JP2007197428A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a piperidine compound having excellent tachykinin receptor antagonistic activity as an active component. <P>SOLUTION: The pharmaceutical composition contains a piperidine compound expressed by general formula [I] or its pharmacologically allowable salt as an active component. In the formula, the ring A is a benzene ring optionally having a substituent; the ring B is a benzene ring optionally having a substituent; R<SP>1</SP>is a hydrogen atom or a substituent for an amino group; R<SP>2</SP>is a hydrogen atom, a (substituted)hydroxy group or the like; Z is an oxygen atom or a group expressed by -N(R<SP>3</SP>)-; R<SP>3</SP>is a hydrogen atom or a (substituted)alkyl group; R<SP>4a</SP>and R<SP>4b</SP>are each independently a hydrogen atom or a (substituted)alkyl group or both groups may be bonded together at the terminals to form an alkylene group. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition comprising a piperidine compound 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)].

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 compound that is sufficiently satisfactory in terms of kinetics and absorbability) has not yet been found. Therefore, development of a compound having an excellent tachykinin receptor antagonistic action and sufficiently satisfactory in clinical effect as a therapeutic agent for the disease state is desired.

  The present invention relates to general formula [I]

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ represents a hydrogen atom or an amino group substituent.
R ² represents a hydrogen atom, a hydroxyl group that may have a substituent, an amino group that may have a substituent, an alkyl group that may have a substituent, or a carbonyl group that has a substituent. Or represents 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.
R ^4a and R ^4b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded to each other at a terminal to form an alkylene 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 which has an excellent tachykinin receptor antagonistic action and which is sufficiently satisfactory clinically in terms of safety, in particular, sustainability (metabolism, pharmacokinetics, absorbability), etc. Is to provide.

  In the present invention, ring A of compound [I] as an active ingredient represents a benzene ring which may have a substituent, and the substituent of the benzene ring may be an alkyl group which may have a substituent, Examples thereof include a halogen atom, a cyano group, an optionally protected 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, and examples of the substituent of the benzene ring include a haloalkyl group, a halogen atom, a cyano group, a phenyl group, Examples of the hetero atom include a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur 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 optionally substituted alkyl group, an optionally protected hydroxyl group or alkoxy B ¹ , B ² and B ³ are the same or different and each represents a hydrogen atom, a haloalkyl group, a halogen atom, a cyano group, a phenyl group or an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. Examples thereof include compounds containing 1 to 4 heterocyclic groups, alkyl groups, hydroxyl groups or alkoxy groups which may be protected. Examples of the substituent of the alkyl group that may have a substituent include a halogen atom. Examples of the haloalkyl group include alkyl groups in which 1 to 3 halogen atoms are the same or different and are substituted, for example, a trihalogenoalkyl group. Examples of the trihalogenoalkyl group include a trifluoromethyl group and trichloromethyl. 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 compound [I] which is an active ingredient of the present invention, the hydroxyl-protecting group which may be protected includes an arylalkyl group which may have a substituent and a silyl group which may have a substituent. And a conventional protecting group such as an acyl group. 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 represents a hydrogen atom or a substituent of an amino group, and the substituent of the amino group in R ¹ is an alkyl group which may have a substituent, A cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an amino group which may have a substituent, a hydroxyl group which may have a substituent, a substituent A carbonyl group having a substituent, a sulfinyl group having a substituent, a sulfonyl group having a substituent, or a heterocyclic group optionally having a substituent.

Among these, R ¹ is preferably an amino group which may have a substituent, a hydroxyl group which may have a substituent or a sulfinyl group which has a substituent, and further has a substituent. An alkylamino group which may have a substituent, a cycloalkylamino group which may have a substituent, an arylamino group which may have a substituent, an alkoxy group which may have a substituent, and a substituent. An alkylsulfinyl group or a hydroxysulfinyl group which may be substituted is preferable.

In the compound [I] which is the active ingredient of the present invention, the substituent of the alkyl group which may have the substituent of R ¹ includes an alkoxycarbonyl group, a morpholinocarbonyl group, and an alkyl group moiety substituted with a hydroxyl group. Dialkylaminocarbonyl group, optionally substituted heterocyclic group, hydroxyl group, hydroxyalkylaminocarbonyloxy group, alkylpiperazinocarbonyl group, alkanoyl group, alkylsulfonyl group, pyrrolidinylsulfonyl group , A cyano group, a carboxyl group, a halogen atom, an alkylthio group or an alkanoylamino group. The alkyl group may have 1 to 3 substituents on the alkyl group. Examples of the substituent of the heterocyclic group which is a substituent of the alkyl group include an alkanoyl group, an alkyl group or an oxo group which may be substituted with a hydroxyl group. Examples of the heterocyclic group include heterocyclic groups containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl , Benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl Quinolyl, isoquinolyl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl Group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group and the like.

In the compound [I] which is an active ingredient of the present invention, examples of the substituent of the cycloalkyl group which may have a substituent of R ¹ include a hydroxyl group, an alkylenedioxy group, an oxo group and the like.

In the compound [I], which is an active ingredient of the present invention, examples of the substituent of the aryl group which may have a substituent of R ¹ include a hydroxyl group, an alkyl group, a cyano group, and a halogen atom. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.

In the compound [I] which is an active ingredient of the present invention, the substituent of the amino group which may have a substituent of R ¹ is
(1) an alkyl group which may have a substituent,
(2) a cycloalkyl group optionally having a substituent,
(3) an aryl group which may have a substituent, or
(4) A heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom, wherein the heterocyclic group is a group which may have a substituent. Can be mentioned.

  Examples of the substituent of the alkyl group which may have the above (1) substituent include a dialkylaminocarbonyl group, an alkoxy group, a dialkylamino group, a cyano group, a morpholino group, a pyridyl group, and a halogen atom.

  Examples of the substituent of the cycloalkyl group having the above (2) substituent include a hydroxyl group, an alkyl group, a cyano group, and a halogen atom.

  Examples of the substituent of the aryl group which may have a substituent (3) include a hydroxyl group, an alkyl group, a cyano group, and a halogen atom. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.

  Examples of the heterocyclic group containing 1 to 4 atoms selected from the nitrogen atom, oxygen atom and sulfur atom as the hetero atom (4) include saturated or unsaturated monocyclic or bicyclic heteroaromatic groups. For example, thienyl group, furyl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group , Pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, morpholinyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, Ki Xalinyl group, cinnolinyl group, quinolyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group, chromanyl group , Indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group and the like. Among these heterocyclic groups, pyridyl group, pyrrolyl group, piperazinyl group, quinolyl group, piperidinyl group, pyrimidinyl group, thiazolyl group, pyrazinyl group, morpholino group, indolyl group, cinnolinyl group, furyl group, thienyl group, pyrrolidinyl group, An imidazolidinyl group or the like is preferably used. Examples of the substituent of the heterocyclic group include a dialkylamino group, an alkoxycarbonyl group, an alkyl group, an alkoxy group, an oxo group, a hydroxyl group, or a halogen atom.

In the compound [I] which is the active ingredient of the present invention, examples of the substituent of the hydroxyl group which may have a substituent of R ¹ include an alkyl group which may have a substituent. As the substituent of the alkyl group which may have the substituent, an hydroxyl group, a dialkylamino 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 pyridyl group, a piperidinyl group, a morpholino group, an isoxazolyl group, a triazolyl group, a tetrazolyl group, a pyrrolidinyl group, and an imidazolidinyl 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 carbonyl group having the substituent of R ¹ is as follows:
(1) an alkyl group which may have a substituent,
(2) a cycloalkyl group optionally having a substituent,
(3) an aryl group which may have a substituent,
(4) a heterocyclic group which may have a substituent,
(5) an amino group which may have a substituent,
(6) The alkoxy group which may have a substituent, or (7) the hydroxyl group which may have a substituent is mentioned.

As the substituent of the alkyl group which may have the above (1) substituent,
(I) a hydroxyl group,
(II) a carbonylamino group having a substituent,
(III) an aminocarbonyl group which may have a substituent,
(IV) an alkanoyl group,
(V) an alkylsulfonyl group,
(VI) The heterocyclic group or (VII) amino group which may have a substituent is mentioned.

  The substituent of the carbonylamino group having the substituent of (II) above includes (i) a hydroxyl group, (ii) an optionally substituted alkyl group, or (iii) a substituent. A heterocyclic group which may be used. The substituent of the alkyl group which may have a substituent of (ii) above is a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hydroxyl group or a hetero atom And the group which may have a substituent is mentioned for the said heterocyclic group. Examples of the substituent of the heterocyclic group include an oxo group, a hydroxyl group, an alkanoyl group, and an alkyl group. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group. Examples of the substituent of the heterocyclic group which may have a substituent (iii) include an alkanoyl group, an oxo group or a hydroxyl group which may be substituted with a hydroxyl group. Examples of the heterocyclic group include heterocyclic groups containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group.

  As the substituent of the aminocarbonyl group which may have a substituent of the above (III), (i) an alkyl group which may have a substituent or (ii) an optionally substituted group. And heterocyclic groups. The substituent of the alkyl group which may have a substituent of (i) above is a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hydroxyl group or a hetero atom And the group which may have a substituent is mentioned for the said heterocyclic group. Examples of the substituent of the heterocyclic group include an oxo group, a hydroxyl group, an alkanoyl group, and an alkyl group. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group. Examples of the substituent of the heterocyclic group which may have a substituent of (ii) include an alkanoyl group, an oxo group or a hydroxyl group which may be substituted with a hydroxyl group. Examples of the heterocyclic group include heterocyclic groups containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group.

  Examples of the substituent of the heterocyclic group which may have a substituent of the above (VI) include an oxo group and an alkyl group. One or two substituents of the heterocyclic group may be substituted on the heterocyclic group. Examples of the heterocyclic group include heterocyclic groups containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group.

  Examples of the substituent (2) of the cycloalkyl group which may have a substituent include a hydroxyl group, an alkyl group, an oxo group, an alkoxycarbonyl group, an oxopyrrolidinyl group, a cyano group, and a halogen atom. One to two substituents of the cycloalkyl group may be substituted on the cycloalkyl group.

  Examples of the substituent of the aryl group which may have a substituent (3) include a hydroxyl group, an alkyl group, a cyano group, and a halogen atom. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.

As the substituent of the heterocyclic group which may have the above (4) substituent,
(I) an oxo group,
(II) an alkanoyl group which may have a substituent,
(III) an alkyl group which may have a substituent,
(IV) a hydroxyl group,
(V) an alkoxycarbonyl group,
(VI) an alkylsulfonyl group,
(VII) pyrimidinyl group,
(VIII) A cyano group or a (IX) dialkylaminocarbonyl group is mentioned. One to three substituents of the heterocyclic group may be substituted on the heterocyclic group. Examples of the heterocyclic group include monocyclic heterocyclic groups containing 1 to 4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom as a hetero atom. Examples of the monocyclic heterocyclic group include piperidinyl group, piperazinyl group, pyridyl group, tetrazolidyl group, pyrrolidinyl group, imidazolidinyl group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group or azetidinyl group. It is done.

  Examples of the substituent of the alkanoyl group which may have the substituent (II) include a hydroxyl group.

  Examples of the substituent of the alkyl group which may have a substituent of (III) above include a hetero atom containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a halogen atom, a hydroxyl group or a hetero atom. Examples of the heterocyclic group include a group that may have a substituent. The alkyl group may have 1 to 3 substituents on the alkyl group. Examples of the substituent of the heterocyclic group include an oxo group, a hydroxyl group, an alkanoyl group, and an alkyl group. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group.

  (5) The substituent of the amino group which may have a substituent is an alkyl group which may be substituted with a hydroxyl group, or an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. A heterocyclic group containing four, and examples of the heterocyclic group include a group which may have a substituent. Examples of the substituent of the heterocyclic group include an oxo group, a hydroxyl group, an alkanoyl group, and an alkyl group. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl, benzothiazolyl, benzisothiazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzimidazolyl, pteridinyl, pyridopyrimidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, tetrahydroquino Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group. One or two amino group substituents may be substituted on the amino group.

  Examples of the substituent of the alkoxy group (6) which may have a substituent include a hydroxyl group.

  The hydroxyl group which may have a substituent of the above (7) is a heterocyclic group containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom, Examples of the cyclic group include a group which may have a substituent. Examples of the substituent of the heterocyclic group include an oxo group, a hydroxyl group, an alkanoyl group, and an alkyl group. 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolin Group, quinolyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group, chromanyl group, indolinyl group , Isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group and the like.

In the compound [I], which is an active ingredient of the present invention, examples of the substituent of the sulfinyl group having the substituent of R ¹ include a hydroxyl group or an optionally substituted alkyl group. 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, the substituent of the heterocyclic group which R ¹ may have a substituent may be an alkanoyl group or alkoxycarbonyl group which may have a substituent. A cycloalkyl group having a substituent, an alkylsulfonyl group, an alkyl group optionally having a substituent, a dialkylaminocarbonyl group, a hydroxyl group, an oxo group, or a pyridyl group having a substituent. It is done. Examples of the substituent of the alkanoyl group that may have the substituent include a hydroxyl group or an oxo group. Examples of the substituent of the cycloalkyl group having the substituent include a hydroxyl group or an oxo group. Examples of the substituent of the alkyl group which may have the substituent include a halogen atom. Examples of the substituent of the pyridyl group having the substituent include a dialkylaminocarbonyl group, an alkylaminocarbonyl group in which the alkyl group portion may be substituted with a hydroxyl group, an aminocarbonyl group, a pyrrolidinylcarbonyl group, or a morpholinocarbonyl group. Groups. As for the substituent of the heterocyclic group of R ¹ , ¹ to 3 substituents may be substituted on the heterocyclic group. Examples of the heterocyclic group include heterocyclic groups containing 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. 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 group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, thiomorpholinyl group , Tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, azetidinyl group, thietanyl group, benzothienyl group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindo Group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, isoquinolyl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl Group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group, chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group, dihydrophthalazinyl group and the like. Among these heterocyclic groups, a piperidinyl group, a pyrazinyl group, a pyrimidinyl group, a pyrrolidinyl group, an oxazolidinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a dioxanyl group, an azetidinyl group, a thietanyl group, and the like are preferable. Preferably a thio group, a tetrahydrothiopyranyl group, an azetidinyl group or a thietanyl group.

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, examples of the substituent of the hydroxyl group which may have a substituent of R ² include an alkyl group which may be substituted with a hydroxyl group.

In the present invention, examples of the substituent of the amino group which may have the substituent of R ² include an alkyl group which may be substituted with a hydroxyl 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 or a hydroxyl group which may be substituted with a hydroxyl group.

In the compound [I] which is an active ingredient of the present invention, the substituent of the carbonyl group having a substituent of R ² is a hydroxyl group, an alkoxy group which may be substituted with a hydroxyl group, or a hydroxyl group. There may be mentioned a good alkylamino group.

In the present invention, examples of Z include an oxygen atom or a group represented by —N (R ³ ) —.

In 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 the active ingredient of the present invention, R ^4a and R ^4b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or bonded to each other at the terminal. Group which forms an alkylene group. Examples of the substituent of the alkyl group that may have a substituent include a hydroxyl 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. Examples of the substituent of the alkyl group include a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group, an alkanoyl group, an alkylsulfonyl group, an alkylimidazolyl group, and an alkylpyrazolily group whose alkyl group portion may be substituted with a hydroxyl group. Nyl group, cyano group, carboxyl group, pyrrolidinylsulfonyl group, halogen atom, alkylthio group, oxadiazolyl group, dialkylisoxazolyl group, oxopyridyl group or alkanoylamino group which may be substituted with alkyl group are preferable.

As the compound which is an active ingredient of the present invention, those in which R ¹ is a cycloalkyl group having a substituent are preferable. The substituent for the cycloalkyl group is preferably a hydroxyl group, an alkylenedioxy group or an oxo group.

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. The substituent of the carbonyl group includes a hydroxyalkyl group; an alkanoylalkyl group; a hydroxycycloalkyl group; an alkylsulfonylalkyl group; an oxopyrrolidinylalkyl group; an oxopyridinylalkyl group substituted with an alkyl group; Group: thiomorpholinoalkyl group; aminoalkyl group; tetrahydropyranyloxy group; alkanoylpiperidinyl group; alkoxycarbonylpiperidinyl group; alkylsulfonylpiperidinyl group; pyrimidinylpiperidinyl group; alkyloxypiperidinyl group; Hydroxypiperidinyl group; oxopiperazino group; alkylpiperazino group: alkanoylpiperazino group; alkoxycarbonylpiperazino group; hydroxyalkylpiperazino group; morpholino group; sulfur atom is oxo group 1 to 2 optionally substituted thiomorpholino groups; hydroxyalkylpyrrolidinyl group; alkyloxopyrrolidinyl group; dioxopyrrolidinyl group; tetrahydrothiopyranyl group; 2 sulfur atoms substituted with oxo groups An optionally substituted tetrahydrothiopyranyl group; a hydroxyalkylamino group; a dialkylamino group whose alkyl moiety may be substituted with a hydroxyl group; an oxopyridyl group; a cyanopyridyl group; an alkanoylazetidinyl group; an alkoxycarbonylazetidinyl group A group; a dialkylaminocarbonylazetidinyl group; an alkylsulfonylazetidinyl group; or an alkoxy group optionally substituted with a hydroxyl group is 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. As the substituent of the sulfinyl group, an alkyl group or a hydroxyl group which may be substituted with a hydroxyl 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, those in which R ¹ is a sulfonyl group having a substituent are preferable. The substituent for the sulfonyl group is preferably an alkyl group.

As the compound which is an active ingredient of the present invention, a heterocyclic group in which R ¹ may have a substituent is preferable. Examples of the heterocyclic group include piperidinyl group, pyrazinyl group, pyrimidinyl group, pyrrolidinyl group, oxazolidinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholino group, thiomorpholino group, pyridyl group, azetidinyl group or A thietanyl group is preferable, and among these, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, an azetidinyl group or a thietanyl group is preferable. In addition, examples of the substituent of the heterocyclic group include an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group, a dialkylaminocarbonyl group, which may be substituted with a hydroxyl group, and an alkyl group which may be substituted with a hydroxyl group. An aminocarbonyl group, aminocarbonyl group, pyrrolidinylcarbonyl group, morpholinocarbonyl group, a cycloalkyl group substituted with a hydroxyl group, an alkyl group, a trihalogenoalkyl group, a hydroxyl group or an oxo group is preferred. One to three substituents of the heterocyclic group may be substituted on the heterocyclic group.

  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, a halogen atom, a cyano group, an alkoxy group or a trihalogenoalkyl group; B ² is a hydrogen atom, an alkyl group, a halogen atom, a cyano group, an alkoxy group or a trihalogenoalkyl group; and B ³ is a hydrogen atom. R ¹ is a hydrogen atom; a dialkylaminocarbonyl group, a morpholinocarbonyl group, a hydroxyl group, an alkoxycarbonyl group, a morpholinoaminocarbonyl group, a hydroxyalkylaminocarbonyloxy group, an alkyl piperazine, in which the alkyl group part may be substituted with a hydroxyl group Nocarbonyl group, alkanoyl group, alkylsulfonyl Group, alkylimidazolyl group, alkylpyrazolinyl group, cyano group, carboxyl group, pyrrolidinylsulfonyl group, halogen atom, alkylthio group, oxadiazolyl group, dialkylisoxazolyl group, oxo optionally substituted with alkyl group An alkyl group optionally substituted with a pyridyl group, an alkanoylamino group or a hydroxyalkylaminocarbonyl group; a trihalogenoalkyl group; a cycloalkyl group optionally substituted with a hydroxyl group, an alkylenedioxy group or an oxo group; a carboxyl group; Hydroxyl group, alkanoyl group, alkylsulfonyl group, oxopyrrolidinyl group, pyrrolidinyl group substituted by alkyl group and oxo group, morpholino group, thiomorpholino group or alkanoyl group optionally substituted by amino group; A tetrahydropyranyloxycarbonyl group; a pyrimidinylaminocarbonyl group; an alkylaminocarbonyl group in which the alkyl group moiety may be substituted with a hydroxyl group or a cyano group; ~ 2 dialkylaminocarbonyl groups which may be substituted; pyridylaminocarbonyl groups in which the pyridyl group moiety is substituted with hydroxyl groups; aminocarbonyl groups substituted with alkylpyridonyl groups and alkyl groups; alkanoyl groups, hydroxyl groups, Piperidinylcarbonyl group substituted by 1 to 2 by oxo group, alkoxycarbonyl group, alkylsulfonyl group, pyrimidinyl group or alkyl group; oxo group, alkyl group, pyrimidinyl group, alkylsulfonyl group, alkanoyl group, A piperazinocarbonyl group substituted with a alkoxycarbonyl group or a hydroxyalkyl group; a morpholinocarbonyl group; a thiomorpholinocarbonyl group in which one or two sulfur atoms may be substituted with an oxo group; a hydroxyalkyl group or a hydroxyl group A substituted pyrrolidinylcarbonyl group; a cycloalkylcarbonyl group substituted with one or two hydroxyl groups, alkyl groups, oxo groups, alkoxycarbonyl groups or oxopyrrolidinyl groups; substituted with alkyl groups or oxo groups An oxopyrrolidinylcarbonyl group; a tetrahydropyranylcarbonyl group; a tetrahydrothiopyranylcarbonyl group in which the sulfur atom may be disubstituted by an oxo group; a pyridylcarbonyl group substituted by an oxo group or a cyano group; alkanoyl Group, An azetidinylcarbonyl group substituted by an alkoxycarbonyl group, a dialkylaminocarbonyl group, an alkylsulfonyl group or a trihalogenoalkyl group; an alkylsulfinyl group optionally substituted by a hydroxyl group; a hydroxysulfinyl group; a hydroxyl group or an alkanoyloxy group An alkylsulfonyl group which may be substituted; a piperidinyl group substituted with an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group; a tetrahydropyranyl group; or one or two sulfur atoms substituted with an oxo group A good tetrahydrothiopyranyl group; a dialkyldioxanyl group; a dioxothiomorpholino group; a morpholino group optionally disubstituted with an oxo group; an oxopyrrolidinyl group; a dioxopyrrole optionally substituted with an alkyl group An azetidinyl group substituted by an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group, a dialkylaminocarbonyl group, a trihalogenoalkyl group, or a cycloalkyl group substituted by a hydroxyl group, which may be substituted by a hydroxyl group; Thietanyl group in which one or two sulfur atoms are substituted with an oxo group; pyrazinyl group; pyrimidinyl group; oxooxazolidinyl group; or dialkylaminocarbonyl group, alkylamino in which the alkyl group part may be substituted with a hydroxyl group A pyridyl group substituted with a group selected from a carbonyl group, an aminocarbonyl group, a pyrrolidinylcarbonyl group and a morpholinocarbonyl group, R ² is a hydrogen atom, Z is an oxygen atom or —N (R ³ ) — in a group represented, R ³ is substituted with a hydroxyl group There is also an alkyl group, optionally R ^4a is replaced by a hydrogen atom or a hydroxyl group is also an alkyl group, R ^4b and the like are compounds which are an alkyl group which may be substituted with a hydrogen atom or a hydroxyl group.

  Of these, ring A has the formula:

And ring B is represented by the formula:

A ¹ is a hydrogen atom, a halogen atom or an alkyl group, A ² is a hydrogen atom or a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenoalkyl group, an alkyl group A group, an alkoxy group or a halogen atom, B ² is a hydrogen atom, a trihalogenoalkyl group, an alkyl group or a halogen atom, B ³ is a hydrogen atom or a halogen atom, R ¹ is a hydrogen atom; Dialkylaminocarbonyl group, morpholinocarbonyl group, hydroxyl group, alkoxycarbonyl group, alkanoyl group, alkylsulfonyl group, alkylimidazolyl group, alkylpyrazolinyl group, cyano group, carboxyl group, pyrrolidinyl which may be substituted with a hydroxyl group Sulfonyl group, halogen atom, alkylthio group, oxadia Zolyl group, dialkylisoxazolyl group, oxopyridyl group which may be substituted with alkyl group or alkyl group which may be substituted with alkanoylamino group; trihalogenoalkyl group; hydroxyl group, alkylenedioxy group or oxo group A cycloalkyl group which may be substituted with: a hydroxyl group, an alkanoyl group, an alkylsulfonyl group, an oxopyrrolidinyl group, an alkyl group and a pyrrolidinyl group substituted with an oxo group, a morpholino group, a thiomorpholino group or an amino group An alkanoyl group; an alkoxycarbonyl group optionally substituted with a hydroxyl group; a tetrahydropyranyloxycarbonyl group; an alkylaminocarbonyl group in which the alkyl group moiety may be substituted with a hydroxyl group; Two are replaced Dialkylaminocarbonyl group; piperidinylcarbonyl group substituted with 1 to 2 alkanoyl group, hydroxyl group, oxo group, alkoxycarbonyl group, alkylsulfonyl group, pyrimidinyl group or alkyl group; oxo group, alkyl group, alkanoyl A piperazinocarbonyl group substituted by an alkoxy group, an alkoxycarbonyl group or a hydroxyalkyl group; a morpholinocarbonyl group; a thiomorpholinocarbonyl group in which one or two sulfur atoms may be substituted by an oxo group; a hydroxyalkyl group or a hydroxyl group A pyrrolidinylcarbonyl group substituted by 1 or 2; a cycloalkylcarbonyl group substituted by 1 or 2 hydroxyl groups, alkyl groups, oxo groups, alkoxycarbonyl groups or oxopyrrolidinyl groups; substituted by alkyl groups or oxo groups An optionally substituted oxopyrrolidinylcarbonyl group; a tetrahydropyranylcarbonyl group; a tetrahydrothiopyranylcarbonyl group in which the sulfur atom may be disubstituted with an oxo group; a pyridylcarbonyl group substituted with an oxo group or a cyano group An azetidinylcarbonyl group substituted with an alkanoyl group, alkoxycarbonyl group, dialkylaminocarbonyl group or alkylsulfonyl group; an alkylsulfinyl group; an alkylsulfonyl group; substituted with an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group Piperidinyl group; tetrahydropyranyl group; tetrahydrothiopyranyl group in which the sulfur atom may be di-substituted by oxo group; dialkyldioxanyl group; dioxothiomorpholino group; di-substituted by oxo group Morpholino group optionally substituted; oxopyrrolidinyl group; dioxopyrrolidinyl group optionally substituted with alkyl group; alkanoyl group optionally substituted with hydroxyl group, alkoxycarbonyl group, alkylsulfonyl group, dialkyl An azetidinyl group substituted with a group selected from an aminocarbonyl group, a trihalogenoalkyl group and a cycloalkyl group substituted with a hydroxyl group; a thietanyl group substituted with 1 to 2 sulfur atoms with an oxo group; a pyrazinyl group; A group selected from a dialkylaminocarbonyl group, an alkylaminocarbonyl group, an aminocarbonyl group, a pyrrolidinylcarbonyl group, and a morpholinocarbonyl group, wherein the alkyl group moiety may be substituted with a hydroxyl group; a pyrimidinyl group; an oxooxazolidinyl group; A pyridine replaced by A group, ^{R 2} is a hydrogen atom, Z is -N ^{(R 3)} - is a group represented by, ^{R 3} is an alkyl ^{group, R 4a} is a hydrogen atom or an alkyl ^{group, R 4b} is a hydrogen atom Or the compound which is an alkyl group is preferable.

  Further, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is a hydrogen atom or an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenomethyl group, and B ² is a trihalogeno group. An alkyl group substituted with an oxopyridyl group, dialkylaminocarbonyl group or alkoxycarbonyl group, which is a methyl group, B ³ is a hydrogen atom, and R ¹ may be substituted with an alkyl group; An alkanoyl group; an alkoxycarbonyl group substituted with a hydroxyl group; an alkylaminocarbonyl group optionally substituted with an alkyl group moiety; a piperidinylcarbonyl substituted with an alkanoyl group, an alkoxycarbonyl group or an alkylsulfonyl group Group; piperazinocarbonyl group substituted by alkanoyl group A cycloalkylcarbonyl group substituted with a hydroxyl group and an alkyl group; a tetrahydropyranylcarbonyl group; an azetidinylcarbonyl group substituted with an alkoxycarbonyl group or an alkylsulfonyl group; substituted with an alkanoyl group or an alkoxycarbonyl group; Tetrahydropyranyl group; tetrahydrothiopyranyl group in which the sulfur atom may be disubstituted with an oxo group; dioxothiomorpholino group; oxopyrrolidinyl group; dioxopyrrolidinyl group; alkanoyl group, alkoxy An azetidinyl group substituted with a carbonyl group, an alkylsulfonyl group or a dialkylaminocarbonyl group; a thietanyl group substituted with 1 to 2 sulfur atoms with an oxo group; or an oxooxazolidinyl group, wherein R ² is hydrogen A compound in which the atom, Z is a group represented by —N (R ³ ) —, R ³ is an alkyl group, R ^4a is a hydrogen atom or an alkyl group, and R ^4b is a hydrogen atom or an alkyl group is preferable. .

  Still further, ring A is represented by the formula:

And ring B is represented by the formula:

A ¹ is a hydrogen atom or an alkyl group, A ² is a halogen atom, A ³ is a hydrogen atom, B ¹ is a trihalogenomethyl group, and B ² is a trihalogeno group. A methyl group, B ³ is a hydrogen atom, R ¹ is a tetrahydropyranyl group; a tetrahydrothiopyranyl group in which the sulfur atom may be disubstituted with an oxo group; an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group Or an azetidinyl group substituted with a dialkylaminocarbonyl group; or a thietanyl group in which one or two sulfur atoms are substituted with an oxo group, R ² is a hydrogen atom, and Z is represented by —N (R ³ ) —. A compound in which R ³ is an alkyl group, R ^4a is a hydrogen atom or an alkyl group, and R ^4b is a hydrogen atom or an alkyl group. Things are preferred.

  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 (BD) or a pharmacologically acceptable salt thereof.

(A) (3S, 4S) -1- (acetylpiperidin-4-yl) carbonyl-4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl -3- (4-fluoro-2-methylphenyl) piperidine,
(B) (3S, 4S) -1- (1-acetylpiperidin-4-yl) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} amino Carbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(C) (3S, 4S) -1- (1-acetylpiperidin-4-yl) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} amino Carbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(D) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (3-hydroxy-3-methylbutyryl) piperidine,
(E) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {3- (S) -hydroxybutyryl} piperidine,
(F) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {3- (R) -hydroxybutyryl} piperidine,
(G) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxotetrahydrothio Pyran-4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(H) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxotetrahydrothio Pyran-4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(I) (3S, 4S) -1- (1-propionylpiperidin-4-yl) carbonyl-4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(J) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylpiperidin-4-yl) piperidine,
(K) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylpiperidin-4-yl) piperidine,
(L) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1-hydroxyacetylpiperidine,
(M) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (2-hydroxy-2-methylpropionyl) piperidine,
(N) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {2- (R) -hydroxypropylaminocarbonyl} piperidine,
(O) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {2- (S) -hydroxypropylaminocarbonyl} piperidine,
(P) (3S, 4S) -1- (4-acetylpiperazinocarbonyl) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl -3- (4-fluoro-2-methylphenyl) piperidine,
(Q) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylpiperidin-4-yl) piperidine,
(R) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylpiperidin-4-yl) piperidine,
(S) (3S, 4S) -1- (1-acetylazetidin-3-yl) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(T) (3S, 4S) -1- (1-acetylazetidin-3-yl) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(U) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-propionylazetidin-3-yl) piperidine,
(V) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-propionylazetidin-3-yl) piperidine,
(W) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-yl) piperidine,
(X) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-yl) piperidine,
(Y) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-Methanesulfonylazetidin-3-yl) piperidine,
(Z) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-Methanesulfonylazetidin-3-yl) piperidine,
(AA) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-dimethylaminocarbonylazetidin-3-yl) piperidine,
(AB) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-dimethylaminocarbonylazetidin-3-yl) piperidine,
(AC) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-oxothietan-3-yl) piperidine,
(AD) (3S, 4S) -4- {N- (R) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1,1-dioxothietan-3-yl) piperidine,
(AE) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1,1-dioxothietan-3-yl) piperidine,
(AF) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (tetrahydrothiopyran-4-yl) piperidine,
(AG) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (tetrahydropyran-4-yl) piperidine,
(AH) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (tetrahydropyran-4-yl) piperidine,
(AI) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (1-oxypyridin-4-yl) methylpiperidine,
(AJ) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (1-oxypyridin-4-yl) methylpiperidine,
(AK) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (2-Methyl-1-oxypyridin-5-yl) methylpiperidine,
(AL) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (2-oxopyrrolidin-1-yl) piperidine,
(AM) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (2-oxo-oxolidin-3-yl) piperidine,
(AN) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (2,5-dioxopyrrolidine- 1-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(AO) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (2,5-dioxopyrrolidine- 1-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(AP) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxothiomorpholine -4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(AQ) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxothiomorpholine -4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(AR) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (trans-4-hydroxy-4-methylcyclohexylcarbonyl) piperidine,
(AS) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (trans-4-hydroxy-4-methylcyclohexylcarbonyl) piperidine,
(AT) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-ylcarbonyl) piperidine,
(AU) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-ylcarbonyl) piperidine,
(AV) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1-ethylaminocarbonyl-2- (4- Fluoro-2-methylphenyl) piperidine,
(AW) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (1-methylethylaminocarbonyl) piperidine,
(AX) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (2-hydroxyethyloxycarbonyl) piperidine,
(AY) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1-dimethylaminocarbonylmethyl-3- (4 -Fluoro-2-methylphenyl) piperidine,
(AZ) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1-dimethylaminocarbonylethyl-3- (4 -Fluoro-2-methylphenyl) piperidine,
(BA) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methanesulfonylpiperidin-4-yl) piperidine,
(BB) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {1- (2-methylpropionyl) piperidin-4-ylcarbonyl} piperidine,
(BC) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (tetrahydropyran-4-yl) carbonylpiperidine, and (BD) (3S, 4S) -4- {N- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1-{(R) -1-methoxycarbonylethyl} piperidine.

  Moreover, the following compounds are preferable among said (A)-(BD).

(G) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxotetrahydrothio Pyran-4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(H) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxotetrahydrothio Pyran-4-yl) -2- (4-fluoro-2-methylphenyl) piperidine,
(S) (3S, 4S) -1- (1-acetylazetidin-3-yl) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(T) (3S, 4S) -1- (1-acetylazetidin-3-yl) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} Aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine,
(U) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-propionylazetidin-3-yl) piperidine,
(V) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-propionylazetidin-3-yl) piperidine,
(W) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-yl) piperidine,
(X) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-methoxycarbonylazetidin-3-yl) piperidine,
(Y) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-Methanesulfonylazetidin-3-yl) piperidine,
(Z) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-Methanesulfonylazetidin-3-yl) piperidine,
(AA) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-dimethylaminocarbonylazetidin-3-yl) piperidine,
(AB) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-dimethylaminocarbonylazetidin-3-yl) piperidine,
(AC) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1-oxothietan-3-yl) piperidine,
(AD) (3S, 4S) -4- {N- (R) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1,1-dioxothietan-3-yl) piperidine,
(AE) (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- (1,1-dioxothietan-3-yl) piperidine,
(AF) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (tetrahydrothiopyran-4-yl) piperidine,
(AG) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) -1- (Tetrahydropyran-4-yl) piperidine, and (AH) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl } Aminocarbonyl-2- (4-fluoro-2-methylphenyl) -1- (tetrahydropyran-4-yl) piperidine.

  Furthermore, in the compound which is an active ingredient of the present invention, another preferable compound is a compound selected from the following (a) to (c) or a pharmaceutically acceptable salt thereof.

(A) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {1- (3-hydroxy-3-methylbutyryl) azetidin-3-yl} piperidine,
(B) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {1- (3-hydroxy-3-methylbutyryl) azetidin-3-yl} piperidine,
(C) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) -1- {1- (3,3,3-trifluoropropyl) azetidin-3-yl} 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 present invention includes any of these optical isomers and mixtures thereof. In the present invention, among these optical isomers, a compound having an S configuration at the 3-position of the piperidine ring (ring A connection position) is preferable, and in particular, the 3-position of the piperidine ring (connection position of ring A) is the S configuration. A compound having an S configuration at the 4-position of the piperidine ring is preferred.

  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 is less likely to lead to toxicity (high safety), and has almost no side effects. Since it is not shown, it is useful as a preventive or therapeutic drug for central nervous system diseases such as vomiting and depression, and micturition abnormalities such as frequent urination.

  The compound which is an active ingredient of the present invention or a pharmacologically acceptable salt thereof can be obtained by, for example, the method described in European Journal of Pharmacology Vol.254, pp. 221-227 (1994). Similarly, the neurokinin-1 receptor binding action can be measured, according to the method described in European Journal of Pharmacology 265, 179-183 (1994), The effect on neurokinin-1 receptor activation can be measured, and is described in Journal of Urology, Vol. 155, No. 1, pages 355-360 (1996). In accordance with, it can be measured pollakiuria inhibitory action.

  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 pharmaceutically 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.
[Method A]
Compound [I] which is an active ingredient of the present invention

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ represents a hydrogen atom or an amino group substituent.
R ² represents a hydrogen atom, a hydroxyl group that may have a substituent, an amino group that may have a substituent, an alkyl group that may have a substituent, or a carbonyl group that has a substituent. Or represents 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.
R ^4a and R ^4b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded to each other at a terminal to form an alkylene group. )
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, rings B, Z, R ^4a and R ^4b have the same meaning as described above.)
It can manufacture by making the compound shown by react.

This [Method A] can be carried out as follows.
[Method A]
The reaction between the compound [II] and the compound [III] is carried out in a solvent in the presence of a condensing agent, or a reactive derivative of the compound [II] (acid halide, acid anhydride, active amide, active ester, mixed) Acid anhydride, etc.) and compound [III] in the presence or absence of a base in a solvent, or the active ester of compound [II] and compound [III] are present in the presence of a condensing agent. It can also be produced by reacting in a solvent. Examples of the base include pyridine, 4-dimethylaminopyridine, N-methylmorpholine, triethylamine, N, N-dimethylaniline, N, N-diethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene. An organic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and other inorganic bases can be used. As the condensing agent, 1,1′-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, propanephosphonic anhydride and the like can be used. Any solvent can be used as long as it does not adversely influence the reaction. For example, N, N-dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, ethyl acetate, 1,3-dimethyl-2-imidazo Lydinone can be used. This reaction suitably proceeds at, for example, -20 ° C to 60 ° C, particularly 5 ° C to 60 ° C. As an active ester of compound [II], N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, ester with p-nitrophenol, or the like can be used. As the acid halide of compound [II], acid chlorides, acid bromides and the like can be suitably used. As the active amide of compound [II], an amide with imidazole or the like can be used.

Also, of the compound which is the active ingredient of the present invention (I), when group R ¹ is a group other than a hydrogen atom, the compound group R ¹ is a hydrogen atom, introducing a group R ¹ by a conventional method, the corresponding Can be manufactured.

The compound [I], which is an active ingredient of the present invention, can also be produced by converting the group R ^{1 of the} compound obtained as described above to another desired substituent. 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 p).

(Method a): In the general formula [I], the compound [I] in which the group R ¹ is a hydrogen atom is obtained by removing the protecting group from the corresponding compound [I] in which the group R ¹ is an amino protecting group. Can be manufactured. 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.

(Method b): In the general formula [I], the compound [I] in which the group R ¹ is a carbonyl group having a substituent is the same as the corresponding compound [I] in which the group R ¹ is a hydrogen atom. It can be produced by reacting an acid compound, an active ester thereof or a carboxylic acid halide 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. As the active ester of the carboxylic acid compound, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, ester with p-nitrophenol, or the like can be used. This reaction can be carried out, for example, at -20 ° C to 50 ° C.

(Method c): In the general formula [I], the compound [I] in which the group R ¹ is an optionally substituted heterocyclic group is the corresponding compound [I] in which the group R ¹ is a hydrogen atom. And a heterocyclic group having a corresponding oxo group can be prepared by subjecting to a reductive condensation reaction. The reductive condensation reaction is, for example, (a) Tetrahedron Letters, 31, 5595, 1990, (b) Journal of Organic Chemistry, 28, 3259. According to the method described on page 1963, etc., it can be suitably carried out in a suitable solvent in the presence of a reducing agent. Any reducing agent can be used as long as it can be suitably used for reductive amination. Such reducing agents include metal reducing agents such as metal hydrides [borane hydrides (diborane, etc.)], metal hydride complexes [lithium aluminum hydride, sodium borohydride, etc.], organometallic complexes [borane-methyl. Sulfide, 9-borabicyclononane (9-BBN), triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.] can be used. Furthermore, if necessary, Lewis acid (titanium tetrachloride, etc.) can be used as an additive. Further, the reductive condensation reaction can be carried out under catalytic hydrogenation conditions instead of the presence of a reducing agent. For example, a suitable catalyst such as a platinum catalyst or palladium-carbon can be used in an appropriate solvent under a hydrogen stream. In addition, a catalytic amount of acids is preferably added to the reductive condensation reaction. Examples of such acids include organic acids such as formic acid, acetic acid, propionic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid. Can be given. This reaction can be suitably carried out under cooling to heating, preferably at 0 ° C to 100 ° C, more preferably at 10 ° C to 50 ° C.

(Method d): In the general formula [I], when the compound [I] in which the group R ¹ is a carbonyl group having a substituent is a compound having a urea bond, the group R ¹ is a hydrogen atom. It can be produced by reacting a corresponding compound [I] with a corresponding amine compound using a urea agent. As the urea agent, those such as 1,1′-carbonyldiimidazole and phosgene are preferable. For example, carbonyl dihalide such as 1,1′-carbonyldiimidazole, triphosgene or phosgene can be used. This reaction can be carried out, for example, at 0 ° C. to 80 ° C., preferably 0 ° C. to 50 ° C. In addition, this reaction can be produced according to the method described in JP-A-10-195037.

(Method e): 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.

Further, the compound group R ¹ is a sulfonyl group having a substituent [I], halogenosulfonyl compounds corresponding compound group R ¹ is a hydrogen atom and [I] is a corresponding compound in the presence of a base It can be produced by reacting. As the base, triethylamine or the like can be used. Furthermore, this reaction can be implemented at 0 degreeC-50 degreeC, for example.

(F) method: 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.

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

Furthermore, 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.

(G Method): In the general formula [I], a compound group wherein R ¹ contains a carbonyl amino group having a substituent (I), the corresponding compound group R ¹ is an amino group-containing And a corresponding carboxylic acid compound or an active ester thereof 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. As the active ester of the carboxylic acid compound, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, ester with p-nitrophenol, or the like can be used. This reaction can be carried out, for example, at -20 ° C to 50 ° C.

(Method h): In the general formula [I], when increasing the group R ¹ of the compound [I], it can be carried out using a Grignard reaction. For example, it can be produced by reacting with a Grignard reagent such as the corresponding alkylmagnesium chloride. This reaction can be carried out at −50 ° C. to 0 ° C.

(Method i): 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 type 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.

(J) 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 k): In the general formula [I], the compound [I] in which the group R ¹ contains an amide bond is the corresponding compound [I] or R ^{1 in} which the group R ¹ contains a free carboxyl group Presence of a condensing agent between a corresponding compound [I] containing an acid ester group and a corresponding amine compound, or a corresponding compound [I] wherein the group R ¹ contains a free amino group and a corresponding carboxylic acid compound It can manufacture by making it react under or absence. 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.

(L 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 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] in which the group R ¹ is an amino group is obtained by converting the corresponding compound [I] in which the group R ¹ is a hydrogen atom into an aminating agent (for example, tert-nitrite nitrite). It can be produced by reacting butyl etc.). This reaction can be carried out, for example, at room temperature to heating under reflux.

Further, from the corresponding compound is an amino group which group R ¹ has a substituent by conventional methods, it can be prepared by removing the protecting group.

(Method o): In the general formula [I], the compound [I] in which the group R ¹ is a cyclized compound (for example, oxopyrrolidinyl group, oxooxazolidino group, etc.) It can manufacture by reacting. This reaction suitably proceeds at −50 ° C. to 200 ° C., particularly at −20 ° C. to 60 ° C.

(Method p): In the general formula [I], the compound [I] in which the group R ¹ is an optionally substituted alkyl group is obtained by subjecting the corresponding compound [I] in which the group R ¹ is a hydrogen atom to a conventional method. It can be produced by alkylation. This reaction can be carried out at 20 ° C to 80 ° C.

  The solvent used in the reactions described in the above (Method a) to (Method p) 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.

  The raw material compound [II] of the present invention is a novel compound and can be produced, for example, as shown in the following chemical reaction formula.

(Wherein R ⁵¹ represents an alkyl group, X ¹ represents a leaving group, X ² represents a leaving group, and rings A and R ¹ have the same meaning as described above.)
That is, pyridine compound [IV] is condensed with aniline to obtain compound [V], and then halogenated to obtain compound [VI], and then aniline is eliminated to obtain compound [VII]. Further, the compound [VII] is esterified, or the compound [VIII] is subjected to a carbon addition reaction, or the acyl group of the compound [IV] is esterified and then halogenated. [IX] is obtained. The compound [IX] and the compound [X] obtained are coupled, or after the compound [VI] and the compound [X] are coupled, the aniline is eliminated from the compound [XI] and then esterified. [XII] is obtained, and the resulting compound [XII] is subjected to a reduction reaction, and then an amino group substituent is introduced to obtain compound [XIII]. Compound [II] is obtained by converting the ester group of the resulting compound [XIII] into a carboxyl group.

Compound [II] has an asymmetric carbon, and optical isomers based on the asymmetric carbon exist. For example, when a cis isomer and a trans isomer are obtained as a mixture, silica gel chromatography or the like A cis isomer and a trans isomer can be obtained by conventional methods. The optical isomer of compound [II] can be obtained, for example, by optical resolution of a compound [XIII] wherein R ¹ is a hydrogen atom or a racemic mixture of compound [II] by a conventional method.

In the case of a compound in which R ¹ of compound [XIII] is a hydrogen atom, the optical resolution is carried out, for example, by reacting compound [XIII] with N-acyl-optically active amino acid, N-sulfonyl-optically active amino acid or optically active carboxylic acid. It can be carried out by separating and collecting one diastereomeric salt using the difference in solubility between the two diastereomeric salts produced. Examples of the acyl group of the N-acyl-optically active amino acid include an acetyl group, propionyl group or benzyloxycarbonyl group, and examples of the sulfonyl group of the N-sulfonyl optically active amino acid include a tosyl group or a mesyl group. Examples of the optically active amino acid include L-phenylalanine, L-leucine, L-glutamine, L-methionine, L-valine, L-threonine, D-phenylalanine or D-phenylglycine. Examples of the optically active carboxylic acid include mandelic acid, malic acid, and tartaric acid derivatives. Examples of the tartaric acid derivative include L-benzoic acid tartrate, di-p-toluoyl tartrate, dibenzoyl tartrate, di-p-toluoyl tartrate, and the like.

  In the case of compound [II], for example, optical resolution utilizes the difference in solubility between two diastereomeric salts produced by reacting compound [II] with an O-alkyl-optically active amino acid or optically active amine derivative. Then, it can be carried out by separating and collecting one diastereomeric salt. Examples of the optically active amino acid include L-phenylalanine, L-leucine, L-glutamine, L-methionine, L-valine, L-threonine, D-phenylalanine or D-phenylglycine. Examples of the alkyl group of the O-alkyl-optically active amino acid include a methyl group and an ethyl group. Examples of the optically active amine derivative include brucine, quinidine, (S) -1-phenethylamine, (R) -1-phenethylamine, (R)-(−)-1-cyclohexylethylamine, (S)-(+)-1- Examples include cyclohexylethylamine.

  Furthermore, in the production of the compound which is the active ingredient of the present invention and its raw material compound, when the raw material compound or each intermediate compound has a functional group, it is suitable for each functional group by a conventional method of synthetic chemistry other than those indicated above. If necessary, these protecting groups may be removed as appropriate.

  For example, in the present specification, examples of the protecting group for an amino group generally include a protecting group used for protecting an amino group when subjected to a reaction. Specifically, for example, a tert-butoxycarbonyl group And an arylalkoxycarbonyl group such as a benzyloxycarbonyl group.

  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. An alkenyl group means, for example, a straight or branched alkenyl group having 2 to 7 carbon atoms, such as a vinyl group, allyl group, propenyl group, or isopropenyl group, and preferably means having 2 to 5 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. Means things. The 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., preferably carbon It means the thing of number 1-4. An alkylene group means a C2-C7 linear or branched alkylene group, such as a methylene group, ethylene group, propylene group, butylene group, etc., preferably a C2-C5 group. . 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 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 with the sample compound prepared to 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 the sample compound 10 nM is calculated. did.

  The results were as shown in Table A1 to Table A6 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 1 mg / kg of the test drug was orally administered to LSC Co., Ltd .: 40-80 g). 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.
Inhibition 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 Tables B1 and B2 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 to female guinea pigs (1.2 g) / 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. In addition, the neck was opened 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.

Production Example 1
2.7 g of (3S) -1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine and (R) -1- (3,5-bistrifluoromethylphenyl) ethyl- To a solution of 2.72 g of 1-methylamine in 50 ml of N, N-dimethylformamide was added 1.92 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1.53 g of 1-hydroxybenzotriazole, Stir at room temperature for 16 hours. Ethyl acetate and brine were added to the reaction solution for liquid separation, and the resulting organic layer was washed with an aqueous sodium bicarbonate solution and water. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give (a) (3S, 4S) -1-tert-butoxycarbonyl-4 described in Table 1 below. -[N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 730 mg and (b) ( 3S, 4R) -1-tert-butoxycarbonyl-4- [N- {1- (R)-(3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-3- (4-fluoro 680 mg of 2-methylphenyl) piperidine was obtained.

Production Example 2-5
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to obtain the compounds shown in Tables 1 to 3 below.

Production Example 6
Trans-1-tert-butoxycarbonyl-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 1.2 g After adding 10 ml of hydrochloric acid in ethyl acetate and stirring for 1 hour, the mixture was concentrated under reduced pressure. A 4M aqueous sodium carbonate solution and ethyl acetate were added to the residue for liquid separation. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4- 600 mg of fluoro-2-methylphenyl) piperidine was obtained.

Production Example 7-12
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to obtain the compounds shown in Table 4 below.

Production Example 13
90 mg of trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine and 24 mg of 3-hydroxy-3-methylbutanoic acid To 3 ml of N, N-dimethylformamide solution, 40 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 31 mg of 1-hydroxybenzotriazole were added and stirred at room temperature for 16 hours. Ethyl acetate and brine were added to the reaction solution for separation, and the organic layer was washed successively with aqueous sodium bicarbonate solution and water. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1), whereby trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 5 below. 75 mg of methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (3-hydroxy-3-methylbutyryl) piperidine was obtained.

Production Example 14-26
The corresponding starting materials were used and treated in the same manner as in Production Example 13 to obtain the compounds shown in Tables 5 to 7 below.

Production Example 27
Trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 143 mg, 1-acetyl-4-piperidone 45 mg and acetic acid Sodium triacetoxyborohydride (110 mg) was added to 0.01 ml of dichloromethane (3 ml), and the mixture was stirred at room temperature for 16 hours. Sodium carbonate was added to the reaction solution, and the mixture was stirred for 1 hour. Chloroform was added, and the mixture was separated and extracted from the aqueous layer with chloroform again. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1), whereby trans-1- (1-acetoxypiperidin-4-yl) -4- {N- described in Table 8 below. 120 mg of (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 28-31
The corresponding starting materials were used and treated in the same manner as in Production Example 27 to give the compounds shown in Table 8 below.

Production Example 32
Trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine in a solution of 145 mg in tetrahydrofuran 2.5 ml -42 mg of carbonyldiimidazole was added, and it stirred at 50 degreeC for 1 hour. After concentrating the reaction solution, 5 ml of acetonitrile and 0.5 ml of methyl iodide were sequentially added and stirred at 70 ° C. for 1 hour. The reaction solution was concentrated again and dissolved in 5 ml of tetrahydrofuran, 120 mg of 2-aminoethanol and 0.04 ml of triethylamine were added, and the mixture was stirred at 40 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1), whereby trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 9 below. 103 mg of methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1-{(2-hydroxyethyl) aminocarbonyl} piperidine was obtained.

Production Example 33-34
The corresponding starting materials were used and treated in the same manner as in Production Example 32 to give the compounds shown in Table 9 below.

Production Example 35
Trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 100 mg in tetrahydrofuran 4 ml solution with 0.3 ml triethylamine and chloride Methanesulfonyl (0.16 ml) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water and ethyl acetate were added to separate the liquid and the organic layer was washed with water. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1), whereby trans-4- {N- (3,5-bistrifluoromethylbenzyl) -N- described in Table 9 below. 93 mg of methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1-methanesulfonylpiperidine was obtained.

Production Example 36
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 10 below.

Production Example 37
(1) (3S, 4S) -1-benzyloxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine 0.80 g in tetrahydrofuran 80 ml solution with a catalytic amount of N, N-dimethylformamide After adding 0.56 g of thionyl chloride and stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. A 20 ml solution of the obtained residue in dichloromethane was cooled to 0 ° C., and 0.26 g of triethylamine and 0.94 g of N- {1- (3,5-bistrifluoromethylphenyl) -1-methyl-ethyl} -N-methylamine were obtained. And stirred at room temperature for 2 days. Chloroform and water were added to the reaction solution for liquid separation. The organic layer was washed successively with saturated aqueous citric acid solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 2: 1) to give (3S, 4S) -1-benzyloxycarbonyl-4 described in Table 10 below. 0.17 g of-[N- {1- (3,5-bistrifluoromethylphenyl) -1-methylethyl} -N-methyl] aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained. .

  (2) 25 mg of 10% palladium on carbon was added to a solution of 0.16 g of the compound obtained in (1) above in 3 ml of methanol and stirred at room temperature for 16 hours in a hydrogen atmosphere. Further, 20 mg of palladium hydroxide and 6 M aqueous hydrochloric acid solution were added. .2 ml was added and stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to obtain (3S, 4S) -4- [N- {1- (3,5-bistrifluoromethylphenyl) -1 shown in Table 10 below. -Methylethyl} -N-methyl] aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine (0.11 g) was obtained.

Production Example 38-103
The corresponding starting materials were used and treated in the same manner as in Production Example 13 to obtain the compounds shown in Tables 11 to 19 below.

Production Example 104
(1) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) 180 mg of 1-hydroxybenztriazole, 1- {3- (N, N-dimethylamino) propyl} in a solution of 400 mg of piperidine and 180 mg of 1-tert-butoxycarbonyl-3-azetidinecarboxylic acid in 5 ml of N, N-dimethylformamide 224 mg of -3-ethylcarbodiimide hydrochloride was added and stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was partitioned with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 50: 50) to give (3S, 4S) -1-{(1-tert-butoxycarbonylazetidine-3- Yl) carbonyl} -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine (539 mg) It was.

  (2) To a solution of 539 mg of the compound obtained in (1) above in 2 ml of ethyl acetate was added 6 ml of 4M hydrogen chloride in ethyl acetate, and the mixture was stirred overnight at room temperature. The obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 9: 1) to give (3S, 4S) -1-{(azetidin-3-yl) carbonyl} -4- {N-1 195 mg of-(S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

  (3) To a solution of 36 mg of the compound obtained in (2) above in 1.5 ml of dichloromethane was added 11 μl of triethylamine at room temperature, and 75 μl of 1.0 M tetrahydrofuran solution of acetyl chloride was added dropwise at 0 ° C., followed by stirring overnight at room temperature. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (chloroform: methanol = 9: 1) to give (3S, 4S) -1-{(1-acetylazetidin-3-yl) carbonyl} described in Table 19 below. 27 mg of -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Examples 105-115
The corresponding starting materials were used and treated in the same manner as in Production Example 104 to obtain the compounds shown in Tables 19 to 21 below.

Production Example 116
A solution of 100 mg of the compound obtained in Production Example 55 in 3 ml of tetrahydrofuran was cooled to −20 ° C., 1 ml of 1.0 M methylmagnesium chloride in tetrahydrofuran was added dropwise, and the mixture was stirred for 1 hour. Aqueous ammonium chloride solution and ethyl acetate were added for liquid separation, and the organic layer was washed with saturated brine. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N-1- (R)-(3,5-bistritium) described in Table 22 below. 100 mg of fluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (4-hydroxy-4-methylpentanoyl) piperidine was obtained.

Production Example 117
The corresponding starting materials were used and treated in the same manner as in Production Example 116, to give compounds as shown in Table 22 below.

Production Example 118
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine, And 2-tert-butoxycarbonylamino-2-methylpropionic acid, followed by treatment in the same manner as in Production Example 13, followed by treatment with 4M hydrochloric acid-ethyl acetate solution (3S, 4S) described in Table 22 below. -1- (2-amino-2-methylpropionyl) -4- {N- (R) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro -2-methylphenyl) piperidine was obtained.

Production Example 119
To a solution of 60 mg of the compound obtained in Production Example 87 in 2 ml of N, N-dimethylformamide, 10 mg of sodium hydride (40% in oil) and 0.05 ml of methyl iodide were added at 0 ° C. and stirred for 2 hours. After completion of the stirring, brine and ethyl acetate were added for liquid separation, and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -1- (azetidin-3-yl) carbonyl-4- {listed in Table 22 below. 45 mg of N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 120-124
The corresponding starting materials were used and treated in the same manner as in Production Example 119, to give compounds as shown in Table 22 below.

Production Example 125-159
The corresponding starting materials were used and treated in the same manner as in Production Example 27 to obtain the compounds shown in Tables 23 to 26 below.

Production Example 160
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 30 mg Is dissolved in 1.5 ml of methanol, 12 μl of acrylonitrile is added at room temperature, and the mixture is allowed to stand for 30 minutes. The reaction solution was purified by silica gel thin layer chromatography (developed with chloroform: methanol = 9: 1, eluted with dichloromethane: ethanol: aqueous ammonia = 100: 10: 1), and then freeze-dried with tert-butanol. (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (2-cyanoethyl)-described in Table 26 below 27 mg of 2- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 161-170
The corresponding starting materials were used and treated in the same manner as in Production Example 160 to obtain the compounds shown in Table 26 and Table 27 below.

Production Example 171
49 mg of (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine To a 1 ml solution of N, N-dimethylformamide, 0.028 ml of triethylamine and 0.012 ml of 2-fluorobromoethane were added at room temperature and stirred overnight. Ethyl acetate and water were added to the reaction solution to separate the layers, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel thin layer chromatography (n-hexane: ethyl acetate = 2: 1) to give (3S, 4S) -4- {N-1- ( 42 mg of R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (2-fluoroethyl) -3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Examples 172-194
The corresponding starting materials were used and treated in the same manner as in Production Example 171, thereby obtaining the compounds shown in Tables 27 to 29 below.

Production Example 195
To 56 mg of the compound obtained in Production Example 179, 2 ml of a 0.5 M potassium hydroxide methanol solution was added at room temperature, and the mixture was stirred overnight. The reaction mixture was neutralized with saturated aqueous citric acid solution and aqueous sodium hydroxide solution, and chloroform was added to separate the layers. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N described in Table 29 below. 48 mg of -methyl} aminocarbonyl-1-carboxymethyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 196
The corresponding starting materials were used and treated in the same manner as in Production Example 195, to give compounds as shown in Table 29 below.

Production Example 197
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 40 mg Was dissolved in 1 ml of acetonitrile and a mixture of 15 mg of 2-chloromethylpyridine N-oxide hydrochloride and 43 μl of diisopropylethylamine was stirred at 80 ° C. for 4 hours. The reaction solution was cooled to room temperature, purified by silica gel thin layer chromatography (developed and eluted with dichloromethane: ethanol: aqueous ammonia = 100: 10: 1), and then freeze-dried using tert-butanol, to obtain (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl 2- (4-fluoro-2-methyl) listed in Table 30 26 mg of phenyl) -1- (1-oxypyridin-2-yl) methylpiperidine was obtained.

Production Example 198-202
The corresponding starting material compounds were used and treated in the same manner as in Production Example 197 to obtain the compounds shown in Table 30 below.

Production Example 203
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 50 mg Into a 2 ml solution of acetonitrile, 32 mg of methyl 2- (toluene-4-sulfonyloxy) propionate and 50 mg of potassium carbonate were added, and the mixture was stirred for 2 hours with heating under reflux. After completion of the stirring, ethyl acetate and water were added to separate the solution, and the organic layer was concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (chloroform: methanol = 19: 1), (3S, 4S) -2- [4- {N- (R)-(3 , 5-Bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidin-1-yl] -propionic acid methyl ester 36 mg was obtained.

Production Example 204
The corresponding starting materials were used and treated in the same manner as in Production Example 203 to give the compounds shown in Table 30 below.

Production Example 205
(3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 100 mg 67.2 mg of 2- (tert-butoxycarbonylamino) ethyl bromide and 55.2 mg of potassium carbonate were added to a 3 ml solution of acetonitrile at room temperature, and the mixture was stirred at 80 ° C. overnight. To the reaction solution, 3 ml of N, N-dimethylformamide and 50 mg of 2- (tert-butoxycarbonylamino) ethyl bromide were added, and the mixture was further stirred at 110 ° C. overnight. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was partitioned with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 91: 9). After adding 2 ml of 4M hydrochloric acid aqueous solution to the obtained compound and stirring for 1 day, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (LC-MS) (water-methanol). The obtained compound was dissolved in 2 ml of dichloromethane, and 14 μl of triethylamine and 7 μl of acetyl chloride were added dropwise and stirred for 3 days. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was separated with dichloromethane, and the organic layer was concentrated under reduced pressure. By purifying the obtained residue by silica gel thin layer chromatography (chloroform: methanol = 9: 1) and column chromatography (LC-MS) (water-methanol), (3S, 4S) described in Table 30 below 1- (2acetylaminoethyl) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) 3.6 mg of piperidine was obtained.

Production Example 206
To a solution of 100 mg of the compound obtained in Production Example 203 in 2 ml of methanol, 2 ml of 2M aqueous sodium hydroxide solution was added and stirred at room temperature for 16 hours. After adding 2.2 ml of 2M hydrochloric acid aqueous solution, the mixture was extracted 3 times with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. To a 2 ml solution of the resulting residue in N, N-dimethylformamide, 0.1 ml of 2-hydroxyethylamine, 40 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 31 mg of 1-hydroxybenzotriazole were added. And stirred at 50 ° C. for 16 hours. After completion of stirring, ethyl acetate and brine were added to separate the layers, and the organic layer was washed twice with an aqueous sodium bicarbonate solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N-1- (R)-(3, listed in Table 31 below). 5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- {1- (R)-(2-hydroxyethylaminocarbonyl) ethyl} piperidine 64 mg Got.

Production Example 207-211
The corresponding starting materials were used and treated in the same manner as in Production Example 206 to give the compounds shown in Table 31 below.

Production Example 212
(1) (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) 150 mg of 1-benzyloxycarbonylazetidin-3-one was added to a solution of piperidine (300 mg) in dichloromethane (5 ml) at room temperature and stirred for 90 minutes. After adding 86 μl of acetic acid to the reaction solution, 648 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 1 night. A sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was separated with chloroform. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) to give (3S, 4S) -1- (1-benzyloxycarbonylazetidin-3-yl)- 330 mg of 4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

  (2) To a solution of 330 mg of the compound obtained in (1) above in 5 ml of methanol was added 70 mg of 10% palladium carbon at room temperature under a nitrogen atmosphere, and the mixture was stirred for 4 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated. The obtained residue was purified by NH silica gel thin layer chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -1- (azetidin-3-yl) -4- {N-1- ( 103 mg of S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

  (3) To a solution of 38 mg of the compound obtained in (2) above in 1.5 ml of dichloromethane was added 24 μl of triethylamine at room temperature, and 1.4 ml of 0.1 M tetrahydrofuran solution of acetyl chloride was added dropwise at 0 ° C. and stirred at room temperature overnight. . The reaction solution was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (chloroform: methanol = 9: 1) to give (3S, 4S) -1- (1-acetoxyazetidin-3-yl) described in Table 31 below. 22 mg of -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Examples 213-222
The corresponding starting materials were used and treated in the same manner as in Production Example 212 to give the compounds shown in Tables 31 to 33 below.

Production Example 223
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine 100 mg 200 mg of potassium carbonate was added to a 2.5 ml acetonitrile solution of 0.2 ml of 2- (2-bromoethoxy) tetrahydropyran and stirred for 2 hours with heating under reflux. The reaction solution was returned to room temperature, diisopropyl ether was added, and the mixture was filtered. After the filtrate was concentrated under reduced pressure, 2 ml of 4M dioxane solution of hydrochloric acid was added and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (chloroform: methanol = 19: 1) to obtain (3S, 4S) -4- {N-1- (R)-described in Table 33 below. 56 mg of (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (2-hydroxyethyl) piperidine was obtained.

Production Example 224-225
The corresponding starting materials were used and treated in the same manner as in Production Example 223, to give compounds as shown in Table 33 below.

Production Example 226
To a solution of 65 mg of the compound obtained in Production Example 152 in 2 ml of dichloromethane was added 55 mg of trifluoroacetic acid, and then cooled to 0 ° C. To this solution, 55 mg of metachloroperbenzoic acid was added and stirred at 0 ° C. for 1 hour. A sodium bicarbonate aqueous solution and chloroform were added and stirred, and then the liquid separation and the organic layer were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (a) (3S, 4S) -4- {N- (R) -2-2 described in Table 33 below. 18 mg of (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (1-oxothietan-3-yl) -piperidine and (b) (3S, 4S) -4- {N- (R) -2- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxothietan-3-yl)- 36 mg of 3- (4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 227
The corresponding starting materials were used and treated in the same manner as in Production Example 226, to give compounds as shown in Table 33 below.

Production Example 228
To a solution of 100 mg of the compound obtained in Production Example 147 in 2.5 ml of dichloromethane, 80 mg of methanesulfonic acid was added and cooled to 0 ° C. To this solution, 100 mg of metachloroperbenzoic acid (70-75%) was added and stirred at 0 ° C. for 2 hours and then at room temperature for 16 hours. 4M Aqueous sodium carbonate solution and chloroform were added and stirred, and then the liquid separation and the organic layer were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N- (R) -2- (3, described in Table 33 below). 55 mg of 5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxotetrahydrothiopyran-4-yl) -3- (4-fluoro-2-methylphenyl) piperidine It was.

Production Example 229-230
The corresponding starting materials were used and treated in the same manner as in Production Example 228, to give compounds as shown in Table 34 below.

Production Example 231-261
The corresponding starting materials were used and treated in the same manner as in Production Example 32 to obtain the compounds shown in Tables 34 to 38 below.

Production Examples 262 to 263
The corresponding starting materials were used and treated in the same manner as in Production Example 226, to give compounds as shown in Table 38 below.

Production Example 264
150 mg of (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) piperidine A solution of 2-chloropyrazine 50 mg in acetonitrile 3 ml was stirred with heating under reflux for 16 hours. The reaction solution was returned to room temperature, an aqueous sodium bicarbonate solution and ethyl acetate were added and stirred, and then the liquid separation and organic layer were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N-1- (R)-(3, listed in Table 38 below). 43 mg of 5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (2-pyrazinyl) piperidine was obtained.

Production Example 265
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine 100 mg Was dissolved in 2 ml of 1,4-dioxane, and a mixture of 26 mg of 2-chloropyrimidine and 39 μl of diisopropylethylamine was stirred at 90 ° C. overnight. After cooling the reaction solution to room temperature, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 2: 1). (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) -1 90 mg of-(2-pyrimidyl) piperidine was obtained.

Production Example 266
The corresponding starting materials were used and treated in the same manner as in Production Example 35, to give compounds as shown in Table 38 below.

Production Example 267
(3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine 100 mg To a 4 ml tetrahydrofuran solution were added 0.07 ml triethylamine and 0.05 ml methyl chlorocarbonate, and the mixture was stirred at 0 ° C. for 2 hours. Ethyl acetate and water were added for liquid separation, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N-1- (R)-(3, listed in Table 38 below). 60 mg of 5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1-methoxycarbonylpiperidine was obtained.

Production Example 268
The corresponding starting materials were used and treated in the same manner as in Production Example 267, to give compounds as shown in Table 38 below.

Production Example 269
(3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine 50 mg To a 1 ml dichloromethane solution was added triphosgene 12 mg and triethylamine 0.014 ml at 0 ° C., and the mixture was stirred at room temperature for 20 minutes and concentrated under reduced pressure. To the obtained residue were added 2 ml of ethylene glycol, 0.014 ml of triethylamine, and 0.5 mg of 4-N, N-dimethylaminopyridine, and the mixture was stirred at 40 ° C. for 16 hours and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (3S, 4S) -4- {N- (S) -2- (3,5-bistrifluoromethylphenyl) ethyl- described in Table 39 below. 52 mg of N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (2-hydroxyethyloxycarbonyl) piperidine was obtained.

Production Example 270
The corresponding starting materials were used and treated in the same manner as in Production Example 269, to give compounds as shown in Table 39 below.

Production Example 271
To a solution of 4-hydroxytetrahydropyran 51 mg in tetrahydrofuran 2.5 ml was added N, N-carbonyldiimidazole 81 mg and stirred at 70 ° C. for 2 hours. Ethyl acetate and water were added for liquid separation, and the obtained organic layer was concentrated under reduced pressure. To the obtained residue, 2.5 ml of tetrahydrofuran and (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4 -Fluoro-2-methylphenyl) piperidine (60 mg) and triethylamine (0.028 ml) were added, and the mixture was stirred at 70 ° C. for 16 hours. Ethyl acetate and water were added for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to give (3S, 4S) -4- {N-1- (R)-(3,5-bistril) described in Table 39 below. 55 mg of fluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- (4-tetrahydropyranyloxycarbonyl) piperidine was obtained.

Production Example 272
(1) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) ) Piperidine (100 mg) was dissolved in dichloromethane (2 ml), and a mixture of tert-butyl nitrite (49 μl) was stirred overnight with heating under reflux. After adding 49 μl of tert-butyl nitrite and further heating and refluxing overnight, 49 μl of tert-butyl nitrite was added and left at room temperature for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in 1 ml of acetic acid and 1 ml of methanol, and a mixture of 107 mg of zinc dust added with ice cooling was stirred at room temperature for 3 hours. The insoluble material was filtered off, washed with methanol, and the filtrate and washings were combined and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the residue, and the mixture was separated and concentrated under reduced pressure to give crude (3S, 4S) -1-amino-4- {N-1- (R)-(3,5- Bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-2-methylphenyl) piperidine was obtained.

  (2) In (1) above, (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro) A compound obtained from 50 mg of 2-methylphenyl) piperidine is dissolved in 1 ml of tetrahydrofuran, and a mixture to which 11 mg of succinic anhydride is added is heated to reflux for 1 hour. After cooling to room temperature, 12 mg of 1,1'-carbonyldiimidazole is added and heated to reflux for 2 hours. The reaction solution was cooled to room temperature, purified by silica gel thin layer chromatography (development and elution with dichloromethane: ethanol: ammonia water = 200: 10: 1), and then freeze-dried from tert-butanol. (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (2,5-dioxo-pyrrolidine-1 36 mg of -yl) -2- (4-fluoro-2-methylphenyl) piperidine were obtained.

Production Example 273
The corresponding starting materials were used and treated in the same manner as in Production Example 272, to give compounds as shown in Table 39 below.

Production Example 274
(1) In Production Example 272 (1), (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4 The compound obtained from 50 mg of (fluoro-2-methylphenyl) piperidine was dissolved in 2 ml of tetrahydrofuran, 17 μl of triethylamine and 12 μl of 4-chlorobutyric chloride were added at room temperature, and the mixture was stirred overnight at the same temperature. Purification by silica gel thin layer chromatography (development with chloroform: methanol = 9: 1, elution with dichloromethane: ethanol: ammonia water = 100: 10: 1) gave (3S, 4S) -4- {N-1- 49 mg of (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (4-chlorobutyrylamino) -2- (4-fluoro-2-methylphenyl) piperidine was obtained. It was.

  (2) 49 mg of the compound obtained in (1) above was dissolved in 2 ml of N, N′-dimethylformamide, and 4 mg of 70% sodium hydride was added with stirring under ice cooling. The mixture was stirred for 6 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the solution was separated with dichloromethane. The organic layer was washed with water and concentrated under reduced pressure. The obtained residue is purified by silica gel thin layer chromatography (development with chloroform: methanol = 9: 1, elution with dichloromethane: ethanol: aqueous ammonia = 100: 10: 1), and then lyophilized with tert-butanol. (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4- 35 mg of fluoro-2-methylphenyl) -1- (2-oxo-pyrrolidin-1-yl) piperidine was obtained.

Production Example 275-277
The corresponding starting materials were used and treated in the same manner as in Production Example 274, to give compounds as shown in Table 39 below.

Production Example 278
In Production Example 272 (1), (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-2- (4-fluoro-) The compound obtained from 50 mg of 2-methylphenyl) piperidine was dissolved in 2 ml of tetrahydrofuran, 17 μl of triethylamine and 12 μl of divinylsulfone were added at room temperature, and the mixture was stirred at the same temperature for 5 hours. Divinyl sulfone (12 μl), triethylamine (12 μl), and methanol were added, and the mixture was stirred overnight at room temperature. After adding 20 μl of divinyl sulfone, the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel thin layer chromatography (development with chloroform: methanol = 9: 1, elution with dichloromethane: ethanol: ammonia water = 100: 10: 1) to obtain (3S, 4S described in Table 40 below) ) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (1,1-dioxo-thiomorpholin-4-yl) -2 20 mg of-(4-fluoro-2-methylphenyl) piperidine was obtained.

Production Example 279
The corresponding starting materials were used and treated in the same manner as in Production Example 278, to give compounds as shown in Table 40 below.

Production Example 280-281
The corresponding starting materials were used and treated in the same manner as in Production Example 272, to give compounds as shown in Table 40 below.

Production Example 282
(3S, 4S) -1-Amino-4- {N-1-S- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) 50 mg of piperidine is dissolved in 10 ml of acetonitrile and 20 ml of water, 42 mg of (2-oxo-ethoxy) acetaldehyde (1,4-anhydroerythritol is dissolved in 1 ml of water, 86 mg of sodium periodate is added, and the reaction is allowed to proceed at room temperature overnight. And a mixture of sodium cyanoborohydride 63 mg was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was separated. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The obtained residue is purified by silica gel thin layer chromatography (development with chloroform: methanol = 9: 1, elution with dichloromethane: ethanol: aqueous ammonia = 200: 10: 1), followed by lyophilization with addition of tert-butanol. (3S, 4S) -4- {N-1- (S)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro) described in Table 40 below There was obtained 18.3 mg of 2-methylphenyl) -1-morpholinopiperidine.

Production Example 283
The corresponding starting materials were used and treated in the same manner as in Production Example 282 to give the compounds shown in Table 40 below.

Production Example 284
(1) (3S, 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) ) 50 mg of piperidine and 21 mg of methyl 2-chloronicotinate were dissolved in 1 ml of dimethyl sulfoxide, and a mixture to which 14 mg of potassium carbonate was added was stirred at 100 ° C. overnight. After cooling to room temperature, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to separate the layers. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel thin layer chromatography (developed with chloroform: methanol = 9: 1, eluted with dichloromethane: ethanol: aqueous ammonia = 100: 10: 1) to give (3S , 4S) -4- {N-1- (R)-(3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-3- (4-fluoro-2-methylphenyl) -1- ( 53 mg of 5-methoxycarbonylpyridin-2-yl) piperidine was obtained.

  (2) The mixture obtained by dissolving 53 mg of the compound obtained in (1) above in 1 ml of ethanol and adding 127 μl of 1M aqueous sodium hydroxide solution was stirred at room temperature for 3 days. After neutralizing by adding 127 μl of 1M aqueous hydrochloric acid solution, the solution was concentrated to dryness under reduced pressure. The obtained residue was suspended in 2 ml of tetrahydrofuran, 68 mg of 1-hydroxybenzotriazole and 97 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added, and the mixture was stirred overnight at room temperature. To the reaction mixture, 45 mg of dimethylamine (50% aqueous solution) was added, and the mixture was further stirred overnight at room temperature. Purification by silica gel thin layer chromatography (development with chloroform: methanol = 19: 1, elution with dichloromethane: ethanol: aqueous ammonia = 100: 10: 1) gave (3S, 4S) -4 described in Table 40 below. -{N-1-R- (3,5-bistrifluoromethylphenyl) ethyl-N-methyl} aminocarbonyl-1- (5-N, N-dimethylaminocarbonylpyridin-2-yl) -3- (4 38 mg of -fluoro-2-methylphenyl) piperidine were obtained.

Production Example 285-295
The corresponding starting materials were used and treated in the same manner as in Production Example 284 to give the compounds described in Tables 40 and 41 below.

Production Examples 296-298
The corresponding starting materials were used and treated in the same manner as in Production Example 13 to give the compounds listed in Table 41 and Table 42 below.

Production Example 299
The corresponding starting materials were used and treated in the same manner as in Production Example 27, to give compounds as shown in Table 42 below.

Production Example 300-305
The corresponding raw material compounds were treated in the same manner as in Production Example 1, and the two kinds of purified diastereomers were separated by silica gel column chromatography to obtain the compounds shown in Tables 43 and 44 below.

Production Examples 306-309
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to give the compounds shown in Table 44 below.

Production Examples 310-313
The corresponding starting materials were used and treated in the same manner as in Production Example 13 to give the compounds shown in Table 44 and Table 45 below.

Production Examples 314-320
The corresponding starting materials were used and treated in the same manner as in Production Example 27, to give compounds as shown in Table 45 below.

Production Examples 321 to 323
The corresponding starting materials were used and treated in the same manner as in Production Example 228, to give compounds as shown in Table 228 below.

Production Examples 324-331
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to obtain the compounds described in Tables 47 and 48 below.

Production Examples 332-335
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to give the compounds shown in Table 48 below.

Production Examples 336-338
The corresponding starting materials were used and treated in the same manner as in Production Example 13, to give compounds as shown in Table 49 below.

Production Examples 339-341
The corresponding starting materials were used and treated in the same manner as in Production Example 27, to give compounds as shown in Table 49 below.

Production Example 342
The corresponding starting materials were used and treated in the same manner as in Production Example 1 to give the compounds shown in Table 50 below.

Production Example 343
The corresponding raw material compounds were treated in the same manner as in Production Example 1 and the two kinds of purified diastereomers were separated by silica gel column chromatography to obtain the compounds described in Table 50 below.

Production Examples 344-345
The corresponding starting materials were used and treated in the same manner as in Production Example 119, to give compounds as shown in Table 50 below.

Production Examples 346-349
The corresponding starting materials were used and treated in the same manner as in Production Example 6 to give the compounds shown in Table 50 below.

Production Examples 350-354
The corresponding starting materials were used and treated in the same manner as in Production Example 13 to give the compounds shown in Table 51 below.

Production Example 355-358
The corresponding starting materials were used and treated in the same manner as in Production Example 27 to give the compounds shown in Table 51 and Table 52 below.

Production Example 359
The corresponding starting materials were used and treated in the same manner as in Production Example 212 to give the compounds shown in Table 52 below.

Reference example 1
(1) A solution of 22.4 ml of diisopropylamine in 320 ml of tetrahydrofuran was cooled to −70 ° C. or lower with a dry ice-acetone bath, and then 100 ml of n-butyllithium (1.6 M hexane solution) was added dropwise, and the same temperature was maintained for 30 minutes Stir. To this solution, 25 ml of 3-bromopyridine in 250 ml of tetrahydrofuran was added dropwise over 4 hours. After all the dropwise addition, the mixture was further stirred at -70 ° C or lower for 1 hour. After 8.8 g of finely crushed dry ice was added to this solution after thoroughly wiping the surface, the mixture was stirred for 1 hour and then slowly warmed to room temperature. After all the solvent and excess carbon dioxide were distilled off under reduced pressure, the residue was dissolved in 300 ml of N, N-dimethylformamide, 27.6 g of potassium carbonate and 12.6 ml of methyl iodide were added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate and aqueous sodium bicarbonate solution were added for liquid separation, and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 13.5 g of methyl 3-bromoisonicotinate described in Table 53 below.

  (2) To a solution of 12 g of the compound obtained in (1) above in 120 ml of N, N-dimethylformamide, 9.3 g of 4-fluoro-2-methylphenylboronic acid, 19.6 g of cesium carbonate, 1.12 g of palladium acetate, 2.63 g of phenylphosphine was added and stirred at 70 ° C. for 1 hour. After completion of the reaction, ethyl acetate and brine were added, and insoluble matters were removed by filtration. The filtrate was washed with brine and water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give methyl 3- (4-fluoro-2-methylphenyl) isonicotinate described in Table 53 below. .9 g was obtained.

  (3) 600 mg of platinum oxide and 8 ml of concentrated hydrochloric acid were added to a solution of 2.5 g of the compound obtained in (2) above in 100 ml of methanol. Next, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere of 101 kPa. 100 ml of water was added to this solution and filtered through Celite, and the filtrate was concentrated under reduced pressure. The remaining aqueous solution was neutralized with sodium carbonate, further added with aqueous ammonia, and extracted twice with chloroform. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. To a 25 ml solution of the residue in dichloromethane was added 5 g of di-tert-butyl carbonate, and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15) to give cis-1-tert-butoxycarbonyl-3- (4-fluoro-2) described in Table 53 below. 1.3 g of -methylphenyl) -4-methoxycarbonylpiperidine was obtained.

  (4) 1.3 g of the compound obtained in (3) above was dissolved in 5 ml of methanol and 5 ml of tetrahydrofuran, 5 ml of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. The mixture was neutralized with 2M aqueous hydrochloric acid and extracted twice with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dried under reduced pressure to give cis-1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine and trans-1 listed in Table 53 below. 560 mg of a mixture of -tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine (cis isomer: trans isomer = 56: 44) was obtained.

(5) 10.5 g of cis-1-tert-butoxycarbonyl-3- (4-fluoro-2-methylphenyl) -4-methoxycarbonylpiperidine is dissolved in 100 ml of methanol, and a 28% methanol solution of sodium methoxide is obtained. 4 ml was added, and the mixture was stirred for 3 hours while heating under reflux. To the reaction solution were added 50 ml of tetrahydrofuran and 2M aqueous sodium hydroxide solution, and the mixture was stirred overnight. After neutralizing with 2M aqueous hydrochloric acid, chloroform was added, and the organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and n-hexane to give trans-1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine described in Table 54 below. 7.15 g was obtained. (6) 84.3 g of trans-1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine was dissolved in 2500 ml of ethyl acetate, and (R) was obtained at room temperature. -A solution of 15.1 g of phenethylamine in 1500 ml of ethyl acetate was added dropwise over 1.5 hours. The precipitated white salt was filtered, washed twice with ethyl acetate, washed with a mixed solvent of 200 ml of diisopropyl ether and 400 ml of methanol, added with a saturated aqueous citric acid solution to the white salt, extracted from chloroform, washed with saturated brine, washed with magnesium sulfate. (A) (3R, 4R) -1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine described in Table 54 below by drying and concentrating under reduced pressure. 3 g was obtained. The furnace liquid obtained by the above operation was combined, a saturated aqueous citric acid solution was added, and the mixture was extracted from chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 2500 ml of ethyl acetate, and a solution of 15.1 g of (S) -phenethylamine in 1500 ml of ethyl acetate was added dropwise at room temperature over 1.5 hours. The precipitated white salt was filtered, washed twice with ethyl acetate, saturated aqueous citric acid solution was added to the white salt, and the mixture was extracted from chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and n-hexane to give (b) (3S, 4S) -1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro) described in Table 54 below. There were obtained 28.1 g of 2-methylphenyl) piperidine.

Reference example 2
(1) A slurry of 50 g of isonicotinic acid chloride hydrochloride in 500 ml of 1,2-dichloroethane cooled to 0 ° C and slowly added a solution of 31.4 g of aniline and 60 g of triethylamine in 50 ml of 1,2-dichloroethane over 25 minutes. It was dripped. After stirring for 30 minutes at room temperature, the mixture was stirred for 1.5 hours under reflux. 100 ml of water was added to the reaction liquid, and it cooled slowly to 0 degreeC. The generated precipitate was collected by filtration, dried under reduced pressure, washed with diethyl ether, and dried under reduced pressure to obtain 45 g of N-phenylisonicotinic acid amide described in Table 55 below.

  (2) A solution of 32 g of the compound obtained in (1) above in 640 ml of tetrahydrofuran was cooled to −78 ° C., 13 ml of n-butyllithium (1.6 M hexane solution) was added dropwise and stirred for 0.5 hours. The reaction solution was slowly warmed to 0 ° C. and stirred for 1.5 hours. After cooling again to −78 ° C., a solution of iodine 40 g in tetrahydrofuran 120 ml was added dropwise and stirred for 3 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was separated and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was tritiated with a mixed solvent of dichloromethane and diisopropyl ether to obtain 31 g of N-phenyl-3-iodoisonicotinic acid amide described in Table 55 below.

  (3) To 25 g of the compound obtained in (2) above, 200 ml of an approximately 25% aqueous hydrochloric acid solution was added, and the mixture was stirred for 16 hours with heating under reflux. The reaction solution was cooled to 0 ° C., and the generated precipitate was collected by filtration. The filtered product was washed with a small amount of water to obtain 14.5 g of 3-iodoisonicotinic acid hydrochloride shown in Table 55 below.

  (4) One drop of N, N-dimethylformamide and then 9.3 g of thionyl chloride were added to 125 ml of ethyl acetate in 14.5 g of the compound obtained in (3) above, and the mixture was stirred for 1 hour while heating under reflux. The reaction solution was concentrated under reduced pressure, 100 ml of methanol was added, and the mixture was stirred for 2 hours with heating under reflux. The residue obtained by concentrating the reaction solution under reduced pressure was tritylated with diethyl ether and dried under reduced pressure to obtain 13.2 g of methyl 3-iodoisonicotinate described in Table 55 below.

  (5) The same procedure as in Reference Example 1 (2) was carried out using 13.2 g of the compound obtained in (4) above and the corresponding starting material compound to give 3- (4-fluoro in Table 55 below. 7.7 g of methyl phenyl) isonicotinate were obtained.

  (6) By treating in the same manner as in Reference Example 1 (3) using 7.0 g of the compound obtained in (5) above and the corresponding starting material compound, cis-1-tert- described in Table 55 below 6.5 g of butoxycarbonyl-3- (4-fluorophenyl) -4-methoxycarbonylpiperidine was obtained.

  (7) By treating in the same manner as in Reference Example 1 (4) using 6 g of the compound obtained in (6) above and the corresponding starting material compound, cis-1-tert-butoxycarbonyl described in Table 56 below Of -4-carboxyl-3- (4-fluorophenyl) piperidine and trans-1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluorophenyl) piperidine (cis isomer: trans isomer = 54: 46) 5.8 g of a mixture was obtained.

Reference example 3
(1) By using the compound obtained in Reference Example 2 (4) and the corresponding starting material compound in the same manner as in Reference Example 2 (5), 3- (2,4- Methyl difluorophenyl) isonicotinate was obtained.

  (2) By using the compound obtained in (1) above and the corresponding starting material compound in the same manner as in Reference Example 2 (6), cis-1-tert-butoxycarbonyl described in Table 56 below is given. 3- (2,4-Difluorophenyl) -4-methoxycarbonylpiperidine was obtained.

  (3) (a) (3S, 4S) -1-tert-butoxy described in Table 56 below by treating in the same manner as in Reference Example 1 (5) using the compound obtained in (2) above. Carbonyl-4-carboxyl-3- (2,4-difluorophenyl) piperidine, and (b) (3R, 4R) -1-tert-butoxycarbonyl-4-carboxyl-3- (2,4-difluorophenyl) piperidine Got.

Reference example 4
(1) To a 200 ml tetrahydrofuran solution of 12.8 g of 3,5-bistrifluoromethylacetophenone, 25 ml of a 3M methylmagnesium tetrahydrofuran solution was added dropwise at −20 ° C. and stirred for 2 hours. Ammonium chloride and ethyl acetate were added to the reaction mixture, and the mixture was concentrated under reduced pressure. At −20 ° C., 27 ml of trimethylsilylcyanide and 16 ml of concentrated sulfuric acid were added and stirred for 3 hours. The reaction solution was dropped into ice, neutralized with 1M aqueous sodium hydroxide solution, extracted with chloroform, and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20 → 50: 50) to give N- {1- (3,5-bistrifluoromethyl) described in Table 57 below. 5.47 g of (phenyl) -1-methyl-ethyl} -N-formamide were obtained.

  (2) To a solution of 5.47 g of the compound obtained in (1) above in 150 ml of N, N-dimethylformamide was added 800 mg of sodium hydride (60% in oil) under a nitrogen atmosphere, and the mixture was stirred for 1 hour and 10 minutes. 7.1 g of methyl iodide was added, and the mixture was stirred for 3 hours and 45 minutes and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 60: 40) to give N- {1- (3,5-bistri) described in Table 57 below. Fluoromethylphenyl) -1-methyl-ethyl} -N-methylformamide was obtained.

  (3) To a 50 ml ethanol solution of the compound obtained in (2) above, a 47% aqueous solution of hydrogen bromide was added at room temperature, stirred overnight, then heated to 60 ° C. and stirred for 2 days. The reaction solution was dropped into an aqueous sodium hydrogen carbonate solution containing ice, extracted with chloroform, and concentrated under reduced pressure. Dichloromethane was added to the resulting residue, the insoluble matter was removed from the furnace, and the filtrate was concentrated under reduced pressure to give N- {1- (3,5-bistrifluoromethylphenyl) -1-methyl-ethyl}-listed in Table 57 below. 3.00 g of N-methylamine was obtained.

Reference Example 5
To a solution of 2.03 g of (3S, 4S) -1-tert-butoxycarbonyl-4-carboxyl-3- (4-fluoro-2-methylphenyl) piperidine in 9 ml of ethyl acetate was added 27 ml of 4M ethyl acetate in hydrochloric acid at room temperature. For 1.5 hours and then concentrated under reduced pressure. Water was added to the residue, the aqueous layer was basified with an aqueous sodium carbonate solution, and the precipitated solid was collected by filtration. 1.9 g of sodium carbonate and 1.12 g of benzyl chloroformate were added to a solution of 25 ml of the obtained solid in 25 ml of water and 25 ml of tetrahydrofuran, stirred at room temperature for 16 hours, and concentrated under reduced pressure. Ethyl acetate, water, and saturated aqueous citric acid solution were added to the residue for liquid separation. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 19: 1) to give (3S, 4S) -1-benzyloxycarbonyl-4-carboxyl-3- ( 4-fluoro-2-methylphenyl) piperidine 1.11 g was obtained.

Reference Example 6
To a solution of 4.8 g of isonipecotic acid ethyl ester in 30 ml of dichloromethane, 3.5 ml of propionic acid chloride and 5.6 ml of triethylamine were added at 0 ° C. and stirred for 2 hours. The reaction solution was separated by adding an aqueous sodium bicarbonate solution and chloroform. The organic layer was washed successively with hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, 30 ml of methanol and 30 ml of 2M aqueous sodium hydroxide solution were added and stirred at room temperature for 16 hours. Methanol was distilled off from the reaction solution under reduced pressure, and the aqueous layer obtained was washed with ether, and the aqueous layer was made weakly acidic with hydrochloric acid and citric acid. The aqueous layer was extracted twice with chloroform, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to obtain 2.5 g of 1-propionylpiperidine-4-carboxylic acid described in Table 57 below.

Reference Example 7
The corresponding starting material compound was used and treated in the same manner as in Reference Example 6 to give 1-isobutyroylpiperidine-4-carboxylic acid described in Table 57 below.

Reference Example 8
To a solution of 500 mg of 2-bromo-2-methylpropionic acid in 1.5 ml of 1-propanol were added 600 mg of morpholine and 0.55 ml of triethylamine, and the mixture was stirred for 16 hours with heating under reflux. After returning to room temperature, 0.3 ml of 10M aqueous sodium hydroxide solution was added, and the mixture was concentrated under reduced pressure. The obtained residue was azeotroped with toluene and then vacuum-dried. 1-Propanol was added to the resulting residue and tritylated to obtain 380 mg of 2-methyl-2- (4-morpholinyl) propionic acid sodium salt described in Table 57 below.

Reference Example 9
(1) A 40 ml toluene solution of 10.2 g of 4-ethoxycarbonylcyclohexanone was added dropwise at 0 ° C. to a 100 ml toluene solution of 60 ml of a 2M hexane solution of trimethylaluminum and stirred for 30 minutes. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution to separate the layers. The organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 75: 25), 3.43 g of trans-4-ethoxycarbonyl-1-methylcyclohexanol described in Table 58 below is obtained. Got.

  (2) To a solution of the compound 2.24 g obtained in (1) above in 24 ml of ethanol was added 580 mg of sodium hydroxide and 12 ml of water, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, acidified with 2M aqueous hydrochloric acid solution, and extracted three times from chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.65 g of trans-4-carboxyl-1-methylcyclohexanol described in Table 58 below.

Reference Example 10
In a solution of 800 mg of cyclohexane-1,4-dicarboxylic acid monomethyl ester in 5 ml of N, N-dimethylformaldehyde, 3.84 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole 06 g and 1.5 ml of 50% dimethylamine aqueous solution were added and stirred at room temperature for 16 hours. Ethyl acetate and brine were added to the reaction solution for liquid separation. The organic layer was washed twice with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. To 680 mg of the residue, 10 ml of methanol and 10 ml of 2M aqueous sodium hydroxide solution were added and stirred at room temperature for 16 hours. The mixture was neutralized with 2M aqueous hydrochloric acid, and methanol was distilled off under reduced pressure. The aqueous layer was extracted twice with chloroform, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dried in vacuum to obtain 430 mg of 4-dimethylcarbamoylcyclohexanecarboxylic acid described in Table 58 below.

Reference Example 11
To a solution of 2-chloroethanesulfonyl chloride (2 g) in dichloromethane (20 ml) were added pyrrolidine (4 ml) and triethylamine (4 ml), and the mixture was stirred at 0 ° C. for 1 hour. Chloroform and 1M aqueous hydrochloric acid solution were added to the reaction solution to separate the layers. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to obtain 580 mg of 1-ethenesulfonylpyrrolidine described in Table 58 below.

Reference Example 12
(1) A solution of 9 g of 3,5-bistrifluoromethylbromobenzene in 90 ml of tetrahydrofuran was dropped into a solution of 800 mg of magnesium powder and 20 mg of iodine in 10 ml of tetrahydrofuran under heating and refluxing, and the mixture was stirred for 2 hours. The reaction solution was cooled to −78 ° C., a solution of 3 g of propionyl aldehyde in 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 2 hours. After cooling to room temperature, an ammonium chloride aqueous solution and ethyl acetate were added for liquid separation. The organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20) to give 1- (3,5-bistrifluoromethylphenyl) -1-propanol 5 described in Table 58 below. .3 g was obtained.

  (2) 1.6 ml of methanesulfonic acid chloride was added at 0 ° C. to a solution of 5.3 g of the compound obtained in the above (1) and 3 ml of triethylamine in 100 ml of dichloromethane, and the mixture was stirred for 3 hours. Water and chloroform were added to the reaction solution for liquid separation. The aqueous layer was re-extracted with chloroform, and the combined organic layers were dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20) to give methanesulfonic acid 1- (3,5-bistrifluoromethylphenyl) -1 described in Table 58 below. 4.3 g of propyl ester were obtained.

  (3) To a solution of 3.5 g of the compound obtained in (2) above in 100 ml of acetonitrile was added 1.3 g of sodium azide, and the mixture was stirred for 3 hours under heating and reflux. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then water and ethyl acetate were added to separate the layers. The organic layer was dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 1- (1-azidopropyl) -3,5-bistrifluoromethylbenzene described in Table 58 below. 2.3 g was obtained.

  (4) A solution of 2.2 g of the compound obtained in the above (3) and a 40 ml methanol solution of 200 mg paradium carbon was stirred for 8 hours under a hydrogen atmosphere of about 1 atm. After removing the catalyst from the reaction solution by filtration, the filtrate was concentrated under reduced pressure to obtain 2 g of 1- (3,5-bistrifluoromethylphenyl) propylamine described in Table 58 below.

Reference Example 13
The corresponding starting materials were used and treated in the same manner as in Reference Example 12 to give the compounds shown in Table 59 below.

  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 (6)

Formula [I]

(In the formula, ring A represents a benzene ring which may have a substituent.
Ring B represents a benzene ring which may have a substituent.
R ¹ represents a hydrogen atom or an amino group substituent.
R ² represents a hydrogen atom, a hydroxyl group that may have a substituent, an amino group that may have a substituent, an alkyl group that may have a substituent, or a carbonyl group that has a substituent. Or represents 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.
R ^4a and R ^4b are the same or different and each represents a hydrogen atom or an alkyl group which may have a substituent, or a group which is bonded to each other at a terminal to form an alkylene group. )
A pharmaceutical composition comprising as an active ingredient a piperidine compound represented by the formula or a pharmacologically acceptable salt thereof. The compound according to claim 1, wherein R ¹ is an amino group which may have a substituent, a hydroxyl group which may have a substituent, or a sulfinyl group which has a substituent. A pharmaceutical composition comprising a salt that can be obtained as an active ingredient. R ¹ has an alkylamino group which may have a substituent, a cycloalkylamino group which may have a substituent, an arylamino group which may have a substituent, and a substituent. A pharmaceutical composition comprising the compound according to claim 2 or a pharmacologically acceptable salt thereof as an active ingredient, which may be an alkoxy group, an alkylsulfinyl group or a hydroxysulfinyl group which may have a substituent. The pharmaceutical composition according to any one of claims 1 to 3, which is a tachykinin receptor antagonist. It is a prophylactic / therapeutic agent for diseases selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, central nervous system diseases, digestive system diseases, nausea, vomiting, abnormal urination, cardiovascular diseases and immune abnormalities. The pharmaceutical composition according to any one of claims 1 to 3. The pharmaceutical composition according to claim 5, wherein the disease is abnormal urination.