JPH1081665A - Mip-1-alpha/rantes receptor antagonistic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicinal agent containing a diphenylmethane derivative, enabling diseases induced by RANTES or MIP-1α to be inhibited. SOLUTION: This medicinal agent contains a compound (salt) of formula I [Ar<1> and Ar<2> are each a (substituted) aromatic group; Q<1> and Q<2> are each a (substituted) divalent 1-6C aliphatic hydrocarbon which may contain O or S atom in the C-chain; R<1> is H, a (substituted) alkyl or (substituted) alkylcarbonyl; R<2> is a (substituted) hydrocarbon or (substituted) acyl; or R<1> and R<2> are joined together with an N atom to form a (substituted) N-contg. heterocycle; a group of formula II is a (substituted) monocycle or condensed N-contg. heterocycle], being useful for prophylaxis/treatment of allergic diseases such as bronchial asthma and atopic dermatitis, inflammatory diseases such as arteriosclerosis and arthroheumatism, and multiple sclerosis, etc. The compound of formula I is low-toxic, having few side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a MIP-1α / RA
It has NTES receptor antagonism, and is used for the prevention and treatment of allergic diseases (eg, bronchial asthma, atopic dermatitis, etc.), inflammatory diseases (eg, arteriosclerosis, rheumatoid arthritis, etc.), multiple sclerosis, etc. It relates to useful compounds and agents.

[0002]

2. Description of the Related Art Chemokines are a group of cytokines that regulate the chemotaxis of leukocytes, and are involved in the progression and exacerbation of the disease state in the acute and chronic phases of inflammation together with other cytokines. This has been revealed in recent years. RANT among chemokines
ES (Regulated on activation, normal T expressed
and secreted) and MIP-1α (Macrophage infla
mmatory protein-1α) belongs to the so-called CC chemokines, mainly acting on lymphocytes, monocytes, eosinophils, and basophils to increase the migration activity, as well as degranulation and various inflammatory mediators. It is known to have a direct leukocyte activating action such as release. (Clinical Immunotherapy Vol. 4, pp. 1-8, 1995). In particular, in synovial fluid of rheumatic patients (Clinical & Experimental Immunology Vol. 101, 398, 1995 and Lancet 343, 547, 1994)
An increase in the amount of RANTES gene expression has been observed in atherosclerotic lesions and atherosclerotic lesions, suggesting involvement in the disease. In addition, it has been reported that the administration of MIP-1α antibody to mice delayed the onset of arthritis and further relieved the symptoms (The Journal of American Society for Clinical Investigation, Vol. 95, p. 2868, 1995). ). However, antibodies are generally macromolecules and have problems in oral absorbability and stability.

The MIP-1α / RANTES receptor is MI
P-1α, RANTES or MCP-3 (monocyte
Common receptors for chemokines such as chemoattractant protein-3) (named CCR1; Nature Medicine; Nature Medicine, 1174, 1996)
It has been revealed that Based on this background, development of the above-mentioned CCR1 receptor antagonist has been desired, and peptide-type antagonists for RANTES and the like have already been known.
stry, 27, 18, 12521-10527 (199
6)] There are problems such as oral absorbability and stability. In addition, eosinophils and basophils are recruited and activated at various sites of inflammation to develop and progress various allergic and inflammatory diseases.
It is being clarified that they are involved in exacerbations, and it is thought that inhibiting the actions of the above chemokines will lead to the prevention and treatment of immune system diseases such as bronchial asthma, atopic dermatitis, arteriosclerosis and rheumatoid arthritis. (Clinical Immunotherapy, Vol. 4, pp. 1-8, 1995)
Year). However, there are no reports of such inhibitors at present. On the other hand, a large number of diphenylmethane derivatives have been synthesized to date (Journal of Medicinal Chemistry, Vol. 34, p. 12, 1991, Arch. In
t. Pharmacodyn., Vol. 107, p. 194, 1956
For example, JP 62-123164A), for example, loperamide
Is marketed as an antidiarrheal drug. Although loperamide is also known to have calmodulin antagonism and the like, it is not known to inhibit cell migration induced by chemokines. Haloperidol, which has a 4-hydroxypiperidyl group and is used as an antipsychotic, is not known to have this effect.

[0004]

SUMMARY OF THE INVENTION MIP-1α / RAN
TES receptor antagonist, and RANTES or MI
There is a need for the development of new drugs that inhibit diseases caused by P-1α.

[0005]

The present inventors have conducted various studies and found that the formula

Embedded image [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Q ¹ and Q ² each have a substituent which may contain oxygen or sulfur in a carbon chain. the not be divalent C _1-6 aliphatic hydrocarbon group, R ¹ is a hydrogen atom, an optionally substituted lower alkyl or optionally substituted lower alkyl - carbonyl R ² represents a hydrocarbon group or an acyl group which may have a substituent, or R ¹ and R ² together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic ring which may have a substituent. May be an expression

Embedded image Represents a monocyclic or condensed nitrogen-containing heterocyclic ring which may have a substituent. ] Or a salt thereof,

Embedded image Based on the specific chemical structure characterized by the following, the present inventors have found that they have unexpectedly excellent MIP-1α / RANTES receptor antagonism, and based on these, completed the present invention.

That is, the present invention relates to (1) a MIP comprising the compound [I] or a salt thereof;
-1α / RANTES receptor antagonist, (2) Ar ¹ and Ar ² are each other than (I) a monocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or (II) a carbon atom A 5- to 11-membered monocyclic or fused aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom (the "aromatic heterocyclic group" Number 6 to 14
(Which may be condensed with two monocyclic or condensed polycyclic aromatic hydrocarbon groups), (a) a halogen atom, (a) a C _1-3 alkylenedioxy group, and (u) a nitro group. (E) a cyano group, (e) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, and (f) a C ₂ alkyl group _optionally having 1 to 3 halogen atoms. _-6 alkenyl group, (g) C _2-6 alkynyl group optionally having 1 to 3 halogen atoms, (h) C _3-6 cycloalkyl group, (q) 1 to 3 halogen atoms A C _1-6 alkoxy group optionally having (C) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms,
(Sa) hydroxyl group, (si) amino group, (su) mono-
C _1-6 alkylamino group, (se) di-C _1-6 alkylamino group, (so) 5- to 7-membered cyclic amino group, (ta) -NH
An acylamino group represented by COOR ³ , -NHCONHR ³ , -NHCOR ^3, or -NHSO ₂ R ³

[R ³ is (i) a C _1-6 alkyl group, (ii) a C _2-6 alkenyl group, (iii) a C _2-6 alkynyl group, (iv) 1 to 3 C _1-6 alkoxy groups the has optionally C _3-6 which may be condensed with a benzene ring which may be cycloalkyl group, (v) C _6-10 aryl group or (vi) C _7-16 aralkyl group, (the "C _1- “ ₆ alkyl group”, “C _2-6 alkenyl group”, “C _2-6 alkynyl group”, “C _3-6 cycloalkyl group”, “C _6-10 aryl group” and “C _7-16 aralkyl group” Are (a) a halogen atom, (b) a C _1-3 alkylenedioxy group,
(C) a nitro group, (d) a cyano group, (e) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms,
(F) a C _3-6 cycloalkyl group, (g) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(H) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) a hydroxyl group, (j)
An amino group, (k) a mono-C _1-6 alkylamino group,
(L) di-C _1-6 alkylamino group, (m) C _1-6 alkyl-carbonyl group, (n) carboxyl group, (o) C
_1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group,
(R) di-C _1-6 alkyl-carbamoyl group, (s) C
_6-10 aryl-carbamoyl group, (t) sulfo group,
(U) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) other than a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom It may have 1 to 5 substituents selected from a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo condensate thereof at a substitutable position. ),

(H) a C _1-6 alkyl-carbonyl group,
(T) carboxyl group, (T) C _1-6 alkoxy-carbonyl group, (T) carbamoyl group, (N) mono-C _1-6
Alkyl-carbamoyl group, (d) di-C _1-6 alkyl-carbamoyl group, (nu) C _6-10 aryl-carbamoyl, (ne) sulfo group, (no) C _1-6 alkylsulfonyl group, (c) Q ₁ and Q ₂ may be substituted with a C _6-10 aryl group or a (ma) C _6-10 aryloxy group.
C may contain oxygen or sulfur in the carbon chain, and may be substituted with an oxo group or a thioxo group.
_{A 1-6} alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group,

R ¹ is (a) a hydrogen atom, (a) (a) a halogen atom, (b) a C _1-3 alkylenedioxy group, (c)
Nitro group, (d) cyano group, (e) C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f)
A C _3-6 cycloalkyl group, (g) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h)
C _{1-6 optionally} having 1 to 3 halogen atoms
Alkylthio group, (i) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-
C _1-6 alkylamino group, (m) C _1-6 alkyl-carbonyl group, (n) carboxyl group, (o) C _1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group , (V) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) a nitrogen atom other than a carbon atom,
A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom, or 1 to 5 substituents selected from benzo condensates thereof at substitutable positions, A C _1-6 alkyl group or

(C) (a) a halogen atom, (b) C _1-3
Alkylenedioxy group, (c) nitro group, (d) cyano group, (e) C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) C _3-6 cycloalkyl Group,
(G) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i A) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group,
(M) a C _1-6 alkyl-carbonyl group, (n) a carboxyl group, (o) a C _1-6 alkoxy-carbonyl group,
(P) carbamoyl group, (q) mono-C _1-6 alkyl-
A carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group,
(T) a sulfo group, (u) a C _1-6 alkylsulfonyl group,
(V) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom A C _1-6 alkyl-carbonyl group which may have 1 to 5 substituents at substitutable positions selected from a 7-membered heterocyclic group or a benzo condensate thereof,

R ² represents (A) a C _1-6 alkyl group;
_2-6 alkenyl group, (c) C _2-6 alkynyl group, (d) 1
A C _3-6 cycloalkyl group optionally condensed with a benzene ring optionally having up to 3 C _1-6 alkoxy,
(E) a C _6-10 aryl group or (f) a C _7-16 aralkyl group, (the “C _1-6 alkyl group”, “C _2-6 alkenyl group”, “C _2-6 alkynyl group”, “ “C _3-6 cycloalkyl group”, “C _6-10 aryl group” and “C _7-16 aralkyl group” are (a) halogen atom, (b) C _1-3 alkylenedioxy group, and (c) nitro Group, (d) cyano group,
(E) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) a C _3-6 cycloalkyl group,
(G) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i A) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group,
(M) a C _1-6 alkyl-carbonyl group, (n) a carboxyl group, (o) a C _1-6 alkoxy-carbonyl group,
(P) carbamoyl group, (q) mono-C _1-6 alkyl-
A carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group,
(T) a sulfo group, (u) a C _1-6 alkylsulfonyl group,
(V) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom It may have 1 to 5 substituents selected from a 7 to 7-membered heterocyclic group or a benzo condensate thereof at substitutable positions. ) Or

(G)-(C = O) -R ⁴ , -SO _2-
^{R 4, -SO-R 4,} - (C = O) NR 5 R 4, - (C =
O) OR ⁴ ,-(C = S) OR ⁴ or-(C = S)
An acyl group represented by NR ⁵ R ⁴ [R ⁴ is (i) a hydrogen atom, (ii) a C _1-6 alkyl group, (iii) a C _2-6 alkenyl group, (iv) a C _2-6 alkynyl group, (V) a C _3-6 cycloalkyl group optionally condensed with a benzene ring optionally having 1 to 3 C _1-6 alkoxy, (vi) a C _6-10 aryl group or (vii) A C _7-16 aralkyl group, (viii) one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom;
(Ix) C _1-6 alkyl-carbonyl group, (x) carboxyl group, (xi) C _1-6 alkoxy-carbonyl group, (xii) mono -C _1-6 alkyl-carbamoyl group, (xiii) di-C _1-6 alkyl-carbamoyl group, (xiv) 5- to 7-membered cyclic amino group or (xv) C _6-10 aryloxy group (the “C _{1 -6} alkyl group "," _C2-6 alkenyl group "," _C2-6 alkynyl group "," _C3-6 cycloalkyl group "," _C6-10 aryl group "," _C7-16 aralkyl group ""A 5- to 11-membered heterocyclic group containing one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzo condensate thereof", "C _{1- 6} alkyl-carbonyl group '', `` carboxyl group '', `` A “C _1-6 alkoxy-carbonyl group”, a “mono-C _1-6 alkyl-carbamoyl group”, a “di-C _1-6 alkyl-carbamoyl group”,
"5- to 7-membered cyclic amino group" and

The "C _6-10 aryloxy group" includes (a) a halogen atom, (b) a C _1-3 alkylenedioxy group, (c) a nitro group, (d) a cyano group, and (e) (e- 1) a halogen atom, (e-2) C _1-3 alkylenedioxy group, (e-3) nitro group, (e-4) cyano group, (e-5) C _3-6 cycloalkyl group, (e −
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (e-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (e-
8) hydroxyl group, (e-9) amino group, (e-1)
0) mono-C _1-6 alkylamino group, (e-11) di-
C _1-6 alkylamino group, (e-12) C _1-6 alkyl-
Carbonyl group, (e-13) carboxyl group, (e-1)
4) C _1-6 alkoxy - carbonyl group, (e-15) carbamoyl group, (e-16) mono -C _1-6 alkyl - carbamoyl group, (e-17) di -C _1-6 alkyl - carbamoyl group , (E-18) C _6-10 aryl-carbamoyl group, (e-19) sulfo group, (e-20) C _1-6 alkylsulfonyl group, (e-21) C _6-10 aryl group,
(E-22) C _6-10 aryloxy group and (e-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A C _1-6 alkyl group,

(F) a C _3-6 cycloalkyl group, (g) a C _1-6 alkoxy group which may have 1 to 3 halogen atoms, and (h) a C _3-6 cycloalkyl group. and a C _1-6 alkylthio group optionally, (i) C _7-16 aralkyl group (j) a hydroxyl group, (k) C _1-6 alkyl - carbonyl amino group which may be substituted with a group, (l ) Mono-C _1-6 alkylamino group, (m) di-C _1-6 alkylamino group, (n) (n-1) halogen atom, (n-2) C _1-3 alkylenedioxy group, (n-3) nitro group, (n-4) cyano group, (n-5) _C3-6 cycloalkyl group, (n-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (n-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (n-
8) hydroxyl group,

(N-9) amino group, (n-10) mono-
C _1-6 alkylamino group, (n-11) di-C _1-6 alkylamino group, (n-12) C _1-6 alkyl-carbonyl group, (n-13) carboxyl group, (n-14) C _1-6
Alkoxy - carbonyl group, (n-15) carbamoyl group, (n-16) mono -C _1-6 alkyl - carbamoyl group, (n-17) di -C _1-6 alkyl - carbamoyl group, (n-18) A C _6-10 aryl-carbamoyl group,
(N-19) sulfo group, (n-20) C _1-6 alkylsulfonyl group, (n-21) C _6-10 aryl group, (n-2
2) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to the _C6-10 aryloxy group and (n-23) carbon atom, or A C _1-6 alkyl-carbonyl group which may be substituted with a substituent selected from a benzo condensate,

(O) a carboxyl group, (p) a C _1-6 alkoxy-carbonyl group, (q) one or three heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms. A 7-membered heterocyclic group or a formyl group which may be substituted with a benzo condensate thereof, (r) a carbamoyl group, (s) a (s-1) halogen atom, and (s-2) a C _1-3 alkylenediyl group. Oxy group, (s-3) nitro group, (s-4) cyano group, (s-5) _C3-6 cycloalkyl group, (s-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (s-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (s-
8) hydroxyl group, (s-9) amino group,

(S-10) mono-C _1-6 alkylamino group, (s-11) di-C _1-6 alkylamino group, (s-
12) C _1-6 alkyl-carbonyl group, (s-13) carboxyl group, (s-14) C _1-6 alkoxy-carbonyl group, (s-15) carbamoyl group, (s-16) mono-C _{1 -6} alkyl - carbamoyl group, (s-17) di -C _1-6 alkyl - carbamoyl group, (s-18) C
_6-10 aryl-carbamoyl group, (s-19) sulfo group, (s-20) C _1-6 alkylsulfonyl group, (s-
21) a C _6-10 aryl group, a (s-22) C _6-10 aryloxy group and a nitrogen atom other than the (s-23) carbon atom,
A mono-C _1-6 alkyl which may be substituted with a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom or a substituent selected from a benzo condensate thereof; A carbamoyl group,

(T) (t-1) halogen atom, (t-
2) C _1-3 alkylenedioxy group, (t-3) nitro group, (t-4) cyano group, (t-5) C _3-6 cycloalkyl group, (t-6) 1 to 3 A C _1-6 alkoxy group optionally having a halogen atom, (t-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, a (t-8) hydroxyl group, (T-9) amino group, (t-10) mono-C _1-6 alkylamino group, (t
-11) di-C _1-6 alkylamino group, (t-12) C
_1-6 alkyl - carbonyl group, (t-13) carboxyl group, (t-14) C _1-6 alkoxy - carbonyl group,
(T-15) carbamoyl group, (t-16) mono-C
_1-6 alkyl-carbamoyl group, (t-17) di-C _1-6
Alkyl-carbamoyl group, (t-18) C _6-10 aryl-carbamoyl group, (t-19) sulfo group, (t-2
0) C _1-6 alkylsulfonyl group, (t-21) C _6-10
A 5- to 7-membered aryl group, a (t-22) C _6-10 aryloxy group and a (t-23) carbon atom, in addition to 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms A di-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a heterocyclic group or a benzo condensate thereof,

(U) C _6-10 which may be halogenated
An aryl-carbamoyl group, (v) a C _6-10 aryl-carbonyl group which may be halogenated, (w) a sulfo group optionally substituted with an amino group, (x) a C _1-6 alkylsulfonyl group, (Y) a C _6-10 aryl group, (z) a C _6-10 aryloxy group, (aa) a C _2-6 alkenylamino group, (bb) a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo condensate thereof, (cc) a 5- to 7-membered group which may be substituted by a hydroxyl group and may have an oxo group Cyclic amino group, (dd) C _1-6 alkoxy-carbamoyl group,
Substituents selected from (ee) carbamoyloxy group, (ff) sulfamoyl group, (gg) mono-C _1-6 alkylsulfamoyl group and (hh) di-C _1-6 alkylsulfamoyl group can be substituted. May be provided in one to five positions. ),

R ⁵ represents (a) a hydrogen atom or (b) a C _1-6 alkyl group. Or R ¹ and R ² can be linked via adjacent nitrogen atoms to (a) a halogen atom, (b) C _1-3
Alkylenedioxy group, (c) nitro group, (d) cyano group, (e) C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) C _3-6 cycloalkyl Group,
(G) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i A) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group,
(M) a C _1-6 alkyl-carbonyl group, (n) a carboxyl group, (o) a C _1-6 alkoxy-carbonyl group,
(P) carbamoyl group, (q) mono-C _1-6 alkyl-
A carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group,
(T) a sulfo group, (u) a C _1-6 alkylsulfonyl group,
(V) at least one nitrogen atom optionally having 1 to 5 substituents selected from a C _6-10 aryl group and (w) a C _6-10 aryloxy group, and further having a carbon atom In addition, a 4- to 8-membered nitrogen-containing heterocyclic group which may contain 1 to 3 ring atoms, such as an oxygen atom and a sulfur atom, or a benzo condensed group thereof may be formed,

Formula

Embedded image The group represented by (a) represents a monocyclic 4- to 9-membered ring or (A) a bicyclic 6- to 14-membered ring, and each represents (i) a C _1-6 alkyl group, and (ii) C _1-6 An alkoxy group,
(Iii) C _1-6 alkylthio group (the “C _1-6 alkyl group”, “C _1-6 alkoxy group” and “C _1-6 alkylthio group” are (a) a halogen atom, and (b) C _{1 -3} alkylenedioxy group, (c) nitro group, (d) cyano group, (e) C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) C _3-6 Cycloalkyl group,
(G) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i A) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group,
(M) a C _1-6 alkyl-carbonyl group, (n) a carboxyl group, (o) a C _1-6 alkoxy-carbonyl group,
(P) carbamoyl group, (q) mono-C _1-6 alkyl-
A carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group,
(T) a sulfo group, (u) a C _1-6 alkylsulfonyl group,
(V) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom It may have 1 to 2 substituents selected from a 7-membered heterocyclic group or a benzo condensate thereof. ),

(Iv) hydroxyl group, (v) amino group, (vi) mono-C _1-6 alkylamino group, (vii) di-C _1-6 alkylamino group, (viii) C _1-6 alkyl- Carbonyl group, (ix) carboxyl group, (x) C _1-6 alkoxy-carbonyl group, (xi) carbamoyl group, (xii) mono-C _1-6 alkyl-carbamoyl group, (xiii) di-C _1-6 (Xiv) C _6-10 aryl-carbamoyl group, (xv) sulfo group, (xvi) C _1-6 alkylsulfonyl group, (xv) C _6-10 aryl group and (xvi) C _6- The receptor antagonist according to the above (1), which may have one or two substituents selected from ₁₀ aryloxy groups and may have one or two unsaturated bonds,

(3) The receptor antagonist according to the above (1), wherein R ¹ is a hydrogen atom or C _1-6 alkyl. (4) The receptor according to the above (1), wherein R ¹ is a hydrogen atom or methyl. (5) the receptor antagonist according to (1), wherein R ¹ is a hydrogen atom; (6) the receptor antagonist according to (1), wherein R ² is an acyl group; (7) an acyl group Is represented by the formula-(C = O) -R ⁴ , -SO _2-
^{R 4, -SO-R 4,} - (C = O) NR 5 R 4, - (C =
O) OR ⁴ ,-(C = S) OR ⁴ or-(C = S)
NR ⁵ R ⁴ , wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a group which may have a substituent Lower alkyl-carbonyl group, carboxyl group, lower alkoxy-carbonyl group optionally having substituent (s), mono-lower alkylaminocarbonyl group optionally having substituent (s), optionally having substituent (s) A di-lower alkylaminocarbonyl group, a 5- to 7-membered cyclic amino group which may have a substituent or an aryloxy group which may have a substituent,
R ⁵ represents a hydrogen atom or a lower alkyl group. ] A is the (6), wherein the receptor antagonist, (8) the acyl group has the formula - (C = O) -R ⁴ or - (C =
O) NR ⁵ -R ⁴ wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, A lower alkyl-carbonyl group, a carboxyl group, a lower alkoxy-carbonyl group optionally having a substituent, a mono-lower alkylaminocarbonyl group optionally having a substituent, A di-lower alkylaminocarbonyl group, a 5- or 7-membered cyclic amino group which may have a substituent or an aryloxy group which may have a substituent. The receptor antagonist according to the above (6), wherein

(9) R ⁴ is the formula (A)

Embedded image Or (a)

Embedded image Group represented by

[Wherein, R ⁶ and R ⁷ are the same or different, and each represents: (a) a hydrogen atom, (b) (b-1) a halogen atom, (b-2) a C _1-3 alkylenedioxy group, (B-3) nitro group, (b-4) cyano group, (b-5) _C3-6 cycloalkyl group, (b-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (b-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (b-
8) hydroxyl group, (b-9) amino group, (b-1)
0) mono-C _1-6 alkylamino group, (b-11) di-
C _1-6 alkylamino group, (b-12) C _1-6 alkyl-
Carbonyl group, (b-13) carboxyl group, (b-1)
4) C _1-6 alkoxy-carbonyl group, (b-15) carbamoyl group, (b-16) mono-C _1-6 alkyl-carbamoyl group, (b-17) di-C _1-6 alkyl-carbamoyl group , (B-18) C _6-10 aryl-carbamoyl group, (b-19) sulfo group, (b-20) C _1-6 alkylsulfonyl group, (b-21) C _6-10 aryl group,
(B-22) a C _6-10 aryloxy group and (b-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A C _1-6 alkyl group,

(C) a C _3-6 cycloalkyl group, (d) a C _1-6 alkoxy group which may have 1 to 3 halogen atoms, and (e) a 1 to 3 halogen atom. and which may be C _1-6 alkylthio group, (f) C _7-16 aralkyl group (g) hydroxyl groups, (h) amino group, (i) mono--C _1-6 alkylamino group, (j) di -C _1-6 alkylamino group, (k) (k-1) halogen atom, (k-2) C _1-3 alkylenedioxy group, (k-3) nitro group, (k-4) cyano group, (K-5) C _3-6 cycloalkyl group, (k-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (k-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (k-
8) hydroxyl group,

(K-9) amino group, (k-10) mono-
C _1-6 alkylamino group, (k-11) di -C _1-6 alkylamino group, (k-12) C _1-6 alkyl - carbonyl group, (k-13) carboxyl group, (k-14) C _1-6
Alkoxy - carbonyl group, (k-15) carbamoyl group, (k-16) mono -C _1-6 alkyl - carbamoyl group, (k-17) di -C _1-6 alkyl - carbamoyl group, (k-18) A C _6-10 aryl-carbamoyl group,
(K-19) sulfo group, (k-20) C _1-6 alkylsulfonyl group, and (k-21) a nitrogen atom in addition to carbon atoms, to 1 selected from oxygen atom and sulfur atom 3 heteroatoms A C _1-6 alkyl-carbonyl group which may be substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof,

(L) a carboxyl group, (m) a C _1-6 alkoxy-carbonyl group, (n) a compound containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A formyl group which may be substituted with a 7- to 7-membered heterocyclic group or a benzo condensate thereof, (o) a carbamoyl group, (p) a (p-1) halogen atom, and (p-2) a C _1-3 alkylenediyl group. Oxy group, (p-3) nitro group, (p-4) cyano group, (p-5) _C3-6 cycloalkyl group, (p-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (p-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (p-
8) hydroxyl group, (p-9) amino group,

(P-10) mono-C _1-6 alkylamino group, (p-11) di-C _1-6 alkylamino group, (p-
12) C _1-6 alkyl - carbonyl group, (p-13) carboxyl group, (p-14) C _1-6 alkoxy - carbonyl group, (p-15) carbamoyl group, (p-16) mono -C _{1 -6} alkyl - carbamoyl group, (p-17) di -C _1-6 alkyl - carbamoyl group, (p-18) C
_6-10 aryl-carbamoyl group, (p-19) sulfo group, (p-20) C _1-6 alkylsulfonyl group, (p-
21) a nitrogen atom other than a C _6-10 aryl group, a (p-22) C _6-10 aryloxy group and a (p-23) carbon atom,
A mono-C _1-6 alkyl which may be substituted with a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom or a substituent selected from a benzo condensate thereof; A carbamoyl group,

(Q) (q-1) halogen atom, (q-
2) C _1-3 alkylenedioxy group, (q-3) nitro group, (q-4) cyano group, (q-5) C _3-6 cycloalkyl group, (q-6) 1 to 3 A C _1-6 alkoxy group optionally having a halogen atom, (q-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, a (q-8) hydroxyl group, (Q-9) amino group, (q-10) mono-C _1-6 alkylamino group, (q
-11) di-C _1-6 alkylamino group, (q-12) C
_1-6 alkyl-carbonyl group, (q-13) carboxyl group, (q-14) C _1-6 alkoxy-carbonyl group,
(Q-15) carbamoyl group, (q-16) mono-C
_1-6 alkyl-carbamoyl group, (q-17) di-C _1-6
Alkyl-carbamoyl group, (q-18) C _6-10 aryl-carbamoyl group, (q-19) sulfo group, (q-2
0) C _1-6 alkylsulfonyl group, (q-21) C _6-10
A 5- to 7-membered aryl group, a (q-22) C _6-10 aryloxy group and a (q-23) carbon atom, in addition to one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A di-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a heterocyclic group or a benzo condensate thereof,

(R) C _6-10 which may be halogenated
Aryl-carbamoyl group, (s) optionally halogenated C _6-10 aryl-carbonyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group, (v) C _6-10 aryl group (W) a C _6-10 aryloxy group, (x) a C _2-6 alkenylamino group, or (y) one to three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom And a 5- to 7-membered heterocyclic group or a benzo condensate thereof. The receptor antagonist according to the above (8), wherein

(10) R ⁴ is the formula (A)

Embedded image Or (a)

Embedded image Group represented by

[In the formula, R ⁶ and R ⁷ are the same or different from each other; (a) a hydrogen atom, (b) (b-1) a hydroxyl group, and (b-2) di-C
_A nitrogen atom other than a _1-6 alkylamino group, a (b-3) C _1-6 alkoxy-carbonyl group and a (b-4) carbon atom,
A 5- or 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom, or a C-substituted group which may be substituted with a substituent selected from a benzo condensate thereof;
_1-6 alkyl group, (c) C _7-16 aralkyl group (d) (d-1) halogen atom, (d-2) mono-C _1-6 alkylamino group (d-3) C _1-6 alkoxy Selected from a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to -carbonyl group and (d-4) carbon atom, or a benzo condensate thereof. A C _1-6 alkyl-carbonyl group which may be substituted with a substituent, (e) a C _1-6 alkoxy-carbonyl group, (f) one selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom A 5- to 7-membered heterocyclic group containing 3 to 3 heteroatoms or a formyl group which may be substituted by a benzo condensate thereof,

(G) (g-1) a halogen atom and (g
-2) a mono-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a C _1-6 alkyl-carbonyl group, (h) an optionally halogenated C _6-10 aryl- A carbamoyl group, (i) a C _6-10 arylcarbonyl group which may be halogenated or (j) a C _6-10 aryloxy group. (11) The receptor antagonist according to ( ¹ ), wherein Q ¹ and Q ² are each a C _1-6 alkylene group _optionally having an oxo group. (12) The receptor antagonist according to the above (1), wherein Q ¹ is a C _1-4 alkylene group, and Q ² is a methylene group.

Equation (13)

Embedded image May have one or two unsaturated bonds, and may have one or two substituents at any position other than N and Z. 9-member ring or 2
A receptor antagonist according to the above (1), which is a cyclic 6- to 14-membered ring;

Embedded image The ring represented by

Embedded image The receptor antagonist according to the above (1), which is

Equation (15)

Embedded image The ring represented by

Embedded image The receptor antagonist according to the above (1), wherein:

Embedded image The ring represented by

Embedded image The receptor antagonist according to the above (1), which is

(17) Z is 1,2-phenylene which may have a substituent,

Embedded image [Wherein, Ar ³ represents an aromatic group which may have a substituent, and n represents an integer of 0 to 3. A group represented by the formula:

Embedded image [Wherein, Ar ³ and n are as defined above, Y is (i) a hydrogen atom, (ii) a lower alkyl group which may be halogenated, and (iii) a lower alkoxy which may be halogenated. Group, (iv) optionally halogenated lower alkylthio group, (v) hydroxyl group, (vi) cyano group, (vii) alkyl-carbonyl group, (viii) lower alkyl-carbonyloxy group, (ix) formyl Amino group, (x) amino group, (xi) mono-lower alkylamino group, (xii) di-lower alkylamino group, (xiii) carboxyl group, (xiv) lower alkoxy-carbonyl group or (xv) lower alkyl- Shows a carbonylamino group. A group represented by

Expression

Embedded image [Wherein, Ar ³ and n are as defined above. Or a group represented by the formula

Embedded image [Wherein, Ar ³ and n are as defined above. ] The receptor antagonist according to the above (13), which is a group represented by the formula: Equation (18)

Embedded image A pyrrolidine in which the ring represented by may have a substituent,
The receptor antagonist according to the above (1), which is piperidine, piperazine, azepine, azocin or a benzo condensate thereof,

(19) Z is a formula

Embedded image [In the formula, Ar ³ represents an aromatic group which may have a substituent, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. (20) 1 to ^{3 wherein} Ar ³ is selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a C _6-14 aryl group or a carbon atom; The 5- to 7-membered heterocyclic group containing three heteroatoms [the "C _6-14 aryl group" and the "5- to 7-membered heterocyclic group" are (i) a halogen atom, (ii) a halogenated atom. 1 selected from a C _1-6 alkoxy group which may be C _1-6 alkyl group and (iii) halogenation be may have a three substituents. The receptor antagonist according to the above (19), wherein

(21) The receptor antagonist according to the above (19), wherein Ar ³ is a phenyl group optionally substituted with a halogen atom. (22) The receptor antagonist according to the above (19), wherein n is 0. (23) the receptor antagonist according to the above (19), wherein Y is a hydroxyl group; (24) Ar ¹ and Ar ² are the same or different and are each a nitrogen atom other than a C _6-14 aryl group or a carbon atom; A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom [the “C _6-14 aryl group” and the “5- to 7-membered heterocyclic group” include (i) A) halogen atom, (ii) optionally halogenated C
_It may have one to three substituents selected from a _1-6 alkyl group and (iii) an optionally halogenated C _1-6 alkoxy group. The receptor antagonist according to the above (1), wherein

(25) Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or
(26) Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; Pyridyl, Q ¹ is a C _1-4 alkylene group, Q ² is a methylene group,

Embedded image The ring represented by

Embedded image And Z is the formula

Embedded image Wherein Ar ³ represents a phenyl group which may be substituted with a halogen atom, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. ]
Wherein R ¹ is a hydrogen atom or methyl;

R ² is (A) (a) a C _1-6 alkoxy-carbonyl group, (b)
C _1-6 which may be substituted with a carboxyl group, (c) a C _1-6 alkyl-carbonyl group or (d) a formyl group.
Alkyl group or (b) below ^{- (C = O) -R 4} , -SO 2 -R 4, - (C =
O) NR ⁵ R ⁴ or — (C ＝ O) O—R ^{4 wherein} R ⁴ is (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) a C _1-6 alkyl-carbonyl group An amino group optionally substituted with
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group, (f) C
_1-6 alkoxy-carbonyl group, (g) mono-C _1-6 alkyl-carbamoyl group, (h) sulfo group optionally substituted with amino group, (i) optionally substituted with hydroxyl group, 5 which may have an oxo group to 7-membered cyclic amino group, (j) C _1-6 alkoxy - 1 to 5 at substitutable positions a substituent selected from carbamoyl groups and (k) carbamoyloxy group C that you may have
_1-6 alkyl group,

(Iii) a C _2-6 alkenyl group, (iv) a C _6-10 aryl group, (v) one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom the 5 comprises one or more to 11-membered heterocyclic group or its benzo-condensed ring, which may be substituted with (vi) C _1-6 alkyl C _1-6
An alkyl-carbonyl group, (vii) a carboxyl group optionally substituted with a C _1-6 alkyl group, (viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl It may be substituted with a 5- to 7-membered heterocyclic group containing one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to the group or carbon atom, or a benzo-fused ring thereof. A C _1-6 alkyl group, (b) a C _7-16 aralkyl group, (c) a halogen atom, a mono-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or a carbon atom other than a nitrogen atom, oxygen One selected from atoms and sulfur atoms
A C _1-6 alkyl-carbonyl group which may be substituted with a 5- to 7-membered heterocyclic group containing at least one kind or three kinds of hetero atoms or a benzo-fused ring thereof,

(D) C _1-6 alkoxy-carbonyl group,
(E) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a formyl group optionally substituted by a benzo condensate thereof , (F) a halogen atom or C
_A mono-C _1-6 alkyl-carbamoyl group optionally substituted with a _1-6 alkyl-carbonyl group, (g) a C _6-10 aryl-carbamoyl group which may be halogenated,
(H) a 5- to 7-membered cyclic amino group optionally having a substituent selected from a halogenated C _6-10 aryl group and (i) a C _1-6 alkoxy-carbamoyl group; or (ix) A) a C _6-10 aryloxy group, and R ⁵ represents a hydrogen atom or a C _1-6 alkyl group].

Equation (27)

Embedded image [Wherein, Ar ¹ , Ar ² and Ar ³ each represent an aromatic group which may have a substituent, and Q ¹ and Q ² each represent a divalent group which may contain oxygen or sulfur in a carbon chain. _Represents a C _1-6 aliphatic hydrocarbon residue, and R ² represents a hydrocarbon group or an acyl group which may have a substituent. Or a salt thereof [provided that N- [5-4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2
-Diphenylpentyl] -1-methanesulfonamide,
N- [5-4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -1-
(P-toluene) sulfonamide and N- [5-4-
(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentyl] -1- (2-thiophene) sulfonamide or a hydrochloride thereof].

(28) R ² is a group represented by the formula — (C ＝ O) —R ⁴ ,
^{(C = O) NR 5 R} 4, - (C = O) O-R 4, - (C =
S) O—R ⁴ , or — (C ＝ S) NR ⁵ R ⁴ , wherein
R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a lower alkyl-carbonyl group which may have a substituent, a carboxyl group, A lower alkoxy-carbonyl group which may have a substituent, a mono-lower alkylaminocarbonyl group which may have a substituent, and a di- group which may have a substituent
It represents a lower alkylaminocarbonyl group or a 5- to 7-membered cyclic amino group which may have a substituent, and R ⁵ represents a hydrogen atom or a lower alkyl group. (29) The compound according to the above (27), wherein R ² is a group represented by the formula — (C） O) —R ⁴ or — (C ＝ O).
NHR ⁴ wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent,
A lower alkyl-carbonyl group optionally having a substituent, a carboxyl group, a lower alkoxy-carbonyl group optionally having a substituent, a mono-lower alkylaminocarbonyl group optionally having a substituent, It represents a di-lower alkylaminocarbonyl group which may have a substituent or a 5- to 7-membered cyclic amino group which may have a substituent, and R ⁵ represents a hydrogen atom or a lower alkyl group. ]
The compound according to the above (27), which is a group represented by:

(30) R ⁴ is the formula (A)

Embedded image Or (a)

Embedded image

[Wherein R ⁶ and R ⁷ are the same or different, and each represents: (a) a hydrogen atom, (b) a (b-1) halogen atom, (b-2) a C _1-3 alkylenedioxy group, (B-3) nitro group, (b-4) cyano group, (b-5) _C3-6 cycloalkyl group, (b-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (b-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (b-
8) hydroxyl group, (b-9) amino group, (b-1)
0) mono-C _1-6 alkylamino group, (b-11) di-
C _1-6 alkylamino group, (b-12) C _1-6 alkyl-
Carbonyl group, (b-13) carboxyl group, (b-1)
4) C _1-6 alkoxy-carbonyl group, (b-15) carbamoyl group, (b-16) mono-C _1-6 alkyl-carbamoyl group, (b-17) di-C _1-6 alkyl-carbamoyl group , (B-18) C _6-10 aryl-carbamoyl group, (b-19) sulfo group, (b-20) C _1-6 alkylsulfonyl group, (b-21) C _6-10 aryl group,
(B-22) a C _6-10 aryloxy group and (b-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A C _1-6 alkyl group,

(C) a C _3-6 cycloalkyl group, (d) a C _1-6 alkoxy group which may have 1 to 3 halogen atoms, and (e) a 1 to 3 halogen atom. and which may be C _1-6 alkylthio group, (f) C _7-16 aralkyl group (g) hydroxyl groups, (h) amino group, (i) mono--C _1-6 alkylamino group, (j) di —C _1-6 alkylamino group, (k) (k-1) halogen atom, (k-2) C _1-3 alkylenedioxy group, (k-3) nitro group, (k-4) cyano group, (K-5) C _3-6 cycloalkyl group, (k-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (k-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (k-
8) hydroxyl group,

(K-9) amino group, (k-10) mono-
C _1-6 alkylamino group, (k-11) di -C _1-6 alkylamino group, (k-12) C _1-6 alkyl - carbonyl group, (k-13) carboxyl group, (k-14) C _1-6
Alkoxy - carbonyl group, (k-15) carbamoyl group, (k-16) mono -C _1-6 alkyl - carbamoyl group, (k-17) di -C _1-6 alkyl - carbamoyl group, (k-18) A C _6-10 aryl-carbamoyl group,
(K-19) sulfo group, (k-20) C _1-6 alkylsulfonyl group, and (k-21) a nitrogen atom in addition to carbon atoms, to 1 selected from oxygen atom and sulfur atom 3 heteroatoms A C _1-6 alkyl-carbonyl group which may be substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof,

(L) a carboxyl group; (m) a C _1-6 alkoxy-carbonyl group; A formyl group which may be substituted by a 7 to 7-membered heterocyclic group or a benzo condensate thereof, (o) a carbamoyl group, (p) a (p-1) halogen atom, and (p-2) a C _1-3 alkylenediyl group. Oxy group, (p-3) nitro group, (p-4) cyano group, (p-5) _C3-6 cycloalkyl group, (p-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (p-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (p-
8) hydroxyl group, (p-9) amino group,

(P-10) mono-C _1-6 alkylamino group, (p-11) di-C _1-6 alkylamino group, (p-
12) C _1-6 alkyl - carbonyl group, (p-13) carboxyl group, (p-14) C _1-6 alkoxy - carbonyl group, (p-15) carbamoyl group, (p-16) mono -C _{1 -6} alkyl - carbamoyl group, (p-17) di -C _1-6 alkyl - carbamoyl group, (p-18) C
_6-10 aryl-carbamoyl group, (p-19) sulfo group, (p-20) C _1-6 alkylsulfonyl group, (p-
21) a nitrogen atom other than a C _6-10 aryl group, a (p-22) C _6-10 aryloxy group and a (p-23) carbon atom,
A mono-C _1-6 alkyl which may be substituted with a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom or a substituent selected from a benzo condensate thereof; A carbamoyl group,

(Q) (q-1) a halogen atom, (q-
2) C _1-3 alkylenedioxy group, (q-3) nitro group, (q-4) cyano group, (q-5) C _3-6 cycloalkyl group, (q-6) 1 to 3 A C _1-6 alkoxy group optionally having a halogen atom, (q-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, a (q-8) hydroxyl group, (Q-9) amino group, (q-10) mono-C _1-6 alkylamino group, (q
-11) di-C _1-6 alkylamino group, (q-12) C
_1-6 alkyl-carbonyl group, (q-13) carboxyl group, (q-14) C _1-6 alkoxy-carbonyl group,
(Q-15) carbamoyl group, (q-16) mono-C
_1-6 alkyl-carbamoyl group, (q-17) di-C _1-6
Alkyl-carbamoyl group, (q-18) C _6-10 aryl-carbamoyl group, (q-19) sulfo group, (q-2
0) C _1-6 alkylsulfonyl group, (q-21) C _6-10
A 5- to 7-membered aryl group, a (q-22) C _6-10 aryloxy group and a (q-23) carbon atom, in addition to one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A di-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a heterocyclic group or a benzo condensate thereof,

(R) C _6-10 which may be halogenated
Aryl-carbamoyl group, (s) optionally halogenated C _6-10 aryl-carbonyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group, (v) C _6-10 aryl group (W) a C _6-10 aryloxy group, (x) a C _2-6 alkenylamino group, or (y) one to three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom And a 5- to 7-membered heterocyclic group or a benzo condensate thereof. (31) the compound according to (27), wherein Q ¹ and Q ² are each a C _1-6 alkylene group which may have an oxo group; The compound according to the above (27), wherein ¹ is a C _1-4 alkylene group and Q ² is a methylene group,

(33) The compound according to the above (27), wherein Ar ³ is a phenyl group optionally substituted with a halogen atom, (34) a C _6-14 aryl group wherein Ar ¹ and Ar ² are the same or different, respectively. Or a 5- to 7-membered heterocyclic group containing 1 to 3 one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom [the “C _6-14 aryl group” and “5- to 7-membered heterocyclic group” includes (i) a halogen atom, (ii) an optionally halogenated C _1-6 alkyl group and (iii) an optionally halogenated C _1-6 alkoxy group. And may have 1 to 3 substituents selected from (35) The compound according to the above (27), wherein Ar ¹ and Ar ² are the same or different and are phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl (27) The compound according to the above,

(36) Ar ¹ and Ar ² are the same or different and are phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or
-Pyridyl, Q ¹ is a C _1-4 alkylene group, Q ² is each a methylene group, and R ² is (a) (a) a C _1-6 alkoxy-carbonyl group, (b)
C _1-6 which may be substituted with a carboxyl group, (c) a C _1-6 alkyl-carbonyl group or (d) a formyl group.
Alkyl group or (b) below ^{- (C = O) -R 4} , -SO 2 -R 4, - (C =
O) NR ⁵ R ⁴ or — (C ＝ O) O—R ^{4 wherein} R ⁴ is (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) a C _1-6 alkyl-carbonyl group An amino group optionally substituted with
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group,

(F) a C _1-6 alkoxy-carbonyl group,
(G) mono-C _1-6 alkyl-carbamoyl group, (h)
A sulfo group optionally substituted with an amino group, (i) a 5- to 7-membered cyclic amino group optionally substituted with a hydroxyl group and optionally having an oxo group, (j) C _1-6 alkoxy A carbamoyl group and (k) a C _1-6 alkyl group _optionally having 1 to 5 substituents at substitutable positions selected from a carbamoyloxy group, (iii) a C _2-6 alkenyl group, (iv A) C _6-10 aryl group, (v) a 5- to 11-membered heterocyclic group containing at least one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, or a benzoyl group thereof. fused ring, optionally substituted with (vi) C _1-6 alkyl C _1-6
An alkyl-carbonyl group, (vii) a carboxyl group optionally substituted with a C _1-6 alkyl group, (viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl It may be substituted by a 5- to 7-membered heterocyclic group containing at least one or three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a group or a carbon atom, or a benzo-fused ring thereof. A C _1-6 alkyl group,

(B) C _7-16 aralkyl group, (c) halogen atom, mono-C _1-6 alkylamino group, C _1-6 alkoxy-carbonyl group or nitrogen atom, oxygen atom and sulfur atom other than carbon atom A C _1-6 alkyl- which may be substituted by a 5- to 7-membered heterocyclic group containing at least one kind of one or three hetero atoms selected from
A carbonyl group, (d) a C _1-6 alkoxy-carbonyl group, (e) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom 5
A 7-membered heterocyclic group or a formyl group optionally substituted with a benzo condensate thereof, (f) a mono-C _1-6 alkyl optionally substituted with a halogen atom or a C _1-6 alkyl-carbonyl group. A carbamoyl group, (g) an optionally halogenated C _6-10 aryl-carbamoyl group, (h) an optionally halogenated C _6-10 aryl-carbonyl group, and (i) a C _1-6 alkoxy. A 5- to 7-membered cyclic amino group which may have a substituent selected from a carbamoyl group or (ix) a C _6-10 aryloxy group, and R ⁵ represents a hydrogen atom or a C _1-6 alkyl group And the compound of the above-mentioned (27), wherein Ar ³ is a phenyl group optionally substituted with a halogen atom,

Equation (37)

Embedded image [Wherein the symbols have the same meanings as described in the above (27). ]
Subjecting the compound represented by or a salt thereof to an acylation reaction;
formula

Embedded image [In the formula, R ² represents an acyl group, and other symbols represent the aforementioned (2
7) Same meaning as described. A method of producing a compound represented by the formula: or a salt thereof,

Embedded image [In the formula, Ph represents a phenyl group, and the other symbols have the same meanings as described in the above (2) 7. Or a salt thereof,

Embedded image [Wherein, R ⁴ represents a hydrogen atom, a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a lower alkyl-carbonyl group optionally having a substituent. , Carboxyl, optionally substituted lower alkoxy-
A carbonyl group, an optionally substituted mono-lower alkylaminocarbonyl group, an optionally substituted di-lower alkylaminocarbonyl group, or an optionally substituted 5- to 7-membered group; It indicates a cyclic amino group, R ⁵
Represents a hydrogen atom or a lower alkyl group. And reacting the compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. ] Or a salt thereof.

(39) The receptor antagonist according to the above (1), which is a prophylactic / therapeutic agent for an inflammatory disease;
(41) the receptor antagonist according to (1), which is an agent for preventing or treating arteriosclerosis, bronchial asthma, atopy, multiple sclerosis or rheumatoid arthritis; (43) a MIP-1α / RANTES receptor antagonist, comprising the compound according to (27); (44) 1- [5 -[4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Piperidin-4-yl) urea, 4- [4- [5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentyl] aminocarbonylamino] piperidino-4-oxobutyrate, N-ethyl-4
-[5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, N-ethoxycarbonylmethyl-4- [5- [4 -(4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide,

Ethyl 3- [4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-3-oxopropionate, 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (1-ethylpiperidin-4-yl)
Urea, 1-[(piperidin-4-yl) carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane, 1-[[(N
-Ethylcarbamoyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane, 1-
[[N- (ethoxycarbonylacetyl) piperidine-4
-Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane, 1-[[N- (3-methoxycarbonylpropionyl) piperidin-4-yl ] Carboxamide] -5-
It relates to the compound of the above-mentioned (27), which is [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane or a salt thereof. In the above formula, Ar ¹ ,
Examples of the aromatic group of the “aromatic group optionally having substituent (s)” represented by Ar ² and Ar ³ include “aromatic hydrocarbon group”, “aromatic heterocyclic group” and the like. And these may be substituted at any position where possible by any number (preferably 1).
To 5, more preferably 1 to 3, more preferably 1 or 2) substituents. Examples of the "aromatic hydrocarbon group" include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples thereof include C _6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl and anthryl. Of these, phenyl, 1-naphthyl and 2-naphthyl are preferred, and phenyl is particularly preferred.

As the “aromatic heterocyclic group”, one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms, preferably one or more other than carbon atoms (for example, 1 to 4 hetero atoms) , Preferably 1 to 3, more preferably 1 or 2), and a 5- to 11-membered monocyclic or fused aromatic heterocyclic group. Specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, furan, isoindolizine, Xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole , Β-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, isochroman etc. One or more (preferably one or two, more preferably one) aromatic rings (for example, the above-mentioned aromatic hydrocarbons) A monovalent group formed by removing an arbitrary hydrogen atom from a ring formed by condensation with a hydrogen group (preferably a benzene ring or the like).
Preferred examples of the “aromatic heterocyclic group” include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,
Quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-
Benzo [b] thienyl, benzo [b] furanyl, 2-thienyl, 3-thienyl and the like can be mentioned. More preferably, 2-thienyl, 3-thienyl, 2-pyridyl,
-Pyridyl, 4-pyridyl, 2-quinolyl, 1-isoquinolyl, 1-indolyl, 2-indolyl, 2-benzothiazolyl and the like. Above all, 2-pyridyl and the like are widely used.

Examples of the substituent of the “aromatic group optionally having a substituent at any position” represented by Ar ¹ , Ar ² and Ar ³ include a halogen atom (for example, fluorine, chlorine, bromine , Iodine, etc.), lower alkylenedioxy groups (eg, C _1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.), nitro groups, cyano groups, lower alkyl groups which may be halogenated, A lower alkenyl group which may be halogenated, a lower alkynyl group which may be halogenated, a lower cycloalkyl group (for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen Lower alkoxy group which may be halogenated, lower alkylthio group which may be halogenated,
Hydroxyl group, amino group, mono-lower alkylamino group (for example, mono-lower alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.)
C, such as _1-6 alkylamino group), di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, and di -C _1-6 alkylamino group such as dibutylamino), 5 to 7-membered cyclic amino Groups (e.g., morpholino, piperazin-1-yl, piperidino,
Pyrrolidin-1-yl, etc.), acylamino group, lower alkylcarbonyl group (eg, C _1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), carboxyl group, lower alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl - carbonyl group), a carbamoyl group, a mono - lower alkylcarbamoyl group (e.g., methylcarbamoyl, mono -C _1-6 alkyl, such as ethylcarbamoyl - such as carbamoyl group), Di-lower alkylcarbamoyl groups (eg, di-C _1-6 alkylcarbamoyl groups such as dimethylcarbamoyl, diethylcarbamoyl, etc.) and aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.) C _6-10 arylcarbamoyl, etc.), sulfo group, lower alkylsulfonyl group (for example,
A C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl, an aryl group (eg, a C _6-10 aryl group such as phenyl and naphthyl), and an aryloxy group (eg, C ₆ such as phenyloxy and naphthyloxy). _6-10 aryloxy group).

The above-mentioned “optionally lower alkyl group” may be, for example, a lower alkyl group which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). (Eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
C such as c-butyl, tert-butyl, pentyl, hexyl, etc.
_1-6 such as an alkyl group) and the like. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoro Ethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, isopentyl, neopentyl, 5,5,5-
Trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like. Examples of the above-mentioned "optionally halogenated lower alkenyl group" and "optionally halogenated lower alkynyl group" include, for example, 1 to 3 halogen atoms (for example, fluorine, chlorine,
A lower alkenyl group optionally having bromine, iodine, etc. (for example, vinyl, propenyl, isopropenyl, 2
A C _2-6 alkenyl group such as -buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like and 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, A lower alkynyl group which may have iodine or the like (for example, a C _2-6 alkynyl group such as 2-butyn-1-yl, 4-pentyn-1-yl or 5-hexyn-1-yl); And so on.

The “optionally halogenated lower alkoxy group” includes, for example, a lower alkoxy group which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) For example, C such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
_1-6 an alkoxy group), and the like, Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n- propoxy, isopropoxy, n-butoxy,
4,4,4-trifluorobutoxy, isobutoxy, se
c-butoxy, pentyloxy, hexyloxy and the like. Examples of the “optionally lower alkylthio group” include, for example, a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (for example, methylthio group). , Ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
and C _1-6 alkylthio groups such as tert-butylthio). Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4
-Trifluorobutylthio, pentylthio, hexylthio and the like. Examples of the “acylamino group” include, for example, —NHCOOR ³ , —NHCONHR ³ ,
—NHCOR ³ or —NHSO ₂ R ³ (R ³ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent). Ar ¹ , A
As the substituent of the “aromatic group optionally having a substituent at any position” represented by r ² and Ar ³ , preferably a halogen atom, an optionally halogenated C _1-6
Examples include an alkyl group, a C _1-6 alkoxy group which may be halogenated, a C _1-3 alkylenedioxy group (particularly, methylenedioxy group), a cyano group, and a hydroxyl group. C that may be
_{A 1-6} alkyl group and an optionally halogenated C _1-6 alkoxy group are preferred, and among them, a halogen atom is widely used. Ar ¹ and Ar ² are each independently phenyl optionally substituted with a halogen atom (eg, phenyl, 4-chlorophenyl, 4-fluorophenyl, etc.), 2-pyridyl, 3-pyridyl, 4-pyridyl Is preferable, and phenyl or 2-pyridyl is more preferable.
Phenyl is generally used as Ar ¹ and Ar ² . A
As r ³ , a C _1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C _1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, or a halogen atom ( Preferably, a phenyl group optionally substituted with chlorine, fluorine and the like (for example, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 4-triphenyl) Fluoromethylphenyl) or 2-
Pyridyl, 3-pyridyl and 4-pyridyl are preferred, of which phenyl which may be substituted with a halogen atom is preferred, and 4-chlorophenyl is particularly preferred.

The “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ² and R ³ is a group obtained by removing one hydrogen atom from a hydrocarbon compound. Examples include chain or cyclic hydrocarbon groups such as, for example, alkyl groups, alkenyl groups, cycloalkyl groups, aryl groups, aralkyl groups and the like. Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable. Among them, a) a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) A C _1-6 alkyl group such as butyl, pentyl, hexyl, etc.), b) a lower alkenyl group (eg, a C _2-6 alkenyl group such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), c A) lower alkynyl group (eg, C _2-6 alkynyl group such as propargyl, ethynyl, butynyl, 1-hexynyl, etc.); d) lower cycloalkyl group (eg, cyclopropyl,
C _3-6 such as cyclohexyl which may be condensed with a benzene ring which may have cyclobutyl, cyclopentyl, 1 to 3 lower alkoxy groups (for example, C _1-6 alkoxy group such as methoxy) and the like. E) aryl group (for example, phenyl, 1-naphthyl, 2
A C _6-14 aryl group such as naphthyl, biphenyl, 2-indenyl, 2-anthryl and the like, preferably a phenyl group), f) a lower aralkyl group (for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthyl) Methyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-
A C _7-16 aralkyl group such as phenylpentyl and the like, preferably a benzyl group) are preferred, and among them, a lower alkyl group, an aryl group and an aralkyl group are preferred.
In particular, lower alkyl groups are widely used.

The “optionally substituted hydrocarbon group” represented by R ² and R ³ has 1 to 5, preferably 1 to 3 substituents at substitutable positions of the hydrocarbon group. And when the number of substituents is two or more, each substituent may be the same or different. As the “substituent” of the “hydrocarbon group which may have a substituent”, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkylenedioxy group (eg, methylenedioxy) Oxy, C _1-3 alkylenedioxy groups such as ethylenedioxy, etc.), nitro group, cyano group, lower alkyl group which may be halogenated, lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) A C _3-6 cycloalkyl group, etc.), a lower alkoxy group which may be halogenated,
An optionally halogenated lower alkylthio group, hydroxyl group, amino group, mono-lower alkylamino group (for example, mono-C such as methylamino, ethylamino, etc.)
_1-6, such as an alkylamino group), di - lower alkylamino group (e.g., dimethylamino, and di -C _1-6 alkylamino group such as diethylamino), lower alkyl - group (e.g., acetyl, such as ethylcarbonyl C _1-6 alkyl-carbonyl group, etc.), carboxyl group, lower alkoxy-carbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl group, mono A lower alkylcarbamoyl group (eg, a mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl and ethylcarbamoyl); a di-lower alkylcarbamoyl group (eg, di-C _1-6 such as dimethylcarbamoyl and diethylcarbamoyl). Alkyl-carba Yl group etc.), a sulfo group, a lower alkylsulfonyl group (e.g., a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl), an aryl group (e.g., phenyl, C _6-10 aryl groups such as naphthyl) An aryloxy group (for example, a C _6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. And a 7-membered heterocyclic group or a benzo condensate thereof. Examples of the above-mentioned "optionally halogenated lower alkyl group", "optionally halogenated lower alkoxy group" and "optionally halogenated lower alkylthio group" include, for example, And the same substituents as those exemplified above. The above “aryl group (preferably phenyl group) and aryloxy group (preferably phenyloxy group)” are the same as the substituents of the above “aromatic group optionally having a substituent at any position”. May have various substituents.

The above-mentioned “5- to 7-membered heterocyclic group or a benzo condensate thereof” includes, for example, one or two or more hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. Preferably 1 or 2
And a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing one heteroatom. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-
Imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1
-Or 2-piperazinyl, morpholino, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
Pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-
Pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-
Examples thereof include isothiazolyl and 3-isoxazolyl, which may be condensed with a benzene ring at an arbitrary position to form a benzo condensate. Further, the “5- to 7-membered heterocyclic group or benzo-fused product thereof” may have 1 to 3 substituents at any substitutable position. Examples of the substituent include the aforementioned Ar ¹ , Ar ² and Ar ³
And the substituents of the “aromatic group which may have a substituent (s)”, and preferred examples thereof include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a lower alkylenediene. An oxy group (eg, methylenedioxy,
A C _1-3 alkylenedioxy group such as ethylenedioxy, etc.), a nitro group, a cyano group, a lower alkyl group which may be halogenated, a lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) A C _3-6 cycloalkyl group), an optionally halogenated lower alkoxy group, an optionally halogenated lower alkylthio group, a hydroxyl group,
Amino group, mono-lower alkylamino group (for example, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-lower alkylamino group (for example, dimethyl Di-C _1-6 alkylamino groups such as amino, diethylamino, dipropylamino, dibutylamino and the like) and 5- to 7-membered cyclic amino groups (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidine-
1-yl, etc.), lower alkylcarbonyl groups (eg, C _1-6 alkylcarbonyl groups such as acetyl and propionyl), carboxyl groups, lower alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) C _1-6 alkoxy such as - carbonyl group), a carbamoyl group, a mono - lower alkylcarbamoyl group (e.g., methylcarbamoyl, mono- -C such ethylcarbamoyl
_{A 1-6} alkyl-carbamoyl group, a di-lower alkylcarbamoyl group (eg, di-C _1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), an arylcarbamoyl group (eg, phenylcarbamoyl, naphthylcarbamoyl) Such as C
_6-10 aryl-carbamoyl group, etc.), sulfo group, lower alkylsulfonyl group (eg, C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), aryl group (eg, C _6- such as phenyl, naphthyl, etc.) ₁₀ aryl groups), aryloxy groups (for example,
And C _6-10 aryloxy groups such as phenyloxy and naphthyloxy). Examples of the “optionally halogenated lower alkyl group”, “optionally halogenated lower alkoxy group” and “optionally halogenated lower alkylthio group” include, for example, the aforementioned Ar ¹ and Ar ² , Ar ³ , the same as those exemplified as the “substituent” of the “aromatic group optionally having substituent (s)”. Particularly preferred examples of the “hydrocarbon group which may have a substituent” as R ² include (i) a C _1-6 alkoxycarbonyl group, (ii) a carboxyl group, and (iii) a C _1-6 alkyl. A carbonyl group or (iv) a C _1-6 alkyl group which may be substituted with a formyl group.

The “acyl group” represented by R ² includes, for example, — (C ＝ O) —R ⁴ , —SO ₂ —R ⁴ , —SO—
^{R 4, - (C = O} ) NR 5 R 4, - (C = O) O-R 4, -
(C ＝ S) O—R ⁴ , — (CＳS) NR ⁵ R ⁴ (R ⁴ is a hydrogen atom, a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent. A cyclic group, a lower alkylcarbonyl group which may have a substituent (for example, C _1-6 alkyl-carbonyl such as acetyl, propionyl and butyryl), a carboxyl, a lower alkoxycarbonyl which may have a substituent Groups (eg, methoxycarbonyl,
C _1-6 alkoxy-carbonyl groups such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), and optionally substituted mono-lower alkylaminocarbonyl groups (eg, methylaminocarbonyl,
Ethylaminocarbonyl, propylaminoarbonyl,
Mono-C _1-6 alkyl- such as butylaminocarbonyl
Carbamoyl group), an optionally substituted di-
A lower alkylaminocarbonyl group (eg, di-C _1-6 alkyl-carbamoyl group such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, etc.); Membered cyclic amino group (preferably 2-piperidyl, 3-piperidyl, 4-piperidyl,
1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl, etc.) or an optionally substituted lower aryloxy group (e.g., a C _6-10 aryloxy group such as phenyloxy) indicates, R ⁵ is Hydrogen atom or lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Preferred are C _1-6 alkyl groups such as butyl, pentyl, hexyl and the like, and particularly preferred are C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl. ). ). Of these, preferably-(C = O) -R
_{^{4, -SO 2 -R 4, -SO}} -R 4, - (C = O) NR
⁵ R ⁴ , — (C ＝ O) O—R ⁴ (R ⁴ and R ⁵ are as defined above), and — (C ＝ O) —R ⁴ , —SO ₂ —R ⁴ , —
(C ＝ O) NR ⁵ R ⁴ and — (C ＝ O) O—R ⁴ (R ⁴ and R ⁵ are as defined above) are more preferred. Above all,-(C
ＯO) —R ⁴ or — (C ＝ O) NHR ⁴ (R ⁴ and R ⁵
Is the same as defined above). As R ² is (1)
(I) a C _1-6 alkoxy-carbonyl group, (ii) a carboxyl group, (iii) a C _1-6 alkyl-carbonyl group, or (iv) a C _1-6 alkyl group optionally substituted with a formyl group or ( 2) An acyl group is preferred.

The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ⁴ is a group obtained by removing one hydrogen atom from a hydrocarbon compound. For example, an alkyl group, an alkenyl group, an alkynyl group,
Examples thereof include a chain or cyclic hydrocarbon group such as a cycloalkyl group, an aryl group, and an aralkyl group. Specific examples include the same groups as the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by the above R ² and R ³ , and among them, C ^{1 to} C ⁴ are preferable. Preferred are 16 chain or cyclic hydrocarbon groups and the like, and particularly preferred is a lower (C _1-6 ) alkyl group, a lower (C _2-6 ) alkenyl group or a C _6-10 aryl group. Among them, lower (C _1-6 ) alkyl groups are widely used. R ^{4 represents} a “hydrocarbon group”, “heterocyclic group”, “lower alkylcarbonyl group”, “carboxyl group”, “lower alkoxycarbonyl group”, “mono-lower alkylaminocarbonyl group”, “di-lower” Preferred substituents that the “alkylaminocarbonyl group”, “5- to 7-membered cyclic amino group” and “lower aryloxy group” may have include, for example, (i) a halogen atom (for example,
(Ii) a lower alkylenedioxy group (eg, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (i.
ii) nitro group, (iv) cyano group, (v) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _{3- 6} cycloalkyl group,
(6) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8 ) Hydroxyl group, (9) amino group, (10) mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (12)
C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) A di-C _1-6 alkyl-carbamoyl group,
(18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10
An aryl group, a (22) C _6-10 aryloxy group and (2
3) substituted with a substituent represented by a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof; A C _1-6 alkyl group, (vi) C
_3-6 cycloalkyl group, (vii) lower alkoxy group which may be halogenated, (viii) lower alkylthio group which may be halogenated, (ix) aralkyl group,
(X) a hydroxyl group, (xi) an amino group optionally substituted with a C _1-6 alkyl-carbamoyl group, (xii) a mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino , A C _1-6 alkylamino group such as butylamino), (xii
i) di-lower alkylamino group (for example, di-lower alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino and the like), (xiv) 5 to 5 which may have a hydroxyl group or an oxo group. 7-membered cyclic amino group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-
(Xv) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (xv) Five)
C _3-6 cycloalkyl group, (6) 1 to 3 substituents C _1-6 alkoxy group optionally having halogen atom, (7) 1 to may have three halogen atoms C _1-6 alkylthio group, (8) hydroxyl group, (9) amino group,
(10) mono-C _1-6 alkylamino group, (11) di-C _1-6
Alkylamino group, (12) C _1-6 alkyl - carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy -
Carbonyl group, (15) carbamoyl group, (16) mono-C
_1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group, (18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group _Containing , in addition to (21) a C _6-10 aryl group, (22) a C _6-10 aryloxy group and (23) a carbon atom, one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A lower alkylcarbonyl group which may be substituted with a substituent represented by a 5- to 7-membered heterocyclic group or a benzo condensate thereof (for example, a C _1-6 alkylcarbonyl group such as acetyl, propionyl and the like), (xvi) carboxyl group, (xvii) a lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl - carbonyl group), ( xviii) a carbamoyl group, (xix) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzocondensate thereof. A formyl group, (xx) (1) a halogen atom, (2) a C _1-3 alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) a C _3-6 cycloalkyl group,
(6) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8 ) Hydroxyl group, (9) amino group, (10) mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (12)
C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) A di-C _1-6 alkyl-carbamoyl group,
(18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10
An aryl group, a (22) C _6-10 aryloxy group and (2
3) substituted with a substituent represented by a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof; Mono-lower alkylcarbamoyl groups (eg, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl and ethylcarbamoyl), (xxi) (1) halogen atom, (2) C _1-3 alkylenedioxy Group, (3) nitro group, (4) cyano group, (5)
C _3-6 cycloalkyl group, (6) 1 to 3 substituents C _1-6 alkoxy group optionally having halogen atom, (7) 1 to may have three halogen atoms C _1-6 alkylthio group, (8) hydroxyl group, (9) amino group,
(10) mono-C _1-6 alkylamino group, (11) di-C _1-6
Alkylamino group, (12) C _1-6 alkyl - carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy -
Carbonyl group, (15) carbamoyl group, (16) mono-C
_1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group, (18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group _Containing , in addition to (21) a C _6-10 aryl group, (22) a C _6-10 aryloxy group and (23) a carbon atom, one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A di-lower alkylcarbamoyl group which may be substituted by a 5- to 7-membered heterocyclic group or a substituent represented by a benzo condensate thereof (for example, di-C _1-6 alkyl- such as dimethylcarbamoyl and diethylcarbamoyl);
A carbamoyl group), (xxii) an optionally halogenated arylcarbamoyl group (for example, a C _6-10 aryl-carbamoyl group such as phenylcarbamoyl and naphthylcarbamoyl), (xxiii) an optionally halogenated aryl Carbonyl group (for example, C _6-10 aryl- such as phenylcarbonyl and naphthylcarbonyl);
A carbonyl group), (xxiv) a sulfo group optionally substituted with an amino group, (xxv) a lower alkylsulfonyl group (for example, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), (xxvi) Aryl groups (for example, C _6-10 aryl groups such as phenyl and naphthyl), (xxvi) aryloxy groups (for example, C _6-10 aryloxy groups such as phenyloxy and naphthyloxy), (xxviii) C _{2 -6} alkenylamino group, (xxi
x) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms or a benzo condensate thereof, (xxx) sulfamoyl group, (xxxi) Mono-lower alkylsulfamoyl groups (eg, mono-C _1-6 alkylsulfamoyl groups such as methylsulfamoyl and ethylsulfamoyl), (xxxii) di-lower alkylsulfamoyl groups (eg, Di-C _1-6 alkylsulfamoyl groups such as dimethylsulfamoyl and diethylsulfamoyl), (xxxiii) lower alkoxycarbamoyl groups (eg, C _1-6 alkoxy-carbamoyl groups such as methoxycarbamoyl and ethoxycarbamoyl) Etc.) and carbamoyloxy groups.

Preferred examples thereof include (i) a lower alkylenedioxy group (for example, a C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy);
(Ii) nitro group, (iii) cyano group, (iv) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _{3 -6} cycloalkyl group, (6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) C _1- optionally substituted with 1 to 3 halogen atoms ₆ alkylthio group, (8) hydroxyl group, (9) amino group, (10) mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (1
2) C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, 17) di-C _1-6 alkyl-carbamoyl group,
(18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10
An aryl group, a (22) C _6-10 aryloxy group and (2
3) substituted with a substituent represented by a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof; A C _1-6 alkyl group, (v) C
_3-6 cycloalkyl group, (vi) lower alkoxy group which may be halogenated, (vii) lower alkylthio group which may be halogenated, (viii) hydroxyl group,
(Ix) a C _7-16 aralkyl group, (x) an amino group optionally substituted with a C _1-6 alkoxy, (xi) a mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropyl A mono-C _1-6 alkylamino group such as amino, butylamino, etc.), a di-lower alkylamino group (eg, di-C 1-6
_1-6 alkylamino group), (xii) a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidone-1
-Yl, 2-pyridone-1-yl, etc.), (xiii)
(1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) 1 to 3 halogens A C _1-6 alkoxy group optionally having an atom, (7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, and (9) an amino group (10) mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (12) C _1-6 alkyl-carbonyl group, (13)
Carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group, ( 18) _C6-10 aryl-carbamoyl group,
(19) a sulfo group, (20) a C _1-6 alkylsulfonyl group,
(21) 5 containing a C _6-10 aryl group, (22) a C _6-10 aryloxy group and (23) one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A 7-membered heterocyclic group or a lower alkylcarbonyl group which may be substituted with a substituent represented by a benzo condensate thereof (for example, a C.sup.2 group such as acetyl,
_1-6 alkyl-carbonyl group), (xiv) carboxyl group, (xv) lower alkoxycarbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (Xvi) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a formyl group optionally substituted by a benzo condensate thereof , (Xv
ii) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) 1 to 3 A C _1-6 alkoxy group optionally having a halogen atom, (7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8) a hydroxyl group, (9) Amino group, (10) mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (12) C _1-6 alkyl-carbonyl group, (13)
Carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group, ( 18) _C6-10 aryl-carbamoyl group,
(19) a sulfo group, (20) a C _1-6 alkylsulfonyl group,
(21) 5 containing a C _6-10 aryl group, (22) a C _6-10 aryloxy group and (23) one to three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the carbon atom. A mono-lower alkylcarbamoyl group optionally substituted with a substituent represented by a 7- to 7-membered heterocyclic group or a benzo condensate thereof (for example, a mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl and ethylcarbamoyl) ), (Xviii) (1) halogen atom, (2) C
_1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) _C3-6 cycloalkyl group, (6) 1-3
C _1-6 alkoxy group optionally having 3 halogen atoms, (7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8) hydroxyl group,
(9) amino group, (10) mono-C _1-6 alkylamino group,
(11) di-C _1-6 alkylamino group, (12) C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C
_1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (1
7) di-C _1-6 alkyl-carbamoyl group, (18) C _6-10
Aryl-carbamoyl group, (19) sulfo group, (20) C
_1-6 alkylsulfonyl group, (21) C _6-10 aryl group,
(22) a C _6-10 aryloxy group and (23) one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the carbon atom
A di-lower alkylcarbamoyl group which may be substituted with a 5- to 7-membered heterocyclic group containing 3 to 3 heteroatoms or a substituent represented by a benzo condensate thereof (for example,
Di-C _1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl), (xix) optionally halogenated arylcarbamoyl groups (for example, C _6-10 aryl-carbamoyl groups such as phenylcarbamoyl and naphthylcarbamoyl) Xx) arylcarbonyl group which may be halogenated (for example, C phenylcarbonyl, naphthylcarbonyl, etc.
_6-10 aryl - carbonyl group), (xxi) optionally sulfo group which may be substituted with an amino group, (xxii) aryl groups (e.g., phenyl, C _6-10 aryl groups such as naphthyl), (xxiii) Selected from aryloxy groups (for example, C _6-10 aryloxy groups such as phenyloxy and naphthyloxy), (xxiv) C _2-6 alkenylamino, (xxv) carbon atoms, nitrogen, oxygen and sulfur A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo condensate thereof, (xxvi) a sulfamoyl group, (xxvii) a mono-lower alkylsulfamoyl group (for example, methylsulfamoyl, ethylsulfamoyl such mono -C _1-6 alkylsulfamoyl group such as moil), (xxviii) di - lower alkylsulfamoyl group (e.g., dimethylsulfamoyl, diethyl And di -C _1-6 alkylsulfamoyl group such as Rusurufamoiru), (xxix) a lower alkoxy carbamoyl group (e.g., methoxy carbamoyl, C _1-6 alkoxy such as ethoxy carbamoyl - such as carbamoyl group) and (xx
x) carbamoyloxy group and the like.

More preferred examples include (i) (1) a halogen atom, (2) a C _1-3 alkylenedioxy group, (3)
Nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) 1 to 3 halogen atoms a C _1-6 alkylthio group optionally having, (8) hydroxyl group, (9) amino group, (10) mono -C _1-6 alkylamino group, (11) di -C _{1 -6} alkylamino group, (1
2) C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, 17) di-C _1-6 alkyl-carbamoyl group,
(18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10
An aryl group, a (22) C _6-10 aryloxy group and (2
3) substituted with a substituent represented by a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof; A C _1-6 alkyl group, (ii) C
_3-6 cycloalkyl group, (iii) C _7-16 aralkyl group,
(Iv) hydroxyl group, (v) amino group, (vi) mono-
Lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (v
ii) di-lower alkylamino groups (eg, di-C _1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (viii)
A 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl,
-Pyrrolidone-1-yl, 2-pyridone-1-yl, etc.), (ix) (1) halogen atom, (2) _C1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (Five)
C _3-6 cycloalkyl group, (6) 1 to 3 substituents C _1-6 alkoxy group optionally having halogen atom, (7) 1 to may have three halogen atoms C _1-6 alkylthio group, (8) hydroxyl group, (9) amino group,
(10) mono-C _1-6 alkylamino group, (11) di-C _1-6
Alkylamino group, (12) C _1-6 alkyl - carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy -
Carbonyl group, (15) carbamoyl group, (16) mono-C
_1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group, (18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group _Containing , in addition to (21) a C _6-10 aryl group, (22) a C _6-10 aryloxy group and (23) a carbon atom, one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A lower alkylcarbonyl group which may be substituted with a substituent represented by a 5- to 7-membered heterocyclic group or a benzo condensate thereof (for example, a C _1-6 alkylcarbonyl group such as acetyl and propionyl), (x) Carboxyl group, (xi) lower alkoxycarbonyl group (for example,
(C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xii) 1 to 3 selected from nitrogen, oxygen and sulfur other than carbon atoms
A 5- to 7-membered heterocyclic group containing at least one heteroatom or a formyl group optionally substituted with a benzo condensate thereof,
(Xiii) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _3-6
Cycloalkyl group, (6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) C _1-6 alkylthio optionally having 1 to 3 halogen atoms Group, (8) hydroxyl group, (9) amino group, (10)
Mono-C _1-6 alkylamino group, (11) di-C _1-6 alkylamino group, (12) C _1-6 alkyl-carbonyl group, (1
3) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group , (18) C _6-10 aryl - carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _{6 -10} aryl group, (22) C _6-10 aryloxy group And (23) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent represented by a benzo condensate thereof. Optionally a mono-lower alkylcarbamoyl group (e.g. methylcarbamoyl,
A mono-C _1-6 alkyl-carbamoyl group such as ethylcarbamoyl), (xiv) an optionally halogenated C _6-13 aryl-carbamoyl group, (xv) an optionally halogenated C _6-13 An aryl-carbonyl group, (xv
i) a sulfo group optionally substituted with amino, (xvii)
An aryl group (such as a C _6-10 aryl group such as phenyl and naphthyl), (xviii) a C _2-6 alkenyl exci group, (xi
x) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom or a benzo condensate thereof, (xx) an aryloxy group (for example, A C _6-10 aryloxy group such as phenyloxy and naphthyloxy; (xxi) a lower alkoxycarbamoyl group (eg, a C _1-6 alkoxy-carbamoyl group such as methoxycarbamoyl and ethoxycarbamoyl); and (xxii) carbamoyloxy And the like. The above-mentioned "optionally halogenated lower alkoxy group" and "optionally halogenated lower alkylthio group" include, for example, the aforementioned Ar
Examples thereof include those similar to those exemplified as the “substituent” of the “aromatic group which may have a substituent” represented by ¹ , Ar ² and Ar ³ .

The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ³ and R ⁴ is, for example, selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. More preferably, one or two or more heteroatoms (e.g., 1 to 4, preferably 1 to 3,
More preferably, it is a 5- to 11-membered (monocyclic or bicyclic) heterocyclic group containing 1 or 2), for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4
-Imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1
-Or a non-aromatic heterocyclic group such as 2-piperazinyl, morpholinyl, 3- or 4-azepinyl (among others, a saturated 5- to 7-membered cyclic amino group (for example, 1- or 2-
And the like, for example) or 2-thienyl, 3-thienyl, 2-pyridyl, 3-
Pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 4
Aromatic heterocycles such as -quinolyl, 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl and 2-isoindolyl And the like. Of these, an aromatic heterocyclic group or a saturated 5- to 7-membered cyclic amino group is preferred. More preferably, for example, a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 preferably 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom (for example, 2-thienyl, 3-
Thienyl, 2-pyridyl, 4-pyridyl and the like) or a saturated 5- to 7-membered cyclic amino group. Especially 2
-, 3- or 4-piperidyl, 1- or 2-pyrazinyl or morpholinyl. Examples of the substituent that the “heterocyclic group” of the “heterocyclic group optionally having” may have include, for example, the “hydrocarbon optionally having a substituent” of R ^4. The same number and the like as the “substituent” which the “group” may have are used.

R ⁴ represents (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) an amino group optionally substituted by a C _1-6 alkylcarbonyl group, (c) mono-C _{1-. 6} alkylamino group, (d) di -C _1-6 alkylamino group, (e) a carboxyl group, (f) C _1-6 alkoxy - carbonyl group, (g) mono--C _1-6 alkyl - carbamoyl group, (H) a sulfo group optionally substituted with an amino group, (i) a 5- to 7-membered cyclic amino group optionally substituted with a hydroxyl group and optionally having an oxo group,
(J) C _1-6 alkoxy - carbamoyl group and (k) carba 1 at substitutable positions a substituent selected from the carbamoyloxy group to five optionally having C _1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _6-10 aryl group, (v) 5 to 5 containing one or more hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom. 11-membered heterocyclic group or its benzo-condensed ring, (vi) C _1-6 alkyl - substituted by a carbonyl group C _1-6 alkyl group, optionally substituted with (vii) C _1-6 alkyl group (Viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or one selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom. 5 or more containing one or more heteroatoms Chair 7
A C _1-6 alkyl group optionally substituted with a membered heterocyclic group or a benzo-fused ring thereof,

(B) C _7-16 aralkyl group, (c) halogen atom, mono-C _1-6 alkylamino group, C _1-6 alkoxy-carbonyl group or nitrogen atom, oxygen atom and sulfur atom other than carbon atom A C _1-6 alkylcarbonyl group optionally substituted by a 5- to 7-membered heterocyclic group containing at least one kind of one or three kinds of heteroatoms selected from the group _{consisting of: 6} alkoxy-carbonyl group,
(E) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a formyl group optionally substituted with a benzo condensate thereof , (F) a halogen atom or C _1-6
Mono- which may be substituted with an alkyl-carbonyl group
C _1-6 alkyl-carbamoyl group, (g) optionally halogenated C _6-10 aryl-carbamoyl group, (h)
(Ix) a 5- to 7-membered cyclic amino group optionally having a substituent selected from a halogenated C _6-10 aryl-carbonyl group and (i) a C _1-6 alkoxy-carbamoyl group; A C _6-10 aryloxy group and the like are preferred.

As more preferred R ⁴ , formula (1)

Embedded image Or (2)

Embedded image [Wherein R ⁶ and R ⁷ are the same or different and are each one of (a) a hydrogen atom, (b) (b-1) a halogen atom, and (b-2) C _1-3 alkylenedioxy Group, (b-3) nitro group, (b-4) cyano group, (b-
5) C _3-6 cycloalkyl group, (b-6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (b
-7) C optionally having 1 to 3 halogen atoms
_1-6 alkylthio group, (b-8) hydroxyl group, (b-9) amino group, (b-10) mono-C _1-6 alkylamino group, (b-1
1) di-C _1-6 alkylamino group, (b-12) C _1-6 alkyl-carbonyl group, (b-13) carboxyl group, (b-14)
C _1-6 alkoxy-carbonyl group, (b-15) carbamoyl group, (b-16) mono-C _1-6 alkyl-carbamoyl group, (b-17) di-C _1-6 alkyl-carbamoyl group, ( b
-18) C _6-10 aryl - carbamoyl group, (b-19) sulfo group, (b-20) C _1-6 alkylsulfonyl group, (b-21)
In addition to a C _6-10 aryl group, a (b-22) C _6-10 aryloxy group and a (b-23) carbon atom, containing one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A C _1-6 alkyl group which may be substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof,

(C) a C _3-6 cycloalkyl group, (d) a C _1-6 alkoxy group which may have 1 to 3 halogen atoms, and (e) a 1 to 3 halogen atom. and which may be C _1-6 alkylthio group, (f) C _7-16 aralkyl group (g) hydroxyl groups, (h) amino group, (i) mono--C _1-6 alkylamino group, (j) di —C _1-6 alkylamino group, (k) (k-1) halogen atom, (k-2) C _1-3 alkylenedioxy group, (k-3) nitro group, (k-4) cyano group, (K-
5) C _3-6 cycloalkyl group, (k-6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (k
-7) C optionally having 1 to 3 halogen atoms
_1-6 alkylthio group, (k-8) hydroxyl group, (k-9) amino group, (k-10) mono-C _1-6 alkylamino group, (k-1
1) di-C _1-6 alkylamino group, (k-12) C _1-6 alkyl-carbonyl group, (k-13) carboxyl group, (k-14)
C _1-6 alkoxy-carbonyl group, (k-15) carbamoyl group, (k-16) mono-C _1-6 alkyl-carbamoyl group, (k-17) di-C _1-6 alkyl-carbamoyl group, ( k
-18) a C _6-10 aryl-carbamoyl group, a (k-19) sulfo group, a (k-20) C _1-6 alkylsulfonyl group, and a (k
-21) substituted with a substituent selected from a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms or a benzo condensate thereof; A C _1-6 alkyl-carbonyl group,

(L) a carboxyl group, (m) a C _1-6 alkoxy-carbonyl group, (n) a compound containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A formyl group which may be substituted with a 7 to 7-membered heterocyclic group or a benzo condensate thereof, (o) a carbamoyl group, (p) a (p-1) halogen atom, and (p-2) a C _1-3 alkylenediyl group. Oxy group, (p-3) nitro group, (p-4) cyano group, (p-
5) C _3-6 cycloalkyl group, (p-6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (p-6)
-7) C optionally having 1 to 3 halogen atoms
_1-6 alkylthio group, (p-8) hydroxyl group, (p-9) amino group, (p-10) mono-C _1-6 alkylamino group, (p-1
1) di-C _1-6 alkylamino group, (p-12) C _1-6 alkyl-carbonyl group, (p-13) carboxyl group, (p-14)
C _1-6 alkoxy-carbonyl group, (p-15) carbamoyl group, (p-16) mono-C _1-6 alkyl-carbamoyl group, (p-17) di-C _1-6 alkyl-carbamoyl group, ( p
-18) C _6-10 aryl - carbamoyl group, (p-19) sulfo group, (p-20) C _1-6 alkylsulfonyl group, (p-21)
In addition to a C _6-10 aryl group, a (p-22) C _6-10 aryloxy group and a (p-23) carbon atom, containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom A mono-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof,

(Q) (q-1) halogen atom, (q-2) C _1-3
Alkylenedioxy group, (q-3) nitro group, (q-4) cyano group, (q-5) _{C3-6cycloalkyl} group, (q-6) having 1 to 3 halogen atoms C _1-6 alkoxy group, (q-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (q-8) hydroxyl group, (q-9) amino Group, (q-10) mono-C _1-6 alkylamino group, (q-11) di-C _1-6 alkylamino group, (q-1
2) C _1-6 alkyl-carbonyl group, (q-13) carboxyl group, (q-14) C _1-6 alkoxy-carbonyl group, (q-1
5) carbamoyl group, (q-16) mono-C _1-6 alkyl-carbamoyl group, (q-17) di-C _1-6 alkyl-carbamoyl group, (q-18) C _6-10 aryl-carbamoyl group ,
(Q-19) sulfo group, (q-20) C _1-6 alkylsulfonyl group, (q-21) C _6-10 aryl group, (q-22) C _6-10 aryloxy groups and (q-23 A) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; Good di
C _1-6 alkyl-carbamoyl group, (r) optionally halogenated C _6-10 aryl-carbamoyl group, (s) optionally halogenated C _6-10 aryl-carbonyl group, (t) A sulfo group, (u) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group, (x) a C _2-6 alkenylamino group, or (y) A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzo condensate thereof. And the like represented by

R ⁶ and R ⁷ are more preferably (a) a hydrogen atom, (b) a (b-1) hydroxyl group, (b-2) a di-C _1-6 alkylamino group, and (b-3) A 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to C _1-6 alkoxy-carbonyl group and (b-4) carbon atom, or a benzoyl group thereof. A C _1-6 alkyl group which may be substituted with a substituent selected from a condensate, (c) a C _7-16 aralkyl group, (d) a (d-1) halogen atom, and (d-2) a mono-C _{1 -6} alkylamino group (d-3) C _1-6 alkoxy - 5 containing a carbonyl group and (d-4) a nitrogen atom in addition to carbon atom, 1 to 3 hetero atoms selected from oxygen atom and a sulfur atom
A C _1-6 alkyl-carbonyl group which may be substituted with a substituent selected from a 7-membered heterocyclic group or a benzo condensate thereof, (e) a C _1-6 alkoxy-carbonyl group, (f) a carbon atom A 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a formyl group optionally substituted with a benzo condensate thereof, (g) ( g-1) a mono-C _1-6 alkyl-carbamoyl group which may be substituted with a substituent selected from a halogen atom and (g-2) a C _1-6 alkyl-carbonyl group, (h) a halogenated C _6-10 aryl-carbamoyl group which may be _substituted , (i) C _6-10 aryl-carbonyl group which may be halogenated, and (j) C _6-10 aryloxy group.

The “lower alkyl group” of the “optionally substituted lower alkyl group” represented by R ¹ is, for example, a linear or branched lower alkyl having 1 to 6 carbon atoms. Groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. The “lower alkylcarbonyl group” of the “lower alkylcarbonyl group optionally having substituent (s)” represented by R ¹ is, for example, an alkyl having 1 to 6 carbon atoms such as methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like. -Carbonyl and the like. Examples of the substituent which the “lower alkyl group” and “lower alkylcarbonyl group” may have include, for example, “an optionally substituted hydrocarbon group” represented by R ^2. The same as the “substituent” which may be used are used. R ¹ is a hydrogen atom or a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)
Are preferred, and a hydrogen atom or a methyl group is particularly preferred.
In particular, a hydrogen atom is widely used.

The “nitrogen-containing heterocyclic group formed by R ¹ and R ² via adjacent nitrogen atoms” is, for example, at least 1
It has nitrogen atoms, oxygen atoms in addition to carbon atoms,
1 to 3 sulfur atoms (preferably 1 to 2
A) a 4- to 8-membered ring which may be contained as a ring-constituting atom, or a benzo-fused group thereof. For example, aromatic heterocyclic groups such as 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 1-pyrazolyl, 2-isoindolyl, 1-indazolyl, morpholino, piperidino, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1 -Azpinyl and other cyclic amino groups or their benzo-condensed groups (eg, 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydro Isoquinoline-2
-Yl, 3-benzazepin-3-yl), phthalimide, succinimide, 2-pyrrolidone-1-yl, 2-
Lactams such as pyridone-1-yl and 2-quinolone-1-yl, and imide groups are exemplified.

The “nitrogen-containing heterocyclic group formed by R ¹ and R ² via an adjacent nitrogen atom” has the “optionally substituted hydrocarbon group” represented by the above R ^2. May have a substituent similar to the `` substituent '' which may be
In the case of a benzo condensed group, a halogen atom (for example, fluorine, chlorine, bromine,
Iodine, etc.), lower alkylenedioxy groups (eg, C _1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.), nitro groups, cyano groups, lower alkyl groups which may be halogenated, halogens Lower alkoxy group which may be halogenated, lower alkylthio group which may be halogenated, hydroxyl group, amino group,
Mono-lower alkylamino groups (e.g., methylamino,
Ethylamino, propylamino, isopropylamino,
A mono-C _1-6 alkylamino group such as butylamino), a di-lower alkylamino group (eg, a di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), Carboxyl group, lower alkoxycarbonyl group (for example, C _1-6 alkoxy- such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.)
It may have one or more (preferably 1 to 5, more preferably 1 to 3, and still more preferably 1 or 2) substituents selected from a carbonyl group and a carbamoyl group. Examples of the above-mentioned "optionally halogenated lower alkyl group", "optionally halogenated lower alkoxy group" and "optionally halogenated lower alkylthio group" include, for example, the aforementioned A
Examples thereof include the same as those exemplified as the “substituent” of the “aromatic group which may have a substituent” represented by r ¹ , Ar ² and Ar ³ . As the “nitrogen-containing heterocyclic group” of the “nitrogen-containing heterocyclic group formed by R ¹ and R ² via adjacent nitrogen atoms”, “1-piperazinyl” is preferable, and “1-piperazinyl” is Those having a substituent on the nitrogen atom are preferred.

As a substituent on the 4-position nitrogen atom of the “1-piperazinyl”, a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
a C _1-6 alkyl group such as sec-butyl, tert-butyl, pentyl, hexyl, etc.), an aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-phenyl)
C _6-14 aryl groups such as indenyl and 2-anthryl, etc., preferably phenyl groups), 2-pyridyl, 3-pyridyl, 4-pyridyl, lower aralkyl groups (eg benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl) , 2-naphthylmethyl, 2-diphenylethyl, 3
- phenylpropyl, 4-phenylbutyl, etc. C _7-16 aralkyl group such as 5-phenyl-pentyl, it is preferred that preferably benzyl) phenacyl or nicotinoyl. Further, the aryl group, lower aralkyl group, phenacyl and nicotinoyl may be a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a lower alkylenedioxy group (eg, methylenedioxy, ethylene) at any position on the aromatic ring. A C _1-3 alkylenedioxy group such as dioxy), a nitro group, a cyano group, a lower alkyl group which may be halogenated, a lower alkoxy group which may be halogenated, and which may be halogenated A lower alkylthio group, a hydroxyl group, an amino group, a mono-lower alkylamino group (eg, a mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
Di-lower alkylamino groups (e.g., dimethylamino,
Di-C _1-6 alkylamino groups such as diethylamino, dipropylamino, dibutylamino, etc.), carboxyl groups, lower alkoxycarbonyl groups (eg, C _1-6 alkoxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) Or a carbamoyl group, or one or more (preferably 1 to 5, more preferably 1 to 3, and still more preferably 1 or 2) substituents selected from a carbamoyl group. . Examples of the above “optionally halogenated lower alkyl group”, “optionally halogenated lower alkoxy group” and “optionally halogenated lower alkylthio group” include, for example, the aforementioned Ar ¹ , A
Examples thereof include the same as those exemplified as the “substituent” of the “aromatic group which may have a substituent” represented by r ² and Ar ³ .

The “divalent” of the term “divalent aliphatic hydrocarbon group which may contain oxygen or sulfur in the carbon chain and may have a substituent” represented by Q ¹ and Q ² The term "aliphatic hydrocarbon group" refers to a group formed by removing one hydrogen atom (two in total) bonded to the same or different carbon atoms of a saturated or unsaturated aliphatic hydrocarbon, preferably 6 or less. Specifically (i) C _2-6 alkylene group _{(e.g., -CH 2 -, - (CH} 2) 2 -, - (CH 2) 3 -, - (CH 2)
_{4 -, - (CH 2)} 5 -, - (CH 2) 6 -, etc.), (ii) C _2-6 alkenylene group (e.g., -CH = CH -, - CH = CH-CH 2 -, - C
H ₂ -CH = CH-CH ₂ -,-(CH ₂ ) ₂ -CH = CH-CH ₂ -,-(CH ₂ ) _{2
-CH = CH- (CH 2) 2} -, - (CH 2) 3 -CH = CH-CH 2 - , etc.),
(iii) C _2-6 alkynylene group (for example,

Embedded image Are used. Preferably, a C _1-6 alkylene group,
Particularly preferred is a C _1-3 alkylene group. These groups may be substituted by oxygen or optionally oxidized may have good sulfur even or oxo or thioxo group in the carbon chain, for example, the formula - (CH ₂₎ a-
T- (CH ₂ ) m- wherein T is a bond, an oxygen atom or a sulfur atom which may be oxidized, and a and m are integers of 0 to 5 and the sum is 1 or more and 6 or less. Is shown. ]
The group represented by is preferred. Q ¹ and Q ² are each preferably a C _1-6 alkylene group _optionally having an oxo group, for example, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ )
_{4 -, - (CH 2)} 2 CO -, - CH 2 CO -, - CO- , and the like. The _{^{Q 1, -CH 2 -, -}} (CH 2) 2 -, - (CH 2) 3 -,
_{- (CH 2) 4 -,} - (CH 2) 2 CO -, - is preferable, CH ₂ CO- optionally C _1-4 alkylene group optionally having an oxo group represented by like, -CH ₂ - ,-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ )
₂ CO—, —CH ₂ CO— and the like are particularly preferred, and — (CH ₂ ) ₃ — and the like are widely used. The _{^{Q 2, -CH 2 -, -}} (CH 2) 2 -, -
(CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH ₂ ) ₂ CO−, −CH ₂ CO−, −C
Are preferred, such as _{O-, -CH 2 -, - (} CH 2) 2 -, - (CH 2)
_3- and the like are particularly preferable, and -CH _2- and the like are widely used.
Moreover, divalent aliphatic hydrocarbon group may contain an ether oxygen or sulfur in the carbon chain, and examples thereof -CH-O-CH -, - CH-O-CH-CH 2 - , -CH ₂ -CH-O-C
_{H-CH 2 -, - (} CH 2) 2 -CH-O-CH-CH 2 -, - (CH 2) 2 -CH
_{-O-CH- (CH 2) 2} -, - (CH 2) 3 -CH-O-CH-CH 2 -, - C
H-S-CH -, - CH-S-CH-CH 2 -, - CH 2 -CH-S-CH-
CH ₂ -,-(CH ₂ ) ₂ -CH-S-CH-CH ₂ -,-(CH ₂ ) ₂ -CH-S
—CH— (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —CH—S—CH—CH _{2 and the} like, and the sulfur atom may be sulfoxide or sulfone.

Formula

Embedded image The “optionally substituted monocyclic or condensed nitrogen-containing heterocyclic ring” represented by is, for example, a group which may have one or two unsaturated bonds, and may be any position other than N and Z. Represents a monocyclic 4- to 9-membered ring or a bicyclic 6- to 14-membered ring which may have one or two substituents, and the above-mentioned "optionally substituted monocyclic nitrogen-containing heterocyclic ring""Asthe" monocyclic nitrogen-containing heterocycle "

Embedded image Especially,

Embedded image Are commonly used. These monocyclic nitrogen-containing heterocycles have 3
To 10-membered cyclic hydrocarbon groups (eg, lower cycloalkanes (eg, C _3-8 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.), lower cycloalkenes (eg, cyclopropene, cyclopentene, cyclohexene, etc.) C _3-6 cycloalkene, etc.), aryl (eg, C
_6-10 aryl etc.) to form a bicyclic 6- to 14-membered fused nitrogen-containing heterocyclic ring. Among them, pyrrolidine, piperidine, azepine or a benzo condensate thereof, particularly piperidine Is preferred.

Examples of the substituent for the above monocyclic or condensed nitrogen-containing heterocyclic ring include a lower alkyl group which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, a C _1-6 alkyl group such as sec-butyl, tert-butyl, pentyl and hexyl), a lower alkoxy group which may have a substituent (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, Isobutoxy, sec-butoxy, tert-
C _1-6 alkoxy such as butoxy), lower alkylthio group which may have a substituent (for example, methylthio, ethylthio, propylthio, isopropylthio, n-
Butylthio, isobutylthio, sec-butylthio, tert-
A C _1-6 alkylthio group such as butylthio), a hydroxyl group, an amino group, a mono-lower alkylamino group (eg, methylamino, ethylamino, propylamino,
Mono-C _1-6 such as isopropylamino and butylamino
Alkylamino group), di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), lower alkylcarbonyl group (eg, acetyl, propionyl) C _1-6 alkyl such as - carbonyl group), a carboxyl group, lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl - carbonyl group), a carbamoyl group, Mono-lower alkylcarbamoyl groups (for example, mono-C such as methylcarbamoyl, ethylcarbamoyl, etc.)
_1-6 alkyl - such as carbamoyl group), di - lower alkylcarbamoyl group (e.g., dimethylcarbamoyl, -C _1-6 alkyl, such as diethylcarbamoyl - such as carbamoyl group), arylcarbamoyl group (e.g., phenylcarbamoyl, naphthylcarbamoyl C _6-10 aryl, such as - such as carbamoyl group), a sulfo group, a lower alkylsulfonyl group (e.g., a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl), an aryl group (e.g., phenyl, naphthyl, etc. A C _6-10 aryl group, an aryloxy group (eg, phenyloxy,
And C _6-10 aryloxy groups such as naphthyloxy).

"Lower alkyl group optionally having substituent (s)", "Lower alkoxy group optionally having substituent (s)"
And as the substituent on the "optionally substituted lower alkylthio group", a lower alkoxy group (for example,
Methoxy, ethoxy, propoxy, isopropoxy, n-
C _1-6 alkoxy such as butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., lower alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio)
A C _1-6 alkylthio group such as butylthio, tert-butylthio, etc.), a hydroxyl group, an amino group, a mono-lower alkylamino group (eg, mono-C such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) _1-6 alkylamino group), di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), lower alkylcarbonyl group (eg,
Acetyl, C _1-6 alkyl-carbonyl group such as propionyl, etc.), carboxyl group, lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), Carbamoyl group, mono-lower alkyl-carbamoyl group (eg, mono-C _1-6 such as methylcarbamoyl, ethylcarbamoyl, etc.)
Alkyl-carbamoyl group), di-lower alkylcarbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), arylcarbamoyl (eg, C _6- such as phenylcarbamoyl, naphthylcarbamoyl, etc.) ₁₀ arylcarbamoyl, etc.), sulfo group, alkylsulfonyl group (eg,
A C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), an aryl group (eg, phenyl,
C _6-10 aryl groups such as naphthyl and the like, and aryloxy groups (eg C _6-10 such as phenyloxy and naphthyloxy)
_6-10 aryloxy group).

Z is 1,2-phenylene which may be substituted;

Embedded image Wherein Ar ³ has the same meaning as described above, and n represents an integer of 0 to 3. A group represented by

Expression

Embedded image Wherein Ar ³ and n have the same meanings as above, and Y is a hydrogen atom, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, an optionally halogenated lower group Alkylthio group, hydroxyl group, cyano group, alkylcarbonyl group (for example, C _1-6 alkyl-carbonyl group such as acetyl and propionyl), lower alkylcarbonyloxy group (for example, C _1-6 such as acetyloxy and propionyloxy) Alkyl-carbonyloxy group, etc., formylamino group, amino group, mono-lower alkylamino group (for example, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) ), Di-lower alkylamino groups (eg, dimethylamino, diethyl Mino, dipropylamino, and di -C _1-6 alkylamino group such as dibutylamino)
A carboxyl group, a lower alkoxycarbonyl group (for example, a C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) or a lower alkylcarbonylamino group (for example, C 1 such as acetylamino or propionylamino _1-6 alkyl-carbonylamino group and the like (“optionally halogenated lower alkyl group”, “optionally halogenated lower alkoxy group”, and “optionally halogenated lower alkylthio group”). ] Has the same meaning as that exemplified as the “substituent” of the “optionally substituted aromatic group” represented by Ar ¹ , Ar ² and Ar ³ ). (Y is preferably a hydrogen atom, a hydroxyl group, a cyano group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group, and among them, a hydrogen atom, a hydroxyl group, An amino group and a mono-C _1-6 alkylamino group are preferred, and a hydrogen atom and a hydroxyl group are particularly preferred, and a hydroxyl group is commonly used.),

Formula

Embedded image [Wherein Ar ³ and n have the same meanings as described above. Or a group represented by the formula

Embedded image [Wherein Ar ³ and n have the same meanings as described above. And the like represented by

The above n is preferably an integer of 0 to 2, more preferably 0 or 1, and particularly preferably 0.
As preferred Z in the above, for example, the formula

Embedded image [In the formula, Ar ³ and n have the same meanings as described above, and Y represents a hydrogen atom or a hydroxyl group (preferably a hydroxyl group). ]. Further, a formula in the case where Z is 1,2-phenylene

Embedded image Examples of the ring represented by

Embedded image Etc., among others,

Embedded image Is preferred.

Z is

Embedded image [In the formula, Ar ³ and n have the same meanings as described above, and Y represents a hydrogen atom or a hydroxyl group (preferably a hydroxyl group). ]

Embedded image The most preferred example of the ring represented by the formula is

Embedded image [Wherein Ar ³ has the same meaning as described above. And the like.

The substituent on the above-mentioned "1,2-phenylene" includes the above-mentioned "aromatic group which may have a substituent".
And the same substituents as mentioned above. Preferred examples include, for example, a halogen atom (particularly preferably, fluorine,
Chlorine), lower alkylenedioxy group (eg, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), nitro group, cyano group, lower alkyl group which may be halogenated, halogenated And a lower alkoxy group which may be substituted. The above “optionally halogenated lower alkyl group” and “optionally halogenated lower alkoxy group” include, for example, “having a substituent represented by Ar ¹ , Ar ² and Ar ³ described above. And the same as those exemplified as the "substituent" of the "aromatic group which may be substituted".

In the above-mentioned receptor antagonist (I) or a salt thereof, Q ¹ represents —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —,
— (CH ₂ ) ₄ — or — (CH ₂ ) ₂ CO—, and Q ² represents —CH ₂
−, − (CH ₂ ) ₂ −, − (CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, −CO
—, —CH ₂ CO— or — (CH ₂ ) ₂ CO—, wherein Ar ¹ and Ar ² are each independently phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4 -Represents pyridyl and has the formula

Embedded image Is a group represented by

Embedded image [Where Z is the formula

Embedded image [Wherein, Ar ³ is a C _1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C _1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms or halogen. A phenyl group optionally substituted with an atom (preferably chlorine, fluorine, etc.)
4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 4-trifluoromethylphenyl, etc.), 2-pyridyl, 3-pyridyl or 4-pyridyl, n represents an integer of 0 to 3. ],

Embedded image Wherein Ar ³ and n are as defined above, and Y is a hydrogen atom, a hydroxyl group, an amino group or mono-C _1-6
It represents an alkylamino group (particularly, a hydrogen atom and a hydroxyl group are preferable). ] Or

Embedded image [Wherein, Ar ³ and n are as defined above. R ¹ represents a hydrogen atom or methyl;

R ² may be substituted by (1) (i) a C _1-6 alkoxy-carbonyl group, (ii) a carboxyl group, (iii) a C _1-6 alkyl-carbonyl group or (iv) a formyl group. A good C _1-6 alkyl group, or (2)-(C =
_{^{O) -R 4, -SO 2 -R}} 4, -SO-R 4, - (C = O)
An acyl group represented by NR ⁵ R ⁴ or — (C ＝ O) O—R ⁴ , wherein R ⁵ represents a hydrogen atom or a C _1-3 alkyl group such as methyl, ethyl, propyl, and isopropyl;
R ⁴ is a hydrogen atom, a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
a C _1-6 alkyl group such as sec-butyl, tert-butyl, pentyl, hexyl, etc., a lower alkenyl group (eg, a C _2-6 alkenyl group such as vinyl, allyl, isopropenyl group, etc.), a lower alkylcarbonyl group (Eg, C _1-6 alkyl-carbonyl such as acetyl, propionyl, butyryl, etc.), carboxyl, lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) Such),
A mono-lower alkylaminocarbonyl group (for example, a mono-C _1-6 alkyl-aminocarbonyl group such as methylaminocarbonyl, ethylaminocarbonyl, propylaminoarbonyl, butylaminocarbonyl, etc.);
Lower alkylaminocarbonyl group (e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylamino arbovirus sulfonyl, di -C _1-6 alkyl, such as dibutyl aminocarbonyl - such as an amino group), C
Compounds representing a _6-10 aryl group (preferably phenyl) or a 5- to 7-membered cyclic amino group (preferably 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl, etc.) preferable.

The “lower alkyl group”, “lower alkenyl group”, “lower alkylcarbonyl group”, “carboxyl group”, “lower alkoxycarbonyl group”, “mono-lower alkylaminocarbonyl group” represented by R ⁴ described above. , A "di-lower alkylaminocarbonyl group" and a "5- to 7-membered cyclic amino group" may have 1 to 3 "substituents" at any carbon atom thereof. Are, for example, (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (eg, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.) Iii) nitro group, (iv) cyano group, (v) (1)
A halogen atom, (2) a C _1-3 alkylenedioxy group,
(3) nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) A C _1-6 alkylthio group optionally having 1 to 3 halogen atoms,
(8) hydroxyl group, (9) amino group, (10) mono-C
_1-6 alkylamino group, (11) di -C _1-6 alkylamino group, (12) C _1-6 alkyl - carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy - carbonyl group,
(15) carbamoyl group, (16) mono-C _1-6 alkyl-
Carbamoyl group, (17) di-C _1-6 alkylcarbamoyl group, (18) C _6-10 aryl-carbamoyl group, (19)
Sulfo group, (20) C _1-6 alkylsulfonyl group, (21)
5- to 7-membered members containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to C _6-10 aryl group, (22) C _6-10 aryloxy group and (23) carbon atom A C _1-6 alkyl group which may be substituted with a substituent represented by a heterocyclic group or a benzo condensate thereof, (v
i) a C _3-6 cycloalkyl group, (vii) an optionally halogenated lower alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoromethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,
Optionally halogenated C such as hexyloxy
_1-6 alkoxy group), (viii) lower alkylthio group which may be halogenated (for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
An optionally halogenated C _1-6 alkylthio group such as 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.), (ix) a C _7-16 aralkyl group,
(X) hydroxyl group, (xi) amino group, (xii) mono-
Lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xii
i) di-lower alkylamino groups (eg dimethylamino,
Di-C _1-6 alkylamino groups such as diethylamino, dipropylamino, dibutylamino, etc.), (xiv) 5 to 7 which may have a hydroxyl group or an oxo group.
Membered cyclic amino groups (eg, morpholino, piperazine-1
-Yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidin-1-yl, 2-pyridin-1-yl and the like),
(Xv) (1) halogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) 1-3 C _1-6 alkoxy group optionally having two halogen atoms, (7) 1-3
Halogen atoms a C _1-6 alkylthio group optionally having, (8) hydroxyl group, (9) amino group, (10) mono -C _1-6 alkylamino group, (11) di -C _{1 -6} alkylamino group, (12) C _1-6 alkyl-carbonyl group, (1
3) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (17) di-C _1-6 alkyl-carbamoyl group , (18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10 aryl group, (22) C _6-10 aryloxy group And (23) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent represented by a benzo condensate thereof. Lower alkylcarbonyl groups (eg, acetyl, propionyl, etc.)
_1-6 alkyl-carbonyl group), (xvi) carboxyl group, (xvii) lower alkoxycarbonyl group (eg, C _1-6 alkoxy- such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl).
Carbonyl group), (xviii) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzocondensate thereof. A formyl group, (xi
x) carbamoyl group, (xx) (1) halogen atom, (2)
C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) C which may have 1 to 3 halogen atoms _1-6 alkoxy group, (7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (8) hydroxyl group,
(9) amino group, (10) mono-C _1-6 alkylamino group,
(11) di-C _1-6 alkylamino group, (12) C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C
_1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, (1
7) di-C _1-6 alkyl-carbamoyl group, (18) C _6-10
Aryl-carbamoyl group, (19) sulfo group, (20) C
_1-6 alkylsulfonyl group, (21) C _6-10 aryl group,
(22) a C _6-10 aryloxy group and (23) one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the carbon atom
A mono-lower alkylcarbamoyl group which may be substituted with a 5- to 7-membered heterocyclic group containing 3 to 3 heteroatoms or a substituent represented by a benzo condensate thereof (for example, a mono-lower alkylcarbamoyl group such as methylcarbamoyl -C
_1-6 alkyl - such as carbamoyl group), (xxi) (1) a halogen atom, (2) C _1-3 alkylenedioxy group, (3)
Nitro group, (4) cyano group, (5) C _3-6 cycloalkyl group, (6) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (7) 1 to 3 halogen atoms a C _1-6 alkylthio group optionally having, (8) hydroxyl group, (9) amino group, (10) mono -C _1-6 alkylamino group, (11) di -C _{1 -6} alkylamino group, (1
2) C _1-6 alkyl-carbonyl group, (13) carboxyl group, (14) C _1-6 alkoxy-carbonyl group, (15) carbamoyl group, (16) mono-C _1-6 alkyl-carbamoyl group, 17) di-C _1-6 alkyl-carbamoyl group,
(18) C _6-10 aryl-carbamoyl group, (19) sulfo group, (20) C _1-6 alkylsulfonyl group, (21) C _6-10
An aryl group, a (22) C _6-10 aryloxy group and (2
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent represented by a benzo condensate thereof; which may di - lower alkylcarbamoyl group (e.g., dimethylcarbamoyl, -C _1-6 alkyl such as diethylcarbamoyl - such as carbamoyl group),
(Xxii) arylcarbamoyl (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiii) sulfo group, (xxiv) lower alkylsulfonyl group (eg, C ₁ such as methylsulfonyl, ethylsulfonyl, etc.) _-6 alkylsulfonyl group),
(Xxv) aryl groups (for example, C _6-10 aryl groups such as phenyl and naphthyl), (xxvi) aryloxy groups (for example, C _6-10 such as phenyloxy and naphthyloxy)
_6-10 an aryloxy group), (xxvii) a sulfamoyl group, (xxviii) mono - lower alkyl sulfamoyl group (e.g., mono--C _1-6 alkylsulfamoyl such as methylsulfamoyl, ethylsulfamoyl etc. groups), (xxix) di - lower alkylsulfamoyl group (e.g., dimethylsulfamoyl, di -C _1-6 alkyl, such as diethylsulfamoyl - sulfamoyl group), (xxx) a lower alkoxy carbamoyl group ( For example, C _1-6 alkoxy-carbamoyl groups such as methoxycarbamoyl, ethoxycarbamoyl and the like) and (xxx
i) carbamoyloxy group and the like.

More preferably, Q ¹ is -CH ₂ -,-(CH
₂ ) _2- or-(CH ₂ ) _3- , and Q ² represents -CH ₂ -,-(C
_{H 2) 2 -, - (} CH 2) 3 -, - CH 2 CO- or - (CH _{2) 2} CO- indicates, independently Ar ¹ and Ar ² are each a phenyl or 2-pyridyl, formula

Embedded image Is a group represented by

Embedded image [Where Z is the formula

Embedded image [In the formula, 1 to 3 Ar ³ (preferably 1 or 2
) Halogen atoms (preferably chlorine, fluorine, etc.)
A phenyl group (for example, phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,
5-dichlorophenyl or 3,5-difluorophenyl) or 2-pyridyl, and n represents 0. ],

Embedded image [Wherein, Ar ³ and n have the same meanings as described above, and Y represents a hydrogen atom or a hydroxyl group. ] Or

Embedded image [Wherein, Ar ³ and n are as defined above. R ¹ represents a hydrogen atom or methyl, R ² represents — (C ＝ O) —R ⁴ , — (C ＝ O) NR ⁵ R ⁴ or — (C ＝ O) Represents an acyl group represented by OR ⁴ ,

R ⁵ represents a hydrogen atom, R ⁴ represents a hydrogen atom, a lower alkyl group which may be substituted (for example, methyl,
A C _1-6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), a carboxyl, a lower alkoxycarbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy-carbonyl group such as butoxycarbonyl), phenyl or 1-piperazinyl, and the above-mentioned “lower alkyl group” represented by R ⁴ is
The carbon atom may have one “substituent” at any carbon atom. Examples of the “substituent” include a hydroxyl group, an amino group, a di-lower alkylamino group (eg, dimethylamino, diethylamino, A di-C _1-6 alkylamino group such as dipropylamino and dibutylamino), a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl, Piperidino, pyrrolidin-1-yl, 2-
Pyrrolidone-1-yl, 2-pyridone-1-yl and the like), lower alkylcarbonyl groups (eg, C _1-6 alkyl-carbonyl groups such as acetyl and propionyl),
Carboxyl group, lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), sulfamoyl group, mono-lower alkylsulfamoyl group (for example, methylsulfur Mono-C _1-6 alkylsulfamoyl groups such as famoyl and ethylsulfamoyl, and di-lower alkylsulfamoyl groups (eg, di-C _1- alkyl groups such as dimethylsulfamoyl and diethylsulfamoyl). ₆ alkylsulfamoyl group and the like).

Particularly preferably, Q ¹ represents — (CH ₂ ) ₃ —, Q ² represents —CH ₂ — or — (CH ₂ ) ₂ —, Ar ¹ represents phenyl or 2-pyridyl, ² represents phenyl;

Embedded image Is a group represented by the formula

Embedded image [Where Z is the formula

Embedded image [Wherein, Ar ³ represents 4-chlorophenyl, n represents 0, and Y represents a hydrogen atom or a hydroxyl group. ] Is shown. R ¹ represents a hydrogen atom, R ² represents — (C ＝ O) —R ⁴ , — (CＣO) NR ⁵ R ⁴ or — (C ＝ O) O—R Represents an acyl group represented by ⁴ ,

R ⁵ represents a hydrogen atom, and R ⁴ represents (1) a hydrogen atom or (2) a 5- to 7-membered cyclic amino which may have (a) a hydroxyl group, (b) a hydroxyl group or an oxo group. Group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidone-1-yl, 2-pyridin-1-yl, etc.) and (c) a sulfamoyl group, A lower alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
a C _1-6 alkyl group such as c-butyl, tert-butyl, pentyl and hexyl). Further, as preferred receptor antagonists, Ar ¹ and Ar ² are the same or different and phenyl, 4-chlorophenyl,
-Fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein Q ¹ is a C _1-4 alkylene group, Q ²
Are each a methylene group, and the formula

Embedded image The ring represented by

Embedded image And Z is the formula

Embedded image [In the formula, Ar ³ represents a phenyl group which may be substituted with a halogen atom, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. And R ¹ is a hydrogen atom or methyl;

R ² is (1) (a) a C _1-6 alkoxy-carbonyl group, (b)
A carboxyl group, (c) a C _1-6 alkyl-carbonyl group or (d) an alkyl group which may be substituted with a formyl group, or (2) a formula — (C ＝ O) —R ⁴ , —SO ₂ —R ⁴ ,-(C =
O) NR ⁵ R ⁴ or — (C ＝ O) O—R ^{4 wherein} R ⁴ is (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) a C _1-6 alkyl-carbonyl group An amino group optionally substituted with
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group, (f) C
_1-6 alkoxy-carbonyl group, (g) mono-C _1-6 alkylcarbamoyl group, (h) sulfo group optionally substituted with amino group, (i) optionally substituted with hydroxyl group, oxo A 5- to 7-membered cyclic amino group which may have a group, (j) a C _1-6 alkoxy-carbamoyl group and (k) a carbamoyloxy group having 1 to 5 substituents at substitutable positions. C that may be
_1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _6-10 aryl group, (v) one or two kinds selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom A 5- to 11-membered heterocyclic group containing at least one hetero atom or a benzo-fused ring thereof, (vi) a C _1-6 alkyl group optionally substituted with a C _1-6 alkyl-carbonyl group, (vii) a C _1-6 alkyl group. _A carboxyl group which may be substituted with a _1-6 alkyl group, (viii)

(A) One or three types selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or a carbon atom A 5- to 7-membered heterocyclic group containing at least one hetero atom or a C _1-6 alkyl group optionally substituted with a benzo-fused ring thereof, (b) a C _7-16 aralkyl group, (c) a halogen atom, A C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom
A 5- to 7-membered heterocyclic group containing at least one kind or three kinds of heteroatoms or a C _1-6 alkyl-carbonyl group which may be substituted by a benzo-fused ring thereof, (d) a C _1-6 alkoxy-carbonyl A group, (e) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof. Formyl group, (f) mono-C _1-6 alkyl-carbamoyl group optionally substituted by halogen atom or C _1-6 alkyl-carbonyl group, (g) C _6-10 aryl optionally halogenated Rucarbamoyl group, (h) optionally halogenated C
_{A 6-10} aryl group and (i) a 5- to 7-membered cyclic amino group optionally having a substituent selected from a C _1-6 alkoxy-carbamoyl group or (ix) a C _6-10 aryloxy group, R ⁵ represents a hydrogen atom or a C _1-6 alkyl group], and an acyl group represented by the following formula:

More preferably, Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, and Q ¹ is C _1-4. An alkylene group and Q ² are each a methylene group;

Embedded image The ring represented by

Embedded image And Z is the formula

Embedded image [In the formula, Ar ³ represents a phenyl group which may be substituted with a halogen atom, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. And R ¹ is a hydrogen atom or methyl;

R ² is a group represented by the formula — (C ＝ O) —R ⁴ , —SO ₂ —
^{R 4, - (C = O} ) NR 5 R 4 or - (C = O) O- R 4
[Wherein R ⁴ is the formula (1)

Embedded image Or (2)

Embedded image [Wherein, R ⁶ and R ⁷ are the same or different from each other; (a) a hydrogen atom, (b) a (b-1) hydroxyl group, and (b-2) a di-C
_A nitrogen atom other than a _1-6 alkylamino group, a (b-3) C _1-6 alkoxy-carbonyl group and a (b-4) carbon atom,
A 5- or 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom, or a C-substituted group which may be substituted with a substituent selected from a benzo condensate thereof;
_1-6 alkyl group, (c) _C7-16 aralkyl group (d) (d-1) halogen atom, (d-2) mono-C
_1-6 alkylamino group (d-3) containing a C _1-6 alkoxy-carbonyl group and (d-4) 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom C-substituted or substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof
_1-6 alkyl-carbonyl group,

(E) a C _1-6 alkoxy-carbonyl group, (f) a 5- to 7-membered heterocyclic ring containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A group or a formyl group which may be substituted with a benzo condensate thereof, (g) (g-1) a halogen atom and (g-2) C _1-6
A mono-C _1-6 alkyl-carbamoyl group which may be substituted with a substituent selected from an alkyl-carbonyl group, (h) a C _6-10 aryl-carbamoyl group which may be halogenated, (i) halogen An optionally _substituted C _6-10 aryl-carbonyl group or (j) a C _6-10 aryloxy group. R ⁵ represents a hydrogen atom or a C _1-6 alkyl group. And the like. A receptor antagonist which is an acyl group represented by the formula:

In the compound (II) or a salt thereof, Q ¹ is —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, or — (CH ₂ ) ₄
-Or-(CH ₂ ) ₂ CO-, and Q ² represents -CH ₂ -,-(CH ₂ ) _{2
-, - (CH 2) 3} -, - (CH 2) 4 -, - CO -, - CH 2 CO- or - (CH _{2) 2} CO- indicates, independently Ar ¹ and Ar ² are each, Phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, wherein Ar ³ is (1) (a) a C ₁ which may be substituted by 1 to 3 halogen atoms; _-3 alkyl group, (b)
C which may be substituted by 1 to 3 halogen atoms
_1-3 alkoxy group or (c) a phenyl group optionally substituted with a halogen atom (preferably chlorine, fluorine or the like) (for example, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 3, 5-dichlorophenyl, 3,5-difluorophenyl, 4-trifluoromethylphenyl) or (2) 2-pyridyl,
Represents 3-pyridyl or 4-pyridyl, wherein R ² is-(C
_{^{= O) -R 4, -SO 2}} -R 4, -SO-R 4, - (C =
O) represents an acyl group represented by NR ⁵ R ⁴ or — (C ＝ O) O—R ⁴ , and R ⁵ represents a hydrogen atom or a C _1-3 alkyl group such as methyl, ethyl, propyl, and isopropyl. , R ⁴ is (i) a hydrogen atom, (ii) a lower alkyl group which may be substituted (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) a C _1-6 alkyl group), (iii) an optionally substituted lower alkylcarbonyl group (e.g., acetyl, propionyl, C _1-6 alkyl, such as butyryl - carbonyl), (iv) carboxyl, (v) An optionally substituted lower alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
C _1-6 alkoxy such as butoxycarbonyl - carbonyl group), (vi) optionally substituted mono - lower alkylamino group (e.g., methylaminocarbonyl, ethylaminocarbonyl, propylamino arbovirus alkenyl, butylaminocarbonyl mono -C _1-6 alkyl such - such as an amino group), optionally substituted (vii) di - lower alkylamino group (e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylamino arbovirus sulfonyl, dibutylamino A di-C _1-6 alkyl-aminocarbonyl group such as carbonyl), (viii) a C _6-10 aryl group (preferably phenyl), or (ix) an optionally substituted 5- to 7-membered cyclic amino group ( Preferably 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl and the like) are preferable,

The “lower alkyl group”, “lower alkyl-carbonyl group”, “lower alkoxy-carbonyl group”, “mono-lower alkylaminocarbonyl group”, “di-lower alkylaminocarbonyl group” represented by R ⁴ described above. "And" 5- to 7-membered cyclic amino group "may have 1 to 3" substituents "at any carbon atom thereof. Examples of the" substituent "include (i) halogen atom (For example, fluorine, chlorine, bromine, iodine, etc.),
(Ii) a lower alkylenedioxy group (for example, a C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy), (iii) a nitro group, (iv) a cyano group,
(V) an optionally halogenated lower alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoromethoxy, propoxy, isopropoxy, butoxy, 4,4,4
-Trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like, and an optionally halogenated C _1-6 alkoxy group), (vi) an optionally halogenated lower alkylthio group (for example, Optionally halogenated C _1-6 alkylthio groups such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.), (Vii) hydroxyl group, (viii) amino group, (ix) mono-lower alkylamino group (eg, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) ), (X) di-lower alkylamino groups (eg, dimethyl Mino, diethylamino, dipropylamino, di -C such dibutylamino
_1-6 alkylamino group), (xi) a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidone-1
-Yl, 2-pyridone-1-yl and the like), (xii) an acylamino group (for example, the "acylamino group" may have a substituent represented by Ar ¹ , Ar ² and Ar ³⁾ Examples of the same as the “acylamino group” described in detail as the “substituent” of the “good aromatic group” include, preferably, —NHCOOR ³ , —NHCONHR ³ , and —NHCO ³ .
R ³ (R ³ is a lower alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
C such as butyl, tert-butyl, pentyl and hexyl
_1-6 alkyl group or the like or lower alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert
-C _1-6 alkoxy group such as butoxy). )
It is. ), (Xiii) a lower alkyl-carbonyl group (eg, C _1-6 alkyl such as acetyl, propionyl, etc.)
Carbonyl group), (xiv) carboxyl group, (xv)
Lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xvi) carbamoyl group, (xvii) mono-lower alkylcarbamoyl group (eg, methyl A mono-C _1-6 alkyl-carbamoyl group such as carbamoyl and ethylcarbamoyl); (xiii) a di-lower alkylcarbamoyl group (eg, a di-C _1-6 alkyl-carbamoyl group such as dimethylcarbamoyl and diethylcarbamoyl) ,
(Xix) arylcarbamoyl (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xx) sulfo group, (xxi) lower alkylsulfonyl group (eg, C ₁ such as methylsulfonyl, ethylsulfonyl, etc.) _-6 alkylsulfonyl group), (xxi
i) aryl groups (for example, C such as phenyl, naphthyl, etc.)
_6-10 aryl group, etc.), (xxiii) aryloxy group (for example, phenyloxy, naphthyloxy, etc.
_6-10 aryloxy group, etc.), (xxiv) sulfamoyl group, (xxv) mono-lower alkylsulfamoyl group (for example, mono-C _1-6 alkylsulfamoyl such as methylsulfamoyl, ethylsulfamoyl and the like) Group), (x
xvi) di-lower alkylsulfamoyl groups (for example, di-C _1-6 alkylsulfamoyl groups such as dimethylsulfamoyl and diethylsulfamoyl) and the like.

More preferably, Q ¹ is -CH ₂ -,-(C
H ₂ ) _2- or-(CH ₂ ) _3- , and Q ² represents -CH ₂ -,-(C
_{H 2) 2 -, - (} CH 2) 3 -, - CH 2 CO- or - (CH _{2) 2} CO- indicates, independently Ar ¹ and Ar ² are each a phenyl or 2-pyridyl, Ar ³ has 1 to 3 (preferably 1 or 2) halogen atoms (preferably chlorine,
A phenyl group (for example, phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl) or 2-pyridyl which may be substituted with R ² , 1)
(I) C _1-6 alkoxy - carbonyl group, (ii) a carboxyl group, (iii) C _1-6 alkyl - carbonyl group or (iv) a C _1-6 alkyl group optionally substituted by a formyl group or, (2) - (C = O ) -R 4, - (C = O)
An acyl group represented by NR ⁵ R ⁴ or — (C ＝ O) O—R ⁴ , R ⁵ represents a hydrogen atom, R ⁴ represents a hydrogen atom, a lower alkyl group which may be substituted (for example, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
C _1-6 alkyl groups such as sec-butyl, tert-butyl, pentyl, hexyl, etc.), carboxyl, lower alkenyl groups (eg, C _2-6 alkenyl groups such as vinyl, allyl, isopropenyl, etc.), lower alkoxy- A compound showing a carbonyl group (for example, a C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), phenyl or 1-piperazinyl,

The above-mentioned "lower alkyl group" represented by R ⁴ may have a "substituent" of 1 to 3 at any carbon atom.
The “substituent” may be, for example, a hydroxyl group, an amino group, a di-lower alkylamino group (eg, di-C ₁ such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.). _-6 alkylamino group), a 5- to 7-membered cyclic amino group optionally having a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, 2-pyrrolidone- 1-yl, 2-pyridone-1-yl, etc.), as an acylamino group ( "acylamino ^group", -NHCOOR 3, -NHCONHR ^3,
-NHCOR ³ (R ³ is a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) or a lower alkoxy group (For example, C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.). ), Lower alkyl-carbonyl groups (eg, C _1-6 alkyl-carbonyl groups such as acetyl, propionyl and the like), carboxyl groups, lower alkoxy-carbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) A C _1-6 alkoxy-carbonyl group),
A sulfamoyl group, a mono-lower alkylsulfamoyl group (eg, a mono-C _1-6 alkylsulfamoyl group such as methylsulfamoyl and ethylsulfamoyl), a di-lower alkylsulfamoyl group (eg, Di-C _1-6 alkylsulfamoyl groups such as dimethylsulfamoyl and diethylsulfamoyl), and the like.

Particularly preferably, Q ¹ represents — (CH ₂ ) ₃ —, Q ² represents —CH ₂ — or — (CH ₂ ) ₂ —, Ar ¹ represents phenyl or 2-pyridyl, ² represents phenyl, Ar ³ represents 4-chlorophenyl, n represents 0, Y represents a hydrogen atom or a hydroxyl group, and R ² represents — (C ＝ O)
^{-R 4, - (C = O} ) NR 5 R 4 or - (C = O) O-
An acyl group represented by R ⁴ , R ⁵ represents a hydrogen atom,
R ⁴ is (1) a hydrogen atom or (2) a 5- to 7-membered cyclic amino group optionally having (a) a hydroxyl group, (b) a hydroxyl group or an oxo group (for example, morpholino, piperazin-1-yl , Piperidino, pyrrolidine-
1-yl, 2-pyrrolidone-1-yl, 2-pyridone-
1-yl or the like and (c) a lower alkyl group optionally having one substituent selected from a sulfamoyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , pentyl, compound a, C _1-6 alkyl group), such as hexyl. Further, Ar ¹ is preferable as the compound (II).
And Ar ² are the same or different and phenyl,
4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, Q ¹ is a C _1-4 alkylene group, Q ² is a methylene group,
R ² is (1) (a) a C _1-6 alkoxy-carbonyl group, (b)
A carboxyl group, (c) an alkyl group which may be substituted with a C _1-6 alkyl-carbonyl group or (d) formyl group, or

(2) Formula-(C = O) -R ⁴ , -SO ₂ -R
^{4, - (C = O)} NR 5 R 4 or - (C = O) O- R
^{4 wherein} R ⁴ represents (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) an amino group optionally substituted with a C _1-6 alkyl-carbonyl group,
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group, (f) C
_1-6 alkoxy-carbonyl group, (g) mono-C _1-6 alkyl-carbamoyl group, (h) sulfo group optionally substituted with amino group, (i) optionally substituted with hydroxyl group, 5 which may have an oxo group to 7-membered cyclic amino group, (j) C _1-6 alkoxy - 1 to 5 at substitutable positions a substituent selected from carbamoyl groups and (k) carbamoyloxy group C that you may have
_1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _6-10 aryl group, (v) one or two kinds selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom A 5- to 11-membered heterocyclic group containing at least one hetero atom or a benzo-fused ring thereof, (vi) a C _1-6 alkyl group optionally substituted with a C _1-6 alkyl-carbonyl group, (vii) a C _1-6 alkyl group. _A carboxyl group optionally substituted by a _1-6 alkyl group, (viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or a nitrogen atom other than a carbon atom; A C _1-6 alkyl group which may be substituted with a 5- to 7-membered heterocyclic group containing at least one kind of one or three hetero atoms selected from an oxygen atom and a sulfur atom or a benzo-fused ring thereof,

(B) C _7-16 aralkyl group, (c) halogen atom, mono-C _1-6 alkylamino group, C _1-6 alkoxy-carbonyl group or nitrogen atom, oxygen atom and sulfur atom other than carbon atom A C _1-6 alkyl- which may be substituted by a 5- to 7-membered heterocyclic group containing at least one kind of one or three kinds of hetero atoms or a benzo-fused ring thereof.
A carbonyl group, (d) a C _1-6 alkoxy-carbonyl group, (e) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom 5
A 7-membered heterocyclic group or a formyl group optionally substituted with a benzo condensate thereof, (f) a mono-C _1-6 alkyl optionally substituted with a halogen atom or a C _1-6 alkyl-carbonyl group. A carbamoyl group, (g) an optionally halogenated C _6-10 aryl-carbamoyl group, (h) an optionally halogenated C _6-10 aryl-carbonyl group, and (i) a C _1-6 alkoxy. A 5- to 7-membered cyclic amino group which may have a substituent selected from a carbamoyl group or (ix) a C _6-10 aryloxy group, and R ⁵ represents a hydrogen atom or a C _1-6 alkyl group And a compound in which Ar ³ is a phenyl group which may be substituted with a halogen atom. More preferably, Ar ¹ and Ar ² are the same or different, respectively. Nil, 4-chlorophenyl, 4-fluorophenyl,
2-pyridyl, 3-pyridyl or 4-pyridyl, Q ¹ is a C _1-4 alkylene group, Q ² is each a methylene group, and R ² is (1) (a) a C _1-6 alkoxy-carbonyl group , (B)
A carboxyl group, (c) an alkyl group which may be substituted with a C _1-6 alkyl-carbonyl group or (d) formyl group, or

(2) Formula-(C = O) -R ⁴ , -SO ₂ -R
^{4, - (C = O)} NR 5 -R 4 or - (C = O) O- R 4
[Wherein R ⁴ is the formula (1)

Embedded image Or (2)

Embedded image [Wherein, R ⁶ and R ⁷ are the same or different from each other; (a) a hydrogen atom, (b) a (b-1) hydroxyl group, and (b-2) a di-C
_A nitrogen atom other than a _1-6 alkylamino group, a (b-3) C _1-6 alkoxy-carbonyl group and a (b-4) carbon atom,
A 5- or 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom, or a C-substituted group which may be substituted with a substituent selected from a benzo condensate thereof;
_1-6 alkyl group, (c) _C7-16 aralkyl group (d) (d-1) halogen atom, (d-2) mono-C
_1-6 alkylamino group (d-3) containing a C _1-6 alkoxy-carbonyl group and (d-4) 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom C-substituted or substituted with a substituent selected from a 5- to 7-membered heterocyclic group or a benzo condensate thereof
_1-6 alkyl-carbonyl group, (e) C _1-6 alkoxy-carbonyl group, (f) 5 to 5 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom. A formyl group optionally substituted with a 7-membered heterocyclic group or a benzo condensate thereof,

(G) (g-1) A halogen atom and (g
-2) a mono-C _1-6 alkyl-carbamoyl group optionally substituted with a substituent selected from a C _1-6 alkyl-carbonyl group, (h) an optionally halogenated C _6-10 aryl- A carbamoyl group, (i) a C _6-10 aryl-carbonyl group which may be halogenated, or (j) a C _6-10 aryloxy group. And R ⁵ represents a hydrogen atom or a C _1-6 alkyl group]
Wherein Ar ³ is a phenyl group which may be substituted with a halogen atom. Preferred compounds include the following. 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1-formylamino-2,2-diphenylpentane hydrochloride, 5- [4- (4-fluorophenyl)
-Piperazin-1-yl] -1-formylamino-2,2-
Diphenylpentane dihydrochloride, 7- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1-formylamino-2,2-diphenylheptane hydrochloride, 1- [5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentyl] -3- (3-hydroxypropyl) urea hydrochloride, 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (4-Hydroxybutyl) urea hydrochloride, 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3-
(3-diethylaminopropyl) urea, 2- [3- [5-
[4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] ureido] ethanesulfonamide hydrochloride, N- [5- [4- (4-chlorophenyl) -4-hydroxypyridino] Peridino] -2,2-diphenyl] pentylmalonamic acid,

N- [5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2,2-diphenyl] pentylglutamic acid, N- [5- [4- (4-chlorophenyl)
-4-Hydroxypiperidino] -2-phenyl-2- (2-
Pyridyl)] pentylsuccinamic acid, 1- [5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentyl] -3- (piperidine-4-
Yl) urea, ethyl 4- [4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylaminopiperidino] -4-oxobutyrate, N-ethyl-4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, N-ethoxycarbonylmethyl-4
-[5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, 3- [4-
Ethyl [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-3-oxopropionate, 1- [5- [4- (4 -Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3-
(1-ethylpiperidin-4-yl) urea, 1-[(piperidin-4-yl) carboxamide] -5- [4- (4-
Chlorophenyl) -4-hydroxypiperidino] -2,2-
Diphenylpentane, 1-[[(N-ethylcarbamoyl) piperidin-4-yl] carboxamide] -5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentane,

1-[[N- (ethoxycarbonylacetyl) piperidin-4-yl] carboxamide] -5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentane or 1-[[N- (3-methoxycarbonylpropionyl) piperidin-4-yl]
Carboxamide] -5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2,2-diphenylpentane or a salt thereof. Among them, 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (piperidin-4-yl) urea, 4- [4- [ Ethyl 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-4-oxobutyrate, N-ethyl-4- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, N-ethoxycarbonylmethyl-4- [5-
[4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, 3- [4- [5-
Ethyl [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-3-oxopropionate,

1- [5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2,2-diphenylpentyl] -3- (1-ethylpiperidin-4-yl) urea, 1
-[(Piperidin-4-yl) carboxamide] -5-
[4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane salt, 1-[[(N-ethylcarbamoyl) piperidin-4-yl] carboxamide] -5- [4- ( 4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane, 1-[[N-
(Ethoxycarbonylacetyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane or 1-[[N- (3-methoxy Carbonylpropionyl) piperidin-4-yl] carboxamide] -5
-[4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane or a salt thereof is preferred. The above-mentioned compound may be any of a free form, a salt, a hydrate and the like. Compound (I) or a salt thereof (hereinafter simply referred to as compound (I)), compound (II)
Alternatively, various methods for producing a salt thereof (hereinafter, simply referred to as compound (II)) can be considered, and typical examples thereof are shown below.
In the following description of the production method, the starting compound and the reaction product may form a salt that does not hinder the reaction.

Production method-1

Embedded image (In the above formula, L represents a leaving group, and other symbols have the same meanings as described above.) The reaction is a usual alkylation reaction of an amino group [eg, organic functional group preparations (ORGANIC FUNCTIONAL GROUP PREPARATIONS)]. Second
Edition, Method described in Academic Press, INC.]. The leaving group L includes a halogen atom (preferably chloro, bromo, iodo), a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a benzenesulfonyloxy group and the like. The reaction is carried out by stirring at room temperature to 100 ° C (preferably room temperature to 50 ° C) for 0.5 to 1 day in an inert solvent. Usually 1 to 3 equivalents of base are added, but this is not necessary. As an inert solvent, an alcohol solvent, an ether solvent, a halogen solvent, an aromatic solvent, acetonitrile, N, N-dimethylformylamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide or the like is used alone or in combination. be able to. Above all, acetonitrile, DM
F, acetone, ethanol and the like are preferred.

Examples of the base include: 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or an alkali metal; Earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal (C _1-4 ) alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.); 2) inorganic bases, for example, hydroxides of alkali metals or alkaline earth metals (eg, water Sodium oxide, potassium hydroxide Lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, hydrogen carbonate) Sodium, potassium bicarbonate, etc.)
3) organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine,
-Dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), DBN
Amines such as (1,5-diazabicyclo [4.3.0] non-5-ene) or pyridine, imidazole,
And basic heterocyclic compounds such as 2,6-lutidine. Compound (I) or compound (II) obtained by the above production method is subjected to general organic synthesis reactions such as hydrolysis, halogenation, oxidation, reduction, alkylation, acylation, and ring formation. Further, it is possible to lead to the object of the present application. Examples of the reaction include the following production methods. For example, when the compound has a carbonyl in the molecule, it can be led to the following compound having a hydroxyl group by a Grignard reaction or the like.

Production method-2

Embedded image (In the formula, M represents a metal used in a so-called Grignard reaction such as lithium, sodium, and bromomagnesium,
Other symbols are as defined above. The Grignard reaction is carried out by reacting a compound (VII) or compound (VI) with 1 to 10 equivalents of a separately prepared so-called Grignard reagent or alkyllithium or alkylsodium.
And I ′) in an ether solvent at room temperature to 80 ° C. (preferably 30 to 60 ° C.) for 1 to 24 hours. The reaction is preferably carried out under deoxygenated and anhydrous conditions, and sometimes it is preferable to use anhydrous cerium chloride (catalytic amount to 2 equivalents, preferably 1 equivalent). When R ¹ or R ² is an acyl group or an alkylcarbonyl group, it can be converted to an alkyl group by a reduction reaction. Examples of the reduction reaction include a method using a metal hydride, a catalytic reduction method, and the like. In the catalytic reduction method, a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium, or palladium-carbon and an inert solvent (for example, an alcoholic solvent) are used at room temperature to 100 ° C. and at a hydrogen pressure of 1 to 100 atm. To 48 hours.

In the reduction reaction with a metal hydride, a metal hydride (eg, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) or a metal (eg, The reaction is easily achieved by using zinc, iron, sodium, potassium or the like) in an inert solvent. Examples of the inert solvent include ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, tert-butanol, etc.), toluene and hexane. Preferred metal hydrides include lithium aluminum hydride. The metal hydride is used in an amount of 4 to 20 equivalents, more preferably 6 to 12 equivalents, and the reaction is carried out at a temperature of -70 ° C to 100 ° C for 30 minutes to 18 hours. The preferred reaction temperature depends on the reducing agent used, but is suitably from 30 ° C to 70 ° C. It is also possible to selectively reduce only the cyano group or only the ester group. When the ketone represented by the compound (VII) or the compound (VII ′) is converted to an alcohol which is —CH (OH) —, a metal hydride (for example, lithium aluminum hydride, sodium borohydride, hydrogen It is easily achieved by reacting lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) in an inert solvent. Examples of the inert solvent include ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, etc.) and alcohol solvents (eg, methanol, ethanol, tert.
-Butanol), toluene, hexane and the like. The metal hydride is used in an amount of 1 to 20 equivalents, more preferably 3 to 12 equivalents, and the reaction temperature is -70 ° C.
To 100 ° C. The preferred reaction temperature and reaction time vary depending on the reducing agent used, but in the case of a metal hydride, 0 ° C to 30 ° C and 30 minutes to 18 hours are appropriate.

When R ¹ or R ² is an acyl group, it can be replaced with another acyl group directly or through a hydrolysis reaction. The hydrolysis reaction includes an alkali hydrolysis reaction and an acid hydrolysis reaction. In the case of “alkali hydrolysis”, the compound is dissolved in a solvent (eg, water, alcohols, ethers alone or a mixture of two or more of these). In the middle, it is reacted with an alkali (eg, a hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc.). As the solvent, a mixed solvent of water and methanol is preferable. As the alkali, sodium hydroxide is preferable. The amount of the alkali used is about 2 to 1 based on the compound.
00 equivalents, preferably about 5 to 10 equivalents. The reaction temperature is about 10 ° C to 120 ° C, preferably about 50 ° C to 120 ° C. The reaction time is about 5 minutes to 100 hours, preferably about 10 to 50 hours. As a preferred reaction example, the solvent is a mixed solvent of water and methanol, the reaction temperature is about 50 ° C. to 120 ° C., and the reaction time is about 10 to 50 hours. The “acid hydrolysis method” is a method in which a compound is dissolved in water or acetic acid or an alcohol solvent in the presence of an excess amount of a mineral acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.) at room temperature to 1
Heating and stirring may be performed at 20 ° C. for 0.5 to 18 hours.
Preferably, the reaction is carried out at room temperature to 60 ° C. in the presence of dilute hydrochloric acid alone or in the presence of acetic acid. When R ¹ or R ² is a so-called “amino-protecting group”, a reduction method, an ultraviolet irradiation method, a hydrazine method, or the like may be used in addition to the hydrolysis method. A typical example of the “reduction method” is a catalytic reduction method. For example, in the presence of a palladium catalyst (for example, palladium acetate, palladium-carbon, palladium black, palladium-barium carbonate, etc.), platinum oxide, a metal catalyst such as Raney nickel (catalytic amount to 1 equivalent), in an inert solvent (for example,
Water, alcohol-based solvent, ethyl acetate, ether-based solvent) at room temperature to 100 ° C. under 1 to 100 atm of hydrogen pressure (preferably 1 to 10 atm.)
Stir for 4 hours. If necessary, a catalytic amount or 2 equivalents of a mineral acid such as hydrochloric acid or an organic acid such as acetic acid may be added.

Production method-3

Embedded image (In the above formula, R ² represents an acyl group, and the others have the same meanings as described above.) The acylation reaction is carried out by a known method [for example, Organic Functional Group Preparations (ORGANIC FU
NCTIONAL GROUP PREPARATIONS) 2nd edition, Method described in ACADEMIC PRESS, INC.]. For example, an acyl group represented by ^{R 2 - (C = O)} -R 4, -SO 2 -R 4, -SO-R
⁴ ,-(C = O) O-R ⁴ , wherein R ⁴ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. Compound (IX) or compound (IX ′) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents, of the corresponding reactive derivative of an organic acid in an inert solvent at a reaction temperature of −20 ° C. to 50 ° C. (preferably, (0 ° C. to room temperature) and a reaction time of 5 minutes to 100 hours. As inert solvents, ether solvents, halogen solvents, aromatic solvents, acetonitrile, N, N-
Dimethylformylamide (DMF), acetone, methyl ethyl ketone, dimethylsulfoxide (DMSO), water, or the like can be used alone or as a mixture thereof. Among them, acetonitrile, dichloromethane, chloroform and the like are preferable. The reaction may proceed more smoothly by coexistence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, bicarbonates, organic acid salts of alkali metals and alkaline earth metals,
Among them, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and potassium hydrogen carbonate are preferred. Tertiary amines such as triethylamine are preferred as the organic base. Examples of the reactive derivative include an acid anhydride, an acid halide (for example, acid chloride and acid bromide), and an active ester. Among them, an acid halide is preferable.

When acylating from a carboxylic acid, 1 to 1.5 equivalents of the carboxylic acid and a dehydrating condensing agent (1 to 1.5 equivalents) such as dicyclohexylcarbodiimide (DCC) are used in an inert solvent (for example, , A halogen-based solvent, acetonitrile) at room temperature for 0.5 to 24 hours. The acyl group represented by R ² is-
(C = O) NH-R 4, - (C = S) NH-R 4, -
In the case of (C = S) O—R ⁴ , — (C ＝ O) O—R ⁴ , wherein R ⁴ is as defined above, the corresponding isocyanate (OCN—R ⁴ (R ⁴ is as defined above) Show the same significance.)),
A reaction temperature of −20 ° C. to 50 ° C. in an inert solvent (eg, a halogen-based solvent, acetonitrile, etc.) using an equivalent amount or an excess of isothiocyanate (SCN-R ⁴ (R ⁴ has the same meaning as described above)). C. (preferably 0.degree. C. to room temperature), and the reaction is performed for 5 minutes to 100 hours. Occasionally, 1 to 10 equivalents of an organic base such as triethylamine are used in order to promote the reaction. Further, the acyl group represented by R ² is -CON
In the case of R ⁵ -R ⁴ (R ⁴ and R ⁵ have the same meanings as described above) (among them, R ⁵ is preferably a hydrogen atom), it can also be produced by the following exchange reaction (Production Method 4) ).

Production method-4

Embedded image (Wherein, Ph represents a phenyl group, the other symbols are as defined above.) The reaction is equivalent to an excess of amine ^{(HN-R 4 -R 5 (} R 4
And R ⁵ are as defined above. )) And compound (X) or compound (X ') in an inert solvent such as acetonitrile, DMF or water in the presence of 1 to 10 equivalents of an inorganic base (eg, potassium carbonate, sodium carbonate, etc.) at room temperature to 50 ° C. The reaction proceeds for 1 to 24 hours.

Production method-5

Embedded image (Wherein each symbol has the same meaning as described above, and L ′ represents a leaving group.) In production method-5, 1 equivalent to excess

Embedded image And the compound (XII ') or the compound (XII') to give the desired product. The reaction conditions are as follows:
1 "is the same as the alkylation reaction for the amino group,
As the base, the above-mentioned strong bases, inorganic bases, organic bases and the like are used. As the leaving group L ′ used in the “Production method-5”, those similar to the aforementioned L can be mentioned, and among them, bromo, iodo and the like are preferable. By using "Production method-5", when "R ¹ and R ² form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom",
The target compound can be synthesized by introducing the corresponding nitrogen-containing heterocycle. For example, morpholino, piperidino, 1-piperazinyl group, 1-imidazolyl, phthalimide and the like can be easily introduced. The compound used as a raw material in the above "Production method-1" and "Production method-2" can be synthesized by combining known synthesis methods in the literature. For example, the following compound used in the above “Production method-1” can be easily obtained or synthesized,

Embedded image Among them, Z is _{-C (OH) - (CH 2} ) a compound of n-Ar ³ can be prepared from the corresponding ketone in the same manner as in "production method 2". Starting compound (II
I) or compound (III ′) can be synthesized by a method known per se, and examples thereof include the following scheme-1.

Scheme-1

Embedded image (Wherein J ¹ represents cyano, carboxyl, lower (C _1-3 ) alkoxycarbonyl, formyl, etc., and J ² represents a group convertible to a leaving group (for example, cyano, carboxyl, lower (C _1-3) ) Alkoxycarbonyl, protected hydroxyl group, etc.), L ″ has the same meaning as L, and other symbols have the same meanings as above.) Compound (XV) and an equivalent or excess of compound (XVI) are ether-based. Solvent, DMF, DMSO, alcohol solvent, acetonitrile, acetone or any other inert solvent alone or in a mixed solvent system in the presence of a catalytic amount or excess base (usually 1 to 3 equivalents) at -20 ° C to 120 ° C for 5 minutes To give a compound (XVII)
Can be led to. Compound (XVII) can also be obtained by heating compound (XV) with excess acrylonitrile and lower alkyl acrylate (2 to 10 equivalents) in the presence of a base catalyst.

Examples of the base include: 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or an alkali metal Earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal (C _1-4 ) alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.); 2) inorganic bases, for example, hydroxides of alkali metals or alkaline earth metals (eg, water Sodium oxide, potassium hydroxide Lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, hydrogen carbonate) Sodium, potassium bicarbonate, etc.)
3) organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), DBN (1,5
Amines such as -diazabicyclo [4.3.0] non-5-ene) or pyridine, imidazole, 2,6-
And basic heterocyclic compounds such as lutidine.

Compound (XVII) can be further prepared by a method known per se, for example, a hydrolysis reaction, a halogenation reaction, an oxidation reaction,
The compound (III) or the compound (III ′) can be obtained by appropriately combining general organic synthesis reactions such as a reduction reaction, an alkylation reaction, an acylation reaction, and a ring formation reaction. Examples of the reaction include the following production methods. Method 1

Embedded image (Wherein T is a bond, an oxygen atom or a sulfur atom which may be oxidized, L and L ″ are leaving groups, a and m are integers of 0 to 5 and the sum is 1 to 6) h represents an integer of 0 to 2, and Q ′ represents a group obtained by removing one methylene group from Q ^2. ) The reduction reaction of compound (XX) and compound (XXIV) may be carried out by a method such as metal hydride or by catalytic reduction. Law. In the catalytic reduction method, a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium or palladium-carbon and an inert solvent (for example, an alcoholic solvent) are used at room temperature to 100 ° C. and a hydrogen pressure of 1 atm.
It is obtained by reacting at atmospheric pressure for 1 to 48 hours.

In the reduction reaction with a metal hydride, a metal hydride (for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) or a metal (for example, The reaction is easily achieved by using zinc, iron, sodium, potassium or the like) in an inert solvent. Examples of the inert solvent include ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, tert-butanol, etc.), toluene and hexane. Preferred metal hydrides include lithium aluminum hydride. The metal hydride is used in an amount of 4 to 20 equivalents, more preferably 6 to 12 equivalents, and the reaction temperature is from -70 ° C to 100 ° C. The preferred reaction temperature depends on the reducing agent used, but is suitably from 30 ° C to 70 ° C. The reaction time is between 30 minutes and 18 hours. It is also possible to selectively reduce only the cyano group or only the ester group. Conversion of a hydroxyl group to a leaving group,
Alternatively, introduction of an amino-protecting group is described in the literature [eg, Comprehensive Organic Transformation VH Publishers (Co.
mprehensive Organic Transformations, VCH Publisher
s Inc.)]. Compound (XXIII) can be derived from compound (XXII) by the Wittig reaction. The reaction is carried out in an inert solvent (alcohol-based solvent, ether-based solvent, etc.) using 1 equivalent to an excess of Wittig reagent (eg, ethyl triphenylphosphoranylidene acetate, ethyl diethylphosphonoacetate) if necessary. It is obtained by reacting at -20 ° C to 60 ° C for 5 minutes to 18 hours in the presence of a base.
Examples of the base include 1) a strong base such as sodium hydride and potassium t-butoxide; 2) an inorganic base (for example, a hydroxide of an alkali metal or an alkaline earth metal (eg, sodium hydroxide, potassium hydroxide, water Lithium oxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate) , Potassium bicarbonate, etc.); 3) organic bases (eg, amines such as triethylamine and DBU).

In the case of reducing a double bond, the above-mentioned catalytic reduction method can be used. Be one of the starting materials

Embedded image Can be prepared from arylacetonitrile, diarylketone and the like by a method known per se (eg, Synthesis, p. 172, 19).
77 years). In each of the above-mentioned reactions and each reaction of the synthesis of the starting compound, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include a C _1-6 alkyl-carbonyl group (eg, formyl, acetyl, ethylcarbonyl, etc.) and a C _1-6 alkyloxycarbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl), a benzoyl group, a _C7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), a trityl group, a phthaloyl group, an N, N-dimethylaminomethylene group, and the like. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups and the like.

Examples of the carboxyl-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a trityl group, a silyl group and the like. Used. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl groups (eg, formyl, acetyl, propionyl, butylcarbonyl, etc.), nitro groups, etc. May be substituted. As the protecting group for the hydroxyl group,
For example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a C _7-10 aralkyl group (eg, benzyl, etc.), formyl, C _1-6 An alkyl-carbonyl group (eg, acetyl, propionyl, etc.), a benzoyl group,
A _C7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), a tetrahydropyranyl group, a tetrahydrofuranyl group, a silyl group and the like are used. These groups are
1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, etc.), phenyl group, C _7-10 aralkyl group (eg, Benzyl)), nitro group and the like. As a method for removing these protecting groups, a method known per se or a method analogous thereto is used.
For example, a method using an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or the like is used.

As the salt of compound (I) or (II),
Examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Salts with N, N'-dibenzylethylenediamine and the like can be mentioned. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, arginine, lysine,
Salts with ornithine and the like can be mentioned, and preferred examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid. Among them, pharmaceutically acceptable salts are preferable, and examples thereof include, when a compound has a basic functional group, a hydrochloride, a sulfate, a phosphate,
Inorganic salts such as hydrobromide, or acetate, maleate, fumarate, succinate, methanesulfonate, p
-Organic salts such as toluenesulfonate, citrate and tartrate, and when having an acidic functional group, for example, an alkali metal salt (sodium salt, potassium salt and the like) or an alkaline earth metal salt (calcium salt) , Magnesium salts, etc.), ammonium salts and the like.

The compounds (I), (II) or salts thereof can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. . The starting compound of the compound (I) or (II) of the present invention or a salt thereof can be isolated and purified by the same known means as described above.
It may be used as a raw material in the next step as a reaction mixture without isolation. When the compound (I), (II) or a salt thereof contains an optical isomer, a stereoisomer, a positional isomer or a rotamer, these are also contained as the compound of the present invention and are known per se. Each can be obtained as a single product by the synthesis method and the separation method. For example, when the compound of the present invention has an optical isomer, the optical isomer resolved from the compound is also included in the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemic mixture according to a conventional method. As the optical resolution method, a method known per se, for example, the following fractional recrystallization method, chiral column method, diastereomer method and the like are used.

1) Fractional recrystallization method A method in which a salt is formed between a racemate and an optically active compound, which is separated by a fractional recrystallization method and, if desired, undergoes a neutralization step to obtain a free optical isomer. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to be separated. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), and water, various buffers (eg, phosphate buffer, etc.), organic solvents (eg, ethanol, The optical isomers are separated by developing a solution of methanol or acetonitrile alone or as a mixture. For example, in the case of gas chromatography, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences). 3) Diastereomer method A racemic mixture is made into a diastereomer mixture by a chemical reaction with an optically active reagent, and the mixture is converted into a single substance by a usual separation means (eg, fractional recrystallization, chromatography, etc.). And then separating optically active reagent sites by a chemical treatment such as a hydrolysis reaction to obtain optical isomers. For example, when the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MPTA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]),
(-)-Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, an amide or ester diastereomer can be obtained by subjecting the compound to an optically active amine or alcohol reagent for a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

The compound (I), (II) or a salt thereof of the present invention can be used as it is or according to a method known per se.
Pharmaceutical compositions mixed with a pharmacologically acceptable carrier, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, (including soft capsules),
It can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as a liquid, injection, suppository, sustained release agent and the like. The content of compound (I) or a salt thereof in the preparation of the present invention is 0.1 to 100% by weight of the whole preparation. The dosage varies depending on the administration subject, administration route, disease and the like. For example, as a therapeutic agent for viral encephalitis, an adult (60 kg) is administered as an oral preparation per day as an active ingredient (compound (I) or a salt thereof). As about 0.
1 to 500 mg, preferably about 1 to 100 m
g, more preferably about 5 to 100 mg,
It can be administered once or several times a day. Pharmaceutically acceptable carriers that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients, lubricants, and binders in solid preparations. Agents, disintegrants; solvents in liquid formulations,
Examples include solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

As the binder, for example, crystalline cellulose,
Examples include sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As a suspending agent, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
Surfactants such as glyceryl monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. As preservatives, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite and ascorbic acid.

The drug containing the diphenylmethane derivative of the present invention and a pharmaceutically acceptable salt thereof has excellent MI.
Since it has P-1α / RANTES receptor antagonism, mammals (eg, humans, dogs, cats, cows, horses, rats,
Various viral or infectious diseases of mice, monkeys, etc. (eg, acute viral encephalitis, acute bacterial meningitis, Helicobacter pylori infection, pneumonia, hepatitis A, hepatitis B, hepatitis C, Herpes simplex virus infection, varicella-zoster virus infection, AIDS infection, influenza infection, invasive staphylococcal infection, tuberculosis, etc., tumor (eg, bladder cancer, breast cancer, cervical cancer, chronic lymphoid) Leukemia, chronic myelogenous leukemia, colorectal cancer, multiple myeloma, malignant myeloma, prostate cancer, lung cancer,
Gastric cancer, Hodgkin's disease, etc.), allergic diseases (eg, bronchial asthma, atopic dermatitis, allergic rhinitis, etc.), inflammatory diseases (eg, arteriosclerosis, arteriosclerosis occurring after heart transplantation, (chronic) joints) Rheumatism, nephritis, etc.), diabetic diseases (eg, diabetes, diabetic nephropathy,
Diabetic complications, diabetic retinopathy, diabetic microangiopathy, etc., central diseases (eg, Alzheimer's disease, epilepsy, fever, pain, dementia, etc.), hyperlipidemia, hypercholesterolemia, platelets due to dialysis Hypoplasia, spinal cord injury, osteoporosis, ulcerative colitis, peptic ulcer, sepsis (shock), reperfusion injury in the lungs and heart, unstable angina, transient ischemic attack, valvular heart disease, organ transplantation It is useful for the prevention and treatment of post-rejection, post-angioplasty restenosis, systemic lupus erythematosus, multiple sclerosis, renal failure, endometriosis, pulmonary fibrosis, adult respiratory obsession, especially allergies It is useful for the prevention and treatment of sexual diseases, inflammatory diseases and multiple sclerosis. The compound used for the MIP-1α / RANTES receptor antagonist of the present invention has low toxicity and few side effects. Acute toxicity by oral administration in rats is 100 m
g / kg or more.

[0140]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, which are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. “Room temperature” in the following Reference Examples and Examples indicates 0 to 30 ° C., and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic solvent. % Means percent by weight unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant (co)
nstant) Hz: Herz CDCl ₃ : deuterated chloroform THF: tetrahydrofuran DMF: N, N-dimethylformylamide DMSO: dimethylsulfoxide ¹ H-NMR: proton nuclear magnetic resonance (normally measured in free form, conformational isomer When only exists, only the main peak was described.) DMEM: Dulbecco's modified
Eagle's medium Dulbecco's modified Eagle's medium PBS: phosphate buffered sa
line

[0141]

【Example】

Reference Example 1-1 3,3-Diphenyl-3-formylpropionitrile A solution of diphenylacetaldehyde (1 g) in tetrahydrofuran (10 ml) was stirred under ice-cooling and stirred with 60% sodium hydride (0.25 g) in tetrahydrofuran (5 ml). The suspension was slowly dropped. After the addition was completed, the mixture was further stirred for 20 minutes. Thereafter, bromoacetonitrile (0.
41 ml) and stirred for a further 30 minutes. The reaction mixture was poured into ice water, and the separated oil was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained residue was purified by silica gel column chromatography to give the title compound (0.85 g)
Was obtained as a colorless oil. Reference Example 1-2 4,4-diphenyl-4-formylbutyronitrile Diphenylacetaldehyde (25.6 g), acrylonitrile (12.5 ml) and DBU (2.5 g) were mixed in isopropanol (250 ml) at 70 ° C. for 6 hours. The mixture was heated and stirred for an hour. After the reaction mixture was concentrated to dryness, the obtained residue was purified by silica gel column chromatography. The crude crystals were washed with isopropyl ether to give the title compound (19.8).
g) was obtained as colorless prisms. Table 1 shows the respective structural formulas and NMR spectra.

Reference Example 2-1 Ethyl 5-cyano-4,4-diphenyl-2-pentenoate 3,3-diphenyl-3-formylpropionitrile (0.85 g) and (carbethoxymethylene) triphenylphosphorane ( 1.46 g) in chloroform (20 m
In l), the mixture was heated under reflux for 7 hours. After the reaction mixture was concentrated to dryness, the residue was purified by silica gel column chromatography to give the title compound (0.7 g) as a colorless oil. Reference Example 2-2 was synthesized in the same manner as Reference Example 2-1. Reference Example 2-2: Ethyl 6-cyano-4,4-diphenyl-2-hexenoate [Table 2] shows each structural formula and NMR spectrum. Reference Example 3-1 (4-chlorophenyl) phenylacetonitrile Mandelonitrile (5 g) and chlorobenzene (15.7)
To the mixture of g), sulfuric acid (9.8 ml) was added dropwise while maintaining the reaction temperature at 5-10 ° C. After the addition was completed, the mixture was further stirred for 1.5 hours. The reaction mixture was poured into ice water, and the separated syrup was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained residue was purified by silica gel column chromatography to give the title compound (3.6 g) as a pale-yellow syrup. Reference Example 3 in the same manner as Reference Example 3-1
-2 and 3 were synthesized respectively.

Reference Example 3-2 (4-methoxyphenyl) phenylacetonitrile Reference Example 3-3: bis (4-chlorophenyl) acetonitrile Table 3 shows the structural formulas and NMR spectra. Reference Example 4-1 Ethyl 4-cyano-4,4-diphenylbutyrate Diphenylacetonitrile (28 g) in ethanol (1
DBU (6 ml) and ethyl acrylate (3
0 ml), and the mixture was heated and stirred at 80 ° C. for 16 hours. After cooling, 2N hydrochloric acid (200 ml) was added to the reaction solution, and the mixture was extracted with isopropyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were recrystallized from hexane-isopropyl ether to give the title compound (34 g). Reference Examples 4-2 to 4 were synthesized in the same manner as Reference Example 4-1. Reference Example 4-2: ethyl 4- (4-chlorophenyl)-
4-cyano-4-phenylbutyrate Reference Example 4-3: Ethyl 4-cyano-4- (4-methoxyphenyl) -4-phenylbutyrate Reference Example 4-4: Ethyl 4,4-bis (4-chlorophenyl ) -4-cyanobutyrate

Reference Example 4-5 Ethyl 5-cyano-5,5-diphenylpentanoate To a solution of diphenylacetonitrile (1 g) in tetrahydrofuran (10 ml) was added 60% sodium hydride (0.25 g) under ice-cooling and stirring. Added in small portions. After the addition was complete, the mixture was stirred for another 20 minutes. Ethyl 4-bromobutyrate (0.94 ml) was added dropwise under ice cooling, and the mixture was further added at room temperature for 15 minutes.
For a minute. The reaction mixture was poured into ice water, and the separated organic layer was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained residue was purified by silica gel column chromatography to give the title compound (0.87 g) as a colorless oil. Reference Example 4-6 Ethyl 5-cyano-4,4-diphenylpentanoate Ethyl 5-cyano-4,4-diphenyl-2-pentenoate (0.7 g) was added to a solution of ethanol (20 ml) in ethanol (20 ml).
0% palladium on carbon (0.24 g) was added and the mixture was catalytically hydrogenated at normal pressure and room temperature. The catalyst in the reaction mixture was filtered, and the filtrate was concentrated to dryness. The obtained residue was purified by silica gel column chromatography to give the title compound (0.1%).
6g) was obtained as a colorless oil. Reference Example 4-7 was synthesized in the same manner as Reference Example 4-6. Reference Example 4-7: Ethyl 6-cyano-4,4-diphenylhexanoate Table 4 shows the structural formulas and NMR spectra.

Reference Example 5-1 5-Amino-4,4-diphenylpentanol ethyl A solution of 4-cyano-4,4-diphenylbutyrate (1.2 g) in tetrahydrofuran (30 ml) was added.
Lithium aluminum hydride (0.44
g) was added in small portions. After the addition was completed, the mixture was heated and stirred at 60 ° C. for 3 hours. After the reaction mixture was again ice-cooled, water (1 ml), 15% sodium hydroxide solution (3 ml) and water (1 ml) were sequentially added. After filtering the precipitated insoluble matter, the filtrate was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained residue was washed with isopropyl ether to give the title compound (0.82 g) as a colorless powder. Reference Example 5
In the same manner as -1, Reference Examples 5-2 to 7 were respectively synthesized. Reference Example 5-2: 5-amino-4- (4-chlorophenyl) -4-phenylpentanol Reference Example 5-3: 5-amino-4- (4-methoxyphenyl) -4-phenylpentanol Reference Example 5 -4: 5-amino-4,4-bis (4-chlorophenyl) pentanol Reference Example 5-5: 6-amino-5,5-diphenylhexanol Reference Example 5-6: 6-amino-4,4-diphenyl Hexanol Reference Example 5-7: 7-amino-4,4-diphenylheptanol [Table 5] shows the structural formula, physical properties and NMR spectrum of each.

Reference Example 6-1 5-Formylamino-4,4-diphenylpentanol 5-amino-4,4-diphenylpentanol (10
g) was dissolved in formic acid (80 ml), followed by acetic anhydride (13 ml).
l) was added and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was concentrated to dryness, the residue was partitioned between chloroform and water.
The aqueous layer was made basic with aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The obtained residue was dissolved in ethanol (30 ml), and stirred at room temperature for 20 minutes together with a 1N sodium hydroxide solution (20 ml). Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. Washing with water and ethyl acetate in that order gave the title compound (9 g) as a colorless powder. Reference Examples 6-2 to 7 were synthesized in the same manner as Reference Example 6-1. Reference Example 6-2: 4- (4-chlorophenyl) -5-formylamino-4-phenylpentanol Reference Example 6
3: 5-formylamino-4- (4-methoxyphenyl) -4-phenylpentanol Reference Example 6-4: 4,4-bis (4-chlorophenyl)-
5- (formylamino) pentanol Reference Example 6-5: 6-formylamino-5,5-diphenylhexanol Reference Example 6-6: 6-formylamino-4,4-diphenylhexanol Reference Example 6-7: 7- Acetylamino-4,4-diphenylheptanol [Table 6] shows the structural formula, physical properties and NMR spectrum of each.

REFERENCE EXAMPLE 7-1 5-Formylamino-1-iodo-4,4-diphenylpentane Chloride was added to a solution of 5-formylamino-4,4-diphenylpentanol (38.3 g) in methylene chloride (600 ml). -Toluenesulfonyl (29.2 g), triethylamine (15 g) and a catalytic amount of 4-dimethylaminopyridine were added and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was concentrated to dryness, sodium iodide (46.6 g) and acetone (600 ml) were added to the residue. After heating and stirring at 50 ° C. for 2 hours, the reaction mixture was concentrated to dryness. The obtained residue was extracted with ethyl acetate and water. The organic layer was separated and washed with an aqueous solution of sodium thiosulfate. After drying over anhydrous sodium sulfate and concentrating to dryness, the resulting residue was purified by silica gel column chromatography to give the title compound (46.
5g) was obtained as a yellow syrup. Reference Examples 7-3 to 7 and 7-9 were synthesized in the same manner as Reference Example 7-1. Reference Example 7-3: 4- (4-chlorophenyl) -5-formylamino-1-iodo-4-phenylpentane Reference Example 7-4: 5-formylamino-1-iodo-4-
(4-methoxyphenyl) -4-phenylpentane Reference Example 7-5: 4,4-bis (4-chlorophenyl)-
5-formylaminopentyl tosylate Reference Example 7-6: 6-formylamino-1-iodo-5
5-diphenylhexane Reference Example 7-7: 6-formylamino-1-iodo-4,
4-diphenylhexane Reference Example 7-9: 7-acetylamino-1-iodo-4,
4-diphenylheptane

Reference Example 7-2 1-iodo-4,4-diphenyl-5- (tosylamino) pentane 5-amino-4,4-diphenylpentanol (1
g), p-toluenesulfonyl chloride (1.65 g), triethylamine (1.2 ml) and a catalytic amount of 4- (dimethylamino) pyridine were stirred in methylene chloride (20 ml) at room temperature overnight. After the reaction mixture was concentrated to dryness, the resulting residue was combined with sodium iodide (0.7 g) in acetone (2 g).
5 ml) at 50 ° C. overnight. After the reaction mixture was concentrated to dryness, the residue was extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound (1
g) was obtained as a pale yellow powder. Reference Example 7-8 was synthesized in the same manner as Reference Example 7-2. Reference Example 7-8: 1-iodo-4,4-diphenyl-6
(Tosylamino) hexane [Table 7] shows the structural formula, physical properties and NMR spectrum of each. Reference Example 8 7- (2-tetrahydropyranyloxy) -4,4-diphenylheptanonitrile 6-cyano-4,4-diphenyl-1-hexanoic acid (1
A solution of 2.5 g) in THF (85 ml) was added to a suspension of sodium borohydride (1.97 g) in THF (85 ml) at room temperature and stirred for 10 minutes. Subsequently, iodine (5.4
A solution of 6 g) in THF (85 ml) was added under ice cooling, and the mixture was stirred for 1 hour, and then 3N hydrochloric acid (20 ml) was added. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate-water, and the organic layer was washed with water and saturated saline. After drying, the solvent was distilled off under reduced pressure to give 6-cyano-4,4.
-Diphenyl-1-hexanol (13 g) was obtained. Next, p-toluenesulfonic acid monohydrate (catalytic amount) and 3,4-dihydro-2H-pyran (4.10 g) were added to a dichloromethane (150 ml) solution of the obtained alcohol (13 g).
98 g) was added under ice-cooling, and the mixture was stirred as it was for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give hexane-ethyl acetate (4:
Elution was carried out under 1) to give the title compound (10 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.41-1.90
(6H, m), 1.91-2.08 (2H, m), 2.08-2.20 (2H,
m), 2.40-2.57 (2H, m), 3.26-3.39 (1H, m), 3.4
0-3.52 (1H, m), 3.60-3.73 (1H, m), 3.74-3.88
(1H, m), 4.49 (1H, br s), 7.02-7.40 (10H, m)

Reference Example 9 1-Formylamino-7- (2-tetrahydropyranyloxy) -4,4-diphenylheptane 7- (2-tetrahydropyranyloxy) -4,4-diphenylheptanenitrile (16.8 g) ) In THF (1
00 ml) solution with lithium aluminum hydride (4.
A suspension of 3 g) in THF (150 ml) was added under ice-cooling, followed by stirring at 60 ° C. for 8 hours. A 1N aqueous sodium hydroxide solution was added, the precipitate was removed by filtration, the mother liquor was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate-water, and the organic layer was washed with water and saturated saline. After drying, the solvent is distilled off under reduced pressure,
7- (2-Tetrahydropyranyloxy) -4,4-diphenylheptanamine (17 g) was obtained. Next, a chloroform (2M, 20 ml) solution of formic acid was added to a chloroform (25 ml) solution of 1,3-dicyclohexylcarbodiimide (4.12 g) under ice-cooling with stirring, and the resulting amine (3. 7 g) of pyridine (25 m
l) The solution was added with stirring under ice-cooling and stirred for 4 hours as it was. After the reaction solution was concentrated under reduced pressure and the precipitate was removed by filtration, the mother liquor was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate-water, and the organic layer was washed with water and saturated saline. After drying, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 2) to give the title compound (1.4 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.37 (2H, m), 1.40-1.90
(8H, m), 2.05-2.20 (4H, m), 3.05-3.40 (3H,
m), 3.40-3.53 (1H, m), 3.56-3.75 (1H, m), 3.7
5-3.90 (1H, m), 4.49 (1H, br s), 5.20-5.60 (1
H, br), 7.05-7.33 (10H, m), 8.12 (1H, d)

Reference Example 10 1-Formylamino-7-iodo-4,4-diphenylheptane Methanol of 1-formylamino-7- (2-tetrahydropyranyloxy) -4,4-diphenylheptane (1.4 g) (20 ml), p-toluenesulfonic acid monohydrate (catalytic amount) was added to the solution at room temperature, and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give 1-formylamino-7.
-Hydroxy-4,4-diphenylheptane (1.2
g) was obtained as an oil. Thereafter, the obtained oil was dissolved in dichloromethane (20 ml), triethylamine (1 ml), 4-dimethylaminopyridine (catalytic amount),
p-Toluenesulfonyl chloride (687 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure,
The obtained residue was dissolved in ethyl acetate-1N hydrochloric acid, and the organic layer was washed with water and saturated saline. After drying, the solvent was distilled off under reduced pressure, and 7-formylamino-4,4-diphenylheptyl 7-p-toluenesulfonate (1.3 g) was used.
Was obtained as an oil. Thereafter, sodium iodide (66 mg) was added to a solution of the obtained tosylate (1.3 g) in acetone (20 ml), and the mixture was stirred at 50 ° C for 4 hours.
The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate-water, and the organic layer was washed with water and saturated saline.
After drying, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 1) to obtain the title compound (1.4 g).
119-121 ° C.

Reference Example 11-1 1-benzyl-4- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxypiperidine 3,5-bis (trifluoromethyl) bromobenzene (1.17 g) ) Was added to a THF (10 ml) solution, and metallic magnesium (97 mg) was added thereto.
And stirred. The prepared Grignard reagent was added under ice-cooling,
1-benzyl-4-piperidone (379 mg) in THF
(2 ml) was added and stirred for 30 minutes. In the reaction solution,
A saturated aqueous ammonium chloride solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
After drying, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 4). After evaporating the solvent, the title compound (62) was obtained.
0 mg). Melting point 89-90 ° C Reference Examples 11-2 to 11-3 were similarly synthesized. Reference Example 11-2: 1-benzyl-4- (4-trifluoromethylphenyl) -4-hydroxypiperidine ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.85 (3H, m), 2.16 (2H,
dt), 2.46 (2H, dt), 2.71 (2H, d), 3.59 (2H,
s), 7.20-7.39 (5H, m), 7.62 (4H, ABq) Reference Example 11-3: 1-benzyl-4- (3,5-dichlorophenyl) -4-hydroxypiperidine Melting point 75-77 ° C

Reference Example 12-1 4- [3,5-bis (trifluoromethyl) phenyl]
-4-Hydroxypiperidine To a solution of 1-benzyl-4- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxypiperidine (1 g) in methanol (5 ml) was added 10% palladium-carbon (100 mg). The mixture was stirred at room temperature for 2 hours under a hydrogen stream. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (600 mg). Melting point 209-210 ° C Reference Example 12-2 4- (4-trifluoromethylphenyl) -4-hydroxypiperidine was synthesized in the same manner. 115-116 ° C

Reference Example 13 4- (3,5-dichlorophenyl) -4-hydroxypiperidine 1-benzyl-4- (3,5-dichlorophenyl) -4
Ethyl chlorocarbonate (217 mg) was added to a mixture of -hydroxypiperidine (200 mg) and potassium carbonate (276 mg) in toluene (5 ml), and the mixture was stirred at 60 ° C for 2 days. Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4: 1) to give oily [4- (3,5-dichlorophenyl) -1-).
Ethoxycarbonylpiperidin-4-yl] ethyl carbonate (190 mg) was obtained. Next, carbonate (19
To a solution of 0 mg) in ethanol (5 ml) was added a 4N aqueous potassium hydroxide solution (5 ml), and the mixture was heated under reflux for 15 hours. After evaporating the solvent under reduced pressure, water and ethyl acetate were added to the residue and mixed well. The organic layer was washed with water and saturated saline, dried, and evaporated under reduced pressure to give the title compound (135 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.75 (4H, m), 1.97 (2H,
dt), 2.91-3.16 (4H, m), 7.26 (1H, d), 7.40
(2H, d)

Reference Example 14 4- (4-chlorophenyl) piperidine Sulfuric acid (0.5 ml) was added to a solution of 4- (4-chlorophenyl) -4-hydroxypiperidine (478 mg) in acetic acid (5 ml).
Was added and stirred at room temperature for 3 hours. The reaction solution was made alkaline with a 4N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure to give 4- (4-chlorophenyl) -1,
2,5,6-tetrahydropyridine (350 mg) was obtained. Next, 4- (4-chlorophenyl) -1,2,5,6
-Tetrahydropyridine (250 mg) in methanol (5
ml) -4N hydrochloric acid (2 ml) solution in 10% palladium-
Carbon (150 mg) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen stream. The catalyst was removed by filtration, the filtrate was made alkaline with a 4N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and evaporated under reduced pressure to give the title compound as an oil (180 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.60 (2H, dq), 1.70-2.05 (3
H, m), 2.50-2.83 (3H, m), 3.19 (2H, dr d), 7.1
5 (2H, d), 7.26 (2H, d)

Reference Example 15 4- (4-chlorophenyl) -4-hydroxyhexamethyleneimine 1) 1-benzyl-4- (4-chlorophenyl) -4
-Hydroxyhexamethyleneimine It was synthesized from 1-benzylhexamethyleneimine-4-one and 4-chlorobromobenzene in the same manner as in Reference Example 11-1. ¹ H-NMR (CDCl ₃ ) δ: 1.49-2.20 (6H, m), 2.32-2.59 (2H,
m), 2.60-2.73 (1H, m), 2.82-3.13 (2H, m), 3.66 (2H,
ABq), 7.21-7.43 (9H, m) 2) 4- (4-chlorophenyl) -4-hydroxyhexamethyleneimine 1-benzyl-4- (4-chlorophenyl) -4-hydroxyhexamethyleneimine (472 mg) and carbonic acid Ethyl vinyl carbonate (426 mg) was added to a mixture of potassium (414 mg) in toluene (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried,
The solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (6: 1) to give [4- (4-chlorophenyl)-
1-vinyloxycarbonyl-hexamethyleneimine-4
-Yl] vinyl carbonate (400 mg) was obtained. To this ethanol (5 ml) solution was added a 4N aqueous potassium hydroxide solution (5 ml), and the mixture was stirred at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, water and ethyl acetate were added to the residue and mixed well. The organic layer was washed with water and saturated saline, dried, and evaporated under reduced pressure to give the title compound (150 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.50-2.85 (9H,
m), 2.85-3.01 (1H, m), 3.
17-3.30 (1H, m), 3.30-3.50
(1H, m), 7.23-7.45 (4H,
m)

Reference Example 16 Ethyl 4-cyano-4-phenyl-4- (2-pyridyl) butyrate 60% sodium hydride (13.2 g) in DMF (40 g)
0 ml) suspension with phenylacetonitrile (35.1).
g) in DMF (20 ml) was added under ice-cooling, and 3
Stirred for 0 minutes. Next, 2-bromopyridine (47.4)
g) in DMF (20 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. Phenyl (2-pyridyl) acetonitrile [ ¹ H-NMR (CDCl ₃ ) δ: 5.32 (1H, s), 7.20-
7.50 (7H, m), 7.70 (1H, dt), 8.60 (1H, dd)]
g was obtained. Next, ethyl acrylate (13 g) and 1,8-diazabicyclo [5,4,0] -7-undecene (1.5 ml) were added to a solution of phenyl (2-pyridyl) acetonitrile (19.4 g) in ethanol (250 ml). The mixture was heated under reflux for 5 hours. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4: 1 to 3: 1) to obtain the title compound as an oil (30 g). ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t), 2.40-2.52 (2H, m),
2.70-2.92 (1H, m), 2.93-3.15 (1H, m), 4.10 (2H, m
q), 7.19-7.55 (8H, m), 7.68 (1H, dt), 8.63 (1H, d)

Reference Example 17 A solution of ethyl 4-cyano-4-phenyl-4- (2-pyridyl) butyrate (2.9 mg) in ethanol (10 ml) 1N aqueous sodium hydroxide solution (15 ml) was added to
Stirred at 30 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, added with water, neutralized with 1N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound (2.7 g). ¹ H-NMR (CDCl ₃ ) δ: 2.45-2.60 (2H,
m), 2.78 (1H, ddd), 3.06
(1H, ddd), 7.20-7.55 (7H,
m), 7.68 (1H, dt), 8.63
(1H, d) Reference Example 18 N- [4-cyano-4-phenyl-4- (2-pyridyl) butyryl] -4- (4-chlorophenyl) -4-hydroxypiperidine 4-cyano-4-phenyl-4 Triethylamine (606 mg) was added to a solution of-(2-pyridyl) butyric acid (1.33 g), 4- (4-chlorophenyl) -4-hydroxypiperidine (1.3 g) and diethyl phosphate cyanide (982 mg) in DMF (20 ml). The mixture was added at room temperature and stirred for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 1) to give the title compound (1.5 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.62-2.00 (4H, m), 2.21 (1H, s),
2.35-2.57 (2H, m), 2.70-2.93 (1H, m), 2.94-3.14 (2
H, m), 3.37-3.74 (2H, m), 4.53 (1H, br d), 7.19-7.5
3 (12H, m), 7.68 (1H, dt), 8.62 (1H, d)

Reference Example 19 5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2-phenyl-2- (2-pyridyl) pentylamine dihydrochloride Lithium aluminum hydride (380 mg) and chloride To a suspension of aluminum (1.3 g) in ether (20 ml) was added N- [4-cyano-4-phenyl-4- (2-pyridyl) butyryl] -4- (4-chlorophenyl) -4-hydroxypiperidine (465 mg). ) Was added under ice-cooling, and the mixture was stirred as it was for 20 minutes. A 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 1). The solvent was distilled off, and the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. The compound (250 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.42 (2H,
m), 1.45-1.90 (5H, m), 1.
90-2.13 (2H, m), 2.14-2.40
(6H, m), 2.66 (2H, br
d), 3.39 (2H, ABq), 6.98-
7.47 (11H, m), 7.55 (1H, d
t), 8.57 (1H, d) Reference Example 20 4-cyano-4,4-diphenylbutyric acid ethyl 4-cyano-4,4-diphenylbutyrate (16.1)
g) was dissolved in THF (60 ml), 1N sodium hydroxide solution (60.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. After acidification with concentrated hydrochloric acid, the mixture was extracted with ethyl acetate, dried, and the solvent was distilled off to obtain an oily residue. The residue was crystallized from isopropyl ether to give the title compound (1
2.0 g). Melting point 164-165 ° C

Reference Example 21 4- (4-chlorophenyl) -1- (4-cyano-4,
4-diphenylbutyryl) -4-hydroxypiperidine 4-cyano-4,4-diphenylbutyric acid (8.0 g), 4
To a solution of-(4-chlorophenyl) -4-hydroxypiperidine (6.4 g) and diethyl cyanophosphate (4.6 ml) in DMF (75 ml) was added triethylamine (8.
4 ml) at 0 ° C. and stirred at room temperature for 2 hours. The mixture was poured into pure water (500 ml), and the formed solid was collected by filtration. The solid was dissolved in ethyl acetate, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The solid residue was suspended and collected in ether to give the title compound (12.6 g). Melting point 205-206 ° C Reference Example 22 1- (5-amino-4,4-diphenylpentanoyl)
-4- (4-chlorophenyl) -4-hydroxypiperidine 4- (4-chlorophenyl) -1- (4-cyano-4,
4-Diphenylbutyryl) -4-hydroxypiperidine (6.9 g) was added to a saturated ammonia ethanol solution (500 g).
ml), and Raney cobalt catalyst (7 g) was added.
The reaction was carried out for 8 hours under a hydrogen atmosphere of 5 atm. After evaporating the catalyst, the mixture was concentrated under reduced pressure to obtain an oily residue (5.4 g). ¹ H-NMR (CDCl ₃ ) δ: 1.57-1.89 (4H, m),
1.99-2.08 (2H, m), 2.43-2.53 (2H, m), 3.01 (1H, d
t), 3.25 (2H, s), 3.22-3.35 (2H, m), 4.51 (1H, br
d), 7.15-7.37 (14H, m).

Reference Example 23 Ethyl 4-cyano-4,4-diphenyl-1-butanol ethyl 4-cyano-4,4-diphenylbutyrate (44.0
g) was dissolved in THF (440 ml) and lithium tetrahydroborate (3.9 g) was carefully added at 0 ° C.
The mixture was heated to room temperature and stirred for 2 days. The reaction solution was poured into cold 1 N hydrochloric acid (440 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 2) to give the title compound (34.
6 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.62-1.76 (2H, m), 2.47-2.55 (2
H, m), 3.69 (2H, t), 7.28-7.42 (10H, m). Reference Example 24 1-bromo-4-cyano-4,4-diphenylbutane triphenylphosphine (27.5 g) was added to acetonitrile (100 ml). ), Cooled to 0 ° C and bromine (5.2
ml) was added dropwise. After completion of the dropwise addition, 4-cyano-4,4-
A solution of diphenyl-1-butanol (25.1 g) in acetonitrile (40 ml) was added at 0 ° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, ether was added to the residue, and triphenylphosphine oxide was filtered off. The filtrate was washed with saturated saline, dried, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with ether, and crystallized from IPE to obtain the title compound (25.6 g). ¹ H-NMR (CDCl ₃ ) δ: 1.93-2.07 (2H, m), 2.527-2.61 (2
H, m), 3.44 (2H, t), 7.26-7.42 (10H, m).

Reference Example 25 4- (4-chlorophenyl) -1- (4-cyano-4,
4-Diphenylbutyl) -4-hydroxypiperidine 1-bromo-4-cyano-4,4-diphenylbutane (22.0 g) was dissolved in acetonitrile (500 ml), and 4- (4-chlorophenyl) -4-hydroxypiperidine was dissolved. (17.8 g), potassium iodide (1.2 g) and potassium carbonate (29 g) were added. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
It was washed with pure water. The organic layer was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (3) as an amorphous powder.
1.4 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.83 (5H, m), 2.06 (2H, d
t), 2.30-2.49 (6H, m), 2.71 (2H, br d), 7.27-7.45
(14H, m). Reference Example 26 1-amino-5- [4- (4-chlorophenyl) -4-
[Hydroxypiperidino] -2,2-diphenylpentane 4- (4-chlorophenyl) -1- (4-cyano-4,
4-Diphenylbutyl) -4-hydroxypiperidine (31.3 g) was added to a saturated ammonia-ethanol solution (5.
00 ml), and Raney cobalt catalyst (20 g) was added. The mixture was stirred at 70 ° C. for 8 hours under a hydrogen pressure of 5 atm.
The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain the title compound (17.8 g). Melting point 116-117 ° C

Reference Example 27 2-Benzoylthiophene cyanohydrin A solution of 2-benzoylthiophene (10 g), trimethylsilyl cyanide (6 g), and zinc iodide (0.15 g) in acetonitrile (50 ml) was stirred at 50 ° C. for 16 hours. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid (60
ml) and ethanol (30 ml), and the mixture was stirred at 55 ° C for 2 hours. After extracting the reaction solution with isopropyl ether, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline.
After drying, the solvent was distilled off under reduced pressure to obtain 11.5 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.68 (1H, br s), 6.98 (1H, d
d), 7.19 (1H, dd), 7.34-7.46 (4H, m), 7.59-7.68
(2H, m) Reference Example 28 Phenyl-2-thienylacetonitrile 2-benzoylthiophencyanhydrin (250 m
g) in ether (1 ml) and sodium borohydride (430 mg) in trifluoroacetic acid (5 ml) at 0 ° C.
The mixture was added under stirring and left as it was at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in a 1N aqueous solution of sodium hydroxide, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (8: 1) to obtain the title compound (110 mg). Was. ¹ H-NMR (CDCl ₃ ) δ: 5.35 (1H, s), 6.97 (1H, dd),
7.05-7.09 (1H, m), 7.27 (1H, dd), 7.32-7.44 (5
H, m)

Reference Example 29 Ethyl 4-cyano-4-phenyl-4- (2-thienyl) butyrate The title compound was synthesized from phenyl-2-thienylacetonitrile by the same reaction as in Reference Example 4-1. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t), 2.41 (1H, dd),
2.56 (1H, dd), 2.80 (2H, dt), 4.10 (2H, q), 6.9
6 (1H, dd), 7.00 (1H, dd), 7.25-7.52 (6H, m) Reference Example 30 5-formylamino-4-phenyl-4- (2-thienyl) pentanol 4-cyano-4-phenyl Ethyl-4- (2-thienyl) butyrate was subjected to the reduction reaction described in Reference Example 5-1 to give 5-amino-4-phenyl-4- (2-thienyl) pentanol, and further described in Reference Example 6-1. The title compound was obtained by the reaction. ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.59 (2H, m), 1.81 (1H,
br s), 2.21 (2H, t), 3.56 (2H, t), 3.98 (2H, d
d), 4.12 (2H, dd), 5.43 (2H, br s), 6.85-7.00
(2H, m), 7.10-7.40 (6H, m), 8.11 (1H, s)

Reference Example 31 5-Formylamino-1-iodo-4-phenyl-4-
(2-Thienyl) pentane 5-Formylamino-4-phenyl-4- (2-thienyl) pentanol was obtained as the title compound by an iodination reaction described in Reference Example 7-1. ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.75 (2H, m), 2.08-2.28
(2H, m), 3.10 (2H, t), 4.03 (2H, dd), 5.18-5.65
(1H, br m), 6.84-7.00 (2H, m), 7.15-7.40 (6H,
m), 8.12 (1H, d) Reference Example 32 4-chloromandelonitrile An aqueous solution of sodium bisulfite (53.2 g) (400
4-chlorobenzaldehyde (60 g) was added to the resulting mixture at 40 ° C. with stirring at 40 ° C., followed by stirring for 1 hour. After cooling to 0 ° C. and adding ether (250 ml), an aqueous solution (100 ml) of sodium cyanide (22.6 g) was added dropwise, and the mixture was further stirred for 2 hours while cooling with ice. After the reaction,
The organic layer was separated, washed with saturated saline, dried, and evaporated under reduced pressure to give 65 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.06 (1H, br d), 5.53 (1H, d),
7.38-7.52 (4H, m)

Example 1-1 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1-formylamino-2,2-diphenylpentane hydrochloride

Embedded image 5-formylamino-1-iodo-4,4-diphenylpentane (5 g), 4- (4-chlorophenyl) -4
To a solution of -hydroxypiperidine (3.9 g) in acetonitrile (150 ml) was added potassium carbonate (7.7 g), and the mixture was stirred at 60 ° C for 15 hours. After distilling off the solvent under reduced pressure,
Water and ethyl acetate were added to the residue and mixed well. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate. After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give the title compound (5.6 g) as an amorphous powder. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.40 (2H, m), 1.58-1.92
(3H, m), 1.93-2.22 (4H, m), 2.23-2.42 (4H,
m), 2.65 (2H, br d), 4.05 (2H, d), 5.13 (1H,
brt), 7.10-7.28 (14H, m), 8.09 (1H, d) Examples 1-2 to 1-10 were synthesized in the same manner as in Example 1-1.

Example 1-2 5- [4- (4-fluorophenyl) piperazine-1-
Yl] -1-formylamino-2,2-diphenylpentane dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 2.10-2.40
(4H, m), 2.45 (4H, t), 3.05 (4H, t), 4.06
(2H, d), 5.10 (1H, br s), 6.80-7.00 (4H, m),
7.10-7.40 (10H, m), 8.10 (1H, d) Example 1-3 1-Formylamino-5- (4-hydroxy-4-phenylpiperidino) -2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.45 (2H, m), 1.72 (2H,
br d), 1.80-2.28 (7H, m), 2.30-2.50 (4H, m),
2.65-2.80 (2H, m), 4.05 (2H, d), 5.15-5.26
(1H, br), 7.13-7.55 (15H, m), 8.10 (1H, d)

Example 1-4 5- [4- (4-trifluoromethylphenyl) -4-
[Hydroxypiperidino] -1-formylamino-2,2
-Diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.26-1.42 (2H, m), 1.67 (2H, b
rd), 1.81-2.26 (4H, m), 2.27-2.45 (4H, m), 2.73
(2H, br d), 4.05 (2H, d), 5.09-5.20 (1H, brt), 7.
13-7.37 (10H, m), 7.55-7.70, 8.09 (1H, d). Example 1-5 5- [4- [3,5-bis (trifluoromethyl) phenyl] -4-hydroxypiperidino ] -1-Formylamino-2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (2H, m), 1.67 (2H, br
d), 1.90-2.24 (4H, m), 2.25-2.45 (4H, m), 2.69 (3
H, br d), 4.03 (2H, d), 5.22 (1H, br t), 7.05-7.40
(10H, m), 7.75 (1H, s), 7.97 (2H, s), 8.04 (1H,
d)

Example 1-6 5- [4- (3,5-dichlorophenyl) -4-hydroxypiperidino] -1-formylamino-2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (2H, m), 1.64 (2H, br
d), 1.94-2.42 (9H, m), 2.62-2.76 (2H, m), 4.05 (2
H, d), 5.16 (1H, br t), 7.10-7.43 (13H, m), 8.08
(1H, d) Example 1-7 5- [4- (4-chlorophenyl) -1,2,3,6-
Tetrahydropyridin-1-yl] -1-formylamino-2,2-diphenylpentane hydrochloride

Embedded image Recrystallization solvent Ethyl acetate / isopropyl ether Melting point 123-125 ° C

Example 1-8 1-Formylamino-2,2-diphenyl-5- (4-
Phenylpiperidino) pentane

Embedded image Recrystallization solvent Ethyl acetate / hexane Melting point 133-135 ° C Example 1-9 5- [4- (4-chlorophenyl) piperidino] -1-
Formylamino-2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (2H, m), 1.50-2.50 (1
1H, m), 2.87 (2H, br d), 4.05 (2H, d), 5.00-5.25
(1H, br), 7.00-7.40 (14H, m), 8.09 (1H, d) Examples 1-10 7- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -1-formylamino- 4,4-diphenylheptane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.30 (4H, m), 1.66 (2H, br
d), 1.77-2.22 (7H, m), 2.22-2.43 (4H, m), 2.56-2.72
(2H, m), 3.22 (2H, q), 5.40-5.64 (1H, br), 7.10-7.
35 (12H, m), 7.42 (2H, d), 8.08 (1H, d)

Example 2-1 5- [4- (4-Fluorophenyl) -4-hydroxypiperidino] -1-formylamino-2,2-diphenylpentane hydrochloride

Embedded image 1-formylamino-5-iodo-2,2-diphenylpentane (1 g), 4-piperidone hydrochloride monohydrate (4
To a solution of 50 mg) in acetonitrile (10 ml) was added potassium carbonate (845 mg), and the mixture was stirred at 45 ° C for 2 days. After evaporating the solvent under reduced pressure, water and ethyl acetate were added to the residue and stirred well. The organic layer was washed with water and saturated saline, dried,
The solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (9: 1) to give 1-formylamino- amorphous powder.
2,2-Diphenyl-5- (4-piperidone-1-yl) pentane (570 mg) was obtained. Next, a 1.6 M n-butyllithium hexane solution (1.25 mg) was added to a THF (5 ml) solution of 4-bromofluorobenzene (298 mg).
ml) was added dropwise at −78 under an argon stream. After stirring for 20 minutes, anhydrous cerium chloride (520 mg) was added to the reaction solution, and the mixture was further stirred for 45 minutes to give the synthesized 1-formylamino-
2,2-Diphenyl-5- (4-piperidone-1-yl) pentane (125 mg) in THF (1 ml) was added.
The temperature was gradually raised to −10 ° C., and 1.5 hours later, water and a 1N aqueous sodium hydroxide solution were added to the reaction solution. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (9: 1). After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. The compound (85 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.42 (2H, m), 1.50-1.95 (3
H, m), 2.00-2.23 (4H, m), 2.24-2.44 (4H, m), 2.70
(2H, br d), 4.06 (2H, d), 5.10-5.23 (1H, br), 7.01
(2H, t), 7.10-7.38 (10H, m), 7.39-7.52 (2H, m),
8.09 (1H, d) Examples 2-2 and 2-3 were synthesized in the same manner as in Example 2-1.

Example 2-2 1-Formylamino-5- [4-hydroxy-4- (4
-Methoxyphenyl) piperidino] -2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.45 (2H, m), 1.50-2.20 (7
H, m), 2.21-2.40 (4H, m), 2.53-2.71 (2H, m), 3.80
(3H, s), 4.05 (2H, d), 5.12-5.22 (1H, br), 6.87 (2
H, d), 7.10-7.45 (12H, m), 8.09 (1H, d) Example 2-3 1-Formylamino-5- [4-hydroxy-4- (2
-Pyridyl) piperidino] -2,2-diphenylpentane dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.53 (2H, m), 1.63 (2H, br
d), 2.16-3.06 (11H, m), 4.06 (2H, d), 5.32-5.42
(1H, br), 7.03-7.40 (11H, m), 7.48 (1H, t), 7.73
(1H, dt), 8.11 (1H, d), 8.50 (1H, d)

Example 3-1 1-acetylamino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4-
[Hydroxypiperidino] -2,2-diphenylpentane (112 mg) in ethyl acetate (3 ml), a saturated aqueous solution of sodium carbonate (5 ml) was added, the mixture was stirred vigorously under ice-cooling, acetic anhydride (24 mg) was added, and the mixture was stirred for 5 minutes. did. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (19: 1). After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. The compound (45 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.42 (2H, m), 1.68 (2H, br
d), 1.85 (3H, s), 2.00-2.20 (3H, m), 2.26-2.28 (4
H, m), 2.72 (2H, br d), 3.98 (2H, d), 5.02 (1H, br
t), 7.13-7.38 (12H, m), 7.42 (2H, d) Examples 3-2 to 3-12 were synthesized in the same manner as in Example 3-1.

Example 3-2 1-acetoacetylamino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.64 (2H, br
d), 1.80-2.20 (8H, m), 2.20-2.40 (4H, m), 2.65 (2
H, br d), 3.26 (2H, s), 4.02 (2H, d), 6.40-6.53 (1
H, br), 7.14-7.44 (14H, m) Example 3-3 Ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] succinamidate Hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.17-1.38 (5H, m), 1.65 (2H, br
d), 1.92-2.14 (5H, m), 2.20-2.37 (6H, m), 2.55-2.
72 (4H, m), 4.01 (2H, d), 4.10 (2H, q), 5.18 (1H, b
rt), 7.16-7.38 (12H, m), 7.43 (2H, d)

Example 3-4 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] succinamidic acid

Embedded image ¹ H-NMR (DMSO-d ₆ ) δ: 1.08-1.29 (2H, m), 1.53 (2H,
br d), 1.80-2.28 (9H, m), 2.29-2.48 (4H, m), 2.53-
2.68 (2H, m), 3.89 (2H, br d), 7.10-7.39 12H, m),
7.48 (2H, d) Example 3-5 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-Ethylurea

Embedded image Recrystallization solvent Ethyl acetate / hexane Melting point 142-144 ° C

Example 3-6 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] methanesulfonamide hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.36 (2H, m), 1.60-1.80 (3
H, m), 2.00-2.43 (8H, m), 2.48 (3H, s), 2.71 (2H, b
rd), 3.82 (2H, d), 4.78-4.92 (1H, br), 7.13-7.40
(12H, m), 7.45 (2H, d) Example 3-7 Phenyl N- [5- [4- (4-chlorophenyl)-
4-Hydroxypiperidino] -2,2-diphenylpentyl] carbamate

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.53-1.74 (2H,
m), 1.96-2.40 (9H, m), 2.19 (2H, br d), 4.02 (2H,
d), 4.89 (1H, br t), 6.95-7.08 (2H, m), 7.10-7.46
(17H, m)

Example 3-8 1-acetylamino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2-phenyl-2
-(2-pyridyl) pentane dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.50 (2H, m), 1.67 (2H, br
d), 1.85 (3H, s), 1.94-2.48 (8H, m), 2.50--2.76 (3
H, m), 3.87 (1H, dd), 4.13 (1H, dd), 6.58 (1H, br
t), 6.95-7.52 (11H, m), 7.60 (1H, dt), 8.57 (1H, d
t) Example 3-9 Ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] oxamate hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (5H, m), 1.64 (2H, br
d), 1.71-2.18 (5H, m), 2.19-2.38 (4H, m), 2.56-2.6
9 (2H, m), 4.05 (2H, d), 4.26 (2H, q), 6.72 (1H, b
rt), 7.14-7.44 (14H, m)

Example 3-10 Ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] malonamide hydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.38 (5H, m), 1.64 (2H, d),
1.95-2.19 (5H, m), 2.20-2.38 (4H, m), 2.57-2.70 (2
H, m), 3.17 (2H, s), 3.98-4.15 (4H, m), 6.58 (1H, b
rt), 7.16-7.45 (14H, m) Example 3-11 Ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] glutamate

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (5H, m), 1.58-1.94 (5H,
m), 1.95-2.16 (6H, m), 2.17-2.39 (6H, m), 2.66 (2H,
br d), 4.01 (2H, d), 4.09 (2H, q), 5.05 (1H, br
t), 7.15-7.38 (12H, m), 7.43 (2H, d) Example 3-12 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2-phenyl-2 -(2-Pyridyl) pentyl] ethyl succinate dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.50 (5H, m), 1.88-2.10 (3H,
m), 2.10-2.48 (8H, m), 2.49-2.74 (6H, m), 3.89 (1H,
dd), 4.05-4.20 (3H, m), 6.66 (1H, brt), 7.05-7.3
7 (11H, m), 7.60 (1H, dt), 8.56-8.62 (1H, m)

Example 4-1 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-Pentamethyleneurea hydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl)-
4-Hydroxypiperidino] -2.2-diphenylpentyl] carbamate (86 mg), piperidine (43 mg)
To a DMF (1 ml) solution of was added potassium carbonate (69 mg), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20: 1). After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. The compound (80 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.60 (2H, m), 1.66 (2H, br
d), 1.80-2.20 (5H, m), 2.20-2.40 (4H, m), 2.67 (2
H, br d), 3.06-3.13 (4H, m), 3.95 (2H, s), 7.17-7.
38 (12H, m), 7.43 (2H, d)

Example 4-2 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(3-hydroxypropyl) urea hydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl)-
To a solution of 4-hydroxypiperidino] -2.2-diphenylpentyl] carbamate (569 mg) and 3-amino-1-propanol (113 mg) in DMF (2 ml) was added potassium carbonate (267 mg) and the mixture was stirred at room temperature for 16 hours. did.
Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl acetate-methanol (9: 9).
The residue obtained after evaporation of the solvent was treated with 4N hydrogen chloride / ethyl acetate to give the title compound (60) as an amorphous powder.
0 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (2H, m), 1.40-1.72 (4
H, m), 1.75-2.18 (6H, m), 2.23-2.43 (4H, m), 2.70
(2H, br d), 3.24 (2H, q), 3.56 (2H, t), 3.92 (2H,
d), 4.18 (1H, br t), 4.48 (1H, br t), 7.18-7.48 (1
4H, m)

Example 4-3 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(4-hydroxybutyl) urea hydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl)-
Potassium carbonate (138 mg) was added to a solution of 4-hydroxypiperidino] -2.2-diphenylpentyl] carbamate (235 mg) and 4-amino-1-butanol (67 mg) in DMF (1 ml), and the mixture was stirred at room temperature for 4 hours. did. Water was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (9: 1). After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. Compound (205 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.43 (2H, m), 1.45-1.56 (2
H, m), 1.68 (2H, d), 1.90-2.52 (12H, m), 2.76 (2H,
br d), 3.07 (2H, q), 3.61 (2H, t), 3.94 (2H, d),
4.08 (1H, br t), 4.53 (1H, br t), 7.14-7.48 (14H,
m) Examples 4-4 to 4-10 were synthesized as in Example 4-1.

Example 4-4 3- [3- [5- [4- (4-Chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] ureido] ethyl propionate

Embedded image Recrystallization solvent Ethyl acetate / hexane Melting point 108-110 ° C Example 4-5 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(2-dimethylaminoethyl) urea

Embedded image Recrystallization solvent Ethyl acetate / ether Melting point 104-105 ° C

Example 4-6 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(3-diethylaminopropyl) urea

Embedded image Recrystallization solvent Ethyl acetate / ether Melting point 122-124 ° C Example 4-7 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[3- (2-pyrrolidone-1-yl) propyl] urea

Embedded image Recrystallization solvent Ether Melting point 115-116 ° C

Example 4-8 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(2-piperidinoethyl) urea

Embedded image Recrystallization solvent Ether / hexane Melting point 122-123 ° C Example 4-9 2- [3- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] ureido] ethanesulfonamide hydrochloride

Embedded image Recrystallization solvent Ether / hexane Melting point 142-145 ° C Example 4-10 2- [3- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] ureido] ethanesulfonic acid

Embedded image Recrystallization solvent methanol / isopropyl ether Melting point 221-224 ° C

Example 5-1 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] succinamidic acid

Embedded image Ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] succinate (1.05 g) in ethanol (10
1N aqueous sodium hydroxide solution (3 ml)
And stirred at 60 ° C. for 2 hours. The reaction solution was concentrated, added with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
After drying the organic layer, the solvent was distilled off under reduced pressure to give the title compound (9
00 mg). Melting point: 180-182 ° C. Examples 5-2 to 5-5 were synthesized in the same manner as in Example 5-1. Example 5-2 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] oxamic acid

Embedded image ¹ H-NMR (DMSO-d ₆ ) δ: 1.08-1.40 (2H, m), 1.40-1.65 (2
H, m), 1.75-2.90 (9H, m), 3.10-3.50 (2H, m), 3.90
(2H, br d), 4.80-5.40 (1H, br), 7.12-7.50 (14H, m)

Example 5-3 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] malonamic acid

Embedded image ¹ H-NMR (DMSO-d ₆ ) δ: 1.17-1.30 (2H, m), 1.46-1.63 (2
H, m), 1.80-2.10 (3H, m), 2.10-2.60 (6H, m), 2.70-
3.20 (4H, m), 3.80-3.92 (2H, m), 6.64-6.90 (1H, b
r), 7.00-7.33 (14H, m) Example 5-4 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] glutamic acid

Embedded image ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.30 (2H, m), 1.40-1.66 (4
H, m), 1.70-2.15 (9H, m), 2.20-2.26 (4H, m), 2.52-
2.66 (2H, m), 3.90 (2H, d), 4.30-5.70 (2H, br), 7.
07-7.39 (12H, m), 7.46 (2H, d) Example 5-5 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2-phenyl-2- (2 -Pyridyl) pentyl] succinamic acid

Embedded image ¹ H-NMR (DMSO-d ₆ ) δ: 1.05-1.52 (2H, m), 1.55-1.72 (2
H, m), 1.90-2.50 (9H, m), 2.60-3.13 (6H, m), 3.83-
4.20 (2H, m), 5.00-5.60 (1H, br), 7.03-7.50 (11H,
m), 7.62-7.73 (1H, m), 8.53 (1H, d)

Example 6-1 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] glycine ethyl ester dihydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4-
[Hydroxypiperidino] -2,2-diphenyl) pentane (340 mg) and potassium carbonate (414 mg) in acetonitrile (5 ml).
mg) and stirred at 60 ° C. for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20: 1). After evaporating the solvent, the obtained residue was treated with 4N hydrogen chloride / ethyl acetate to give an amorphous powder. The compound (200 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.36 (5H, m), 1.50-1.85 (4H,
m), 2.06 (2H, dt), 2.16-2.42 (6H, m), 2.67 (2H, br
d), 3.26 (2H, s), 3.31 (2H, s), 4.12 (2H, q), 7.1
4-7.35 (12H, m), 7.43 (2H, d) Example 6-2 was synthesized in the same manner as in Example 6-1. Example 6-2 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -4
-Ethyl aminobutyrate dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.03-1.34 (5H, m), 1.35-1.77 (6H,
m), 2.04 (2H, dt), 2.15-2.40 (8H, m), 2.55 (2H,
t), 2.66 (2H, br d), 3.21 (2H, s), 4.08 (2H, q),
7.12-7.34 (12H, m), 7.42 (2H, d) Examples 7-1 and 2 were synthesized in the same manner as in Example 5-1.

Example 7-1 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] glycine

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.40 (2H, m), 1.45-1.73 (2H,
m), 1.83-2.27 (4H, m), 2.28-2.80 (6H, m), 2.97 (2H,
s), 3.17 (2H, s), 3.50-4.50 (3H, br), 6.90-7.50
(14H, m) Example 7-2 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -4
-Aminobutyric acid

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.43 (2H, m), 1.52-1.83 (4H,
m), 2.05-2.34 (7H, m), 2.40-2.80 (6H, m), 2.81-3.04
(2H, m), 3.28 (2H, s), 4.10-4.80 (2H, br), 7.08-7.
50 (14H, m)

Example 8-1 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(3-hydroxypyrrolidin-1-yl) propanamide

Embedded image 1) 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1- (3-chloropropionylamino) -2,2-diphenylpentane 1-amino-5- [4- (4-chlorophenyl) ) -4-
[Hydroxypiperidino] -2,2-diphenylpentane (0.9 g) in THF (20 ml) was added with saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred vigorously under ice-cooling to give 3-chloropropionyl chloride (0.21 ml). The mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with pure water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (7: 3) to give amorphous powder. -[4- (4-chlorophenyl) -4-
[Hydroxypiperidino] -1- (3-chloropropionylamino) -2,2-diphenylpentane (0.82
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.43 (2H, m), 1.63-1.75 (2
H, m), 2.10-2.59 (10H, m), 2.75-2.97 (2H, m), 3.74
(2H, t), 4.05 (2H, d), 5.21 (1H, br s), 7.14-7.38
(12H, m), 7.43 (2H, d). 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1- (3-chloropropionylamino)-
2,2-Diphenylpentane (0.19 g) was dissolved in ethanol, and potassium carbonate (0.10 g) and 3-hydroxypyrrolidine (0.045 ml) were added.
Stirred for hours. The reaction solution was diluted with ethyl acetate, washed with pure water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (1: 1) to give the title as an amorphous powder. The compound (0.08 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.32-1.47 (2H, m), 1.64-1.75 (2
H, m), 1.87-2.38 (12H, m), 2.41-2.90 (8H, m), 4.02-
4.18 (2H, m), 4.22-4.28 (1H, m), 7.18-7.36 (12H,
m), 7.43 (2H, d), 7.93 (1H, brs). Examples 8-2 and 8-3 were synthesized in the same manner as in Example 8-1.

Example 8-2 5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-1- (3-pyrrolidin-1-yl-propionylamino) pentane

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.40 (2H, m), 1.49-1.72 (8
H, m), 1.94-2.15 (4H, m), 2.22-2.37 (8H, m), 2.50
(2H, t), 2.65 (2H, br d), 3.83 (2H, d), 4.04 (2H,
d), 7.10-7.36 (12H, m), 7.43 (2H, d), 8.22 (1H, b
r) Example 8-3 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1- [3- (dimethylamino) propionylamino] -2,2-diphenylpentane

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.43 (2H, m), 1.52-1.79 (4
H, m), 1.92 (6H, s), 2.03-2.52 (10H, m), 2.62-2.82
(2H, br), 4.03 (2H, d), 7.10-7.46 (14H, m), 8.22
(1H, br) Example 9 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(T-butoxycarbonyl) aminopropanamide

Embedded image 1- (5-amino-4,4-diphenylpentyl) -4
-(4-Chlorophenyl) -4-hydroxypiperidine (0.8 g) was dissolved in DMF (5 ml) and N-Boc was dissolved.
-Β-alanine (0.38 g), triethylamine (0.56 ml), diethyl cyanophosphate (0.28 m
l) was added at 0 ° C. After reacting at room temperature for 1 hour, the mixture was poured into pure water (20 ml). After extraction with ethyl acetate, the extract was washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (0.85 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.39 (2H, m), 1.47 (9H,
s), 1.61-1.75 (2H, m), 1.98-2.16 (4H, m), 2.18-2.3
8 (10H, m), 2.67-2.81 (2H, m), 3.30-3.42 (2H, m),
4.01 (2H, d), 5.08 (1H, brs), 5.79 (1H, br s), 7.1
6-7.35 (12H, m), 7.42 (2H, d).

Example 10 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-Aminopropanamide dihydrochloride

Embedded image N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(T-Butoxycarbonyl) aminopropanamide (0.8 g) was dissolved in ethyl acetate (10 ml), and 4N hydrochloric acid-ethyl acetate solution (2.5 ml) was added.
For 3 hours. The solvent was distilled off under reduced pressure, the residue was suspended in ethyl acetate, and the title compound (0.
74 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.60-1.73 (2
H, m), 1.96-2.19 (6H, m), 2.23-2.39 (4H, m), 2.59-
2.71 (2H, m), 2.83 (2H, t), 4.03 (2H, d), 6.52-6.6
2 (1H, m), 7.18-7.33 (12H, m), 7.42 (2H, d).

Example 11 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Acetylamino) propanamide

Embedded image N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-Aminopropanamide dihydrochloride (0.16 g)
After adding to HF (3 ml) -saturated aqueous sodium hydrogen carbonate (3 ml), acetic anhydride (0.03 ml) was added and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate, and the residue was crystallized from isopropyl ether to give the title compound (0.07 g). 128-130 ° C

Example 12 N- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Propionylamino) propanamide

Embedded image The same procedure as in Example 11 was performed to obtain the title compound (0.02 g). Recrystallization solvent Isopropyl ether Melting point 128-130 ° C Example 13 1- [4,4-Diphenyl-5- (phenyloxycarbonylamino) pentanoyl] -4- (4-chlorophenyl) -4-hydroxypiperidine

Embedded image 1- (5-amino-4,4-diphenylpentanoyl) -4- (4-chlorophenyl) -4- obtained in Reference Example 22
Hydroxypiperidine (2.32 g) was added to THF (50 m
l), and triethylamine (1.39 ml) and phenyl chlorocarbonate (0.69 ml) were added at 0 ° C.
Stirred for hours. The reaction solution was diluted with ethyl acetate and washed with pure water and saturated saline. After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (3: 7) to obtain the title compound (2.90 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.57-2.34 (8H, m), 2.56 (2H,
t), 2.91-3.04 (2H, m), 3.25-3.50 (2H, m), 3.87-4.17
(2H, m), 4.43-4.57 (2H, m), 4.83-4.92 (2H, m), 7.
00 (2H, d), 7.14-7.42 (12H, m).

Example 14 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] -3- [3- (hydroxy) propyl] Urea

Embedded image The title compound was obtained in the same manner as in Example 11 using 1- [4,4-diphenyl-5- (phenyloxycarbonylamino) pentanoyl] -4- (4-chlorophenyl) -4-hydroxypiperidine (0.41 g). Compound (0.32
g) was obtained. Recrystallization solvent Ethyl acetate Melting point 192-194 ° C Example 15 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] -3- [ 3- (dimethylamino) ethyl) urea

Embedded image The title compound was obtained in the same manner as in Example 11. Recrystallization solvent Ethyl acetate Melting point 223-225 ° C

Example 16 1- (5-acetylamino-4,4-diphenylpentanoyl) -4- (4-chlorophenyl) -4-hydroxypiperidine

Embedded image 1- (5-amino-4,4-diphenylipentanoyl)
-4- (4-Chlorophenyl) -4-hydroxypiperidine (0.46 g) was dissolved in THF (10 ml), triethylamine (0.28 ml), acetic anhydride (0.1 m
l) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution is diluted with ethyl acetate and washed with pure water and saturated saline.
After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (9: 1). Crystallization from ethyl acetate-ether gave the title compound (0.36 g). Melting point 191-192 [deg.] C Example 17 ethyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] succinamidate

Embedded image 1- (5-amino-4,4-diphenylipentanoyl) -4- (4-chlorophenyl) in the same manner as in Example 16.
Using -4-hydroxypiperidine (0.56 g), it was acylated with ethylsuccinyl chloride and crystallized from ether to give the title compound (0.53 g). 94-96 ° C

Example 18 N- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] succinamidic acid

Embedded image Ethyl 4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] succinate (0.3 g) was added to THF.
(1 ml), 1N aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature for 2 hours. After acidification with 1N hydrochloric acid, the mixture is extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (9: 1). Crystallization from ethyl acetate gave the title compound (0.36 g). Mp 177-180 ° C. Example 19 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenyl-5-oxopentyl] -3- [3- (2- Oxo-1-pyrrolidino)
Propyl) urea

Embedded image The title compound was obtained in the same manner as in Example 16. Recrystallization solvent Ethyl acetate Melting point 194-197 ° C

Example 20 5- [3- (4-Chlorophenyl) -3-hydroxypyrrolidin-1-yl] -2,2-diphenyl-1formylpentanamine

Embedded image 3- (4-chlorophenyl) -3-hydroxypyrrolidine (Medicinal Chemistry Research, vol. 3, 459-4)
67, 1993) to obtain the title compound in the same manner as in Example 1-1. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.38 (2H, m), 1.95 (1H, b
r), 2.13-2.55 (8H, m), 2.91 (1H, d), 3.01-3.14 (1H,
m), 3.86-4.08 (2H, m), 5.12 (1H, br s), 7.16-7.44
(14H, m), 8.10 (1H, s). Example 21 1- [5- [4- (4-Chlorophenyl) -3-hydroxypiperidi] -2,2-diphenylpentyl] -3-
[3- (hydroxy) propyl] urea

Embedded image 5- [3- (4-chlorophenyl) -3-hydroxypyrrolidin-1-yl] -2,2-diphenyl-1formylpentanamine (0.92 g) was added to ethanol (5 ml).
And a 4N aqueous sodium hydroxide solution (5 ml) was added thereto, followed by stirring at 90 ° C for 16 hours. The reaction solution was extracted with ethyl acetate, washed with a saturated saline solution and dried, and the solvent was distilled off under reduced pressure to obtain a formyl derivative (0.81 g). The obtained deformyl form (0.65 g) was dissolved in THF (15 ml), and triethylamine (0.42 ml) was added. 0 ° C
Then, phenyl chlorocarbonate (0.21 ml) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (4: 1). The solvent was distilled off under reduced pressure to obtain a phenyl carbamate as an oily residue. Then, the title compound (0.2 g) was obtained in the same manner as in Example 4-1. Recrystallization solvent Ether / hexane Melting point 150-153 ° C

Example 22 1-Formylamino- [5- [4-hydroxy-4-
(4-Chlorophenyl) hexamethyleneimin-1-yl] -2,2-diphenylpentane hydrochloride

Embedded image The title compound was obtained in the same manner as in Example 1-1 using 4- (4-chlorophenyl) -4-hydroxyhexamethyleneimine. ¹ H-NMR (CDCl ₃ ) δ: 1.17-1.40 (2H, m), 1.50-2.23 (9
H, m), 2.25-2.97 (6H, m), 4.06 (2H, d), 5.20-5.35 (1H,
br), 7.05-7.42 (14H, m), 8.08 (1H, d).

Embedded image 5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -1-formylamino-2-phenyl-2-
(2-thienyl) pentane hydrochloride 5-formylamino-1-iodo-4 described in Reference Example 31
Using -phenyl-4- (2-thienyl) pentane, the title compound was obtained by the same reaction as described in Example 1-1. Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.58 (2H, m), 1.66 (2H, d),
1.97-2.50 (9H, m), 2.61-2.77 (2H, m), 4.03 (2H, d
d), 5.40-5.51 (1H, br), 6.83-6.99 (2H, m), 7.13-7.
48 (10H, m), 8.08 (1H, d)

Example 24 2,2-Bis (4-chlorophenyl) -5- [4- (4
-Chlorophenyl) -4-hydroxypiperidino] -1
-Formylaminopentane hydrochloride

Embedded image The title compound was obtained by the method described in Example 1-1 using 4,4-bis (4-chlorophenyl) -5-formylaminopentyl-1-tosylate described in Reference Example 7-5. Amorphous powder 1H-NMR (CDCl3) δ: 1.05-1.38 (2H, m), 1.60-1.80 (2
H, m), 1.85-2.15 (5H, m), 2.23-2.40 (4H, m), 2.58-
2.75 (2H, m), 4.00 (2H, d), 5.08-5.20 (1H, br), 7.
00-7.20 (4H, m), 7.29 (6H, d), 7.42 (2H, d), 8.10
(1H, s)

Example 25 N- [2,2-bis (4-chlorophenyl) -5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]] ethyl pentyl succinamidate hydrochloride

Embedded image (1) 2,2-bis (4-chlorophenyl) -5- [4
Preparation of-(4-chlorophenyl) -4-hydroxypiperidino] -1-pentylamine dihydrochloride 2,2-bis (4-chlorophenyl) -5- [4- (4
-Chlorophenyl) -4-hydroxypiperidino] -1
-A 6N aqueous sodium hydroxide solution (1) was added to a solution of formylaminopentane (1.7 g) in ethanol (30 ml).
0 ml) and stirred at 100 ° C. for 14 hours. After evaporating the solvent under reduced pressure and dissolving the residue in ethyl acetate, the organic layer was washed with water and saturated saline and dried. The solvent was distilled off under reduced pressure, and 4N hydrogen chloride-ethyl acetate was added to obtain the title compound (1.6 g, amorphous powder). ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.55 (4H, m), 1.58-1.73 (2
H, m), 1.94-2.16 (5H, m), 2.20-2.40 (4H, m), 2.59-
2.72 (2H, m), 3.26 (2H, s), 7.03-7.18 (4H, m), 7.2
0-7.35 (6H, m), 7.35-7.45 (2H, m) (2) N- [2,2-bis (4-chlorophenyl) -5
Preparation of ethyl [-(4- (4-chlorophenyl) -4-hydroxypiperidino]] pentylsuccinamidate hydrochloride The acylation reaction described in Example 3-1 using the compound obtained in the above (1). Afforded the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.40 (5H, m), 1.59-1.74 (2
H, m), 1.84-2.15 (5H, m), 2.22-2.40 (6H, m), 2.53-
2.72 (4H, m), 3.94 (2H, d), 4.09 (2H, q), 5.24 (1
H, br t), 7.05-7.20 (4H, m), 7.20-7.34 (6H, m), 7.
42 (2H, d)

Example 26 N- [2,2-bis (4-chlorophenyl) -5- [4
-(4-chlorophenyl) -4-hydroxypiperidino]] pentylsuccinamic acid

Embedded image N- [2,2-bis (4-chlorophenyl) -5- [4
-(4-Chlorophenyl) -4-hydroxypiperidino]] ethyl pentyl succinamidate was prepared in Example 5-1.
The title compound was obtained by subjecting it to the hydrolysis reaction described. Amorphous powder ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.50 (2H, m), 1.60-1.76
(2H, m), 1.97-2.42 (9H, m), 2.75-3.20 (6H, m), 3.75
-4.00 (2H, m), 5.25-5.60 (1H, br), 7.17 (4H, d), 7.
30-7.55 (8H, m) Example compounds 27-1 to 23 similar to Example 4-1
Was synthesized.

Example 27-1 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[(1-ethoxycarbonyl) piperidin-4-yl] urea

Embedded image Recrystallization solvent Ethyl ether Melting point 223-226 ° C Example 27-2 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[2- (1-pyrrolidino) ethyl] urea

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 132-133 ° C Example 27-3 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[2- (diethylamino) ethyl] urea

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 134-136 ° C

Example 27-4 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(3-aminopropyl) -3-methylurea

Embedded image Recrystallization solvent Ethyl acetate Melting point 92-94 ° C Example 27-5 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(5-hydroxypentyl) urea

Embedded image Recrystallization solvent; ethyl acetate / ethyl ether, melting point 149-151 ° C

Example 27-6 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[2- (dimethylamino) ethyl] -3-methylurea

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.58-1.71 (2
H, m), 1.99 (6H, s), 2.00-2.17 (4H, m), 2.22-2.38
(6H, m), 2.61-2.75 (2H, m), 2.73 (3H, s), 3.12 (2
H, t), 3.97 (2H, d), 5.23 (1H, brs), 7.17-7.33 (12
H, m), 7.43 (2H, d). Example 27-7 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3.
-[2- (methylamino) ethyl] -3-methylurea

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.38 (2H, m), 1.65 (2H, br
d), 1.95-2.42 (8H, m), 2.20 (3H, s), 2.53-2.78 (4H,
m), 2.72 (3H, s), 3.12 -3.24 (2H, m), 3.95 (2H,
d), 5.20 (1H, brs), 6.82-6.93 (1H, m), 7.15-7.34
(11H, m), 7.42 (2H, d).

Example 27-8 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(2-hydroxyethyl) -3-methylurea

Embedded image 1H-NMR (CDCl3) δ: 1.27-1.39 (2H, m), 1.67 (2H, br
d), 2.02-2.18 (2H, m), 2.25-2.43 (2H, m), 2.60-2.78
(2H, m), 2.68 (3H, s), 3.32 (2H, t), 3.97 (2H, t),
4.28 (1H, brs), 6.82-6.94 (1H, m), 7.16-7.34 (11
H, m), 7.42 (2H, d). Example 27-9 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3.
-[2- (acetylamino) ethyl] urea

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 210-213 ° C Example 27-10 Ethyl 4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] ureidobutyrate

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 121-123 ° C

Example 27-11 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(3-hydroxypropyl) urea

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 101-102 ° C Example 27-12 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(1-benzylpiperidin-4-yl) urea

Embedded image Recrystallization solvent Isopropyl ether / ethyl ether Melting point 176-178 ° C Example 27-13 N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -4
-Methylpiperazine-1-carboxamide

Embedded image Recrystallization solvent Isopropyl ether / ethyl ether Melting point 156-157 ° C

Example 27-14 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
4-benzylpiperazine-1-carboxamide

Embedded image Recrystallization solvent isopropyl ether / ethyl ether Melting point 142-143 ° C Example 27-15 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
1,2,4,5-tetrahydro-3-benzazepine-
3-carboxamide

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.44 (2H, m), 1.57-1.80 (2
H, m), 1.98-2.20 (4H, m), 2.23-2.47 (4H, m), 2.62-
2.82 (6H, m), 3.32-3.37 (4H, m), 3.97-4.06 (3H,
m), 7.02-7.19 (4H, m), 7.21-7.43 (14H, m).

Example 27-16 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
3- (trifluoroacetylamino) pyrrolidine-1-
Carboxamide

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.30 (2H, br), 1.61-1.75 (2H,
m), 1.96-2.42 (11H, m), 2.70 (2H, br), 3.12-3.24 (2
H, m), 3.27-3.48 (2H, m), 3.72-3.80 (1H, m), 3.83-
4.07 (2H, m), 4.42 (1H, br), 7.17-7.42 (14H, m). Example 27-17 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino]- 2,2-diphenylpentyl]-
4- (t-butoxycarboxamide) piperidine-1-
Carboxamide

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.37 (2H, m), 1.43 (9H,
s), 1.60-1.91 (6H, m), 1.97-2.16 (4H, m), 2.22-2.3
9 (4H, m), 2.57-2.79 (4H, m), 3.43-3.65 (3H, m),
3.95 (3H, br), 4.42 (1H, br), 7.15-7.37 (12H, m),
7.40-7.45 (2H, m).

Example 27-18 [4- [3- [5- [4- (4-chlorophenyl) -4]
-Hydroxypiperidino] -2,2-diphenylpentyl] ureido] piperidino] ethyl acetate

Embedded image Recrystallization solvent isopropyl ether / ethyl ether Melting point 116-118 ° C Example 27-19 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[1- (trifluoroacetyl) piperidin-4-yl] urea

Embedded image Recrystallization solvent Ethyl ether Melting point 192-193 ° C Example 27-20 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
4-formyl-1-piperazinecarboxamide

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 191-192 ° C

Example 27-21 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
4- (3-hydroxypropyl) -1-piperazinecarboxamide

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 125-127 ° C Example 27-22 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
4- (ethoxycarbonyl) -1-piperazinecarboxamide

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.37 (2H, m), 1.25 (3H,
t), 1.61-1.68 (2H, m), 1.97-2.17 (4H, m), 2.21-2.3
8 (4H, m), 2.60-2.72 (2H, m), 3.03-3.20 (4H, m),
3.34-3.41 (4H, m), 3.92-4.00 (1H, br), 3.96 (2H,
s), 4.12 (2H, q), 7.17-7.44 (14H). Examples 27-23 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl ]-
4- (morpholinocarbonylmethyl) -1-piperazinecarboxamide

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point: 163 to 165 ° C. Example compounds 28-1 and 28 were synthesized in the same manner as in Example 5-1.

Example 28-1 3- [3- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] ureido] propionic acid

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.46 (2H, br), 1.71 (2H, brd),
2.17-2.60 (6H, m), 2.72-3.03 (4H, m), 3.15-3.45 (4
H, m), 3.92 (2H, brd), 4.87 (1H, br), 5.71 (1H, b
r), 7.12-7.45 (14H, m). Example 28-2 4- [3- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] ureido] butyric acid

Embedded image Recrystallization solvent Water Melting point 137-139 ° C

Example 29 1N- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] vinylsulfonamide

Embedded image Triethylamine (0) was added to a solution of 1-amino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane (0.9 g) obtained in Reference Example 26 in THF (20 ml). .84 ml) and added 2-chloroethanesulfonyl chloride (0.21 m) at room temperature.
l) was added and stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with pure water, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (7: 3) to give an amorphous powder. The title compound (0.82 g) was obtained. Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.35 (2H, m), 1.60-1.73 (2
H, m), 2.07-2.45 (8H, m), 2.65-2.79 (2H, m), 3.70
(2H, br s), 5.55 (1H, dd), 6.11 (1H, d), 6.12 (1H,
d), 7.14-7.48 (14H, m).

Example 30 1N- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl]-
2- (pyrrolidino) ethylsulfonamide

Embedded image 1N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] vinylsulfonamide (0.27 g) was dissolved in ethanol, and pyrrolidine (0.062 ml) was added. In addition, at room temperature
Stir for 6 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and ethyl acetate-methanol (7: 7) was added.
Elution was performed in 3) to obtain the title compound (0.10 g). Recrystallization solvent Ethyl acetate / Ethyl ether Melting point 140-142 ° C

Example 31 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[3- (carbamoyloxy) propyl] urea

Embedded image 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (3-hydroxypropyl) obtained in Example 27-11
Urea was dissolved in THF (5 ml), and chlorosulfonyl isocyanate (0.044 ml) was added.
Stirred for hours. Then, a saturated aqueous sodium hydrogen carbonate solution (5 ml) was added and 4
Stirred at 5 ° C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (4: 1) to obtain the title compound. Was. Recrystallization solvent Ethyl ether Melting point 152-154 ° C

Example 32 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Piperidin-4-yl) urea

Embedded image 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-obtained in Example 27-19.
Diphenylpentyl] -3- [1- (trifluoroacetyl) piperidin-4-yl] urea (2.35 g) was dissolved in THF (10.5 ml), and 0.5N sodium hydroxide (10.5 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-ether to give the title compound (1.92 g). Melting point 194-196 ° C

Example 33-1 4- [4- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] ethyl piperidino-4-oxobutyrate

Embedded image 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Piperidin-4-yl) urea (0.29 g)
Dissolved in HF (10 ml) and triethylamine (0.21
ml) was added. Ethyl succinyl chloride (0.07
7 ml) and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (4: 1) to obtain the title compound (0.28 g). Recrystallization solvent: ethyl acetate / ethyl ether, melting point 173-175 ° C. Example compounds 33-2 to 5 were synthesized in the same manner. Example 33-2 N-ethyl-4- [5- [4- (4-chlorophenyl)]
-4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide

Embedded image Recrystallization solvent Ethyl acetate / Ethyl ether Melting point 193-195 ° C

Example 33-3 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(1-acetylpiperidin-4-yl) urea

Embedded image Recrystallization solvent Ethyl ether Melting point 146-148 ° C Example 33-4 N-ethoxycarbonylmethyl-4- [5- [4- (4
-Chlorophenyl) -4-hydroxypiperidino]-
2,2-Diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide

Embedded image Recrystallization solvent Ethyl acetate Melting point 220-221 ° C Example 33-5 3- [4- [5- [4- (4-chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-3-oxopropionate

Embedded image Recrystallization solvent Ethyl ether Melting point 173-175 ° C

Example 34-1 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(1-ethylpiperidin-4-yl) urea

Embedded image 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-(Piperidin-4-yl) urea (0.29 g) was added to D
Dissolved in MF (5 ml) and added potassium carbonate (0.14 g). Ethyl iodide (0.12 ml) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (0.14 g). Melting point: 154 to 157 ° C.
34-4 was synthesized. Example 34-2 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[1- (2-hydroxyethyl) piperidin-4-yl] urea

Embedded image Recrystallization solvent Ethyl acetate Melting point 177-180 ° C

Example 34-3 3- [4- [5- [4- (4-Chlorophenyl) -4-]
[Hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylaminopiperidino] ethyl propionate

Embedded image Recrystallization solvent Ethyl acetate / ethyl ether Melting point 148-151 ° C Example 34-4 1- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3
-[1- (3-hydroxypropyl) piperidine-4-
Il] Urea

Embedded image Recrystallization solvent Ethyl acetate / Ethyl ether Melting point 194-197 ° C

Example 35 1-[(Piperidin-4-yl) carboxamide] -5
-[4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane dihydrochloride

Embedded image Triethylamine (0.6 g) was added to a solution of 1-trifluoroacetylpiperidine-4-carboxylic acid (1.2 g) in acetonitrile (30 ml), and the reaction solution was cooled to -15 ° C. Add isopropyl chlorocarbonate (0.6
7 g) was slowly added dropwise, and the mixture was stirred at the same temperature for 2 minutes.
THF of amino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane (2.5 g) and triethylamine (0.5 g)
The solution (50 ml) was added dropwise. After stirring at room temperature for 24 hours,
Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried, concentrated under reduced pressure, the residue was dissolved in a mixed solvent of ethanol-water (2: 1), sodium hydroxide (2 g) was added, and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure,
Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, applied to an alumina column, and purified by elution with ethyl acetate / ethanol (4: 1). After concentration of the eluate, the residue was dissolved in ethyl acetate and excess 4N
After adding hydrochloric acid / ethyl acetate, the mixture was concentrated under reduced pressure to obtain the title compound. Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.70 (9H, m), 1.87-2.18 (6H,
m), 2.20-2.39 (4H, m), 2.42-2.70 (4H, m), 3.05 (2H,
dt), 3.98 (2H, d), 5.02 (1H, t), 7.14-7.48 (14H,
m)

Example 36-1 1-[(N-ethylpiperidin-4-yl) carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane 2 Hydrochloride

Embedded image 1-[(piperidin-4-yl) carboxamide] -5
-[4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane (0.4 g) in acetonitrile (10 ml) was mixed with potassium carbonate (0.5 ml).
g) and iodoethane (0.2 ml) were added.
Stirred for hours. The reaction solution was dissolved in ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue was applied to an alumina column and eluted with ethyl acetate. After concentrating the eluate, the residue was dissolved in ethyl acetate, excess 4N-hydrochloric acid / ethyl acetate was added, and the mixture was concentrated under reduced pressure to obtain the title compound. Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t), 1.20-1.85 (14H, m),
1.80-2.35 (8H, m), 2.65 (2H, m), 2.90 (2H, m), 3.99 (2
H, d), 5.04 (1H, t), 7.14-7.48 (14H, m) Examples 36-2 to 36-4 in the same manner as in Example 36-1.
I got

Example 36-2 1-[[N- (Ethoxycarbonylmethyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2 −
Diphenylpentane dihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t), 1.20-1.85 (10H, m),
1.80-2.40 (8H, m), 2.65 (2H, m), 2.90 (2H, m), 3.16 (2
H, s), 3.98 (2H, d), 4.16 (2H, q), 5.04 (1H, t), 7.14-7.
48 (14H, m) Example 36-3 1-[[N- (2-morpholinoethyl) piperidine-4
-Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane trihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.85 (12H, m), 1.80-2.50 (1
2H, m), 2.46 (4H, s), 2.65 (2H, m), 2.90 (2H, m), 3.70 (4
H, m), 3.98 (2H, d), 5.01 (1H, t), 7.14-7.48 (14H, m)

Example 36-4 1-[[N- (2-Dimethylaminoethyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2 , 2-
Diphenylpentane trihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.85 (12H, m), 2.12 (6H, s),
2.40 (4H, s), 1.80-2.50 (12H, m), 2.65 (2H, m), 2.89 (2
H, m), 3.98 (2H, d), 5.02 (1H, t), 7.14-7.48 (14H, m) Example compounds 37-1 to 37-8 as in Example 33-1.
Was synthesized.

Example 37-1 1-[[(N-ethylcarbamoyl) piperidine-4-
Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t), 1.10-2.10 (14H, m),
2.20-2.40 (4H, m) 2.45-2.95 (4H, m), 3.20 (2H, m), 3.85-
3.91 (2H, m), 4.00 (2H, d), 4.38 (1H, t), 5.02 (1H, t),
7.14-7.48 (14H, m) Example 37-2 1-[[(N-methylcarbamoyl) piperidine-4-
Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (8H, m), 1.90-2.15 (4H,
m), 2.20-2.40 (4H, m), 2.60-2.85 (4H, m), 3.67 (3H, s),
3.95-4.20 (2H, d), 4.00 (2H, d), 4.38 (1H, t), 5.02 (1
H, t), 7.14-7.48 (14H, m)

Example 37-3 1-[[(N-phenylcarbamoyl) piperidine-4
-Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-2.10 (14H, m), 2.20-2.40 (4H,
m), 2.50-2.90 (4H, m), 4.00 (2H, d), 4.00-4.20 (2H,
m), 5.04 (1H, t), 6.43 (1H, m), 7.14-7.48 (19H, m) Example 37-4 1-[[(N- (4-chlorobenzoyl) piperidine-
4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-2.40 (14H, m), 2.50-2.90 (5H,
m), 3.75 (1H, m), 3.98 (2H, d), 3.90-4.20 (2H, m), 4.5
0 (1H, m), 5.04 (1H, t), 7.14-7.48 (17H, m), 7.93 (2H,
d).

Example 37-5 1-[[N- (Ethoxycarbonylacetyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2
-Diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t), 1.10-2.30 (15H, m), 2.
42-2.80 (4H, m), 3.00 (1H, t), 3.43 (2H, s), 3.60 (1H,
m), 3.98 (2H, d), 3.80-4.00 (2H, m), 4.19 (2H, q), 4.43
(1H, m), 5.04 (1H, t), 7.10-7.58 (14H, m) Example 37-6 1-[[N- (3-methoxycarbonylpropionyl)
Piperidin-4-yl] carboxamide] -5- [4-
(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentane hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (10H, m), 1.90-2.50 (8
H, m), 2.59 (4H, m), 2.60-2.80 (2H, m), 2.96 (1H, t), 3.6
8 (3H, s), 3.80-4.00 (4H.m), 4.40 (1H, d), 5.18 (1H, m),
7.00-7.50 (14H, m)

Example 37-7 1-[[N- (nicotinoyl) piperidin-4-yl]
Carboxamide] -5- [4- (4-chlorophenyl)
-4-Hydroxypiperidino] -2,2-diphenylpentane dihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (10H,
m), 1.90-2.50 (8H, m), 2.6
0 (2H, m), 2.80-3.10 (2H, m),
3.70 (1H, m), 4.02 (2H.d),
4.50 (1H, m), 5.04 (1H, m),
7.00-7.50 (15H, m), 7.73 (1
H, dt), 8.61 (1H, d), 8.66 (1
H, dd) Example 37-8 1-[[N- (4-Dimethylaminobutyryl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] −2,2
-Diphenylpentane dihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (10H,
m), 2.16 (6H, s), 1.90-2.50 (15H, m), 2.60 (2H, m), 2.80
-3.10 (1H, m), 3.70-3.90 (1H, m), 4.01 (2H.m), 4.50 (1H, m
d), 5.004 (1H, t), 7.00-7.50 (14H, m) Example 38 was obtained in the same manner as in Example 36-1.

Example 38 1-[(N-propylpiperidin-4-yl) carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane
Dihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t), 1.20-1.85 (16H, m),
1.80-2.35 (8H, m), 2.64 (2H, m), 2.87 (2H, m), 3.98
(2H, d), 5.05 (1H, t), 7.14-7.48 (14H, m) Example 37
Example 39 and Example 40 were obtained in the same manner as -1. Example 39 1-[[N-3-pyridylacetyl) piperidine-4-
Yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane dihydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.80 (8H, m), 1.90-2.40 (8H,
m), 2.60 (2H, m), 2.80 (3H, m), 3.04 (1H, m), 3.68 (2
H, s), 3.80-4.00 (2H, m), 4.00 (2H, d), 4.48 (1H, m),
5.04 (1H, m), 7.00-7.50 (15H, m), 7.65 (1H, d), 8.43
(2H, d)

Example 40 1-[[N-ethylcarbamoyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane 2 Hydrochloride

Embedded image Amorphous powder ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t), 1.10-1.80 (8H, m),
1.90-2.15 (4H, m), 2.20-2.40 (4H, m), 2.60-2.85 (4H, m
m), 3.05 (1H, m), 3.75 (1H, m), 3.95-4.20 (2H, d), 4.2
2 (2H, q), 4.47 (1H, t), 5.07 (1H, t), 7.14-7.48 (14H,
m)

Formulation Example 1 (1) 10.0 g of the compound of Example 4-2 (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g 10.0 g of the compound obtained in Example 4-2 and lactose
0 g and a mixture of 35.0 g of corn starch were mixed with 30 ml of a 10% by weight aqueous solution of gelatin (3.0 g as gelatin).
Using g), the mixture was granulated through a 1 mm mesh sieve, dried at 40 ° C. and sieved again. The obtained granules were mixed with 2.0 g of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia.
Polish the coated tablets with beeswax to 100
0 coated tablets were obtained. Formulation Example 2 (1) Compound of Example 4-2 10.0 g (2) Lactose 70.0 g (3) Corn starch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium stearate 2.0 g Example 4 -G of 10.0 g of the compound obtained in -2 and 3.0 g of magnesium stearate in an aqueous solution of soluble starch 70
after granulation in 7 ml (7.0 g as soluble starch), dried, 70.0 g lactose and 5 g corn starch.
0.0 g. The mixture was compressed to give 1000 tablets.

[0230] ^{1 2 5} I-RANT with Experimental Example 1 Human MIP-1α / RANTES receptor expressing CHO cells (CHO (CCR) cells)
Measurement of ES binding inhibitory activity 96-well microplate (CulturPlat)
e, Packard Instrument Comp
any, Meriden, CT, USA)
O (CCR) cells 5 × 10 ⁴ / 100μl / well
And cultured for 24 hours. After removing the medium, 35 μl /
well DMEM / 0.5% BSA, then DMEM
Test compound diluted with 0.5% / 0.5% BSA
ll, further ^{1 2 5} I-RANT of 10 [mu] l / well
ES (final concentration: 200 pM) was added sequentially, and the solution was added at room temperature for 40 minutes.
Incubated for minutes. Then 200μl / well
Was washed twice with PBS, and 25 μl / well of ethanol was added thereto, followed by stirring. Further, a 200 μl / well scintillator (MicroScint-20, Pac
After攪袢Kard Instrument Company) was added, ^{1 2 5} I-RAN cell bound
The radioactivity of TES was measured using TopCount (Packard).
Instrument Company). 100% binding amount when no test compound is added,
CHO cells transfected with the vector plasmid pAKKO-111H (mock transfect
The amount of binding of the ants) and ^{0%, 1 2 5 I-} RANT
Binding of ES was determined concentration (IC _{5 0} value) that inhibits 50%. Compound No. Human RANTES human MIP-l [alpha] receptor antagonism receptor antagonism _{IC 5 0 (μM) IC 5} 0 (μM) Example 1-1 0.04 0.2 Example 1-9 0.2 Example 3 -4 0.01 Example 3-5 0.04 Example 4-2 0.02 0.05 Example 4-3 0.01 Example 4-5 0.02 Example 4-7 0.04 Example 4-8 0.05 Example 32 0.0065 Example 33-2 0.02 0.6 Example 33-5 0.01 3 Example 34-1 <0.01 Example 35 0.035 Example Example 37-1 0.03 0.1 Example 37-5 0.03 0.1 Example 37-6 0.05 0.09 loperamide 3

Experimental Example 2 Measurement of Compound Inhibitory Activity by Migration Assay Using CHO (CCR) Cells A 96-well microchemotaxis chamber (Neur)
oProbe, Inc. , Cabin John,
(MD, USA). 5μm pore size polycarbonate frame filter (N
euroProbe) was diluted with PBS to 10 μg /
A pretreatment was performed by immersing in 10 ml of bovine fibronectin solution at room temperature for 10 minutes and air-drying. D in lower room
37 μl of 40 nM in MEM / 0.5% BSA
RANTES was added, and DMEM / 0.5 was added to the upper chamber first.
100 μl of the test compound diluted with% BSA was added, and then 2 × 10 ⁶ cells / ml of CHO (CCR)
100 μl of cells were added. After incubating at 37 ° C. for 4 hours, the CHO cells that migrated to
If-Quick), the absorbance at 595 nm was measured. When 40 nM RANTES was added to the lower chamber and the test compound was not added to the upper chamber, the absorbance was 100%.
When only EM / 0.5% BSA was added and the test compound was not added to the upper chamber, the absorbance was set to 0%, and CHO (CCR)
The migration of cells was determined concentration (IC _{5 0} value) that inhibits 50%. Each analyte compound migrates CHO (CCR) cells by 1
0μM inhibited in the following IC _{5 0} value.

[0232]

[Table 1]

[0233]

[Table 2]

[0234]

[Table 3]

[0235]

[Table 4]

[0236]

[Table 5]

[0237]

[Table 6]

[0238]

[Table 7]

[0239]

According to the present invention, there is provided a preparation comprising an allergic disease, a diphenylmethane derivative and a pharmaceutically acceptable salt thereof. It has excellent MIP-1α / RANTES receptor antagonism as a prophylaxis / treatment for inflammatory diseases and the like.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/445 ABF A61K 31/445 ABF ABG ABG ABM ABM ABX ABX ACF ACF ADA ADA AED AED 31/495 AAB 31/495 AAB AAG AAG AAA AAH ACV ACV ADN ADN ADP ADP ADU ADU ADU ADV ADV ADY ADY ADZ ADZ 31/535 ABJ 31/535 ABJ 31/55 ABN 31/55 ABN 021 / 58 211/58 211/62 211/62 211/70 211/70 223/08 223/08 295/12 295/12 A 401/04 211 401/04 211 401/06 211 401/06 211 401/12 207 401/12 207 223 223 401/14 211 401/1 4 211 409/06 211 409/06 211 // (C07D 401/04 211: 52 213: 16) (C07D 401/06 211: 52 213: 38) (C07D 401/12 207: 26 211: 52) (C07D 401/12 207: 12 211: 52) (C07D 401/12 211: 52 223: 16) (C07D 401/14 211: 52 211: 60 213: 38)

Claims (44)

[Claims] (1) Formula (1) [Wherein, Ar ¹ and Ar ² each represent an aromatic group which may have a substituent, and Q ¹ and Q ² each have a substituent which may contain oxygen or sulfur in a carbon chain. the not be divalent C _1-6 aliphatic hydrocarbon group, R ¹ is a hydrogen atom, an optionally substituted lower alkyl or optionally substituted lower alkyl - carbonyl R ² represents a hydrocarbon group or an acyl group which may have a substituent, or R ¹ and R ² together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic ring which may have a substituent. The formula may be Represents a monocyclic or condensed nitrogen-containing heterocyclic ring which may have a substituent. ] Or a salt thereof, a MIP-1α / RANTES receptor antagonist. 2. Ar ¹ and Ar ² each represent (I) a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or (II) a carbon atom, a nitrogen atom, a sulfur atom and an oxygen atom. A 5- to 11-membered monocyclic or condensed aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of one or more heteroatoms (the "aromatic heterocyclic group" is a monocyclic group having 6 to 14 carbon atoms). (Which may be condensed with a cyclic or condensed polycyclic aromatic hydrocarbon group), (1) a halogen atom, (2) a C _1-3 alkylenedioxy group, (3) a nitro group, and (4) A) cyano group, (5) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, and (6) a C _2-6 alkenyl optionally having 1 to 3 halogen atoms. (7) C ₂ which may have 1 to 3 halogen atoms _-6 alkynyl group, (8) C _3-6 cycloalkyl group, (9) C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (10) 1 to 3 halogen atoms a C _1-6 alkylthio group optionally having, (11) hydroxyl group, (12) amino group, (13) mono -C _1-6 alkylamino group, (14) di -C _1-6 alkylamino group, (15) 5- to 7-membered cyclic amino ^{group, (16) -NHCOOR 3, -NHCONHR} 3, -N
An acylamino group represented by HCOR ³ or —NHSO ₂ R ³ [R ³ is (i) a C _1-6 alkyl group, (ii) a C _2-6 alkenyl group, (iii) a C _2-6 alkynyl group, (iv) A C _3-6 cycloalkyl group optionally condensed with a benzene ring optionally having 1 to 3 C _1-6 alkoxy, (v) a C _6-10 aryl group or (vi) a C _{7- 16} aralkyl group, (the “C _1-6 alkyl group”, “C _2-6 alkenyl group”, “C _2-6 alkynyl group”, “C _3-6 cycloalkyl group”, “C _6-10 aryl group "And" C _7-16 aralkyl group "are (a) a halogen atom, (b) a C _1-3 alkylenedioxy group,
(C) a nitro group, (d) a cyano group, (e) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms,
(F) a C _3-6 cycloalkyl group, (g) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(H) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) a hydroxyl group, (j)
An amino group, (k) a mono-C _1-6 alkylamino group,
(L) di-C _1-6 alkylamino group, (m) C _1-6 alkyl-carbonyl group, (n) carboxyl group, (o) C
_1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group,
(R) di-C _1-6 alkyl-carbamoyl group, (s) C
_6-10 aryl-carbamoyl group, (t) sulfo group,
(U) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) other than a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom It may have 1 to 5 substituents selected from a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo condensate thereof at a substitutable position. ), (17) C _1-6 alkyl-carbonyl group, (18) carboxyl group, (19) C _1-6 alkoxy-carbonyl group, (20) carbamoyl group, (21) mono-C _1-6 alkyl-carbamoyl Group, (22) di-C _1-6 alkyl-carbamoyl group, (23) C _6-10 aryl-carbamoyl, (24) sulfo group, (25) C _1-6 alkylsulfonyl group, (26) C _{6- 10} aryl group, or (27) C _6-10 may be substituted with an aryloxy group, Q ¹ and Q ² are each substituted with well-oxo or thioxo group optionally contain oxygen or sulfur in the carbon chain A C _1-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, wherein R ¹ is (1) a hydrogen atom, (2) (a) a halogen atom, (b) C _1-3 alkylenedioxy group, (c) Toromoto, (d) cyano group, (e) 1
To three C _1-6 alkyl group which may have a halogen atom, (f) C _3-6 cycloalkyl group, (g) 1 to 3 optionally C ₁ may have a halogen atom _-6 alkoxy group, (h) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di -C _1-6 alkylamino group, (m) C _1-6
Alkyl-carbonyl group, (n) carboxyl group,
(O) C _1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group,
(S) C _6-10 aryl-carbamoyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group, (v) C _6-10
An aryl group, (w) a C _6-10 aryloxy group and (x) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms Or a C _1-6 alkyl group which may have 1 to 5 substituents at substitutable positions selected from the benzo condensates, (3) (a) a halogen atom, and (b) C _1-3 alkyl Rangeoxy group, (c) nitro group, (d) cyano group, (e) 1
To three C _1-6 alkyl group which may have a halogen atom, (f) C _3-6 cycloalkyl group, (g) 1 to 3 optionally C ₁ may have a halogen atom _-6 alkoxy group, (h) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di -C _1-6 alkylamino group, (m) C _1-6
Alkyl-carbonyl group, (n) carboxyl group,
(O) C _1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group,
(S) C _6-10 aryl-carbamoyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group, (v) C _6-10
An aryl group, (w) a C _6-10 aryloxy group and (x) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms Or a C _1-6 alkyl-carbonyl group which may have 1 to 5 substituent (s) at a substitutable position selected from the benzo condensate, and R ² represents (1) a C _1-6 alkyl group, (2) C _2-6 alkenyl group, (3) C _2-6 alkynyl group, (4) C which may be condensed with a benzene ring which may have 1 to 3 C _1-6 alkoxy. _3-6 cycloalkyl group, (5) C _6-10 aryl group or (6) C _7-16 aralkyl group (the “C _1-6 alkyl group”, “C _2-6 alkenyl group”, “C ₂ “ _-6 alkynyl group”, “C _3-6 cycloalkyl group”, “C _6-10 aryl group” and “C _7-16 aralkyl group” (A) a halogen atom, (b) a C _1-3 alkylenedioxy group,
(C) a nitro group, (d) a cyano group, (e) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms,
(F) a C _3-6 cycloalkyl group, (g) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms,
(H) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) a hydroxyl group, (j)
An amino group, (k) a mono-C _1-6 alkylamino group,
(L) di-C _1-6 alkylamino group, (m) C _1-6 alkyl-carbonyl group, (n) carboxyl group, (o) C
_1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6 alkyl-carbamoyl group,
(R) di-C _1-6 alkyl-carbamoyl group, (s) C
_6-10 aryl-carbamoyl group, (t) sulfo group,
(U) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) other than a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom It may have 1 to 5 substituents selected from a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo condensate thereof at a substitutable position. ) Or (7) - (C = O ) -R 4, -SO 2 -R 4, -SO-
^{R 4, - (C = O} ) NR 5 R 4, - (C = O) O-R 4, -
An acyl group represented by (C = S) O—R ⁴ or — (C ＝ S) NR ⁵ R ⁴ [R ⁴ is (i) a hydrogen atom, (ii) a C _1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _2-6 alkynyl group, (v) 1 to 3 amino C _1-6 optionally C _3-6 cycloalkyl be a fused and also benzene ring optionally having alkoxy An alkyl group, (vi) a C _6-10 aryl group or (vii) a C _7-16 aralkyl group, (viii) one or two hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom 1
(Ix) C _1-6 alkyl-carbonyl group, (x) carboxyl group, (xi) C _1-6 alkoxy-carbonyl group, (xii) mono -C _1-6 alkyl-carbamoyl group, (xiii) di-C _1-6 alkyl-carbamoyl group, (xiv) 5- to 7-membered cyclic amino group or (xv) C _6-10 aryloxy group (the “C _{1 -6} alkyl group "," _C2-6 alkenyl group "," _C2-6 alkynyl group "," _C3-6 cycloalkyl group "," _C6-10 aryl group "," _C7-16 aralkyl group ""A 5- to 11-membered heterocyclic group containing one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzo condensate thereof", "C _{1- 6} alkyl-carbonyl group '', `` carboxyl group '', `` A “C _1-6 alkoxy-carbonyl group”, a “mono-C _1-6 alkyl-carbamoyl group”, a “di-C _1-6 alkyl-carbamoyl group”,
“5- to 7-membered cyclic amino group” and “C _6-10 aryloxy group” are respectively (a) a halogen atom, (b) a C _1-3 alkylenedioxy group, (c) a nitro group, and (d) a cyano group. (E) (e-1) a halogen atom, (e-2) _C1-3 alkylenedioxy group, (e-3) nitro group, (e-4) cyano group, (e-5) _{C3- 6} cycloalkyl group, (e-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (e-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (e-
8) hydroxyl group, (e-9) amino group, (e-1)
0) mono-C _1-6 alkylamino group, (e-11) di-
C _1-6 alkylamino group, (e-12) C _1-6 alkyl-
Carbonyl group, (e-13) carboxyl group, (e-1)
4) C _1-6 alkoxy - carbonyl group, (e-15) carbamoyl group, (e-16) mono -C _1-6 alkyl - carbamoyl group, (e-17) di -C _1-6 alkyl - carbamoyl group , (E-18) C _6-10 aryl-carbamoyl group, (e-19) sulfo group, (e-20) C _1-6 alkylsulfonyl group, (e-21) C _6-10 aryl group,
(E-22) C _6-10 aryloxy group and (e-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; also a C _1-6 alkyl group, (f) C _3-6 cycloalkyl group, (g) 1 to 3 of a C _1-6 alkoxy group optionally having halogen atom, (h) 1 to 3 A C _1-6 alkylthio group optionally having one halogen atom, (i) a C _7-16 aralkyl group, (j) a hydroxyl group, and (k) a C _1-6 alkyl-carbonyl group Good amino group, (l) mono-C _1-6 alkylamino group, (m) di-C _1-6 alkylamino group, (n) (n-1) halogen atom, (n-2) C _1-3 alkylenedioxy group, (n-3) a nitro group, (n-4) a cyano group, (n-5) C _3-6 Black alkyl group, (n-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (n-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (n-
8) hydroxyl group, (n-9) amino group, (n-1)
0) mono-C _1-6 alkylamino group, (n-11) di-
C _1-6 alkylamino group, (n-12) C _1-6 alkyl-
Carbonyl group, (n-13) carboxyl group, (n-1)
4) C _1-6 alkoxy - carbonyl group, (n-15) carbamoyl group, (n-16) mono -C _1-6 alkyl - carbamoyl group, (n-17) di -C _1-6 alkyl - carbamoyl group , (N-18) C _6-10 aryl-carbamoyl group, (n-19) sulfo group, (n-20) C _1-6 alkylsulfonyl group, (n-21) C _6-10 aryl group,
(N-22) C _6-10 aryloxy group and (n-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; also C _1-6 alkyl - carbonyl group, (o) a carboxyl group, (p) C _1-6 alkoxy - carbonyl group, (q) a nitrogen atom in addition to carbon atoms, to 1 selected from oxygen atom and a sulfur atom A 5- to 7-membered heterocyclic group containing three heteroatoms or a formyl group optionally substituted with a benzo condensate thereof, (r) carbamoyl group, (s) (s-1) halogen atom, (s- 2) C _1-3 alkylenedioxy group, (s-3) nitro group, (s-4) cyano group, (s-5) C _3-6 cycloalkyl group, (s-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (s-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (s-
8) hydroxyl group, (s-9) amino group, (s-1)
0) mono-C _1-6 alkylamino group, (s-11) di-
C _1-6 alkylamino group, (s-12) C _1-6 alkyl-
Carbonyl group, (s-13) carboxyl group, (s-1)
4) C _1-6 alkoxy - carbonyl group, (s-15) carbamoyl group, (s-16) mono -C _1-6 alkyl - carbamoyl group, (s-17) di -C _1-6 alkyl - carbamoyl group A (s-18) C _6-10 aryl-carbamoyl group, a (s-19) sulfo group, a (s-20) C _1-6 alkylsulfonyl group, a (s-21) C _6-10 aryl group,
(S-22) C _6-10 aryloxy group and (s-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; Mono-C _1-6 alkyl-carbamoyl group, (t) (t-1) halogen atom, (t-2) C _1-3 alkylenedioxy group, (t-3) nitro group, (t-4 ) Cyano group, (t-5) C _3-6 cycloalkyl group, (t-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (t-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (t-
8) hydroxyl group, (t-9) amino group, (t-1)
0) mono-C _1-6 alkylamino group, (t-11) di-
C _1-6 alkylamino group, (t-12) C _1-6 alkyl-
Carbonyl group, (t-13) carboxyl group, (t-1
4) C _1-6 alkoxy - carbonyl group, (t-15) carbamoyl group, (t-16) mono -C _1-6 alkyl - carbamoyl group, (t-17) di -C _1-6 alkyl - carbamoyl group , (t-18) C _6-10 aryl - carbamoyl group, (t-19) sulfo group, (t-20) C _1-6 alkylsulfonyl group, (t-21) C _6-10 aryl group,
(T-22) C _6-10 aryloxy group and (t-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A di-C _1-6 alkyl-carbamoyl group, (u) an optionally halogenated C _6-10 aryl-carbamoyl group, and (v) an optionally halogenated C _6-10 aryl-carbonyl group. (W) a sulfo group optionally substituted with an amino group, (x) a C _1-6 alkylsulfonyl group, (y) a C _6-10 aryl group, (z) a C _6-10 aryloxy group, (aa) A) C _2-6 alkenylamino group, (bb) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, or a benzo condensate thereof , (Cc) hydroxyl In may be substituted, 5 to may have an oxo group 7-membered cyclic amino group, (dd) C _1-6 alkoxy - carbamoyl group,
Substituents selected from (ee) carbamoyloxy group, (ff) sulfamoyl group, (gg) mono-C _1-6 alkylsulfamoyl group and (hh) di-C _1-6 alkylsulfamoyl group can be substituted. May be provided in one to five positions. ) And R ⁵ are (a) a hydrogen atom or (b)
It represents a C _1-6 alkyl group. Or R ¹ and R ²
Is via an adjacent nitrogen atom (a) a halogen atom,
(B) a C _1-3 alkylenedioxy group, (c) a nitro group,
(D) a cyano group, (e) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) a C _3-6 cycloalkyl group, (g) 1 to 3 halogen atoms A C _1-6 alkoxy group optionally having an atom, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i) a hydroxyl group, and (j) an amino group (K) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group, (m) C _1-6 alkyl-carbonyl group,
(N) carboxyl group, (o) C _1-6 alkoxy-carbonyl group, (p) carbamoyl group, (q) mono-C _1-6
Alkyl-carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group, (t) sulfo group, (u) C _1-6 alkylsulfonyl group, (v ) Having at least one nitrogen atom which may have 1 to 5 substituents selected from a C _6-10 aryl group and (w) a C _6-10 aryloxy group; A 4- to 8-membered nitrogen-containing heterocyclic group which may contain 1 to 3 ring atoms, such as an oxygen atom and a sulfur atom, or a benzo-fused group thereof may be formed. The group represented by (1) represents a monocyclic 4- to 9-membered ring or (2) a bicyclic 6- to 14-membered ring, and each represents (i) a C _1-6 alkyl group, and (ii) C _1-6 An alkoxy group,
(Iii) C _1-6 alkylthio group (the “C _1-6 alkyl group”, “C _1-6 alkoxy group” and “C _1-6 alkylthio group” are (a) a halogen atom, and (b) C _{1 -3} alkylenedioxy group, (c) nitro group, (d) cyano group, (e) C _1-6 alkyl group _optionally having 1 to 3 halogen atoms, (f) C _3-6 Cycloalkyl group,
(G) a C _1-6 alkoxy group optionally having 1 to 3 halogen atoms, (h) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (i A) hydroxyl group, (j) amino group, (k) mono-C _1-6 alkylamino group, (l) di-C _1-6 alkylamino group,
(M) a C _1-6 alkyl-carbonyl group, (n) a carboxyl group, (o) a C _1-6 alkoxy-carbonyl group,
(P) carbamoyl group, (q) mono-C _1-6 alkyl-
A carbamoyl group, (r) di-C _1-6 alkyl-carbamoyl group, (s) C _6-10 aryl-carbamoyl group,
(T) a sulfo group, (u) a C _1-6 alkylsulfonyl group,
(V) a C _6-10 aryl group, (w) a C _6-10 aryloxy group and (x) a carbon atom containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom It may have 1 to 2 substituents selected from a 7-membered heterocyclic group or a benzo condensate thereof. ), (Iv) hydroxyl group, (v) amino group, (vi) mono-C _1-6 alkylamino group, (vii) di-C _1-6 alkylamino group, (viii) C _1-6 alkyl-carbonyl (Ix) carboxyl group, (x) C _1-6 alkoxy-carbonyl group, (xi) carbamoyl group, (xii) mono-C _1-6 alkyl-carbamoyl group, (xiii) di-C _1-6 alkyl A carbamoyl group, (xiv) a C _6-10 aryl-carbamoyl group, (xv) a sulfo group, (xvi) a C _1-6 alkylsulfonyl group, (xv) a C _6-10 aryl group and (xvi) a C _6-10 The receptor antagonist according to claim 1, which may have one or two substituents selected from an aryloxy group, and may have one or two unsaturated bonds. 3. The receptor antagonist according to claim ¹ , wherein R ¹ is a hydrogen atom or C _1-6 alkyl. 4. The receptor antagonist according to claim ¹ , wherein R ¹ is a hydrogen atom or methyl. 5. The receptor antagonist according to claim ¹ , wherein R ¹ is a hydrogen atom. 6. The receptor antagonist according to claim 1, wherein R ² is an acyl group. 7. An acyl group represented by the formula-(C = O) -R ⁴ , -SO ₂
^{-R 4, -SO-R 4,} - (C = O) NR 5 R 4, - (C =
O) OR ⁴ ,-(C = S) OR ⁴ or-(C = S)
NR ⁵ R ⁴ , wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a group which may have a substituent Lower alkyl-carbonyl group, carboxyl group, lower alkoxy-carbonyl group optionally having substituent (s), mono-lower alkylaminocarbonyl group optionally having substituent (s), optionally having substituent (s) A di-lower alkylaminocarbonyl group, a 5- to 7-membered cyclic amino group which may have a substituent or an aryloxy group which may have a substituent,
R ⁵ represents a hydrogen atom or a lower alkyl group. 7. The receptor antagonist according to claim 6, wherein 8. An acyl group represented by the formula-(C = O) -R ⁴ or-
(C ＝ O) NR ⁵ R ⁴ wherein R ⁴ has a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, and a substituent Optionally lower alkyl-
Carbonyl group, carboxyl group, optionally substituted lower alkoxy-carbonyl group, optionally substituted mono-lower alkylaminocarbonyl group, optionally substituted di-lower group It represents an alkylaminocarbonyl group, a 5- to 7-membered cyclic amino group which may have a substituent or an aryloxy group which may have a substituent. 7. The receptor antagonist according to claim 6, wherein 9. R ⁴ has the formula (1) embedded image Or (2) [Wherein R ⁶ and R ⁷ are the same or different and each represents (a) a hydrogen atom, (b) a (b-1) halogen atom, or (b-2) a C _1-3 alkylenedioxy Group, (b-3) nitro group, (b-4) cyano group, (b-5) _C3-6 cycloalkyl group, (b-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (b-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (b-
8) hydroxyl group, (b-9) amino group, (b-1)
0) mono-C _1-6 alkylamino group, (b-11) di-
C _1-6 alkylamino group, (b-12) C _1-6 alkyl-
Carbonyl group, (b-13) carboxyl group, (b-1)
4) C _1-6 alkoxy-carbonyl group, (b-15) carbamoyl group, (b-16) mono-C _1-6 alkyl-carbamoyl group, (b-17) di-C _1-6 alkyl-carbamoyl group , (B-18) C _6-10 aryl-carbamoyl group, (b-19) sulfo group, (b-20) C _1-6 alkylsulfonyl group, (b-21) C _6-10 aryl group,
(B-22) a C _6-10 aryloxy group and (b-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; also a C _1-6 alkyl group, (c) C _3-6 cycloalkyl group, (d) 1 to 3 of a C _1-6 alkoxy group optionally having halogen atom, (e) 1 to 3 C _1-6 alkylthio group optionally having one halogen atom, (f) C _7-16 aralkyl group, (g) hydroxyl group, (h) amino group, (i) mono-C _1-6 alkylamino Group, (j) di-C _1-6 alkylamino group, (k) (k-1) halogen atom, (k-2) C _1-3 alkylenedioxy group, (k-3) nitro group, (k -4) cyano group, (k-5) C _3-6 cycloalkyl group, (k-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (k-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (k-
8) hydroxyl group, (k-9) amino group, (k-1)
0) mono-C _1-6 alkylamino group, (k-11) di-
C _1-6 alkylamino group, (k-12) C _1-6 alkyl-
Carbonyl group, (k-13) carboxyl group, (k-1
4) C _1-6 alkoxy - carbonyl group, (k-15) carbamoyl group, (k-16) mono -C _1-6 alkyl - carbamoyl group, (k-17) di -C _1-6 alkyl - carbamoyl group , (K-18) C _6-10 aryl-carbamoyl group, (k-19) sulfo group, (k-20) C _1-6 alkylsulfonyl group, and (k-21) in addition to carbon atom, nitrogen atom, oxygen A C _1-6 alkyl-carbonyl group optionally substituted with a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from an atom and a sulfur atom, or a substituent selected from a benzo condensate thereof (L) carboxyl group, (m) C _1-6 alkoxy-carbonyl group, (n) 5 to 7 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom. Membered heterocyclic group or Benzofused formyl group which may be substituted by coalescence, (o) a carbamoyl group, (p) (p-1 ) halogen atoms, (p-2) C _1-3 alkylenedioxy group, (p-3) nitro Group, (p-4) cyano group, (p-5) C _3-6 cycloalkyl group, (p-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (p-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (p-
8) hydroxyl group, (p-9) amino group, (p-1)
0) mono-C _1-6 alkylamino group, (p-11) di-
C _1-6 alkylamino group, (p-12) C _1-6 alkyl-
Carbonyl group, (p-13) carboxyl group, (p-1
4) C _1-6 alkoxy-carbonyl group, (p-15) carbamoyl group, (p-16) mono-C _1-6 alkyl-carbamoyl group, (p-17) di-C _1-6 alkyl-carbamoyl group , (p-18) C _6-10 aryl - carbamoyl group, (p-19) sulfo group, (p-20) C _1-6 alkylsulfonyl group, (p-21) C _6-10 aryl group,
(P-22) C _6-10 aryloxy group and (p-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; Mono-C _1-6 alkyl-carbamoyl group, (q) (q-1) halogen atom, (q-2) C _1-3 alkylenedioxy group, (q-3) nitro group, (q-4 ) Cyano group, (q-5) C _3-6 cycloalkyl group, (q-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (q-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (q-
8) hydroxyl group, (q-9) amino group, (q-1)
0) mono-C _1-6 alkylamino group, (q-11) di-
C _1-6 alkylamino group, (q-12) C _1-6 alkyl-
Carbonyl group, (q-13) carboxyl group, (q-1
4) C _1-6 alkoxy - carbonyl group, (q-15) carbamoyl group, (q-16) mono -C _1-6 alkyl - carbamoyl group, (q-17) di -C _1-6 alkyl - carbamoyl group , (q-18) C _6-10 aryl - carbamoyl group, (q-19) sulfo group, (q-20) C _1-6 alkylsulfonyl group, (q-21) C _6-10 aryl group,
(Q-22) C _6-10 aryloxy group and (q-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A di-C _1-6 alkyl-carbamoyl group, (r) an optionally halogenated C _6-10 aryl-carbamoyl group, and (s) an optionally halogenated C _6-10 aryl-carbonyl group. (T) a sulfo group, (u) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group, (x) a C _2-6 alkenylamino group or (Y) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzo condensate thereof. 9. The receptor antagonist according to claim 8, wherein 10. The compound according to claim 1, wherein R ⁴ is of the formula (1) Or (2) [Wherein R ⁶ and R ⁷ are the same or different and are each selected from the group consisting of (a) a hydrogen atom, (b) (b-1) a hydroxyl group, and (b-2) di-C _1-6 alkyl 5 to 7 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than amino, (b-3) C _1-6 alkoxy-carbonyl and (b-4) carbon. A C _1-6 alkyl group which may be substituted with a substituent selected from a membered heterocyclic group or a benzo condensate thereof, (c) a C _7-16 aralkyl group, (d) a (d-1) halogen atom, d-2) a mono-C _1-6 alkylamino group (d-3) a C _1-6 alkoxy-carbonyl group and (d-4) other than carbon atoms, 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom 5- to 7-membered heterocyclic group containing 3 hetero atoms or benzo thereof C _1-6 alkyl optionally substituted with a substituent selected from the coalesced - carbonyl group, (e) C _1-6 alkoxy - carbonyl group, a nitrogen atom, an oxygen atom and a sulfur atom in addition to (f) carbon atoms A selected 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms or a formyl group optionally substituted with a benzo condensate thereof, (g) a (g-1) halogen atom and (g-2) ) C _1-6
A mono-C _1-6 alkyl-carbamoyl group which may be substituted with a substituent selected from an alkyl-carbonyl group, (h) a C _6-10 aryl-carbamoyl group which may be halogenated, (i) halogen A C _6-10 aryl-carbonyl group or (j) a C _6-10 aryloxy group. 9. The receptor antagonist according to claim 8, wherein 11. The receptor antagonist according to claim 1, wherein Q ¹ and Q ² are each a C _1-6 alkylene group _optionally having an oxo group. 12. The receptor antagonist according to claim 1, wherein Q ¹ is a C _1-4 alkylene group and Q ² is a methylene group. 13. A compound of the formula May have one or two unsaturated bonds, and may have one or two substituents at any position other than N and Z. 9-member ring or 2
The receptor antagonist according to claim 1, which is a cyclic 6- to 14-membered ring. 14. A compound of the formula The ring represented by is The receptor antagonist according to claim 1, which is: 15. A compound of the formula The ring represented by is The receptor antagonist according to claim 1, which is: 16. A compound of the formula The ring represented by is The receptor antagonist according to claim 1, which is: 17. Z is 1,2-phenylene which may have a substituent, a compound represented by the formula: [Wherein, Ar ³ represents an aromatic group which may have a substituent, and n represents an integer of 0 to 3. A group represented by the formula: [Wherein, Ar ³ and n are as defined above, Y is (i) a hydrogen atom, (ii) a lower alkyl group which may be halogenated, and (iii) a lower alkoxy which may be halogenated. Group, (iv) optionally halogenated lower alkylthio group, (v) hydroxyl group, (vi) cyano group, (vii) alkyl-carbonyl group, (viii) lower alkyl-carbonyloxy group, (ix) formyl Amino group, (x) amino group, (xi) mono-lower alkylamino group, (xii) di-lower alkylamino group, (xiii) carboxyl group, (xiv) lower alkoxy-carbonyl group or (xv) lower alkyl- Shows a carbonylamino group. A group represented by the formula: [Wherein, Ar ³ and n are as defined above. Or a group represented by the formula: [Wherein, Ar ³ and n are as defined above. The receptor antagonist according to claim 13, which is a group represented by the formula: 18. A compound represented by the formula: A pyrrolidine in which the ring represented by may have a substituent,
The receptor antagonist according to claim 1, which is piperidine, piperazine, azepine, azocin or a benzo condensate thereof. (19) Z is a compound represented by the formula: [In the formula, Ar ³ represents an aromatic group which may have a substituent, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. The receptor antagonist according to claim 13, which is a group represented by the formula: 20. A 5- to 7-membered heterocyclic group wherein Ar ³ contains a C _6-14 aryl group or one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. “C _6-14 aryl group” and “5- to 7-membered heterocyclic group” include (i) a halogen atom, (ii) an optionally halogenated C _1-6 alkyl group, and (iii) a halogenated group. It may have 1 to 3 substituents selected from C _1-6 alkoxy groups which may be substituted. 20. The receptor antagonist according to claim 19, wherein 21. The receptor antagonist according to claim 19, wherein Ar ³ is a phenyl group optionally substituted with a halogen atom. 22. The receptor antagonist according to claim 19, wherein n is 0. 23. The receptor antagonist according to claim 19, wherein Y is a hydroxyl group. 24. Ar ¹ and Ar ² each being the same or different and each containing a C _6-14 aryl group or one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. 7-membered heterocyclic group [the "C
_The “ _6-14 aryl group” and “5- to 7-membered heterocyclic group” include (i) a halogen atom, (ii) a C _1-6 alkyl group which may be halogenated, and (iii) a halogenated atom. It may have 1 to 3 substituents selected from good C _1-6 alkoxy groups. The receptor antagonist according to claim 1, wherein 25. The receptor antagonist according to claim 1, wherein Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. 26. Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, and Q ¹ is a C _1-4 alkylene group. , Q ² is a methylene group, and a compound represented by the formula: The ring represented by And Z is of the formula Wherein Ar ³ represents a phenyl group which may be substituted with a halogen atom, n represents an integer of 0 to 3, and Y represents a hydrogen atom or a hydroxyl group. ]
Wherein R ¹ is a hydrogen atom or methyl, and R ² is (1) (a) a C _1-6 alkoxy-carbonyl group, (b)
C _1-6 which may be substituted with a carboxyl group, (c) a C _1-6 alkyl-carbonyl group or (d) a formyl group.
Alkyl group or (2) ^{- (C = O) -R 4} , -SO 2 -R 4, - (C =
O) NR ⁵ R ⁴ or — (C ＝ O) O—R ^{4 wherein} R ⁴ is (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) a C _1-6 alkyl-carbonyl group An amino group optionally substituted with
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group, (f) C
_1-6 alkoxy-carbonyl group, (g) mono-C _1-6 alkyl-carbamoyl group, (h) sulfo group optionally substituted with amino group, (i) optionally substituted with hydroxyl group, 5 which may have an oxo group to 7-membered cyclic amino group, (j) C _1-6 alkoxy - 1 to 5 at substitutable positions a substituent selected from carbamoyl groups and (k) carbamoyloxy group C that you may have
_1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _6-10 aryl group, (v) one or two kinds selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom 5 to 11-membered heterocyclic group or its benzo-condensed ring containing one or more hetero atoms, (vi) C _1-6 optionally substituted by an alkyl group C _1-6
An alkyl-carbonyl group, (vii) a carboxyl group optionally substituted with a C _1-6 alkyl group, (viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl It may be substituted with a 5- to 7-membered heterocyclic group containing one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to the group or carbon atom, or a benzo-fused ring thereof. A C _1-6 alkyl group, (b) a C _7-16 aralkyl group, (c) a halogen atom, a mono-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or a carbon atom other than a nitrogen atom, oxygen One selected from atoms and sulfur atoms
A 5- to 7-membered heterocyclic group containing at least one kind or three kinds of heteroatoms or a C _1-6 alkyl-carbonyl group which may be substituted by a benzo-fused ring thereof, (d) a C _1-6 alkoxy-carbonyl A group, (e) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof. Formyl group, (f) mono-C _1-6 alkyl-carbamoyl group optionally substituted by halogen atom or C _1-6 alkyl-carbonyl group, (g) C _6-10 aryl optionally halogenated -Carbamoyl group, (h) 5- to 7-membered cyclic amino optionally having substituent (s) selected from optionally halogenated C _6-10 aryl group and (i) C _1-6 alkoxy-carbamoyl group Base (Ix) C _6-10 or an aryl group, R ⁵ receptor antagonist according to claim 1, wherein a represents a hydrogen atom or a C _1-6 alkyl group]. 27. The formula [Wherein, Ar ¹ , Ar ² and Ar ³ each represent an aromatic group which may have a substituent, and Q ¹ and Q ² each represent a divalent group which may contain oxygen or sulfur in a carbon chain. _Represents a C _1-6 aliphatic hydrocarbon residue, and R ² represents a hydrocarbon group or an acyl group which may have a substituent. Or a salt thereof [provided that N- [5-4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2
-Diphenylpentyl] -1-methanesulfonamide,
N- [5-4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -1-
(P-toluene) sulfonamide and N- [5-4-
(4-chlorophenyl) -4-hydroxypiperidino]
-2,2-diphenylpentyl] -1- (2-thiophene) sulfonamide or a hydrochloride thereof]. 28. R ² is a group represented by the formula-(C = O) -R ⁴ ,-(C =
^{O) NR 5 R 4, -} (C = O) O-R 4, - (C = S) O
—R ⁴ , or — (C ＝ S) NR ⁵ R ⁴ , wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic ring which may have a substituent Group, a lower alkyl-carbonyl group optionally having a substituent, a carboxyl group, a lower alkoxy-carbonyl group optionally having a substituent,
A mono-lower alkylaminocarbonyl group which may have a substituent, a di-lower alkylaminocarbonyl group which may have a substituent or a 5- to 7-membered cyclic amino group which may have a substituent And R ⁵ represents a hydrogen atom or a lower alkyl group. 28. The compound according to claim 27, which is a group represented by the formula: 29. R ² has the formula - (C = O) -R ⁴ or - (C
ＯO) NH—R ⁴ wherein R ⁴ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, A lower alkyl-carbonyl group, a carboxyl group, a lower alkoxy-carbonyl group optionally having a substituent, a mono-lower alkylaminocarbonyl group optionally having a substituent, A di-lower alkylaminocarbonyl group or a 5- to 7-membered cyclic amino group optionally having substituent (s), and R ⁵ represents a hydrogen atom or a lower alkyl group. 28. The compound according to claim 27, which is a group represented by the formula: (30) R ⁴ is represented by the formula (1): Or (2) [Wherein, R ⁶ and R ⁷ are the same or different, respectively; (a) hydrogen atom, (b) (b-1) halogen atom, (b-2) C _1-3 alkylenedioxy group, (b- 3) nitro group, (b-4) cyano group, (b-5) _C3-6 cycloalkyl group, (b-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (b-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (b-
8) hydroxyl group, (b-9) amino group, (b-1)
0) mono-C _1-6 alkylamino group, (b-11) di-
C _1-6 alkylamino group, (b-12) C _1-6 alkyl-
Carbonyl group, (b-13) carboxyl group, (b-1)
4) C _1-6 alkoxy-carbonyl group, (b-15) carbamoyl group, (b-16) mono-C _1-6 alkyl-carbamoyl group, (b-17) di-C _1-6 alkyl-carbamoyl group , (B-18) C _6-10 aryl-carbamoyl group, (b-19) sulfo group, (b-20) C _1-6 alkylsulfonyl group, (b-21) C _6-10 aryl group,
(B-22) a C _6-10 aryloxy group and (b-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; also a C _1-6 alkyl group, (c) C _3-6 cycloalkyl group, (d) 1 to 3 of a C _1-6 alkoxy group optionally having halogen atom, (e) 1 to 3 C _1-6 alkylthio group optionally having one halogen atom, (f) C _7-16 aralkyl group, (g) hydroxyl group, (h) amino group, (i) mono-C _1-6 alkylamino Group, (j) di-C _1-6 alkylamino group, (k) (k-1) halogen atom, (k-2) C _1-3 alkylenedioxy group, (k-3) nitro group, (k -4) cyano group, (k-5) C _3-6 cycloalkyl group, (k-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (k-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (k-
8) hydroxyl group, (k-9) amino group, (k-1)
0) mono-C _1-6 alkylamino group, (k-11) di-
C _1-6 alkylamino group, (k-12) C _1-6 alkyl-
Carbonyl group, (k-13) carboxyl group, (k-1
4) C _1-6 alkoxy - carbonyl group, (k-15) carbamoyl group, (k-16) mono -C _1-6 alkyl - carbamoyl group, (k-17) di -C _1-6 alkyl - carbamoyl group , (K-18) C _6-10 aryl-carbamoyl group, (k-19) sulfo group, (k-20) C _1-6 alkylsulfonyl group, and (k-21) in addition to carbon atom, nitrogen atom, oxygen A C _1-6 alkyl-carbonyl group optionally substituted with a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from an atom and a sulfur atom, or a substituent selected from a benzo condensate thereof (L) carboxyl group, (m) C _1-6 alkoxy-carbonyl group, (n) 5 to 7 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom. Membered heterocyclic group or Benzofused formyl group which may be substituted by coalescence, (o) a carbamoyl group, (p) (p-1 ) halogen atoms, (p-2) C _1-3 alkylenedioxy group, (p-3) nitro Group, (p-4) cyano group, (p-5) C _3-6 cycloalkyl group, (p-
6) C optionally having 1 to 3 halogen atoms
_{A 1-6} alkoxy group, (p-7) a C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (p-
8) hydroxyl group, (p-9) amino group, (p-1)
0) mono-C _1-6 alkylamino group, (p-11) di-
C _1-6 alkylamino group, (p-12) C _1-6 alkyl-
Carbonyl group, (p-13) carboxyl group, (p-1
4) C _1-6 alkoxy-carbonyl group, (p-15) carbamoyl group, (p-16) mono-C _1-6 alkyl-carbamoyl group, (p-17) di-C _1-6 alkyl-carbamoyl group , (p-18) C _6-10 aryl - carbamoyl group, (p-19) sulfo group, (p-20) C _1-6 alkylsulfonyl group, (p-21) C _6-10 aryl group,
(P-22) C _6-10 aryloxy group and (p-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; Mono-C _1-6 alkyl-carbamoyl group, (q) (q-1) halogen atom, (q-2) C _1-3 alkylenedioxy group, (q-3) nitro group, (q-4 ) Cyano group, (q-5) C _3-6 cycloalkyl group, (q-
6) C optionally having 1 to 3 halogen atoms
_1-6 alkoxy group, (q-7) C _1-6 alkylthio group optionally having 1 to 3 halogen atoms, (q-
8) hydroxyl group, (q-9) amino group, (q-1)
0) mono-C _1-6 alkylamino group, (q-11) di-
C _1-6 alkylamino group, (q-12) C _1-6 alkyl-
Carbonyl group, (q-13) carboxyl group, (q-1
4) C _1-6 alkoxy - carbonyl group, (q-15) carbamoyl group, (q-16) mono -C _1-6 alkyl - carbamoyl group, (q-17) di -C _1-6 alkyl - carbamoyl group , (q-18) C _6-10 aryl - carbamoyl group, (q-19) sulfo group, (q-20) C _1-6 alkylsulfonyl group, (q-21) C _6-10 aryl group,
(Q-22) C _6-10 aryloxy group and (q-2)
3) a 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo condensate thereof; A di-C _1-6 alkyl-carbamoyl group, (r) an optionally halogenated C _6-10 aryl-carbamoyl group, and (s) an optionally halogenated C _6-10 aryl-carbonyl group. (T) a sulfo group, (u) a C _1-6 alkylsulfonyl group, (v) a C _6-10 aryl group, (w) a C _6-10 aryloxy group, (x) a C _2-6 alkenylamino group or (Y) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, or a benzo condensate thereof. 29. The compound according to claim 28, wherein 31. The compound according to claim 27, wherein Q ¹ and Q ² are each a C _1-6 alkylene group _optionally having an oxo group. 32. The compound according to claim 27, wherein Q ¹ is a C _1-4 alkylene group and Q ² is a methylene group. 33. The compound according to claim 27, wherein Ar ³ is a phenyl group optionally substituted with a halogen atom. 34. Ar ¹ and Ar ² are the same or different and each has 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms other than C _6-14 aryl group or carbon atom. A 5- to 7-membered heterocyclic group [the "C _6-14 aryl group" and the "5- to 7-membered heterocyclic group" include (i) a halogen atom, and (ii) an optionally halogenated C _It may have 1 to 3 substituents selected from a _1-6 alkyl group and (iii) an optionally halogenated C _1-6 alkoxy group. 28. The compound according to claim 27, wherein 35. The compound according to claim 27, wherein Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. 36. Ar ¹ and Ar ² are the same or different and each is phenyl, 4-chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, and Q ¹ is a C _1-4 alkylene group. , Q ² are each a methylene group, and R ² is (1) (a) a C _1-6 alkoxy-carbonyl group, (b)
C _1-6 which may be substituted with a carboxyl group, (c) a C _1-6 alkyl-carbonyl group or (d) a formyl group.
Alkyl group or (2) ^{- (C = O) -R 4} , -SO 2 -R 4, - (C =
O) NR ⁵ R ⁴ or — (C ＝ O) O—R ^{4 wherein} R ⁴ is (i) a hydrogen atom, (ii) (a) a hydroxyl group, (b) a C _1-6 alkyl-carbonyl group An amino group optionally substituted with
(C) mono-C _1-6 alkylamino group, (d) di-C _1-6
Alkylamino group, (e) carboxyl group, (f) C
_1-6 alkoxy-carbonyl group, (g) mono-C _1-6 alkyl-carbamoyl group, (h) sulfo group optionally substituted with amino group, (i) optionally substituted with hydroxyl group, 5 which may have an oxo group to 7-membered cyclic amino group, (j) C _1-6 alkoxy - 1 to 5 at substitutable positions a substituent selected from carbamoyl groups and (k) carbamoyloxy group C that you may have
_1-6 alkyl group, (iii) C _2-6 alkenyl group, (iv) C _6-10 aryl group, (v) one or two kinds selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom 5 to 11-membered heterocyclic group or its benzo-condensed ring containing one or more hetero atoms, (vi) C _1-6 optionally substituted by an alkyl group C _1-6
An alkyl-carbonyl group, (vii) a carboxyl group optionally substituted with a C _1-6 alkyl group, (viii) (a) a hydroxyl group, a di-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl It may be substituted with a 5- to 7-membered heterocyclic group containing one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to the group or carbon atom, or a benzo-fused ring thereof. A C _1-6 alkyl group, (b) a C _7-16 aralkyl group, (c) a halogen atom, a mono-C _1-6 alkylamino group, a C _1-6 alkoxy-carbonyl group or a carbon atom other than a nitrogen atom, oxygen One selected from atoms and sulfur atoms
A 5- to 7-membered heterocyclic group containing at least one kind or three kinds of heteroatoms or a C _1-6 alkyl-carbonyl group which may be substituted by a benzo-fused ring thereof, (d) a C _1-6 alkoxy-carbonyl A group, (e) a 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a benzo condensate thereof. Formyl group, (f) mono-C _1-6 alkyl-carbamoyl group optionally substituted by halogen atom or C _1-6 alkyl-carbonyl group, (g) C _6-10 aryl optionally halogenated A 5- to 7-membered group which may have a substituent selected from a carbamoyl group, (h) an optionally halogenated C _6-10 aryl-carbonyl group and (i) a C _1-6 alkoxy-carbamoyl group. Ring Shows the amino group or (ix) C _6-10 aryloxy group, claims R ⁵ represents a hydrogen atom or a C _1-6 alkyl group and Ar ³ is a phenyl group which may be substituted by a halogen atom 28. The compound according to 27. 37. The formula [Wherein the symbols have the same meanings as in claim 27. Or a salt thereof is subjected to an acylation reaction to give a compound of the formula [Wherein, R ² represents an acyl group, and the other symbols represent claims 27.
The meaning is as described. ] Or a salt thereof. 38. The formula Wherein Ph is a phenyl group, and the other symbols are as defined in claim 2
Same as described in 7. Or a salt thereof, and [Wherein, R ⁴ represents a hydrogen atom, a hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a lower alkyl-carbonyl group optionally having a substituent. , Carboxyl, optionally substituted lower alkoxy-
Carbonyl group, mono-lower alkylaminocarbonyl group optionally having substituent (s), di-lower alkylaminocarbonyl group optionally having substituent (s) or 5- or 6-membered group optionally having substituent (s) It indicates a cyclic amino group, R ⁵
Represents a hydrogen atom or a lower alkyl group. Or a salt thereof, and reacting with a compound of the formula [Wherein the symbols have the same meanings as described above. ] Or a salt thereof. (39) the agent which is a prophylactic / therapeutic agent for an inflammatory disease;
The receptor antagonist of the above. (40) the receptor antagonist according to (1), which is an agent for preventing or treating allergic diseases; 41. The receptor antagonist according to claim 1, which is a preventive / therapeutic agent for arteriosclerosis, bronchial asthma, atopy, multiple sclerosis or rheumatoid arthritis. 42. A pharmaceutical composition comprising the compound according to claim 27. 43. A MIP-1α / RANTES receptor antagonist comprising the compound according to claim 27. 44. 1- [5- [4- (4-chlorophenyl)-
4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (piperidin-4-yl) urea, 4- [4-
Ethyl [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-4-oxobutyrate, N-ethyl-4- [5- [4 -(4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, N-
Ethoxycarbonylmethyl-4- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino-1-piperidinecarboxamide, 3- [4- [5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] aminocarbonylamino] piperidino-3
-Ethyl oxopropionate, 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (1-ethylpiperidin-4-yl) urea, 1-[(piperidin-4-yl) carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentane, 1-
[[(N-ethylcarbamoyl) piperidin-4-yl]
Carboxamide] -5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2,2-diphenylpentane, 1-[[N- (ethoxycarbonylacetyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidi No] -2,2-diphenylpentane, 1-[[N- (3-methoxycarbonylpropionyl) piperidin-4-yl] carboxamide] -5- [4- (4-chlorophenyl) -4-hydroxypiperidino] 28. The compound according to claim 27, which is -2,2-diphenylpentane or a salt thereof.