WO2009110519A1

WO2009110519A1 - Novel 1-aminocarbonylpiperidine derivative

Info

Publication number: WO2009110519A1
Application number: PCT/JP2009/054093
Authority: WO
Inventors: 道律小澤; 智也城; 慶介柿口; 眞里伊藤
Original assignee: 大日本住友製薬株式会社
Priority date: 2008-03-04
Filing date: 2009-03-04
Publication date: 2009-09-11
Also published as: JP2011102241A

Abstract

Disclosed is a novel compound useful as an antiallergic agent, namely a novel 1-aminocarbonylpiperidine derivative represented by formula (I) or a physiologically acceptable salt thereof. (In the formula, ring A represents an azetidin-1-yl group, a pyrrolidin-1-yl group, a piperidino group, a piperazin-1-yl group, a morpholino group or the like; R¹ represents an optionally substituted phenyl group, an optionally substituted C_3-8 cycloalkyl group or the like; R² represents an optionally substituted phenyl group or the like; R³ and R⁴ may be the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C_1-6 alkyl group or the like; and m represents 1, 2 or 3.)

Description

Novel 1-aminocarbonylpiperidine derivatives

The present invention relates to a novel 1-aminocarbonylpiperidine derivative having an excellent antiallergic action, a physiologically acceptable salt thereof, and a pharmaceutical composition containing them.

In recent years, allergic diseases such as bronchial asthma, allergic rhinitis, urticaria, atopic dermatitis and contact dermatitis have increased due to air pollution and changes in house structure (sealing, heating and cooling, etc.) . Currently, steroids are mainly used to treat these allergic diseases, but steroids often cause serious side effects. In recent years, several drugs that have immunosuppressive effects are also said to be effective in the prevention and treatment of allergic diseases, but their use is also restricted because of serious side effects. . On the other hand, existing antihistamines and anti-inflammatory agents are also used for the treatment of allergic diseases as symptomatic treatments, but these drugs do not show a sufficient therapeutic effect particularly in atopic dermatitis. Therefore, a new non-steroidal antiallergic agent effective by oral administration for the prevention and treatment of allergic diseases is eagerly desired.

Patent Document 1 discloses a protein inhibitor represented by the following general formula. It is described that the compound is used for the treatment of osteoporosis, periodontal disease, osteoarthritis and the like. The nitrogen atom of the piperidine ring of the compound of the present invention is substituted with —C (═O) —NH—R ¹ , and the corresponding substituent R ⁵ of the following compound has such a substituent. Not. Therefore, the chemical structure is clearly different from the compound of the present invention.

[Wherein Y is Ar or NR ¹ R ² ;
R ¹ is R ″, R ″ C (O), R ″ C (S), R ″ SO ₂ , R ″ OC (O), R ″ R′NC (O), or R ′. 'R'NC (S);
R ² is H, C _1-6 alkyl, C _2-6 alkenyl, Ar—C _0-6 alkyl, or Het-C _0-6 alkyl;
R ³ is H, C _2-6 alkenyl, C _2-6 alkynyl, Het, Ar, etc .;
R ⁴ is Ar—C _0-6 alkyl, Het-C _0-6 alkyl, etc .;
R ⁵ represents R ⁶ —N (R ¹ ) —C (R ⁷ ) —Z—, Ar—C _0-6 alkyl, Het—C _0-6 alkyl, adamantyl-C (O) —, Ar—C (O )-, Or Het-C (O)-;
Each R ′ is independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar—C _0-6 alkyl, or Het-C _0-6 alkyl;
Each R '' are independently _{C 1-6} _{alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl or _{Het-C 0-6} alkyl;
R ′ ″ is H, C _1-6 alkyl and the like;
R ⁶ is R ″, R ″ C (O), R ″ C (S), R ″ SO ₂ , R ″ OC (O), R ″ R′NC (O), etc .;
R ⁷ is _{C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} alkyl and the like;
Z is C (O) or CH ₂ ;
n is 1, 2 or 3. ]

Patent Document 2 discloses a PGD2 receptor antagonist represented by the following general formula. The compound is described to be used for the treatment of inflammatory diseases (allergic rhinitis, allergic asthma, atopic dermatitis, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease or skin disorder) Yes. The compound has a piperidine ring, but this piperidine ring is a condensed bicyclic heterocyclic ring that is always condensed with another monocyclic aromatic ring, and the chemical structure is clearly different from the compound of the present invention. .

[Wherein ring A is an optionally substituted monocyclic aromatic ring;
R is —X ₁ —R ¹ ;
R ^x is —X ₂ —R ⁴ ;
R ³ is an optionally substituted cycloaliphatic group, aromatic group or the like;
X is —C (R ² ) ₂ — and the like;
X ₁ and X ₂ are each independently a bond, C (O), C (O) NH, etc .;
R ¹ is H or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
R ² is independently H, —X ₄ —R ^{8 and the} like;
R ⁴ is H, —X ₆ —R ¹⁰ or the like;
X ₄ and X ₆ are each independently a linear or branched hydrocarbyl group, wherein the hydrocarbyl group is optionally selected from one or more selected from the group consisting of halo, —OH, ═O, and the like. Substituted with a group of
R ⁵ and R ⁶ are each independently H or C ₁ -C ₃ alkyl; and
R ⁸ and R ¹⁰ are each independently H, a cycloaliphatic group, an aromatic group, a non-aromatic heterocyclic group, or the like; ]

Patent Document 3 discloses a PGD2 receptor antagonist represented by the following general formula. The compounds are described for use in the treatment of inflammatory diseases (allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease, atopic dermatitis or allergic asthma). The compound has a piperidine ring, but this piperidine ring is a condensed bicyclic heterocyclic ring that is always condensed with another monocyclic aromatic ring, and the chemical structure is clearly different from the compound of the present invention. .

[Wherein ring A is an optionally substituted monocyclic aromatic ring;
R is —X ₁ —R ¹ ;
R ^x is —X ₂ —R ⁴ ;
X ₁ and X ₂ are each independently C (O), C (O) NH, etc .;
R ¹ is a substituted 5- to 6-membered aromatic ring group or heteroaromatic ring group;
R ² is a C _1-3 alkyl group;
R ³ is an optionally substituted monocyclic or bicyclic group selected from an aromatic ring, a heteroaromatic ring, a non-aromatic carbocycle, or a non-aromatic heterocycle;
R ⁴ is an optionally substituted C _1-6 alkyl group or the like; ]

Patent Document 4 discloses a serotonin and noradrenaline reuptake inhibitor represented by the following general formula. The compound may be used in the treatment of diseases involving the inhibition of both serotonin and noradrenaline (urinary incontinence) and diseases that inhibit reuptake of either serotonin or noradrenaline (pain, depression, etc.) Are listed. These uses are completely different from those of the present invention. Furthermore, the examples of this document only disclose compounds in which R ¹ is a hydrogen atom, and the group R ³ corresponding to the — (CH ₂ ) _m — ring A moiety of the compounds of the present invention is het. ^There is also no specific disclosure of compounds that are ^3- C _1-4 alkyl-groups.

[Wherein, R ¹ is —H, —C (A) Y, —C _3-8 cycloalkyl, —aryl, —het, etc., and these cycloalkyl, aryl or het are selected from B Substituted with at least any one independent substituent,
A is S or O;
Y is -aryl, -het, etc.
B is —C _1-8 alkyl, —C _1-8 alkoxy, —OH, —halo, —CF ₃ , —OCF ₃ , C _1-4 alkoxy-C _1-6 alkyl-, etc.
R ² is aryl ¹ or het ¹ , each optionally substituted with at least one independent substituent selected from D;
Aryl ¹ is independently selected from phenyl, naphthyl, etc.
het ¹ is a 5- to 10-membered aromatic heterocycle containing at least one N, O or S heteroatom, optionally containing an aryl group,
D represents —C _1-8 alkyl, —C _1-8 alkoxy, —OH, —halo, —CF ₃ , —OCF ₃ , C _1-4 alkoxy-C _1-6 alkyl-, —C _3-8 cyclo Alkyl, etc.
R ³ is -het ³ , het ³ -C _1-4 alkyl-, etc., and het ³ etc. is optionally substituted with at least one independent substituent selected from G;
het ³ is a 4-, 5- or 6-membered non-aromatic heterocycle containing at least one N, O or S heteroatom, optionally a 5- or 6-membered carbocycle or at least Fused with another 4-, 5- or 6-membered heterocycle containing one N, O or S heteroatom,
G is —C _1-8 alkyl, —C _1-6 alkoxy, —OH, —halo, —CF _3, etc., and the alkyl group here may have a substituent,
X is a single bond, —C _1-8 alkyl or the like,
When n is 1, m is 0 or 1 or the like. ]

Non-Patent Document 1 discloses compounds represented by the following general formula, and describes that these compounds are useful as analgesics and local anesthetics. When X is N (CH ₃ ), the compound is a compound having a piperidine ring, but since the only substituent of the nitrogen atom of the piperidine ring is only a methyl group, it is clearly the compound of the present invention. The chemical structure is different.

[Wherein, R ¹ is a methyl group, R ² and R ³ are a hydrogen atom or a methyl group,
NR ⁴ R ⁵ is N (CH ₂ ) ₂ , N (CH ₂ CH ₃ ) ₂ , pyrrolidinyl group, piperidinyl group or morpholinyl group,
X is an oxygen atom, a sulfur atom or N (CH ₃ ). ]
JP-T-2001-525809 Special table 2006-508077 gazette International Publication WO2005 / 100321 Pamphlet International Publication WO2006 / 064351 Pamphlet Chemical Abstract 95: 24753 [Khimiko-Farmasevticeskii Zhurnal (1981), 15 (3), 43-49]

Since existing antiallergic agents and antihistamines have almost no inhibitory effect on inflammation in human atopic dermatitis, new therapeutic agents for atopic dermatitis other than steroids and immunosuppressants with strong side effects are required. ing.

As a result of intensive studies to solve the above problems, the present inventors have found a novel compound having a non-steroidal chemical structure and exhibiting an excellent antiallergic action, and completed the present invention. . According to the present invention, a novel 1-aminocarbonylpiperidine derivative represented by the following general formula (I) or a physiologically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) and the present invention A pharmaceutical composition containing the compound is provided.

(1) A compound represented by the following formula (I) or a physiologically acceptable salt thereof:

[In the formula, ring A is azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, piperazin-1-yl group, morpholino group, hexahydroazepin-1-yl group, hexahydrodiazepine- 1-yl group, aziridin-1-yl group, perhydroisoquinolin-2-yl group, perhydroquinolin-1-yl group, 1,2,3,4-tetrahydroisoquinolin-2-yl group, 1,2, 3,4-tetrahydroquinolin-1-yl group, 2,3-dihydroindol-1-yl group, perhydroindol-1-yl group, 1,3-dihydroisoindol-2-yl group, perhydroisoindole -2-yl group, pyrazolidin-1-yl group, tetrahydroimidazol-1-yl group, hexahydro-1,4-oxaazepin-4-yl group, oxazolid -3-yl group, thiazolidin-3-yl group, thiomorpholin-4-yl group, hexahydropyridazin-1-yl group, hexahydropyrimidin-1-yl group, tetrazolyl group, 2-pyrrolin-1-yl group Or represents a 3-pyrrolin-1-yl group,
R ¹ represents an optionally substituted phenyl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted heterocyclic group (wherein the heterocyclic group is a pyridyl group, pyrimidinyl) Group, pyrazinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, azaindolyl group, indazolyl group, indolinyl group, isoindolinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, cinnolinyl group, furyl group, Represents a pyranyl group, a benzofuranyl group, a chromenyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group or a benzoisoxazolyl group),
The optionally substituted phenyl group in R ¹ is a halogen atom, a hydroxy group, a C _1-6 alkyl group (the C _1-6 alkyl group is a halogen atom, a hydroxy group, a C _1-3 alkoxy group, and a trialkyl group). Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of fluoromethyl groups), C _1-6 alkoxy groups, trifluoromethoxy groups, cyano groups, nitro groups, carboxyl groups, phenyl groups [ The phenyl group is a halogen atom, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C _1-3 alkoxy-C _{1- 3} alkyl groups, C _1-3 alkoxy-carbonyl groups, C _1-3 alkyl-carbonyl groups, C _1-3 alkylthio groups, C _1-3 alkyls Substituted with 1 to 4 atoms or groups selected from the group consisting of a sulfonyl group and an amino group (the amino group may be substituted with one or two identical or different C _1-3 alkyl groups) A C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group includes a halogen atom, a hydroxy group, a C _1-3 alkyl group, a C _1-3 alkoxy group, a trifluoromethyl group, and Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of trifluoromethoxy groups), C _1-6 alkoxy-carbonyl groups, C _1-6 alkyl-carbonyl groups, trifluoromethylcarbonyl groups , A C _1-3 alkylthio group, a C _1-3 alkylsulfonyl group, an aminocarbonyl group (the aminocarbonyl group is the same or different two C _1-6 alkyls). Optionally substituted with a kill group) and an amino group (the amino group may be substituted with one or two identical or different C _1-3 alkyl groups, or a C _1-3 alkyl-carbonyl group). A phenyl group optionally substituted with 1 to 5 atoms or groups selected from the group consisting of:
The optionally substituted C _3-8 cycloalkyl group for R ¹ is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an amino group. A group (the amino group may be substituted by one or two identical or different C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) and a phenyl group [the phenyl group is a halogen atom; , Hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C _1-3 alkoxy-C _1-3 alkyl group, C _{1- 3} alkoxy - carbonyl _{group, C 1-3} alkyl - carbonyl group, a trifluoromethyl _{group, C 1-3} alkylthio _{group, C 1-3} A Alkylsulfonyl group and an amino group (said amino group may contain one or two identical or different C _1-3 alkyl optionally substituted with a group) with 1 to 4 atoms or groups selected from the group consisting of Means an optionally substituted C _3-8 cycloalkyl group substituted with 1 to 4 atoms or groups selected from the group consisting of:
The optionally substituted heterocyclic group for R ¹ is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, or a nitro group. A carboxyl group, a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, C _{1 -3} alkoxy-C _1-3 alkyl group, C _1-3 alkoxy-carbonyl group, C _1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C _1-3 alkylthio group, C _1-3 alkylsulfonyl group and amino group (said amino group may be substituted by one or two identical or different C _1-3 alkyl group It may be substituted with 1 to 4 atoms or groups selected from the group consisting _{of], C 3-8} cycloalkyl _{group, C 1-3} alkoxy _{-C 1-3} alkyl _{group, C 1-6} alkoxy - A carbonyl group, a C _1-6 alkyl-carbonyl group, a trifluoromethylcarbonyl group, a C _1-3 alkylthio group, a C _1-3 alkylsulfonyl group, an oxo group, an aminocarbonyl group (the aminocarbonyl groups may be the same or different 2 And optionally substituted with two C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups which may be substituted with one C _1-6 alkyl group and an amino group. A heterocyclic group which may be substituted with 1 to 4 atoms or groups selected from the group consisting of (optionally substituted),
R ² represents a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or a carboxyl group. C _1-3 alkoxy-C _1-3 alkyl group, C _1-3 alkoxy-carbonyl group, C _1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C _1-3 alkylthio group, C _1-3 alkyl 1 selected from the group consisting of a sulfonyl group and an amino group (the amino group may be substituted with one or two identical or different C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) Optionally substituted with up to 5 atoms or groups] or a C _3-8 cycloalkyl group wherein the C _3-8 cycloalkyl group is a halogen An atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two C _{1-3, which} are the same or different) And optionally substituted with 1 to 4 atoms or groups selected from the group consisting of an alkyl group or a C _1-3 alkyl-carbonyl group).
R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, or a C _1-6 alkyl. -Carbonyl group, amino group [the amino group is one or the same or different two C _1-6 alkyl groups, C _1-3 alkyl-carbonyl group or aminocarbonyl group (the aminocarbonyl groups are the same or different _May be substituted with two C _1-6 alkyl groups)], a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _{1- 6} alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (said amino group may contain one or two identical or different C _1-3 Alkyl optionally substituted with 1 to 5 atoms or groups selected from the group consisting of a may be) optionally substituted with a group], a benzyl group [said benzyl group, a halogen atom, hydroxy group, C _{1- A 6} alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group may be substituted with one or two identical or different C _1-3 alkyl groups) The benzoyl group may be substituted with 1 to 5 atoms or groups selected from the group consisting of: a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 An alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group is substituted by one or two identical or different C _1-3 alkyl groups) _Optionally substituted with 1 to 5 atoms or groups selected from the group consisting of C _3-8 cycloalkyl groups, aminocarbonyl groups (the aminocarbonyl groups may be the same or different Which may be substituted with a C _1-6 alkyl group), a pyrrolidylcarbamoyl group or a C _1-6 alkyloxadiazolyl group,
m represents 1, 2 or 3. ].

(2) Group: In the above (1), ring A is an azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, morpholino group, piperazin-1-yl group or hexahydroazepin-1-yl group Or a physiologically acceptable salt thereof.

(3) R ¹ is a halogen atom, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, carboxyl group, phenyl group [phenyl Group includes a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two of the same or different _Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of a C _1-3 alkyl group), a C _3-8 cycloalkyl group, a C _1-6 alkoxy - carbonyl _{group, C 1-6} alkyl - carbonyl group, a trifluoromethyl _{group, C 1-3} alkylthio _{group, C 1-3} alkylsulfonyl group Amino group and (said amino group may contain one or two identical or different C _1-3 alkyl group or a C _1-3 alkyl - may be substituted by carbonyl group) 1 to 5 selected from the group consisting of Phenyl group which may be substituted with one atom or group; halogen atom, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, amino group (the amino group) The group may be substituted with one or two identical or different C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) and a phenyl group (the phenyl group is a halogen atom, a hydroxy group, C _1-6 _{alkyl, C 1-6} alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (said amino group, one or the Or different two C _1-3 1 ~ 4 is selected from the group consisting of may also] be substituted with 1 to 5 atoms or groups selected from the group consisting of may also) be substituted by an alkyl group A cyclohexyl group optionally substituted with one atom or group; or a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group The amino group may be one or four atoms or groups selected from the group consisting of one or two identical or different C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) The compound or physiologically acceptable salt thereof according to any one of the above (1) or (2), which is a pyridyl group optionally substituted with.

(4) R ¹ is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or the same or A phenyl group optionally substituted with 1 to 5 atoms or groups selected from the group consisting of two optionally substituted C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) Or a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one, or two identical or different C 1-4 atom or cyclohexyl group der optionally substituted with a group selected from _1-3 group consisting of alkyl optionally substituted with a group) Compound or a physiologically acceptable salt thereof according to any one of the above (1) to (3).

(5) R ² is a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or an amino group (the amino group is Substituted with 1 to 5 atoms or groups selected from the group consisting of one or two identical or different C _1-3 alkyl groups or optionally substituted with C _1-3 alkyl-carbonyl groups) The compound or a physiologically acceptable salt thereof according to any one of the above (1) to (4), which is an optionally _substituted phenyl group; or a C _3-8 cycloalkyl group.

(6) R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkyl-carbonyl group, trifluoromethyl A group, an aminocarbonyl group (the aminocarbonyl group may be substituted with two identical or different C _1-6 alkyl groups) and an amino group (the amino group is one or two identical or different The compound according to any one of (1) to (5) above, which may be substituted with a C _1-3 alkyl group or a C _1-3 alkyl-carbonyl group, or a physiologically acceptable product thereof salt.

(7) The compound or a physiologically acceptable salt thereof according to any one of (1) to (6) above, wherein m is 1 or 2.

(8) Group: Ring A is a pyrrolidin-1-yl group, piperidino group, morpholino group or piperazin-1-yl group,
R ¹ is a phenyl group which may be substituted with 1 to 5 atoms or groups selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a trifluoromethyl group. ,
R ² is a phenyl group;
R ³ and R ⁴ are the same or different and are a hydrogen atom or a C _1-6 alkyl group,
The compound or a physiologically acceptable salt thereof according to the above (1), wherein m is 1 or 2.

(9) N- (4-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (of Example 1 Compound),
N- (4-trifluoromethylphenyl) -4- [N- (2-morpholin-4-ylacetyl) -N-phenylamino] piperidine-1-carboxamide (compound of Example 2),
N- (4-methoxyphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 3),
N- (4-fluorophenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 4),
N- (3-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 5),
N- (4-isopropylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (the compound of Example 6),
N- (2-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (the compound of Example 7), And N- (4-trifluoromethylphenyl) -4- [N- (3-pyrrolidin-1-ylpropionyl) -N-phenylamino] piperidine-1-carboxamide (compound of Example 8)
The compound according to the above (1) or a physiologically acceptable salt thereof selected from the group consisting of

(10) A pharmaceutical composition comprising the compound according to any one of (1) to (9) above or a physiologically acceptable salt thereof as an active ingredient.

(11) The pharmaceutical composition according to the above (10) for use in the prevention and / or treatment of allergic diseases.

(12) The pharmaceutical composition according to the above (11), wherein the allergic disease is atopic dermatitis or contact dermatitis.

Since the compound of the present invention has an excellent antiallergic action in an atopic dermatitis model, examples of antiallergic agents include allergic dermatitis, allergic rhinitis, bronchial asthma, atopic dermatitis, contact dermatitis It can be used for the prevention and / or treatment of allergic diseases such as urticaria, eczema, allergic ophthalmitis, hay fever, and other inflammatory diseases.

The physiologically acceptable salt of the compound represented by the formula (I) means a physiologically acceptable acid addition salt. Specifically, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, fumarate, malonate, lactic acid Organic salts such as salts, malates, citrates, tartrate, benzoates, methanesulfonates, p-toluenesulfonates, gluconates and the like.

Since the compounds of the present invention may be crystalline or amorphous and may exist in the form of hydrates and / or solvates, these hydrates and / or solvates Are also encompassed by the compounds of the present invention. Compounds containing various amounts of water obtained by methods such as stoichiometric amounts of hydrates and lyophilization are also within the scope of the present invention.

In addition, some of the compounds represented by the formula (I) have an asymmetric carbon atom, and these stereoisomers, mixtures thereof and racemates are also included in the present invention. Also included in the compounds of the invention are compounds of formula (I) substituted with isotopes.

The terms used in this specification are explained below.

In the present specification, “C _1-6 ”, “C _3-8 ” or “C _1-3 ” means that the carbon number of the substituent described immediately thereafter is 1 to 6, 3 to 8, or 1 to 3 means. Thus, for example, “C ₁ alkyl-carbonyl” means an acetyl group.

“C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include, for example, methyl group, ethyl group, propyl group, isopropyl group Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group and the like. Of these, a methyl group and the like are preferable.
Specific examples of the “C _1-3 alkyl group” include a substituent having 1 to 3 carbon atoms in the above examples.

The “C _1-6 alkoxy group” may be linear or branched, and specific examples thereof include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec -Butoxy group, tert-butoxy group and the like. Of these, a methoxy group and the like are preferable.
Specific examples of the “C _1-3 alkoxy group” include a substituent having 1 to 3 carbon atoms in the above examples.

The “C _1-3 alkoxy-C _1-3 alkyl group” may be either linear or branched, and specific examples thereof include, for example, methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxy group Examples thereof include a methyl group, a methoxyethyl group, an ethoxyethyl group, a propoxypropyl group, and an isopropoxypropyl group.

The “C _1-6 alkoxy-carbonyl group” may be either linear or branched, and specific examples thereof include, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxy A carbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group and the like can be mentioned.
Specific examples of “C _1-3 alkoxy-carbonyl group” include a substituent having 1 to 3 carbon atoms in the alkoxy moiety in the above examples.

The “C _1-6 alkyl-carbonyl group” may be either linear or branched, and specific examples thereof include, for example, acetyl group, ethylcarbonyl group, propylcarbonyl group, isopropylcarbonyl group, butylcarbonyl group , Isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group and the like. Specific examples of the “C _1-3 alkyl-carbonyl group” include a substituent having 1 to 3 carbon atoms in the alkyl moiety in the above examples.

The “C _1-3 alkylthio group” may be either linear or branched, and specific examples thereof include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.

The “C _1-3 alkylsulfonyl group” may be linear or branched, and specific examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group.

“C _3-8 cycloalkyl group” means a monovalent group of a cycloalkane having 3 to 8 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

The “C _1-6 alkyloxadiazolyl group” may have either a linear or branched C _1-6 alkyl moiety. Specific examples thereof include, for example, methyloxadiazolyl group, ethyloxadiazolyl group Group, propyloxadiazolyl group, isopropyloxadiazolyl group, butyloxadiazolyl group, isobutyloxadiazolyl group, sec-butyloxadiazolyl group, tert-butyloxadiazolyl group, pentyloxadiazolyl group, isopentyl An oxadiazolyl group, a hexyl oxadiazolyl group, etc. are mentioned.

The “optionally substituted C _3-8 cycloalkyl group” means a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group at each substitutable position. , A trifluoromethoxy group, an amino group (the amino group may be substituted with one or the same or different two C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups) and a phenyl group [ The phenyl group is a halogen atom, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C _1-3 alkoxy-C _{1- 3} alkyl _{group, C 1-3} alkoxy - carbonyl _{group, C 1-3} alkyl - carbonyl group, a trifluoromethyl _{group, C 1-3} alkyl O group, C _1-3 alkylsulfonylamino group and an amino group (said amino group may contain one or two identical or different C _1-3 alkyl optionally substituted by a group) 1 selected from the group consisting of Means a C _3-8 cycloalkyl group optionally substituted with 1 to 4 atoms or groups selected from the group consisting of: [optionally substituted with 4 atoms or groups].
Preferable specific examples of the C _3-8 cycloalkyl group which may be substituted include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, 4-methylcyclohexyl group, 4-tert- Butylcyclohexyl group, 4,4-dimethylcyclohexyl group, 3,3,5,5-tetramethylcyclohexyl group, 4-fluorocyclohexyl group, 4-hydroxycyclohexyl group, 4-trifluoromethylcyclohexyl group, 4-methoxycyclohexyl group 4-phenylcyclohexyl group, 4- (4-chlorophenyl) cyclohexyl group, and the like.

The “optionally substituted phenyl group” is a halogen atom, a hydroxy group, or a C _1-6 alkyl group at each substitutable position (the C _1-6 alkyl group is each at a substitutable position). Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of a halogen atom, a hydroxy group, a C _1-3 alkoxy group and a trifluoromethyl group), a C _1-6 alkoxy group, trifluoro Methoxy group, cyano group, nitro group, carboxyl group, phenyl group (the phenyl group is a halogen atom, hydroxy group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, Cyano group, nitro group, C _1-3 alkoxy-C _1-3 alkyl group, C _1-3 alkoxy-carbonyl group, C _1-3 alkyl-carbonyl A group, a C _1-3 alkylthio group, a C _1-3 alkylsulfonyl group and an amino group (the amino group may be substituted with one, or two identical or different C _1-3 alkyl groups) Optionally substituted with 1 to 4 atoms or groups selected from the group], a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group is a halogen atom, Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of a hydroxy group, a C _1-3 alkyl group, a C _1-3 alkoxy group, a trifluoromethyl group and a trifluoromethoxy group), C _1-6 alkoxy - carbonyl _{group, C 1-6} alkyl - carbonyl group, a trifluoromethyl _{group, C 1-3} alkylthio _{group, C 1-3} alkylsulfonyl group, A Bruno carbonyl group (said amino group may be the same or different two C _1-6 alkyl which may be substituted with a group) and an amino group (said amino group may contain one or two identical or different C _{1 A} phenyl group that may be substituted with 1 to 5 atoms or groups selected from the group consisting of a _-3 alkyl group or a C _1-3 alkyl-carbonyl group.
Preferable specific examples of the optionally substituted phenyl group include, for example, a phenyl group, a 3-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 2-methylphenyl group, 4- (1,1,1, 1,3,3,3-hexafluoro-2-hydroxypropyl) phenyl group, 2-methoxyphenyl group, 4-trifluoromethylphenyl group, 4-trifluoromethoxyphenyl group, 4-cyanophenyl group, 4-chloro -3-nitrophenyl group, 4-phenylphenyl group, 4- (4-chlorophenyl) phenyl group, 4-cyclohexylphenyl group, 3-carboxylphenyl group, 4-methoxycarbonylphenyl group, 2-acetylphenyl group, 4- (2,2,2-trifluoroacetyl) phenyl group, 4-methylthiophenyl group, 4-methyls Phonylphenyl group, 2-hydroxyphenyl group, 4-dimethylaminophenyl group, 4- (3,3,5,5-tetramethylcyclohexylamino) phenyl group, 2- (tetrahydro-2H-pyran-4-ylamino) phenyl group 3,4-dichlorophenyl group, 2,4,6-trichlorophenyl group, 2-methoxy-4-chlorophenyl group, 2,5-difluoro-4-chlorophenyl group, 2-fluoro-4-trifluoromethylphenyl group, 4-fluorophenyl group, 3-chloro-4-fluorophenyl group, 2-trifluoromethylphenyl group, 2-chlorophenyl group, 3-fluoro-4-chlorophenyl group, 3-fluoro-4-trifluoromethylphenyl group, 2,3-difluoro-4-trifluoromethylphenyl group, 4-methylphenyl 4-isopropylphenyl group, 4-methoxymethylphenyl group, 4-fluoromethylphenyl group, 4- (1-chloro-2,2,2-trichloroethyl) phenyl group, 2,4-ditrifluoromethylphenyl group, Examples include 3-chlorophenyl group, 4-methoxyphenyl group, 3-dimethylaminophenyl group, 3-methoxyphenyl group, 3-trifluoromethylphenyl group, 2-fluorophenyl group and the like. Of these, 4-trifluoromethylphenyl group, 4-fluorophenyl group, 2-trifluoromethylphenyl group, 4-isopropylphenyl group, 4-methoxyphenyl group, 3-trifluoromethylphenyl group and the like are preferable.

`` Heterocyclic group '' means a pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, benzoimidazolyl group, indolyl group, isoindolyl group, azaindolyl group, indazolyl group, indolinyl group, isoindolinyl group, quinolyl group, An isoquinolyl group, a quinazolinyl group, a cinnolinyl group, a furyl group, a pyranyl group, a benzofuranyl group, a chromenyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group, or a benzoisoxazolyl group. "Heterocyclic group" means a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group at each substitutable position. , Carboxyl group, Le group [the phenyl group, a halogen atom, hydroxy _{group, C 1-6} _{alkyl, C 1-6} alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro _{group, C 1-3} alkoxy - A C _1-3 alkyl group, a C _1-3 alkoxy-carbonyl group, a C _1-3 alkyl-carbonyl group, a trifluoromethylcarbonyl group, a C _1-3 alkylthio group, a C _1-3 alkylsulfonyl group, and an amino group The amino group may be substituted with 1 to 4 atoms or groups selected from the group consisting of 1 or 2 identical or different C _1-3 alkyl groups), C _3-8 cycloalkyl _{group, C 1-3} alkoxy _{-C 1-3} alkyl _{group, C 1-6} alkoxy - carbonyl _{group, C 1-6} alkyl - carbonyl group, Trifluoromethyl group, C _1-3 alkylthio group, C _1-3 alkylsulfonyl group, an oxo group, an amino group (said amino group is substituted by the same or different two C _1-6 alkyl groups And an amino group (which may be substituted with one or two identical or different C _1-3 alkyl groups or C _1-3 alkyl-carbonyl groups). A heterocyclic group which may be substituted with 1 to 4 atoms or groups.
Preferable specific examples of the heterocyclic group which may be substituted with these substituents at each substitutable position include, for example, each of the above heterocyclic groups, 3-phenylfuryl group, 2-trifluoromethylpyridyl. Group, 2-chloropyridyl group, 2-hydroxypyridyl group, 2-methoxypyridyl group, N-methylpiperidyl group, 2-phenylpiperidyl group, 2- (3,3,5,5-tetramethylcyclohexylamino) pyridyl group 2- (tetrahydro-2H-pyran-4-ylamino) pyridyl group, 4-methoxy-2-quinolyl group, 5-chloroindolyl group, 5-nitrobenzofuranyl group, 2-methylbenzoimidazolyl group, 1-methylpyrrolyl Group, 2-methylthiopyridyl group, 2,6-dichloropyridyl group, 2,3-dichloropyridyl group, 2- (cyclohexane Chiruamino) pyridyl group, and the like.

“Halogen atom” means fluorine, chlorine, bromine or iodine.

Group: Ring A is preferably a pyrrolidin-1-yl group, piperidino group, morpholino group, piperazin-1-yl group, etc., more preferably pyrrolidin-1-yl group, morpholino group, piperazine-1 -Yl group and the like.
R ¹ is preferably an optionally substituted phenyl group, and more preferably selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a trifluoromethyl group. And a phenyl group which may be substituted with 1 to 5 atoms or groups.
R ² is preferably a phenyl group.
R ³ and R ⁴ are preferably a hydrogen atom or a C _1-6 alkyl group.
m is preferably 1 or 2.

Specific examples of the compound of the present invention include compounds of Examples 1 to 8 described later.

Preferred compounds of the present invention include the following compounds or physiologically acceptable salts thereof.
N- (4-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 1),
N- (4-trifluoromethylphenyl) -4- [N- (2-morpholin-4-ylacetyl) -N-phenylamino] piperidine-1-carboxamide (compound of Example 2),
N- (4-methoxyphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 3),
N- (4-fluorophenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 4),
N- (3-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (compound of Example 5),
N- (4-isopropylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (the compound of Example 6),
N- (2-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide (the compound of Example 7), And N- (4-trifluoromethylphenyl) -4- [N- (3-pyrrolidin-1-ylpropionyl) -N-phenylamino] piperidine-1-carboxamide (compound of Example 8).

Next, a method for producing the compound of the present invention will be described below.
The compound of this invention represented by general formula (I) can be manufactured by the manufacturing method shown below.

[Production method]: Formula (II) below

[Wherein, R ¹ means the same as described in (1) above. ]
And a compound represented by the following formula (III)

[Wherein R ² , R ³ , R ⁴ , m and group: ring A means the same as described in (1) above. ]
A process for producing a compound represented by the formula (I), comprising reacting a compound represented by formula (I):

The reaction between the compound of formula (II) and the compound of formula (III) is carried out in the absence of a solvent or in a suitable solvent. Examples of the solvent to be used include toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. These solvents are each alone or in combination of two or more. Used in combination. This reaction is performed in the presence of a base as necessary. Specific examples of the base include an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or triethylamine. And organic bases such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine. Also, when an excess amount of the compound of formula (III) is added to the reaction, the compound functions as a base. The reaction temperature is usually −40 ° C. to 200 ° C., but preferably −20 ° C. to 70 ° C.

Next, a method for producing the compounds represented by formula (II) and formula (III) will be described below.

The compound of the formula (II) can be obtained, for example, by purchasing a commercially available compound or producing it by a known method in which the corresponding carboxylic acid (R ¹ —COOH or the like) is used as a raw material to perform the Curtius rearrangement.

The compound of the formula (III) can be produced by the method shown in the following scheme.

[Wherein, PG means a protecting group, R ² , R ³ , R ⁴ , m and group: ring A means the same as described in the above (1). ]

[Step 1]
Compound (2-3) is prepared by reductive alkylation using compound (2-1) and the corresponding primary monoamine (R ² —NH ₂ ) available in a suitable solvent. This reaction is carried out using a reducing agent such as sodium borohydride, sodium triacetoxyborate, sodium cyanoborohydride, picoline-borane, or catalytic reduction using a metal catalyst such as palladium in a hydrogen atmosphere. Do that. Examples of the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, methanol, ethanol and the like, and these solvents are used alone or in combination of two or more. In addition, this reaction proceeds more suitably when an acid such as acetic acid or hydrochloric acid is added as a reaction catalyst. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

Compound (2-3) is obtained by reacting the corresponding bromo-substituted aryl or chloro-substituted heteroaryl and compound (2-2) with a palladium catalyst [eg, tris (dibenzylideneacetone) dipalladium], phosphine ligand (eg, 2 ′, 6'-dimethoxy-2-dicyclohexylphosphinobiphenyl) and an organic base (for example, t-butoxy sodium) in the presence. Examples of the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, dimethylformamide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is usually 0 ° C. to 150 ° C., preferably 25 ° C. to 120 ° C.

[Step 2]
Compound (2-4) is produced by reacting compound (2-3) with a corresponding acid halide such as chloroacetic acid chloride, bromoacetic acid bromide, or chloropropionic acid chloride in an appropriate solvent. Examples of the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, chloroform, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. These solvents are used alone or in combination of two or more. Used. This reaction is carried out in the presence of a base as required. Specific examples of the base include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, Examples thereof include organic bases such as N-methylmorpholine, dimethylaminopyridine, and pyridine. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 120 ° C.

[Step 3]
Compound (2-5) is produced by reacting compound (2-4) with the corresponding ring A compound in the absence of a solvent or in a suitable solvent. Examples of the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, dimethylformamide and the like, and these solvents are used alone or in combination of two or more. This reaction is carried out in the presence of a base as required. Specific examples of the base include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, Examples thereof include organic bases such as N-methylmorpholine, dimethylaminopyridine, and pyridine. Also, by adding an excess amount of the corresponding ring A compound to the reaction solution, the compound functions as a base. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 120 ° C.

[Step 4]
Compound (III) can be obtained by deprotecting the protecting group of compound (2-5) according to a conventional method. Specific examples of the protecting group include groups that form carbamates such as t-butoxycarbonyl group and benzyloxycarbonyl group, and groups that form benzylamines such as benzyl group and trityl group.

The compound of formula (I) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, silica gel column chromatography, recrystallization, and reprecipitation. As the extraction solvent, diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene or the like is used. Purification by silica gel column chromatography uses acidic, basic, or various chemically treated silica gel or alumina, and developing solvents include, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, Acetonitrile / water, methanol / water, etc. can be used.

When the compound of the formula (I) is a racemate, conventional methods such as chromatography using an optically active column, an optical resolution method using an optically active acid or a synthetic chiral resolution agent, a preferential crystallization method, a diastereomer method, etc. According to the above, each enantiomer can be separated and purified. The optically active compound of formula (I) can also be produced from the reaction of an optically active compound of formula (III) with a compound of formula (II). For example, separation into enantiomers using an optically active acid is performed by forming a diastereomeric salt according to a conventional method, separating the diastereomeric salt, and then converting this into a free base. Examples of the optically active acid used as the optical resolution agent include (+)-or (−)-camphoric acid, (1S)-(+)-or (1R)-(−)-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-(−)-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or (−)-dibenzoyl-L- Examples include tartaric acid.

The compound of formula (I) having a hydroxy group can be synthesized by protecting and deprotecting the hydroxy group according to a conventional method.

The compound of the formula (I) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (I) can be converted to an acid addition salt by treating with various acids according to a conventional method.

As will be described later, the compound of the present invention has an excellent antiallergic action as a non-steroidal drug, so that it can be expected to be used as a safe antiallergic agent with few side effects on humans and mammals. The compounds of the present invention can prevent allergic diseases such as allergic dermatitis, allergic rhinitis, bronchial asthma, atopic dermatitis, contact dermatitis, hives, eczema, allergic ophthalmitis, hay fever. And / or useful as a therapeutic agent.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc. In the case of oral administration, usually about 0.01 to 100 mg, more preferably about 0.1 to 10 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 1 μg to 10 mg, more preferably about 10 μg to 1 mg per kg body weight of a human or mammal can be administered.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above. As the pharmaceutical carrier, a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth, bentonite, veegum, karuboki Vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide Hydrochloric acid, water, physiological saline, Ringer's solution human serum albumin, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol, phosphate buffer, sodium acetate buffer and the like.

Examples of the dosage form of the preparation include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coating agents, patches, inhalants and the like. . These preparations can be prepared according to a conventional method. In addition, these formulations may contain other therapeutically valuable ingredients.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but these do not limit the present invention. The compound was identified using elemental analysis, hydrogen nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), LS-MS, melting point, optical rotation and the like. For basic silica gel column chromatography in Reference Examples and Examples, Chromatolex NH manufactured by Fuji Silysia Chemical Ltd. was used.

In order to simplify the description, the following abbreviations may be used in Reference Examples, Examples and Tables.
As abbreviations used as substituents, Me means a methyl group, Ph means a phenyl group, and i-Pr means an isopropyl group.

Abbreviations used for ¹ H-NMR include: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is a multiple line, br is wide, brs is a wide single line, brd is a wide double line, brt is a wide triple line, and J is a coupling constant.

Reference Example 1 (1): N-phenyl-N- (piperidin-4-yl) -2- (piperidin-1-yl) acetamide

[Step 1]
Acetic acid (24.2 ml) was added to a solution of 1-t-butyloxycarbonylpiperidin-4-one (50.0 g) and aniline (19.5 g) in dichloromethane (250 ml), and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, sodium triacetoxyborohydride (40.9 g) was added to the reaction mixture, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction mixture, and extraction was performed with chloroform (100 ml × 3 times). The organic layer was washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized using ethyl acetate / diisopropyl ether, and the crystals were collected by filtration to give 4-phenylaminopiperidine-1-carboxylic acid t-butyl ester (48.7 g, yield 84%). Got.

[Step 2]
To a solution of 4-phenylaminopiperidine-1-carboxylic acid t-butyl ester (15.0 g) and triethylamine (18.9 ml) obtained in Step 1 above in dichloromethane (200 ml) was added chloromethane under nitrogen substitution and ice cooling. Acetyl chloride (9.2 ml) was added dropwise. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (50 ml × 3 times). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- [N- (2-chloroacetyl) -N-phenylamino] piperidine-1-carboxylic acid t -The butyl ester (crude oil) was obtained.

[Step 3]
To the mixture of 4- [N- (2-chloroacetyl) -N-phenylamino] piperidine-1-carboxylic acid t-butyl ester and potassium carbonate (26.3 g) obtained in Step 2 above in acetonitrile (300 ml). Piperidine (16.1 ml) was added and stirred for 12 hours under reflux. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml × 3 times). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 4- [N-phenyl-N- (2-piperidin-1-ylacetyl) amino] piperidine-1-carboxylic acid t-Butyl ester (16.9 g, yield 77% in two steps, step 2 and step 3) was obtained.

[Step 4]
To a solution of 4- [N-phenyl-N- (2-piperidin-1-ylacetyl) amino] piperidine-1-carboxylic acid t-butyl ester (16.9 g) obtained in Step 3 above in dichloromethane (100 ml), Trifluoroacetic acid (15.6 ml) was added and stirred at room temperature for 12 hours. Under ice-cooling, the reaction mixture was neutralized with a 1 mol / L aqueous sodium hydroxide solution (50 ml), and then extracted with chloroform (50 ml × 3 times). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the desired product (15.7 g, yield 100%).

By using the corresponding acid chloride and the corresponding cyclic amine in the same manner as in Step 2, Step 3 and Step 4 of Reference Example 1 (1), the following Reference Examples 1 (2) to 1 (4) To give a compound.
Reference Example 1 (2): 2- (morpholin-4-yl) -N-phenyl-N- (piperidin-4-yl) acetamide Reference Example 1 (3): 3- (4-methylpiperazin-1-yl) -N-phenyl-N- (piperidin-4-yl) propionamide Reference Example 1 (4): N-phenyl-N- (piperidin-4-yl) -3- (pyrrolidin-1-yl) propionamide

Example 1 : N- (4-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide

3- (4-Methylpiperazin-1-yl) -N-phenyl-N- (piperidin-4-yl) propionamide trihydrochloride (1.57 g) in dichloromethane as described in Reference Example 1 (3) To the (10 ml) solution, triethylamine (2.5 ml) was added, and 4-trifluoromethylphenyl isocyanate (1.5 g) was added at 0 ° C., and the temperature was raised to room temperature after 5 minutes, followed by stirring for 5 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (20 ml × 3 times). The organic layer was washed with aqueous sodium hydrogen carbonate solution (20 ml) and saturated brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (elution solvent was chloroform / methanol) to give the object product (1.65 g, yield 86%) as a white solid.

The corresponding starting materials were used and reacted in the same manner as in Example 1 to obtain the compounds of Examples 2 to 8. These compounds are shown in Table 1.

Table 2 below shows the ¹ H-NMR data of the above-mentioned Example compounds.

Pharmacological tests and results of representative compounds of the present invention will be described below.

Test Example: TMA (Trimellitic anhydride) Inhibitory effect on repeated application dermatitis model Male BALB / cAnNCrlCrlj mice were used. Sensitization was performed by applying 100 μL of a 10 wt% TMA (acetone: olive oil = 4: 1) solution to the abdomen of the mouse shaved using a thick injector (single blade; Chic Japan) on the previous day. Five days later, 100 μL of 10 wt% TMA solution was applied to the abdomen again for additional sensitization, and further 5 days later, 10 wt% TMA solution was applied to the right ear for 3 consecutive days. Eight or nine days after the final application operation day, 25 μL of 10 wt% TMA solution was applied to both ears to induce. Ear thickness 8 hours after induction was measured using dial gauge thickness. The degree of ear reaction was expressed as the difference between the measured value of ear thickness at 8 hours and the pre-induction value, and the inhibition rate was calculated in comparison with that of the solvent control group. The test drug was dissolved in DMSO (dimethyl sulfoxide) to a final concentration of 2.5% by weight the previous day, and then prepared in a 0.5% by weight methylcellulose (MC) solution for use as a comparative control compound. Prednisolone, a steroidal agent, was prepared at 1 mg / mL. Each was orally administered twice at 0.5 mL / animal 30 minutes before induction and 4 hours after induction.

As is apparent from Table 3 above, the compound of the present invention represented by the above formula (I) has an inhibitory effect equivalent to or higher than that of a steroid agent on the skin inflammatory reaction of an atopic dermatitis model animal. It was. This suggests that the compound of the present invention has an excellent antiallergic action and further has an anti-inflammatory action.

As is clear from the above test examples, the compound of the present invention has an excellent antiallergic action in an atopic dermatitis model, and as an antiallergic agent, for example, allergic dermatitis, allergic rhinitis, bronchial Desirably alone for the prevention and / or treatment of asthma, atopic dermatitis, contact dermatitis, urticaria, eczema, allergic ophthalmitis, hay fever, and other inflammatory diseases If necessary, it can be used in combination with existing drugs.

This application is based on Japanese Patent Application No. 2008-053068 filed in Japan, the contents of which are incorporated in full herein.

Claims

A compound represented by the following formula (I) or a physiologically acceptable salt thereof:

[In the formula, ring A is azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, piperazin-1-yl group, morpholino group, hexahydroazepin-1-yl group, hexahydrodiazepine- 1-yl group, aziridin-1-yl group, perhydroisoquinolin-2-yl group, perhydroquinolin-1-yl group, 1,2,3,4-tetrahydroisoquinolin-2-yl group, 1,2, 3,4-tetrahydroquinolin-1-yl group, 2,3-dihydroindol-1-yl group, perhydroindol-1-yl group, 1,3-dihydroisoindol-2-yl group, perhydroisoindole -2-yl group, pyrazolidin-1-yl group, tetrahydroimidazol-1-yl group, hexahydro-1,4-oxaazepin-4-yl group, oxazolid -3-yl group, thiazolidin-3-yl group, thiomorpholin-4-yl group, hexahydropyridazin-1-yl group, hexahydropyrimidin-1-yl group, tetrazolyl group, 2-pyrrolin-1-yl group Or represents a 3-pyrrolin-1-yl group,
R 1 represents an optionally substituted phenyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted heterocyclic group (wherein the heterocyclic group is a pyridyl group, pyrimidinyl) Group, pyrazinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, azaindolyl group, indazolyl group, indolinyl group, isoindolinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, cinnolinyl group, furyl group, Represents a pyranyl group, a benzofuranyl group, a chromenyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group or a benzoisoxazolyl group),
The optionally substituted phenyl group in R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, a hydroxy group, a C 1-3 alkoxy group, and a trialkyl group). Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of fluoromethyl groups), C 1-6 alkoxy groups, trifluoromethoxy groups, cyano groups, nitro groups, carboxyl groups, phenyl groups [ The phenyl group is a halogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C 1-3 alkoxy-C 1- 3 alkyl groups, C 1-3 alkoxy-carbonyl groups, C 1-3 alkyl-carbonyl groups, C 1-3 alkylthio groups, C 1-3 alkyls Substituted with 1 to 4 atoms or groups selected from the group consisting of a sulfonyl group and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups) A C 3-8 cycloalkyl group (the C 3-8 cycloalkyl group includes a halogen atom, a hydroxy group, a C 1-3 alkyl group, a C 1-3 alkoxy group, a trifluoromethyl group, and Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of trifluoromethoxy groups), C 1-6 alkoxy-carbonyl groups, C 1-6 alkyl-carbonyl groups, trifluoromethylcarbonyl groups , A C 1-3 alkylthio group, a C 1-3 alkylsulfonyl group, an aminocarbonyl group (the aminocarbonyl group is the same or different two C 1-6 alkyls). Optionally substituted with a kill group) and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups, or a C 1-3 alkyl-carbonyl group). A phenyl group optionally substituted with 1 to 5 atoms or groups selected from the group consisting of:
The optionally substituted C 3-8 cycloalkyl group for R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an amino group. A group (the amino group may be substituted by one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) and a phenyl group [the phenyl group is a halogen atom; , Hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C 1-3 alkoxy-C 1-3 alkyl group, C 1- 3 alkoxy - carbonyl group, C 1-3 alkyl - carbonyl group, a trifluoromethyl group, C 1-3 alkylthio group, C 1-3 A Alkylsulfonyl group and an amino group (said amino group may contain one or two identical or different C 1-3 alkyl optionally substituted with a group) with 1 to 4 atoms or groups selected from the group consisting of Means an optionally substituted C 3-8 cycloalkyl group substituted with 1 to 4 atoms or groups selected from the group consisting of:
The optionally substituted heterocyclic group for R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, or a nitro group. A carboxyl group, a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, C 1 -3 alkoxy-C 1-3 alkyl group, C 1-3 alkoxy-carbonyl group, C 1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C 1-3 alkylthio group, C 1-3 alkylsulfonyl group and amino group (said amino group may be substituted by one or two identical or different C 1-3 alkyl group It may be substituted with 1 to 4 atoms or groups selected from the group consisting of], C 3-8 cycloalkyl group, C 1-3 alkoxy -C 1-3 alkyl group, C 1-6 alkoxy - A carbonyl group, a C 1-6 alkyl-carbonyl group, a trifluoromethylcarbonyl group, a C 1-3 alkylthio group, a C 1-3 alkylsulfonyl group, an oxo group, an aminocarbonyl group (the aminocarbonyl groups may be the same or different 2 And optionally substituted with two C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups which may be substituted with one C 1-6 alkyl group and an amino group. A heterocyclic group which may be substituted with 1 to 4 atoms or groups selected from the group consisting of (optionally substituted),
R 2 represents a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or a carboxyl group. C 1-3 alkoxy-C 1-3 alkyl group, C 1-3 alkoxy-carbonyl group, C 1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C 1-3 alkylthio group, C 1-3 alkyl 1 selected from the group consisting of a sulfonyl group and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) Optionally substituted with up to 5 atoms or groups] or a C 3-8 cycloalkyl group wherein the C 3-8 cycloalkyl group is a halogen An atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two C 1-3, which are the same or different) And optionally substituted with 1 to 4 atoms or groups selected from the group consisting of an alkyl group or a C 1-3 alkyl-carbonyl group).
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, or a C 1-6 alkyl. -Carbonyl group, amino group [the amino group is one or the same or different two C 1-6 alkyl groups, C 1-3 alkyl-carbonyl group or aminocarbonyl group (the aminocarbonyl groups are the same or different May be substituted with two C 1-6 alkyl groups)], a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1- 6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (said amino group may contain one or two identical or different C 1-3 Alkyl optionally substituted with 1 to 5 atoms or groups selected from the group consisting of a may be) optionally substituted with a group], a benzyl group [said benzyl group, a halogen atom, hydroxy group, C 1- A 6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups) The benzoyl group may be substituted with 1 to 5 atoms or groups selected from the group consisting of: a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 An alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group is substituted by one or two identical or different C 1-3 alkyl groups) Optionally substituted with 1 to 5 atoms or groups selected from the group consisting of C 3-8 cycloalkyl groups, aminocarbonyl groups (the aminocarbonyl groups may be the same or different Which may be substituted with a C 1-6 alkyl group), a pyrrolidylcarbamoyl group or a C 1-6 alkyloxadiazolyl group,
m represents 1, 2 or 3. ].
2. The compound according to claim 1, wherein ring A is azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, morpholino group, piperazin-1-yl group or hexahydroazepin-1-yl group Its physiologically acceptable salt.
R 1 is a halogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, carboxyl group, phenyl group [phenyl group is A halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group is one or two C 1- Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of 3 and 7 alkyl groups), C 3-8 cycloalkyl groups, C 1-6 alkoxy-carbonyl groups , C 1-6 alkyl - carbonyl group, a trifluoromethyl group, C 1-3 alkylthio group, C 1-3 alkylsulfonyl group and Amino group (said amino group, one or two identical or different C 1-3 alkyl group or a C 1-3 alkyl - may be substituted by carbonyl group) 1 to 5 selected from the group consisting of A phenyl group which may be substituted with an atom or group of: a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an amino group (the amino group) Is optionally substituted by one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) and a phenyl group (the phenyl group is a halogen atom, a hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (said amino group, one or the same if 1-4 selected from the group consisting of different two C 1-3 substituted by an alkyl group which may be substituted with 1 to 5 atoms or groups selected from the group consisting of may also be)] is A cyclohexyl group optionally substituted with one atom or group; or a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group The amino group may be one or four atoms or groups selected from the group consisting of one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) The compound or physiologically acceptable salt thereof according to any one of claims 1 and 2, which is a pyridyl group which may be substituted with.
R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (the amino group is one or two of the same or different A phenyl group optionally substituted with 1 to 5 atoms or groups selected from the group consisting of a C 1-3 alkyl group or a C 1-3 alkyl-carbonyl group of An atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two C 1-3, which are the same or different) A cyclohexyl group which may be substituted with 1 to 4 atoms or groups selected from the group consisting of (optionally substituted with an alkyl group) Compound or a physiologically acceptable salt thereof according to any one of 1 to 3.
R 2 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or an amino group (the amino group is one Or may be substituted with 1 to 5 atoms or groups selected from the group consisting of the same or different two C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups. The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 4, which is a good phenyl group; or a C 3-8 cycloalkyl group.
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl-carbonyl group, a trifluoromethyl group, an amino group carbonyl group (said amino group may be the same or different two C 1-6 optionally substituted by an alkyl group) and an amino group (said amino group may contain one or two identical or different C 1- The compound or a physiologically acceptable salt thereof according to any one of claims 1 to 5, which may be substituted with a 3 alkyl group or a C 1-3 alkyl-carbonyl group.
7. The compound according to any one of claims 1 to 6 or a physiologically acceptable salt thereof, wherein m is 1 or 2.
Group: ring A is a pyrrolidin-1-yl group, piperidino group, morpholino group or piperazin-1-yl group;
R 1 is a phenyl group which may be substituted with 1 to 5 atoms or groups selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group and a trifluoromethyl group. ,
R 2 is a phenyl group;
R 3 and R 4 are the same or different and are a hydrogen atom or a C 1-6 alkyl group,
2. The compound according to claim 1, wherein m is 1 or 2, or a physiologically acceptable salt thereof.
N- (4-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide;
N- (4-trifluoromethylphenyl) -4- [N- (2-morpholin-4-ylacetyl) -N-phenylamino] piperidine-1-carboxamide;
N- (4-methoxyphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide;
N- (4-fluorophenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide;
N- (3-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide;
N- (4-isopropylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide;
N- (2-trifluoromethylphenyl) -4- [N- [3- (4-methylpiperazin-1-yl) propionyl] -N-phenylamino] piperidine-1-carboxamide, and N- (4-tri 2. The compound according to claim 1 selected from the group consisting of fluoromethylphenyl) -4- [N- (3-pyrrolidin-1-ylpropionyl) -N-phenylamino] piperidine-1-carboxamide or physiologically thereof Acceptable salt.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a physiologically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 10 for use in the prevention and / or treatment of allergic diseases.
The pharmaceutical composition according to claim 11, wherein the allergic disease is atopic dermatitis or contact dermatitis.