WO2004037817A1 - N-oxide compounds - Google Patents

Abstract

A compound represented by the following general formula (1): (1) wherein each symbol is as defined in the description, provided that at least one of the nitrogen atoms in the formula has been oxidized; its optical isomer or its pharmaceutically acceptable salt. Thus, it is possible to provide drugs which have an affinity for a chemokine receptor and are usable in treating and/or preventing immune and inflammatory diseases.

Description

 Specification

 N-oxide compound

 Technical field

 The present invention relates to a novel N-oxide compound having affinity for a chemokine receptor, wherein the compound or a salt thereof plays an important role in the onset, progress, and maintenance of a disease state by a cell having a chemokine receptor. Diseases, such as atherosclerosis, rheumatoid arthritis, chronic osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergies, ulcers It is useful as a therapeutic and / or prophylactic agent for ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis, rejection response during organ transplant surgery, human immunodeficiency syndrome, and the like.

 Background art

As chemotactic substances that induce infiltration of migration and local leukocytes such as neutrophils and monocytes, degradation product C 3 a or C5a of complement, l eukot riene B Arakidon acid metabolites such as _4, platelet activity There are classic chemotactic factors such as chemotactic factors and bacterially-formylated peptides. These are mainly secondary products associated with tissue damage. On the other hand, a series of cytokins (chemokines), which are produced by new gene expression and are responsible for inducing and activating specific leukocytes, were purified by Matsushima et al. In 1987. erl euk in (IL) 18 (CXCL 8) proved its existence (for example, see Non-Patent Documents 1 and 2).

To date, 45 chemokines have been identified, and chemokines have been classified into four subgroups based on their amino acid sequence characteristics. C chemokines, CC chemokines, CXC chemokines and CX ₃ C chemokines.

XCL1, which belongs to the C chemokine, has a chemotactic activity on T cells and NK cells. In contrast, CC chemokines exhibit chemotactic activity on monocytes other than neutrophils, lymphocytes, Langerhans cells, dendritic cells, eosinophils, mast cells, and basophils. Et al., Mainly to neutrophils as CXC chemokines are represented by CXCL8 is, CX ₃

C chemokines mainly affect NK cell migration. These chemokines exert their effects by binding to G protein-coupled receptors (chemokine receptors). However, to date, 18 types of chemokine receptors have been identified (for example, see Non-Patent Documents 3 and 4).

 Therefore, substances that inhibit the binding of chemokines to their receptors inhibit the selective migration and activation of leukocytes, and acute and chronic inflammatory diseases, including allergic diseases, and human immunodeficiency syndrome, etc. It is considered to be useful as a medicament for the prevention or treatment of the disease.

 In view of the above, compounds having affinity for chemokine receptors can be expected to be useful as pharmaceuticals for preventing or treating immune and inflammatory diseases.

 Further, for example, the following patent documents are disclosed as therapeutic agents for immunological and inflammatory diseases having affinity for chemokine receptors. Patent Document 1 discloses diphenylmethane derivatives, Patent Document 2 discloses arylpyrazine derivatives, and other compounds having affinity for chemokine receptors.Patent Documents 3, 4, and 5 disclose compounds having affinity for chemokine receptors. Patent Literatures 6 and 7 disclose a phenylalanine derivative having an affinity for a chemokine receptor, and Patent Literature 8 disclose a pyrazine having an affinity for a chemokine receptor. Patent Documents 9, 10, 11, and 12 disclose piperidine derivatives having affinity for chemokine receptors. Patent Documents 13 and 14 disclose morpholine derivatives having affinity for chemokine receptors. Patent Document 15 discloses a cyclic amine derivative having a CCR3 antagonistic action.

 However, to date, no compound has been reported that is effective in models such as allergic diseases by oral administration. Compounds that show efficacy in such disease models, etc., inhibit the selective migration and activation of leukocytes, and are useful in the treatment or treatment of acute and chronic inflammatory diseases, including allergic diseases, and human immunodeficiency syndrome. It is expected to be a medicine for prevention.

 [Non-Patent Document 1]

 P rocNatl.Acad.Sci.USA, 84, 9232-9223, p. 1978

[Non-patent document 2] J. Exp. Med., Vol. 167, pp. 1883-1893, 1988

[Non-Patent Document 3]

Cell Engineering, Vol. 17, pp. 1022-1029, 1998

 [Non-Patent Document 4]

 Immunity, 12 volumes, 121-127, 20 years 0 years [Patent Document 1]

International Publication No. WO 97/24325 Pamphlet

 [Patent Document 2]

International Publication No. WO 98/25617 Pamphlet

 [Patent Document 3]

International Publication No. WO 98/02151 Pamphlet

 [Patent Document 4]

International Publication No. WO 98/04554 Breadlet

 [Patent Document 5]

International Publication No. WO 00/34278 Breadlet

 [Patent Document 6]

International Publication No. WO 99/55324 Pamphlets ''

 [Patent Document 7]

International Publication No. WO 99/55330 pamphlet

 [Patent Document 8]

International Publication No. WO 00/58305 Breadlet

 [Patent Document 9]

International Publication No. WO 00/31033 Pamphlet

 [Patent Document 10]

International Publication No. WO 00/53600 Breadlet

 [Patent Document 11]

International Publication No. WO 01Z14333 Pamphlet

 [Patent Document 12]

International Publication No. WO02 ノ 66460 Breadlet [Patent Document 13]

 International Publication No. WO O 2/2 6 7 2

 [Patent Document 1 4]

 International Publication No. WO 0 2/2 6 7 2 3

 [Patent Document 15]

 International Publication No. WO 0 2/1 8 3 3 5

 Disclosure of the invention

 An object of the present invention is to provide a medicament having an affinity for a chemokine receptor and for treating and / or preventing an immune and inflammatory disease.

 In view of the above circumstances, the present inventors have conducted intensive studies to find a non-peptidic compound exhibiting chemokine receptor antagonism. As a result, an N-oxide compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is obtained. Has a high affinity for the chemokine receptor and inhibits the binding of the chemokine to its receptor. In addition, the N-oxidized compounds of the present invention include conventional non-oxidized compounds, their optical isomers or their pharmaceutically acceptable salts [see, for example, Patent Documents 1 to 15 described above. Compounds shown above] have higher affinity for chemokine receptors and are found to be pharmacokinetically improved. Therefore, the compound of the present invention suppresses the selective migration and activation of leukocytes, and can be a medicament for treating or preventing acute and chronic inflammatory diseases including allergic diseases, and human immunodeficiency syndrome. This led to the completion of the present invention.

 That is, the present invention relates to the following compounds [1] to [8], optical isomers thereof, or pharmaceutically acceptable salts thereof.

 [1] General formula (1):

(In the formula, Ring A represents an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent,

R ^a and R ^b are the same or different from each other, a hydrogen atom, an alkyl, halogen atom, hydroxy, alkoxy, Shiano, Aminokaruponiru, carboxy or alkoxycarbonyl; or, taken R ^a and R ^b gar緖R ^a and R ^b may form a ring together with the atom to which they are bonded,

 p represents an integer from 0 to 2,

 m represents an integer from 0 to 5,

 n represents an integer from 0 to 5,

V represents a bond, an optionally substituted Ci-e alkylene, one CO— or —S 0 _2— ,

W represents — CH, _CH ₂ —, — N, one NH—, an oxygen atom or a sulfur atom,

X is a bond, —NH—, —NR ¹ — (wherein R ¹ represents alkyl),

One CO—, one CONRc— or one NR ^c CO— (where R ^c represents a hydrogen atom or alkyl), -NR ² CONR ^3- (wherein R ² is the same or different Each represents a hydrogen atom or an alkyl, or H ² and R ³ may be taken together to form a ring together with the atom to which they are bonded)), an oxygen atom, a sulfur atom, —SO— , — S0 ₂ —, one NR ^c S0 ₂ — or

— S0 ₂ NR. I (wherein,:. Rc is indicating a hydrogen atom or alkyl), optionally have a substituent C _i-6 alkylene, C ₂ _ ₆ alkenylene, C ₂ - ₆ alkynylene, -O- substituent the have they may be C i_ ₆ alkylene mono- or monosubstituted group which may have a C i-6 alkylene one 0-, - S- optionally substituted C Bok ₆ Al Killen one Or an optionally substituted Ci-e alkylene mono-S-, mono-SO- optionally substituted Ci- ₆ alkylene mono- or mono-substituted C- ₆ alkylene one S 0-, in one NRc- substituted optionally also have a good C doctor ₆ Al Killen one or monosubstituted group C i-6 alkylene one NRc- (wherein,

R ^c represents a hydrogen atom or alkyl. ), One S0 ₂ - may have a substituent May have one or more mono- or mono-alkylene substituents — 6 alkylenes S

0 ₂ -, -C (two N-C0 ₂ - alkyl) one one C (= N- S0 ₂ - alkyl) one one _{C (= N- S0 2 NH 2} ) -, one C (= CH-N0 ₂ ) One or one C (= N-CN)

Y is a bond, one NH—, —NR ⁴ — (wherein, R ⁴ represents alkyl),

— CO—, one CONR ^d — or one NR ^d CO— (wherein, R ^d represents a hydrogen atom or alkyl), -NR ⁶ CONR ^6- (wherein, R ⁵ and R ⁶ are the same or Each may represent a hydrogen atom or an alkyl, or R ⁵ and R ⁶ may be taken together to form a ring together with the atom to which they are attached.), An oxygen atom, a sulfur atom, —SO—, — S〇 ₂ —, one NR ^d S0 ₂ —or

- (wherein, R ^d represents a hydrogen atom or alkyl.), Optionally have a substituent C _{i-6 alkylene, C 2 - - S0 2 NR} d 6 alkenylene, C ₂ - ₆ alkynylene, -0- may have an optionally substituted C i_ ₆ alkylene mono- or monosubstituted group C ₆ alkylene - 0, which may have an S- substituent C 1- ₆ alkylene mono- or mono-substituted C ₆ alkylene mono-S-,

One SO—C i_ ₆ alkylene optionally having substituent (s) or one —C alkylene optionally having substituent (s) —S 0—, —NR ^d —Ci-optionally having substituent (s) Ci- e alkylene one or - alkylene one may have a substituent group NR ^d - (wherein, R ^d represents a hydrogen atom or alkyl.), one S0 ₂ - may have a substituent group C丄-6 may have alkylene one or monosubstituted group C n alkylene - S0 ₂ -, one C (= N- C0 ₂ - alkyl) mono-,

-C (= N- S0 ₂ - alkyl) one one _{C (= N- S0 2 NH 2} ) -,

_{- C (= CH- N0 2)} - or single C (= N-CN) - indicates,

Z is a bond, optionally C ₆ alkylene which may have a substituent, C ₂ one ₆ alkenylene, C ₂ _ ₆ alkynylene, oxygen atom, sulfur atom, -SO-, one S0 ₂ -,

One NH-, -NR ⁷ - (R ⁷ represents an alkyl.), One CO-, - C0 ₂ - one 0- CO- one C0NR ⁸ - or single NR ⁸ C0- (wherein, R ⁸ Represents a hydrogen atom or an alkyl.), One NR ⁸ CONR ⁹ — (wherein R ⁸ and R ⁹ may be the same or different and each represents a hydrogen atom or an alkyl. ⁸ And R ⁹ may be linked to form a ring together with the atoms to which they are attached. ), - NR ⁸ S0 ₂ - or - S0 ₂ NR ⁸ - (wherein, R ⁸ represents a hydrogen atom or alkyl Le), one 0- CO- NR ⁸ -. Or a NH ⁸ - CO- 0- (wherein, R ⁸ is. represents a hydrogen atom or an alkyl), one Q丄one substituted optionally also have a good C ₆ § alkylene mono- or monosubstituted group C i_ ₆ alkylene one Qi- [wherein represents an oxygen atom, a sulfur atom, - SO-, one S0 ₂ -, one NH-, -NR ⁷ - (. wherein, R ⁷ is showing a alkyl), one CO-, one OCO-, one C0 ₂ -,

- CONR ⁸ -, or single NR ⁸ CO- (wherein, R ⁸ represents a hydrogen atom or an ^{alkyl.), -NR 8 -CO-NR} 9 - ( wherein, R ^8, R ⁹ are the same or different Each represents a hydrogen atom or an alkyl, or R ⁸ and R ⁹ may be linked together to form a ring together with the atom to which they are attached.)

— NR ⁸ S0 ₂ — or — S0 ₂ NR ⁸ — (wherein R ⁸ represents a hydrogen atom or an alkyl.) Or 1 0—CO—NR ⁸ —or 1 NR ⁸ —CO—0— (formula In the formula, R ⁸ represents a hydrogen atom or an alkyl.). ]

A is a group selected from a bond, a divalent hydrocarbon ring group which may have a substituent and a divalent heterocyclic group which may have a substituent, or> CH—R ¹⁰ Or> N—R ^1Q (wherein, R ^1Q is selected from a hydrocarbon ring group which may have a substituent and a heterocyclic group which may have a substituent Base),

 B represents a hydrogen atom, an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent.

 However, at least one of the nitrogen atoms contained in the formula is oxidized. ]

Or an optical isomer or a pharmaceutically acceptable salt thereof.

 [In this specification, the compound of the general formula (1) or the compound (1) may be referred to as abbreviated in some cases. ]

[2] The compound represented by the general formula (1) To Ar

Β, _ζ -Α, _γ ζ (.Η2) _η , _χ

(In the formula,

 Ar represents an aryl which may have a substituent,

 η represents an integer from 1 to 5,

 r represents 0 or 1,

X is a bond, — ΝΗ—, -NR ¹ — (wherein, R ¹ represents alkyl),

— CO—, one CONH—, — NHCO—, — NR ² CONR ³ — (where R ² ,

R ³ may be the same or different and each represents a hydrogen atom or an alkyl. ), An oxygen atom, a sulfur _{atom, -SO-, - S0 2 -,} - NHS0 2 - or - S0 ₂ NH- indicates,

Y is a bond, one NH—, —NR ⁴ — (wherein R ⁴ represents alkyl),

— CO—, one CONH—, —NHCO—, _NR ⁵ CONR ⁶ — (where R ⁵ ,

R ⁶ may be the same or different and each represents a hydrogen atom or an alkyl. ), An oxygen atom, a sulfur atom, One _{SO-, - S0 2 -, -} NHS0 2 - or - S0 ₂ NH- indicates,

Z is a bond, which may have a substituent — 4 alkylene, an oxygen atom, a sulfur atom, one SO—, —SO ₂ —, —NH—, one NR ⁷ — (R ⁷ represents alkyl. ),

_{- CO-, -Q 2 - (CH} 2) q - or a _{(CH 2) q -Q 2 -} [ wherein, Q ₂ is, - NH-, -NR ⁷ - (wherein, R ⁷ is an alkyl Represents an oxygen atom, a sulfur atom, —SO— or 1 S 一₂ —, and q represents an integer of 1 to 4. ]

 A represents a bond, arylene which may have a substituent, heteroarylene which may have a substituent, or cycloalkylene which may have a substituent, B represents an aryl which may have a substituent, a heteroaryl which may have a substituent, or a cycloalkyl which may have a substituent.

However, when r = 0, at least one of the other nitrogen atoms contained in the formula is oxidized. ]- 3013591. The compound according to the above [1], an optical isomer or a pharmaceutically acceptable salt thereof.

 [3] In general formula (1),

 n is an integer from 1 to 4,

 The compound according to the above [2], wherein A is a bond, arylene optionally having a substituent or heteroarylene optionally having a substituent, an optical isomer thereof or a pharmaceutically acceptable salt thereof. Acceptable salts.

 [4] In the general formula (1),

 n is an integer from 1 to 4,

X is —CO—, —CONH—, —NHCO—, —NR ² CONR ³ — (wherein RR ³ may be the same or different and each represents a hydrogen atom or an alkyl). SO-, one S0 ₂ -, one NHS0 ₂ - or a single S0 ₂ NH-, a is a bond, Teroari one Ren to may have an optionally substituted Ariren or substituent And

 The compound according to the above [2] or [3], wherein B is aryl which may have a substituent or heteroaryl which may have a substituent, an optical isomer thereof or a pharmaceutically acceptable salt thereof. Salt.

 [5] — In general formula (1),

 n is an integer from 1 to 4,

X is one CO—, one CONH—, one NHCO—, —NR ² CONR ³ — (wherein, R ² and R ³ may be the same or different and each represent a hydrogen atom or an alkyl.) And

 Y is a bond, an oxygen atom or a sulfur atom,

 Z is a bond,

 A is a bond, arylene which may have a substituent or heteroarylene which may have a substituent,

The compound according to any one of the above [2] to [4], wherein B is aryl which may have a substituent or heteroaryl which may have a substituent, an optical isomer thereof, or a compound thereof. Pharmaceutically acceptable salts. 13591

[6] (1) [4- (3-cyanophenyl) thiazo-l-2u-fluoro] -N- [1- (3,4-dichlorobenzene) -1-oxopiperidine-1-4-yl] acetamide ,

 (2) [4- (4-Cyanophenyl) thiazole-2-ylthio] -1-N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-4-1-fur] acetamide,

 (3) N- [1- (3,4-dichroic benzyl) -11-oxopiperidine-14-yl] -1- (4-phenylthiazolyl-2-ylthio) acetamide,

 (4) N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] -one [4-1- (3-pyridyl) thiazo-1-ru-2-ylthio] acetamide,

(5) N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl]-[4-1- (4-pyridyl) thiazo-1-ru-2-ylthio] acetamide,

(6) N— [1— (3,4 dicyclomouth benzyl) 1-1-oxopiperidine-1-4-yl] 1- [4— (4-Methoxycarbonylphenyl) thiazo-1-l 2-ylthio] Acetamide,

 (7) N— [1— (3,4-dichlorobenzyl) -1-oxopiperidine—1 4-fur] —1-4- (3-Methoxycarbonylphenyl) thiazo-1-l-2-ylthio] acetami Do

 (8) [4- (3-Carboxyphenyl) thiazo-1-yl 2-^^ fluorothio] — N — [11- (3,4-dichlorobenzyl) -1 1-oxopiperidine-1-4-yl] acetami Do

 (9) [4- (4-Carboxyphenyl) thiazo-1-yl-2-ylthio] — N— [1— (3,4-dichlorobenzyl) —1-oxopiperidine—4-yl] acetamide,

 (10) N— [1— (3,4-dichloro mouth benzyl) piperidin-1-yl]-[4- (1-oxopyridine_41-yl) thiazo-1-l-2-ylthio] acetamide,

(1 1) N— [1— (3,4-dichlorobenzyl) piperidin-1 4-yl] 1- [1 4- (1-oxopyridine-1 3-yl) thiazo-1-ru 2-ylthio] acetate Amid,

 (12) N- [1- (3,4-dichlorobenzyl) -11-oxopiperidine-14-yl] -one [4-1- (2-pyridyl) thiazo-1-ru-2-ylthio] acetamide,

 (13) Ν— [1 _ (3,4-dichlorobenzyl) 1 1-oxopiperidine—4-yl] 1- (4-pyrazinylthiazo-1-lu-2-ylthio) acetamide,

(14) (5-Amino-1,3,4-thiadiazol-1-2-ylthio) — Ν-[1-(3,4-dichrobenzyl) -1 1-oxopiperidine-1 4-yl] acetami Do

 (15) Ν— [1— (3,4-dichloro mouth benzyl) 1-1-oxopiperidine 1-4-yl] 1- (5—Feneru 1,3,4,1-oxadiazo-1-ru 2 _ylchio) Acetamide,

 (16) Ν— [1— (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- [5— (4-pyridyl) —1,3,4-oxaziaziro-2-ylthio ] Acetamide,

 (17) Ν— [1— (3,4 dicyclo mouth benzyl) — 1-oxopiperidine 1-4_yl] 1- [5— (4-pyridyl) -1,3,4-thiadiazolone 2— Ruthio] acetamide, and

 (18) (6-aminobenzo, thiazolu-2-ylthio) _Ν— [1-(3,4-dichlorobenzyl) 1 1-oxopiperidine 1 4 ^^ ル .l] acetoamide Or the pharmaceutically acceptable salt thereof according to any one of the above [1] to [5].

 [7] (1) [4- (3-cyanophenyl) thiazolyl-2-ylthio] -Ν- [1- (3,4-dichlorobenzyl) -1-1-oxopiperidine-1-4-yl] acetamide ,

 (4) Ν— [1- (3,4-dichrolic benzyl) -11-oxopiperidine-14-yl] — [4- (3-pyridyl) thiazol-2-ylthio] acetamide,

(5) Ν— [1- (3-, 4-dichloro- mouth benzyl) 1-oxopiperidine

4-yl]-[4- (4-pyridyl) thiazo-l- 2- 2-l-thio] acetoamide, (7) N- [1— (3,4-dichroic benzyl) 1-1-oxopiperidine-14-yl] -1- [3- (3-methoxycarbonylphenyl) thiazo-1-yl 2-ylthio ] Acetamide,

 (9) [4- (4-Carboxyphenyl) thiazo-1-yl-2-ylthio] — N — [1— (3,4-Dichlorobenzyl) -1-1-oxopiperidine-14-yl] acetamide , and

 (10) N_ [l— (3,4-dichlorobenzyl) piperidine-1fr]-[4- (1-oxopyridine-14-yl) thiazol-1-2-ylthio] acetamide,

Or a pharmaceutically acceptable salt thereof.

 [8] (19) [4- (3-caproluvylphenyl) thiazo-l-2-ylthio] — N— [1- (3,4-dichlorobenzyl) -1-1-oxopiperidine-1 Yl] acetamide,

 (20) [4-(4-Lubamoylphenyl) thiazolyl-2-ylthio] — N— [1-(3,4-dichloromethylbenzyl) 1 1-oxopiperidine-1 4-yl ] Acetamide,

 (2 1) N— [1-(3,4-dicyclobenzyl)-1-oxopiperidine —4-yl] 1 {4— [3-((imidazo-l-ru-l-methyl) -amino) phenyl ] Thiazolyl-2-ylthio} acetamide,

 (22) N-[1-(3,4 dicyclo-mouth benzyl)-1-oxopiperidine 1-41-yl] 1-{4-[3-((imidazo-1-2-ylmethyl) amino) phenyl] thiazo 1-ru 2-irthio} acetoamide,

 (23) N— [1— (3,4-dichlorobenzyl) 1 1-oxopiperidine 1-4-yl] 1 {4-1- [3— (imidazo-1-ru 4-ylcarboxamide) phenyl] thiazo 2-ylthioacetamide, and

 (24) {4- [3- (L-alanylamino) phenyl] thiazo-l- 2-dithio} — N— [1- (3,4-dichlorobenzyl) 1-oxopiperidine —4-yl] acetami Do

Or a pharmaceutically acceptable salt thereof. The present invention also relates to the following pharmaceutical composition [9] or [10].

 [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] above, an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

 [10] The above-mentioned agent for preventing or treating chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome [ 9] The pharmaceutical composition according to the above.

 Further, the present invention relates to the following.

 [11] A chronic rheumatoid arthritis, asthma, allergic rhinitis, comprising the compound according to any one of the above [1] to [8], an optical isomer thereof or a pharmaceutically acceptable salt thereof. Prevention and treatment of allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome.

 [12] Chronic rheumatoid arthritis, asthma, allergic rhinitis, which comprises administering the compound according to any one of the above [1] to [8], an optical isomer thereof or a pharmaceutically acceptable salt thereof. How to prevent and treat allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome.

 [13] Prevention of chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome [1] ] Use of the compound according to any one of [8] to [8], an optical isomer thereof or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

 Terms and symbols used in this specification are defined as follows.

 The “hydrocarbon group” of the “hydrocarbon ring group optionally having substituent (s)” means a monocyclic to tricyclic hydrocarbon ring group having 3 to 20 carbon atoms. The “hydrocarbon ring group” includes a saturated ring, an aromatic ring and a partially hydrogenated ring group.

 Examples of the “hydrocarbon ring group” include “aryl” (including partially hydrogenated aryl) as defined below, and “cycloalkyl”.

When the “hydrocarbon ring group” has a “substituent”, the type and number of the substituent are not particularly limited, and the substituent selected from the “substituents” defined below is Have one to three in possible positions.

The "Ariru" in "optionally having a substituent which may Ariru", C (carbon number) monocyclic-tricyclic means ₆ _ ₁₄ § Li Ichiru, for example, Fuweniru, naphthyl, Antori Le And the like. The c ₆ _ ₁₄ Ariru may be condensed with c ₃ _ ₈ cycloalkyl, the C _{6 14} Ariru condensed with C ₃ _ ₈ cycloalkyl, for example, indanyl and tetrahydronaphthyl and the like. Further, the above “aryl” may be partially hydrogenated. The site to be hydrogenated is not particularly limited. Partially hydrogenated aryls include, for example, dihydronaphthyl and the like.

 When “aryl” has a “substituent”, its type and number are not particularly limited, and a substituent selected from the “substituents” defined below is placed at a substitutable position.

Have one to three.

“Cycloalkyl” in “cycloalkyl optionally having substituent (s)” includes C _{3 to} C ₁₀ monocyclic to tricyclic cycloalkyl (including “bridged cycloalkyl”). '.), For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl Etc. ο

 When the “cycloalkyl” has a “substituent”, the type and number thereof are not particularly limited, and one or more substituents selected from the “substituents” defined below may be substituted at the substitutable position. Have three.

 As the “hydrocarbon ring group”, preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2. 2] octyl, phenyl, naphthyl, anthryl, indanyl, tetrahydronaphthyl, etc. o

The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” refers to one to three heterocyclic groups selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring atom. 5- to 7-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 atoms You. “Heterocyclic group” includes a saturated ring and an aromatic ring (including “heteroaryl” as defined below. Also, includes a partially hydrogenated ring group).

 “Heterocyclic group” includes “saturated heterocyclic group” containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring atoms. Examples of the “heterocyclic group” include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, thiazolidinyl, homopiperazinyl and the like. Further, a “heterocyclic group” is a “cross-linked heterocyclic group” containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring atoms. And the cross-linked ring group includes, for example, 3-azabicyclo [3.2.2] nonane-3-yl, 8-azabicyclo [3.2.1] octane-18-yl and the like. Can be Further, the “heterocyclic group” contains at least one nitrogen atom other than a carbon atom as a 璟 atom, and may further contain a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Nitrogen-containing saturated heterocyclic group ". Examples of the “nitrogen-containing saturated heterocyclic group” include, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, homopiperazinyl and the like.

 When the “hetero group” has a “substituent”, the type and number thereof are not particularly limited, and one or more substituents selected from the “substituents” defined below may be substituted at the substitutable position. Have three.

The "heteroaryl" of the "heteroaryl optionally having substituent (s)" is selected from the above-mentioned "heterocyclic group" as a ring atom selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom. Refers to a 5- to 7-membered aromatic heterocyclic (monocyclic) group containing 1 to 4 heteroatoms, for example, furyl, chenyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, Isooxazolyl, isothiazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4 monooxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,5-triazinyl, 1, 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azepinyl, diazepinyl and the like. “Heteroaryl” also includes a 5- to 7-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms as ring atoms. Also included are groups derived from an aromatic heterocyclic ring (bicyclic or higher) formed by condensing a ring with a benzene ring or the above aromatic heterocyclic group, for example, indolyl, isoindolyl, benzo [b] furyl, Benzo [b] phenyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzo'isothiazolyl, quinolyl, isoquinolyl and the like.

 Further, the above “heteroaryl” may be partially hydrogenated. The position to be hydrogenated is not particularly limited. Partially hydrogenated heteroaryls include, for example, indolinyl, tetrahydrobenzoimidazolyl, chromanyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrofuranyl, and the like.

 When the “heteroaryl” has a “substituent”, the type and number thereof are not particularly limited, and one to three substituents selected from the “substituents” defined below may be substituted at the substitutable positions. Contained.

 As the “heterocyclic group”, preferably, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, tetraquinolyl, isoquinolyl Quinolyl, 1,2,4-oxadiazolyl, 1,3,4—oxadiazolyl, 1,2,3—triazolyl, 1,2,4-triazolyl, 1,3,5—triazinyl, 1,2,4-thiadiazolyl , 1,3,4-thiadiazolyl, piperidinyl, piperazinyl, azepinyl, azepanyl, diazepanyl, diazepinyl, tetrahydrofuranyl, morpholinyl, indolyl, isoindolyl, indolinyl, tetrahydrobenzoimidazo , Chromanyl, 3-azabicyclo [3.2.2] nonane-3-yl, 8-azabicyclo [3.2.1] octane-8-yl, benzo [b] furyl, benzo [b] chenyl, Benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl and the like.

“The divalent hydrocarbon ring group which may have a substituent” and “the divalent hetero ring group which may have a substituent” are the above “hydrocarbon ring group” and “heterocyclic group”. Ring group '' Means a divalent group having a bond at any position. The position of the bonding hand is not particularly limited, and can be appropriately selected depending on the type of the group.

 When the “divalent hydrocarbon ring group” and the “divalent heterocyclic group” have a “substituent”, the type and number thereof are not particularly limited, and the “substituent” defined below It contains one to three selected substituents at substitutable positions.

 The “arylene” of the “arylene which may have a substituent” means a divalent group having a bond at any position of the “aryl” included in the above “hydrocarbon ring group”. Examples thereof include divalent groups such as phenylene and naphthylene.

 When “arylene” has a substituent, the type and number thereof are not particularly limited, and a substituent selected from the “substituents” defined below may be replaced by one to three at the substitutable position. Have

 “Cycloalkylene” in “cycloalkylene optionally having substituent (s)” refers to a divalent group having a bond at any position of “cycloalkyl” included in the above “hydrocarbon ring group”. Means a group, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene and the like.

 When the “cycloalkylene” has a “substituent”, the type and number thereof are not particularly limited, and one to three substituents selected from the “substituents” defined below may be substituted at the substitutable position. Have

 The “heteroarylene” of the “heteroarylene optionally having substituent (s)” is a divalent group having a bond at any position of the “heteroaryl” included in the “heterocyclic group”. And includes, for example, furylene, cherenylene, pyrrolylene, thiazolylen, pyrazolylen, oxazolylen, isosoxazolenylene, isotizazo'rylene, imidazolylene, 1,2,4-oxoxadiazolylene, 1,3, 4-oxosadiazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene,

1,3,5—Triazidinylene, 1,2,4—Thiadiazolylene, 1,3,4—Thiadiazolylene, pyridylene, pyrimidinylene, pyrazinylene, pyridazinylene, azepinylene, diazepinylene, indylene, isodoindylene, Indolinylene, benzo [b] furylene, benzo [b] chenylene, benzimidazolylene, Benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, quinolylene, isoquinolylene and the like.

 When the “heteroarylene” has a “substituent”, the type and number thereof are not particularly limited, and one or more substituents selected from “substituents” defined below can be substituted. Have three.

 “Alkyl” means straight or branched chain —6 alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. —Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3 —Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2 -Methylpropyl, 1-ethyl-1-methylpropyl and the like. “Alkyl” may have 1 to 3 “substituents” defined below at substitutable positions, and the type and number of the substituents are not particularly limited.

C alkyl are preferred in R ^1, the R ² C i _ ₆ alkyl rather preferable, C WINCH ₆ alkyl are preferred in R ^3, the R ⁴ (preparative ₆ alkyl laid preferred, the C WINCH _e alkyl in R ⁵ preferably, the R ⁶ -. 6 alkyl virtuous preferred, the C i _ ₆ alkyl in R ⁷ preferably, C iota _ ₆ alkyl is preferable in R ^8, and, in R ⁹ C ₆ alkyl is preferred in addition, R ^a preferably d-6 alkyl Te odor, preferably C i-6 alkyl in R ^b, C WINCH ₆ alkyl is preferable to have you to Rc, and, C alkyl is not preferable in R ^d.

 “(^ Alkylene)” in “C i -e alkylene optionally having substituent (s)” means an alkylene chain having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, Pentamethylene, hexamethylene, etc.

0

When “0 ^ -6 alkylene” has “substituent”, its type and number are particularly There is no limitation, and one to three substituents selected from the “substituents” defined below at substitutable positions are provided.

 When the “(^ -6 alkylene” is substituted by one or more of the following “substituents” —a branched alkylene chain (eg, methylmethylene, dimethylmethylene, 1— Methyl ethylene, 2-methyl ethylene, 1,1-dimethyl ethylene, 2,2-dimethyl ethylene, ethyl methylene, getyl methylene, 1-ethyl ethylene, 2-ethyl ethylene, 1-methyl trimethylene, 1,1-dimethyl trimethylene, 2 —Methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltrimethylene, etc.) You.

 “(^ -4 alkylene)” in “alkylene optionally having substituent (s)” means an alkylene chain having 1 to 4 carbon atoms in the above “(^ -6 alkylene)”.

When “(^ _ ₄ alkylene” has a “substituent”, its type and number are not particularly limited, and a substituent selected from the “substituents” defined below can be substituted at the substitutable position. Has one to three.

The "C ₂ _ ₆ alkenylene", "above" ₍₆ alkylene "," C ₂ - ₆ alkylene down "any Aruke carbon number 2-6 straight or branched chain having a double bond in the position of The position and number of the double bond are not particularly limited.

The - "C _{2 6} alkynylene", above - the "(^ 6 alkylene" - the "C _{2 6} alkylene down" the number of carbon atoms of straight or branched chain having a triple bond at any position from 2 to 6 alkylene The position and number of the triple bond are not particularly limited.

R ^a and R ^b are the same or different from each other and represent a hydrogen atom, an alkyl, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a hydroxy (-OH), an alkoxy (—0— Alkyl (alkyl is as defined above), cyano (one CN :), aminocarbonyl (one CONH ₂ ), carboxy (one COQ

H) or alkoxycarbonyl (one CO ₂ - alkyl (alkyl is as described above for definition)); or, taken R ^a and R ^b gar cord, may form a Okiso group, or R ^a and R ^b becomes 緖 together with the atoms to which they are attached It may form a ring.

"R ^a and R ^b are linked together to form a ring together with the atom to which they are bonded" is a ring in which R ^a and R ^b are bonded to a spiro ring as ^a C ₆ alkylene which may be interrupted by a hetero atom. Alternatively, a bridged ring may be formed. The term "interrupted by even a C Bok have ₆ alkylene with heteroatoms", as defined above C I ₆ alkylene, Or, the above-defined - 6 middle or end to an oxygen atom of the alkylene, sulfur atom Contact and nitrogen represents one heteroatom selected from atoms or two has been inserted group, the sulfur atom may have been oxidized (SO or S0 _2), nitrogen atom, hydrogen atom or (^ _ ₆ Having alkyl, for example, one CH ₂ CH ₂ —,

One 0—CH ₂ CH ₂ —, _CH ₂ _0-CH ₂ —, One 0—CH ₂ CH ₂ —0 _,

— CH ₂ -S— CH ₂ _, -CH ₂ -S (0) One CH ₂ —,

—CH ₂ —N (CH ₃ ) —CH ₂ — and the like.

One NR ² CONR ³ — represented by X, wherein R ² and R ³ may be the same or different and each represent a hydrogen atom or an alkyl; or R ² and R ³ May form a ring together with the atom to which they are bonded.) In the “ring formed by R ² and R ³ together with the atom to which they are bonded” The term “cyclic group” includes “nitrogen-containing saturated heterocycle”.

One NR ⁵ CONR ⁶ — represented by Y, wherein R ⁵ and R ⁶ may be the same or different and each represent a hydrogen atom or an alkyl; or R ⁵ and R ⁶ is and may form a ring together with the atoms to which they are attached. Contact Keru to) "becomes R ⁵ and R ⁶ gar cord ring formed together with the atoms to which they are attached" includes the above defined "heteroaryl The term “cyclic group” includes “nitrogen-containing saturated heterocycle”.

Represented by Z, one NR ⁸ CONR ⁹ -. (Wherein, R ^8, R ⁹ may be the same or have different dates, or show it it hydrogen atom or alkyl, R ⁸ and R ⁹ gar cord And may form a ring together with the atoms to which they are attached.): ": The ring formed by R ⁸ and R ⁹ together with the atoms to which they are attached" is defined as above "Nitrogen-containing saturated heterocycle" included in "heterocyclic group".

Represented by Z, mono-Q — optionally substituted C ₆ -alkylene or mono-substituted — 6 alkylene — — wherein, is an oxygen atom Child, a sulfur atom, One _{SO-, -S0 2 _, - NH-} , -NR 7 - (. Wherein,: R ⁷ is showing a § alkyl), One Co_, -OCO-, One C0 ₂ -, One CONR ⁸ — or one NR ⁸ CO— (wherein R ⁸ represents a hydrogen atom or alkyl),

^{-N 8 -CO-NR 9 -.} ( Wherein, R ^8, R ^9, which may be identical or different, it it a hydrogen atom or an alkyl or become R ⁸ and R ⁹ gar緖They may form a ring with the atoms to which they are attached.)

One NR ⁸ S0 ₂ — or one S〇 ₂ NR ⁸ — (wherein R ⁸ represents a hydrogen atom or an alkyl.) Or one 0—CO—NR ⁸ — or one NR ⁸ —CO— 0— ( In the formula, R ⁸ represents a hydrogen atom or an alkyl.). Among them]

_Q ₂ — (CH ₂ ) _q — and one (CH ₂ ) _q -Q _2-where Q ₂ is —NH—, —NR ⁷ — (wherein R ⁷ represents alkyl), oxygen atom, a sulfur atom, -SO- or an S0 ₂ - indicates, q is an integer of 1 to 4. ] Is preferred.

The “substituent” is not particularly limited, and includes, for example, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), ( ₆ alkyl (eg, methyl, ethyl, n-propyl, isopropyl) , N-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl Xyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1, Charcoal such as 2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyl Alkyl Le group) a straight or branched chain of. 1 to 6, C _{3 8} cycloalkyl (e.g., cyclopropyl, cyclobutyl, shea Kuropenchiru, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, norbornene two Le, bicyclo [ 2.2.1] heptyl or bicyclo [2.2.2] Okuchiru etc.), C _{3 8} cycloalkyl O alkoxy (e.g., cyclopropyl O alkoxy, Shikurobu Chiruokishi, Puchiruo carboxymethyl cyclopentyloxy Ruo alkoxy, cyclohexane Kishiruokishi, cyclohexylene , Cyclooctyloxy, norbornyloxy, bicyclo [2.2.1] butyloxy or bicyclo [2.2.2] octyloxy, etc.), — 6-halo Alkyl (for example, the above-mentioned Ct-6 alkyl having at least one halogen atom such as trifluoromethyl, difluoromethyl, etc.), C i-e alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, A straight-chain or branched-chain alkyloxy group having 1 to 6 carbon atoms such as isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc .; ( ₆ ) haloalkoxy (for example, at least the above halogen atom such as trimalomethoxy, difluoromethoxy, etc.) one Yusuke that the C I ₆ alkoxy), C ₆ - _{1 4} § Li Ichiru (e.g., phenyl, naphthyl, § Ntoriru etc.), C ₆ - _{1 4} Ariruokishi (e.g., Fuweniruokishi, Nafuchiruoki shea, Antoriruokishi etc.) , Hydroxy, nitro, amino, mono or g

- 6 alkyl) Amino (e.g., Mechiruamino, Echiruamino, Jimechirua Mino, Jechiruamino, propylamino, isopropyl § Mino, Puchiruamino, diisopropylamino etc.), mono- or di- (c ₃ - ₈ cycloalkyl) Amino (e.g., cyclopropyl § Mino , Cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, norbornylamino, bicyclo [2.2.1] heptylamino, bicyclo [2.2.2] octylamino, dicyclo Propylamino, dicyclobutylamino, dicyclopentylamino, dicyclohexylamino, dicycloheptylamino, dicyclooctylamino, dinorbornylamino, di (bicyclo [2.2.1] heptyl) amino, di (Bicyclo [2.2. 2] Okuchiru) Amino etc.), mono- or di one (C ₆ one _{1 4} Ariru) Amino (e.g., Fueniruamino, Nafuchiruamino, § Ntoriruamino, Jifue two Ruamino etc.), (g Ashiru [e.g., one ₇ Al force Noiru (e.g., formyl, Asechiru, propionyl, Puchiriru, Isopuchiriru, valeryl, isovaleryl, Piparoiru etc.), c ₃ _ ₇ Arukenoiru (e.g., § click acryloyl, main evening acryloyl, Kurotonoiru etc.), C ₃ - ₇ Alkynyl (eg, propioloyl, etc.), C ₇ — aroyl (eg, benzoyl, 1 _ naphthoyl,

2-naphthoyl, etc.), etc.], mono- or di one ((I _{1 4} Ashiru) Amino (e.g., § Sechiruamino, Amino having the C i-Ashiru such Benzoiruamino), mono- or di one (C _{1 4} alkoxy one carbonyl ) Amino (for example, methoxycarbonylamino, phenoxycarbonylamino, etc.), sulfonylamino, amino C- ₆ alkyl (for example, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, etc.), mono- or dialkyl) amino-alkyl (for example, methylaminomethyl, methylaminoethyl, ethylaminoethyl, etc.), c ₃ - ₈璟状amino, hydrazino, Guanijino, amidino, human Dorokishiamijino, alkoxy amidino (e.g., main Tokishiamijino, E Tokishiamijino, propoxy amidino, isopropoxycarbonyl amidino, Putokishiami Gino etc.), aminomethylene § Mino, imino, formyl, C i - e alkyl one carboxy alkenyl (e.g., Kisanoiru like Asechiru, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl to,), c ₆ - _{1 4} Ariru - carbonyl (e.g., Benzoyl, naphthoyl, 2-naphthoyl, 1-anthryl, etc., carbonyl, alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, Pentoxycarbonyl, etc.), carboxamide, carbamoyl, mono or di

(C i- ₆ alkyl) aminocarbonyl (for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, sec-butylaminocarbonyl, tert-butyl) Aminocarbonyl, dimethylaminocarbonyl, acetylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, diisopropylaminocarbonyl, etc.)

(C _e - _{1 4} Ariru) § amino carbonyl (e.g., phenylalanine § amino carbonyl, 1 one naphthyl § amino carbonyl, 2-naphthyl § amino carbonyl, 1-Antori Rua amino carbonyl, etc.), Shiano, C ₇ _ _{2 0} Aralkyl (e.g., benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 1- (1-naphthyl) ) Ethyl, 2— (1—naphthyl) ethyl,

1 one (2-naphthyl) Echiru, 2- (2-naphthyl) and the like Echiru of C ₆ - _{1 4} C alkyl with § Li one Le), mono- or di one (C ₇ one _{2 0} Ararukiru) Aminokaru Boniru (e.g. , Benzylaminocarbonyl, 2-phenylethylaminocarbo Nil, etc.), heteroaryl (eg, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxaziazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridine C i- ₆ alkyl (eg, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1- (2-pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (4-pyridyl) ethyl, 2- (2-pyridyl) Echiru, 2- (3-pyrid-Le) Echiru, 2- (4-pyridyl) Echiru, 3- (2-pyridyl) above C i _ ₆ alkyl having heteroaryl above propyl) , Mono or gee (hetero reel C Bok ₆ alkyl) § amino carbonyl (e.g., 2-pyridylmethyl amino carbonyl, 3-pyridylmethyl § amino carbonyl, etc.), mono- or di one (heteroaryl - C Bok ₆ alkyl) Amino (e.g., (imidazo Ichiru I-2-ylmethyl) amino, (imidazo-1-ylmethyl) amino, etc.), heteroarylcarboxamide (for example, imidazole-2-ylcarboxamide, imidazole-4-ylcarboxamide), amino acid residue Group-amino [eg, amino having amino acid residues such as glycyl, alanyl, phenylalanyl and the like (eg, alanylamino and the like) and the like. The amino acid residue may be of natural or non-natural origin, and the amino group contained in the amino acid residue may be protected with a protecting group (for example, tert-butoxycarbonyl group and the like). ], Hydroxy, mercapto, C i _ ₆ alkylthio (e.g., methylthio, Echiruchio, propylthio, isopropoxy Ropiruchio, Puchiruchio etc.), C ₆ - _{1 4} § Li one thio (e.g., phenylene thioether, 1 one-naphthylthio, 2-naphthylthio , 1-anthrylthio, etc.), 1 S 0 ₃ H or 1 S 0 ₂ NH _{2 and the} like.

 These substituents may be further substituted with the above-mentioned substituents, and the kind and number of the substituents are not particularly limited, and one to three substituents are present at the substitutable positions.o

Examples of the substituent include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a Ci- ₆ alkyl [if necessary, the above halogen atom, the above de-e alkoxy or phenyl ( If necessary, the above halogen atom, Alkyl, C i- ₄ alkoxy or trifluoromethyl), one R ^A1 , one S (0) ₂ R ^A2 ,

— S (0) ₂ NR ^A3 R ^A4 , one NR ^A5 S (0) ₂ R ^A6 , -C (〇) R ^A7 ,

C (0) NR ^A8 R ^A9 , -NR ^A1 ° C (0) R ^A11 , — NR ^A12 R ^A13 ,

-NR ^A14 C (0) NR ^A15 R ^A16 , methylenedioxy, nitro or cyano include:

 A 1 A 3 p A4 p A 5 p A8 p A 9 p A 10 p A 1 1 T ^ A12 A 13

R ^A14 , R ^A15 and R ^A16 are independently the above halogen atom or — 6 alkyl (optionally substituted by the above C alkoxy) or phenyl (optionally the above halogen Atom, alkyl, substituted with Ci- ₄ alkoxy or trifluoromethyl);

R ^A2 and R ^A6 are independently the Ci-e alkyl [optionally the C丄_ ₆ alkoxy, or phenyl (optionally the halogen atom, § alkyl, C i_ ₄ alkoxy or Torifuruo And it may be substituted with methyl.). ]

R ^A7 represents a hydrogen atom, if the CI_ ₆ alkyl [required, the an alkoxy or phenyl (optionally the halogen atom, the alkyl, optionally substituted on Symbol C Bok ₄ alkoxy or triflate Ruo B methyl . it may be) in replacement which may also be or the CI- _C6 alkoxy [unsubstituted or optionally the C Bok ₆ alkoxy, or phenyl (necessary, the halogen atom, (^ - 47 alkyl, C ₄ May be substituted with alkoxy or trifluoromethyl).

Examples of the substituent include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), -cycloalkyl, one heterocyclic group, aryl, —OH, —OH, —O—Ci-ealkyl, Aryl, _0-cycloalkyl, 10-heterocyclic group, -NH-aryl, —NH-cycloalkyl, —NH-heterocyclic group, 1 NH ₂ , 1 NH—Ci- ₆ alkyl, 1 N (C Medicine ₆ alkyl) _2, -CONH _2, one CONH- CI- _C6 alkyl, - NHCO- ₍₆ alkyl, -CON (C _x _ _{6 alkyl) 2, - C0 2 - d-} 6 alkyl, - C0 ₂ H, —S0 ₃ H, —S0 ₂ NH ₂ , 1 N 0 ₂ and —CN [cycloalkyl, heterocyclic group, aryl and alkyl are as defined above].

Examples of the substituent include alkyl, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), an alkyl (eg, trifluoromethyl), and a C-OH-substituted C atom. ₆ alkyl, C i_ ₆ alkyl substituted with 1 COOH, — alkyl substituted with CONH ₂ and C i- ₆ alkyl substituted with 1 CN [alkyl is as defined above].

Further, examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), - OH, - CN, One N_〇 _2, One NH _2, One CONH _2, -C0 ₂ - alkyl , A halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a C i_ ₃ alkyl, —0— (halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom) , phenyl substituted with a group selected from is optionally may CI- ₃ alkyl) and single so ₂ _ substituted by an iodine atom, etc.) (which may be substituted by a halogen atom C _i-3 alkyl) No.

Further, examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine _{^{atom), - R B1, C 2}} _ 6 alkenyl (wherein, C ₂ _ ₆ alkenyl, the above "(3 ^ 6 alkyl "is alkenyl having carbon number 2 to 6 straight or branched chain have a double bond at any position of the" C ₂ _ ₆ alkyl ". position and number of double bonds Not particularly limited), C ₂ _ ₆ alkynyl (where C ₂ _ ₆ alkynyl is a straight-chain or straight-chain having a triple bond at any position of “C ₂ — ₆ alkyl” of “(^ _ ₆ alkyl)” It is an alkynyl having a branched chain carbon number of 2 to 6. The position and number of the triple bond are not particularly limited.), —OH, —SH, one N (R ^B2 ) ₂ , —CHO,

One C0 ₂ R ^B2 , -CON (R ^B2 ) ₂ , — NR ^B2 CO_R ^{B 1} , -NR ^B2 CO- (optionally substituted aryl), -NR ^B2 -CO-NR ^B3 -R ^B one ^{_{NR B2 S0 2 - R B1,}} - NR B2 S0 2 - ( good § Li one le may have a substituent), one 0 - R ^B1, one S - R ^B1, one SO - R ^B1ヽone S0 ₂ — R ^B1 ,

One S0 ₂ NR ^B2 — R ^B1 or — S0 ₂ — NR ^B2 — (optionally substituted aryl) includes: R ^{B 1} is optionally substituted — 6 alkyl, and 1? ^ ^{2 and} 11 ^ are the same or different and are each a hydrogen atom or (ぃ₆ alkyl; or R ^B2 and R ^B3 is the above defined "heteroaryl but" ring formed together with the atom to which they are bonded in R ^B2 and R ^{B 3} gar緖"they are attached to optionally form a ring together with the atom (Te summer together "Ring group" includes "nitrogen-containing saturated heterocycle").

 In the compound of the general formula (1), "at least one of the nitrogen atoms contained in the formula is oxidized" means that the "oxidizable nitrogen atom" contained in the formula is known to those skilled in organic synthesis. Means that it may be oxidized by the above method. The "oxidizable nitrogen atom" is not particularly limited as long as it is a nitrogen atom.

The “oxidizable nitrogen atom” is preferably a compound represented by the general formula (1):

Is a bonded nitrogen atom. A nitrogen atom contained in the heterocyclic group (including heteroaryl) represented by B is also preferable.

The ring A, good Ariru preferably have a substituent, as of V, a C bets ₆ alkylene preferably have a substituent, especially methylene down among them (one CH ₂ -) is preferable.

Therefore, in the general formula (1), the group:

Is preferably Ar—CH ₂ — (Ar represents an aryl which may have a substituent).

 As the “aryl” of the “aryl which may have a substituent” represented by Ar, phenyl is preferable, and the “substituent” is preferably a chlorine atom. As the “aryl which may have a substituent”, 3,4-dichlorophenyl is preferable.

^Ra and ^Rb are preferably both hydrogen atoms.

p represents an integer of 0 to 2, and is preferably 1. m represents an integer of 0 to 5, preferably an integer of 0 to 3, and more preferably 0.

 n represents an integer of 0 to 5, preferably an integer of 1 to 5, more preferably an integer of 1 to 4, and still more preferably 1.

 r represents 0 or 1. r = l is preferred.

W is preferably one CH, —CH ₂ —, one N, —NH— or an oxygen atom, more preferably one CH or one CH ₂ —, and even more preferably one CH < .

X is preferably a bond, —NH—, —NR ¹ — (wherein R ¹ represents alkyl), —CO—, —CONH—, —NHCO—, —NR ² CONR ³ — (wherein , R ^2, R ^3, which may be the same or different and is shown it hydrogen atom or alkyl Le), an oxygen atom, a sulfur atom, one SO_, -. S0 ₂ _ one NHS0 ₂ - or an S0 ₂ NH—, more preferably _CO—, one CONH—,

One NHCO-, -NR ² CONR ³ - (wherein, R ^2, R ^3, which may be the same or different and is shown it hydrogen atom or _{alkyl.), -SO-, - S0 2} -, - NHS0 ₂ - or _S0 a ₂ NH-, even more preferably one CO-, - CONH-, -NHCO-, -NR 2 CONR 3 - ( wherein, R ^2, R ³ can also be the same or different Often, each represents a hydrogen atom or an alkyl.) And even more preferably —CONH— (where the carbon atom of _CONH_ is bonded to-(CH ₂ ) _n — and the nitrogen atom is one (CH ₂ ) _m —).

Y is preferably a bond, —NH—, —N ⁴ — (wherein R ⁴ represents alkyl), one CO—, one CONH—, one NHCO—, and —NR ⁵ CONR ^e — (wherein , R ^5, R ^6, which may be the same or different, it indicates it hydrogen atom or alkyl Le), an oxygen atom, a sulfur atom, -. SO-, one S0 ₂ -, - NHS0 ₂ - or one S0 ₂ NH—, more preferably a bond, an oxygen atom or a sulfur atom, more preferably a sulfur atom.

Z is preferably a bond, may be substituted - 4 alkylene, SansoHara child, a sulfur atom, One SO-, One S0 ₂ -, One NH-, -NR ⁷ - (R ⁷ is alkyl ), One CO—, one Q ₂ — (CH ₂ ) _q — or one (CH ₂ ) _q -Q _2- Q ₂ is, _NH-, -N ⁷ - (wherein, R ⁷ represents an alkyl.), An oxygen atom, a sulfur atom, one SO- or _S0 ₂ - indicates, q is an integer of 1 to 4. And more preferably a bond.

 A is preferably a bond, arylene optionally having substituent (s), heteroarylene optionally having substituent (s) or cycloalkylene optionally having substituent (s), and Preferred is arylene which may have a bond or a substituent or heteroarylene which may have a substituent, and even more preferably, it has a bond or a substituent. Heterogenes are good and still more preferably heteroarylenes which may have a substituent. Among them, thiazolylene, oxadiazolylene (for example, 1,3,4-oxadiazolylene and the like), and thiadiazolylene (for example, 1,3,4-thiadiazolylene and the like) are preferable.

B is preferably aryl which may have a substituent, heteroaryl which may have a substituent or cycloalkyl which may have a substituent, and more preferably has a substituent. And heteroaryl which may have a substituent. Of these, phenyl, pyridyl, pyrazinyl, thiaziazolyl (for example, 1,3,4-thiadiazolyl, etc.) and benzothiazolyl are preferred. Examples of the substituent, Amino, Shiano, (for example, methoxycarbonyl, etc.) C I ₆ alkoxy one carbonyl, carboxy, force Rubamoiru, mono- or di one (to Teroari one Lou C i-e alkyl) Amino (e.g., (imidazo 1-yl 2-ylmethyl) amino, (imidazoyl 4-ylmethyl) amino, etc., heteroaryl carboxamide (eg, imidazole-4-ylcarboxamide, etc.), amino acid residue amino (eg, L-aralanylamino, etc.) Are preferred. Further, as the heteroaryl which may have a substituent represented by B, N-oxidepyridyl is preferable.

 Preferred compounds of the general formula (1) include:

 (1) [4- (3-Cyanophenyl) thiazo-1-yl-2-ylthio] _N— [1- (3,4-Dichlorobenzyl) -1-oxopiperidine-1 4-f] acetamide,

(2) [4- (4-Cyanophenyl) thiazo-l-u2-thiol] — N— [1- (3,4-dichlorobenzyl) -11-oxopiperidine-14-yl] acetamide,

 (3) N_ [1— (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — (4-phenylthiazo-1-ru-2-ylthio) acetamide,

 (4) N— [11- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] -1- [4- (3-pyridyl) thiazo-1-l-2-ylthio] acetamide,

(5) N- [1- (3,4-dichroic benzyl) -11-oxopiperidine-14-yl] -1- [4- (4-pyridyl) thiazole-1-2-ylthio] acetamide,

(6) N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl]-[4-1- (4-methoxycarbonylphenyl) thiazo-l-2-ylthio] Acetamide,

 (7) N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-yl] -1- [3- (3-methoxycarbonylphenyl) thiazo-1-yl 2-ylthio] Acetamide,

 (8) [4- (3-carboxyphenyl) thiazole-1-ylthio] -1-N- [1- (3,4-dichrobenzyl) _1-oxopiperidine-1-4-yl] acetamide,

 (9) [4- (4-carboxyphenyl) thiazolyl-2-ylthio] — N- [1- (3,4-dichlorobenzyl) — 1-oxopiperidine-1-4-yl] acetami Do

 (10) N— [1— (3,4-dichlorobenzyl) piperidine-1-4-yl] -1- [4 -— (1-oxopyridine-14-yl) thiazolyl-1-ylthio] acetamide ,

 (11) N— [1— (3,4-dichlorobenzyl) piperidine-1-4-yl] -1- [4 -— (1-oxopyridine-3-yl) thiazo-1-yl 2-ylthio] acetamide,

(12) N— [l— (3,4-dichroic benzyl) -11-oxopiperidine-14-yl] -1- [4- (2-pyridyl) thiazole-1-2-ylthio] acetamide, (13) N— [11- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- (4-pyrazinylthiazole-2-ylthio) acetamide,

(14) (5-Amino-1,3,4-thiadiazo, 1-2-ylthio) 1 N-1 [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-1 4-yl] acetamide ,

 (15) N— [1— (3,4-dichlorobenzyl) 1-1-oxopiperidine—4-yl] — (5-phenyl-1,3-, 4-oxaziazolu-l-2-ylthio) acetami Do

 (16) N— [1— (3,4-Dichroic benzyl) —1-oxopiperidine—4-yl] — [5— (4-pyridyl) -1-1,3,4-oxoxadiazo-2-ol Filcio] Acetamide,

 (17) N— [1— (3,4-dichlorobenzyl) 1 1-oxopiperidine 1-4_yl] 1 [5— (4-pyridyl) 1 1,3,4—thiadiazo-2-yl Lucio] Acetamide,

 (18) (6-aminobenzoti-zol-2-ylthio) 1 N— [1— (34 dicyclomouth benzyl) 1-oxopiperidine-1 4-yl] acetamide,

(19) [4-(3-rubamoylphenyl) thiazolyl-2-^ T-lthio] -N- [1-(3,4-dichloromouth benzyl)-1-oxopiperidine 1- Yl] acetamide,

 (20) [4-(4 rubamoylphenyl) thiazo-l- 2-ylthio] -N- [1-(3,4-dichroic benzyl)-1 -oxopiperidine-1-4-yl] acetamide ,

 (2 1) N— [1— (3,4-dichlorobenzyl) 11-year-old oxopiperidine 1-4-yl] 1- {4-1-[((imidazole-1-41-methyl) amino) phenyl] thiazo 2-l-thiol} acetamide,

 (22) N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- {4-1-((imidazo-l-2-ylmethyl) amino) phenyl] thiazo 1-ru 2-irthio} acetoamide, '

(23) N— [1- (3,4-dichlorobenzene) 1-oxopiperidine _4-yl] 1- {4- 1- [3- (imidazo-1-ylcarboxamide) phenyl] thiazole-2-ylthio} acetamide, and

 (24) {4- [3- (L-alanylamino) phenyl] thiazole-1-ylthio} —N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] acetamide Can be

 Among the above compounds, compounds (1) to (18) are preferable.

 (1) [4- (3-Cyanophenyl) thiazolyl-2-ylthio] — N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine_4-yl] acetamide,

 (4) N— [1— (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — [4- (3-pyridyl) thiazolyl-2-ylthio] acetamide,

(5) N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- [4- (4-pyridyl) thiazo-1-ru-2-ylthio] acetamide,

(7) N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — [4- (3-methoxycarbonylphenyl) thiazo-l-2-ylthio] acetami Do

 (9) [4- (4-carboxyphenyl) thiazolyl-2-ylthio] -1-N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] acetamide , and

 (10) N— [1- (3,4-dichloro mouth benzyl) piperidin-4-yl] — [4- (1-oxopyridine-14-yl) thiazo-1-ru-2-ylthio] acetamide is preferred.

 The compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate (eg, an ethanol solvate). Objects are also included in the present invention. When the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are also included in the present invention.

The compound of the general formula (1) can be produced by the following methods (1) to (8) and methods according to these methods, and is used in the following methods (1) to (8) The starting compounds can be obtained by methods known to those skilled in the art of organic synthesis, and methods according to the methods described in Patent Documents 1 to 15 (Patent Documents 1 to 15 are incorporated herein by reference). And the like.

In the following methods (1) to (8), the compound of the general formula (1) is shown in a preferred embodiment so that those skilled in the art can easily understand the production method of the compound of the present invention. That is, in the general formula (1), the group:

Is Ar—CH ₂ — (Ar represents aryl which may have a substituent); ρ = 1; m = 0; W = —CH; ^Ra and R ^b are both hydrogen Is an atom. Further, the position of Noxide (N—◦) in the compound of the general formula (1) is not particularly limited.

 The following methods (1) to (8) illustrate the method for producing the compound of the present invention (the compound of the general formula (1)), and do not limit the method for producing the compound of the present invention. Should understand.

 The term “substituent necessary for the construction of heteroaryl (including heteroarylene)” used in the following description of the synthesis method means, in many cases, an addition reaction or water or alcohol, depending on acid or base catalyst, light, heat, etc. , Acid, hydrogen halide, etc. means a substituent necessary for constructing a heteroaryl by a condensation reaction accompanied by elimination. Specific examples of the above "substituents required for heteroaryl construction" include any of a combination of promoacetyl and thioamide when constructing thiazolyl, and hydrazide when constructing 1,3,4-oxoxadiazole. Either one of the combinations of carboxylic acids, one of the combination of acetyl oxime and carboxylic acid ester when constructing 1,2,4-oxadiazole, or the combination of hydrazide and carboxylic acid when constructing isoxazole. One of the combinations, one of the combinations of S-methylthioamide and hydrazide when constructing 1,2,4-triazole, etc.ο

 Method (1)

General formula (2): B, _z , 丫,

(Wherein each symbol is as defined above) or a salt thereof (eg, an acid addition salt (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) Is a base addition salt (for example, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc.), etc.) and a suitable solvent which does not inhibit the reaction (for example, dichloromethane, dichloroethane, chloroform). Halogenated hydrocarbons such as, for example, or any mixed solvent of these), in an oxidizing agent such as methylbenzoate perbenzoic acid, or in a carboxylic acid solvent such as acetic acid, trifluoroacetic acid, or formic acid. The reaction is usually carried out at a temperature of 30 to 80 ° C, preferably at a temperature of 110 to 60 ° C, for 0.5 to 24 hours by using an oxidizing agent such as plain water. Equation (1):

(Wherein each symbol is as defined above).

In the above reaction, when an amino group which does not participate in the reaction is present in the reactant, the substituent may be protected with an appropriate protecting group, then the reaction may be carried out, and the protecting group may be removed after the reaction. Examples of the protecting group for the amino group used in this case include tert-butoxycarbonyl (B oc), benzyloxycarbonyl and other such sulfamates, formyl, acetyl, trifluoroacetyl, benzoyl and other amides, benzyl, P— And arylalkyl such as methoxybenzyl and trityl. Removal of these protecting groups can be performed, for example, by solvolysis using an acid such as hydrochloric acid, formic acid, or trifluoroacetic acid, or a base such as sodium hydroxide or lithium hydroxide, reduction using a metal hydride complex, or palladium. —Catalytic reduction using carbon catalyst or Raney nickel, 2, It can be performed by oxidation using 3-dichloro-5,6-dicyanor ρ-benzoquinone or the like.

 Method (2)

 In the general formula (1), when X is -CONH-, the compound can also be synthesized by the following method.

General formula (3):

(Wherein each symbol is as defined above) or an acid addition salt thereof (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) and a compound represented by the general formula (4 ):

(Wherein each symbol is as defined above) or an acid addition salt thereof (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) inhibits the reaction. In a suitable solvent (for example, tetrahydrofuran (hereinafter abbreviated as THF), dichloromethane, Ν, Ν-dimethylformamide (hereinafter abbreviated as DMF) or a mixed solvent of any of these), triethylamine, In the presence of a tertiary amine such as diisopropylethylamine, a condensing agent [eg, dicyclohexylcarpoimide (hereinafter abbreviated as DCC), 、 — (3-dimethylaminopropyl) -N′— Ethylcarboimide (hereinafter abbreviated as EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (hereinafter abbreviated as EEDQ), carbodiimidazole Hereinafter, it is abbreviated as CDI.), Getyl phosphoryl cyanide, benzotriazo-1-yl-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (hereinafter abbreviated as PyBOP), diphenylphosphoryl azide (hereinafter abbreviated as PyBOP). , Abbreviated as DPPA), isoptyl chloroformate, getyl acetyl chloride, trimethyl acetyl chloride and the like. ] Alone or N-hydroxys Cucinimide (hereinafter abbreviated as HONSu), hydroxybenzotriazole (hereinafter abbreviated as HOBT), or 3-hydroxy-14-oxo-3,4-dihydro-1,2,3-be A combination of additives such as benzotriazine (hereinafter abbreviated as HOOBT) or 4-dimethylaminopyridine (hereinafter abbreviated as DMAP) is usually used at a temperature of 30 to 80 ° C, preferably By reacting at a temperature of 10 to 25 ° C for 1 to 24 hours, the general formula (1):

0

 To N Ar

B, _z , A, (CH2) _nヽ ,, (1)

(Wherein each symbol has the same meaning as described above. However, represents one CONH—).

 In addition, the compound represented by the general formula (1) can be obtained by performing the same reaction as the reactive derivative (for example, acid chloride, acylimidazole, etc.) using the compound of the general formula (3). .

 Usually, this reaction is carried out in a suitable solvent that does not hinder the reaction (eg, THF, dichloromethane, chloroform, benzene, or any mixed solvent thereof) in the presence of a tertiary amine such as triethylamine or pyridine. Perform under ice-cooling or at room temperature for 1 to 24 hours.

 Method (3)

 In the general formula (1), when X is -NHCO-, it can be synthesized by the following method.

General formula (5): z, _A / Y \ _(CH2) MH2 ₍₅₎

(Wherein each symbol is as defined above) or an acid addition salt thereof (for example, hydrochloride, hydrobromide, sulfate, oxalate, etc.) and a general formula

(6):

 (Wherein each symbol is as defined above) or an acid addition salt thereof (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) inhibits the reaction. In a suitable solvent (eg, THF, dichloromethane, DMF or a mixed solvent thereof) in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, etc., a condensing agent (method (2) above) Is reacted with ice-cooling or room temperature for 1 to 24 hours to obtain a compound represented by the general formula (1):

(Wherein each symbol has the same meaning as described above, provided that X represents —NHCO—).

 In addition, the compound represented by the general formula (1) can be obtained by performing the same reaction as the reactive derivative (acid chloride, acylimidazole, etc.) using the compound of the general formula (6).

 Method (4)

 In the general formula (1), when Y is —NH—, an oxygen atom and a sulfur atom, it can be synthesized by the following method.

 General formula (7):

Β Τ ^Υ , Η (7)

(Wherein Y represents _NH—, an oxygen atom or a sulfur atom. Other symbols are as defined above) or an acid addition salt thereof (for example, hydrochloride, hydrobromide) , Sulfates, oxalates, etc.) in a suitable solvent that does not interfere with the reaction (for example, Chloromethane, chloroform, dichloroethane, geethylether, dimethylformamide, water or a mixture of any of these) in the general formula (8):

(Wherein L ¹ represents a leaving group such as chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above. Or a salt thereof with an acid (eg, hydrochloride, acetate, hydrobromide, sulfate, oxalate, etc.), triethylamine, pyridine, DMAP, potassium carbonate, hydrogen carbonate By reacting in the presence of a base such as sodium and sodium hydroxide under ice cooling or at room temperature for 1 to 24 hours, the general formula (1):

(In the formula, each symbol is as defined above, provided that Y represents —NH—, an oxygen atom or a sulfur atom.)

The compound represented by is obtained.

 Method (5)

 When A represents heteroarylene which may have a substituent in the general formula (1), it can be synthesized by the following method. That is, the general formula (9):

(Wherein G ¹ represents a substituent necessary for heteroaryl construction, and other symbols are as defined above) or an acid addition salt thereof (for example, hydrochloride, hydrobromic acid) Salts, sulfates, oxalates, etc.) with the general formula (10): O

 il to Ar

G ² , _Y CH2) _n , _x J \ ^ J (10)

(Wherein G ² represents a substituent necessary for heteroaryl construction, and other symbols are as defined above) or an acid addition salt thereof (for example, hydrochloride, hydrobromic acid) Salts, sulfates, oxalates, etc.) to obtain the general formula (1):

0

 ', Ar

B,, (CH2) _n , _x J \ ^ J (1)

(Wherein, A represents heteroarylene which may have a substituent, and other symbols are as defined above).

 Method (6)

 In the case where B represents a heteroaryl which may have a substituent in the general formula (1), it can also be synthesized by the following method.

That is, the general formula (11):

G ³ -H (11)

(Wherein, G ³ represents a substituent necessary for building a heteroaryl) or an acid addition salt thereof (for example, hydrochloride, hydrobromide, sulfate, sulfuric acid) ) Is represented by the general formula (12):

( ¹² )

(Wherein G ⁴ represents a substituent necessary for heteroaryl construction, and other symbols are as defined above) or an acid addition salt thereof (eg, hydrochloride, hydrobromic acid) Salts, sulfates, oxalates, etc.) to obtain the general formula (1): 0

 N ヽ Ar

Β, _ζ Αγ (.Η2) _η , _χ ^ (1)

(Wherein Β represents a heteroaryl which may have a substituent, and other symbols are as defined above.).

 Method (7)

In the general formula (1), Ζ represents —Q ₂ — (CH ₂ ) _q— , wherein Q ₂ represents —NH—, —NR ⁷ — (wherein R ⁷ represents alkyl), an oxygen atom or Represents a sulfur atom, and q represents an integer of 1 to 4. ] Can also be synthesized by the following method.

That is, the general formula (13):

(13) [wherein, G ⁵ represents —NH ₂ , —NHR ⁷ (where R ⁷ represents alkyl), —OH or one SH, and the other symbols are as defined above. ) Or an acid addition salt thereof (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) in a suitable solvent that does not inhibit the reaction (eg, dichloromethane, chloroform-form) , Dichloroethane, geethylether, water or a mixed solvent thereof) in the general formula (14):

(Wherein L ² represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above). Compound or its acid addition salt (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) and base (eg, triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogencarbonate, hydroxide) Reaction in the presence of sodium, etc., on ice or at room temperature for 1 to 24 hours. General formula (1):

[In the formula, Z is —Q ₂ _ (CH ₂ ) _q — [wherein Q ₂ is one NH—, one NR ⁷ — (wherein, R ⁷ represents alkyl.), An oxygen atom or sulfur Represents an atom, and q represents an integer of 1 to 4. ]. Other symbols are as defined above. ] The compound represented by these is obtained.

 Method (8)

In the general formula (1), Z is one (CH ₂ ) _q -Q _2- , wherein Q ₂ is one NH—, —NR ⁷ — (where R ⁷ represents alkyl), and an oxygen atom Or a sulfur atom, and q represents an integer of 1 to 4. ] Can also be synthesized by the following method.

That is, the general formula (15):

B " ^(Cn2) ^ L ³ (15)

(Wherein, L ³ represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and other symbols are as defined above). Compound or its acid addition salt (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) with a suitable solvent that does not interfere with the reaction (eg, dichloromethan, chloroform, dichloroform) Even, getyl ether, water or a mixed solvent of any of these) in the general formula (16):

[Wherein, G ⁶ represents —NH ₂ , one NHR ⁷ (where R ⁷ represents alkyl), one OH or —SH, and the other symbols are as defined above. ] To the compound represented by Or its acid addition salts (eg, hydrochloride, hydrobromide, sulfate, oxalate, etc.) and bases such as triethylamine, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, etc. The reaction is performed under ice-cooling or at room temperature for 1 to 24 hours to obtain the general formula (1):

0

To ^Ar

B ヽ ge A, _Y , (ch _n , _x A ^ J (1)

Wherein, Z _{is, - (CH 2) q _Q} 2 - [ wherein, Q ₂ one NH-, -NR ⁷ - (. Wherein, R ⁷ is showing a alkyl), an oxygen atom or a sulfur atom And q represents an integer of 1 to 4. ]. Other symbols are as defined above. ] The compound represented by these is obtained.

 In the above methods (2) to (8), N-oxides of the compounds represented by the general formulas (4), (6), (8), (10), (12), (14), and (16) The nitrogen atom in the portion (N → 0) may not be oxidized, and in such a case, the reaction of the above methods (2) to (8) is performed using a compound in which the nitrogen atom is not oxidized. Thereafter, the nitrogen atom (which is not particularly limited as long as it is a nitrogen atom) contained in the obtained product is oxidized by the method (1) or a method analogous to the method (1) and a method known in the art. Is also good. Further, as the starting compound, a compound in which another nitrogen atom is oxidized by a method known in the art may be used.

Examples of the pharmaceutically acceptable salt of the compound of the general formula (1) include an acid addition salt with an inorganic acid or an organic acid. The compound of the general formula (1) can be converted into an inorganic acid (eg, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, etc.), organic acids (for example, acetic acid, trifluoroacetic acid, tosylic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, It can be converted to a salt by treating with ascorbic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, camphorsulfonic acid, ascorbic acid, and the like. Alternatively, a pharmaceutically acceptable salt of the compound of general formula (1) is a base addition salt (Eg, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc.). Hydrates and solvates (for example, ethanol solvates) of the compound of the general formula (1) are also included in the present invention.

 The compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization and column chromatography. When the obtained product is a racemic form, it is separated into a desired optically active substance by, for example, fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier. can do. Individual diastereomers can be separated by means such as fractional crystallization or column chromatography. These can also be obtained by using an optically active starting compound or the like. Stereoisomers can be isolated by recrystallization, column chromatography, or the like.

 When the N-oxide compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is used as a medicament, the compound of the present invention can be used in a pharmaceutically acceptable carrier (eg, excipient, binder, disintegrant, corrigent, etc.). Compositions or preparations (eg, tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs) obtained by mixing with pharmaceutical agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc. Preparations, suspensions, solutions, injections, drops, suppositories, etc.) orally or parenterally.

 The pharmaceutical composition can be formulated according to a usual method. In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like.

 Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound may comprise at least one excipient, for example, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans , Pectins, tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers

-Or glycerides. Such dosage forms may also contain additional additives (eg, inert diluents, lubricants such as magnesium stearate, Preservatives such as parabens and sorbins, antioxidants such as ascorbic acid, heart tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, perfumes Agent etc.).

 Tablets and pills can additionally be prepared with enteric coating. Solutions for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which are inert diluents commonly used in the art, such as water. May be included.

 Injectable preparations (eg, sterile injectable aqueous or oleaginous suspensions) should be prepared using known dispersing or wetting agents and suspending agents and by methods known in the art. Can be. The preparation for injection may also be, for example, a sterile injectable solution or suspension using a diluent or a solvent such as water. Examples of the vehicle or solvent that can be used include water, Ringer's solution, isotonic saline and the like. In addition, usually sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose, any bland fixed oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration are solid at room temperature, including the drug and suitable nonirritating excipients, for example, cocoa balm and polyethylene glycols, but are liquid at intestinal tract temperatures and intrarectal. It can be manufactured by mixing with a substance that releases the drug by melting it.

 The dosage depends on the patient's age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated at that time. It is determined in consideration of other factors. The compound of the present invention is low-toxic and can be used safely. The daily dose varies depending on the condition and weight of the patient, the type of the compound, the administration route and the like. 1 to 1

0.000 mg / kg body weight / day, preferably 0.05 to 50 mg / kg body weight / day, administered once to several times a day, and parenterally subcutaneously or intravenously. About 0.01 to 5 O mg / kg body weight per day, preferably 0.01 to 1

It is preferred to administer SO mg / kg body weight / day. Diseases that can be treated and / or prevented include, for example, diseases in which cells with chemokine receptors play an important role in the onset, progression, and maintenance of the disease state, such as atherosclerosis and rheumatoid arthritis , Osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy, ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis Rejection at the time of organ transplant surgery, human immunodeficiency syndrome, and the like.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to raw material synthesis examples, examples, and experimental examples, but the present invention is not limited thereto.

The ¹ H-NMR spectrum of the compound was measured at 300 MHz. Chemical shifts in ifi-NMR were expressed in relative per million (d) values in ppm using tetramethylsilane (TMS) as the internal standard. Coupling constants indicate trivial multiplicity in hertz (Hz), s (single rate), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet). ), Brs (broad singlet), etc. Column chromatography was performed using silica gel manufactured by Fuji Silicon Chemicals.

Raw material synthesis example 1

 Synthesis of 2-Chloro-N— [1— (3,4-dichrolic benzyl) piperidine-1-4-yl] acetamide

After completely dissolving 50 g of 4-amino-1- (3,4-dichlorobenzil) piperidine dihydrochloride in 300 ml of chloroform, add 300 ml of aqueous sodium hydrogen carbonate solution, and then add 14.3 ml of chloroacetyl chloride. Was added and stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was extracted with chloroform, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from isopropyl ether / hexane to give the title compound (44.1 g) as a white powder. ^ -NMR (DMSO- d ₆ ) δ: 1.36-1.50 (2H, m), 1.65-1.78 (2H, m), 1.97-2.09 (2 H, m) , 2.66-2.76 (2H, m), 3.45 (2H, s), 3.47-3.60 (1H, m), 4.01 (2H, s), 7.25 -7.34 (1H, m), 7.53-7.62 (2H, m), 8.10-8.17 (1H, m).

Raw material synthesis example 2

 Synthesis of 2-N- [1- (3,4-dicyclobenzyl) -1-oxopiperidin-4-yl] acetamide acetate

After completely dissolving 3 g of the product of Raw Material Synthesis Example 1 in 20 ml of acetic acid, 1 ml of 30% hydrogen peroxide solution was added, and the mixture was stirred at 70 ° C for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was extracted with chloroform, washed with saturated saline and dried, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from chloroform-forminoisopropyl ether to give the title compound (3.2 g) as a white powder. ifi—NMR (DMSO-d ₆ ) δ: 1.66-1.72 (2Η, m), 1.85 (3H, s), 1.99-2.15 (2H, m), 3.07- 3.15 (2H, m), 3.37-3.46 (2H, m), 3.66-3.81 (lH, m), 4.00 (2H, s), 4.51 (2H, m) s), 7.53 (1H, d, J = 8.1Hz), 7.69 (1H, d, J = 8.1Hz), 7.86 (1H, s), 8.42 ( 1H, d, J = 7.5 Hz).

Raw material synthesis example 3

 [4-(3-Cyanophenyl) thiazolu-l- 2-thiol] —N— [1-(3

Synthesis of 4-dichlorobenzyl) piperidine-1-yl] acetoamide

[4- (3-Cyanophenyl) thiazo-l-2-ylthio] acetic acid 10 g and 4- Dissolve 13.2 g of amino 1- (3,4-dichloro mouth benzyl) piperidine dihydrochloride in 300 ml of dichloromethan, then 1 lml of triethylamine, 6.7 g of HOBT, 8.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid hydrochloride was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried and dried. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform / isopropyl ether to give the title compound (17.4 g) as a white powder.

! H-NMR (CD C 1 3) δ: 1. 30 - 1. 44 (2 Η, m), 1. 80- 1. 94 (2H, m), 2. 02- 2. 1 5 (2 H , m), 2.56-2.68 (2 H, m), 3.32 (2 H, s), 3.74-3.86 (1 H, m), 3.91 (2 H, m) s), 7.0 1 -7.10 (2 H, m), 7.3 1 -7.36 (2 H, m), 7.50 (1 H, s), 7.55 (1 H , D, J = .8 Hz, 7.62-7.67 (1 H, m), 8.05 -8.10 (1 H, m), 8.15 (1 H, s) .

Raw material synthesis example 4

 Synthesis of N- [1- (3,4-dichlorobenzyl) piperidin-4-yl] -1- [4- (3-pyridyl) thiazolyl-2-ylthio] acetoamide

 1.68 g of 2-mercapto-1- (3-pyridyl) thiazole was dissolved in 5 OmL of dimethylformamide, and 3.3 g of potassium carbonate was added. Subsequently, 3.3 g of the product of Raw Material Synthesis Example 1 was added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated saline, and dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from chloroform-Z-isopropyl ether to give 0.72 g of the title compound as a white powder.

_{iH- NMR (CD C 1 3)} δ: 1. 20 - 1. 44 (2Η, m), 1. 8 1 - 1. 87 (2 H, m), 2. 03- 2. 12 (2 H, m), 2.53-2.60 (2 H, m), 3.30 (2 H, s), 3.73-3.86 (1 H, m), 3.91 (2 H, s ), 7.05 -7.21 (2H, m), 7.31-7.41 (3H, m), 7. 51 (1H, s), 8.11-8.17 (1H, m), 8.59-8.63 (1H, m), 9.09—9.11 (1H, m).

Raw material synthesis example 5

 Synthesis of N- [1- (3,4-dichroic benzyl) piperidine-1-yl] -1- [4- (4-pyridyl) thiazo-l-2-ylthio] acetamide

 From 3.4 g of 2-mercapto-1-41- (4-pyridyl) thiazole and 3.3 g of the product of Synthesis Example 1, 3.0 g of the title compound was obtained as a white powder in the same manner as in Synthesis Example 4 for material. Was.

^ -NMR (DMSO—d ₆ ) δ: 1.37-1.49 (2Η, m), 1.65 — 1.77 (2H, m), 1.97-2.10 (2H, m), 2.64-2.72 (2H, m), 3.43 (2 H, s), 3.50-3.62 (1 H, m), 4.03 (2 H, s), 7. 24- 7.30 (1H, m), 7.52 (1H, s), 7.55-7.60 (1H, m), 7.89 (2H, d, J = 5.1Hz), 8 23 1 8.27 (1H, m), 8.37 (1H, s), 8.63 (2H, d, J = 5.1 Hz).

Raw material synthesis example 6

 Synthesis of N- [1- (3,4-dichlorobenzyl) piperidine-1-yl]-[4- (4-methoxycarbonylphenyl) thiazo-l-2-ylthio] acetamide

 From 14.5 g of 2-mercapto-1- (4-methoxycarbonylphenyl) thiazol and 20 g of the product of Synthesis Example 1 as in the case of Synthesis Example 4, 19. method, 19.6 g of the title compound Was obtained as a white powder.

^ H-NMR (DMSO-d ₆ ) δ: 1.28—1.48 (2Η, m), 1.66 — 1.75 (2H, m), 1.97-2.09 (2 H, m), 2.62-2.72 (2H, m), 3.42 (2 H, s), 3.49 - 3. 63 (1 H, m ) 3 3. 8 7 (3H, s), 4. 03 (2H, s), 7. 25 - 7. 30 (lH, m), 7. 51 (1 H, s), 7.54-7.60 (1 H, m), 8.01 (2H, d, J = 7.9 Hz), 8.10 (2H, d, J = 7.9 Hz), 8 .22-8.29 (2 H, m).

Raw material synthesis example Ί

 Synthesis of Ν— [11- (3,4-dichroic benzyl) piperidine-1-4-yl] — [4- (3-methoxycarbonylphenyl) thiazo-l-u-2-thiothioacetamide

 From 5.0 g of 2-mercapto-1-4_ (3-methoxycarbonylphenyl) thiazol and 6.7 of the product of Synthesis Example 1, 5.5 g of the title compound was obtained in the same manner as in Synthesis Example 4 of starting material. Was obtained as a white powder.

! H-NMR (DMSO-d ₆ ) 6: 1.35-1.5 1 (2 H, m), 1.67-1.75 (2 H, m), 1.98-2.06 (2 H, m), 2.63-2.7 1 (2 H, m), 3.42 (2H, s), 3.47-3.60 (1 H, m), 3.89 (3 H , S), 4.01 (2 H, s), 7.25-7.29 (lH, m), 7.50-7.63 (3 H, m), 7.90-7.95 ( 1 H, m), 8.17-8.27 (3 H, m), 8.48 (1 H, s).

Raw material synthesis example 8

Synthesis of [4-(3-carboxyphenyl) thiazol-1--2-ylthio] -1-N— [1- (3,4-dichloromouth benzyl) piperidin-1-yl] acetamide sodium salt 0.5 g of the product obtained in Starting Material Synthesis Example 7 was dissolved in 10 ml of methanol and 1 Oml of tetrahydrofuran, 3 ml of a 1 mo 1 / L aqueous sodium hydroxide solution was added, and the mixture was stirred at 60 ° C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. After the solvent was washed with saturated saline and dried, the solvent was distilled off under reduced pressure to obtain 0.5 g of the title compound as a colorless amorphous solid.

NMR (DMS 0-d ₆ ) δ: 1.36-1.54 (2 Η, m), 1.69-1.80 (2H, m), 2.00-2.25 (2H, m) , 2.67-2.80 (2H, m), 3.40 -3.67 (3 H, m), 4.03 (2H, s), 7.23-7.30 (1H, m) , 7.50-7.61 (3H, m), 7.89-7.9

3 (1H, m), 8 14-8.26 (3H, m), 8.46 (1H, s) Raw material synthesis example 9

 Synthesis of N— [1- (3,4-dichlorobenzyl) piperidine-1-yl] — [5 -— (4-Pyridyl) -1 1,3,4-thiadiazo-1-ruthio] acetoamide

 [5— (4-pyridyl) — 1,3,4-thiadiazole_2T-thio] Acetic acid 390 mg and 4-amino-11 (3,4-dichlorobenzyl) piperidine dihydrochloride 51 lmg By a method similar to that of Synthesis Example 3, 689 mg of the title compound was obtained as white crystals.

! H-NMR (DMSO- d ₆ ) δ: 1.3-1.5 (2H, m), 1.6-1.8 (2H, m), 1.9-2.1 (2H, m) , 2.6—2.8 (2H, m), 343 (2H, s), 3.4—3.6 (1H, m), 4.11 (2H, s), 7.1-7. 2 (1H, m), 7.5-7.6 (2H, m), 7.8-7.9 (2H, m), 8.2-8.3 (1H, m), 8.7- 8.8 (2H, m).

Raw material synthesis example 10

 N- [2-[[N— (1- (3,4-dichlorobenzyl) piperidin-1-yl) caprubamoyl] methylthio} benzothiazo-1-yl 6_yl] captamyl tert-butyl ester Synthesis

(6-Aminobenzothiazole-2-ylthio) -N- [1- (3,4-dichlorobenzyl) piperidine-41-yl] acetamide (144mg) is suspended in 30mL of DMF, and (Boc) ₂₀ 1. 3 g and 1.25 mL of triethylamine were added, followed by stirring at room temperature for 24 hours. Further (Bo c) ₂ 0 0. The 6 g and Toryechi Ruamin 0. 6 mL was added and攪袢overnight at room temperature. Water was added to the reaction mixture, and insolubles were collected by filtration. The obtained solid was dissolved in chloroform and purified by silica gel column chromatography using a mixed solvent of chloroform and ethanol as an eluent. The solvent was distilled off from the eluate to give the title compound (43 lmg) as a pale-yellow solid.

_{^ -NMR (CDC 1 3) δ} : 1. 3 - 1. 5 (2Η, m), 1. 54 (9H, s), 1. 8- 1. 9 (2H, m), 2. 0- 2 . 2 (2 H, m), 2.4-2.6 (2H, m), 3.28 (2 H, s), 3.7-3.9 (1 H, m) ₃ 3.89 ( 2H, s), 6.60 (lH, s), 6.9—7.5 (5H, m), 7.7-7.8 (1H, m), 8.16 (1H, s) .

Raw material synthesis example 11

 Synthesis of [4-(3-carbamylphenyl) thiazo-1-yl 2-ylthio] — N— [11- (3,4-dichlorobenzyl) piperidine-1_4-yl] acetoamide 2.0 g of the obtained product was added to 10 ml of methanol, and

After dissolving in hydrochloric acid gas under ice cooling for 3 hours, water was added to the reaction solution, Extracted with loroform. The solvent was washed with a saturated saline solution and a 1M aqueous solution of sodium hydroxide, and dried.The residue obtained by distilling off the solvent under reduced pressure was purified by HPLC (Devilosil C30-UG-5, 0.05% TFA). Purification with water: acetonitrile 2: 8-0: 10) afforded 42 Omg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.50 (2Η, m), 1.65-1.78 (2H, m), 1.94-2.11 (2H, m) , 2.60-2.74 (2H, m), 3.42 (2H, s), 3.48-3.60 (1H, m), 4.03 (2H, s), 7.23 -7. 31 (1H, m), 7.43-7.60 (4 H, m), 7.80-7.91 (1H, m), 8.00-8.18 (3 H, m) , 8.12-8.33 (1H, m), 8.40 (1H, s).

Raw material synthesis example 12

 [4- (4-carboxyphenyl) thiazolyl-2-ylthio] — N_ [1-

Synthesis of (3,4-dichlorobenzyl) piperidine-1-4-yl] acetoamide From 55 lmg of the product obtained in Raw Material Synthesis Example 6, the title compound 561 was obtained in the same manner as in Raw Material Synthesis Example 8. mg was obtained as a white solid.

iH—NMR (DMSO—d ₆ ) δ: 1.33—1.49 (2Η, m), 1.66—1.78 (2 H, m), 1.95—2.10 (2 H, m ), 2. 61-2.74 (2H, m), 3.43 (2H, s), 3.48-3.60 (1H, m), 4.03 (2H, s), 7 24- 7.30 (1H, m), 7.52-7.60 (3H, m), 7.87-7.91 (4H, m), 8.06 (1H, s), 8 28 (1Hd, J = 7.7Hz), 13.0 (1H, brs).

Raw material synthesis example 13

[4-(4 rubumoylphenyl) thiazo 1-ru 2-thiol] 1 N— [1- (3,4-Dichloro mouth benzyl) Synthesis of piperidine-41-yl] acetoamide 536 mg of the product obtained in Raw Material Synthesis Example 12 was dissolved in 5 mL of tetrahydrofuran and 5 mL of dimethylformamide, and triethylamine 153〃 L and 144 mL of isobutyl chloroformate were added, and the mixture was stirred at room temperature for 1 hour. A 7 mol / L ammonia solution was added to the reaction solution, and the mixture was stirred at room temperature for 19 hours. Lmol to the reaction solution

/ L aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (form: form: acetone = 1: 1-0: 1) to give 29 Omg of the title compound as a white solid.

! H-NMR (DMSO-d ₆ ) δ: 1.32-1.50 (2Η, m), 1.64-1.78 (2H, m), 1.94-2.10 (2H, m) , 2.60-2.74 (2H, m), 3.43 (2H, s), 3.48-3.62 (1H, m), 4.03 (2H, s), 7.23 -7.31 (1H, m), 7.37-7.42 (1H, brs), 7.51-7.59 (2H, m), 7.92-8.10 (5H, m), 8.16 (1H, s), 8.24 (1H, d, J = 7.5 Hz).

Raw material synthesis example 14

 N— [1— (3,4-Dichlorobenzyl) piperidin-1-yl] — {4 -— (3-((imidazo-1-ylmethyl) amino) phenyl] thiazolu-2-ylthio} acetoamidini Synthesis of hydrochloride

[4- (3-Aminophenyl) thiazol-2-ylthio] -1-N- [1- (3,4-dichlorobenzyl) piperidine-1-4-yl] acetoamide 507 mg and 4-imidazolecarbaldehyde 96 mg in dichloromethane 5 mL And 424 mg of acetic acid 57 jh sodium triacetoxyborohydride was added thereto, followed by stirring at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (cloth form: methanol = 20: 1). Get The resulting residue was dissolved in 0.5 mL of ethanol, and 0.5 mL of a 4 mo 1 / L solution of ethyl acetate in hydrochloric acid was added. The resulting crystals were collected by filtration to obtain 239 mg of the title compound as a white powder.

— NMR (DMSO-d ₆ ) δ: 1.76-2.18 (4H, m), 2.91 1-3.20 (2H, m), 3.22-3.38 (2H, m), 3.69—3.88 (1H, m), 4.02 (2H, s), 4.27 (2H, s), 4.46 (2H, s), 6.72-6.77 ( 1H, m), 7.15-7.42 (3H, m), 7.56-7.77 (3H, m), 7.91-8.03 (2H, m), 8.68 (1 H, d, J = 7.2 Hz), 9.07 (1H, s), 11.31-11.58 (1H, brs), 14.38-14.62 (1H, brs), 14. _{70- 15. 04 (1 H 5 brs} ).

Raw material synthesis example 15

 N- [1-(3,4-dichloromouth benzyl) piperidine-1-yl: 1

 [3-((imidazole-2-ylmethyl) amino) phenyl] thiazo-1-ylthio} Synthesis of acetamidoni hydrochloride

 [4- (3-Aminophenyl) thiazole-2-ylthio] — N_ [1- (3,4-dichlorobenzyl) piperidine-1 4-yl] Raw material from 507 mg of acetoamide and 96 mg of 2-imidazolecarbaldehyde 107 mg of the title compound was obtained as a white powder in the same manner as in Synthesis Example 14.

! H-NMR (DMSO-d ₆ ) δ: 1.76-2.13 (4H, m), 2.88-3.20 (2H, m), 3.21-3.38 (2H, m ), 3.68-3.87 (1H, m), 4.01 (2H, s), 4.26 (2H, s), 4.72 (2H, s), 6.57-6.70 _{(1 H 5 m), 7.} 09 - 7. 33 (3H, m), 7. 50 - 7. 78 (4H, m), 8. 00 (2H, s), 8. 64 (1H, d, J = 7.2Hz), 11.22-11.52 (1H, brs), 13.18-13.45 (2H, brs). Raw material synthesis example 16

 N- [1- (3,4-dichloro mouth benzyl) piperidine-1-yl] -1- {4- [3- (imidazo-1-yl-4-ylcarboxamide) phenyl] thiazol-1-ylthio} acetoamide Synthesis

 [4- (3-Aminophenyl) thiazole_2-ylthio] _N— [1- (3,4-dichlorobenzyl) piperidine-1 4-yl] acetoamide 500mg and imidazo-l-ru 4 4-force rubonic acid 135 The title compound was purified by HPLC (Develosil C30-UG-5, 0.05% TFA water: acetonitrile 2: 8-0: 10) from the obtained residue. 18 Omg of the compound was obtained as a white amorphous solid.

 ^ -NMR (CDC 13) δ: 1.28-1.47 (2Η, m), 1.78-1.83 (2H, m), 2.00-2.07 (2H, m), 2. 45-2. 49 (2H, m), 3.22 (2H, s), 3.75—3.85 (1H, m), 3.92 (2H, s), 6.99 (1H , dd, J = l. 8, 8. lHz), 7.29 (1H, s), 7.38-7.49 (3 H, m), 7.57-7.68 (3H, m), 7.73 (1H, s), 8.32 (1H, s), 9.21 (1H, s), 11.08 (1H, brs).

 Raw material synthesis example 17

 (4-—3— [N- (tert-butoxycarbonyl) _L-aralanylamino] phenyl} thiazolyl-1-ylthio) —N— [1— (3,4-dichlorobenzyl) piperidine Synthesis of 4-yl] acetoamide

[4- (3-aminophenyl) thiazo-l- 2-ylthio] _N— [1- (3, 4-Dichloro-1-benzyl] piperidine-4-yl] acetoamide 3.0 g of N- (tert-butoxycarbonyl) -L-alanine The title compound 4. 0 g was obtained as a white powder.

_{- NMR (CDC1 3) ^:} . 1. 45 - 1. 53 (14 H, m), 1. 75 - 1. 88 (2 H, m), 2. 01-2 15 (2 H, m), 2.47-2.65 (2H, m), 3.30 (2H, dd, J = 1.2, 6.7Hz), 3.76-3.85 (1H, m), 3.82- 3.97 (2H, m), 4.30-4.40 (1H, m), 5.45 (1H, brs), 7.06 (1H, d, J = 8.1 Hz), 7. 28- 7.45 (6 H, m), 7.57 (1 H, d, J = 7.3 Hz), 8.24 (1H, s), 8.71 (1H, s).

Example 1

 Synthesis of [4-(3-cyanophenyl) thiazo-1-yl-2-ylthio] —N— [1-(3,4-dichlorobenzyl) -1-oxopiperidin-1-yl] acetamide

 After dissolving 1 g of the product of Raw Material Synthesis Example 3 in 15 mL of dichloromethane, 0.43 g of m-chloroperbenzoic acid was added. After stirring at room temperature for 3 hours, water was added to the reaction solution, extracted with chloroform, washed with a saturated saline solution and a saturated aqueous sodium hydrogen carbonate solution, dried, and the solvent was distilled off under reduced pressure. The resulting residue was crystallized from chloroform to give 0.34 g of the title compound as a white powder.

— NMR (DMSO-d ₆ ) δ: 1.55-1.63 (2Η, m), 2.05-2.12 (2 H, m), 2.73 -2.80 (2H, m), 3. 24-3.3. 31 (2 H, m) ₅ 3.60-3.75 (1 H, m), 4.03 (2 H, s), 4.26 (2H, s), 7. 50-7.55 (1H, m), 7.59-7.69 (2H, m), 7.78-7.83 (1H, m), 7.87 (1H, s), 8.24 (1H, s), 8.25-8.30 (1H, m), 8.38 (1H, s), 8.47-8.52 (1H, m). Example 2

 [4 -— (4-Cyanophenyl) thiazo-1-yl-2-ylthio] _N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine_4-yl] acetamide

 From 0.4 g of 4- (4-cyanophenyl) -1-2-mercaptothiazole and 0.6 g of the product of Synthesis Example 2, 0.47 g of the title compound was obtained in the same manner as in Synthesis Example 4 of the starting material. Obtained as a white powder.

— NMR (DMSO-d ₆ ) δ: 1.57-1.63 (2 Η, m), 2.06-2.13 (2H, m), 2.73-2.81 (2 H, m) , 3.24-3.30 (2H, m), 3.61-3.76 (1H, m), 4.02 (2H, s), 4.26 (2H, s), 7. 50-7.54 (lH, m), 7.58-7.63 (1 H, m), 7.86-7.92 (3 H, m), 8.09-8.14 (2H, m ), 8.28 (1H, s), 8.48-8.53 (1H, m).

Example 3

 Synthesis of N- [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl]-(4-phenylthiazol-2-ylthio) acetamide

 From 0.25 g of 2-mercapto-1-phenylthiazole and 0.46 g of the product of Synthesis Example 2, the title compound was obtained in a similar manner to that of Synthesis Example 4 to obtain 0.1 g of the title compound. Obtained as a powder.

^ -NMR (DMSO ~ d ₆ ) δ: 1.55—1.63 (2Η, m), 2.07-2.22 (2H, m), 2.72-2.80 (2H, m) , 3.22-3.30 (2H, m), 3.60-3.77 (1H, m), 4.00 (2H, s), 4.28 (2H, s), 7.32 -7.44 (3H, m), 7.50-7.57 (1H, m), 7.62-7.66 (1H, m), 7.83-7.97 (3H, m) ₃ 8.02 (1H, s), 8.42-8.49 (1H , m).

Example 4

 Synthesis of N— [1— (3,4-dichloromouth benzyl) -1-oxopiperidine-14-yl] -1- [4- (3-pyridyl) thiazo-1-ru-2-ylthio] acetamide Raw material synthesis example 4 From 0.46 g of the above compound, 0.1 g of the title compound was obtained as a white powder in the same manner as in Example 1.

_{^ -NMR (DMSO - d 6)} δ:. 1. 56 - 1. 69 (2 Η, m), 2. 02 -2 18 (2H, m), 2. 83- 2. 87 (2 H, m ), 3.62-3.79 (2H, m), 4.03 (2H, s), 4.08-4.18 (1H, m), 4.31 (2H, s), 7 42-7.54 (2H, m), 7.62-7.67 (1H, m), 7.86 (1H, s), 8.18 (1H, s), 8.25-8.29 (1 H, m), 8.45-8.55 (2 H, m), 8.15 (1 H, s).

Example 5

 Synthesis of N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- [4- (4-pyridyl) thiazolyl-2-ylthio] acetamide Raw material synthesis example 5 From 0.3 g of the above compound, 0.26 g of the title compound was obtained as a white powder in the same manner as in Example 1.

_{^ -NMR (CD C 1 3)} δ: 1. 75 - 1. 83 (2 Η, m), 2. 20- 2.

35 (2H, m), 3.07-3.20 (4H, m), 3.81-3.93 (1H, m), 3.95 (2H, s), 4.24 (2H, m s), 7.31-7.40 (2H, m), 7.42-7.50 (1H, m), 7.57-7.65 (2H, m), 7.

67- 7.72 (2 H, m), 8.61-8.67 (2H, m). Example 6

 Synthesis of N- [1- (3,4-dichroic benzyl) -1-oxopiperidine-14-yl]-[4- (4-methoxycarbonylphenyl) thiazo-1-ru-2-ylthio] acetamide

 From product 2 obtained in Starting Material Synthesis Example 6, 1.6 g of the title compound was obtained as a white powder in the same manner as in Example 1.

— NMR (DMSO-d ₆ ) δ: 1.55-1.62 (2H, m), 2.04-2.21 (2H, m), 2.71-2.81 (2H , M), 3.20-3.25 (2H, m), 3.57 -3. 74 (1H, m), 3.86 (3H, s), 4.02 (2H, s), 4.25 (2 H, s), 7.50-7.55 (1 H, m), 7.60— 7.67 (1 H, m), 7.87 (1 H, s), 8.00 (2 H, d, J = 8.6 Hz), 8.08 (2 H, d, J = 8.6 Hz), 8.22 (1 H, s), 8.4 1-8.46 (1 H, m).

Example 7

 Synthesis of N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — [4- (3-methoxycarbonylphenyl) thiazo-1-yl-2-ylthio] acetamide

 From 2 g of the product obtained in Starting Material Synthesis Example 7, 0.5 g of the title compound was obtained as a white powder in the same manner as in Example 1.

^X H-NMR (DMSO-d ₆ ) δ: 1.59-1.69 (2 H, m), 2.02-2.19 (2H, m), 2.80 -2.91 ( 2 H, m), 3.2 2-3. 3 1

(2H, m), 3.62 -3.75 (1H, m), 3.88 (3H, s), 4.01 (2H, s), 4.31 (2H, s) ), 7.50-7.69 (3 H, m), 7. 86 (1H, s), 7.89-7.93 (lH, m), 8.17-8.22 (2 Hm), 8.46 (1H, s), 8.48-8.52 (1 H, m).

Example 8 '

 Synthesis of [4-(3-carboxyphenyl) thiazo-1-yl-2-ylthio] —N— [1- (3,4-dichlorobenzyl) -11-oxopiperidine-14-yl] acetamide

 From 0.12 g of the product obtained in Starting Material Synthesis Example 8, 4 Omg of the title compound was obtained as a white powder in the same manner as in Example 1.

— NMR (DMSO-d ₆ ) δ: 1.85-2.01 (4H ₅ m), 3.52 — 3.95 (2H, m), 3.64-3.78 (2H, m), 3 80—3.95 (1H, m), 4.03 (2H, s), 4.84 (2H, s), 7.51-7.60 (2H, m), 7.78 (1H , s), 7.80 -7.87 (1H, m), 7.91-7.97 (1H, m), 8.15—8.19 (2H, m), 8.45-8. 55 (2H, m).

 Synthesis of [4- (4-carboxyphenyl) thiazo-1-yl-2-ylthio] — N— [1- (3,4-dichloromouth benzyl) -1-oxopiperidine-1-41] acetamide

 From 0.5 g of the product obtained in Example 6, 0.47 g of the title compound was obtained as a white powder in the same manner as in Raw Material Synthesis Example 8.

^ -NMR (DMSO-d ₆ ) δ: 1.81-1.98 (4H, m), 3.55

-3.62 (2H, m), 3.64-3.78 (2H, m), 3.80-3.95

(lH, m), 4.04 (2H, s) ₃ 4.85 (2H, s), 7.52-7.5 7 (1 H, m), 776-7.86 (2H, m), 7.95-8.01 (2H, m), 8.03-8 07 (2H, m), 8.21 (1H , s), 8. 53-8. 57 (1 H 3 m).

Example 10

 Synthesis of N— [1- (3,4-dichroic benzyl) piperidine-14-yl] -1- [4- (1-oxopyridine-4-yl) thiazolyl-1-2-ylthio] acetamide

 From 0.2 g of the product obtained in Raw Material Synthesis Example 1 and 2-mercapto-141- (1-oxopyridine-14-yl) thiazol 0.4, a method similar to that of Raw Material Synthesis Example 4 was used. Thus, 6 Omg of the title compound was obtained as a white powder.

! H-NMR (DMSO-d ₆ ) δ: 1.32-1.44 (2Η, m), 1.65 — 1.74 (2 H, m), 1.97-2.07 (2H, m), 2.64-2.75 (2 H, m), 3.43 (2 H, s), 3.50-3.62 (1 H, m), 4.0 2 (2 H, s ), 7.25-7.31 (lH, m), 7.50-7.61 (2H, m), 7.90-7.95 (2H, m), 8.20-8.31 (4H, m).

Example 11

 Synthesis of N— [1- (1,4-dichlorobenzyl) piperidine-1-yl] -1- [4-(1-oxopyridine-3-yl) thiazo-1-ru-2-ylthio] acetoamide

 From 0.27 g of the product obtained in Raw Material Synthesis Example 1 and 0.35 g of 2-mercapto-4- (1-oxopyridine-13-yl) thiazol, in the same manner as in Raw Material Synthesis Example 4, 0.2 g of the compound was obtained as a white powder.

! H-NMR (DMSO— d ₆ ) δ: 1.32-1.50 (2Η, m), 1.67 — 1.80 (2H, m), 1.95-2.13 (2H, m), 2.62-2.77 (2H, m), 3.43 (2H, s), 3.50-3 60 (1H, m), 4.03 (2H, s), 7.20-7.31 (1H, m), 7.45-7.60 (3H, m), 7.80 -7.91 (1H, m), 8.16 -8.27 (2H, m), 8.30 (1H, s), 8.79 (1H, s).

Example 12

 Synthesis of N- [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl]-[4- (2-pyridyl) thiazolyl-2-ylthio] acetamide 2-mercapto-1 The title compound (175 mg) was obtained as a brown powder from 107 mg of 4- (2-pyridyl) thiazol and 206 mg of the product of Raw Material Synthesis Example 2 in the same manner as in Raw Material Synthesis Example 4.

— NMR (DMSO-d ₆ ) 6: 1.5-1-1.68 (2H, m), 2.06 — 2.13 (2H, m), 2.73-2.86 (2H, m), 3.2 1—3.37 (2H, m), 3.59-3.77 (1H, m), 4.03 (2H, s), 4.27 (2H, s), 7. 32-7.37 (1H, m), 7.50-7.57 (1H, m), 7.58-7.65 (lH, m), 7.80-7.92 (2H, m ), 7.98-8.08 (lH, m), 8.17 (1H, s), 8.48—8.63 (2Hm).

Example 13

 Synthesis of N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — (4-pyrazinylthiazol-1--2-ylthio) acetamide

From 107 mg of 2-mercapto-14-pyrazinylthiazole and 206 mg of the product of Raw Material Synthesis Example 2, 150 mg of the title compound was obtained in the same manner as in Raw Material Synthesis Example 4. Was obtained as a brown powder.

— NMR (DMSO-d ₆ ) δ: 1.50-1.63 (2 Η, m), 2.06-2.22 (2H, m), 2.69-2.80 (2H, m), 3. 21-3. 33 (2H, m), 3.60-3.77 (1 H, m), 4.06 (2H, s), 4.25 (2H, s), 7.0— 7.55 (1H, m), 7.56-7.65 (1H, m), 7.87 (1H, s), 8.31 (1H, s), 8.49-8.68 (3 H, m), 9.27 (1 H, s).

 Example 14

 Synthesis of (5-amino-1,3,4-thiadiazol-2-ylthio) -1-N- [1- (3,4-dichloromouth benzyl) 1-1-oxopiperidine-14-yl] acetoamide

 From 133 mg of 5-amino-2-mercapto-1,3,4-thiadiazol and 412 mg of the raw material of Synthesis Example 2, 92 mg of the title compound was obtained as a white powder in the same manner as in Raw Material Synthesis Example 4. Obtained.

NMR (DMSO-d ₆ ) δ: 1.50-1.65 (2 Η, m), 2.00-2.18 (2H, m), 2.72-2.83 (2H, m) , 3.22-3.30 (2 H, m), 3.55 -3. 70 (1 H, m), 3.71 (2 H, s), 4.27 (2H, s), 7 22-7.34 (2H, m), 7.50-7.57 (1H, m), 7.62-7.66 (1H, m), 7.95 (1H, s), 8.24-8.34 (1H, m).

Example 15

 Synthesis of N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- (5-phenyl-1,3,4-oxoxadiazol-2-ylthio) acetamide

 From the 2-mercapto-1-5-phenyl-1,3,4-oxaziazol 187 mg and the starting material synthesis example 2 product 4 12 mg, the title compound 15 l mg was obtained in the same manner as the starting material synthesis example 4. Obtained as a white powder.

! H-NMR (DMSO-d ₆ + CD ₃ OD) 6: 1.7-1.8 (2 H, m), 2.0-2.2 (2 H, m), 2.9-3. 0 (2H, m), 3.3—3.5 (2H, m), 3.7-3.8 (lH, m), 4.07 (2H, s), 4.35 (2 H, s), 7.5—7.7 (5H, m), 7.8—7.9 (1 H, m), 8.0—8.1 (2 H, m).

 Example 16

 N— [1— (3,4-Dichroic benzyl) _1—Oxopiperidine-1-4-yl] [5- (4-Pyridyl) —1,3,4-oxoxadiazo-1-yl-2-ylcho] Synthesis of acetoamide

 2-mercapto-5- (4-pyridyl) _1,3,4-oxadiazole 18

From 8 mg and 12 mg of the product 4 of Raw Material Synthesis Example 2, 108 mg of the title compound was obtained as a white powder in the same manner as in Raw Material Synthesis Example 4.

! H-NMR (DMSO-d ₆ ) δ: 1.2—1.3 (2Η, m), 1.7— 1. 9 (2H, m), 2.4-2.6 (2H, m), 2.9—3.1 (2H, m), 33-3-3.5 (1H, m), 3.82 (2H , s), 3.97 (2 H, s), 7.2-7.4 (2H, m), 7.60-7.65 (3 H, m), 8.2-8.3 (1 H m), 8.50 (2H, d, J = 6Hz).

 Example 17

 N— [1- (3,4-Dicyclomethylbenzyl) -1-oxopiperidine-1-4-yl] — [5- (4-pyridyl) _1,3,4-thiadiazoyl-2-ylthio] acetamide Synthesis

 145 mg of the title compound was obtained as white crystals from 396 mg of the product obtained in Starting Material Synthesis Example 9 in the same manner as in Example 1.

! H-NMR (DMSO-d ₆ + CD ₃ OD) δ: 1.7-1.8 (2Η, m), 2.0-2.2 (2 H, m), 2.9-3.0 (2H, m), 3.3-3.5 (2 H, m), 3.7-3.8 (1H, m), 4.0-4.2 (2H: m), 4.3- . 4 (2H, m), 7.5-7.6 (1H, m), 7.6-77 (1H, m): 7.8—7.9 (3H, m), 8.7 — 8.9 (2H, m).

 Example 18

 (6-Aminobenzothiazol-1--2-ylthio) 1 N— [1— (3,4-Dichlorobenzyl) 1-1-oxopiperidine-1 4-yl] Synthesis of acetoamide trifluoroacetate

Starting from 43 lmg of the product of Synthesis Example 10, N- [2- {[N- (1-(3,4-dichlorobenzyl) 11-year-old oxopiperidine 14-yl) potassium-rubumoyl] methylthio} benzothiazo-1-yl 6-yl] potassium rubbamate tert-butyl ester 1 12 mg was obtained as a pale yellow solid.

NMR (DMSO-d ₆ ) d: 1.46 (9 H, s), 1.5—1.7 (2 H, m), 2.0—2.2 (2 H, m), 2. 7-2. 8 (2H, m) , 3. 2- 3. 4 (2H, m) 5 3. 5- 3. 7 (1H, m), 4. 05 (2H, s), 4. 25 ( 2H, s), 7.3-7.4 (1H, m), 7.4.7.7 (3H, m), 7.87 (1H, s), 8.15 (1H, s), 8.3-8.5 (1H, m), 957 (1H, s).

 1-2 mg of the above product was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added at room temperature. After stirring at room temperature for 2 hours, the solvent was distilled off, and the obtained solid was recrystallized from ethanol to give the title compound (85 mg) as white crystals.

! H-NMR (DMSO-d ₆ ) δ: 1.5—1.7 (2Η, m), 2.0—2

2 (2H, m), 2.7-2.8 (2H, m), 3.2-3.4 (2H, m), 35-3.7 (1H, m), 3. 99 (2 H, s), 4.27 (2 H, s), 5.3

3 (2H, s), 6.65-6.75 (1H, m), 6.98 (1H, s), 7.4-7.7 (3H, m), 7.88 (1H , s), 8.4-8. 5 (1H, m).

 Synthesis of [4-(3-carbamylphenyl) thiazo-1-yl-2-ylthio] -N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] acetamide

 From 5 Omg of the product obtained in Starting Material Synthesis Example 11, 3 Omg of the title compound was obtained as a white solid in the same manner as in Example 1.

tH—NMR (DMSO-d ₆ ) δ: 1.55-1.64 (2Η, m), 2.06-2.19 (2H, m) ₃ 2.73-2.81 (2 H, m ), 3. 24-3.3. 34

(2 H, m), 3.60-3.74 (1 H, m), 4.02 (2 H, s), 4.2 6 (2 H, s), 7.46-7.55 (3 H, m), 7.60-7.64 (1 H, m) ₅ 7.8 1-7.89 (2 H, m ), 8.05 -8.13 (3H, m), 8.38 (1H, s), 8.48-8.53 (1H, m).

 Example 20

 [4 -— (4-Lubemoylphenyl) thiazolyl-2-ylthio] -N- [1- (3,4-dichloromethylbenzyl) -11-oxopiperidine-14-yl] acetamide Synthesis

 From 248 mg of the product obtained in Starting Material Synthesis Example 13, 19 Omg of the title compound was obtained as a white solid in the same manner as in Example 1.

LH—NMR (DMS 0-d ₆ ) δ: 1.50-1.63 (2Η, m), 2.04-2.2 1 (2 H, m), 2.70-2.80 (2 H, m), 3.24-3.34 (2H, m), 3.52-3.73 (1H, m), 4.02 (2H, s), 4.25 (2H, s), 7.34-7.40 (1H, m), 7.50-7.54 (1H, m), 7.58-7.62 (1H, m), 7.81- 8.09 (6H, m), 8.16 (1H, s), 8.45 (1H, d, J = 7.5Hz).

 Example 2 1

 N— [1— (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- {4 -— (3-((imidazo-1-ru-methyl) amino) phenyl] thiazo-ru Synthesis of 2-ylthioacetamide

 From 0.93 g of the product obtained in Starting Material Synthesis Example 14, 0.72 g of the title compound was obtained as a slightly yellow solid in the same manner as in Example 1.

E S I -MS (m / z): 603 [M + H]

Example 22

 N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- {3-((imidazo-1-yl-2-ylmethyl) amino) phenyl] thiazole Synthesis of 2-ylthio} acetoamide

 From the product (294 mg) obtained in Starting Material Synthesis Example 15, 254 mg of the title compound was obtained as a slightly yellow solid in the same manner as in Example 1.

ES I-MS (m / z): 603 [M + H]

Example 23

 N— [1— (3,4-dichlorobenzyl) 1-11 year old xopiperidine 1-4—yl] 1—4—1 [3— (imidazole_4—ylcarboxamide) phenyl] thiazo, 1 Of 2-acetamide

 From 30 lmg of the product obtained in Starting Material Synthesis Example 16, 323 mg of the title compound was obtained as a slightly yellow solid in the same manner as in Example 1.

NMR (DMSO-d ₆ ) 6: 1.50-1.78 (2H, m), 2.04 1-2.18 (2H, m), 2.60-2.99 (2 H, m), 3. 24-3.3. 34 (2H, m), 3.57-3.78 (1H, m), 4.00 (2H, s), 4.32 (2H, s), 7.30 -8.01 (9H, m), 8.25-8.38 (1H, m), 8.42 -8.58 (1H, m), 9.90 (1H, brs), 13.0 (1 H, brs).

 Example 24

{4-[3- (L-alanylamino) phenyl] thiazo-l-u-l-thiol} — N— [1-(3,4-dichro-benzyl) -l-oxopiperidine-l- 4-yl] acetamide

 174 mg of the title compound was obtained as a white powder from 339 mg of the product obtained in Starting Material Synthesis Example 17 in the same manner as in Example 18.

^-• NMR (DMSO—d ₆ ) δ: 1.21 (3 H, d, J = 6.8 Hz), 1.

58--1.66 (2 H, m), 2.04 1.23 (2 H, m), 2.68-2 •

81 (2H, m), 3. 24-3.34 (2 H, m), 3.55-3. 73 (1 H, m), 4.00 (2H, s), 4.27 (2H , s), 7.32-7. 38 (1 H, m), 7.50-7.64 (3 H, m), 7.68-7.77 (1 H, m), 7.

86--7.88 (1H, m), 7, 96 (1H, s), 8.06-8.08 (1H, m), 8.32 (1H, s), 8.49 ( 1 H, d, J = 7.6 Hz) • Experimental example 1: Inhibition test of binding of chemokine to human eosinophils

Human eosinophils were isolated from anticoagulated peripheral blood of healthy humans by the CD16 negative selection method (for example, J. Immunol. Methods, 145, 105-110, 1991). Separated eosinophils (2 x 10 ⁵ ), 50 pmo 1 / L [ ¹²⁵ I]-eot axin (2000 Ci / mmoL, manufactured by Amersham Pharmacia Biotech) and 0.1 mL of test compound Buffer solution (50 mmol / L HEPES, 1 mmol / L CaCl ₂ , 5 mmol / L MgCl ₂ , 0.5% serum albumin (BSA), 0.1% sodium azide, pH 7.6 ) And incubated at 25 ° C for 1 hour in a multi-screen plate (Millipore). After completion of incubation, filtration and the reaction solution in the multithreading clean plates at Bakiyuumu, Hiyaarai purification buffer of 0. 6 mL (50 mmo 1 / L HEPES, 1 mmo 1 / LC a C 1 2, 5 mmo After washing with 1 / L MgCl ₂ , 0.5 mo 1 / L NaCl, 0.1% sodium azide, pH 7.6), the radioactivity retained on the filter was measured. The compounds of the present invention had chemokine binding inhibitory activity in this test. IC ₅ for some of the compounds of the present invention. Values ([ ¹²⁵ 1] for human eosinophils) The concentrations of the test compounds required to reduce eot axin binding by 50% were as follows. table 1

Experimental example 2: Effect on intracellular calcium concentration

 The effect of the compound of the present invention on intracellular calcium during stimulation of CCL 11 in healthy human peripheral blood eosinophils was examined by the following method.

 Eosinophils isolated from peripheral blood of a healthy individual were suspended in a measurement buffer (hanks s' ba 1 anced sal tso lut ion containing 10 mmol / L HE PES and 0.5%% serum albumin). The mixture was turbid and incubated at 37 ° C. for 45 minutes in the presence of 5 μmo 1 / L Fura-2AM (manufactured by Dojindo Laboratories).

 After the incubation, the cells were washed three times with a measurement buffer to remove Fura-2AM that was not taken up into the cells.

Finally, cells were prepared in a measurement buffer so as to be 1 × 10 ⁶ cells / mL, and stored in a dark place until measurement. Intracellular calcium was measured using FDSS6000 manufactured by Hamamatsu Photonics KK. That is, a cell suspension (0.1 mL) loaded with Fura-2AM was placed in a 96-well plate for measurement, set on the FDSS6000, and the fluorescence intensity by the excitation light at wavelengths of 340 11111 and 380 nm was measured. The intracellular calcium concentration was calculated by measuring and calculating the ratio of the fluorescence intensity to the excitation light of the two wavelengths. The agonist used CCL11 (0.3 nmol / L), which is a selective ligand for CCR3, and the gonist activity was determined by treating eosinophils with various concentrations of the compound of the present invention 5 minutes before stimulation with the agonist. ₅₀ % inhibition rate (IC ₅₀ value) of the increase in intracellular calcium concentration at that time. Table 2

Industrial applicability

 According to the present invention, diseases in which cells having chemokine receptors play an important role in the onset, progress, and maintenance of the disease state, for example, atherosclerosis, rheumatoid arthritis, osteoarthritis, Psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy, ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis, rejection during organ transplant surgery Reaction and / or human immunodeficiency syndrome can be treated and / or prevented.

 Therefore, according to the present invention, it is possible to provide a medicament having affinity for chemokine receptors and for treating and / or preventing or preventing immune and inflammatory diseases. This application is based on a patent application No. 2002-23111960 filed in Japan, the contents of which are incorporated in full herein.

 In addition, references, including patents and patent applications, cited herein are hereby incorporated by reference to the same extent as if their entire contents were disclosed.

Claims

The scope of the claims

 General formula (1)

 (In the formula,

 Ring A represents an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent,

R ^a and R ^b are the same or different from each other, a hydrogen atom, an alkyl, halogen atom, hydroxy, alkoxy, Shiano, § amino carbonyl, carboxy or alkoxycarbonyl; or become R ^a and R ^b gar緖To form an oxo group, or R ^a and R ^b may be linked to form a ring together with the atom to which they are bonded,

 p represents an integer from 0 to 2,

 m represents an integer from 0 to 5,

 n represents an integer from 0 to 5,

V is a bond, may be substituted CI- e alkylene, single CO- or a S0 ₂ - indicates,

W represents — CH, — CH ₂ —, — N, — NH—, oxygen or sulfur,

X is a bond, one NH—, —NR ¹ — (wherein R ¹ represents alkyl), one CO—, —CONR. One or one NH ^c CO— (wherein, R ^c represents a hydrogen atom or alkyl), -NR ² CON ^3- (wherein, R ² and R ³ may be the same or different, Each represents a hydrogen atom or an alkyl, or R ² and

R ³ may be linked to form a ring together with the atoms to which they are bonded. ), An oxygen atom, a sulfur atom, -SO-, one S0 ₂ -, one NR ^c S0 ₂ - or

(Wherein, Rc represents a hydrogen atom or alkyl.), Optionally have a substituent C i-6 alkylene, C ₂ _ _{6 alkenylene, C 2 - - -S0 2 N} c 6 Aruki two Len , —0_ optionally substituted Ci- ₆ alkylene mono- or mono-substituted Ci- ₆ alkylene-0-, mono-S-optionally substituted C i_ ₆ alkylene mono- or mono-substituted C ₆ alkylene mono-S-, mono-so-substituted C i-e alkylene optionally substituted or mono-substituted good not C Bok ₆ alkylene one S_〇 one be one NRc- may have an optionally substituted C Bok ₆ Al Killen one or monosubstituted group CI- e alkylene one NRc- ( In the formula, R ^c represents a hydrogen atom or an alkyl.), One SO ₂ —an optionally substituted C 1 alkylene or an optionally substituted C i- ₆ alkylene _{S 0 2 -, -C (=} N- C0 2 _ alkyl) one, - C (= N- S 0 2 - alkyl) -, - C (= N -S0 2 NH 2) one, -C (= CH -N0 ₂ ) one or one C (= N -CN) —

Y is a bond, one NH—, —NR ⁴ — (wherein R ⁴ represents alkyl), —CO—, one CONR ^d — or one NR ^d CO— (where R ^d is hydrogen showing the atom or alkyl), one NR ⁵ CONR ⁶ -.. (in the formula, R ^5, R ^6, which may be identical or different one, each represent a hydrogen atom or an alkyl or, R ⁵ and R ⁶ . which together may form a ring together with the atoms to which they are attached Te summer to), an oxygen atom, a sulfur atom, one _{SO-, -S0 2 -, - NR} d S0 2 - or

(Wherein, R ^d represents a hydrogen atom or alkyl.), Optionally have a substituent C I ₆ alkylene, C ₂ _ ₆ alkenylene, C ₂ - - one S0 ₂ NR ^d ₆ alkynylene, - 0 may have a substituent group C i-e alkylene mono- or monosubstituted group which may have a C alkylene one 0-, C WINCH ₆ Al have an S- substituent The alkylene may have one or one substituent ( ₆ alkylene-one S-,

-so—may have a substituent (^ -6 alkylene may have one or one substituent C ₆ alkylene _S 0_, _NR ^d —may have a substituent

 Ci-e alkylene or monoalkylene optionally having one substituent

(Wherein, R ^d represents a hydrogen atom or alkyl.), One S0 ₂ - - N ^d which may have a substituent C Interview -6 alkylene one or - which may have a substituent C alkylene one S0 ₂ —, — C (= N—CO ₂ —alkyl) one,

_{- C (= N- S 0 2} - alkyl) _{one, - C (= N- S0 2} NH 2) -, -C (= CH-N0 ₂₎ one or single C (= N-CN) shows one,

Z is a bond, substituents Ci- may have e alkylene, c ₂ _ ₆ alkenylene, c ₂ _ ₆ alkynylene, oxygen atom, sulfur atom, -SO-, - so ₂ -,

^{- NH-, -NR 7 - (R} 7 represents an alkyl.), One CO-, One _{C0 2 -, - 0- CO-,} -CONR 8 - or single NR ⁸ C0- (wherein, R ⁸ is was or hydrogen atom an ^{alkyl), _NR 8 CONR 9 -.} . ( wherein, R ^8, R ^9, which may be the same or different and is shown it hydrogen atom or an alkyl or, R ⁸ and becomes R ⁹ gar cord may form a ring together with the atoms to which they are attached), _NR ⁸ S0 ₂ -. or a S0 ₂ NR ⁸ - (wherein, R ⁸ is a hydrogen atom or alkyl 1—CO—NR ⁸ — or 1 NR ⁸ —C〇10— (wherein R ⁸ represents a hydrogen atom or an alkyl), and has a 1—substituent. also a C § alkylene - or a substituent which may have a C丄_ ₆ alkylene one - wherein the oxygen atom, a sulfur atom, -SO-, - S0 ₂ -, one NH-, - NR ⁷ - (formula , R ⁷ is an alkyl), One CO-, -0 C0-, -. C0 2 -,

- C0NR ⁸ - or - NR ⁸ C0- (wherein, R ⁸ represents a hydrogen atom or an ^{alkyl.), -NR 8 -CO-NR} 9 - ( wherein, R ^8, R ⁹ are the same or different Each represents a hydrogen atom or an alkyl, or R ⁸ and R ⁹ may be linked together to form a ring together with the atom to which they are attached.)

_NR ⁸ S0 ₂ — or 1 S0 ₂ NR ⁸ _ (wherein R ⁸ represents a hydrogen atom or an alkyl.) Or 1 0—CO—NR ⁸ — or 1 NR ⁸ — CO— 0— (wherein , R ⁸ represents a hydrogen atom or alkyl.). ]

A is a bond, a group selected from a divalent hydrocarbon ring group which may have a substituent and a divalent heterocyclic group which may have a substituent, or> CH—R ^{1 Q} or is> N-R ^1Q (wherein, R ^{1 Q} is selected from the heterocyclic groups may have a may have a substituent hydrocarbon Hajime Tamaki and a substituted group Group),

 B represents a hydrogen atom, an aryl which may have a substituent, a heterocyclic group which may have a substituent, or a cycloalkyl which may have a substituent.

However, at least one of the nitrogen atoms contained in the formula is oxidized. ] Or an optical isomer or a pharmaceutically acceptable salt thereof.

2. The compound represented by the general formula (1)

(In the formula,

 Ar represents an aryl which may have a substituent,

 n represents an integer from 1 to 5,

 Indicates 0 or 1,

X is a bond, —NH—, —NR ¹ — (wherein, R ¹ represents alkyl),

—CO—, — CONH—, — NHCO—, -NR ² CONR ^3- (where R ² ,

R ³ may be the same or different and each represents a hydrogen atom or an alkyl. ), An oxygen atom, a sulfur _{atom, - SO_, - S0 2 -} , one NHS 0 ₂ - or

— S0 ₂ NH—

Y is a bond, —NH—, —NR ⁴ — (wherein, R ⁴ represents alkyl),

— CO—, one CONH—, one NHCO—, -NR ⁵ CONR ^6- (where R ⁵ ,

R ⁶ may be the same or different and each represents a hydrogen atom or an alkyl. ), An oxygen atom, a sulfur _{atom, - SO-, - S0 2 -} , one NHS0 ₂ - or

One S0 ₂ NH—

Z is a bond, an alkylene which may have a substituent, an oxygen atom, a sulfur atom, one SO-, One S0 ₂ -, One NH-, -NR ⁷ - (R ⁷ represents an alkyl.) _{, - CO-, - Q 2 -} (CH 2) q - or _{- (CH 2) q -Q 2} - [ wherein, Q ₂ is, - NH-, -NR ⁷ - (wherein, R ⁷ is an alkyl Represents an oxygen atom, a sulfur atom,

— Indicates SO— or S0 ₂ —, and q indicates an integer from 1 to 4. ]

A represents a bond, arylene which may have a substituent, heteroarylene which may have a substituent, or cycloalkylene which may have a substituent; Is aryl which may have a substituent, hetero which may have a substituent And aryl or cycloalkyl which may have a substituent.

 However, when: r = 0, at least one of the other nitrogen atoms contained in the formula is oxidized. ]

The compound according to claim 1, which is an optical isomer or a pharmaceutically acceptable salt thereof.

3. In general formula (1),

 n is an integer from 1 to 4,

 3. The compound according to claim 2, wherein A is a bond, arylene optionally having a substituent or heteroarylene optionally having a substituent, an optical isomer thereof or a pharmaceutically acceptable substance thereof. Acceptable salts.

4. In the general formula (1),

 n is an integer from 1 to 4,

X is —CO—, one CONH—, —NHCO—, —N ² CONR ³ — (wherein, R ² and R ³ may be the same or different and each represent a hydrogen atom or an alkyl.) , _SO_, one _{S0 2 -, - NHS 0 2} - or a single S0 ₂ NH-, a is a bond, may have a good § Li one Ren may have a substituent or substituents Heterogeneous

 4. The compound according to claim 2, wherein B is an aryl which may have a substituent or a heteroaryl which may have a substituent, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

5. In the general formula (1),

 n is an integer from 1 to 4,

X is —CO—, one CONH—, —NHCO—, —NR ² CONR ³ — (wherein R ² and R ³ may be the same or different and each represents a hydrogen atom or an alkyl. )

 Y is a bond, an oxygen atom or a sulfur atom,

Is a bond, A is a bond, arylene which may have a substituent or heteroarylene which may have a substituent,

 5. The compound according to any one of claims 2 to 4, wherein B is aryl which may have a substituent or heteroaryl which may have a substituent, or an optical isomer thereof or a pharmaceutical thereof. Acceptable salts.

6. (1) [4- (3-cyanophenyl) thiazol-1--2-ylthio] _N_ [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] acetamide,

 (2) [4- (4-cyanophenyl) thiazolyl-2-ylthio] _N— [1— (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] acetamide,

 (3) N- [1— (3,4 dicyclomouth benzyl) 1-1-oxopiperidine-14-yl] — (4-phenylthiazo-1-ru-2-ylthio) acetamide,

 (4) N- [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl]-[4- (3-pyridyl) thiazo-l-u2- 2- ^ T-lthio] acetamide,

(5) N— [1— (3,4-dichlorobenzyl) 1-1-oxopiperidine-1-4-yl] — [4- (4-pyridyl) thiazo-1-l-2-ylthio] acetamide,

(6) N- [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl]-[4- (4-Methoxycarbonylphenyl) thiazol-2-ylthio ] Acetamide,

 (7) N— [1— (3,4-dichlorobenzyl) -11-oxopiperidine-14-yl] — [4-1- (3-methoxycarbonylphenyl) thiazo-1-yl-2-ylthio] Acetamide,

 (8) [4- (3-carboxyphenyl) thiazolyl-2-ylthio] -1-N-1- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] acetami Do

(9) [4- (4-Carboxyphenyl) thiazo-1-yl-2-ylthio] -1-N- [1-1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] α Cetamide,

 (10) N— [1- (3,4-dichlorobenzyl) piperidin-4-yl] -1- [4 -— (1-oxopyridine-14-yl) thiazo-1-ru-2-ylthio] acetamide,

 (1 1) N— [1- (3,4-dichlorobenzyl) piperidine-1 4-yl] 1- [4— (1-oxopyridine-13-yl) thiazo-1-l 2-ylthio] acetamide,

 (12) N- [1- (3,4-dichlorobenzyl) 11-year-old oxopiperidine—4-yl] — [4- (2-pyridyl) thiazo-l-uyl 2-ylthio] acetamide,

 (13) N— [1- (3,4-dichlorobenzyl) -1-oxopiperidine-14-yl] -1- (4-pyrazinylthiazo-1-ru-2-ylthio) acetamide,

(14) (5-amino-1,3,4-thiadiazo'-2-ylthio) -1-N- [1- (3,4-dichlorobenzyl) _1-oxopiperidine-1-4-yl] Cetamide,

 (15) N— [1— (3,4-dichroic benzyl) 1-1-oxopiperidine—4-yl] — (5-phenyl-1, 3,4—oxaziaziro-l 2-ylthio) acetami Do

 (16) N-[1-(3,4-dichlorobenzyl) 1-1-oxopiperidine-1-4-yl]-1-5-(4-Pyridyl) 1-1, 3, 4 _ oxaziazo-1-2-ylthio ] Acetamide,

 (17) N— [1-(3,4 dicyclo mouth benzyl) 1 1 1 year old oxopiperidine —4-yl] ― [5— (4-pyridyl) 1 1, 3, 4 —thiadiazoyl 2— ^ Γlucio] acetoamide, and

(18) Claim 1 which is selected from the group consisting of (6-aminobenzothiazolyl-2-ylthio) —N— [1— (3,4-dichlorobenzyl) -11-oxopiperidine-14_yl] acetamide. Or a pharmaceutically acceptable salt thereof.

7. (1) [4- (3-Cyanophenyl) thiazo-1-yl-2-ylthio] -1-N- [1- (3,4-dichlorobenzyl) -1-oxopiperidine-1-4-yl] acetamide ,,

 (4) N— [11- (3,4-dichroic benzyl) -1-oxopiperidine-1-4-yl] -1- [4- (3-pyridyl) thiazo-1-l-2-ylthio] acetamide,

(5) N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — [4-1- (4-pyridyl) thiazo-1-ru-2-ylthio] acetamide,

(7) N— [1- (3,4-dichlorobenzyl) 1-1-oxopiperidine-14-yl] — [4- (3-methoxycarbonylphenyl) thiazo-1-yl-2-ylthio] Acetamide,

 (9) [4- (4-Carboxyphenyl) thiazo-1-yl-2-ylthio] -N- [1- (3,4-dichlorobenzyl) -1-1-oxopiperidine-14-yl] acetamide , and

 (10) N— [1- (3,4-dichlorobenzyl) piperidin-1-yl] — [4- (1-oxopyridine-14-yl) thiazolyl-2-ylthio] acetamide,

7. The compound according to claim 6, which is selected from: or a pharmaceutically acceptable salt thereof.

8.

(1 9) [4-I- (3-caproluvylphenyl) thiazo-l-2-ylthio] — N— [1- (3,4-dichlorobenzyl) -1-1-oxopiperidine-14-yl ] Acetamide,

 (20) [4- (4-Carpamoylphenyl) thiazo-1-yl-2-ylthio] -N- [1- (3,4-dichlorobenzyl) -11-oxopiperidine-14-yl] acetamide,

 (2 1) N— [1— (3,4-dichlorobenzyl) 11-year-old oxopiperidine 14-yl] 1- {4-1-[(3-((imidazole_ 4-ylmethyl) amino) phenyl] thiazo 1-ru 2-irthio} acetoamide,

 (22) N- [1-(3,4-dichlorobenzyl) -1-oxopiperidine

—4-Ill] — {4-I- [3— ((Imida V—Lou 2—ylmethyl) amino) Nil] thiazolyl-2-ylthio} acetamide,

 (23) N— [1— (3,4-dichlorobenzyl) 1-oxopiperidine —4 ^^ T1] 1 {4−1 [3— (imidazo-1-ru 4-ylcarpoxamide) Thiazolyl 2-ylthio} acetoamide, and

 5 (24) {4- [3- (L-alanylamino) phenyl] thiazo-lu-2-ylthio} -N- [1- (3,4-dichloromouth benzyl) 1-1-oxopiperidine-1-4-yl] Acetoamide,

 2. The compound according to claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

10 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency symptoms

10. The pharmaceutical composition according to claim 9, which is a prophylactic or therapeutic agent for 15 groups.

1 1. The compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof, comprising: rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, Allergic myelitis, atopic dermatitis, large ulcer

20 Prevention and treatment of enteritis or human immunodeficiency syndrome.

12. Chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic, characterized by administering a compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof. Conjunctivitis, allergic myelitis, atopic skin

How to prevent and treat Z5 inflammation, ulcerative colitis or human immunodeficiency syndrome.

13. A method for producing a prophylactic / therapeutic agent for a group of chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome. The compound according to any one of to 8 above, Use of an optical isomer or a pharmaceutically acceptable salt thereof.