amino group substituted by alkanoyl group and alkyl group, alkoxy group, halogen atom, tetrazolyl group, pyridyl group, furyl Group, hydroxyl group, alkylthio group, 2-oxopyrrolidino group, 2-aminothiazolyl group, 2-thiol-4-alkylthiazolyl group, 2,2-dialkyl-1,3-dioxolanyl group, cycloalkyl group, alkylsulfinyl group, Alkylsulfonyl , Thienyl group or 5-methyl-2,4 (IH, 3H) include pyrimidinedione group. Examples of the substituent of the alkoxy group which may have the substituent include an alkoxy group, a halogen atom, and a hydroxyl group. Examples of the substituent of the allyl group which may have the substituent include a nitro group or an amino group, and examples of the allyl group include a phenyl group, a naphthyl group, a phenanthonyl group, and an anthracenyl group. Examples of the substituent of the amino group having the substituent include an alkyl group which may be substituted with a group selected from a halogen atom, an alkoxy group and a hydroxyl group, and are mono-substituted or di-substituted. Examples of the heterocyclic group include saturated or unsaturated monocyclic or bicyclic heteroaromatic groups such as thienyl group, furyl group, tetrahydrofuryl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, Isothiazolyl, isoxazolyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholinyl, thiomorpholinyl, benzothienyl, benzofuryl, Group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group Quinazolinyl group, phthalazinyl group, benzoxazolyl group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group, chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, And dihydrophthalazinyl group. Among these heterocyclic groups, pyridyl, pyrrolidinyl, piperazinyl, quinolyl, piperidinyl, pyrimidinyl, thiazolyl, pyrazinyl, morpholino, thiomorpholino, indolyl, cinnolinyl, furyl, tetrahydrofuryl Group, thienyl group and the like are preferably used. Examples of the substituent of the heterocyclic group include a dialkylamino group, an alkoxycarbonyl group, a hydroxyalkyl group, an alkyl group, a benzyloxy group, an alkoxycarbonyl group, an alkanoyl group, a hydroxyl group, an oxo group, and a formyl group. ) Examples of the substituent of the sulfonyl group having a substituent include an alkyl group, a cyanophenyl group, a dialkylamino group, or an alkenyl group which may have a substituent. Examples of the substituent of the alkyl group which may have the substituent include a halogen atom or a hydroxyl group.

Examples of the substituent of the alkyl group which may have a substituent (3) of R ¹² include a dialkylaminocarbonyl group, an alkoxy group, a dialkylamino group, a cyano group, a morpholino group, a pyridyl group or a halogen atom. It is done.

In the compound [I] which is an active ingredient of the present invention, R ² has a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, or a substituent. And an optionally substituted alkyl group, a carbonyl group having a substituent, or a halogen atom.

In the compound [I] which is an active ingredient of the present invention, the substituent of the hydroxyl group which may have a substituent of R ² includes an alkyl group.

In compound [I] which is an active ingredient of the present invention, examples of the substituent of the amino group which may have a substituent of R ² include an alkyl group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the alkyl group which may have a substituent of R ² include an alkoxy group.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the carbonyl group having the substituent of R ² include a hydroxyl group, an alkoxy group, and an alkylamino group.

In the compound [I] which is an active ingredient of the present invention, examples of Z include an oxygen atom or a group represented by -N (R ³ )-.

In the compound [I] which is an active ingredient of the present invention, examples of R ³ include a hydrogen atom or an alkyl group which may have a substituent. Examples of the substituent of the alkyl group that may have a substituent of R ³ include a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group, and an alkylamino group.

In the compound [I] which is an active ingredient of the present invention, examples of R ⁴ include a hydrogen atom or an alkyl group which may have a substituent. Examples of the substituent of the alkyl group that may have a substituent of R ⁴ include a halogen atom, an alkoxy group, and an alkylamino group.

As the compound which is an active ingredient of the present invention, those in which R ¹ is an alkyl group which may have a substituent are preferable. As the substituent of the alkyl group, a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group or a hydroxyalkylaminocarbonyloxy group is preferable.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a hydroxyl group which may have a substituent are preferable. Of these, those in which R ¹ is an optionally substituted alkoxy group are preferred. Among these, what is a carbonyloxy group which has a substituent is preferable. The substituent of the alkoxy group is preferably a hydroxyl group, an alkylsulfonyloxy group, a tetrahydropyranyloxy group, a triazolyl group, a tetrazolyl group or an alkoxy group which may be substituted with an alkyl group, and further a hydroxyl group or a tetrahydropyranyloxy group. Groups are preferred. As the substituent of the carbonyloxy group, morpholino group; imidazolyl group; hydroxyl group, morpholinocarbonyl group, dialkylaminocarbonyl group, alkylaminocarbonyl group, alkylthio group, alkoxy group, alkylsulfonyl group, alkanoyloxy group or carboxyl group and alkyl Alkylamino group which may be substituted in the group part; hydroxyl group, alkoxycarbonyl group, carboxyl group, hydroxyalkylaminocarbonyl group, alkoxyalkylaminocarbonyl group, alkylthioalkylaminocarbonyl group, alkylsulfinylalkylaminocarbonyl group, alkylsulfonylalkyl Piperidino groups substituted by aminocarbonyl groups or hydroxyalkyl groups; hydroxyalkanoyl groups or alkoxy A piperidinylamino group substituted with a lucanoyl group; a thiomorpholino group in which the sulfur atom may be oxidized; an oxopyrrolidinyl group; an oxotetrahydrothiazolinyl group; or a dialkylaminosulfonylamino group; A morpholino group; an alkylamino group in which the alkyl group moiety may be substituted with a hydroxyl group; or a thiomorpholino group in which a sulfur atom is oxidized is preferable.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a thiol group having a substituent are preferable. The substituent of the thiol group is an alkanoyl group; or a hydroxyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkoxycarbonylamino group, a hydroxyalkanoylamino group, a morpholinocarbonylamino group, a hydroxyalkylamino group or an alkanoyloxy group. An alkyl group which may be substituted is preferred.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a carbonyl group having a substituent are preferred. Examples of the substituent for the carbonyl group include an alkoxy group; an amino group which may be substituted with a pyrimidyl group or an alkylpyrido group; an alkylamino group whose alkyl group moiety may be substituted with a hydroxyl group or a cyano group; A pyridylamino group in which the pyridyl group moiety is substituted with a hydroxyl group; a piperidino group substituted with a hydroxyl group or an oxo group; a piperazino group substituted with an oxo group, an alkylsulfonyl group or an alkanoyl group; a morpholino group; A thiomorpholino group; or a pyrrolidino group substituted with a hydroxyalkyl group or a hydroxyl group is preferred, and a pyrimidinylamino group or a hydroxypiperazino group is more preferred.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a sulfinyl group having a substituent are preferable. The substituent for the sulfinyl group is preferably an alkyl group or a hydroxyl group which may be substituted with a hydroxyl group, and more preferably an alkyl group which may be substituted with a hydroxyl group.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a sulfonyl group having a substituent are preferable. As the substituent of the sulfonyl group, an alkyl group which may be substituted with a hydroxyl group or an alkanoyloxy group is preferable, and an alkyl group which may be substituted with a hydroxyl group is more preferable.

As the compound which is an active ingredient of the present invention, R ¹ is represented by the formula:

A group represented by
R ¹¹ is preferably a carbonyl group having a substituent or a sulfonyl group having a substituent, and R ¹² is preferably a hydrogen atom or an alkyl group which may have a substituent. Of these, R ¹¹ is preferably a carbonyl group having a substituent, R ¹² is preferably a hydrogen atom or an alkyl group, and R ¹¹ has an alkanoyl group or a substituent which may have a substituent. An aminocarbonyl group, a morpholinocarbonyl group, and a piperidinylcarbonyl group optionally substituted with an alkanoyl group are preferable. Among these, those in which R ¹¹ is a sulfonyl group having a substituent and R ¹² is a hydrogen atom or an alkyl group are preferable. Examples of the substituent of the alkanoyl group include an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminocarbonyl group, an alkoxycarbonylamino group, an alkanoylamino group, an alkoxycarbonyl group, and an amino group substituted with an alkyl group, alkanoyl Group, an amino group substituted with an alkyl group, an alkoxy group optionally substituted with a phenyl group, a furyl group, a tetrazolyl group, a hydroxyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a 2-aminothiazolyl group, 2- An oxopyrrolidino group, a 2-thiol-4-alkylthiazolidinyl group or a cycloalkyl group is preferable, and an alkoxy group, a hydroxyl group or a cycloalkyl group is more preferable. As the substituent of the aminocarbonyl group, an alkyl group which may be substituted with a halogen atom, a hydroxyl group or an alkoxy group is preferable, and an alkyl group is more preferable. As the substituent of the sulfonyl group, an alkyl group, an alkenyl group or a dialkylamino group which may be substituted with a hydroxyl group or a halogen atom is preferable, and an alkyl group is more preferable.

  As compound [I] which is an active ingredient of the present invention, ring A is represented by the formula:

And ring B is represented by the formula:

Wherein A ¹ is a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, A ² is a hydrogen atom or a halogen atom, A ³ is a hydrogen atom, B ¹ is a hydrogen atom, An alkyl group or a trihalogenoalkyl group, B ² is a hydrogen atom, an alkyl group or a trihalogenoalkyl group, B ³ is a hydrogen atom, and R ¹ is a hydroxyl group; a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, Alkyl group substituted by alkoxycarbonyl group, morpholinoaminocarbonyl group, hydroxyalkylaminocarbonyloxy group or alkylpiperazinocarbonyl group; dihydroxypyrimidinylthio group; alkanoylthio group; hydroxyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group , Al Alkoxythio group optionally substituted with a alkoxycarbonylamino group, hydroxyalkanoylamino group, morpholinocarbonylamino group, hydroxyalkylaminocarbonylamino group or alkanoyloxy group; dialkylthionium group; hydroxyl group, alkylsulfonyloxy group, tetrahydropyrani An alkoxy group optionally substituted with an alkoxy group; a morpholinocarbonyloxy group; an imidazolylcarbonyloxy group; a hydroxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl Group, alkylaminocarbonyl group, alkoxy group, alkanoyloxy group or carboxyl group in which the alkyl group moiety may be substituted. Bonyloxy group; substituted with hydroxyl group, alkoxycarbonyl group, carboxyl group, hydroxyalkylaminocarbonyl group, alkoxyalkylaminocarbonyl group, alkylthioalkylaminocarbonyl group, alkylsulfinylalkylaminocarbonyl group, alkylsulfonylalkylaminocarbonyl group or hydroxyalkyl group Piperidinocarbonylcarbonyl group; dialkylaminocarbonyloxy group optionally substituted by hydroxyl group; piperidinylaminocarbonyloxy group substituted by hydroxyalkanoyl group or alkoxyalkanoyl group; sulfur atom substituted by oxo group Optionally substituted thiomorpholinocarbonyloxy group; oxopyrrolidinylcarbonyloxy group; dialkylaminosulfonylamino group A carboxyl group; an alkoxycarbonyl group; an aminocarbonyl group substituted with a pyrimidinyl group; an aminocarbonyl group substituted with a pyrimidinyl group and an alkyl group; even if the alkyl group moiety is substituted with a hydroxyl group or a cyano group A good alkylaminocarbonyl group; a di (hydroxyalkyl) aminocarbonyl group; a pyridylaminocarbonyl group in which the pyridyl group moiety may be substituted with a hydroxyl group; an aminocarbonyl group substituted with an alkylpyrido group; and a substituted with an alkylpyrido group and an alkyl group A piperidinocarbonyl group substituted with a hydroxyl group or an oxo group; a piperazinocarb substituted with an oxo group, an alkyl group, a pyrimidinyl group, an alkylsulfonyl group or an alkanoyl group Morpholinocarbonyl group; thiomorpholinocarbonyl group; pyrrolidinocarbonyl group substituted by hydroxyalkyl group or hydroxyl group; alkylsulfinyl group optionally substituted by hydroxyl group; hydroxysulfinyl group; substituted by hydroxyl group or alkanoyloxy group An optionally substituted alkylsulfonyl group; or

R ¹¹ is an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminocarbonyl group, an alkanoylamino group, an alkoxycarbonylamino group, an alkanoyl group and an amino group substituted with an alkyl group, an alkoxy group Amino group substituted with carbonyl group and alkyl group, halogen atom, alkoxy group optionally substituted with phenyl group, furyl group, tetrazolyl group, hydroxyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, 2-amino Thiazolinyl group, 2-oxopyrrolidino group, 2,2-dialkyl-1,3-dioxiranyl group, 2-thiol-4-alkylthiazolinyl group, cycloalkyl group and 5-alkyl-2,4 (1H, 3H ) Selected from pyrimidinedione groups An alkanoyl group that may be substituted with a group; a phenylcarbonyl group that may be substituted with an amino group or a nitro group; a pyridylcarbonyl group that may be substituted with an alkyl group or a hydroxyl group; a formyl group or a hydroxyalkyl group Optionally substituted furylcarbonyl group; thienylcarbonyl group; pyrazinylcarbonyl group optionally substituted with alkanoyl group; morpholinocarbonyl group; substituted with benzyloxy group, alkoxycarbonyl group, alkanoyl group, hydroxyl group or oxo group An optionally substituted pyrrolidinylcarbonyl group; a tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group substituted by an alkoxycarbonyl group or an alkanoyl group; a thiomorpholino in which a sulfur atom may be substituted by an oxo group 3-alkyl-2,4 (1H, 3H) pyrimidinedionecarbonyl group; an alkylaminocarbonyl group in which the alkyl group moiety may be substituted with a halogen atom, a hydroxyl group or an alkoxy group; an alkoxy group, a hydroxyl group or a halogen atom An alkoxycarbonyl group optionally substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a group selected from a hydroxyl group, a dialkylamino group optionally substituted with a hydroxyl group and a halogen atom; or an alkenylsulfonyl group, and R ^A compound in which ¹² is a hydrogen atom; or an alkyl group, R ³ is an alkyl group or an alkanoyl group optionally substituted with a hydroxyl group, and R ⁴ is an alkyl group optionally substituted with a hydrogen atom or a hydroxyl group. Can be mentioned.

  In the compound which is an active ingredient of the present invention, as a preferable compound, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, and B ² is a trihalogenoalkyl group. Yes, B ³ is a hydrogen atom, R ¹ is an alkylthio group; a dialkylthionium group; an alkoxy group substituted with a hydroxyl group; an alkylaminocarbonyloxy group substituted with an alkyl group moiety by a hydroxyl group; substituted with a hydroxyl group Dialkylaminocarbonyloxy group; a thiomorpholinocarbonyloxy group in which the sulfur atom is substituted with an oxo group; an aminocarbonyl group substituted with a pyrimidinyl group and an alkyl group; an alkylaminocarbonyl in which the alkyl group moiety is substituted with a hydroxyl group Groups; alkylpyrido groups and aminocarbs substituted with alkyl groups A piperidinocarbonyl group substituted by a hydroxyl group; a piperazinocarbonyl group substituted by an alkanoyl group; an alkylsulfinyl group in which the alkyl group moiety may be substituted by a hydroxyl group; substituted by a hydroxyl group Or an alkylsulfonyl group; or

R ¹¹ is selected from an alkanoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkanoylamino group, an alkanoyl group, and an amino group substituted with an alkyl group, an alkoxy group, a hydroxyl group, and a cycloalkyl group. An alkanoyl group optionally substituted with a group; a pyridylcarbonyl group substituted with a hydroxyl group; a morpholinocarbonyl group; a pyrrolidinylcarbonyl group substituted with an oxo group; a piperidinylcarbonyl substituted with an alkanoyl group 3-alkyl-2,4 (1H, 3H) pyrimidinedionecarbonyl group; an alkylaminocarbonyl group in which the alkyl group moiety is substituted with a hydroxyl group; a hydroxyalkoxycarbonyl group; or an alkylsulfonyl group, and R ¹² is hydrogen Atom; Is an alkyl group, R ² is a hydrogen atom, Z is -N (R 3) ^- is a group represented by, R ³ is an alkyl group, compounds wherein R ⁴ is a hydrogen atom or an alkyl group Can be mentioned.

  In the compound which is an active ingredient of the present invention, as another preferred compound, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, and B ² is a trihalogenoalkyl group. An alkylthio group in which B ³ is a hydrogen atom and R ¹ may be substituted with a hydroxyl group; an alkoxy group substituted with a hydroxyl group; an alkylaminocarbonyloxy group in which the alkyl group moiety may be substituted with a hydroxyl group A thiomorpholinocarbonyloxy group in which the sulfur atom is substituted with an oxo group; an aminocarbonyl group substituted with a pyrimidinyl group and an alkyl group; an alkylaminocarbonyl group in which the alkyl group moiety is substituted with a hydroxyl group; a hydroxyl group or an oxo group; A substituted piperidinocarbonyl group; substituted with an alkanoyl group or an alkylsulfonyl group A substituted piperazinocarbonyl group; an alkylsulfinyl group in which the alkyl group moiety may be substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or the formula:

In a group represented may alkanoyl group optionally R ¹¹ is substituted by a hydroxyl group or a halogen atom; a or alkylsulfonyl group, R ¹² is a hydrogen atom; pyridylcarbonyl group is an alkyl group, R ² is Examples thereof include a compound that is a hydrogen atom, Z is a group represented by —N (R ³ ) —, R ³ is an alkyl group, and R ⁴ is a hydrogen atom or an alkyl group.

  Furthermore, in the compound which is an active ingredient of the present invention, as another preferable compound, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, and B ² is a trihalogenoalkyl group. An alkoxy group in which B ³ is a hydrogen atom and R ¹ is substituted with a hydroxyl group; an alkylaminocarbonyloxy group in which the alkyl group moiety is substituted with a hydroxyl group; a thiomorpholino in which the sulfur atom is substituted with an oxo group A carbonyloxy group; an alkylaminocarbonyl group in which the alkyl group portion is substituted with a hydroxyl group; a piperazinocarbonyl group substituted with an alkanoyl group; an alkylsulfinyl group in which the alkyl group portion may be substituted with a hydroxyl group; An optionally substituted alkylsulfonyl group; or

In a group represented, R ¹¹ is substituted by a hydroxyl group which may alkanoyl group; a morpholinocarbonyl group; piperazinocarbonyl group substituted by an alkanoyl group is, or an alkylsulfonyl group, R ¹² is a hydrogen atom Or an alkyl group, a compound wherein R ² is a hydrogen atom, Z is a group represented by —N (R ³ ) —, R ³ is an alkyl group, and R ⁴ is a hydrogen atom or an alkyl group; Is mentioned.

  Furthermore, in the compound which is an active ingredient of the present invention, as another preferred compound, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, and B ² is a trihalogenoalkyl group. An alkylthio group in which B ³ is a hydrogen atom and R ¹ may be substituted with a hydroxyl group; an alkoxy group substituted with a hydroxyl group; an alkylaminocarbonyloxy group in which the alkyl group moiety may be substituted with a hydroxyl group A thiomorpholinocarbonyloxy group in which the sulfur atom is substituted with an oxo group; an aminocarbonyl group substituted with a pyrimidinyl group; an aminocarbonyl group substituted with a pyrimidinyl group and an alkyl group; an alkyl group moiety is substituted with a hydroxyl group; Alkylaminocarbonyl groups; piperidinocarbonyl groups substituted by hydroxyl groups; alkanos A piperazinocarbonyl group substituted with an yl group; an alkylsulfinyl group optionally substituted with a hydroxyl group; an alkylsulfonyl group optionally substituted with a hydroxyl group; or the formula:

In a group represented, R ¹¹ is a hydroxyl group, which may alkanoyl group substituted with an alkoxy group or cycloalkyl group; with an alkylsulfonyl group; a morpholinocarbonyl group; alkoxycarbonyl groups pyridylcarbonyl group substituted by hydroxyl group R ¹² is a hydrogen atom; or an alkyl group, R ² is a hydrogen atom, Z is a group represented by —N (R ³ ) —, R ³ is an alkyl group, and R ⁴ is a hydrogen atom. Examples include compounds that are atoms or alkyl groups.

  Of these compounds, ring A has the formula:

And ring B is represented by the formula:

A ¹ is an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, and B ² is a trihalogenoalkyl group. And B ³ is a hydrogen atom, R ¹ is an alkylthio group; an alkylaminocarbonyloxy group in which the alkyl group moiety is substituted with a hydroxyl group; a thiomorpholinocarbonyloxy group in which a sulfur atom is substituted with an oxo group; An alkylaminocarbonyl group substituted with an alkyl group; a piperidinocarbonyl group substituted with a hydroxyl group; a piperazinocarbonyl group substituted with an alkanoyl group; an alkylsulfinyl substituted with an alkyl group moiety with a hydroxyl group A group; an alkylsulfonyl group optionally substituted by a hydroxyl group; or a formula:

Wherein R ¹¹ is an alkanoyl group substituted with a hydroxyl group, R ¹² is a hydrogen atom, R ² is a hydrogen atom, and Z is represented by —N (R ³ ) —. A compound in which R ³ is an alkyl group and R ⁴ is a hydrogen atom or an alkyl group is preferable.

Furthermore, in the compound which is an active ingredient of the present invention, a preferable compound is a compound selected from the following (A) to (AP) or a pharmaceutically acceptable salt thereof.
(A) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-methylpropionylamino) piperidine,
(B) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylamino Piperidine,
(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- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-methoxyacetylaminopiperidine,
(E) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-methoxycarbonylaminopiperidine,
(F) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylamino-2- ( 4-fluoro-2-methylphenyl) piperidine,
(G) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-methanesulfonylaminopiperidine,
(H) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxyethoxy) piperidine,
(I) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-hydroxyacetylaminopiperidine,
(J) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (3-hydroxypropoxy) piperidine,
(K) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (2-cyclopropyl-2) -Hydroxyacetylamino) -2- (4-fluoro-2-methylphenyl) piperidine,
(L) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxy-2-methylpropionylamino) piperidine,
(M) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-((S) -3-hydroxybutyrylamino) piperidine,
(N) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxyethylaminocarbonyloxy) piperidine,
(O) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-methanesulfinylpiperidine,
(P) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-methanesulfonylpiperidine,
(Q) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) ) Piperidine,
(R) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-methoxypropionylamino) piperidine,
(S) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (N-methanesulfonyl-N-methylamino) piperidine,
(T) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine,
(U) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (3-hydroxy-3-methylbutyrylamino) piperidine,
(V) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxyethanesulfinyl) piperidine,
(W) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-((S) -2-hydroxypropionylamino) piperidine,
(X) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-((R) -3-hydroxybutyrylamino) piperidine,
(Y) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxy-2-methylpropanesulfonyl) piperidine,
(Z) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxyethanesulfinyl) piperidine,
(AA) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxy-2-methylpropanesulfinyl) piperidine,
(AB) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-((S) -2-hydroxypropanesulfonyl) piperidine,
(AC) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((S ) -3-hydroxybutyrylamino) piperidine,
(AD) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((R ) -3-hydroxybutyrylamino) piperidine,
(AE) (2R, 4S) -4- (4-acetylpiperidinocarbonyl) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] Aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine,
(AF) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1- Oxothiomorpholinocarbonyloxy) piperidine,
(AG) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxyethanesulfonyl) piperidine,
(AH) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (4-hydroxypiperidinocarbonyl) piperidine,
(AI) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine ,
(AJ) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((R ) -2-hydroxypropionyl) piperidine,
(AK) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxypiperidin-5-ylcarbonylamino) piperidine,
(AL) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (N-pyrimidin-4-ylaminocarbonyl) piperidine,
(AM) (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,
(AN) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxyacetylamino) piperidine,
(AO) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (1-methylethylthio) piperidine, and
(AP) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2- (S) -hydroxypropylaminocarbonyl) piperidine.

Furthermore, as a particularly preferable compound, a compound selected from the following (a) to (s) or a pharmaceutically acceptable salt thereof.
(A) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxy-2-methylpropionylamino) 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- Hydroxyethylaminocarbonyloxy) piperidine,
(D) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (3-hydroxy-3-methylbutyrylamino) 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-hydroxypropanesulfonyl) piperidine,
(I) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((S ) -3-hydroxybutyrylamino) piperidine,
(J) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((R ) -3-hydroxybutyrylamino) piperidine,
(K) (2R, 4S) -4- (4-acetylpiperidinocarbonyl) -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- Oxothiomorpholinocarbonyloxy) piperidine,
(M) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxyethanesulfonyl) piperidine,
(N) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (4-hydroxypiperidinocarbonyl) piperidine,
(O) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methanesulfonylpiperidine ,
(P) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-((R ) -2-hydroxypropionyl) piperidine,
(Q) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2-hydroxyacetylamino) piperidine,
(R) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (1-methylethylthio) piperidine, and
(S) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (2- (S) -hydroxypropylaminocarbonyl) piperidine.

  Compound [I], which is an active ingredient of the present invention, can be used for pharmaceutical use in a free form or in the form of a pharmacologically acceptable salt.

  Examples of the pharmacologically acceptable salt of the compound [I] which is an active ingredient of the present invention include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, and fumaric acid. And organic acid salts such as salts, oxalates, citrates, methanesulfonates, benzenesulfonates, tosylates, maleates, succinates and tartrates.

  In addition, the compound [I] which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof includes any of its internal salts, solvates or hydrates thereof.

The compound [I] which is an active ingredient of the present invention can exist as an optical isomer based on an asymmetric atom, but the compound which is an active ingredient of the present invention includes any of these optical isomers and mixtures thereof. Of these optical isomers, the compound which is the active ingredient of the present invention is preferably a compound in which the 2-position of the piperidine ring (ring A connecting position) is R, and particularly the 2-position of the piperidine ring (ring A connecting position). ) Is R, and the compound in which 4-position (the connecting position of R ¹ ) is S is preferable.

  The compound [I] which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof has an excellent tachykinin receptor antagonistic action, particularly an SP receptor antagonistic action, and is suitable for mammals (eg, mice, guinea pigs, gerbils). , Ferrets, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) or inflammation or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, Rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, ophthalmitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, and central nervous system diseases (eg, schizophrenia, Parkinson's disease) , Depression, anxiety, psychosomatic disease, morphine dependence, dementia (eg, Alzheimer's disease, etc.), digestive disorders (eg, irritable bowel disease, ulcer Abnormalities caused by ulcerative colitis, Crohn's disease, urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori) (eg, gastritis, gastric ulcer, etc.), nausea, vomiting, dysuria (eg, frequent urination, Urinary incontinence, etc.), cardiovascular diseases (for example, angina pectoris, hypertension, heart failure, thrombosis, etc.) and safe abnormalities such as immune abnormalities are useful. In particular, the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has a high ability to enter the brain and has no ability to induce phospholipidosis. It is useful as a preventive and therapeutic agent for central nervous system diseases such as vomiting and depression, and urinary abnormalities such as frequent urination, especially as a prophylactic / therapeutic agent for abnormal urination.

  Compound [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, can be administered orally or parenterally, using a pharmaceutical carrier usually used for oral or parenteral administration. Thus, a suitable preparation can be obtained. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants ( Examples thereof include magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (anhydrous sodium lauryl sulfate, etc.). In addition, in the case of oral administration, these pharmaceutical preparations may be solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, in the case of parenteral administration, for example, injection water, physiological saline, glucose aqueous solution or the like can be used as an injection, a drip infusion, or a suppository.

  The dose of compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition, or degree of disease, but is usually administered per day. The amount is 0.1-20 mg / kg, especially 0.1-10 mg / kg for oral administration, 0.01-10 mg / kg, especially 0.01-1 mg / kg for parenteral administration. kg is preferred.

  Compound [I] which is an active ingredient of the present invention can be produced, for example, by the following [Method A] to [Method E].

[Method A]
Among the compounds [I] which are the active ingredients of the present invention, the compound represented by the general formula [I ′]

(In the formula, ring A represents an optionally substituted benzene ring, ring B represents an optionally substituted benzene ring, and R ¹ represents an optionally substituted alkyl. Group, a hydroxyl group which may have a substituent, a thiol group having a substituent, a carbonyl group having a substituent, a sulfinyl group having a substituent, and a substituent Sulfonyl group or formula:

R ¹¹ represents a carbonyl group having a substituent or a sulfonyl group having a substituent, and R ¹² represents a hydrogen atom or an alkyl group which may have a substituent. R ² represents a hydrogen atom, a hydroxyl group which may have a substituent, an amino group which may have a substituent, an alkyl group which may have a substituent, or a substituent. A carbonyl group or a halogen atom is represented, R ³ represents a hydrogen atom or an alkyl group which may have a substituent, and R ⁴ represents a hydrogen atom or an alkyl group which may have a substituent. )
For example, the compound represented by the general formula [II]

(In the formula, ring A, R ¹ and R ² have the same meaning as described above.)
And a compound of the general formula [III]

(In the formula, ring B, R ³ and R ⁴ have the same meaning as described above.)
In the presence of a urea agent (eg, 1,1′-carbonyldiimidazole, triphosgene, phosgene, etc.) in a suitable solvent (eg, acetonitrile, dichloromethane, tetrahydrofuran, etc.) at 0 ° C. to 80 ° C. (Preferably, it can be produced by reacting at 0 ° C. to 50 ° C.) and, if desired, a pharmacologically acceptable salt thereof can be obtained.

[Method B]
Of the compounds [I] which are active ingredients of the present invention, the compound represented by the general formula [Ia]

(In the formula, Z represents an oxygen atom or a group represented by —N (R ³ ) —, and ring A, ring B, R ² , R ³ and R ⁴ have the same meaning as described above.)
For example, the compound represented by the general formula [IV]

(In the formula, ring A, ring B, R ² , Z, R ³ and R ⁴ have the same meaning as described above.)
In a suitable solvent (eg, ethanol, tetrahydrofuran, dichloromethane, etc.) in the presence of a reducing agent (eg, sodium borohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, etc.). The compound can be produced by reduction at -70 ° C to reflux (preferably -70 ° C to 20 ° C), and if desired, a pharmacologically acceptable salt thereof can be obtained.

[Method C]
Among the compounds of the present invention, the general formula [Ib]

(In the formula, ring A, ring B, R ¹¹ , R ¹² , R ² , Z, R ³ and R ⁴ have the same meaning as described above.)
The compound represented by the general formula [IV]

(In the formula, ring A, ring B, R ² , Z, R ³ and R ⁴ have the same meaning as described above.)
And a compound of the general formula [V]

(In the formula, X ¹ represents a hydrogen atom, a hydroxyl group, a silicon atom, a lithium atom or a magnesium atom, and R ¹¹ and R ¹² have the same meaning as described above.)
In a suitable solvent (for example, dichloromethane, acetic acid, ethanol, methanol, etc.) at −10 ° C. to 80 ° C. (preferably 0 ° C. to 30 ° C.) under acidic conditions. , Sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) or by reductive amination reaction by hydrogenation with a reduction catalyst (eg palladium catalyst, etc.) If desired, the pharmacologically acceptable salt thereof can be obtained.

[Method D]
Among the compounds that are active ingredients of the present invention, the compound represented by the general formula [Ic]

(In the formula, ring A, ring B, R ² , Z, R ³ and R ⁴ have the same meaning as described above, and R ¹³ represents a carboxyl group which may have a substituent.)
The compound represented by the general formula [IV]

(In the formula, ring A, ring B, R ² , Z, R ³ and R ⁴ have the same meaning as described above.)
And a compound of the general formula [VI]
X ² CH ₂ R ¹³ [VI]
(Wherein X ² represents a leaving group such as a diethylphosphono group or a triphenylphosphinyl group, and R ¹³ has the same meaning as described above.)
In the presence of a base (eg, potassium tert-butoxide, triethylamine, sodium hydroxide, etc.) in a suitable solvent (eg, tetrahydrofuran, dichloromethane, etc.) at −30 ° C. to 80 ° C. (preferably The general formula [VII] obtained by the reaction at −20 ° C. to 30 ° C.)

(In the formula, ring A, ring B, R ¹³ , Z, R ² , R ³ and R ⁴ have the same meaning as described above.)
Can be produced by hydrogenating in a suitable solvent (eg, methanol, ethanol, etc.) with a reduction catalyst (eg, palladium catalyst, etc.) and reducing at 0 ° C. to 50 ° C., If desired, it can be a pharmacologically acceptable salt thereof.

[Method E]
Among the compounds that are the active ingredients of the present invention, the general formula [I '']

(In the formula, ring A, ring B, R ¹ , R ² and R ⁴ have the same meaning as described above.)
The compound represented by the general formula [II]

(In the formula, ring A, R ¹ and R ² have the same meaning as described above.)
And a compound represented by the general formula [III ']

(In the formula, ring B and R ⁴ have the same meaning as described above.)
In the presence of a urea agent (eg, 1,1′-carbonyldiimidazole, triphosgene, phosgene, etc.) in a suitable solvent (eg, acetonitrile, dichloromethane, tetrahydrofuran, etc.) at 0 ° C. to 80 ° C. (Preferably, it can be produced by reacting at 0 ° C. to 50 ° C.) and, if desired, a pharmacologically acceptable salt thereof can be obtained.

The compound [I], which is an active ingredient of the present invention, can also be produced by converting the group R ¹ and the group R ³ of the compound obtained as described above into other desired substituents. Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as in the following (Method a) to (Method q).

(Method a): In the general formula [I], the group R ¹ has a substituent having a hydroxyl group (for example, an alkoxy group which may have a substituent, a substituent having The compound [I] which is a carbonyloxy group or an alkylsulfonyloxy group can be prepared by alkylating, acylating or sulfonylating a corresponding compound containing a hydroxyl group in the group R ¹ by a conventional method. it can. For example, alkylation can be carried out at −10 ° C. to 80 ° C., acylation can be carried out at 5 ° C. to 80 ° C., and sulfonylation can be carried out at 5 ° C. to 80 ° C.

(Method b): In the general formula [I], the compound [I] in which the group R ¹ contains an amino group having a substituent is a corresponding compound containing an amino group in the group R ^1. According to a conventional method, a substituent of an amino group (for example, an alkoxycarbonyl group such as tert-butoxycarbonyl group, an arylalkoxycarbonyl group such as benzyloxycarbonyl group, an alkanoyl group such as formyl group, acetyl group, propionyl group, methyl Group, alkyl group such as ethyl group and propyl group, alkylsulfonyl group such as methanesulfonyl group and ethanesulfonyl group, alkenylsulfonyl group such as vinylsulfonyl group, heterocyclic group such as pyridyl group and the like) Or carbamate synthesis such as N, N'-succinimidyl carbonate Using reagents, it can be prepared by reacting, for example, alkoxyalkyl alcohol. The substitution can be appropriately performed by a conventional method such as alkylation, acylation, sulfonylation, allylation and the like depending on the kind of the substituent. Further, a di-substituted product can be obtained by substituting the hydrogen atom of the amino group with a substituent. This reaction can be carried out at −20 ° C. to 50 ° C.

In addition, when the compound [I], which is a substituent containing an amino group in which the group R ¹ has a substituent, is a compound having a urea bond, a corresponding amine compound and a urea agent are used, It can be produced by reacting in the same manner as in [Method A] or according to the method described in JP-A-10-195037.

Furthermore, in the general formula [I], the compound [I] in which the group R ¹ is a substituent containing an amino group having a substituent is a corresponding compound containing a carbon-carbon double bond in the group R ^1. It can be produced by adding a compound containing an amino group by a conventional method. This reaction can be performed, for example, with the solvent heated under reflux or without a catalyst.

Method (c): In the general formula [I], a compound group wherein R ¹ contains an amino group [I], the corresponding compound (I) from the protecting group is an amino group which is protected groups R ¹ It can be manufactured by removing. The protecting group can be removed by a conventional method (for example, acid treatment, base treatment, catalytic reduction, etc.). Among these reactions, the reaction by acid treatment can be carried out, for example, at 5 ° C. to 120 ° C., the reaction by base treatment can be carried out at 5 ° C. to 40 ° C., and the reaction by catalytic reduction can be carried out at 10 ° C. to 40 ° C.

Also, in the general formula [I], the compound [I] in which the group R ¹ contains an amino group is prepared by reducing the corresponding compound [I] in which the group R ¹ contains a nitro group. Can do. The reduction can be carried out by reacting tin dichloride, zinc or the like in the presence of an acid. This reaction can be performed, for example, by heating the solvent under reflux.

Further, in the general formula [I], the compound [I] in which the group R ¹ contains an amino group is obtained by subjecting the corresponding compound [I] in which the group R ¹ contains a carboxyl group to a Curtius rearrangement reaction or the like. Can be manufactured. The Curtius rearrangement reaction can be performed, for example, by the method described in Advanced Organic Chemistry 4th edition, page 1054. That is, it can be carried out by converting the carboxyl group to acid chloride with thionyl chloride or the like, then azidating with sodium azide or the like and then hydrolyzing.

(D Method): In the general formula [I], a compound group wherein R ¹ contains a hydroxy group [I], the protecting from the corresponding compounds containing hydroxyl group R ¹ is protected (I) It can be prepared by removing the group by a conventional method. The removal of the protecting group can be carried out by acid treatment, base treatment, catalytic reduction or the like depending on the kind of the protecting group. This reaction suitably proceeds at, for example, 0 ° C to 80 ° C, particularly 5 ° C to 50 ° C.

In addition, in the general formula [I], the compound [I] in which the group R ¹ contains a hydroxyl group can be prepared by reducing the corresponding compound [I] in which the group R ¹ contains a formyl group. it can. The reduction can be carried out by reacting in the presence of a reducing agent such as sodium borohydride. This reaction suitably proceeds, for example, at -80 ° C to 80 ° C, particularly at -70 ° C to 20 ° C.

Further, in the general formula [I], the radicals R ¹ is a compound containing a hydroxyl group (I) is manufactured by radical R ¹ is reduction of the corresponding compound containing an ester or a carboxyl group (I) be able to. The reduction can be carried out by reacting in the presence of a reducing agent such as lithium aluminum hydride. This reaction suitably proceeds at, for example, -50 ° C to 200 ° C, particularly -20 ° C to 60 ° C.

(Method e): In the general formula [I], when the group R ¹ is a hydroxyl group and has an asymmetric center at the R ¹ bond, for example, the Mitsunobu method (Synthesis) 1 to 28, 1981), the steric configuration can be converted to the reverse configuration. Specifically, it can be converted by reacting in a suitable solvent in the presence of triphenylphosphine, benzoic acid and diethyl azodicarboxylate. This reaction suitably proceeds at, for example, 0 ° C. to 60 ° C., particularly 5 ° C. to 40 ° C.

(Method f): In the general formula [I], the compound [I] containing a thiol group which the group R ¹ may have a substituent is a corresponding compound having a hydroxyl group in the group R ¹ The corresponding compound containing [I] and a thiol group can be produced, for example, by reacting according to Mitsunobu's method (Synthesis, pages 1 to 28, 1981). Specifically, it can be carried out by reacting in a suitable solvent in the presence of triphenylphosphine and diethyl azodicarboxylate. This reaction can be carried out, for example, under reflux of a solvent.

In the general formula [I], the compound [I] containing a thiol group in which the group R ¹ may have a substituent is represented by the corresponding compound [I] containing a halogen atom in the group R ^1. It can be produced by reacting a corresponding compound containing a thiol group. This reaction suitably proceeds at, for example, -50 ° C to 150 ° C, particularly 10 ° C to 100 ° C.

Also, compounds containing more alkylthio groups radical R ^1, protected the corresponding compound [I] or thiol group containing a thiol group to group R ¹ (for example, thiol groups were acetylated) corresponding compound Can be prepared by alkylation in the presence of a base. This reaction suitably proceeds at, for example, -10 ° C to 80 ° C, particularly 5 ° C to 50 ° C.

(Method g): In the general formula [I], the compound [I] containing an amino group in which the group R ¹ has a substituent is the corresponding compound [I] containing a hydroxyl group in the group R ¹ ] Can be produced by amination according to the method of Mitsunobu (Synthesis, pages 1 to 28, 1981).

(H) method: atmospheric in the formula [I], the compound group R ¹ contains a free carboxyl group (I), the corresponding compound group R ¹ is contained esterified carboxyl group [I] Deesterification (for example, hydrolysis with a base such as sodium hydroxide, acid treatment with trifluoroacetic acid, hydrogen chloride, hydrogen bromide, etc., depending on the type of ester residue, palladium (black) under hydrogen atmosphere , Reduction using palladium carbon or the like). Among the deesterification reactions, for example, a hydrolysis reaction with a base can be performed at 5 ° C to 70 ° C, an acid treatment can be performed at 5 ° C to 80 ° C, and a reduction can be performed at 10 ° C to 40 ° C.

(Method i): In the general formula [I], the compound [I] in which the group R ¹ contains an amide bond is the corresponding compound [I] in which the group R ¹ contains a free carboxyl group and the corresponding amine compound Or the corresponding compound [I] in which the group R ¹ contains a free amino group and the corresponding carboxylic acid compound in the presence or absence of a condensing agent. As the condensing agent, 1,1′-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, which is usually used for amide bond forming reaction from carboxylic acid and amine A salt, isobutyl chloroformate, N-methylmorpholine, or the like can be used. This reaction can be carried out, for example, at -20 ° C to 50 ° C.

(Method j): In the general formula [I], a group containing a heterocyclic group in which the nitrogen atom of the substituent in the group R ¹ is substituted with an oxo group (the nitrogen atom is oxidized) (for example, N-oxo The compound [I] which is a morpholino group or the like is obtained by converting the corresponding compound [I] in which the group R ¹ contains a heterocyclic group into an oxidizing agent (for example, 3-chloroperbenzoic acid, hydrogen peroxide, Peracetic acid, oxone, etc.). This reaction suitably proceeds at, for example, 5 ° C to 50 ° C.

(Method k): In the general formula [I], in addition to the above (Method j), the group R ¹ contains a heterocyclic group in which a nitrogen atom is oxidized (for example, an N-alkyl-4-morpholinio group, etc. Compound [I] can be produced by reacting the corresponding compound [I] in which the group R ¹ contains a heterocyclic group with an alkyl halide. This reaction suitably proceeds at, for example, 20 ° C to 80 ° C.

(Method l): In the general formula [I], the compound [I] in which the group R ³ is an alkyl group is prepared by alkylating the corresponding compound [I] in which the group R ³ is a hydrogen atom by a conventional method. can do. The alkyl group may have a substituent. This reaction suitably proceeds at, for example, 20 ° C to 80 ° C.

(Method m): In the general formula [I], the compound [I], which is a group containing a group in which the sulfur atom of the substituent in the group R ¹ is substituted with one oxo group (for example, a sulfinyl group), Prepared by treating the corresponding compound [I] wherein the group R ¹ is a group containing a thio group with an oxidizing agent (eg, 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxone, etc.). be able to. This reaction suitably proceeds at, for example, -80 ° C to 150 ° C, particularly 0 ° C to 40 ° C.

(Method n): In the general formula [I], the compound [I] which is a group containing a group in which two sulfur atoms of the substituent in the group R ¹ are substituted with oxo groups (for example, a sulfonyl group, etc.) Prepared by treating the corresponding compound [I] wherein the group R ¹ is a group containing a thio group with an oxidizing agent (eg, 3-chloroperbenzoic acid, peracetic acid, sodium periodate, oxone, etc.). be able to. This reaction suitably proceeds at, for example, -80 ° C to 150 ° C, particularly 0 ° C to 40 ° C.

(Method o): In the general formula [I], the compound [I] in which the group R ¹ contains an amino group is the corresponding compound [I] in which the group R ¹ contains a carbonyl group. It can be produced by subjecting to a reductive amination reaction. This reaction can be carried out by treating in the same manner as in the above [Method C].

(Method p): In the general formula [I], the compound [I] in which the group R ¹ contains a sulfinic acid is the corresponding compound [I] in which the group R ¹ contains an alkylsulfinyl group, for example, the literature ( It can be manufactured in accordance with Sinlett, April, 375-377, 1997).

(Method q) In the general formula [I], the compound [I] in which the group R ¹ contains an imidazolidinyl group or a hexahydropyrimidinyl group cyclizes the corresponding compound in which the group R ¹ contains an aminoalkylamino group Can be manufactured. This reaction can be carried out in the presence of a condensing agent such as 1,1′-carbonyldiimidazole. This reaction can be carried out, for example, at -20 ° C to 50 ° C.

  The solvent used in the reactions described in the above (Method a) to (Method q) is not particularly limited as long as it does not inhibit the reaction. For example, dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphospho Laamide, benzene, tetrahydrofuran, toluene, ethyl acetate, alcohol, dichloromethane, carbon tetrachloride, 1,3-dimethyl-2-imidazolidine, acetic acid, diethyl ether, methoxyethane, dimethyl sulfoxide, acetonitrile, water or a mixed solvent thereof Can be appropriately selected and used.

  In addition, the raw material compound [IV] of the compound which is an active ingredient of the present invention can be produced, for example, as shown in the following chemical reaction formula.

Wherein R ⁵¹ represents an alkyl group, R ⁶¹ represents an amino-protecting group, R ⁵² represents an alkyl group which may be bonded at the terminal, X ³ represents a leaving group, and X ⁴ Represents a leaving group, and ring A, ring B, R ³ and R ⁴ have the same meaning as described above.)
That is, the pyridine compound [IX] and the Grignard compound [X] are condensed to further protect the amino group to obtain the compound [XI], and then subjected to a reduction reaction to obtain the compound [XII]. Further, the carbonyl group of compound [XII] is protected with a ketal to produce compound [XIII], and then the amino-protecting group is eliminated to obtain compound [XIV]. Subsequently, the compound [XIV] and the compound [XV] are subjected to a condensation reaction to obtain the compound [XVI] and reacted with the compound [XVII], or the compound [XIV] and the compound [III] are subjected to a condensation reaction. And the protecting group of the resulting compound [XVIII] is removed to obtain compound [IV].

  Compound [IV] has an asymmetric carbon, and optical isomers based on the asymmetric carbon exist. By using the optical isomer of compound [XIV], the desired optical isomer compound [ IV] can be obtained.

  The optical isomer of compound [XIV] can be obtained by optical resolution of a racemic mixture of compound [XIV] by a conventional method. The optical resolution is carried out, for example, by reacting the compound [XIV] with an N-acyl-optically active amino acid or N-sulfonyl-optically active amino acid and using the difference in solubility between the two diastereomeric salts produced. It can be carried out by separating and collecting the stereomeric salt.

  Examples of the acyl group of the N-acyl-optically active amino acid include an acetyl group, a propionyl group, a tosyl group, and a benzyloxycarbonyl group. Examples of the optically active amino acid include L-phenylalanine, L-leucine, L- Examples include glutamine, L-methionine, L-valine, L-threonine, D-phenylalanine or D-phenylglycine.

  Of the raw material compound [II] of the compound which is the active ingredient of the present invention, compound [II-a] can be produced, for example, as shown in the following chemical reaction formula.

(In the formula, ring A, R ¹¹ , R ¹² , R ⁶¹ and X ¹ have the same meaning as described above.)
That is, compound [II-a] is obtained by subjecting compound [XII] and compound [V] to a reductive amination reaction and removing the amino-protecting group of compound [XIX] obtained. The reductive amination can be carried out in the same manner as in [Method C].

  In the production of the above compound [IV], not only the intermediate compounds shown in the chemical reaction formula, but also salts thereof or reactive derivatives thereof can be appropriately used as long as they are not involved in the reaction.

  Of the raw material compound [II] of the compound which is an active ingredient of the present invention, compound [II-b] can be produced, for example, as shown in the following chemical reaction formula.

(In the formula, R ⁵³ represents an alkyl group, X ⁵ represents a halogen atom, and ring A has the same meaning as described above.)
That is, the compound [II-b] is obtained by condensing the pyridine compound [XX] and the compound [XXI] and reducing the resulting compound [XXII].

  Moreover, among the raw material compounds of the compound which is an active ingredient of the present invention, the general formula [II-c]:

(In the formula, the symbols have the same meaning as described above.)
The compound shown by can be manufactured as follows.

(In the formula, the symbols have the same meaning as described above.)
That is, compound [II-c] can be produced by reducing compound [XII] to obtain compound [XXIII] and deprotecting the amino group of the obtained compound [XXIII].

  Although compound [II-c] has an optical isomer, it can be produced by optical resolution from a racemic mixture in the same manner as the optical resolution of compound [XIV].

  Furthermore, in the production of the compounds which are the active ingredients of the present invention and the raw material compounds, when the raw material compounds or each intermediate compound has a functional group, in addition to the above, in addition to the above, each functional group is converted to each functional group by a conventional method of synthetic chemistry. Appropriate protecting groups are introduced, and if necessary, these protecting groups may be removed as appropriate.

  In this specification, the alkyl group is, for example, a straight chain or branched chain having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and an isopentyl group. An alkyl group, preferably having 1 to 4 carbon atoms. The alkenyl group means a straight or branched alkenyl group having 2 to 7 carbon atoms such as a vinyl group, aryl group, propenyl group, isopropenyl group, etc., preferably one having 1 to 4 carbon atoms. To do. The alkoxy group means, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a butoxy group, and preferably 1 to 4 carbon atoms. An alkanoyl group means, for example, a linear or branched alkanoyl group having 1 to 6 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, tert-butylcarbonyl group, etc. And preferably means having 1 to 4 carbon atoms. The cycloalkyl group means, for example, a cycloalkyl group having 3 to 8 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and preferably 3 carbon atoms. Means ~ 6. Furthermore, examples of the halogen atom include chlorine, bromine, fluorine, and iodine.

Experimental example

Experimental Example 1 Neurokinin-1 (NK1) receptor binding inhibitory activity According to the method described in European Journal of Pharmacology Vol. 254, pp. 221-227 (1994), IM-9 cells (4 × 10 ⁶ cell / tube) is 0.3 nM [ ³ H] (Sar ⁹ , Met ¹¹ (O ₂ )) Substance P (Kd value: 0.17 nM) and 10 nM of the sample compound and 150 mM NaCl, 3 mM In 0.5 ml of 50 mM Tris-HCl (pH 7.4, 25 ° C.) containing MnCl ₂ , 40 μg / ml bacitracin, 4 μg / ml leupeptin, 4 μg / ml chymostatin, 4 μg / ml phosphoramidon, 0.02% bovine serum albumin 60 minutes at room temperature It was. Suction filtered through a GF / C glass filter pretreated with 0.3% polyethyleneimine, washed twice with 3 ml of ice-cold reaction buffer containing no bovine serum albumin and various protease inhibitors, and filtered with a liquid scintillation counter The upper radioactivity (dpm) was measured. The specific binding amount is obtained by subtracting the non-specific binding amount (L-703606 (2 μM) having NK1 receptor antagonistic action) from the total binding amount, and the inhibition rate for the specific binding of the labeled ligand of 10 nM of the sample compound is calculated. did.

  The results were as shown in Table A1 and Table A2 below.

Experiment 2 Effect on Neurokinin-1 Receptor Agonist Induced Behavior According to the method described in European Journal of Pharmacology 265, 179-183 (1994), male gerbil LSC Co., Ltd .: 40-80 g) was orally administered 1 mg / kg of the test drug. One hour after oral administration, under halothane anesthesia, GR73632 (5 pmol / 5 μl / head), an NK1 receptor agonist dissolved in distilled water at a depth of 1 mm and 4.5 mm in the side of the head bull bear, was injected into the ventricle. Administered. After intraventricular administration, the gerbil was moved to the observation gauge, and the time during which foot tapping was caused for 5 minutes after restoration of the right-angle reflex was measured. The inhibition rate (%) of foot tapping of the test drug was calculated by the following formula.
Suppression rate of foot tapping (%) = {1− (tapping time in administration of test drug) / (tapping time in administration of solvent)} × 100
The results were as shown in Table B below.

  As is apparent from Table B, it can be seen that the compound which is the active ingredient of the present invention has a high ability to migrate to the center.

Experimental Example 3 Action on Frequent Urination According to the method described in Journal of Urology, 155, No. 1, pp. 355-360 (1996), subcutaneous administration of urethane (1.2 g) to female guinea pigs / Kg), anesthesia was induced and the dorsal position was fixed, and then the lower abdomen was incised through the midline to expose the bladder and urethra. A cannula was inserted into both ureters to ensure a urinary tract. A cannula was inserted into the bladder through an 18G needle from the top of the bladder toward the lumen and fixed. The cannula was connected to a three-way stopcock, physiological saline was continuously infused from one end (room temperature, 12 ml / hr), and the intravesical pressure was measured from the other end. A urine collection tube was placed at the mouth of the external urethra, and urine output was measured by receiving urine in a container connected to an isotonic transducer. Further, a cannula for intraduodenal administration was inserted into the duodenum via a 22G injection needle and fixed, and then the lower abdomen was sutured. The neck was further dissected and a cannula was inserted into the trachea and right carotid artery. A continuous infusion of physiological saline was performed every 30 minutes, and parameters of micturition kinetics were measured. After the urination dynamics became stable, the saline was replaced with a physiological saline solution containing 0.1% acetic acid, and the urination dynamics were similarly observed. After obtaining the pre-drug value, the drug (3 mg / kg) was administered into the duodenum, and the increase in bladder capacity due to the drug was evaluated as a percentage of the pre-dose value.

  The results were as shown in Table C below.

  As is apparent from Table C, it can be seen that the compound which is the active ingredient of the present invention has a strong bladder capacity increasing action.

Experimental Example 4 Phospholipidosis According to the method described in Biochemical Pharmacology, 62, 1661-1673 (2001), CHL / IU cells were seeded on an 8-chamber slide, and 10% fetal bovine serum For 24 hours in Eagle's minimal medium. The test substance dissolved in dimethyl sulfoxide has a final concentration of 5 to 80 μM, and the final concentration of dimethyl sulfoxide is 1% or less. N- (7-nitrobenz-2-oxa-1,3- It was added to the same culture broth containing cyanazol-4-yl) -1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt. After 24 hours of culture, the cells were observed with a fluorescence microscope, and the ability to induce phospholipidosis was evaluated based on the size and number of intracellular fluorescent inclusions. 2. A cell exposed to 1.5625 to 25 μM of amiodarone is used as a positive control, and a cell to which no test substance is added is used as a negative control (−). When inclusion bodies equal to or higher than those exposed to 125 μM amiodarone were confirmed, the test substance was judged positive.

  The results were as shown in Table D below, with negative (-) and positive (+).

  Known substances 1 to 6 in Table D above are the following compounds.

  Known substance 1: 4- (S)-(4-acetyl-piperazin-1-yl) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate (compound described in WO02 / 32867).

  Known substance 2: 4- (S)-(4-acetyl-piperazin-1-yl) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-(3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (compound described in WO02 / 32867).

  Known substance 3: 4- (S) -dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl ) -Methylamide hydrochloride (compound described in WO 03/065589).

  Known substance 4: 4- (S) -dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-(3,5- Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (compound described in WO 03/065589).

  Known material 5: 4- (S)-(2-fluoroethyl) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-( 3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (compound described in WO 03/065589).

  Known substance 6: 4- (S)-(2-fluoroethyl) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5-bis-tri Fluoromethyl-benzyl) -methylamide hydrochloride (compound described in WO03 / 0665889).

  As is apparent from Table D, the compound which is an active ingredient of the present invention does not have the ability to induce phospholipidosis, so that it is less likely to lead to toxicity and is highly safe.

Production example

Production Example 1
(1) 1.43 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine in 30 ml of ethanol After dissolution, 114 mg of sodium borohydride was added and stirred at room temperature for 3 hours. Aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution and stirred, followed by liquid separation. The organic layer was washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (chloroform: acetone = 4: 1) to give 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2 described in Table 1 below. 0.99 g of-(4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

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

Production Example 2
(2R) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4 -200 mg of oxopiperidine was dissolved in 10 ml of tetrahydrofuran, and 60 mg of sodium borohydride was added and refluxed. While continuing to reflux, a mixed solvent of 1 ml of methanol and 5 ml of tetrahydrofuran was added dropwise. After 5 hours, the reaction solution was poured into water and separated, and the aqueous layer was extracted with ethyl acetate. The entire organic layer was washed with water and saturated brine, dried and evaporated, and the residue was subjected to silica gel chromatography (hexane). : Ethyl acetate = 1: 1 → 1: 2), and the following (a) (2R, 4R) -1- [N- {1- (S)-(3,5- Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine 33 mg and (b) (2R, 4S) -1- [N- {1 160 mg of-(S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

Production Example 3
(2R) -1- [N- (3,5-Bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine (A) (2R, 4R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- () described in Table 2 below. 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 was obtained.

Production Example 4
150 mg of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine is dissolved in 5 ml of dimethylformamide, hydrogen 40 mg of sodium halide (60%) was added at 0 ° C. To this solution, 0.2 ml of methyl iodide was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to this solution and stirred, followed by liquid separation. The organic layer was washed with water and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and (a) cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 3 below. 72 mg of methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxypiperidine and (b) trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} 36 mg of aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxypiperidine was obtained.

Production Example 5
4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (1.06 g) in dichloromethane (20 ml) was added with triethylamine 0 .42 ml and dibutyloxycarbonate 660 mg were added and stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and (a) trans-1- {N- (3,5- 130 mg of bis (trifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine and (b) cis-1- {N- (3,5 -Bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine (120 mg) was obtained.

Production Example 6
60 mg of 4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine is dissolved in 1.2 ml of dichloromethane, Under ice cooling, 0.02 ml of triethylamine and 0.013 ml of propionyl chloride were added and stirred for 20 minutes under ice cooling. The reaction solution was poured into saturated brine and separated, and the aqueous layer was extracted with dichloromethane. All organic layers were washed with saturated brine, dried and evaporated, and the residue was purified by thin layer silica gel chromatography (chloroform: methanol = 9: 1) to obtain (a) trans described in Table 5 below. -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine 40 mg and (b) cis-1 -{N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propionylaminopiperidine (27 mg) was obtained.

Production Example 7-22
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to give the compounds shown in Table 6-14 below.

Production Example 23
4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (98 mg) in dichloromethane (4 ml) and triethylamine (0.056 ml) 0.028 ml of acetyl chloride was sequentially added at 0 ° C., and the mixture was stirred at 0 ° C. for 0.5 hour. After the reaction, an aqueous sodium hydrogen carbonate solution and chloroform were added, and the mixture was stirred and 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), dried under vacuum, and powdered 4-acetylamino-1- {N- (3,5-bistrifluoromethyl) described in Table 15 below. 86 mg of benzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 24
Cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (4-nitrobenzoyl) aminopiperidine 320 mg 480 mg of tin dichloride was added to 25 ml of an ethanol solution, and the mixture was stirred for 4 hours while heating under reflux. After the reaction, ethanol was distilled off under reduced pressure, and diethyl ether and 2M aqueous sodium hydroxide solution were added for liquid separation. The organic layer was washed again with 2M aqueous sodium hydroxide and further washed 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 resulting oil was treated with 4M hydrochloric acid in ethyl acetate. The reaction solution was concentrated under reduced pressure and then crystallized with isopropyl ether to give cis-4- (4-aminobenzoyl) amino-1- {N- (3,5-bistrifluoromethylbenzyl) described in Table 16 below. ) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride 152 mg was obtained.

Production Example 25
To 60 ml of tetrahydrofuran solution of 3.91 g of N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine was added 2.34 g of 1,1′-carbonyldiimidazole, and 40 ° C. And stirred overnight. After the solvent was distilled off, ethyl acetate was added, and the entire organic layer was washed with water and saturated brine and dried. White crystals obtained by distilling off the solvent were collected by filtration with diisopropyl ether. The obtained white crystals were dissolved in 60 ml of acetonitrile, added with 3.5 ml of methyl iodide and reacted at 60 ° C. for 2 hours, and then the solvent was distilled off. 224 mg of the residue was dissolved in 2 ml of dichloromethane. Under ice cooling, 100 mg of cis-2- (4-fluoro-2-methylphenyl) -4- (propanoylamino) piperidine and 0.11 ml of triethylamine were added and stirred overnight at room temperature. . The reaction solution was poured into water and separated, and the aqueous layer was extracted with dichloromethane. The entire organic layer was washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 3) to give (2R, 4S) -1- [N- {1- (R)-(3,5- Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine (83.5 mg) was obtained.

Production Example 26-34
The corresponding starting materials were used and treated in the same manner as in Production Example 25, to give compounds as shown in Tables 17-19 below.

Production Example 35
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -To 71 ml of dichloromethane solution of 253 mg of methylphenyl) piperidine and 0.139 ml of triethylamine, 0.071 ml of methanesulfonyl chloride is added under ice-cooling and stirred for 1 hour. The reaction solution is poured into water, and the liquid separation and aqueous layer are extracted with chloroform. All organic layers were washed with saturated brine, dried and evaporated, and then the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain (2R, 4S) described in Table 20 below. -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-methanesulfonylamino-2- (4-fluoro-2-methylphenyl) ) 243 mg of piperidine was obtained.

Production Example 36
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -Methylphenyl) piperidine and ethanesulfonyl chloride were treated in the same manner as in Production Example 35 to give (2R, 4S) -1- [N- {1- (R)-(3,5- Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethanesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 37
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-methanesulfonylamino-2- (4-fluoro To 1 ml of a dimethylformamide solution of 58.4 mg of 2-methylphenyl) piperidine, 4.6 mg of sodium hydride is added under ice-cooling. After stirring for 30 minutes, 0.010 ml of methane iodide is added and further stirred for 1 hour. The reaction solution was poured into water, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried and evaporated, and the residue was chromatographed on silica gel (hexane: ethyl acetate = 2: 1). (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl- described in Table 20 below. 46.7 mg of 4- (N-methanesulfonyl-N-methyl) amino-2- (4-fluoro-2-methylphenyl) piperidine are obtained.

Production Example 38
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) (2R, 4S) -1- [N- {1- (R)-(3,5) described in Table 20 below by treatment in the same manner as in Production Example 37 using -4-ethanesulfonylaminopiperidine. -Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (N-methyl-N-ethanesulfonyl) aminopiperidine.

Production Example 39
985 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and tetrabutyl To 20 ml of toluene solution of 129 mg of ammonium bromide and 10 ml of 10 M aqueous sodium hydroxide solution, 1.21 ml of 2- (2-bromoethoxy) tetrahydropyran is added at room temperature, and the temperature is raised to 60 ° C.-70 ° C. and stirred overnight. Further, 2.42 ml of 2- (2-bromoethoxy) tetrahydropyran is added and stirred overnight. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried and evaporated, and the residue is purified by silica gel chromatography (hexane: ethyl acetate = 3: 2). (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) described in Table 21 below 1.12 g of -4- {2- (tetrahydropyran-2-yloxy) ethoxy} piperidine was obtained.

Production Example 40
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (tetrahydropyran To 30 ml of methanol solution of 1.04 g of 2-yloxy) ethoxy} piperidine, 64 mg of p-toluenesulfonic acid monohydrate is added at room temperature and stirred for 20 minutes. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (chloroform: ethyl acetate = 1: 1) to give (2R, 4S) -1- {N- (3 , 5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) piperidine (703 mg) was obtained.

Production Example 41
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) To 2 ml of tetrahydrofuran solution of 53.6 mg of piperidine, 13.8 mg of 4H- [1,2,4] -triazole and 24.4 mg of triphenylphosphine, 0.092 ml of 40% toluene solution of diethyl azodicarboxylate was added under ice cooling. The mixture is heated to room temperature and stirred overnight, and further heated to 50 ° C., 24.4 mg of triphenylphosphine is added, and the mixture is stirred for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was chromatographed on silica gel (chloroform: ethyl acetate = 1: 1 and chloroform: methanol = 19). 1), the (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro) described in Table 21 below is obtained. -2-methylphenyl) -4- {2- (1,2,4) triazolylethoxy} piperidine (43.2 mg) was obtained.

Production Examples 42-43
The corresponding starting material compounds were treated in the same manner as in Production Example 41 to obtain the compounds shown in Table 21 below.

Production Example 44
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxy) To 2 ml of dichloromethane solution of 215 mg of piperidine and 0.084 ml of triethylamine, 0.037 ml of methanesulfonyl chloride is added under ice cooling and stirred for 30 minutes. The reaction solution was poured into water, extracted with chloroform, the organic layer was washed with saturated brine, dried and evaporated, and the residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1). (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- listed in Table 21 below 189 mg of (2-methanesulfonyloxyethoxy) piperidine was obtained.

Production Example 45
200 ml of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was added to 2 ml of dichloromethane. Next, 0.1 ml of ethyl isocyanate and 0.1 ml of triethylamine were added, and the mixture was heated and stirred at 60 ° C. for 3 days. After the reaction solution was cooled to room temperature, water and chloroform were added to separate the layers. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and (2R, 4S) -1- {N- (3,5) described in Table 21 below. 78 mg of -bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 46
200 ml of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was added to 2 ml of dichloromethane. Then, 0.1 ml of morpholine-4-carboxylic acid chloride and 0.1 ml of triethylamine were added, and the mixture was heated and stirred at 60 ° C. for 3 days. After the reaction solution was cooled to room temperature, water and chloroform were added to separate the layers. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and (2R, 4S) -1- {N- (3,5) described in Table 21 below. 68 mg of -bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonyloxypiperidine was obtained.

Production Example 47
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine (248 mg) was added to 5 ml of tetrahydrofuran. Then, 81 mg of 1,1′-carbonyldiimidazole was added, and the mixture was stirred with heating at 60 ° C. for 16 hours. After the reaction solution was cooled to room temperature, water and chloroform were added to separate the layers. The aqueous layer was extracted again with chloroform, and the combined organic layers were washed again with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting concentrated residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 1: 1) and (2R, 4S) -1- {N- (3,5-bistrifluoromethyl) described in Table 21 below. Benzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolyl) carbonyloxypiperidine (135 mg) was obtained.

Production Example 48
(1) Cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine 5 g, triphenylphosphine 10.5 g and 4.88 g of benzoic acid were dissolved in 100 ml of tetrahydrofuran, and then 18.3 ml of a 40% toluene solution of diethyl azodicarboxylate was added under ice cooling, followed by stirring at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and stirred for 30 minutes. The solution was separated, and the resulting 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), and trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-benzoyloxy- 4.36 g of 2- (4-fluoro-2-methylphenyl) piperidine was obtained.

  (2) 1.4 g of the compound obtained in (1) above was dissolved in 10 ml of methanol, then 325 mg of potassium carbonate was added and stirred at room temperature for 16 hours. After distilling off the solvent by concentration under reduced pressure, water and ethyl acetate were added for liquid separation. 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), and trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl described in Table 22 below. 0.68 g of -2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

Production Example 49
Trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine 98 mg and 4,6-dihydroxy- 144 mg of 3-mercaptopyrimidine and 262 mg of triphenylphosphine were dissolved in 10 mg of tetrahydrofuran, 0.48 ml of a 40% toluene solution of diethyl azocarboxylate was added, and the mixture was stirred at 0 ° C. for 2 hours, and then stirred overnight at room temperature. A sodium bicarbonate aqueous solution and chloroform were added to the reaction solution and the phases were separated, and then the organic layer was dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1 → chloroform: methanol: acetic acid = 85: 15: 3) to obtain cis-1- {N- (3,5-bistri) described in Table 22 below. 28 mg of fluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (4,6-dihydroxypyrimidin-2-ylthio) -2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 50
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) By using -4-hydroxypiperidine in the same manner as in Production Example 48 (1) and (2), (2R, 4R) -1- [N- {1- (R) described in Table 23 below is given. -(3,5-Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

Production Example 51
(1) 30 ml of a tetrahydrofuran solution of 1.2 ml of triethylphosphonoacetate is ice-cooled, and sodium hydride is added little by little. After stirring for 30 minutes at the same temperature, (2R) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- ( 30 ml of a tetrahydrofuran solution of 3.02 g of 4-fluoro-2-methylphenyl) -4-oxopiperidine is added dropwise and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The entire organic layer was washed with water and saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1). Purified colorless liquid (2R) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethylidene-2- (4-Fluoro-2-methylphenyl) piperidine was obtained.

  (2) The compound obtained in (1) above was dissolved in 50 ml of methanol, 500 mg of palladium-carbon was added, and the mixture was stirred overnight at room temperature under hydrogen pressure. The catalyst was removed, methanol was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give (2R) -1- [N- {1] described in Table 23 below. -(R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethyl-2- (4-fluoro-2-methylphenyl) piperidine (3.23 g) was obtained. .

Production Example 52
(1) (2R) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethyl-2- (4- (Fluoro-2-methylphenyl) piperidine (3.23 g) was dissolved in methanol (20 ml), 2M aqueous sodium hydroxide solution (5.73 ml) was added, and the mixture was stirred at room temperature overnight. After neutralization with 2M hydrochloric acid, methanol was distilled off and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and the solvent was evaporated to give (2R) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) as a yellow powder. Ethyl} -N-methyl] aminocarbonyl-4-carboxymethyl-2- (4-fluoro-2-methylphenyl) piperidine 2.97 g was obtained.

  (2) 200 mg of the compound obtained in (1) above is dissolved in 2 ml of dimethylformamide, 84 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 65 mg of 1-hydroxy-1H-benzotriazole, morpholine 0.037 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous citric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried, the solvent was distilled off, and the resulting residue was purified by NH silica gel chromatography (hexane: ethyl acetate = 2: 1) and (2R) -1- [N- {1] described in Table 23 below. 138 mg of-(R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylmethylpiperidine are obtained.

Production Example 53-55
The corresponding starting materials were used and treated in the same manner as in Production Example 52 (2) to give the compounds shown in Table 23 below.

Production Example 56-64
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to give the compounds described in Tables 24-26 below.

Production Example 65
(2R) -4-amino-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (263 mg) was dissolved in dichloromethane (2 ml). Then, at room temperature, 52 μl of 2-chloroethyl isocyanate and 167 μl of triethylamine were added and stirred for 2 hours. Saturated sodium hydrogen carbonate was added to the solution, the dichloromethane layer was separated, and the aqueous layer was extracted again with chloroform. All organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) to give (2R) -4- (2-chloroethyl) ureido-1- [N- (3,5-bistri] described in Table 26 below. 109 mg of (fluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 66
2.65 g of (2R) -4-amino-1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride 1 g of 5-formylfuran-2-carboxylic acid is dissolved in 20 ml of dimethylformamide, 1.92 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.6 g of 1-hydroxy-1H-benzotriazole and 1.4 ml of triethylamine was added and stirred at room temperature for 3 hours. After the reaction, an aqueous citric acid solution and ethyl acetate were added for liquid separation. The organic layer was washed again 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 (a) (2R, 4S) -1- [N- (3,5-bistrifluoro] described in Table 27 below. Methylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine 289 mg and (b) (2R, 4R) -1 -[N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine 185 mg Got.

Production Examples 67-93
The corresponding starting materials were used and treated in the same manner as in Production Example 66, to give compounds as shown in Tables 28-32 below.

Production Example 94
(2R, 4S) -4-amino-1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -80 mg of methylphenyl) piperidine was dissolved in 1 ml of tetrahydrofuran, and 25.7 mg of 1,1'-carbonyldiimidazole was added under ice cooling, followed by stirring for 30 minutes under ice cooling. Under ice cooling, 19 μl of 2-aminoethanol and 44 μl of triethylamine were added to the solution, followed by stirring at room temperature for 22 hours. After the solvent was distilled off, water and dichloromethane were added to the residue for liquid separation. The organic layer was washed with saturated brine, dried and concentrated. Isopropyl ether was added to the residue, and the precipitated white crystals were collected by filtration to give (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethyl) described in Table 32 below. Phenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) ureidopiperidine (74 mg) was obtained.

Production Examples 95-98
The corresponding starting materials were used and treated in the same manner as in Production Example 94, to give compounds as shown in Table 32 below.

Production Example 99-102
The corresponding starting materials were used and treated in the same manner as in Production Example 35 to give the compounds shown in Table 33 below.

Production Example 103
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -Methylphenyl) piperidine (1.01 g) and triethylamine (0.558 ml) are dissolved in dichloromethane (10 ml). Under ice cooling, 2-chloroethanesulfonyl chloride (0.314 ml) is added, and the mixture is stirred for 4 hours. The solution is poured into water and separated, and the aqueous layer is extracted again with dichloromethane. The entire organic layer is washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (2R, 4S) -1- [N- {1- (R)-(3,5) described in Table 33 below. -Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethylenesulfonylamino-2- (4-fluoro-2-methylphenyl) piperidine (725 mg) was obtained.

Production Example 104
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) By treating with -4-methylaminopiperidine in the same manner as in Production Example 103, (2R, 4S) -1- [N- {1- (R)-(3,5- Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (N-ethylenesulfonyl-N-methylamino) -2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Examples 105-106
The corresponding starting materials were used and treated in the same manner as in Production Example 35, to give compounds as shown in Table 34 below.

Production Examples 107-108
The corresponding starting materials were used and treated in the same manner as in Production Example 37 to give the compounds shown in Table 34 below.

Production Example 109
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) (2R, 4S) -1- [N- {1- (S)-] described in Table 34 below by treating in the same manner as in Production Example 39 using 4-hydroxypiperidine and 2-methoxyethyl chloride. (3,5-Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methoxyethoxy) piperidine was obtained.

Production Example 110-113
The corresponding starting materials were used and treated in the same manner as in Production Example 39 and Production Example 40, to give compounds as shown in Tables 34-35 below.

Production Example 114
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) By using -4- (2-hydroxyethoxy) piperidine and methanesulfonyl chloride in the same manner as in Production Example 44, (2R, 4S) -1- [N- {1- ( R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methanesulfonyloxyethoxy) piperidine was obtained. .

Production Examples 115-116
The corresponding starting materials were used and treated in the same manner as in Production Example 47, to give compounds as shown in Table 36 below.

Production Example 117
197 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was added to toluene. It melt | dissolved in the mixed liquid of 3.3 ml and dichloromethane 0.4 ml, 1, 1'- carbonyldiimidazole 78mg was added, and it stirred at 60 degreeC for 4 hours. Distilled water was added, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 3.7 ml of acetonitrile, 100 μl of methyl iodide was added, and the mixture was stirred at 50 ° C. for 3 hours. After concentrating the solution under reduced pressure, 3.6 ml of toluene and 156 μl of thiomorpholine were added to the residue, and the mixture was stirred at 70 ° C. for 16 hours. Distilled water was added, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 → 1: 2) to give (2R, 4S) -1- [N- (3,5-bistrifluoromethyl) described in Table 37 below. Benzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine (197 mg) was obtained.

Production Examples 118-122
The corresponding starting materials were used and treated in the same manner as in Production Example 117, to give compounds as shown in Tables 37-38 below.

Production Example 123
(2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-4- (5-formylfuran-2-yl) carbamoyl-2- (4-fluoro- 124 mg of 2-methylphenyl) piperidine was dissolved in 4 ml of ethanol, 3.8 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the solution, stirred for 10 minutes, and then concentrated to distill off ethanol. Ethyl acetate and water were added to the residue for liquid separation, and the organic layer was dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 39 below. 68 mg of methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (5-hydroxymethylfuran-2-yl) carbamoylpiperidine was obtained.

Production Examples 124-126
The corresponding starting materials were used and treated in the same manner as in Production Example 117, to give compounds as shown in Table 39 below.

Production Example 127
(2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine 62 mg Was dissolved in 1.9 ml of dichloromethane, and 22 mg of 3-chloroperbenzoic acid was added under ice cooling, followed by stirring at 0 ° C. for 30 minutes. A 0.1 M aqueous sodium hydroxide solution and ethyl acetate were added to the solution for extraction. 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 (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl)-described in Table 39 below. N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxothiomorpholino) carbonyloxypiperidine (63 mg) was obtained.

Production Example 128
79 mg of (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-thiomorpholinocarbonyloxypiperidine Was dissolved in 2.4 ml of dichloromethane, 68 mg of 3-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 4 hours. A 0.1 M aqueous sodium hydroxide solution and ethyl acetate were added to the solution for extraction. 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 (2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl)-described in Table 39 below. 76 mg of N-methyl] aminocarbonyl-4- (1,1-dioxothiomorpholino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 129
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) 78 mg of -4- (2,2,5-trimethyl- [1,3] dioxolan-5-yl) carbamoylpiperidine was dissolved in 1 ml of tetrahydrofuran, 0.5 ml of 2M hydrochloric acid aqueous solution was added under ice cooling, and 15 minutes later. The mixture was warmed up to 30 minutes and stirred for another 30 minutes. The solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 2: 1) to give (2R, 4S) -1- [N- {1- (R)-(3,5- Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {1,1-di (hydroxymethyl) ethyl} carbamoylpiperidine (64 mg) was obtained.

Production Example 130
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -50.5 mg of methylphenyl) piperidine was dissolved in 1 ml of dichloromethane, 25.3 mg of methyl isocyanate was added under ice cooling, and the mixture was warmed to room temperature and stirred for 30 minutes. The solution was poured into water, the dichloromethane layer was separated, and the aqueous layer was extracted again with chloroform. All organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- [N- {1- (R)-(3,5-bistritium] described in Table 40 below. Fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-methylureido) piperidine (47.9 mg) was obtained.

Production Example 131
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -(2R, 4S) -1- [N- {1- (R)-described in Table 40 below by treating in the same manner as in Production Example 130 using methylphenyl) piperidine and tert-butyl isocyanate. (3,5-Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-tert-butylureido-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 132
(2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -Methylphenyl) piperidine (50.5 mg) was dissolved in dichloromethane (1 ml). Under ice cooling, triethylamine (42 μl) and dimethylcarbamoyl chloride (18 μl) were added, and the mixture was warmed to room temperature and stirred overnight. The solution was poured into water, the dichloromethane layer was separated, and the aqueous layer was extracted again with chloroform. All organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 39: 1) to give (2R, 4S) -1- [N- {1- (R)-(3,5-bistritium] described in Table 40 below. Fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (3,3-dimethylureido) -2- (4-fluoro-2-methylphenyl) piperidine (41.8 mg) was obtained.

Production Example 133-138
The corresponding starting materials were used and treated in the same manner as in Production Example 130 or Production Example 132 to obtain the compounds listed in Table 41 below.

Production Example 139
(2R, 4S) -4-amino-1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -100 mg of methylphenyl) piperidine was dissolved in 2 ml of dichloromethane, 33 μl of triethylamine and 19 μl of methyl chloroformate were added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. The solution was poured into water, the dichloromethane layer was separated, and the aqueous layer was extracted again with dichloromethane. All organic layers were washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- [N- {1- (S)-(3,5-bistritium] described in Table 41 below. 80 mg of fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methoxycarbamoylpiperidine was obtained.

Production Example 140-142
The corresponding starting materials were used and treated in the same manner as in Production Example 139, to give compounds as shown in Table 42 below.

Production Example 143
22 mg of 2-ethoxy-ethanol was dissolved in 1.2 ml of acetonitrile, 94 mg of N, N′-disuccinimidyl carbonate and 0.1 ml of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off, the residue was extracted with a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in 0.8 ml of dichloromethane and (2R, 4S) -4-amino-1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] amino was dissolved. Carbonyl-2- (4-fluoro-2-methylphenyl) piperidine (80 mg) and triethylamine (33 μl) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the solution for extraction. All 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 (2R, 4S) -1- [N- {1- (S)-(3,5) described in Table 42 below. -Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (2-ethoxyethoxy) carbamoyl-2- (4-fluoro-2-methylphenyl) piperidine (85 mg) was obtained.

Production Example 144
3-hydroxy-3-methylbutanol and (2R, 4S) -4-amino-1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl By treating with 2- (4-fluoro-2-methylphenyl) piperidine in the same manner as in Production Example 143, (2R, 4S) -1- [N- {1- ( S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-hydroxy-3-methylbutoxy) carbamoylpiperidine Got.

Production Example 145
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) 101 mg of -4-hydroxypiperidine was dissolved in a mixed solution of 1.6 ml of dimethylformamide and 0.2 ml of dichloromethane, and 39 mg of (S)-(-)-2-pyrrolidone-5-carboxylic acid, 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg) and 4- (dimethylamino) pyridine (12 mg) were added, and the mixture was stirred at room temperature for 6 hours and then stirred at 60 ° C. for 4 days. To the solution was added 5% aqueous citric acid solution, extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (chloroform: acetone = 4: 1 → 2: 1) to give (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 64 mg was obtained.

Production Example 146
(1) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- 179 mg of methylphenyl) -4-hydroxypiperidine was dissolved in a mixed solution of 3.2 ml of toluene and 0.4 ml of dichloromethane, 69 mg of 1,1′-carbonyldiimidazole was added, and the mixture was stirred at 60 ° C. for 3 hours. Distilled water was added, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 3.2 ml of acetonitrile, 88 μl of methyl iodide was added, and the mixture was stirred at 50 ° C. for 3 hours. After concentrating the solution, 3.2 ml of toluene and 114 μl of thiazolidine were added to the residue, followed by stirring at 70 ° C. for 16 hours. Distilled water was added, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to give (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoro Methylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1,3-tetrahydrothiazol-3-yl) carbonyloxypiperidine (141 mg) was obtained.
(2) 62 mg of the compound obtained in (1) above was dissolved in 2 ml of dichloroethane, 22 mg of 3-chloroperbenzoic acid was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added for extraction, and 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 (2R, 4S) -1- [N- {1- (S)-(3,5) described in Table 43 below. -Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-oxo-1,3-tetrahydrothiazol-3-yl) carbonyloxypiperidine 42 mg was obtained.

Production Example 147
(1) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4-hydroxypiperidine (101 mg) was dissolved in toluene (1.9 ml), ethyl isocyanatoacetate (46 μl) and acetic acid (1 drop) were added, and the mixture was stirred at 70 ° C. for 16 hours. The solution was concentrated and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give (2R, 4S) -1- [N- {1- (S)-(3 , 5-Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonylmethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.
(2) 106 mg of the compound obtained in (1) above was dissolved in a mixture of 1.35 ml of tetrahydrofuran and 0.15 ml of methanol, 92 μl of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the solution, a 10% aqueous citric acid solution was added, and the precipitate was collected by filtration and washed with water to give (2R, 4S) -1- [N- {1- (S) described in Table 43 below. 92 mg of-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine are obtained.

Production Example 148
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxymethylaminocarbonyloxy-2- (4 -Fluoro-2-methylphenyl) piperidine (61 mg) was dissolved in dimethylformamide (0.9 ml), morpholine (9 μl), 1-hydroxybenzotriazole monohydrate (15 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 19 mg was added and stirred at room temperature for 1 day. Distilled water was added to the solution, extracted with chloroform, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- [N- {1- (S)-(3,5-bistritium] described in Table 43 below. Fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-morpholinocarbonylmethylaminocarbonyloxypiperidine (50 mg) was obtained.

Production Example 149
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) 101 mg of -4-hydroxypiperidine was dissolved in 1.9 ml of toluene, 37 μl of chlorosulfonyl isocyanate was added, and the mixture was stirred at room temperature for 10 minutes. To this was added 207 μl of diethylamine and stirred at room temperature for 1 hour. Distilled water was added to the solution, extracted with chloroform, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- [N- {1- (S)-(3,5-bistritium] described in Table 43 below. 116 mg of fluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-diethylaminosulfonylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 150
(2R, 4S) -1- [N- (3,5-bistrifluoromethylbenzyl) -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine and (S) -(-)-2-Pyrrolidone-5-carboxylic acid was used in the same manner as in Production Example 145 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 was obtained.

Production Example 151-152
The corresponding starting materials were used and treated in the same manner as in Reference Example 6 to give the compounds described in Tables 44-45 below.

Production Example 153
(1) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-ethoxycarbonyl-2- (4 -Fluoro-2-methylphenyl) piperidine (800 mg) was dissolved in tetrahydrofuran (5 ml), 2M aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified with aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solution was concentrated to (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- 700 mg of (4-fluoro-2-methylphenyl) piperidine was obtained.

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

Production Examples 154-156
The corresponding starting materials were used and treated in the same manner as in Production Examples 153 (1) and (2) or Production Example 153 (2) to obtain the compounds described in Table 45 below.

Production Example 157
(1) (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- 2 g of methylphenyl) -4-hydroxypiperidine was dissolved in 40 ml of tetrahydrofuran, 1.59 g of carbon tetrabromide and 1.26 g of triphenylphosphine were added, and the mixture was stirred at room temperature for 2 hours. 80 ml of diethyl ether was added to the solution and stirred, and the precipitated insoluble matter was removed by filtration. After the organic layer was concentrated, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 10: 1) to give (2R, 4R) -1- [N- {1- (S)-(3 , 5-Bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-bromo-2- (4-fluoro-2-methylphenyl) piperidine 1.26 g was obtained.

  (2) 1.14 g of the compound obtained in (1) above was dissolved in 20 ml of dimethylformamide, 1.14 g of potassium thioacetate was added, and the mixture was stirred at 80 ° C. for 2 hours. After cooling the solution to room temperature, the aqueous citric acid solution was separated by adding ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 6: 1) to give (2R, 4S) -4-acetylthio-1- [N- {1- (S) described in Table 46 below. 920 mg of-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 158-159
The corresponding starting materials were used and treated in the same manner as in Production Examples 157 (1) and (2) to obtain the compounds described in Table 46 below.

Production Example 160
(2R, 4S) -4-acetylthio-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2 -Methylphenyl) piperidine (880 mg) was dissolved in methanol (10 ml), methyl iodide and 1 M aqueous sodium hydroxide solution (5 ml) were added, and the mixture was stirred at room temperature for 2 hours. The solution was neutralized with an aqueous citric acid solution, and then methanol was distilled off. To the residue were added ethyl acetate and saturated brine, and the mixture was separated, and the organic layer was dried and concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 6: 1) to give (2R, 4S) -1- [N- {1- (R)-(3 560 mg of 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-methylthiopiperidine was obtained.

Production Examples 161-166
The corresponding starting materials were used and treated in the same manner as in Production Example 160, to give compounds as shown in Tables 46-47 below.

Production Example 167-173
The corresponding starting materials were used and treated in the same manner as in Production Example 127, to give compounds as shown in Tables 48-49 below.

Production Examples 174-181
The corresponding starting materials were used and treated in the same manner as in Production Example 128, to give compounds as shown in Tables 50-51 below.

Production Example 182-215
The corresponding starting materials were used and treated in the same manner as in Production Example 66, to give compounds as shown in Tables 51 to 57 below.

Production Example 216
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-[{(2S, 4R) -4-benzyloxy-1-tert-butoxycarbonyl Pyrrolidin-2-ylcarbonyl} amino] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (361 mg) was added to 4.2 ml of 4M hydrochloric acid-ethyl acetate solution and stirred at room temperature for 1 hour. The solution was concentrated, hexane was added to the residue and crystallized, and then the solvent was removed. To the residue were added 4 ml of methylene chloride, 0.158 ml of triethylamine and 0.36 ml of acetyl chloride, and the mixture was stirred at ice temperature for 1 hour. Ice water was added to the solution, and the solution was separated with chloroform. The organic layer was separated, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 49: 1 → 19: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethyl) described in Table 57 below. Benzyl) -N-methyl} aminocarbonyl-4-[{(2S, 4R) -4-benzyloxy-1-acetylpyrrolidin-2-ylcarbonyl} amino] aminocarbonyl-2- (4-fluoro-2-methyl) 304 mg of phenyl) piperidine was obtained.

Production Example 217-220
The corresponding starting materials were used and treated in the same manner as in Production Example 216, to give compounds as shown in Tables 57-58 below.

Production Example 221
The corresponding starting materials were used and treated in the same manner as in Production Example 66, to give compounds as shown in Table 58 below.

Production Example 222-232
The corresponding starting materials were used and treated in the same manner as in Production Example 117, to give compounds as shown in Tables 59-61 below.

Production Example 233
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} amino described in Table 62 below by treating in the same manner as in Production Example 51 using the corresponding starting material compound Carbonyl-2- (4-fluoro-2-methylphenyl) -4- (ethoxycarbonylmethyl) -piperidine was obtained.

Production Example 234
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-ethoxycarbonylmethylpiperidine2. 03 g was dissolved in 20 ml of tetrahydrofuran, 450 mg of lithium aluminum hydride was added under ice cooling, and the mixture was stirred for 1 hour. After slowly adding 2 ml of water and stirring for 10 minutes, 5 ml of 1M aqueous sodium hydroxide solution was added and further stirred for 10 minutes. The produced white precipitate was removed, and diethyl ether and water were added to the filtrate for liquid separation. The organic layer was washed again with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2) to give (2R, 4S) -1- {N- (3,5-bistrifluoro) described in Table 62 below. 830 mg of methylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) piperidine was obtained.

Production Example 235
(1) (2R, 4S) -4-Ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine (2.12 g) was treated in the same manner as in Production Example 151 to give (2R , 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (3.8 g) was obtained. .

  (2) By treating the compound obtained in (1) above in the same manner as in Production Example 153 (1), the compound (2R, 4S) -1- {N- (3,5- 2.3 g of bis (trifluoromethylbenzyl) -N-methyl} amino-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 236-239
The corresponding starting materials were used and treated in the same manner as in Production Example 153 (2), to give compounds as shown in Table 62 below.

Production Example 240
(1) Using 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting material compound, the same treatment as in Production Example 151 was followed 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 was obtained.

  (2) (2R, 4S) -1- [N- {1- described in Table 63 below by treating in the same manner as in Production Example 153 (1) using the compound obtained in (1) above. (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Examples 241-248
(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 compound were treated in the same manner as in Production Example 153 (2) to give the compounds described in Tables 63-64 below.

Production Example 249
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2 -Methylphenyl) piperidine (1.62 g) was dissolved in tetrahydrofuran (12 ml), and borane dimethyl sulfide complex (about 10 M) was added dropwise under ice-cooling, followed by stirring at room temperature for 16 hours. 10 ml of methanol was added to the reaction solution and stirred for 0.5 hour. After completion of foaming, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give (2R, 4S) -1- [N- {1 described in Table 64 below. -(S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine (1.32 g) was obtained.

Production Example 250-251
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) The compounds described in Table 64 below were obtained by treating in the same manner as in Production Example 117, using -4-hydroxymethylpiperidine and the corresponding starting material compounds.

Production Example 252
By treating in the same manner as in Production Example 240 using 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine and the corresponding starting compound, the compound (2R, 4S)- 1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2-methylphenyl) piperidine Obtained.

Production Examples 253-263
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2 The compound described in Tables 65-66 below was obtained by treating in the same manner as in Production Example 153 (2) using -methylphenyl) piperidine and the corresponding starting material compound.

Production Example 264
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-carboxy-2- (4-fluoro-2 -Methylphenyl) piperidine was treated in the same manner as in Production Example 249 to give (2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoro] described in Table 66 below. Methylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxymethylpiperidine was obtained.

Production Example 265
1.07 g of the compound obtained in Production Example 171 was dissolved in 20 ml of toluene and 20 ml of acetic anhydride, 165 mg of sodium acetate was added, and the mixture was stirred for 16 hours with heating under reflux. After cooling to room temperature, an aqueous sodium bicarbonate solution was added little by little until no bubbles appeared. Water and ethyl acetate were added for liquid separation, and the aqueous layer was extracted again with ethyl acetate. 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 (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl)-described in Table 67 below. 980 mg of N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-acetoxymethylthiopiperidine was obtained.

Production Example 266
(2R, 4S) -4-Acetoxymethylthio-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (2R, 4S) -4-acetoxymethylsulfonyl-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl described in Table 67 below by treating in the same manner as in Example 128. -2- (4-Fluoro-2-methylphenyl) piperidine was obtained.

Production Example 267
200 mg of (2R, 4S) -4-acetoxymethylsulfonyl-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine It was dissolved in 10 ml of tetrahydrofuran and 5 ml of 2M aqueous sodium hydroxide solution and stirred at room temperature for 3 hours. The reaction solution was neutralized with 2M hydrochloric acid and extracted twice with ethyl acetate. The combined organic layer was dried and concentrated under reduced pressure to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- described in Table 67 below. 80 mg of (4-fluoro-2-methylphenyl) -4-hydroxysulfinylpiperidine was obtained.

Production Example 268
130 mg of the compound obtained in Production Example 164 was dissolved in 2.5 ml of acetonitrile, 0.5 ml of methyl iodide was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was concentrated, and the residue was washed with diethyl ether to give (2R, 4S)-[1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl iodide described in Table 67 below. } 117 mg of aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidin-4-yl] dimethylsulfonium was obtained.

Production Example 269
10.7 g of (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was added to tetrahydrofuran. After dissolving in 100 ml, 20 ml of pyridine and 20 ml of acetic anhydride were added and stirred at room temperature for 5 hours. An aqueous sodium hydrogen carbonate solution and diethyl ether were added to the reaction solution, and the mixture was stirred for 1 hour and then separated. The organic layer was washed twice with water, dried and concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, 1.5 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 0.5 hours. After adding an aqueous ammonium chloride solution to the reaction solution and stirring for 30 minutes, the solvent was distilled off. Water was added to the residue and extracted twice with chloroform. 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 (2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3, described in Table 68 below. 9.6 g of 5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

Production Example 270-273
(2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxy The compounds shown in the following Table 68 were obtained by treating in the same manner as in Production Example 117, using the starting compound corresponding to piperidine.

Production Example 274
(2R, 4S) -1- {N- (3-acetoxypropyl) -N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2- Methylphenyl) piperidine (600 mg) was dissolved in methanol (5 ml), 2M aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was neutralized with 2M aqueous hydrochloric acid and extracted twice with chloroform. The combined organic layers were dried, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain (2R, 4S) -1- {N- (3,5) described in Table 69 below. 550 mg of -bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-4-ethylaminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 275-278
The corresponding starting materials were used and treated in the same manner as in Production Example 274, to give compounds as shown in Table 69 below.

Production Example 279
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-4-thiomorpholinocarbonyloxy-2- (4-fluoro-2- (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- (listed in Table 69 below) by treating in the same manner as in Production Example 127 using methylphenyl) piperidine. 3-hydroxypropyl)} aminocarbonyl-4- (1-oxothiomorpholino) carbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 280
(1) (2R, 4S) -1- {N-acetoxypropyl-N- (3,5-bistrifluoromethylbenzyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine (2R, 4S) -1- {N-acetoxypropyl-N- (3,5-bistrifluoromethylbenzyl)} amino by treating in the same manner as in Production Example 157 (1) and (2). Carbonyl-2- (4-fluoro-2-methylphenyl) -4-acetylthiopiperidine was obtained.

  (2) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N is treated in the same manner as in Production Example 160 using the compound obtained in (1) above. -Hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-iso-propylthio) piperidine was obtained.

  (3) The compound obtained in (2) above was treated in the same manner as in Production Example 127 to give (2R, 4S) -1- {N- (3,5-bistritium described in Table 69 below. Fluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (iso-propane-2-sulfinyl) piperidine was obtained.

Production Example 281
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-iso- (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-hydroxypropyl described in Table 69 below by treating in the same manner as in Production Example 128 using propylthio) piperidine. } Aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (iso-propane-2-sulfonyl) piperidine was obtained.

Production Example 282
Treat in the same manner as in Reference Example 6 using 148 mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and the corresponding starting compound. (2R, 4S) -1- {N- (3,5-dimethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- described in Table 70 below 36 mg of (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

Production Example 283
(2R, 4S) -1- {N- (3,5-dichlorobenzyl) -N-methyl} aminocarbonyl described in Table 70 below by treatment using the corresponding starting material compound in the same manner as in Production Example 282. -2- (4-Fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

Production Example 284
676 mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-acetoxyethylaminocarbonyloxy) piperidine hydrochloride is dissolved in 10 ml of tetrahydrofuran, and triethylamine is added to 0.28 ml of 30. Stir for minutes. To the reaction solution, 330 mg of 1,1′-carbonyldiimidazole was added and stirred at 65 ° C. for 2 hours. After the solvent was distilled off, the residue was dissolved in 5 ml of chloroform. The solution was washed with water and saturated brine, and the organic layer was dried. The solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of acetonitrile. 1 ml of methyl iodide was added to the solution and stirred at 60 ° C. for 2 hours to distill off the solvent. The residue was dissolved in 20 ml of tetrahydrofuran, 600 mg of N- {1- (3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methylamine and 0.5 ml of triethylamine were added, and the mixture was stirred at 70 ° C. for 3 hours. . Ethyl acetate and water were added to the reaction solution for liquid separation. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give the compound (a) (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1 shown in Table 71 below. -[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 780 mg of a mixture of -methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 285
122 mg of the compound obtained in Production Example 284 was dissolved in 2 ml of methanol, 1 ml of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was neutralized with 6M aqueous hydrochloric acid and the solvent was distilled off. Chloroform and water were added to the residue for liquid separation. The aqueous layer was extracted again with chloroform, and the combined organic layers were dried and concentrated under reduced pressure. The residue was vacuum-dried and the compound (a) (2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N described in Table 79 below was obtained. -Methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2R, 4S) -1- [N- {1- ( R)-(3,5-bistrifluoromethylphenyl) -2-hydroxyethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) ) 88 mg of a mixture of piperidine was obtained.

Production Example 286
(1) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine 4 .92 g was dissolved in 50 ml of dichloromethane, and 2.43 g of 1,1′-carbonyldiimidazole was added to the solution at room temperature, followed by stirring for 1.5 hours. Water was added to the reaction solution, and the mixture was separated with dichloromethane. The organic layer was washed with saturated brine, dried and evaporated to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl. ) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1-imidazolylcarbonyloxy) piperidine (5.99 g) was obtained.

  (2) 1.17 g of the compound obtained in the above (1) was dissolved in a toluene 12 ml-N, N-dimethylformamide 5 ml solution, 0.925 ml of ethyl nipecotate was added at room temperature, and the mixture was stirred overnight. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried and evaporated, and the residue was purified by silica gel chromatography (chloroform: methanol = 39: 1). (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4- (4-ethoxycarbonylpiperidinocarbonyloxy) -2- (4-fluoro- 1.24 g of 2-methylphenyl) piperidine was obtained.

Production Example 287
1.08 g of the compound obtained in Production Example 286 was dissolved in 15 ml of ethanol, 4.8 ml of 1M ethanol solution of potassium hydroxide was added at room temperature, the temperature was raised to 50 ° C., and the mixture was stirred for 3 hours. 2M hydrochloric acid aqueous solution was added to the reaction solution, ethanol was distilled off, water was added, and the mixture was separated with chloroform. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 72 below. 1.05 g of methyl} aminocarbonyl-4- (4-carboxypiperidinocarbonyloxy) -2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 288
64.8 mg of the compound obtained in Production Example 287 and 18.6 mg of ethanolamine were dissolved in 1 ml of dichloromethane, 48.6 mg of 1,1-carbonyldiimidazole was added at room temperature, and the mixture was stirred overnight at room temperature. Saturated ammonium chloride solution was added, and the mixture was separated with dichloromethane, dried and evaporated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 72 below. 17.8 mg of methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {4- (2-hydroxyethylaminocarbonyl) piperidinocarbonyloxy} piperidine was obtained.

Production Example 289-295
The compound described in Tables 72-73 below was obtained by treating in the same manner as in Production Example 288 using the compound obtained in Production Example 287 and the corresponding starting material compound.

Production Example 296
(1) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (1- 1.17 g of imidazolylcarbonyloxy) piperidine was dissolved in 12 ml of toluene, and 1.14 g of 4-amino-1-benzylpiperidine was added at room temperature, followed by stirring for 3 days. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-4 0.89 g of-(1-benzylpiperidin-4-yl) aminocarbonyloxy-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

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

  (3) 14.2 mg of 3-hydroxy-3-methyl-butanoic acid was dissolved in 2 ml of dichloromethane, 21.1 mg of 1,1'-carbonyldiimidazole was added at room temperature, and the mixture was stirred overnight at room temperature. To the reaction solution was added 61.9 mg of the compound obtained in (2) above, and the mixture was further stirred overnight. Water was added to the reaction solution, and the mixture was separated, dried and evaporated with chloroform, and the residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) described in Table 74 below. -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {1- (3-hydroxy-3-methylbutyryl) ) 57.5 mg of piperidin-4-yl} aminocarbonyloxypiperidine was obtained.

Production Example 297-299
The compound shown in Table 74 below was obtained by treating the compound obtained in Production Example 296 (2) and the corresponding starting material compound in the same manner as in Production Example 296 (3).

Production Example 300
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-ethyl} obtained by treating the compound obtained in Reference Example 11 (2) in the same manner as in Production Example 2. By treating aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine with the corresponding starting compound in the same manner as in Production Example 117, the compounds listed in Table 75 below were obtained.

Production Example 301
The corresponding starting material compounds were treated in the same manner as in Production Example 117 to obtain the compounds shown in Table 75 below.

Production Example 302
The compound shown in Table 75 below was obtained by treating the compound obtained in Production Example 301 in the same manner as in Production Example 127.

Production Example 303
The compound shown in Table 75 below was obtained by treating the compound obtained in Production Example 301 in the same manner as in Production Example 128.

Production Examples 304-310
The corresponding starting materials were treated in the same manner as in Production Example 160 to give the compounds described in Tables 76-77 below.

Production Example 311
1.17 g of (2R, 4S) -4-acetylthio-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine After dissolving in 50 ml of methanol and adding 1.17 g of 2-bromoethylcarbamic acid tert-butyl ester at room temperature, 25 ml of 1M aqueous sodium hydroxide solution was added dropwise. After stirring the reaction solution for 5 minutes, the solvent was distilled off, and the mixture was separated with dichloromethane, washed with saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N described in Table 77 below. 710 mg of -methyl} aminocarbonyl-4- (2-tert-butoxycarbonylaminoethylthio) -2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 312
(1) To 681 mg of the compound obtained in Production Example 311 was added 2 ml of 4M hydrochloric acid-ethyl acetate solution at ice temperature, followed by stirring at room temperature for 1 hour. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, extracted with chloroform, dried and evaporated to give (2R, 4S) -4- (2-aminoethylthio) -1- {N- (3,5 612 mg of -bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride was obtained.

  (2) 55.2 mg of the compound obtained in the above (1) and 9.1 mg of glycolic acid are dissolved in 1 ml of N, N-dimethylformamide, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide / hydrochloride is obtained. 24.9 mg and 19.9 mg of N-hydroxybenzotriazole monohydrate were added, and the mixture was stirred overnight at room temperature. After adding ethyl acetate, washing with water and saturated brine, drying and distilling off, the residue was purified by silica gel chromatography (chloroform: methanol = 19: 1). 2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (hydroxyacetylamino) ) 28.8 mg of ethylthio} piperidine was obtained.

Production Examples 313-316
The compound shown in Table 78 below was obtained by treating the compound obtained in Production Example 311 and the corresponding starting material compound in the same manner as in Production Example 66 and Reference Example 44.

Production Example 317
55.2 mg of the compound obtained in Production Example 312 (1) is dissolved in 1 ml of N, N-dimethylformamide, 9.1 mg of 1,1-carbonyldiimidazole is added, and the mixture is stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, dried and evaporated. The residue was dissolved in 1 ml of acetonitrile, 0.025 ml of methane iodide was added, and the mixture was stirred overnight at 50 ° C. Then, 0.025 ml of methane iodide was further added, and the mixture was stirred overnight at the same temperature. After distilling off N, N-dimethylformamide and methane iodide, 1 ml of toluene and 0.040 ml of morpholine were added, and the mixture was stirred at room temperature for 5 days. Water was added to the reaction solution, followed by liquid separation with ethyl acetate, drying and evaporation, and then the residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to obtain (2R described in Table 78 below). , 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-morpholinocarbonylaminoethylthio) ) 38.0 mg of piperidine was obtained.

Production Example 318
By treating the compound obtained in Production Example 312 (1) and the corresponding starting material compound in the same manner as in Production Example 317, (2R, 4S) -1- {N- (3,5-bistri of the following Table 78 is given. Fluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- {2- (2-hydroxyethylamino) carbonylaminoethylthio} piperidine was obtained.

Production Example 319
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- described in Table 78 below by treating the corresponding starting material compound in the same manner as in Production Example 127. 2- (4-Fluoro-2-methylphenyl) -4- {4- (2-methylsulfinylethylaminocarbonyl) piperidinocarbonyloxy} piperidine was obtained.

Production Example 320
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl described in Table 78 below by treating the corresponding starting material compound in the same manner as in Production Example 128. -2- (4-Fluoro-2-methylphenyl) -4- {4- (3-methylsulfonylpropylaminocarbonyl) piperidinocarbonyloxy} piperidine was obtained.

Production Examples 321 to 322
The corresponding starting materials were used and treated in the same manner as in Production Example 117, to give compounds as shown in Table 79 below.

Production Example 323
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylthioethylamino) Carbonyloxy) piperidine (82.0 mg) was dissolved in dichloromethane (1.5 ml), m-chloroperbenzoic acid (99.5 mg) was added at room temperature, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was separated with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1), whereby (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 79 below. 48.6 mg of methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-methylsulfonylethylaminocarbonyloxy) piperidine was obtained.

Production Example 324
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (3-methylthiopropylamino (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl described in Table 79 below by treating carbonyloxy) piperidine in the same manner as in Production Example 323. -2- (4-Fluoro-2-methylphenyl) -4- (3-methylsulfonylpropylaminocarbonyloxy) piperidine was obtained.

Production Example 325-328
The corresponding starting material compounds were treated in the same manner as in Production Example 94 to obtain the compounds shown in Table 80 below.

Production Example 329-330
The corresponding starting material compounds were treated in the same manner as in Production Example 127 to give the compounds shown in Table 81 below.

Production Examples 331-332
The corresponding starting material compounds were treated in the same manner as in Production Example 128 to give the compounds listed in Table 81 below.

Production Example 333
130 mg of imidazole-1-carboxylic acid N- (3,5-bis-trifluoromethylbenzyl) -N- (2-methoxyethyl) amide was dissolved in 2.8 ml of acetonitrile, and 411 μl of methyl iodide was added thereto. After stirring at 0 ° C. for 3 hours, the reaction solution was concentrated under reduced pressure. The residue was suspended in 2.7 ml of dichloromethane, to which 89 mg of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and 50 μl of triethylamine were added, Stir at room temperature for 20 hours. A 5% aqueous citric acid solution was added to the reaction solution, extracted with chloroform, 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 (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) described in Table 82 below. 63 mg of -N- (2-methoxyethyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine are obtained.

Production Example 334
94 mg of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was dissolved in 2.7 ml of dichloromethane, and this was dissolved in 3-[(3,5-bis-triiodide iodide. Fluoromethylbenzyl) -methyl-carbamoyl] -1-methyl-3H-imidazol-1-ium 163 mg and triethylamine 50 μl are added and stirred at room temperature for 18 hours. Distilled water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by thin layer silica gel column chromatography (chloroform: methanol = 19: 1) to give 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} described in Table 82 below. 84 mg of aminocarbonyl-2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

Production Example 335
201 mg of imidazole-1-carboxylic acid N-[(S) -1- (3,5-bistrifluoromethylphenyl) ethyl] -N-methylamide was dissolved in 5.2 ml of acetonitrile, and 137 μl of methyl iodide was added thereto. After stirring at 50 ° C. for 3 hours, the reaction solution was concentrated. The residue was dissolved in 4.5 ml of dichloromethane, and 132 mg of 4- (2-hydroxyethylcarbamoyloxy) -2-phenylpiperidine and 84 μl of triethylamine were added thereto, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 5% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by thin layer silica gel chromatography (chloroform: acetone = 4: 1) to give (2R, 4R) -1- [N-{(S) -1- (3, listed in Table 82 below]. 75 mg of 5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine was obtained.

Production Example 336
(1) 127 mg of imidazole-1-carboxylic acid 1- (3,5-bistrifluoromethylphenyl) ethyl ester was dissolved in 3 ml of acetonitrile, 448 μl of methyl iodide was added thereto, and the mixture was stirred at 50 ° C. for 3 hours. The solution was concentrated. The residue was suspended in 2.7 ml of dichloromethane, and 102 mg of acetic acid 2-[(2R, 4S) -2- (4-fluoro-2-methylphenyl) piperidin-4-yloxycarbonylamino] ethyl ester and 50 μl of triethylamine were added thereto. The mixture was further stirred at room temperature for 18 hours. Distilled water was added to the reaction solution, extracted with chloroform, and the organic layer was dried and concentrated. The residue was purified by thin layer silica gel chromatography (hexane: ethyl acetate = 1: 1) to give (2R, 4S) -4- (2-acetoxyethylaminocarbonyloxy) -1-{(S) -1 43 mg of-(3,5-bistrifluoromethylphenyl) ethyl} oxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.
MS (m / z): 623 [M ⁺⁺ 1].

  (2) 43 mg obtained in (1) above was dissolved in a mixed solution of 0.9 ml of tetrahydrofuran and 0.1 ml of methanol, 103 μl of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Distilled water was added to the reaction solution, 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 (2R, 4S) -1-{(S) -1- (3,5- 37 mg of bis (trifluoromethylphenyl) ethyl} oxycarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

Production Example 337
50 mg of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine is dissolved in 2.4 ml of N, N-dimethylformamide, and 0.044 ml of triethylamine is obtained at room temperature under a nitrogen stream. 99.3 mg of N- (3,5-bistrifluoromethylbenzyl) -N-methyl-aminocarbonyl chloride was added. The reaction solution was stirred at room temperature for 21 hours. The reaction solution was poured into water and extracted twice 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 → 1: 2) to give (2R, 4S) -1- {N- (3,5-bistrifluoro) described in Table 83 below. 128 mg of methylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was obtained.

Production Example 338
560 mg of (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine was added to dichloromethane 2 In a nitrogen stream, 0.22 ml of pyridine and 0.314 ml of phenyl chloroformate in 1.5 ml of dichloromethane were added. The reaction solution was stirred at 0 ° C. to 5 ° C. for 3.5 hours, and further stirred at room temperature for 16 hours. The reaction solution was poured into water, dichloromethane was added and extracted twice. The organic layers were combined, washed twice with 1M aqueous hydrochloric acid solution, further washed with saturated brine, dried and concentrated. The residue was dissolved in 11 ml of N, N-dimethylformamide, 0.274 ml of ethanolamine was added at room temperature under a nitrogen stream, and the mixture was stirred at 60 ° C. for 26 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 39: 1) to give (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N described in Table 83 below. 493 mg of -methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

Production Example 339
(2R) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (1.0 g) was added to dichloromethane (8 ml). Then, 0.31 ml of triethylamine and 466 mg of di-tert-butyloxycarbonate were added and stirred at room temperature for 16 hours. Add water to the reaction solution and extract twice with dichloromethane. The organic layers were combined, washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (a) (2R, 4R) -1- {N- (3,5-bistrifluoromethyl) described in Table 83 below. Benzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine 481 mg and (b) (2R, 4S) -1- {N- (3 There were obtained 516 mg of 5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine.

Production Examples 340-343
The corresponding starting materials were used and treated in the same manner as in Production Example 66, to give compounds as shown in Table 84 below.

Production Examples 344-345
The corresponding starting materials were used and treated in the same manner as in Production Example 117 to give the compounds shown in Table 84 below.

Production Examples 346-361
The corresponding starting materials were used and treated in the same manner as in Production Example 153 (2), to give compounds as shown in Tables 85-87 below.

Production Example 362
52. (2R, 4S) -4-Amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride To 1 ml of 8 mg dichloromethane solution, 0.017 ml triethylamine and 24.3 mg carbodiimidazole were added at room temperature and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was separated with dichloromethane. The organic layer was washed with saturated brine, dried and evaporated. After adding 0.025 ml of methyl iodide to 1 ml of the acetonitrile solution of the residue and stirring overnight at 60 ° C., the solvent and excess reagent were distilled off under reduced pressure. 24.4 mg of aminoethanol was added to 1 ml of a toluene-acetonitrile (7: 3) solution of the residue, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was separated, dried and evaporated with ethyl acetate. The residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) to give (2R, 4S described in Table 88 below). ) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonylamino) piperidine 53.1 mg was obtained.

Production Examples 363-372
The corresponding starting materials were used and treated in the same manner as in Production Example 362, to give compounds as shown in Tables 88-89 below.

Production Example 373
To 1 ml of ethylene glycol 12.4 mg in dichloromethane solution was added 1,1′-carbonyldiimidazole 32.4 mg at room temperature, stirred at room temperature for 7.5 hours, and then (2R, 4S) -4-amino-1- { N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (52.8 mg) and triethylamine (0.021 ml) were added, and the mixture was stirred overnight. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) to give (2R, 4R) -1- {N- described in Table 90 below. 16.4 mg of (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethoxycarbonylamino) piperidine was obtained.

Production Example 374
(1) A solution of 58 mg of triphosgene in 3 ml of dichloromethane, 138 mg of [2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl] methylamine and 201 μl of triethylamine dissolved in 2 ml of dichloromethane, The solution was added dropwise at -60 ° C, and the temperature was raised to 0 ° C. After concentrating the reaction solution, the residue was dissolved in 2 ml of dichloromethane and added to (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -2- (4-fluoro-2-methyl-phenyl) piperidine. A solution prepared by dissolving 135 mg and 84 μl of triethylamine in 2 ml of dichloromethane is added dropwise and stirred at room temperature for 1 day. Distilled water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (chloroform: acetone = 10: 1) to give (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -1- [N- 44 mg of {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methyl-phenyl) piperidine was obtained.
MS (m / z): 652 [M ⁺⁺ 1].
(2) (2R, 4S) -4- (2-acetyloxyethylaminocarbonyloxy) -1- [N- {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl} -N -Methyl] aminocarbonyl-2- (4-fluoro-2-methyl-phenyl) piperidine (44 mg) was dissolved in a mixture of 0.8 ml of tetrahydrofuran and 0.1 ml of methanol, and 101 μl of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. Stir. Distilled water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel column chromatography (chloroform: methanol = 19: 1) to give (2R, 4S) -2- (4-fluoro-2-methyl-) described in Table 90 below. Phenyl) -1- [N- {2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzyl} -N-methyl] aminocarbonyl-4- (2-hydroxyethylaminocarbonyloxy) piperidine 36 mg Get. MS (m / z): 610 [M + H] < ⁺ >.

Reference example 1
To a Grignard solution prepared from 14.2 g of magnesium, 93.1 g of 2-bromo-5-fluorotoluene and 500 ml of tetrahydrofuran, 50 ml of 4-methoxypyridine was added dropwise at −20 ° C. under a nitrogen stream. After completion of dropping, the mixture was stirred at the same temperature for 20 minutes. Furthermore, the reaction solution was cooled to −50 ° C., and 85 ml of benzyl chlorocarbonate was added dropwise while maintaining the temperature at −40 ° C. or lower. After completion of the dropwise addition, the temperature of the reaction solution was slowly raised, and 200 g of ice was added at −15 ° C. and stirred for 30 minutes. Furthermore, 200 ml of 5M aqueous citric acid solution was added and stirred at room temperature for 1 hour. From the reaction solution, tetrahydrofuran was distilled off under reduced pressure, and 200 ml of ethyl acetate was added to the residue and extracted twice. The organic layers were combined, washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was filtered and washed with isopropyl ether, and 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-2,3-dihydro-1H-pyridine described in Table 91 below 146. 5 g was obtained.

Reference example 2
190 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-2,3-dihydro-1H-pyridine is dissolved in 4600 ml of acetic acid, 91 g of zinc dust is added, and 24 g at room temperature. Stir for hours. Insolubles were filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. To the residue was added 400 ml of ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1), and 1-benzyloxycarbonyl-2- (4-fluoro-2-methyl) described in Table 91 below. 166 g of phenyl) -4-oxopiperidine were obtained.

Reference example 3
To 132 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine, 650 ml of methanol, 84 ml of trimethoxymethane and 2 g of strongly acidic resin IR-120 (manufactured by Organo Corporation) were added, Stir at room temperature for 3 days. Insoluble matter was filtered off from the reaction solution, the solvent was distilled off under reduced pressure, and 146 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxy-piperidine described in Table 91 below. Got.

Reference example 4
30 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxy-piperidine and 3.0 g of 10% palladium-carbon were added to 300 ml of ethanol, and at room temperature under a hydrogen atmosphere for 3 hours. Stir. The insoluble material was filtered off from the reaction solution, the solvent was evaporated under reduced pressure, and 300 ml of ethyl acetate was added to the residue. Under ice cooling, 20 ml of 4M hydrochloric acid-ethyl acetate solution was slowly added dropwise. The crystals were collected by filtration and washed with ethyl acetate. After drying, it was added to dichloromethane-sodium carbonate water and stirred. After separating the organic layer, the aqueous layer was re-extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 16.7 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine described in Table 91 below.

Reference Example 5
After 35 ml of methanol was added to a suspension of 130 ml of ethyl acetate in 10.1 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3.18 g of LN-acetylvaline, the mixture was dissolved by heating. And allowed to cool at room temperature. After 3.5 hours, the precipitated crystals were collected by filtration, washed with 20 ml of ethyl acetate, and the obtained crystals were dried under reduced pressure. Next, 50 ml of chloroform was added, washed with 30 ml of 2M sodium hydroxide aqueous solution and 30 ml of saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. Ether was added to the resulting residue, and the precipitated crystals were further concentrated under reduced pressure to give (2R) -2- (4-fluoro-2-methylphenyl) -4,4-dimethoxy listed in Table 91 below. 2.94 g of piperidine (optical purity: 97.0% ee) was obtained.

Reference Example 6
To 36 ml of a tetrahydrofuran solution of 5.0 g of N- (3,5-bistrifluoromethylbenzyl) -N-methylamine, 3.47 g of 1,1′-carbonyldiimidazole was added and stirred at 65 ° C. for 20 minutes. After the solvent was distilled off, dichloromethane was added and the entire organic layer was washed with saturated brine, dried and evaporated. The residue was dissolved in 26 ml of acetonitrile, 4.84 ml of methyl iodide was added and stirred at 60 ° C. for 2 hours, and then the solvent was distilled off. The residue was dissolved in 80 ml of dichloromethane, and 5.17 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3 ml of triethylamine were added under ice-cooling and stirred at room temperature for 2 hours. The reaction solution was poured into water, the liquid separation and the aqueous layer were extracted with dichloromethane, and the entire organic layer was washed with saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 3) to give 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- described in Table 92 below. 9.7 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine was obtained.

Reference Example 7
Dissolve 9.7 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine in 180 m of tetrahydrofuran. Under ice cooling, 70 ml of 1M aqueous sulfuric acid solution was added, and the mixture was stirred at room temperature for 1 hour. After adjusting the pH to 8-9 with 1M aqueous sodium hydroxide solution, tetrahydrofuran was distilled off, and water and ethyl acetate were added to the residue for liquid separation. The aqueous layer was extracted with ethyl acetate, and the entire organic layer was washed with saturated brine and dried. Diisopropyl ether was added to the residue obtained by distilling off the solvent, and white crystals were collected by filtration to give 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl described in Table 92 below. } 7.86 g of aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was obtained.

Reference Example 8
To 60 ml of a tetrahydrofuran solution of 3.91 g of N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine was added 2.34 g of 1,1′-carbonyldiimidazole, and the mixture was heated to 40 ° C. And stirred overnight. After the solvent was distilled off from the reaction solution, ethyl acetate was added, and the whole organic layer was washed with water and saturated brine and dried. White crystals obtained by distilling off the solvent were collected by filtration with diisopropyl ether. The obtained white crystals were dissolved in 60 ml of acetonitrile, added with 3.4 ml of methyl iodide and reacted at 60 ° C. for 2 hours, and then the solvent was distilled off. The residue was dissolved in dichloromethane (40 ml). Under ice cooling, 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine (3.47 g) and triethylamine (3.82 ml) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and separated, and the aqueous layer was extracted with dichloromethane. All organic layers were washed with water and saturated brine, dried and evaporated. The residue was dissolved in 90 ml of tetrahydrofuran, 30 ml of 1M sulfuric acid aqueous solution was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After adjusting the pH to 8-9 with 1M aqueous sodium hydroxide solution, tetrahydrofuran was distilled off, water and ethyl acetate were added to the residue for liquid separation, and the aqueous layer was extracted with ethyl acetate. All organic layers were washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give (2R) -1- [N- {1- (S)-(3,5-bistrifluoro] described in Table 92 below. 2.12 g of methylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was obtained.

Reference Example 9-11
The corresponding starting materials were used and treated in the same manner as in Reference Example 8 to give the compounds described in Tables 92-93 below.

Reference Example 12
16.7 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine is dissolved in 140 ml of ethanol, and 3.74 g of hydroxylamine hydrochloride and 4.41 g of sodium acetate are added to room temperature. Stirring under 2 hours. Ethanol was distilled off, water and ethyl acetate were added to the residue, liquid separation was performed, the aqueous layer was extracted with ethyl acetate, the whole organic layer was washed with saturated brine, dried and evaporated. The residue was dissolved in 500 ml of methanol, 23.2 g of nickel chloride hexahydrate was added and stirred, 3.7 g of sodium borohydride was slowly added under ice cooling, and the mixture was stirred for 4 hours under ice cooling. Methanol was distilled off, aqueous ammonia and dichloromethane were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated, the aqueous layer was extracted with dichloromethane, and the entire organic layer was washed with saturated brine, dried and evaporated. The residue was dissolved in 480 ml of dichloromethane, and 8.2 ml of triethylamine and 5.1 ml of propionyl chloride were added under ice cooling, followed by stirring for 1 hour under ice cooling. The reaction solution is poured into a saturated saline solution, and the mixture is separated. The aqueous layer is extracted with dichloromethane, and the entire organic layer is washed with a saturated saline solution, dried and evaporated, and the residue is chromatographed on silica gel (hexane: ethyl acetate = 1: (A) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine (6.43 g) and (b) described in Table 93 below were purified by 1). ) 5.65 g of cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine was obtained.

Reference Example 13
By treating in the same manner as in Reference Example 12 using 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine and isobutyroyl chloride, a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-isobutanoylaminopiperidine and (b) cis-1-benzyloxycarbonyl-2- (4-fluoro-2) -Methylphenyl) -4-isobutanoylaminopiperidine was obtained.

Reference Example 14
1.73 g of trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-propanoylaminopiperidine was dissolved in 17 ml of ethanol, and palladium-carbon (50.9% 280 mg of water) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and ethanol was distilled off. The residue was purified by NH silica gel chromatography (chloroform: hexane: ethyl acetate = 5: 5: 2) to obtain trans-2- (4-fluoro-2-methylphenyl) -4-propylene described in Table 95 below. 772 mg of noylaminopiperidine was obtained.

Reference Example 15-17
The corresponding starting materials were used and treated in the same manner as in Reference Example 14 to give the compounds as shown in Tables 95-96 below.

Reference Example 18
110 g of 1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine is dissolved in 900 ml of ethanol, and 24.8 g of hydroxylamine hydrochloride and 29.3 g of sodium acetate are added thereto at room temperature. For 5 hours. Ethanol was distilled off, water and ethyl acetate were added to the residue, liquid separation was performed, the aqueous layer was extracted with ethyl acetate, the whole organic layer was washed with saturated brine, dried and evaporated. The residue was dissolved in 2.4 l of methanol, 92.5 g of nickel chloride hexahydrate was added and stirred, 18.4 g of sodium borohydride was slowly added under ice cooling, and the mixture was stirred for 4 hours under ice cooling. Methanol was distilled off, aqueous ammonia and dichloromethane were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated, the aqueous layer was extracted with dichloromethane, and the entire organic layer was washed with saturated brine, dried and evaporated. The residue was dissolved in 1.2 l of dichloromethane, and 45.2 ml of triethylamine and 74.5 ml of di-tert-butyl dicarbonate were added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution is poured into a saturated saline solution, and the mixture is separated. The aqueous layer is extracted with dichloromethane, and the entire organic layer is washed with a saturated saline solution, dried and evaporated. The residue is chromatographed on silica gel (hexane: ethyl acetate = 4: By purifying with 1), 36.7 g of (a) trans-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine described in Table 97 below and (B) 37.9 g of cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine was obtained.

Reference Example 19
37.0 g of cis-1-benzyloxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine was dissolved in 350 ml of ethanol, and palladium-carbon (50. (9% moisture) 5.5 g was added and stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and ethanol was distilled off to obtain 25.8 g of cis-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine described in Table 98 below. .

Reference Example 20
To 1.34 g of 3-hydroxyl-2-hydroxymethyl-2-methylpropionic acid and 13 ml of acetone dimethyl acetal, 95 mg of p-toluenesulfonic acid monohydrate is added at room temperature and stirred for 6 hours. Further, 95 mg of p-toluenesulfonic acid monohydrate is added and stirred overnight. The solution was concentrated and then poured into water and extracted. The aqueous layer was extracted with chloroform, and then the entire organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol = 19: 1) to obtain 333 mg of 2,2,5-trimethyl- [1,3] dioxolane-5-carboxylic acid described in Table 98 below.

Reference Example 21
21.5 g of 2-chloroisonicotinic acid was dissolved in 400 ml of tetrahydrofuran, 32.5 g of 1,1′-carbonyldiimidazole was added, and the mixture was stirred for 1 hour under ice cooling. To this solution, 50 ml of ethanol was added and 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 then the residue was vacuum dried to obtain 35.6 g of 2-chloroisonicotinic acid ethyl ester described in Table 98 below.

Reference Example 22
20 g of 2-chloroisonicotinic acid ethyl ester and 20 g of 2-methyl-4-fluorophenylboronic acid are dissolved in a mixed solvent of 250 ml of toluene and 50 ml of ethanol, 5.8 g of palladium tetrakistriphenylphosphine and 2M aqueous sodium carbonate solution. 250 ml was added and it stirred at 50-70 degreeC for 2 hours. The solution was cooled to room temperature, and extracted with ethyl acetate and water. The organic layer was washed again with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 24.8 g of 4-ethoxycarbonyl-2 (4-fluoro-2-methylphenyl) pyridine described in Table 98 below. It was.

Reference Example 23
5.2 g of 4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) pyridine and 1.5 g of platinum oxide were dissolved in 200 ml of ethanol. To this solution was added 15 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After adding 200 ml of water and stirring for 30 minutes, insoluble matters were removed by Celite filtration. The insoluble material was washed with ethanol, and the filtrate and the washing solution were combined and concentrated. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the aqueous layer was confirmed to be sufficiently alkaline, and then extracted. The aqueous layer was extracted three times with ethyl acetate, and the entire organic layer was dried over sodium sulfate and concentrated to give 2,4-cis-4-ethoxycarbonyl-2 (4-fluoro-) described in Table 98 below. 3.6 g of 2-methylphenyl) piperidine were obtained.

Reference Example 24
(1) 2,4-cis-4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) piperidine (7.4 g) and Np-toluenesulfonyl-D-phenylalanine (4.0 g) were mixed with 50 ml of ethyl acetate and diethyl. It was dissolved in 50 ml of ether by heating. The solvent was heated and concentrated, and 30 ml of diisopropyl ether was added and stirred. The precipitated crystals were removed, and the mother liquor was washed with concentrated aqueous ammonia solution, dried and concentrated under reduced pressure. To the residue, 4.0 g of Np-toluenesulfonyl-L-phenylalanine was added, 50 ml of ethyl acetate and 30 ml of diisopropyl ether were added and 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 then dried. Np-toluenesulfonyl of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine -L-phenylalanine salt 4.0g was obtained.

  (2) The compound obtained in (1) above was dissolved in an aqueous ammonia solution and confirmed to be sufficiently basic, and then extracted twice with chloroform. The combined organic layers were dried, concentrated under reduced pressure, and 2.6 g (96% ee) of (2R, 4S) -4-ethoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-piperidine described in Table 99 below. )

Reference Example 25
(1) 7.5 g of 3-aminopropanol was dissolved in 50 ml of N, N-dimethylformamide, 16 g of tert-butyldimethylsilyl chloride and 6.8 g of imidazole were added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added 11 g of citric acid, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. 2M aqueous sodium hydroxide solution and diethyl ether were added to the residue for liquid separation. The organic layer was dried and concentrated under reduced pressure. The residue and 12.1 g of 3,5-bistrifluoromethylbenzaldehyde were dissolved in 300 ml of dichloromethane, 21.2 g of sodium triacetoxyborohydride and 2.9 ml of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. 2M sodium carbonate aqueous solution was added to the reaction solution, stirred for 30 minutes, and extracted twice with chloroform. The combined organic layers were dried, concentrated under reduced pressure, purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and purified by N-3-tert-butyldimethylsiloxypropyl-N- (3,5-bistrifluoromethylbenzyl). 20 g of amine was obtained.

  (2) Using the compound obtained in (1) above (12.5 g) and the compound obtained in Reference Example 5 in the same manner as in Reference Example 6, (2R) -1- {N- (3 19 g of 5-bistrifluoromethylbenzyl) -N- (3-tert-butyldimethylsiloxypropyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine was obtained.

  (3) Using 19.0 g of the compound obtained in (2) above and treating in the same manner as in Reference Examples 6 and 7, compound (2R) -1- {N- (3,5) described in Table 99 below 19 g of -bistrifluoromethylbenzyl) -N- (3-hydroxypropyl)} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine was obtained.

Reference Example 26
(1) 4.8 g of the compound obtained in Reference Example 5 was dissolved in 40 ml of dichloromethane, 4.4 g of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 ml of acetone, 200 mg of strongly acidic resin IR-120 (manufactured by Organo Corporation) was added, and the mixture was stirred at room temperature for 3 days. The resin was removed from the reaction solution and concentrated under reduced pressure. 2. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and (R) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine. 9 g was obtained.

  (2) 3.9 g of the compound obtained in the above (1) was dissolved in 20 ml of ethanol, and 400 mg of sodium borohydride was added at −20 ° C. and stirred for 1 hour. After adding an aqueous ammonium chloride solution to the reaction solution, ethanol was distilled off. Ethyl acetate and water were added to the residue for liquid separation, followed by washing with water again. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and (2R, 4S) -1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-hydroxypiperidine. 3.1 g was obtained.

  (3) (2R, 4S) -1-tert-butoxycarbonyl-2- (3) is treated in the same manner as in Production Example 117 using 3.1 g of the compound obtained in (2) above and the corresponding starting material compound. 2.3 g of 4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine was obtained.

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

  (5) 1.5 g of the compound obtained in (4) above was dissolved in 25 ml of 1M aqueous sodium hydroxide solution and extracted twice with 25 ml of chloroform. The combined organic layers were dried and concentrated under reduced pressure. The residue was dried to obtain 1.5 g of (2R, 4S) -2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine described in Table 99 below. .

Reference Example 27
4.8 g of 3,5-bistrifluoromethylbenzaldehyde is dissolved in 250 ml of acetonitrile, 6.6 g of trimethyl sulfonyl iodide, 3.2 g of ground potassium hydroxide and 0.5 ml of water are added, and in the presence of alumina balls, The mixture was stirred at 65 ° C-70 ° C for 16 hours. After completion of the reaction, insoluble matters were removed, and ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was washed with water, dried and concentrated under reduced pressure. To the residue was added 50 ml of a 40% methylamine methanol solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give 1.23 g of 1- (3,5-bistrifluoromethylphenyl) -2-hydroxyethylamine described in Table 99 below. Got.

Reference Example 28
(1) 3,5-bis-trifluoromethylbenzaldehyde (2.45 g), 2-methoxyethylamine (835 mg) and acetic acid (687 μl) were dissolved in dichloromethane (43 ml). To this, triacetoxy sodium borohydride (3.12 g) was added, and under a nitrogen atmosphere, Stir at room temperature for 1 hour. The reaction solution was washed with 0.5 M 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 → 9: 1) to obtain 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.
MS (m / z): 302 [M ⁺⁺ 1] ⁺ .
(2) 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine was dissolved in a mixed solution of 37 ml of toluene and 4 ml of methylene chloride, and 1.78 g of 1,1′-carbonyldiimidazole was added thereto, For 3 hours. Distilled water was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. By purifying the residue with silica gel column chromatography (chloroform: acetone = 9: 1 → 2: 1), imidazole-1-carboxylic acid 3,5-bistrifluoromethylbenzyl-2-methoxy described in Table 99 below. 3.45 g of ethylamide was obtained.

Reference Example 29
(1) Dissolve 3.94 g of 2-bromo-5-fluorophenol and 1.62 ml of methyl iodide in 15 ml of N, N-dimethylformamide, add 5.08 g of potassium carbonate little by little under ice cooling, and add 3 at room temperature. Stir for hours. Insoluble material was removed 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 is dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 9: 1) to obtain 4.10 g of 1-bromo-4-fluoro-2-methoxybenzene.
MS (m / z): 204/206 (M ⁺⁺ 1).

(2) 486 mg of magnesium and a small amount of iodine were added to 7 ml of tetrahydrofuran, and a solution obtained by adding 4.10 g of the compound obtained in the above (1) to 16 ml of tetrahydrofuran was added dropwise to prepare a grinal reagent. To the solution, a solution obtained by adding 1.96 g of 4-methoxypyridine to 7 ml of tetrahydrofuran at −60 ° C. or lower under a nitrogen atmosphere was dropped, and then a solution of 3.75 g of benzyl chloroformate added to 18 ml of tetrahydrofuran was dropped. Stir for hours. The mixture was warmed to room temperature, 40 ml of 5% aqueous citric acid solution was added, extracted with ethyl acetate, and washed with saturated brine. Concentrate after drying with organic layer. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2) to give 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-oxo- 2.15 g of 2,3-dihydro-1H-pyridine was obtained.
MS (m / z): 356 [M ⁺⁺ 1].

(3) 3.15 g of the compound obtained in (2) above was dissolved in a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuran, 706 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated, distilled water was added to the residue, extracted with chloroform, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone = 19: 1 → 9: 1) to give 1-benzyloxycarbonyl-2- (4-fluoro-2-methoxyphenyl) -4-hydroxypiperidine 1 .62 g was obtained.
MS (m / z): 360 [M ⁺⁺ 1].

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

  (5) 1.81 g of the compound obtained in (4) above was dissolved in 20 ml of methanol, 90 mg of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The insoluble material is removed by filtration, and the filtrate is concentrated. Diethyl ether was added to the residue and the precipitate was collected by filtration to obtain 1.30 g of 2- (4-fluoro-2-methoxyphenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine described in Table 100 below. It was.

Reference Example 30
(1) 5.46 g of 4-methoxypyridine was dissolved in 40 ml of tetrahydrofuran, and 55 ml of 1M phenylmagnesium bromide tetrahydrofuran solution was added dropwise at −60 ° C. or lower under a nitrogen atmosphere, and then 10.24 g of benzyl chloroformate was added to 50 ml of tetrahydrofuran. The solution added to was added dropwise and stirred for 3 hours. The temperature was raised to room temperature, 120 ml of 5% aqueous citric acid solution was added, and 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 obtain 8.51 g of 1-benzyloxycarbonyl-4-oxo-2-phenyl-2,3-dihydro-1H-pyridine.
MS (m / z): 308 [M ⁺⁺ 1].

(2) 8.48 g of the compound obtained in (1) above was dissolved in 260 ml of acetic acid, 3.61 g of zinc powder was added thereto, and the mixture was stirred at room temperature for 18 hours. Next, 1.8 g of zinc dust was added, and after stirring for 6 hours at room temperature, 1.8 g of zinc dust was further added and stirred at 50 ° C. for 3 days. The insoluble material is removed by filtration, and the filtrate is concentrated. The residue was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried and concentrated to obtain 8.54 g of 1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine.
MS (m / z): 310 [M ⁺⁺ 1].

(3) 619 mg of the compound obtained in the above (2) was dissolved in 15 ml of tetrahydrofuran, and 4 ml of 1M diisobutylaluminum hydride toluene solution was added dropwise at −60 ° C. or lower under a nitrogen atmosphere, followed by stirring for 10 minutes. To the reaction solution was added 667 μl of 6M aqueous hydrochloric acid, and the mixture was concentrated. Distilled water was added to the residue, extracted with ethyl acetate, and washed with saturated brine. The organic layer is dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to obtain 553 mg of 1-benzyloxycarbonyl-4-hydroxy-2-phenylpiperidine.
MS (m / z): 312 [M ⁺⁺ 1].

(4) 511 mg of the compound obtained in the above (3) was dissolved in a mixed solution of 14 ml of toluene and 1.6 ml of dichloromethane, 319 mg of 1,1′-carbonyldiimidazole was added, and the mixture was stirred at 60 ° C. for 2 hours. Ethanolamine (396 μl) was added thereto, and the mixture was stirred at 60 ° C. for 3 hours. Distilled water was added to the reaction solution, extracted with chloroform, and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone = 9: 1 → 2: 1) to give 462 mg of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2-phenylpiperidine. Obtained.
MS (m / z): 399 [M ⁺⁺ 1].

  (5) 430 mg of the compound obtained in (4) above was dissolved in 10 ml of methanol, 30 mg of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature for 5 days in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated to obtain 348 mg of 4- (2-hydroxyethylaminocarboxyoxy) -2-phenylpiperidine described in Table 100 below.

Reference Example 31
(1) 2.61 g of 3,5-bis-trifluoromethyl-acetophenone is dissolved in 47 ml of ethanol, 478 mg of sodium borohydride is added thereto, and the mixture is stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution and concentrated. The residue is extracted with ethyl acetate, washed with saturated brine, and the organic layer is dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1) to obtain 2.51 g of 1- (3,5-bistrifluoromethylphenyl) -ethanol.
MS (m / z): 258 [M ⁺⁺ 1].
(2) 2.49 g of the compound obtained in the above (1) was dissolved in a mixed solution of 40 ml of toluene and 4 ml of acetonitrile, and 1.72 g of 1,1′-carbonyldiimidazole was added thereto, followed by stirring at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried and concentrated under reduced pressure to obtain 3.40 g of imidazole-1-carboxylic acid 1- (3,5-bistrifluoromethylphenyl) ethyl ester described in Table 100 below.

Reference Example 32
A small amount of iodine was added to 1.74 g of magnesium and 40 ml of tetrahydrofuran, and 10.4 g of 2-bromo-5-fluorotoluene was added dropwise over 40 minutes at room temperature under a nitrogen stream. The reaction solution was heated to reflux for 1 hour to prepare a Grignard reagent solution. To the adjusted Grignard reagent solution, 5.46 g of 4-methoxypyridine was added dropwise over 20 minutes at −40 ° C. under a nitrogen stream. After completion of dropping, the mixture was stirred at -40 ° C to -30 ° C for 30 minutes. Next, the reaction solution was cooled to −40 ° C., and a solution in which 12 g of di-tert-butyl dicarbonate was dissolved in 20 ml of tetrahydrofuran was added dropwise while maintaining the temperature at −40 ° C. or lower. After completion of the dropwise addition, the reaction solution was slowly warmed, ice was added at −15 ° C. and stirred for 20 minutes, and an aqueous citric acid solution was further added and stirred at room temperature for 40 minutes. Ethyl acetate was added to the residue obtained by evaporating tetrahydrofuran and extracted twice. The organic layers were combined, washed with saturated brine, dried and concentrated. Diisopropyl ether was added to the residue, and the resulting crystals were collected by filtration with diisopropyl ether to give 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo- described in Table 100 below. 1,1.9 g of 2,3-dihydro-1H-pyridine was obtained.

Reference Example 33
916 mg of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-2,3-dihydro-1H-pyridine and 110 mg of 10% palladium-carbon (water 50.5%) were added to ethanol. In addition to 6.0 ml, the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the solvent was distilled off. The residue is dissolved in 15 ml of toluene and cooled to -78 ° C. To this solution, 1.8 ml of aluminum butyllithium hydride (65 wt% toluene solution) was slowly added dropwise under a nitrogen stream. A 1M aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred for 10 minutes. The resulting precipitate was filtered off using celite and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous ammonium chloride and saturated brine, and the organic layer was dried and concentrated. 7.5 ml of ethyl acetate was added to the residue, and 7.5 ml of 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, it was added to ethyl acetate-1M aqueous sodium hydroxide solution and stirred. After separating the organic layer, the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over sodium sulfate, and the solvent was evaporated to obtain 471 mg of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine described in Table 100 below.

Reference Example 34
831 ml of triphosgene was dissolved in 3.0 ml of dichloromethane, and a solution of 1.08 g of N- (3,5-bistrifluoromethylbenzyl) -N-methylamine and 1.76 ml of triethylamine in 5.0 ml of dichloromethane under nitrogen flow and ice cooling. Was added dropwise over 10 minutes. The reaction solution was stirred at 0 ° C. to 5 ° C. for 30 minutes. The solvent was distilled off and the residue was dried. Water and dichloromethane were added to the residue and extracted twice. The organic layers were combined, washed with saturated brine, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 10: 1) to give N- (3,5-bistrifluoromethylbenzyl) -N-methyl-aminocarbonyl chloride described in Table 100 below. 760 mg was obtained.

Reference Example 35
24.5 g of 3,5-bistrifluoromethylbenzaldehyde was dissolved in 20 ml of methanol, and 60 ml of ethylamine (2M tetrahydrofuran solution) was added thereto under ice cooling. Next, 4.38 g of sodium borohydride was added little by little, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction solution and concentrated. The residue is extracted with dichloromethane, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → chloroform: methanol = 9: 1) to give N- (3,5-bistrifluoromethylbenzyl)-described in Table 101 below. 6.35 g of N-ethylamine was obtained.

Reference Example 36
(1) Magnesium 1.34 g and a small amount of iodine were added to 20 ml of tetrahydrofuran, and a solution obtained by adding 9.50 g of 2-bromotoluene to 45 ml of tetrahydrofuran was added dropwise to prepare a grinal reagent. A solution obtained by adding 5.46 g of 4-methoxypyridine to 20 ml of tetrahydrofuran at −60 ° C. or lower under a nitrogen atmosphere was added dropwise to this Grignard reagent, and then a solution of 10.24 g of benzyl chloroformate added to 50 ml of tetrahydrofuran was −40 ° C. Was added dropwise and stirred for 3 hours. The temperature was raised to room temperature, 120 ml of 5% aqueous citric acid solution was added, and 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 collected by filtration to obtain 11.15 g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-2,3-dihydro-1H-pyridine.
MS (m / z): 322 [M ⁺⁺ 1].

(2) 11.15 g of 1-benzyloxycarbonyl-2- (2-methylphenyl) -4-oxo-2,3-dihydro-1H-pyridine was dissolved in a mixed solution of 125 ml of ethanol and 35 ml of tetrahydrofuran, and hydrogenated. 2.76 g of sodium boron was added and stirred at room temperature for 1 day. Further, 1.38 g of sodium borohydride was added and stirred at room temperature for 1 day. Concentrate the reaction solution, add distilled water to the residue, extract with chloroform, dry, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (chloroform: acetone = 49: 1 → 9: 1) to obtain 6.18 g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine. It was.
MS (m / z): 326 [M ⁺⁺ 1].

(3) 1.63 g of 1-benzyloxycarbonyl-4-hydroxy-2- (2-methylphenyl) piperidine is dissolved in 21 ml of toluene, 973 mg of 1,1'-carbonyldiimidazole is added, and the mixture is heated at 60 ° C for 1 hour. Stir. Ethanolamine 1.21ml was added to this solution, and it stirred at 60 degreeC for 6 hours. Distilled water was added to the reaction solution, extracted with chloroform, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 9: 1 → chloroform: methanol = 19: 1) to give 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- 1.34 g of (2-methylphenyl) piperidine was obtained.
MS (m / z): 413 [M ⁺⁺ 1].

  (4) 1-Benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine (1.33 g) was dissolved in methanol (30 ml), and 10% palladium-carbon (70 mg) was added thereto. The mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated to obtain 880 mg of 4- (2-hydroxyethylaminocarbonyloxy) -2- (2-methylphenyl) piperidine described in Table 101 below.

Reference Example 37
(1) 1-Benzyloxycarbonyl-2- (4-fluorophenyl) -4-oxo-2,3-dihydro was treated in the same manner as in Reference Example 1 using 25 g of 4-fluoro-1-bromobenzene. 22.3 g of -1H-pyridine was obtained.

  (2) 20 g of the compound obtained in (1) above was dissolved in 400 ml of ethanol, 7.6 g of sodium borohydride was added, and the mixture was stirred at −20 ° C. for 2 hours. After completion of the reaction, an aqueous citric acid solution was slowly added and stirred until no foaming occurred. After the solvent was distilled off, chloroform and water were added for liquid separation. The aqueous layer was extracted again with chloroform, and then 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 (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine. (B) 6.3 g of a mixture of (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4-hydroxypiperidine was obtained.

  (3) Using 6.2 g of the compound obtained in the above compound (2) and treating in the same manner as in Production Example 117, (a) (2R, 4S) -1-benzyloxycarbonyl-2- (4- Fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine (b) (2S, 4R) -1-benzyloxycarbonyl-2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) ) 7.3 g of a mixture of piperidine was obtained.

  (4) By using 6.3 g of the compound obtained in (3) above and treating in the same manner as in Reference Example 4, (a) (2R, 4S) -2- (4-fluoro) described in Table 101 below 1. A mixture of phenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine and (b) (2S, 4R) -2- (4-fluorophenyl) -4- (2-hydroxyethylaminocarbonyloxy) piperidine. 6 g was obtained.

Reference Example 38
After dissolving 0.639 g of N-tosyl-D-phenylalanine in 5 ml of methanol and heating to 59 ° C., 0.418 g of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine was added to 1.3 ml of methanol. Dissolved and added dropwise. When the crystals began to precipitate, the crystals were grown for 20 minutes, and then the remaining methanol solution of 2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine was added dropwise over 5 minutes. Thereafter, the temperature was cooled from 59 ° C. to 30 ° C. over 1 hour, and the crystals were further grown under stirring conditions for 1 hour. The obtained crystals were collected by filtration, washed with ice-cold methanol, and air-dried at 60 ° C. overnight to give (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine. 0.325 g of the diastereomeric salt of was obtained. To the obtained crystals, 0.62 ml of 2M hydrochloric acid was added, and ethyl acetate was added for liquid separation. To the aqueous layer was added 0.3 ml of 5M aqueous sodium hydroxide solution, and the mixture was extracted 4 times with ethyl acetate (1 ml). The organic layer was dried and concentrated under reduced pressure to obtain 0.129 g of (2R, 4S) -2- (4-fluoro-2-methyl) phenyl-4-hydroxypiperidine described in Table 102 below.

Reference Example 39
2.72 g of 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde was dissolved in 40 ml of dichloromethane, and 2.5 ml of 8M methylamine-ethanol solution, 572 μl of acetic acid and sodium triacetoxyborohydride were dissolved therein. 3.12 g was added and stirred at room temperature for 6 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 49: 1 → 4: 1) to give N- [2-methoxy-5- (5-trifluoromethyl) described in Table 102 below. 2.2 g of tetrazol-1-yl) benzyl] -N-methylamine were obtained.

Reference Example 40
1.45 g of 1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine is dissolved in 20 ml of acetic acid, 3.85 g of ammonium acetate and 5 g of sodium sulfate were added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 1.18 g of sodium triacetoxyborohydride was added and stirred at room temperature for 24 hours. After the reaction, 2M aqueous sodium carbonate solution, chloroform and water were added and stirred for 0.5 hour, followed by liquid separation. 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 obtained oily substance was treated with 4M hydrochloric acid in ethyl acetate, concentrated under reduced pressure, and then crystallized with isopropyl ether to give 4-amino-1- {N- (3,5-bistriline described in Table 103 below. 1.16 g of fluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride was obtained.

Reference Example 41
Reference example using (2R) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine (2R) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4) described in Table 103 below by treating in the same manner as in No. 40. -Fluoro-2-methylphenyl) piperidine hydrochloride was obtained.

Reference Example 42
100 mg of trans-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine was added to 4M hydrochloric acid. With ethyl acetate solution. The precipitate formed by adding ether and hexane was collected by filtration, washed with hexane, dried under vacuum, and trans-4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) described in Table 103 below. ) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine hydrochloride 56 mg was obtained.

Reference Example 43
Reference using cis-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine By treating in the same manner as in Example 42, cis-4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4- Fluoro-2-methylphenyl) piperidine hydrochloride was obtained.

Reference Example 44
(2R, 4S) -1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) To 1 ml of ethyl acetate solution of 212 mg of -4-tert-butoxycarbonylaminopiperidine was added 2 ml of 4M hydrochloric acid-ethyl acetate solution under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. After the solvent was distilled off, chloroform and a 2M aqueous sodium hydroxide solution were added to the residue for separation, the aqueous layer was extracted with chloroform, and the entire organic layer was dried and evaporated to give (2R, 4S) -4-amino-1- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) 177 mg of piperidine was obtained.

Reference Example 45
(2R, 4S) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) Treatment with -4-tert-butoxycarbonylaminopiperidine in the same manner as in Reference Example 44 results in (2R, 4S) -4-amino-1- [N- {1- (S )-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine.

Reference Example 46
(1) (2R) -1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) 1.49 g of 4-oxopiperidine is dissolved in 10 ml of ethanol, and 226 mg of hydroxylamine hydrochloride and 267 mg of sodium acetate are added and stirred overnight. Ethanol is distilled off, water is added to the residue and the mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine and dried. The solvent is distilled off to obtain a resinous compound.

  (2) The compound obtained in (1) above is dissolved in 50 ml of methanol, 844 mg of nickel chloride is added and ice-cooled, and 224 mg of sodium borohydride is gradually added thereto. After stirring overnight, the mixture is concentrated, water and ethyl acetate are added, and the mixture is separated, and the organic layer is washed with saturated brine and dried. The solvent was distilled off, and (2R) -4-amino-1- [N- {1- (S)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] amino described in Table 105 below was used. 1.44 g of carbonyl-2- (4-fluoro-2-methylphenyl) piperidine are obtained.

Reference Example 47
(2R) -1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine By treating in the same manner as in Example 46 (1) and (2), (2R) -4-amino-1- {N- (3,5-bistrifluoromethylphenyl) methyl-N- Methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Reference Example 48
(2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-tert-butoxycarbonylaminopiperidine 700 mg was dissolved in 3.5 ml of ethyl acetate, 3.5 ml of 4M hydrochloric acid-ethyl acetate solution was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. After the solvent is distilled off, ethyl acetate is added to the residue and the mixture is collected by filtration. Chloroform and 2M aqueous sodium hydroxide solution were added to the filtered product, and the mixture was separated, and the aqueous layer was extracted with chloroform. By drying and concentrating all organic layers, (2R, 4S) -4-amino-1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl- described in Table 105 below 489 mg of 2- (4-fluoro-2-methylphenyl) piperidine was obtained.

The compound which is an active ingredient of the present invention has an excellent tachykinin receptor antagonistic action. In addition, the compound which is an active ingredient of the present invention is highly safe and excellent in terms of absorbability, intracerebral transferability, metabolic stability, blood concentration, sustainability, and the like, and thus exhibits excellent medicinal effects.

Claims (4)

Formula [I]

(Wherein ring A has the formula:

And ring B is represented by the formula:

A ¹ , A ² and A ³ are the same or different and each represents a hydrogen atom; a halogen atom; an alkyl group; an arylalkyl group; a tert-butyldimethylsilyl group; a tert-butyldiphenylsilyl group; A hydroxyl group which may be protected with an acyl group; or an alkoxy group, and B ¹ , B ² and B ³ are the same or different and are a hydrogen atom; a trihalogenoalkyl group; a halogen atom; a cyano group; a phenyl group; A group; an alkyl group; an arylalkyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group or a hydroxyl group optionally protected with an acyl group; or an alkoxy group,
R ¹ is a hydroxyl group; an alkylsulfonyloxy group; a tetrahydropyranyloxy group; a triazolyl group; a tetrazolyl group that may be substituted with an alkyl group; or an alkoxy group that may be substituted with an alkoxy group;
A morpholino group; an imidazolyl group; a hydroxyl group, a morpholinocarbonyl group, a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an alkylthio group, an alkoxy group, an alkylsulfonyl group, an alkanoyloxy group or an alkyl group in which the alkyl group moiety may be substituted Amino group; substituted with hydroxyl group, alkoxycarbonyl group, carboxyl group, hydroxyalkylaminocarbonyl group, alkoxyalkylaminocarbonyl group, alkylthioalkylaminocarbonyl group, alkylsulfinylalkylaminocarbonyl group, alkylsulfonylalkylaminocarbonyl group or hydroxyalkyl group Piperidino groups; piperidini substituted with hydroxyalkanoyl groups or alkoxyalkanoyl groups Amino groups; sulfur atoms may be optionally oxidized thiomorpholino; oxopyrrolidinyl group; oxotetrahydro-thiazolyl sulfonyl group; or a carbonyl group substituted with a dialkylamino sulfonylamino group,
Represents
R ² represents a hydrogen atom,
Z represents a group represented by —N (R ³ ) —,
R ³ represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group,
R ⁴ represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group. )
A pharmaceutical composition comprising a piperidine derivative represented by the formula (1) or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising as an active ingredient a compound selected from the following (a) and (b) or a pharmacologically acceptable salt thereof.
(A) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4- (2- Hydroxyethylaminocarbonyloxy) piperidine, and (b) (2R, 4S) -1- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-2- (4-fluoro-2- Methylphenyl) -4- (1-oxothiomorpholinocarbonyloxy) piperidine. The pharmaceutical composition according to any one of claims 1 and 2 , which is a tachykinin receptor antagonist. The pharmaceutical composition according to any one of claims 1 and 2 , which is a prophylactic / therapeutic agent for abnormal urination diseases.