WO2004037817A1 - N-oxide compounds - Google Patents

N-oxide compounds

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Publication number
WO2004037817A1
WO2004037817A1 PCT/JP2003/013591 JP0313591W WO2004037817A1 WO 2004037817 A1 WO2004037817 A1 WO 2004037817A1 JP 0313591 W JP0313591 W JP 0313591W WO 2004037817 A1 WO2004037817 A1 WO 2004037817A1
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WO
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Patent type
Prior art keywords
le
alkyl
substituent
nr
iruchio
Prior art date
Application number
PCT/JP2003/013591
Other languages
French (fr)
Japanese (ja)
Inventor
Yoshihito Tanaka
Shuzo Takeda
Hidemitsu Azuma
Original Assignee
Mitsubishi Pharma Corporation
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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- Okishido Compound

Technical field

The present invention related to novel N- Okishido compounds having affinity for chemokine receptors, the compound or a salt thereof, onset cells pathologies with chemokine receptors, progress, play an important role in the maintenance diseases are, for example, atherosclerosis, chronic rheumatoid arthritis, osteoarthritis, psoriasis, asthma, allergic rhinitis, allergic - conjunctivitis, allergic myelitis, atopic one dermatitis, food allergies, ulcers sex colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis, rejection reactions during organ transplant surgery, is useful as a therapeutic and / or prophylactic agents, such as human immunodeficiency syndrome.

BACKGROUND

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 factor, there are classical chemotactic factors such as formylated peptides derived from bacteria. These are secondary products associated with injury of mainly tissue. On the other hand, produced by the new gene expression, a series of site force in responsible for induction and activation of specific white blood cells, called chemokines (chemokine s) are and purified by Matsushima et al. 1987 Gene black-learning has been i nt its presence by erl EuK in (IL) one 8 (CXCL 8) has been demonstrated (e.g., non-Patent documents 1 and 2 reference.).

To date, been identified 45 types of chemokines, chemokine, from the characteristics of the amino acid sequence, it has been classified into four subgroups. Ie, C chemokines, CC chemokines, a CXC chemokine and CX 3 C chemokines.

XCL 1 belonging to C chemokine shows the chemotactic activity for T cells and NK cells. CC chemokines contrast shows the chemotactic activity against 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 act primarily on the migration of NK cells. These chemokines exert their effects by binding to G tamper click-coupled receptors (chemokine receptors), a chemokine receptor to date have been identified 1 8 one (e.g., Non-Patent Documents 3 and 4 reference.).

Therefore, a substance that inhibits the binding between chemokine and its receptor suppresses selective migration and activation of leukocytes, acute Contact Yopi chronic inflammatory diseases including allergic diseases, further human immunodeficiency syndrome it is considered to be useful as a medicament for the prevention or treatment of.

In view of the above, the compound having affinity for chemokine receptors is useful as a medicament for the prevention or treatment of immune Contact and inflammatory diseases can be expected.

Also, it has therapeutic Nitsu immune and inflammatory diseases having affinity for chemokine receptors, for example, Patent Document described below have been published. Jifue two Rumetan derivative in Patent Document 1, Arirupi Bae Rajin derivatives in Patent Document 2, compounds having an affinity for chemokine receptors, Patent Document 3, 4 and 5, the affinity for chemokine receptors heteroaromatic derivatives to tricyclic included in the Patent documents 6 and 7, Fuweniruaranin derivatives having affinity for chemokine receptors, in Patent Document 8, piperidines Rajin having affinity for chemokine receptors derivatives, and, Patent Document 9, 1 0, 1 1 and 1 2, piperidine derivatives having affinity for chemokine receptors have been disclosed. In Patent Document 1 3 and 1 4, morpholine derivatives having affinity for chemokine receptors have been disclosed. Patent Document 1 5, a cyclic amine derivative having CCR 3 antagonism are disclosed.

However, to date, compounds that show efficacy in models such as allergic diseases by oral administration have not been reported. Such compounds which show efficacy in disease models, etc., suppresses the selective migration and activation of leukocytes, acute and chronic inflammatory diseases including allergic diseases, treatment or the like further human immunodeficiency syndrome is expected can be a medicament for the prevention.

Non-Patent Document 1]

P roc N atl. A cad. S ci. USA, 8 4 Volume 9 2 2 3 9 2 3 7 pages, 1 9 8 7 years

[Non-Patent Document 2] J. Exp. Med., 167 Certificates, 1883- 1893, pp. 1988

Non-Patent Document 3]

Cell Engineering, 17 Certificates, 1022- 1029 pages, 1998

Non-Patent Document 4]

Immunity, 12 Certificates, 121- 127 pages, 20 Fei 0 years [Patent Document 1]

International Publication No. WO 97/24325 No. Panfuredzu door

[Patent Document 2]

International Publication No. WO 98/25617 No. Panfuredzu door

[Patent Document 3]

International Publication No. WO 98/02151 No. Panfuretsu door

[Patent Document 4]

International Publication No. WO 98/04554 No. Panfuretsu door

[Patent Document 5]

International Publication No. WO 00/34278 No. Panfuretsu door

[Patent Document 6]

International Publication No. WO 99/55324 No. Panfuredzu bet '

[Patent Document 7]

International Publication No. WO 99 Bruno 55330 No. pamphlet

[Patent Document 8]

International Publication No. WO 00/58305 No. Panfuretsu door

[Patent Document 9]

International Publication No. WO 00/31033 No. Panfuredzu door

[Patent Document 10]

International Publication No. WO 00/53600 No. Panfuretsu door

[Patent Document 11]

International Publication No. WO 01Z14333 No. pamphlet

[Patent Document 12]

Panfuretsu door International Publication No. WO02 Roh 66460 [Patent Document 1 3]

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

[Patent Document 1 4]

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

Patent Document 1: 5]

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

Disclosure of the Invention

The present invention has an affinity for chemokine receptors, and to provide a medicament for the treatment you and / or prevention of immune Contact Yopi inflammatory diseases.

The present inventors have been made in view of the above circumstances, as a result of extensive studies to find non-peptidic compounds exhibiting chemokine receptor antagonism, N- Okishido compound, its optical isomers or a pharmaceutically acceptable salt thereof There have a high affinity for chemokine receptors, it was found to inhibit the binding of a chemokine to its receptor. Furthermore, the onset Ming N- old Kishido compounds, compounds which are not conventional N- Okishido of its optical science isomers or a pharmaceutically acceptable salt thereof [e.g., open in Patent Documents 1 to 1 5 above compared to indicate compounds etc.], it has a higher affinity for chemokine receptors, and found to be improved or pharmacokinetic basis. Accordingly, the compounds of the present invention inhibit the selection 択的 of leukocyte migration and activation, acute and chronic inflammation inflammatory diseases including Arerugi disease, further can become a medicament for the treatment or prevention such as human immunodeficiency syndrome has led to the completion of the present invention found a Rukoto.

That is, the present invention provides the following compounds [8] [1], an optical isomer or about salts their pharmaceutically acceptable.

[1] the general formula (1):

Wherein Ring A represents an optionally substituted Ariru, substituted terrorist ring group to be or cycloalkyl which may have a substituent group,

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, may form a Okiso group, or; R a and R b gar緖since it may form a ring together with them you bonded atoms,

p is an integer from 0 to 2,

m represents an integer of 0 5,

n represents an integer of 0 5,

V is a bond, optionally Ci-e alkylene optionally having substituent one CO- or - S 0 2 - indicates,

W is, - CH rather, _CH 2 -, - N rather one NH-, an oxygen atom or a sulfur atom,

X is a bond, -NH-, -NR 1 -, (wherein, R 1 is an alkyl.)

One CO-, one CONRc- or a NR c CO- (wherein, R c represents a hydrogen atom or an alkyl.), -NR 2 CONR 3 - ( wherein, R 2, are the same or different Tsutei and may each represent a hydrogen atom or an alkyl. Alternatively, Te summer together H 2 and R 3 may form a ring together with the atoms to which they are attached.), 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 a substituent having optionally be good Ci-e alkylene one S-, but it may also have an SO- substituent may have a CI- 6 alkylene mono- or monosubstituted group 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 is a hydrogen atom or an alkyl. ), One S0 2 - may have but it may also be substituted Ci-e alkylene mono- or monosubstituted group - 6 alkylene one 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) Single or single C (= N-CN) shows one,

Y is a bond, One NH-, - NR 4 -, (wherein, R 4 represents an alkyl.)

- CO-, one CONR d - (wherein, R d represents a hydrogen atom or an alkyl.) Or single NR d CO-, -NR 6 CONR 6 - ( wherein, R 5, R 6 are the same or may be different One they each represent a hydrogen atom or an alkyl. Alternatively, R 5 and R 6 Te summer together may form a ring together with the atoms 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 Al Killen may have one or a substituent C Bok 6 alkylene one S-,

One SO- may have a substituent group C i_ 6 alkylene one or - which may have a substituent C alkylene - S 0-, -NR d - or substituted 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 is was or hydrogen atom an alkyl), one NR 8 CONR 9 -.. (wherein, R 8, R 9, which may be identical or different, or show it it hydrogen atom or alkyl, 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 - S0 2 NR 8 - (wherein, R 8 is a hydrogen atom or an alkyl Le), one 0- CO- NR 8 -. or a NH 8 -. CO- 0- (wherein, R 8 is showing a hydrogen atom or alkyl), have a one Q丄monosubstituted group during and optionally also optionally C i_ also have a good C 6 § alkylene mono- or monosubstituted group 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 Tei at best, it it a hydrogen atom or an alkyl. Alternatively, may form a ring together with the atoms connecting them become R 8 and R 9 Gar together.)

- NR 8 S0 2 - or - S0 2 NR 8 - (wherein, R 8 represents a hydrogen atom or alkyl Le.) Or single 0- CO- NR 8 - or single NR 8 - CO- 0- (formula among, R 8 represents a represents a hydrogen atom or alkyl.). It shows],

Group A is a bond, is selected optionally have a hydrocarbon ring group and a substituted group which may have a substituent to be or divalent of a heterocyclic group or> CH- R 10, during or is> N-R 1Q (wherein,: R 1Q is selected from the heterocyclic groups may have a well may hydrocarbon Hajime Tamaki and a substituted group optionally having substituent represents a group),

B represents a hydrogen atom, which may have a substituent Ariru, substituted heterocyclic group to be or cycloalkyl which may have a substituent group.

Provided that at least one nitrogen atom contained in the formula is that is Okishido of. ]

Compounds, salts acceptable optical isomers thereof, or its pharmaceutically represented by.

[Herein, there are also cases that referred to as a compound or compounds of the general formula (1) (1) is omitted. ]

[2] The compound represented by the general formula (1) is to, Ar

Β, ζ -Α, γ ζ ( .Η2) η, χ

[In the formula,

Ar represents a good § Li Ichiru may have a substituent,

η is an integer of from 1 to 5,

r represents 0 or 1,

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

- CO-, one CONH-, - NHCO-, - NR 2 CONR 3 - ( wherein, R 2,

R 3 may be the same or different, shows the it it 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 an alkyl.)

- CO-, one CONH-, -NHCO-, _NR 5 CONR 6 - ( wherein, R 5,

R 6, which may be the same or different, shows the hydrogen atom or an alkyl, respectively. ), An oxygen atom, a sulfur atom, One SO-, - S0 2 -, - NHS0 2 - or - S0 2 NH- indicates,

Z is a bond, may be substituted - 4 alkylene, oxygen atom, sulfur atom, one SO-, _S0 2 -, -NH-, one NR 7 - (R 7 represents an 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 . shown), an oxygen atom, a sulfur atom, -SO- or a S_〇 2 - indicates, q is an integer of 1 to 4. It shows],

A is a bond, optionally § Li one alkylene which may have a substituent group, a Yoi cycloalkylene optionally having Teroari one lens to have good may have a substituent or substituents, B shows § may have a substituent group Li Ichiru, hetero Ariru to which may have a substituent, and the cycloalkyl which may have a substituent if.

Provided that when r = 0, at least one other nitrogen atom contained in the formula is O key Sid reduction. ] - 3013591 is, the above-mentioned [1] compound, its optical isomers or a pharmaceutically acceptable salt thereof as claimed.

[3] In general formula (1),

n is an integer from 1 to 4,

A is a bond, the compounds of the above-mentioned [2], wherein have good § Li one Ren may have a substituent or substituents is Teroari one Ren also to good, its optical isomers or its pharmaceutically acceptable salt thereof.

[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, which may be the same or different, showing it it hydrogen atom or alkyl Le), one 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 It is in,

B is, the above-mentioned [2] or [3] The compound according a heteroaryl which may have even better Ariru or a substituent substituted, its optical isomers or acceptable their pharmaceutically salt that may.

[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, R 3, which may be the same or different, each represent a hydrogen atom or alkyl le.) It is in,

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

Z is a bond,

A is a bond, to which may have a good § Li one Ren may have a substituent or substituents Teroari - a lens,

B is A compound according to any one of [4] [2] is a Te Roariru to may have also good Ariru or substituents have a substituent, or its optical Isomers pharmaceutically acceptable salts. 13591

[6] (1) [4 i (3 Shianofuweniru) thiazole one Roux 2 f thio]-N-[1 - (3, 4-dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] Asetoami de ,

(2) [4- (4 one Shianofueniru) Chiazoru 2 Iruchio] one N-[1- (3, 4-dichloro port benzyl) one 1-O Kiso piperidin one 4 one ^ f le] § cell Toami de,

(3) N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4 one I le] i (4-phenylene Ruchiazo Ichiru 2- Iruchio) Asetoamido,

(4) N-[1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] one [4 i (3-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,

(5) N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4 one I le] one [4 i (4 one-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,

(6) N- [1- (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] one [4- (4-menu butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio ' Asetoami de,

(7) N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4 f le] one [4- (3-main butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio 'Asetoami de,

(8) [4 - (3-carboxy-phenylalanine) thiazole one Roux 2-^ f thio] - N - [1 one (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de,

(9) [4 - (4 one carboxymethyl phenylalanine) thiazole one Roux 2 Iruchio] - N one [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de,

(10) N-[1-(3, 4 Jikuro port benzyl) piperidine one 4-I le] - [4- (1 one Okisopirijin _ 4 one I le) thiazole one Roux 2- Iruchio] Aseto Ami de,

(1 1) N- [1- (3, 4- dichlorobenzyl) piperidine one 4 one I le] one [4 one (1 one Okisopirijin one 3-I le) thiazole one Roux 2- Iruchio] Aseto Ami de ,

(12) N- [1 - (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] one [4 one (2-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,

(13) Ν- [1 _ (3, 4- dichloro base Njiru) one 1-O Kiso piperidine -4 one I le] i (4 one Piraji two Ruchiazo one Lu 2 Iruchio) Asetoamido,

(14) (5-amino-1, 3, 4-thiadiazole Ichiru one 2-Iruchio) - New - [1 - (3, 4-dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de,

(15) Ν- [1- (3, 4- dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] i (5-phenylene Lou 1, 3, 4 one Okisajiazo one Roux 2 _ Iruchi O) Asetoami de,

(16) Ν- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one [5- (4-pyridyl) -1, 3, 4 Okisajiazo one Lou 2- Iruchio ] Asetoami de,

(17) Ν- [1- (3, 4 Jikuro port benzyl) - 1 over O Kiso piperidine one 4_ I le] one [5- (4-pyridyl) -1, 3, 4-thiadiazole one Lou 2- I Lucio] Asetoami de, and

(18) (6-Amino base down zone, thiazole one Lu 2 Iruchio) _Ν- [1 -. (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one ^ gamma le] Asetoami de, selected from compound or a pharmacologically acceptable salt thereof according to any one of [5] the above [1] to be.

[7] (1) [4 i (3 Shianofuweniru) thiazole Ichiru one 2- Iruchio] -Ν- [1- (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] Asetoami de ,

(4) Nyu- [1 one (3, 4-dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] - [4 i (3-pyridyl) Chiazoru 2 Iruchio] Asetoami de,

(5) Ν- [1 one (3, 4 Jikuro port benzyl) Single 1 over O Kiso piperidine one

4 one I le] one [4 i (4 one-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de, (7) N- [1- (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4 one I le] one [4 i (3 main butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio] Asetoami de,

(9) [4- (4 one carboxy off We sulfonyl) thiazole one Roux 2 Iruchio] - N - [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de , and

(10) N_ [l-(3, 4-dichlorobenzyl) piperidine one 4 f le] - [4- (1-Okisopirijin one 4-I le) thiazole Ichiru one 2- Iruchio] Aseto Ami de,

The [6] the compound or a pharmacologically acceptable salt thereof according selected from.

[8] (19) [4 i (3-force Le Bamo Irufu We sulfonyl) thiazole one Roux 2 I thio] - N- [1- (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] Asetoami de,

(20) [4 - (4 Ichiriki Le Bamo Irufu We sulfonyl) thiazole Ichiru - 2 Iruchio] - N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4- I le ] Asetoami de,

(2 1) N-[1 - (3, 4 Jikuro port benzyl) - 1 over O Kiso-4-I le] one {4- [3 - ((imidazo one Lu 4 one Irumechiru) Amino) off We sulfonyl ] thiazole Ichiru - 2 Iruchio} Asetoami de,

(22) N-[1 - (3, 4 Jikuro port benzyl) - 1 over O Kiso piperidine one 4 one I le] one {4- [3- ((imidazo one Lu 2 Irumechiru) Amino) Hue sulfonyl] thiazole one Lou 2- Iruchio} Asetoami de,

(23) N-[1- (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] one {4 one [3- (imidazo one rule 4 I le carboxamide) phenylene le] thiazole Ichiru - 2 Iruchio} Asetoami de, and

(24) {4- [3- (L- Araniruamino) Fuweniru] thiazole one Roux 2 Iruchio} - N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso-4-I le] Asetoami de,

[1] a compound or a pharmacologically acceptable salt thereof according selected from. Also relates to pharmaceutical compositions of the present invention the following [9] or [10].

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

[10] Chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic one property binding meningitis, allergic myelitis, atopic dermatitis, which is an agent for preventing or treating ulcerative colitis or human immune insufficiency syndrome above [ 9] the pharmaceutical composition according.

Furthermore, the present invention relates to the following.

[1 1] The compound according the above [1] to one of [8], comprising a salt acceptable optical isomers thereof, or its pharmaceutically, chronic rheumatoid arthritis, asthma, allergic one rhinitis, allergic conjunctivitis, allergic one myelitis, atopic dermatitis, an agent for the prophylaxis or treatment of ulcerative colitis or human immunodeficiency syndrome.

[12] The compound according the above [1] to one of [8], which comprises administering a salt acceptable optical isomers thereof, or its pharmaceutically, chronic rheumatoid arthritis, asthma, allergic rhinitis , allergic conjunctivitis, allergic myelitis, atopic dermatitis, prevention and treatment methods for ulcerative colitis or human immunodeficiency syndrome.

[13] Chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome prevention 'above for the manufacture of a therapeutic agent [1 a compound according to any one of from [8], the use of salt acceptable optical isomers thereof, or its pharmaceutically. Detailed Description of the Invention

The terms and symbols used herein are defined as follows.

The "hydrocarbon 璟基" of the "optionally may hydrocarbon ring group having a substituent" means a monocyclic-tricyclic hydrocarbon ring group having 3 to 20 pieces of TansoHara child. "Hydrocarbon ring group" includes a saturated ring, an aromatic ring and partially hydrogenated ring group.

The "hydrocarbon ring group", for example, "Ariru" (partially containing hydrogenated Ariru.) And "cycloalkyl" and the like as defined below.

If the "hydrocarbon ring group" has "substituent", its type and number of the substituents is not particularly limited, a substitutable substituents selected from the "substituents" defined below position 1 to the three Yu.

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 etc. the. 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 "§ Li one Le" may be partially hydrogenated. Site to be hydrogenated is not particularly limited. The partially Ariru which is hydrogenated, for example, dihydronaphthyl, etc. can be mentioned, et al are.

If "Ariru" has "substituent", the type and particular restrictions on the number rather than a substituent selected from the "substituents" defined below at its substitutable position

One to be three Yes.

The term "cycloalkyl" of "cycloalkyl which may be substituted" includes C (carbon number) of 3 _ 10 mono--tricyclic cycloalkyl ( "bridged a cycloalkyl" '.) means, for example, cyclopropyl, cyclobutyl, Shikurobe pentyl, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, norbornyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] Okuchiru etc. include the catch ο

When "cycloalkyl" has "substituent (s)", one for the type and is not particularly limited constant in the number, a substituent selected from the "substituents" defined below their substitutable positions - three to Yes.

As the "hydrocarbon ring group", preferably, cyclopropyl, Shikuropuchiru, shea Kuropenchiru, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru, norbornene two Le, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Okuchiru, Hue, naphthyl, anthryl, indanyl, that tetrahydronaphthyl and the like o

The "heterocyclic group" of the "heterocyclic group which may have a substituent", the nitrogen atom in addition to carbon atoms as a ring atom, 1 to 3 kinds of hetero selected from sulfur and oxygen atoms atoms from 1 to 4 for a monocyclic - tricyclic 5- to 7-membered containing that means the heterocyclic group. "Heterocyclic group" includes a saturated ring and aromatic ring (including "Heteroariru" as defined below. Also includes a partially hydrogenated ring group thereof.).

"Heterocyclic group" is an oxygen atom in addition to carbon atoms as ring atoms, and include "saturated heterocyclic group" containing 1 to 4 heteroatoms selected from sulfur atom and nitrogen atom, "saturated as heterocyclic group "to, for example, pyrrolidinyl, piperidinyl, piperazinyl piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, thiazol Jiniru, homopiperazinyl, and the like. Further, "heterocyclic group" is an oxygen atom in addition to carbon atoms as a ring atom, 1-4 containing TeroHara element to be selected from sulfur atom and nitrogen atom "heterocyclic group bridged" It encompasses, as the bridged ring group, for example, 3- Azabishikuro [3.2. 2] nonane one 3-I le, 8- Azabishi black [3.2. 1] octane one 8-I le etc. It is. Further, "heterocyclic group" contains at least one nitrogen atom in addition to carbon atoms as 璟原 element further oxygen atom, which may contain heteroatoms selected from sulfur atom and a nitrogen atom " embraces heterocyclic group "nitrogen-containing saturated. As the "nitrogen-containing heterocyclic group saturated", if example embodiment, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Chiomoruho Riniru, thiazolidinyl, homopiperazinyl, and the like.

If the "hetero 璟基" has "substituent", the kind and number to is not particularly limited, one of the substituent in the substitutable positions selected from the "substituents" defined below ~ three to Yes.

The "Heteroari Ichiru" of the "heteroaryl which may have a substituent", among the above SL of "heterocyclic group", the nitrogen atom in addition to carbon atoms as ring atoms, selected from sulfur atom and an oxygen atom that 1-3 kinds of the containing four from hetero atoms 1 for 5-7 membered aromatic heterocyclic (monocyclic) refers to the group, for example, furyl, thienyl, pyrrolyl, Ji Azoriru, pyrazolyl, Okisazoriru, Isookisazoriru, isothiazolyl, imidazolyl, 1, 2, 4-Okisajiazoriru, 1, 3, 4 one Okisajiazoriru, 1, 2, 3 Toriazoriru, 1, 2, 4-Toriazoriru, 1, 3, 5-triazine, cycloalkenyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, Rireru include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Azepiniru, Jiazepiniru the like. The "Heteroariru" is nitrogen atom in addition to carbon atoms as ring atoms, aromatic 5-7 membered containing from 4 from hetero atoms 1 to the 1-3 kind selected from sulfur atom and an oxygen atom complex ring also includes groups derived from an aromatic heterocyclic ring comprising fused to a benzene ring or the aromatic heterocyclic group (bicyclic or above), for example, I Ndoriru, isoindolyl, benzo [b] furyl, benzo [b] thienyl, Ben Zoimidazoriru, benzo O hexa benzisoxazolyl, benzoisoxazolyl O hexa benzisoxazolyl, Benzochiazo Lil, benzo 'isothiazolyl, quinolyl, isoquinolyl, and the like.

Further, the "Heteroari Ichiru" may be partially hydrogenated. Position to be hydrogenated is not particularly limited. The partially Heteroariru which is hydrogenated, for example, indolinyl, tetrahydro base Nzoimidazoriru, chromanyl, tetra Hidorokinoriru, tetrahydroisoquinolyl, dihydrofuranyl, and the like.

If "Heteroariru" has "substituent", the kind and are not particularly limited constant in the number, as defined below one substituent group selected from the "substituents" in its substitutable position 1-3 pieces containing.

As "heterocyclic group", preferably, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, thienyl, furyl, Ji Azoriru, pyrazolyl, isothiazolyl, Okisazoriru, Isookisazoriru, key Noryl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinoline quinolyl, 1, 2, 4-Okisajiazoriru, 1, 3, 4 - Okisajiazoriru, 1, 2, 3 - tri Azoriru, 1, 2, 4-Toriazoriru, 1, 3, 5 - triazinyl, 1, 2, 4 Chiajiazoriru , 1, 3, 4-thiadiazolyl, piperidinyl, piperazinyl, Azepiniru, Azepaniru, Jiazepaniru, Jiazepiniru, tetrahydrofuranyl, morpholinyl, indolyl, isoindolyl, indolinyl, tetrahydronaphthyl Ben Zoimidazo Le, chromanyl, 3 Azabishikuro [.. 3 2 2] nonane one 3-I le, 8 Azabishikuro [3 2 1..] Octan one 8 - I le, benzo [b] furyl, benzo [b] thienyl, benzimidazolyl, O hexa benzisoxazolyl, Benzoiso Okisazoriru, benzothiazolyl, benzisothiazolyl, and the like.

The "2 may have a substituent monovalent hydrocarbon ring group" and "may have a substituent divalent to heterocyclic group", the "hydrocarbon ring group" and "heteroaryl It means a divalent group having a bond at any position of the ring group. " The position of the bond is not particularly limited, it can be appropriately selected depending on the type of group.

From the "divalent hydrocarbon ring group" If and the "divalent The heterocyclic group" has "substituent" are not particularly limited to the type and number, the "substituents" defined below contain one to three substituents that are selected on the substitutable positions.

The "Ariren" of the "optionally substituted Ariren" means a divalent group having a further bond to any position of "Ariru" encompassed by the above-mentioned "hydrocarbon ring group" , for example, Fuweniren, divalent groups of naphthylene.

If "§ Li one alkylene" has a substituent group is not particularly limited to the kind and number, one of the substituent in the substitutable positions selected from the "substituents" defined below to 3 the number Yes.

"Optionally cycloalkylene optionally having a substituent" and "cycloalkylene", the are encompassed in the "hydrocarbon ring group" of divalent having further binding Gote at any position of "cycloalkyl" refers to the group, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexylene heptylene, Shikurookuchiren and the like.

When "cycloalkylene" has "substituent", the kind and no particular limitation on the number, 1 to 3 substituents on its substitutable positions selected from the "substituents" defined below the number Yes.

The "Heteroari one Ren" in "heteroarylene to which may have a substituent", the divalent group having a further bond to any position of "Heteroariru" encompassed by the above-mentioned "heterocyclic group" means, for example, furylene, Choi two Ren, pyrrolylene, Ji Azoriren, pyrazolylene, Okisazoriren, I Soo hexa sled Ren, Isochiazo 'rylene imidazolylene, 1, 2, 4-O hexa di § sled Ren, 1, 3, 4 Oki Sajiazoriren, 1, 2, 3 - triazolylene, 1, 2, 4-triazolylene,

1, 3, 5 - triazine two Ren, 1, 2, 4-thiadiazolylene, 1, 3, 4.- Ji Ajiazoriren, pyridylene, pyrimidinylene, Piraji two Ren, pyridazinylene, Azepi two Ren, Jiazepiniren, indolylene, isoindolylene, Indorini Ren, benzo [b] furylene, benzo [b] Choi two Ren, benzimidazolylene Ren, benzo O hexa sled Ren, benzoisoxazolyl O hexa sled Ren, benzothiazolyl Ren, Ben zo isothiazolinone Ren, quinolylene, isoquinolylene etc. and the like.

If the "Heteroari one Ren" has "substituent", 1 to its type and is not particularly limited to the number, which can be substituted a substituent selected from the "substituents" defined below position - three to Yes.

The term "alkyl", straight chain or branched chain of from 1 to 6 carbon atoms - means 6 alkyl, e.g., methyl, Echiru, n-propyl, isopropyl, n- heptyl, isobutyl, sec- butyl, tert - heptyl, pentyl, isopentyl, neopentyl pentyl, tert- pentyl, 1 Mechirubuchiru, 2-methylbutyl, 1, 2-dimethylpropyl, 1 one Echirupuropiru, hexyl, cyclohexyl isohexyl, 1-methyl pentyl, 2-methylpentyl, 3 - methylpentyl, 1, 1-dimethyl-heptyl, 1, 2-dimethylbutyl, 2, 2-dimethyl-heptyl, 1 Echirubuchiru, 1, 1, 2-trimethyl-propyl, 1, 2, 2-trimethyl-propyl, 1-Echiru 2 - methylpropyl, 1-Echiru - 1-methylpropyl, and the like. "Alkyl Le" may have three from one to "substituent" as defined in its substitutable position below, there is no particular limitation on the kind and number of substituents.

C alkyl are preferred in R 1, the R 2 C i _ 6 alkyls 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.

"Optionally substituted C i - e alkylene" and "(^ alkylene" of, means an alkylene chain having 6 carbon atoms of 1, for example, methylene, ethylene, trimethylene, tetramethylene, pentamine, Kisamechiren and the like to

0

If - "0 ^ 6 alkylene" has "substituent", 1 is not particularly limited to the type and number, a substituent selected from the "substituents" defined below at its substitutable position number - to three Yes.

The "(^ -6 alkylene" is defined in the "substituent" of one or more following - 6 when substituted by alkyl, branched alkylene chain (e.g., methylcarbamoyl Rumechiren, dimethylmethylene, 1 methylethylene, 2-methylethylene, 1, -1-dimethylethylene, 2, 2-dimethylethylene, Echirumechiren, Jechiru methylene, 1 one Echiruechiren, 2 Echiruechiren, -1-methyltrimethylene, 1, 1-dimethyl trimethylene, 2 - methyltrimethylene, 2, 2-Jimechiruto Rimechiren, 3-methyltrimethylene, 3, 3-dimethyl trimethylene, 1-E tilt Li methylene, 2-E tilt Li methylene, 3-E shows a tilt Li methylene, etc.) It is.

The the "alkylene which may be substituted", "(^ -4 alkylene", the number of carbon atoms of the above "(^ -6 alkylene" means an alkylene chain of 1-4.

If "(^ _ 4 alkylene" has "substituent", the type you Yopi number is not particularly limited, its substitutable position a substituent selected from the "substituents" defined below 1 to the three Yu.

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 a two alkylene. position and number of double bonds 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 . a two lens positions and number of the triple bond are not particularly limited. -

R a and R b are the same or different from each other, a hydrogen atom, an alkyl, halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), hydroxy sheet (one OH), alkoxy (-0- alkyl (as alkyl is defined above)), Shiano (one CN :), § iminocarbonyl (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 becomes R b gar緖may form a ring together with the atoms to which they are attached.

"Become R a and R b gar cord ring formed together with the atoms to which they are attached" includes ring and spiro ring R a and R b are attached as a C Bok 6 alkylene optionally interrupted with a hetero atom or it may form a bridged ring. 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 . with alkyl eg, 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.

Represented by X, one NR 2 CONR 3 -. (Wherein, R 2, R 3 may be the same or have different dates, each represent a hydrogen atom or alkyl or, R 2 and R 3 gar cord is and may form a ring together with the atoms to which they are attached.) to your Keru "becomes R 2 and R 3 gar cord ring formed together with the atoms to which they are attached" includes the above defined "heteroaryl It encompasses "terrorist ring to the nitrogen-containing saturated" that is included in the ring group ".

Represented by Y, one NR 5 CONR 6 -. (Wherein, R 5, R 6 s may be the same or have different dates, each represent a hydrogen atom or alkyl or, R 5 and R 6 gar cord 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 It encompasses "terrorist ring to the nitrogen-containing saturated" that is included in the ring group ".

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 Contact Keru since it may form a ring together with the atoms to which they are attached) to. ": turned R 8 and R 9 gar cord ring formed together with the atoms to which they are attached" is defined above It encompasses "nitrogen-containing heterocycle saturated" included in the "heterocyclic group".

Represented by Z, one Q - may have a C Bok 6 alkylene mono- or monosubstituted group which may have a substituent - 6 alkylene one - wherein the SansoHara child, 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 a 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together with the atoms to which they are attached may form a ring.) [as defined above],

One NR 8 S0 2 - or single S_〇 2 NR 8 - (wherein, R 8 represents a hydrogen atom or alkyl Le.) Or single 0- CO- NR 8 - or single NR 8 - CO- 0- ( wherein, R 8 indicates a.) of a hydrogen atom or an alkyl. Among the also],

_Q 2 - (CH 2) q - and single (CH 2) q -Q 2 - [ wherein, Q 2 is, -NH-, - NR 7 - ( . Wherein, R 7 is showing an alkyl), oxygen atom, a sulfur atom, -SO- or an S0 2 - indicates, q is an integer of 1 to 4. ] Is preferred.

As the "substituent" is not particularly limited, for example, a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), (6 alkyl (e.g., methylation, Echiru, n- propyl, isopropyl , n- heptyl, isobutyl, sec- butyl, t Ert- butyl, pentyl, isopentyl, neopentyl, t ert one pentyl, 1 Mechirubuchiru, 2-methylbutyl, 1, 2-dimethylpropyl, 1-Echirupuropiru, hexyl, isohexyl hexyl, 1-methylpentyl, 2-methylcarbamoyl Rupenchiru, 3-methylpentyl, 1, -1-dimethylbutyl, 1, 2-dimethyl-heptyl, 2, 2-dimethylbutyl, 1 Echirubuchiru, 1, 1, 2-trimethyl-propyl, 1, 2, 2-trimethyl-propyl, 1-Echiru - 2-methylpropyl, charcoal and 1-Echiru 1 one 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 , cycloalkyl O Chi Ruo alkoxy, norbornyl O carboxymethyl, bicyclo Puchiruokishi or bicyclo to [2.2.1] [2.2.2] Okuchiruokishi etc.), - 6 Haroa alkyl (e.g., triflate Ruo Russia methyl, Jifuruoromechiru etc. the C t-6 alkyl) in which the having at least one said halogen atom, C i - e alkoxy (e.g., main Butoxy, ethoxy, n- Purobokishi, isopropoxy, butoxy, isobutoxy, tert- butoxy, straight or branched chain Arukiruokishi group of carbon number 1-6 such as Kishiruokishi Penchiruokishi to,), (I 6 haloalkoxy (e.g., Torimaru Orome butoxy, the halogen atom at least one Yusuke that the C I 6 alkoxy such Jifuruorome butoxy), 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 di-

- 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 , cycloalkyl Petit Rua Mino, Puchiruamino cyclopentyl Rua Mino, Kishiruamino cyclohexane, cycloheptane, cyclo O Chi Rua Mino, Norubo Runiruamino, bicyclo [2.2. 1] heptyl amino, bicyclo [2.2. 2] Okuchiruamino, dicyclohexyl propylamino, di cyclobutyl § Mino, Jishiku port Penchiruamino, Kishiruamino dicyclohexyl, Puchiruamino dicyclohexyl, Jishiku Rookuchiruamino, Gino norbornyl § amino, di (bicyclo Petit Le to [2.2. 1]) 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 Arukinoiru (e.g., propioloyl etc.), C 7 - Aroiru (e.g., Benzoiru, 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 (e.g., main Tokishikaru Boniruamino, phenoxyethanol carbonyl § amino etc.), Suruhoniruamino, amino one C - 6 alkyl (e.g., aminomethyl, aminoethyl, Aminopuropiru, amino isopropyl, aminobutyl, etc.), mono- or di Primary alkyl) amino - alkyl (e.g., methylaminomethyl, methylaminoethyl, Echiru aminoethyl, 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., Benzoiru, naphthoyl, 2-naphthoyl, 1 one anthryl), force Rubokishi, alkoxy one carbonyl (e.g., main butoxycarbonyl, ethoxy alkoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy carbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl Ruo alkoxycarbonyl, etc.), Karubokisami de force Rubamoiru, mono- or di-

(C i-6 alkyl) § amino carbonyl (e.g., methyl § amino carbonyl, E Ji Rua amino carbonyl, propyl aminocarbonyl, isopropylamino carbonylation le, butyl § amino carbonyl, sec- Petit Rua amino carbonyl, tert- blanking Chill § iminocarbonyl, dimethyl § amino carbonyl, Jefferies chill § amino carbonyl, E chill methyl § amino carbonyl, dipropyl aminocarbonyl, methyl propyl § amino carbonyl, diisopropylamino carbonyl, etc.), mono- or di one

(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 Ararukiru (e.g., benzyl, 1-Fueniruechiru, 2 Fueniruechiru, 1-phenylpropyl, 3-Fuenirupu port pills, 1 one-phenylbutyl, 4- Fuenirupuchiru, 1 one naphthylmethyl, 2-naphthylmethyl, 1 i (1-naphthyl ) Echiru, 2- (1-naphthyl) Echiru,

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. , benzyl § amino carbonyl, 2-phenylpropyl E chill § amino carbonitrile sulfonyl, etc.), Heteroariru (e.g., pyrrolyl, furyl, thienyl, imidazol Le, pyrazolyl, thiazolyl, isothiazolyl, Okisazoriru, Isookisazori Le, Toriazoriru, Okisajiazoriru, thiadiazolyl, pyridyl , pyrazinyl, pyrimidinyl, pyridazinyl, Azepiniru, Jiazepiniru etc.), Heteroariru - C i-6 alkyl (e.g., 2-pyridylmethyl, 3-pyridylmethyl, 4-pin Rijirumechiru, 1 i (2-pyridyl) Echiru, 1 i ( 3-pyridyl) Echiru, 1 - (4 - pyridyl) Echiru, 2- (2-pyridyl) Echiru, 2- (3-pyrid-Le) Echiru, 2- (4-pyridyl) Echiru, the C having a heteroaryl 3- (2-pyridyl) propyl and the like of the i _ 6 alkyl), mono- or di- (Heteroa Lille - 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 one 2- Irume chill) Amino, (imidazo one Lu 4 Irumechiru) Amino etc.), Heteroari one Luca Rubokisami de (e.g., imidazo Ichiru - 2 Irukarubokisami de, imidazo Ichiru 4 Irukarubokisami de, etc.), amino acid residues one amino [e.g., glycyl, § Ranil, phenyl Amino having amino acid residues such Ranil (e.g., Araniru amino, etc.) and the like. Also amino acid residue is a naturally occurring, may be non-naturally occurring, amino protecting groups contained in the amino acid residue (e.g., tert- butoxycarbonyl group) may be protected by. ], 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- Antoriruchio etc.), one S 0 3 H or as single S 0 2 NH 2 and the like.

These substituents, that further may be substituted with the above substituents, the type and number of the substituent is not particularly limited, Yusuke one to three substituents on the substitutable position o

Further, examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), C i-6 alkyl [optionally the halogen atom, the upper Symbol d-e alkoxy, or phenyl ( if necessary, the halogen atom, alkyl, optionally substituted with yet good) optionally substituted with C i-4 alkoxy, or triflate Ruo b methyl] one 〇_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,

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

-NR A14 C (0) NR A15 R A16, Mechirenjiokishi, a nitro or Shiano:

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 can be, independently, a halogen atom or - 6 Al Kill (. May optionally be substituted by the above C alkoxy), or phenyl (optionally the halogen atom, alkyl, CI- 4 may be substituted by an alkoxy or triflate Ruo ii methyl);

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 it may be substituted with but it may also be substituted with Romechiru.). It is a;

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 alkoxy or optionally substituted with triflate Ruo b-methyl) may be monosubstituted.] it is.

Further, examples of the substituent include a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, an iodine atom), over a cycloalkyl, heterocyclic group one, Ariru, - OH, - O- Ci-e alkyl, One 0- § Li Ichiru, _0- cycloalkyl, single 0-hetero ring group, -NH- Ariru, -NH- cycloalkyl, - NH- heterocyclic group, one NH 2, one NH- CI- 6 alkyl, one 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, [ as cycloalkyl, heterocyclic group, § Li Ichiru and alkyl as defined above] in which one N0 2 and -CN are exemplified.

As the substituent, an alkyl, a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) alkyl substituted with (e.g., triflate Ruo b methyl, etc.), substituted with one OH C Bok 6 alkyl, C i_ 6 alkyl is substitution in one COOH, - alkyl substituted by CONH 2, include C i-6 alkyl substituted with one CN [as alkyl 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 (e.g., fluorine atom, chlorine atom, odor atom, an iodine atom, etc.) good C i_ 3 alkyl optionally substituted with, -O- (halo gen atom (e.g., fluorine atom, chlorine atom, 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) the recited Ru.

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 ., especially not limited), C 2 _ 6 alkynyl (wherein, C 2 _ 6 alkynyl, the above-mentioned "(^ _ 6 alkyl" - straight having a triple bond at any position of the "C 2 6 alkyl" or the number of carbon atoms of branched 2 is a 6 alkynyl positions 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- ( Ariru may have a substituent group), -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 - include (an optionally substituted § Lille): R B 1 may be substituted - 6 alkyl There, 1 ^ 2 Oyobi 11 ^ are the same or different from each other, hydrogen atom or (I 6 alkyl;? and or R B2 and R B3 are Te summer together with the atoms to which they are attached to form a ring which may ( "turned R B2 and R B 3 gar緖ring formed together with the atoms to which they are attached" includes "nitrogen-containing heterocycle saturated" included in the "heterocyclic group" defined above. ).

By "at least one of the nitrogen atom contained in the formula have been Okishido of" in the compound of the general formula (1), a known "Okishido of possible nitrogen atoms" included in the formula to those skilled in the art of organic synthesis to agree taste that may be Okishido by such methods. It is not particularly limited as long as it is a nitrogen atom as the "Okishido of available nitrogen atom".

The "Okishido of possible nitrogen atom" preferably, in compounds of the general formula (1), based on: There is a nitrogen atom to which they are attached. Nitrogen atom contained Hajime Tamaki represented by B (a Heteroariru including) the also preferred.

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.

Thus, in the general formula (1), based on: Preferably, Ar- CH 2 - in which (in Ar, represents an § reel may have a substituent).

Phenyl is preferably an "Ariru." In "optionally may be Ariru having substituents" represented by Ar, a chlorine atom is preferred as the "substituent". As the "optionally substituted Ariru", 3, 4-dichlorophenyl are preferred.

R a and R b are preferably both hydrogen atoms.

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

n represents an integer of 0 5, preferably an integer of from 1 to 5, more rather preferably is an integer from 1 to 4, even more preferably 1.

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

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

X is preferably a bond, One NH-, -NR 1 - (wherein, R 1 is shown to an alkyl.), - CO-, One 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 a 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 well, that is it represents a hydrogen atom or alkyl), Note (wherein the carbon atom of _CONH_ - (CH 2) even more preferably -CONH-. n - bonded to the nitrogen atom is one (CH 2 ) m - is attached is) to.

Y is preferably a bond, - NH-, -N 4 - (wherein, R 4 is shown to an alkyl.), One CO-, One CONH-, One NHCO-, -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 an S0 2 NH-, more preferably 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 . which are shown), one CO- one Q 2 - (CH 2) q - or a (CH 2) q -Q 2 - [ wherein, Q 2 is, _NH-, -N 7 - (wherein, R 7 is an alkyl), an oxygen atom, a sulfur atom, one SO- or _S0 2 -. indicates, q is an integer of 1 to 4. A], and more preferably a bond.

A is preferably a bond, good § Li one Ren have a substituent, may Shikuroarukire emissions have a Teroari one alkylene or substituent to which may have a substituent, more preferably a bond, a heteroarylene to may have a good § Li one alkylene or location substituent may have a substituent, it is even more preferably been coupled or may have a substituent a Teroari one lens to better still rather more preferably more a Teroari one lens to which may have a substituent. Among them, Chiazorire down, O hexa di § sledding Len (e.g., 1, 3, 4-O hexa di § sled Ren, etc.), thia Jiazoriren (e.g., 1, 3, 4-thiadiazolylene, etc.) are preferable.

B is preferably an optionally substituted Ariru, cycloalkyl which may have a heteroaryl or a substituent to which may have a substituent, yo Ri preferably have a substituent is Teroariru also to have good have also good Ariru or substituent have. Of these, phenyl, pyridyl, pyrazinyl, Chiaji Azoriru (e.g., 1, 3, 4-thiadiazolyl, etc.), benzothiazolyl favored arbitrariness. 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 one Lou 2 Irume chill) amino, (imidazo one Lu 4 one Irumechiru) amino etc.), Heteroari one Luca Rubokisamido (e.g., imidazole over 4-I le carboxaldehyde mi de, etc.), amino acid residue amino (eg, L Araniruamino etc.) etc. are preferred. As the heteroaryl may have a substituent group represented by B, N-Okishidopirijiru are preferred.

Preferred compounds of general formula (1),

(1) [4 - (3-Shianofueniru) thiazole one Roux 2- Iruchio] _N- [1 - (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4 f le] § cell Toamido,

(2) [4 - (4 one Shianofueniru) thiazole one Roux 2 Iruchio] - N-[1 - (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] § cell Bok ami de,

(3) N_ [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - (4 one phenylene Ruchiazo one Lu 2 Iruchio) Asetoami de,

(4) N-[1 one (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] one [4 i (3-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,

(5) N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4 one I le] one [4 i (4-pyridyl) thiazole one 2- Iruchio] Asetoami de,

(6) N- [1- (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4 i (4-menu butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio ' Asetoami de,

(7) N- [1 - (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one [4 i (3 main butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio ' Asetoami de,

(8) [4 - (3-carboxy-phenylalanine) thiazole one 2- Iruchio] one N - [1-(3, 4-dichloro port benzyl) _ 1 over O Kiso piperidine one 4-I le] § Setoami de,

(9) [4 (4-carboxyphenyl off We sulfonyl) thiazole Ichiru one 2-Iruchio] - N - [1-(3, 4-dichlorobenzyl) - 1 over O Kiso piperidine one 4-I le] § Setoami de,

(10) N- [1- (3, 4- dichlorobenzyl) piperidine one 4 one I le] one [4- (1 one Okisopirijin one 4-I le) thiazole Ichiru one 2- Iruchio] Aseto Ami de ,

(11) N-[1-(3, 4-dichlorobenzyl) piperidine one 4 one I le] one [4- (1 one Okisopirijin - 3-I le) thiazole one Roux 2- Iruchio] Aseto Ami de,

(12) N-[l-(3, 4-dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] one [4 one (2-pyridyl) thiazole one 2- Iruchio] Asetoami de, (13) N-[1 one (3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4 one I le] i (4 one Piraji two Ruchiazoru 2 Iruchio) Asetoami de,

(14) (5-amino-1, 3, 4-thiadiazole, One Lu 2 Iruchio) Single N one [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de ,

(15) N-[1- (3, 4-dichlorobenzyl) one 1-O Kiso-4-I le] - (5-phenylene Lou 1, 3, 4 _ Okisajiazo one Roux 2 Iruchi O) Asetoami de,

(16) N-[1- (3, 4-dichloro port benzyl) - 1-O Kiso-4-I le] - [5- (4-pyridyl) one 1, 3, 4 Okisajiazo one Lou 2- Iruchio] Asetoami de,

(17) N-[1-(3, 4-dichlorobenzyl) one 1 - O Kiso piperidine one 4_ I le] one [5- (4-pyridyl) one 1, 3, 4-thiadiazole one Lou 2- I Lucio] Asetoami de,

(18) (6-Amino base Nzochi zone one Lu 2 Iruchio) one N-[1- (3 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] Asetoami de,

(19) [4 - (3-force Le Bamo Irufu We sulfonyl) thiazole Ichiru - 2-^ T thio] -N- [1- (3, 4- dichloro port benzyl) - 1-O Kiso piperidin one 4- I le] Asetoami de,

(20) [4 - (4 Ichiriki Rubamoirufue sulfonyl) thiazole one Roux 2 Iruchio] -N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] Asetoami de ,

(2 1) N- [1- (3, 4- dichlorobenzyl) Single 1 one year old Kiso piperidine one 4 one I le] one {4 one [3 - ((imidazol-one 4 one Irumechiru) Amino) Hue sulfonyl] thiazole Ichiru one 2- Iruchio} Asetoami de,

(22) N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4 one I le] one {4 one [3- ((imidazo one Lu 2 Irumechiru) Amino) Hue sulfonyl] thiazole one Lou 2- Iruchio} Asetoami de '

(23) N-[1 one (3, 4-dichloro port benzyl) one 1-O Kiso piperidine _4 one I le] one {4 one [3- (Imidazo one Lu 4-I le carboxamide) phenylene le] Chiazoru 2 Iruchio} Asetoamido and,

(24) {4 - [3 - (L Araniruamino) Fuweniru] thiazole one 2-Iruchio} - N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4_ I le] include Asetoamido It is.

Among the above compounds, compounds (1) to (18) are preferred, in particular,

(1) [4- (3-Shianofuweniru) thiazole Ichiru one 2-Iruchio] - N-[1-(3, 4-dichloro port benzyl) one 1 over O Kiso piperidine _ 4 Iru] § cell Toamido,

(4) N-[1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4- (3-pyridyl) thiazole Ichiru - 2 Iruchio] Asetoamido,

(5) N-[1 - (3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one [4- (4 one-pyridyl) thiazole one Roux 2- Iruchio] Asetoamido,

(7) N- [1 - (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4- (3-methoxycarbonylphenyl) thiazole one rule 2 I le Chio 'Asetoami de,

(9) [4 i (4 _ carboxymethyl off We sulfonyl) thiazole Ichiru one 2- Iruchio] one N - [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § acetamide , and

(10) N-[1- (3, 4 Jikuro port benzyl) piperidines Rijin 4 one I le] - [4 one (1 Okisopirijin one 4-I le) thiazole one Roux 2- Iruchio] Aseto amides are preferred.

The compounds and their pharmaceutically acceptable salts of the general formula (1) include hydrates or solvates (e.g., ethanolate, etc.) so may exist in the form of, their hydrates, solvated objects are also encompassed by the present invention. The compound of the general formula (1) at least two kinds of optical isomers are present in the case of having an asymmetric atom. These optical isomers and racemates thereof are also encompassed by the present invention.

Compounds of general formula (1), the following methods (1) to (8) and can be prepared by quasi-Ji methods to these methods, also the raw material compounds used in the following manner (1) to (8) the methods known to those skilled in the art of organic synthesis, and by a method or the like according to the way described in Patent Document 15 (Patent documents 1 to 15 of which is incorporated by reference herein.) it can be synthesized.

In the following methods (1) to (8), as those skilled in the art can easily understand the production method of the present invention compounds exhibit a compound of the general formula (1) in a preferred embodiment. That is, in one general formula (1), based on:

It is, Ar- CH 2 - (Ar represents an optionally Ariru be substituted) Ri Der; ρ = 1; m = 0 ; W = - CH rather; R a and R b are both hydrogen is an atom. The position of the N Okishido in compounds of the general formula (1) (N-◦) is not particularly limited.

The following methods (1) to (8), illustrate the preparation of the present compound (Compound of the general formula (1)), the process of the invention compounds, such is limited to Ikoto it is to be understood.

The following terms used in the description of the synthesis of the "Heteroariru (including Heteroari one alkylene) substituent necessary for construction", acid or base catalyst, light, by heat or the like, in many cases the addition reaction or water, an alcohol , acid, by condensation reaction with the elimination of such hydrogen halide is meant a substituent necessary for building Heteroariru. Specific above-mentioned "Heteroariru substituent necessary for construction" includes any combination of Promo acetyl and thioamide in building thiazole Ichiru, 1, 3, 4 - hydrazide in building Okisajiazo Ichiru and either the combination of carboxylic acids, 1, 2, 4-Okisajiazo Ichiru in building Asechiruokishimu and carboxy phosphate esters or a combination of, the Hydra disilazide and carboxylic acids for building the Isookisazo Ichiru any combination, 1, 2, Ru include any such combination of S- methyl thio amide and hydrazide when you build a 4-Toriazoru is ο

Methods (1)

Formula (2): B, z,丫,

(Wherein each symbol is as defined above.) And a compound represented by or, a salt thereof (eg, the acid addition salts (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt) The base addition salts (e.g., lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, Anmoniumu salt etc.) etc.), if example a suitable solvent (e.g. it does not inhibit the reaction, Jikurorome Yun, Jikuroroetan, black hole Holm halogenated hydrocarbons or in any mixture of these solvents, etc.) etc., and have use an oxidizing agent such as main evening black port perbenzoic acid, or acetic acid, Torifuruoro acetic acid in a solvent such as formic acid, peroxide using an oxidizing agent Motomi like, usually, -. 3 0~8 0 ° C temperature, preferably at a temperature in the first 1 0~6 0 ° C, 0 by 5-2 4 hours, generally equation (1):

(Wherein each symbol has the same meaning as defined above.) The compound represented by can be obtained.

Where an amino group which does not participate in the reaction among the reactant in the reaction is present, the substituent carrying out the reaction after protecting with a suitable protecting group, may be removed by dividing the protecting group after the reaction. The protecting group of the Amino group used in the, tert - butoxycarbonyl (B oc), the force and benzyl O butoxycarbonyl Rubameto, formyl, Asechiru, triflumizole Ruo b acetyl, Ami de such Benzoiru, benzyl, P- methoxybenzyl, and § reel alkyl such trityl and the like. Their removal protecting group may be removed, formic acid, such as Torifuruoro sodium acetate or hydroxide of, solvolysis using a base such as hydroxide force potassium, reduction with metal hydride complexes, palladium - catalytic reduction using carbon catalyst or Raney one nickel, 2, 3-dichloro-one 5 can be carried out by oxidation or the like using the 6-Jishiano ρ- benzoquinone.

The method (2)

In the general formula (1), in the case of X gar CONH-, it can synthesis by the following method.

The general formula (3):

(Wherein each symbol is as defined above.) The compound or its acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt) represented as the general formula (4 ):

(Wherein each symbol is as defined above.) Represented by the compound or its acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt, etc.), and inhibits the reaction such have a suitable solvent (e.g., tetrahydrofuran (hereinafter, abbreviated as THF.), dichloro methane, New, Nyu- dimethylformamidine de (hereinafter, abbreviated as DMF.), or any mixed solvent) in, Toryechiruamin, (. hereinafter, abbreviated as DCC) the presence of a tertiary Amin such diisopropyl E chill § Min, condensing agent [e.g., cyclohexyl Cal positive I bromide dicyclohexyl, Nyu- (3- dimethyl § amino propyl) Single N '- Echirukaru Pojiimido (. hereinafter abbreviated as EDC) or a hydrochloride salt, 2 _ Etokishi 1 over E Tokishikaruponiru - (. hereinafter abbreviated as EEDQ) 1, 2-dihydroxy-quinoline, Karubojiimidazo Ichiru Hereinafter referred to as CD I.), Jefferies chill phosphorylase Lucia two de, benzotriazole one route 1 over I Ruo carboxymethyl tris pyrrolidinopyridine phosphonyl © beam to Kisafuru Orohosufeto (hereinafter, abbreviated as PyBOP.), Diphenyl phosphoryl azide (hereinafter abbreviated as DPPA.), Isopuchiru chloroformate, Jechiruasechiru chloride, salts spoon trimethyl § cetyl like. ] The alone or N- hydroxysuccinimide Kushin'imi de (hereinafter, abbreviated as HONSu.), Hydroxybenzotriazole Ichiru (hereinafter, abbreviated as HOB T.), Or 3-hydroxy one 4 _ Okiso one 3, 4 - dihydro one 1, 2, 3-base Nzotoriajin (. hereinafter abbreviated as HOOBT), or 4-dimethyl chill § amino pyridine (hereinafter, abbreviated as DMAP.) used in combination with additives such as generally - 30 temperature to 80 ° C, preferably by reacting 1 to 24 hours at a temperature in the first 10 ~ 25 ° C, the general formula (1):

0

Ar to N

B, z, A, (CH2 ) nヽ,, (1)

(Wherein each symbol is as defined above. However, shows. An CONH-) compounds more represented in is obtained.

In general formula (3) compounds reactive derivative (e.g., acid Kurori de, Ashirui Midazo Ichiru etc.) By carrying out the reaction as a, it is possible to obtain a compound represented by the general formula (1) .

Typically, this reaction is carried out in a suitable solvent that does not inhibit the reaction (e.g., THF, dichloro methane, black hole Holm, benzene or any of these mixed solvents) in the presence of such tertiary Amin or pyridine such Toryechi Ruamin performed under ice cooling or at room temperature for 1 to 24 hours.

The method (3)

In the general formula (1), in the case of X gar NHCO-, it can synthesis by the following method.

Formula (5): z, A / Y \ (CH2) MH 2 (5)

(Wherein each symbol is as defined above.) The compound or its acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt) represented as the general formula

(6):

(Wherein each symbol is as defined above.) Represented by the compound or its acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt, etc.), and inhibits the reaction such have a suitable solvent (e.g., THF, dichloromethane, DMF or the like of any of these mixed solvent) in, Toryechiruamin, the presence of a third Kyua Min such diisopropyl E chill § Min, condensing agent (the method (2) . by condensing agent as defined according) are reacted for 1 to 24 hours under ice-cooling or at room temperature and has the general formula (1):

(Wherein each symbol is as defined above, however, X is, -. NHCO- shown) by Ri compound represented are obtained.

In general formula (6) compounds reactive derivative by carrying out the reaction as a (acid Kurori de, Ashiruimidazo one Le etc.), it is possible to obtain a compound represented by the general formula (1).

The method (4)

In general formula (1), Y is - NH-, in the case of an oxygen atom and a sulfur atom, can be synthesized by the method below.

The general formula (7):

Β Τ Υ, Η (7)

(Wherein, Y is _NH-, an oxygen atom or a sulfur atom. Other symbols are as defined above.) The compound or its acid addition salt thereof (e.g., hydrochloride, Nioikamizu periodate , sulfate, oxalic acid salt, etc.), in a suitable solvent that does not inhibit the reaction (e.g., di-chloromethane Yun, black hole Holm, Jikuroroetan, Jechirue one ether, dimethylformamide, water, or any of these mixed solvents), the general formula (8):

(Wherein, L 1 is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy O carboxymethyl, p one toluenesulfonyl O carboxymethyl, Torifuruorome evening a leaving group such as a down-sulfonyl O carboxymethyl, the other symbols having the same definition as above there.) a compound or a salted with an acid (e.g. expressed, hydrochloride, acetate, hydrobromide, sulfate, and oxalate salts), preparative Riechiruamin, pyridine, DMAP, potassium carbonate, bicarbonate sodium in the presence of a base, such as water oxidation Natoriumu, by reacting under ice-cooling or at room temperature 1-24 h, the general formula (1):

(Wherein each symbol is as defined above, however, Y is -. NH-, an oxygen atom or a sulfur atom.)

Compounds represented by is obtained.

The method (5)

In the general formula (1), A may shows the Teroari one lens to which may have a substituent can be synthesized by the following method. In other words, the general formula (9):

(Wherein, G 1 represents a substituent necessary for Teroariru construction to, and the other symbols are as defined above.) Compound represented by or an acid addition salt (e.g., hydrochloride, hydrobromide , sulphate, oxalic acid salt, etc.), the general formula (10): O

Ar to il

G 2, Y CH2) n, x J \ ^ J (10)

(Wherein, G 2 represents a substituent necessary for Teroariru construction to, and the other symbols are as defined above.) Compound represented by or an acid addition salt (e.g., hydrochloride, hydrobromide , sulfates, by reaction with oxalic acid salt, etc.), the general formula (1):

0

', Ar

B,, (CH2) n, x J \ ^ J (1)

(In the formula, A to which may have a substituent indicates Teroari one lens, and the other symbols are as defined before follow.) The compound represented by can be obtained.

Method (6)

In the general formula (1), if B represents a heteroaryl which may have a substituent can be synthesized by the following method.

In other words, the general formula (11):

G 3 -H (11)

(Wherein, G 3 represents a substituent necessary for Teroari Ichiru搆築to.) By represented by reduction compound or an acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalic the salt, etc.), the general formula (12):

(12)

(Wherein, G 4 represents a substituent necessary for Teroariru construction to, and the other symbols are as defined above.) Compound represented by or an acid addition salt (e.g., hydrochloride, hydrobromide , sulfates, by reaction with oxalic acid salt, etc.), the general formula (1): 0

N ヽ Ar

Β, ζ Αγ (.Η2) η , χ ^ (1)

(Wherein, beta represents a heteroaryl which may have a substituent group and the other symbols are of the same meaning.) The compound represented by can be obtained.

Method (7)

In the general formula (1), Zeta gar Q 2 - in [wherein, Q 2 is - - (CH 2) q NH- , -NR 7 - (. Wherein, R 7 is showing an alkyl), an oxygen atom or a sulfur atom, q is an integer of 1 to 4. ] For, it can also be synthesized by the following method.

In other words, the general formula (13):

(13) wherein, G 5 is, _NH 2, (wherein, R 7 represents an alkyl.) -NHR 7, shows a -OH or a SH, and the other symbols are as defined above. ] The compound or the acid addition salt thereof (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt) represented a suitable solvent which does not, and to inhibit the reaction (e.g., dichloromethane, black hole Holm , dichloro Roetan, Jechirue one ether, water or any of these mixed solvents), the general formula (14):

Table (wherein, L 2 is chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, Torifuruorome evening a leaving group such as a down-sulfonyl O carboxymethyl, and the other symbols are as defined above.) The the compound or an acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt, etc.) and a base (e.g., Toryechiru Amin, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate, hydroxide the presence of sodium, etc.), by reacting under ice-cooling or at room temperature for 1 to 24 hours, the general formula (1):

Wherein, Z is, -Q 2 _ (CH 2) q - [ wherein, Q 2 is one NH-, One NR 7 - (. Wherein, R 7 is showing an alkyl), an oxygen atom or a sulfur It represents an atomic, q is an integer of 1 to 4. It shows a]. And the other symbols are as defined above. A compound represented by] can be obtained.

Method (8)

In formula (1), Z is one (CH 2) q -Q 2 - in [wherein, Q 2 is one NH-, - NR 7 - (. Wherein, R 7 is showing an alkyl), an oxygen atom or a sulfur atom, q is an integer of 1 to 4. ] For, it can also be synthesized by the following method.

In other words, the general formula (15):

B "(Cn2) ^ L 3 (15)

Table (wherein, L 3 is chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, Torifuruorome evening a leaving group such as a down-sulfonyl O carboxymethyl, and the other symbols are as defined above.) The the compound or an acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt, etc.), suitable solvent does not inhibit the reaction (e.g., Jikurorome Yun, black hole Holm, Jikuroroe Yun, Jechiruete Le, water or any of these mixed solvents) in the general formula (16):

Wherein, G 6 is, - NH 2, one NHR 7 (. Wherein, R 7 is showing a alkyl), shows an OH or -SH, and other symbols have the same meanings as defined above. ] The compound or the acid addition salt thereof (e.g., hydrochloride, hydrobromide, sulfate, oxalate salt) expressed as, Toryechiruamin, pyridine, DMAP, potassium carbonate, sodium hydrogen carbonate, hydroxide the presence of a base such as sodium, the Rukoto 1 to 24 hours under ice-cooling or at room temperature, the general formula (1):

0

Ar to

Bヽgate 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 shows, q is an integer of 1 to 4. It shows a]. And the other symbols are as defined above. A compound represented by] can be obtained.

In the above method (2) to (8), the general formula (4), (6), (8), (10), (1 2), (14), of the compounds represented by (16) N-Okishido nitrogen atom of the moiety (N → 0) may not be Okishido reduction, in which case the nitrogen atom with a compound that is not Okishido of perform the reaction of the method (2) - (8) , then (if the nitrogen atom is not particularly limited) the nitrogen atom contained in the resulting et product was O Kishido by methods well known methods in the art pursuant to the method (1) or method (1) it may be. Further, as a starting compound may be a compound which other nitrogen atom is Okishido by methods known in the art.

Pharmaceutically acceptable salts of the compounds of the general formula (1), acid addition salts with inorganic or organic acids can be mentioned a conventional method with an inorganic acid compounds of the general formula (1) (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid), organic acids (e.g., acetic acid, Torifuruoro acetate, tosylate, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, Kuen acid, Asukorubin acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, isethionic acid, force down fur sulfonic acid may be a salt by treatment with Asukorubin acid). Alternatively, pharmaceutically acceptable salts of the compounds of the general formula (1) are base addition salts (e.g., lithium salt, sodium salt, potassium salt, calcium salt, Maguneshiu arm salts, Anmoniumu salt, etc.). Also, hydration of a compound of the general formula (1), solvates (e.g., ethanolate and the like) are also included in the present invention.

Thus the present invention compound obtained is recrystallized, can be isolated and purified by a conventional method such as column chromatography. The resulting product can as a racemate resolution, e.g., by fractional crystallization of salts with optically active acid, or by passing through a column packed with optically active responsible body, the desired optically active substance can do. Individual Jiasutereoma one fractional crystallization, can be thus separated means such column chromatography. It also depending on the use of optically active starting compounds is obtained. Further, stereoisomers recrystallization, can be isolated more column chromatography.

N- Okishido compounds of the present invention, when using a salt acceptable optical isomers thereof, or its pharmaceutically as a pharmaceutical the present invention the compound a pharmaceutically acceptable carrier (e.g., excipient, binder, disintegrant, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, and the like) and mixed to the obtained pharmaceutical composition or preparation (e.g., tablets, pills, capsules, granule, powder, syrup, Emarujiyon, elixirs Gill, suspensions, solutions, injectables, in be administered orally or parenterally in the form of drops or suppositories etc.).

The pharmaceutical compositions may be formulated according to conventional methods. In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, is intended to include intraperitoneal injection or drip infusion or the like.

Solid dosage forms for oral administration, for example, powders, granules, tablets, pills, and the like as described above in capsules, and the like. In such form, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, Arugine Ichito, chitins, chitosans , pectin acids, tragacanth acids, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers

- it may be mixed with s or glycerin earths. Such dosage forms thereof may also further additives (for example, an inert diluent, a magnesium lubricants stearates such as parabens, preservatives such as sorbic acids, Asukorubin acid, shed - tocopherol, shea Sutin etc. antioxidants, disintegrants, binders, thickeners, buffers, sweeteners imparting agent, frame bars imparting agents may include Pafuyu Ichimu agent).

Tablets and pills can be prepared further E down Teri brute coating. The solutions for oral administration, Emarujiyon agent a pharmaceutically acceptable, Shirodzu flop, elixirs, suspensions, solutions and the like, usually inert diluent used in their art, such as water, etc. it may contain a.

Injectable preparations (e.g., sterile injectable aqueous or oily suspensions, etc.), it is prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents can. Injectable preparations may also, for example, may be a solution or suspension capable of sterile injectable with diluent or solvent such as water. Vehicles or solvent that can therefore be used, for example, water, Ringer's solution, and isotonic sodium chloride solution or the like. Further, usually, as a solvent or suspending solvent, sterile fixed oils may also be used. For this purpose, any nonvolatile oil or fatty acid can be used, natural or synthetic or semisynthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic Monoguriseri de, diglycerides or triglyceride such are also included. Suppositories for rectal administration, the drug with a suitable non-irritating excipients, for example, in the Kokoaba evening one or polyethylene glycols and time was room temperature is solid, liquid at temperatures in intestinal, rectal in melted as possible out be prepared by mixing or the like as to release the drug.

Dose, the patient's age, weight, general health, sex, diet, administration time, administration method, excretion rate, drug combination, depending on the extent of the condition is carried out treatment at that time of the patient, they or It is determined in consideration of the other factors. The compounds of the present invention, can be safely used at low toxicity, the daily dose is the patient's condition and body weight, type of compound, varies depending the route of administration and the like, for example, the orally 0.0 1 to 1

0 0 O mg / kg body weight / day, preferably 0. 0 5~5 0 O m gZk g and a weight / day, is administered in a day to several times, also parenterally subcutaneous, intravenous among them, in or rectally intramuscular, about 0. 0 1~5 O mg / kg body weight day, preferably 0.0 1

Preferably administered SO mg / kg body weight / day. Diseases to be treated and or prophylaxis, for example, the onset cells pathologies with chemokine receptors, progress, disease plays an important role in the maintenance, for example, atherosclerosis, chronic rheumatoid arthritis , osteoarthritis, psoriasis, asthma, allergic one rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, food allergy, ulcerative colitis, multiple sclerosis, chronic obstructive respiratory disease, myocarditis , rejection during organ transplant surgery, human immunodeficiency syndrome.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, examples of the present invention raw material synthesis examples, and will be described in detail by experimental examples, the present invention should not be construed as being limited thereto.

Incidentally, 1 H- NMR spectrum of the compound was determined by 300 MHz. Ifi- NMR chemical shifts, have use tetramethylsilane (TMS) as an internal standard, and expressed relative Dell evening (d) is value Pas one Dzupamirion (ppm). Kadzupu ring constants are indicated by Ruth f trivial multiplicity (Hz), s (Shinguredzuto), d (Dabure' DOO), t (triplet), q (quartet), m (multiplet), dd (doublet O Bed Daburedzudzu ), it was expressed as brs (broad singlet), and the like. Column chromatography was performed using silica gel manufactured by Fuji Shirishia Chemical Company.

Starting Material Synthesis Example 1

2 _ chloro N- [1- (3, 4- dichloro port benzyl) piperidine one 4-I le Synthesis of Asetoami de

4-amino-1- After complete dissolution of the a (3, 4 Jikuro port benzyl) piperidine dihydrochloride 50 g black port Holm 300 ml, aqueous solution of sodium hydrogen carbonate 30 0 ml was added, further chloroacetyl chloride 14. 3 ml the mixture was stirred for 2.5 hours at room temperature. After completion of the reaction, and extracted with black port Holm, followed by washed with saturated brine, dried and evaporated under reduced pressure. The residue obtained was recrystallized from key Sun to isopropyl E one ether / to afford the title compound 44. 1 g as a white powder.^ -NMR (DMSO- d 6) δ : 1. 36 - 1. 50 (2H, m), 1. 65 one 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 (1 H, m), 4. 0 1 (2H, s), 7. 25 - 7. 34 (1H, m), 7. 53 -. 7. 62 (2H, m), 8. 10-8 17 (1H, m).

Starting Material Synthesis Example 2

2 Black port one N- [1 - (3, 4- dichloro port benzyl) Single 1- Okisopiperiji Hmm 4 I le Synthesis of Asetoamido-acetate

After the product 3 g of Starting Material Synthesis Example 1 was completely dissolved in acetic acid 20 ml, 30% hydrogen peroxide water lml added and stirred for 3.5 hours at 70 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure, the resulting residue was extracted with black port Holm, followed by washed with saturated brine, dried and evaporated under reduced pressure. By obtained residue was recrystallized in black port Holm Bruno isopropyl 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, s), 7. 53 (1 H, d, J = 8. 1 H z), 7. 69 (1H, d, J = 8. 1Hz), 7. 86 (1 H, s), 8. 42 ( 1H, d, J = 7. 5 Hz).

Starting Material Synthesis Example 3

[4 - (3-Shianofuweniru) thiazole one Roux 2 Iruchio]-N-[1 - (3

4- dichlorobenzyl) piperidine one 4 one I le] Asetoamido Synthesis of

[4- (3-Shianofueniru) thiazole one Roux 2- Iruchio] acetate 10 g of 4-Amino one 1- (3, 4-dichloro port benzyl) piperidine dihydrochloride 13. Jikurorome Yun 300 2 g was dissolved ml, and subsequently, Toriechiruamin 1 lml, HO BT 6. 7 g, 1 Echiru 3- (3-dimethylaminopropyl § amino propyl) carbodiimide hydrochloride 8. 4 g was added, stirred for 1 5 hr at room temperature did. Water was added to the reaction solution, followed by extraction with black port Holm, saturated aqueous sodium bicarbonate, washed with brine, dried - and 燥. The solvent was distilled off under reduced pressure. The residue was recrystallized from a black hole Holm / isopropyl ether to give the title compound 1 7. 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. 9 1 (2 H, s), 7. 0 1 -7. 1 0 (2 H, m), 7. 3 1 -7. 36 (2 H, m), 7. 50 (1 H, s), 7. 55 (1 H , d, J = 8 H z), 7. 62 -.. 7. 6 7 (1 H, m), 8. 05 -8 10 (1 H, m), 8. 1 5 (1 H, s) .

Starting Material Synthesis Example 4

N-[1 - (3, 4-dichlorobenzyl) piperidine one 4-I le] one [4- (3-pyridyl) thiazole Ichiru - 2 Iruchio Synthesis of Asetoamido

Mercapto one 4 scratch (3-pyridyl) thiazole Ichiru 1. 68 g was dissolved in Jimechiruhoru Muami de 5 OML, potassium carbonate was added 3. 3 g. Subsequently, the product of Starting Material Synthesis Example 1 3. 3 g, and the mixture was stirred at room temperature for 3 hours. Acetate Echiru example pressurized to the reaction solution, washed with water and saturated brine, and dried. The solvent was distilled off under reduced pressure, the resulting residue was recrystallized from black port Holm Z isopropyl ether to give the title compound 0. 72 g 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. 9 1 (2 H, s ), 7. 05 -7 2 ​​1 (2 H, m), 7. 3 1 -.. 7. 4 1 (3 H, m), 7. 51 (1H, s), 8. 11-8 17 ( 1H, m), 8. 59 - 8. 63 (1H, m), 9. 09- 9. 11 (1 H, m).

Starting Material Synthesis Example 5

N- [1 - (3, 4- dichloro port benzyl) piperidine one 4-I le] one [4 i (4-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de Synthesis of

From 2-mercapto one 4 one (4 one-pyridyl) thiazole 3. 4 g and the product of Starting Material Synthesis Example 1 3. 3 g, in the same manner as Starting Material Synthesis Example 4, the title compound 3. 0 g as a white powder It 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. 0 3 (2 H, s), 7. 24- 7. 30 (1 H, m), 7. 52 (1H, s), 7. 55 - 7. 60 (1H, m), 7. 89 (2H, d, J = 5. 1Hz), 8 . 23 one 8. 27 (1H, m), 8. 37 (1H, s), 8. 63 (2H, d, J = 5. 1Hz).

Starting Material Synthesis Example 6

N-[1 - (3, 4-dichlorobenzyl) piperidine one 4-I le] - [4- (4-menu butoxycarbonyl phenylalanine) thiazole one Roux 2- Iruchio] Asetoami de Synthesis of

From 2-mercapto-one 4 one (4 main butoxycarbonyl phenylalanine) thiazole Ichiru 14. 5 g and Starting Material Synthesis Example 1 product 20 g, the same ø manner as Starting Material Synthesis Example 4, the title compound 19. 6 g 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. 0 1 ( 2H, d, J = 7. 9 Hz), 8. 10 (2H, d, J = 7. 9Hz), 8. 22 - 8. 29 (2 H, m).

Starting Material Synthesis Example Ί

Nyu- [1 one (3, 4-dichloro port benzyl) piperidine one 4-I le] - [4- (3-main butoxycarbonyl phenylalanine) thiazole one Roux 2- Iruchio] Asetoami de Synthesis of

From 2-mercapto one 4_ (3 main butoxycarbonyl phenylalanine) thiazole Ichiru 5. 0 g and Starting Material Synthesis Example 1 product 6.7, in the same manner as Starting Material Synthesis Example 4, the title compound 5. 5 g 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. 8 9 (3 H , s), 4. 0 1 (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).

Starting Material Synthesis Example 8

[4 - (3-carboxy-phenylalanine) thiazole Ichiru one 2- Iruchio] one N-[1 - (3, 4-dichloro port benzyl) piperidine one 4-I le Synthesis of Asetoami de sodium salt the product 0. 5 g obtained in Starting material synthesis example 7 was dissolved in methanol 10 ml, tetrahydro furan 1 Oml, 1 mo 1 / L hydroxide Natoriumu solution 3 ml, and the mixture was stirred for 2 hours at 60 ° C. Water was added to the reaction solution, and extracted with black port Holm. The solvent was washed with brine, dried, and evaporated under reduced pressure to give the title compound 0. 5 g as a colorless amorphous solid.

One 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. 2 3 -.. 7. 30 (1H, m) , 7. 50-7. 61 (3H, m), 7. 89-7. 9

3 (1 H, m), 8 14-8. 26 (3H, m), 8. 46 (1H, s) Starting Material Synthesis Example 9

N-[1-(3, 4-dichlorobenzyl) piperidine one 4 one I le] - [5- (4 one-pyridyl) one 1, 3, 4-thiadiazole one Roux 2- Iruchio Synthesis of Asetoamido

[5- (4-pyridyl) - 1, 3, 4-thiadiazole _ 2 T thio] acetic acid 390mg of 4-amino-1 one (3, 4-dichlorobenzyl) from piperidine-2 salt salt 51 lmg, raw in the same manner as in synthesis example 3, to give the title compound 689M g 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), 3 43 (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).

Starting Material Synthesis Example 10

N- [2 - {[N- (1 - (3, 4 Jikuro port benzyl) piperidine one 4-I le) force Rubamoiru] methylthio} benzothiazole one Roux 6 _ I le] force Rubamin acid tert one-heptyl ester synthesis

(6-Amino base Nzochiazoru 2 Iruchio) one N-- [1 (3, 4 Jiku Rorobenjiru) piperidine one 4 one I le] Asetoamido 144mg suspended in DMF30m L, there (Boc) 2 0 1. the 3 g and Toriechiruamin 1. 25 mL, and the mixture was stirred overnight at room temperature. 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, was filtered off the insoluble matter. The resulting solid was dissolved in black port Holm by silica gel column outlet Matogurafi one was purified mixture of black port Holm and ethanol as eluent. The solvent was evaporated from the eluent to yield 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 (1 H, m), 8. 16 (1 H, s) .

Starting Material Synthesis Example 11

[4 - (3-force Le Bamo Irufu enyl) thiazole one Roux 2 Iruchio] - N- [1 one (3, 4-dichlorobenzyl) piperidine one 4_ I le] Synthesis Starting Material Synthesis Example 3 of Asetoamido the resulting product 2. 0 g of main evening Nord 10 ml, black hole Holm 1

It was dissolved in 0 ml, under ice-cooling, after 3 hours bubbled HCl gas, water was added to the reaction mixture, followed by extraction with chloroform. The solvent was washed with saturated saline, with 1M sodium hydroxide solution, dried, the residue obtained by evaporating the solvent under reduced pressure, HPLC (Deve l os il C30-UG-5, 0. 05% TFA water: Asetonitoriru 2: 8-0: purified 10) to give the title compound 42 Omg as a white solid.

1 H-NMR (DMSO-d 6) δ:. 1. 32 - 1. 50 (2Η, m), 1. 65 one 1. 78 (2H, m), 1. 94-2 11 (2H, m) , 2. 60-2 74 (2H, m), 3. 42 (2H, s), 3. 48 -. 3. 60 (1 H, m), 4. 0 3 (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).

Starting Material Synthesis Example 12

[4 i (4 one carboxymethyl phenylalanine) thiazole Ichiru one 2-Iruchio] - N_ [1 -

(3, 4-dichlorobenzyl) from the product obtained 55 lmg in Synthesis Starting Material Synthesis Example 6 of piperidine one 4-I le] Asetoami de, by the same method as in Starting Material Synthesis Example 8 connexion, the title compound 561 It was obtained mg 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 (2 H, m), 3. 43 (2H, s), 3. 48 -. 3. 60 (1 H, m), 4. 0 3 (2H, s), 7 . 24- 7. 30 (1 H, m), 7. 52 -. 7. 60 (3 H, m), 7. 87-7 91 (4H, m), 8. 06 (1H, s), 8 . 28 (1 H d, J = 7. 7Hz), 13. 0 (1 H, brs).

Starting Material Synthesis Example 13

[4 - (4 Ichiriki Le Bamo Irufu enyl) thiazole one Roux 2- Iruchio] one N- [1 - (3, 4- dichloro port benzyl) piperidine one 4 one I le] Synthesis Starting Material Synthesis Example of Asetoami de tetrahydrofuran 5mL product 536 mg was obtained in 12 is dissolved in di-methyl formamide 5 mL, Toryechiruamin 153〃L, a black hole isobutyl 144〃L added and stirred at room temperature for 1 hour. The reaction solution 7Mo l / L § Nmoniame evening Nord solution was added. Followed by stirring at room temperature for 19 hours. lmo l in the reaction solution

/ L aqueous sodium hydroxide was added and extracted with black port Holm. The extract was washed with saturated saline, dried, the solvent was distilled off under reduced pressure. The resulting residue silica gel column chromatography (black port Holm: acetone = 1: 1-0: 1) to give the title compound 29 Omg 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 (1 H, m), 4. 0 3 (2H, s), 7. 23 -7. 31 (1H, m), 7. 37- 7. 42 (1H, brs), 7. 51-7. 59 (2 H, m), 7. 92-8. 10 (5H, m), 8. 16 (1 H, s), 8. 24 (1H, d, J = 7. 5 Hz).

Starting Material Synthesis Example 14

N-[1-(3, 4-dichlorobenzyl) piperidine one 4-I le] - {4- [3 - ((imidazo one Lu 4 one Irumechiru) Amino) phenyl] thiazole one Roux 2 - Iruchio} Asetoamidoni the synthesis of the hydrochloride salt

[4 i (3 Aminofuweniru) Chiazoru 2 Iruchio] one N- [1 - (3, 4 Jikuro port) piperidin one 4-I le] Asetoamido 507mg and 4 one Imidazo one Le-carbaldehyde 96 mg of 5 mL of dichloromethane It was suspended in the acetic acid 5 7 jh trisodium § Seto carboxymethyl borohydride 424mg was added, and stirred between 3:00 at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with black port Holm. The extract was washed with saturated Japanese brine, dried and evaporated. The obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 20: 1). Resulting et the residue dissolved in E evening Nord 0. 5 mL, can be isolated by crystallization caused by adding 4 mo 1 / L hydrochloric acid monoacetate Echiru solution 0. 5 mL, to give the title compound 239mg as a white powder .

- NMR (DMSO - d 6) δ:. 1. 76-2 18 (4H, m), 2. 9 1- 3. 20 (2H, m), 3. 22 - 3. 38 (2H, m), 3. 69- 3. 8 8 (1H, m), 4. 02 (2H, s), 4. 27 (2H, s), 4. 46 (2 H, s), 6. 72 - 6. 77 ( . 1H, m), 7. 15-7 42 (3H, m), 7. 56 -. 7. 77 (3 H, m), 7. 91-8 03 (2H, m), 8. 68 (1 H, d, J = 7. 2 Hz), 9. 07 (1H, s), 11. 31- 11. 58 (1 H, brs), 14. 38 - 14. 62 (1H, brs), 14. 70- 15. 04 (1 H 5 brs ).

Starting Material Synthesis Example 15

N- [1 - (3, 4- dichloro port benzyl) piperidine one 4-I le: 1 one {4 one

[3- ((imidazo Ichiru one 2- Irumechiru) Amino) phenyl] thiazole synthesis of single Lu 2 Iruchio} Asetoami Denis hydrochloride

[4 i (3 Aminofueniru) Chiazoru 2 Iruchio] - N_ [1- (3, 4- dichlorobenzyl) piperidine one 4 one I le] Asetoami de 507mg and raw material from 2-Imidazo one Le carbaldehyde 96 mg Table title compound 107 mg 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. 8 8 - 3. 20 (2H, m), 3. 21-3 38 (2H, m ), 3. 68-3 8 7 (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. 4 5 (2 H, brs) Starting material synthesis example 16

N- [1 - (3, 4 Jikuro port benzyl) piperidine one 4 one I le] one {4 one [3- (imidazo one Lou 4- Irukarubokisami de) phenyl] thiazole Ichiru one 2- Iruchio} of Asetoamido synthesis

[4- (3-Aminofueniru) thiazole _ 2 Iruchio] _N- [1 - (3, 4- dichlorobenzyl) piperidine one 4 one I le] Asetoami de 500mg and Imi Dazo one route 4 Ichiriki carboxylic acid 135 the residue obtained by the same method as in Starting material synthesis example 3 mg, HPLC (Devel os il C30-UG- 5, 0. 05% TFA water: Asetonitoriru 2: 8:00 to 0:10) to give the title purified by to obtain a I spoon compound 18 Omg 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 (1 H, m), 3. 9 2 (2 H, 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 (1 H, brs).

Starting Material Synthesis Example 17

(4- {3- [N- (tert- butoxycarbonyl) _L Araniruami Bruno] Hue sulfonyl} thiazole Ichiru one 2-Iruchio) - N- [1- (3, 4- Jikurorobe Njiru) piperidine one the synthesis of 4-I-le] Asetoamido

[4 i (3 Aminofuweniru) thiazole one Roux 2- Iruchio] _N- [1 one (3, 4 Jikuro port benzyl) piperidine one 4 one I le] Asetoamido 3. 0 g and N- (t ert- butoxycarbonyl ) by -L Aranin 2. same manner from 3 g as a starting material in synthesis example 3, to give the title compound 4. 0 g 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 (2 H, 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 (1 H, 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

[4 - (3-Shianofuweniru) thiazole one Roux 2 Iruchio]-N-[1 - (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] Asetoamido of synthesis

After the product was dissolved lg ingredients Synthesis Example 3 in dichloromethane 15 mL, it was added m- black port perbenzoic acid 0. 43 g. After stirring for 3 hours at room temperature, the reaction mixture was extracted with click adding water chloroform, followed by saturated brine, washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated under reduced pressure. The residue obtained by sintering crystallized from in black port Holm, to give the title compound 0. 34 g as a white ^ powder.

- NMR (DMSO - d 6) δ:. 1. 55 - 1. 63 (2Η, m), 2. 05 one 2. 12 (2 H, m) , 2. 73 -2 80 (2H, m), . 3. 24-3 31 (2 H, m) 5 3. 60 - 3. 75 (1 H, m), 4. 03 (2 H, s), 4. 2 6 (2H, s), 7. 50 - 7. 55 (1H, m), 7. 59 - 7. 69 (2H, m), 7. 78 - 7. 83 (1 H, m), 7. 87 (1H, s), 8. 24 (1 H, s), 8. 25 -.. 8. 30 (1 H, m), 8. 38 (1H, s), 8. 47-8 52 (1H, m) example 2

[4- (4-Shianofuweniru) thiazole one Roux 2- Iruchio] _N- [1 - (3, 4 Jikuro port benzyl) one 1-O Kiso piperidine _ 4 I le] Asetoami de of synthesis

4 - (4 one Shianofueniru) and one 2-Merukaputochiazo Ichiru 0. 3 g, from the product 0. 6 g of the material if Narurei 2, in the same manner as Starting Material Synthesis Example 4, the title compound 0. 47 g It was obtained as a white powder.

- NMR (DMSO - d 6) δ:. 1. 57 - 1. 63 (2 Η, m), 2. 06 one 2. 13 (2H, m), 2. 73-2 81 (2 H, m) , 3. 24-3. 30 (2H, m), 3. 61-3. 76 (1 H, m), 4. 02 (2H, s), 4. 2 6 (2 H, 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 (1 H, s), 8. 48- 8. 53 (1 H, m).

Example 3

N-[1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] - (4-phenylene Ruchiazo Ichiru - 2 Iruchio) Asetoami de Synthesis of

From 2 _ mercapto one 4-phenylene Ruchiazo Ichiru 0. 25 g of the raw material Synthetic Example 2 product 0. 46 g, in the same manner as Starting Material Synthesis Example 4, yellow title I 匕合 was 0. lg It was obtained as a powder.

^ -NMR (DMSO ~ d 6) δ: 1. 55- 1. 63 (2 Η, 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. 2 8 (2 H, s), 7. 32 - 7. 44 (3H, m), 7. 50- 7. 57 (1 H, m), 7. 62 - 7. 66 (1 H, m), 7. 83 - 7. 97 (3 H, m ) 3 8. 02 (1H, s ), 8. 42 - 8. 49 (1 H, m).

Example 4

N-[1-(3, 4-dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] one [4- (3-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de Synthesis Starting Material Synthesis Example 4 from product 0. 46 g of the same manner as in example 1 to give the title compound 0. 1 g as a white powder.

^ -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 (1 H, m), 4. 3 1 (2 H, 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

N-[1-(3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one [4- (4 one-pyridyl) thiazole Ichiru - 2 Iruchio Synthesis of Asetoami de Starting Material Synthesis Example 5 from product 0. 3 g of the same manner as in example 1 to obtain a Hyodaii匕 compound 0. 26 g as a white powder.

^ -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 (1 H, m), 3. 95 (2 H, s), 4. 24 (2H, . s), 7. 31-7 40 (2 H, 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

N-[1-(3, 4-dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] - [4 i (4-methoxycarbonylphenyl) thiazole one Roux 2- Iruchio Synthesis of Asetoamido

From the product obtained 2 in Starting Material Synthesis Example 6, 'depending on the same method as in Example 1 to give the table title compound 1. 6 g as a white powder.

- NMR (DMSO - d 6) δ: 1. 5 5 - 1. 62 (2H, m), 2. 04 one 2. 2 1 (2H, m) , 2. 7 1 - 2. 8 1 (2 H , m), 3. 20- 3. 2 5 (2H, m), 3. 57 -3. 74 (1 H, m), 3. 86 (3 H, s), 4. 0 2 (2 H, s), 4. 2 5 (2 H, s), 7. 50 - 7. 5 5 (1 H, m), 7. 60- 7. 67 (1 H, m), 7. 87 (1 H, s), 8. 00 (2 H, d, J = 8. 6 H z), 8. 08 (2 H, d, J = 8. 6Hz), 8. 22 (1 H, s), 8. 4 1 - 8. 46 (1 H, m).

Example 7

N-[1-(3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] - [4- (3-methoxycarbonylphenyl) thiazole one Roux 2- Iruchio] Asetoami de Synthesis of

From the product obtained 2 g in Starting Material Synthesis Example 7, by the same method as in Example 1 to give the table title compound 0. 5 g as a white powder.

X H-NMR (DMSO - d 6) δ:. 1. 5 9 - 1. 6 9 (2 H, m), 2. 02 one 2. 19 (2H, m), 2. 80 -2 9 1 ( 2 H, m), 3. 2 2-3. 3 1

(2H, m), 3. 62 -3. 75 (1 H, m), 3. 88 (3 H, s), 4. 0 1 (2 H, s), 4. 3 1 (2 H, s ), 7. 50 - 7. 6 9 (3 H, m), 7. 86 (1H, s), 7. 89 -. 7. 93 (lH, m), 8. 17-8 22 (2 H m ), 8. 46 (1 H, s), 8. 48 -8. 52 (1 H, m).

Example 8 '

[4 - (3-carboxy-phenylalanine) thiazole one Roux 2 Iruchio] -N- [1 - (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] Asetoami de Synthesis of

From the product 0. 12 g obtained in Starting Material Synthesis Example 8, Te cowpea the same manner as in Example 1 to give the title compound 4 Omg as a white powder.

- 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 (2 H, s), 7. 51-7. 6 0 (2H, m), 7. 78 (1H , s), 7. 80 -7. 87 (1H, m), 7. 91-7. 97 (1H, m), 8. 15- 8. 19 (2 H, m), 8. 45-8. 55 (2 H, m).

[4 i (4-carboxy-phenylalanine) thiazole one Roux 2 Iruchio] - N- [1 - (3, 4- dichloro port benzyl) one 1 over O Kiso piperidine one 4 one I le Synthesis of Asetoami de

0.5 from 5 g of the product obtained in Example 6, in the same manner as Starting Material Synthesis Example 8 was obtained. The title compound 0.1 47 g as a white powder.

^ -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), 7 76 -. 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

N- [1 - (3, 4- dichloro port benzyl) piperidine one 4 _ I le] one [4 one (1 one Okisopirijin 4-I le) thiazole Ichiru one 2- Iruchio Synthesis of Asetoamido

From the raw material obtained in Synthesis Example 1 product 0. 2 g of 2-mercapto-one 4 one (1 one Okiso pyridine one 4-I le) thiazole Ichiru 0.4, in the same manner as Starting Material Synthesis Example 4 connexion, the title compound 6 Omg as a white powder.

! H-NMR (DMSO-d 6) δ: 1. 32 - 1. 44 (2 Η, 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 (2 H, m), 7. 90 -... 7. 95 (2 H, m), 8. 20-8 31 (4H, m).

Example 11

N-[1 one (3, 4 Jikuro port) piperidin one 4-I le] one [4 - (1-Okisopirijin - 3-I le) thiazole one Roux 2- Iruchio] Asetoami de Synthesis of

From the raw material the product obtained in Synthesis Example 1 0. 27 g of 2-mercapto-4 (1 Oki Sopirijin one 3-I le) thiazole Ichiru 0. 35 g, in the same manner as Starting Material Synthesis Example 4, the title compound 0. 2 g 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 (1 H, m), 4. 0 3 (2 H, s), 7. . 20-7 3 1 (1H, m), 7. 45 -.. 7. 60 (3H, m), 7. 80 -7 9 1 (1 H, m), 8. 16 -8 27 (2H, m), 8. 30 (1 H, s), 8. 79 (1 H, s).

Example 12

N- [1 - (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] - [4- (2-pyridyl) thiazole Ichiru - 2 Iruchio] Asetoami de Synthesis 2-mercapto one 4- and (2-pyridyl) thiazole Ichiru 107 mg, from product 206mg of Starting material synthesis example 2 by a similar method as Starting material synthesis example 4, to give the 1 75 mg title compound as a brown powder.

- 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 (1 H, m), 4. 03 (2H, s), 4. 2 7 (2 H, s), 7. 32 - 7. 37 (1 H, m), 7. 50 - 7. 57 (1H, m), 7. 58- 7. 65 (l H, m), 7. 80 - 7. 92 (2H, m ), 7. 98- 8. 08 (l H, m), 8. 17 (1 H, s), 8. 48- 8. 63 (2 H m).

Example 13

N- [1 - (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] - (4 one Piraji two Ruchiazo Ichiru one 2- Iruchio) Asetoami de Synthesis of

From 2 _ mercapto one 4- Piraji two Ruchiazoru 107 mg and the product of Starting Material Synthesis Example 2 206 mg, in the same manner as Starting Material Synthesis Example 4, to give the title compound 150mg 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. 2 5 (2H, s), 7. 0- 7. 55 (1 H, 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

(5-Amino - 1, 3, 4-thiadiazole Ichiru - 2 Iruchio) one N-[1 - (3, 4-dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] Asetoami de Synthesis of

5-amino-2 _ mercapto one 1, 3, 4 than thiadiazole Ichiru 133 mg and product 412mg of Starting Material Synthesis Example 2 By a similar method as Starting Material Synthesis Example 4, the Hyodaii匕 compound 92 mg as a white powder Obtained.

One NMR (DMSO-d 6) δ : 1. 50 - 1. 65 (2 Η, m), 2. 00 - 2. 18 (2H, m), 2. 72 - 2. 83 (2 H, m) , 3. 22-3. 30 (2 H, m), 3. 55 -3. 70 (1 H, m), 3. 71 (2 H, s), 4. 2 7 (2H, s), 7 . 22 - 7. 34 (2H, m), 7. 50- 7. 57 (1 H, m), 7. 62 - 7. 66 (1 H, m), 7. 95 (1 H, s), 8. 24-8. 34 (1 H, m).

Example 15

N-[1 - (3, 4 Jikuro port benzyl) Single 1 over O Kiso piperidine one 4-I le] i (5-phenyl - 1, 3, 4 Okisajiazo Ichiru - 2 Iruchio) Aseto -amide

Mercapto one 5-phenylene Lou 1, 3, 4 from Okisajiazo Ichiru 18 7 mg and Starting Material Synthesis Example 2 of product 4 12 mg, in the same manner as Starting Material Synthesis Example 4, Table title compound 1 5 l mg It was 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 (2 H, m), 3. 3- 3. 5 (2 H, m), 3. 7 - 3. 8 (l H, m), 4. 07 (2 H, s), 4. 3 5 (2 H, s), 7. 5- 7. 7 (5H, m), 7. 8- 7. 9 (1 H, m), 8. 0- 8. 1 (2 H, m).

Example 1 6

N-[1- (3, 4-dichloro port benzyl) _ 1 O Kiso piperidin one 4-I le] one [5- (4 one-pyridyl) - 1, 3, 4 Okisajiazo one Roux 2- Iruchi O] synthesis of Asetoami de

2-mercapto one 5- (4-pyridyl) _ 1, 3, 4-O hexa di § tetrazole 18

From 8 mg and products 4 12 mg of starting material in Synthesis Example 2, by the same method as in Starting Material Synthesis Example 4 connexion, the title compound 1 08Mg was obtained as a white powder.

! 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), 3 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-dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] - [5- (4-pyridyl) - 1, 3, 4-thiadiazole one Roux 2- Iruchio] Asetoamido of synthesis

From the product 396 mg was obtained in Starting Material Synthesis Example 9, Te cowpea the same manner as in Example 1 to obtain the title I 匕合 was 145mg as white crystals.

! H-NMR (DMSO - d 6 + CD 3 OD) δ:. 1. 7- 1. 8 (2Η, m), 2. 0-2 2 (2 H, m), 2. 9 one 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. 6-7 7 (1 H, m): 7. 8- 7. 9 (3H, m), 8. 7 - 8. 9 (2H, m).

Example 18

(6-Amino base Nzochiazo Ichiru one 2- Iruchio) Single N- Synthesis of [1- (3, 4-dichlorobenzoyl Rorobenjiru) one 1-O Kiso piperidin one 4-I le] Asetoami de Torifuruo port acetate

Starting Material Synthesis Example 10 product 43 N-in the same manner as in Example 1 from lmg [2- {[N- (1 of - (3, 4-dichlorobenzyl) Single 1 one year old Kiso piperidine one 4-I le ) was obtained as a force Rubamoiru] methylthio} benzothiazole one rule 6 I le] force Rubamin acid tert one butyl ester 1 Ί 2 mg of a pale yellow solid.

One 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 (1 H, m), 7. 4-7 7 (3H, m), 7. 87 (1 H, s), 8. 1 5 (1 H, s), 8. 3 - 8. 5 (1 H, m), 9 57 (1 H, s).

The above product 1 Ί 2mg dissolved in Jikurorome Yun 5 mL, was added at room temperature Torifuruo port acetate 5 mL. After stirring for 2 hours at room temperature, the solvent was distilled off, the resulting solid was recrystallized from ethanol to give the 85 mg title compound 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 (2 H, m), 3. 2 - 3. 4 (2 H, m), 3 5 - 3. 7 (1 H, m), 3. 99 (2 H, s), 4. 27 (2 H, s), 5. 3

3 (2H, s), 6. 65 - 6. 75 (1H, m), 6. 98 (1 H, s), 7. 4- 7. 7 (3 H, m), 7. 88 (1 H , s), 8. 4-8. 5 (1H, m).

[4 - (3-force Le Bamo Irufu We sulfonyl) thiazole one Roux 2 Iruchio]-N-[1 - (3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le Synthesis of Aseta bromide

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

tH- NMR (DMSO - d 6) δ:. 1. 55 - 1. 64 (2Η, m), 2. 06 -2 19 (2H, m) 3 2. 73 - 2. 8 1 (2 H, m ), 3. 24-3. 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. 5 5 (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 (1 H, s), 8. 48 - 8. 53 (1 H, m).

Example 20

[4- (4 Ichiriki Le Bamo Irufu enyl) thiazole Ichiru one 2- Iruchio "-N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4-I le] Aseta bromide synthesis

From the product 248mg obtained in Starting Material Synthesis Example 1 3, Ri by the same method as in Example 1 to give the title compound 1 9 Omg as white solid.

LH- NMR (DMS 0-d 6 ) δ:.. 1. 5 0 - 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 (1 H, m), 4. 02 (2 H, s), 4. 2 5 (2 H, s), 7. 34 - 7. 40 (1 H, m), 7. 50 - 7. 54 (1 H, m), 7. 58 - 7. 62 (1 H, m), 7. 8 1 - 8. 09 (6H, m), 8. 16 (1 H, s), 8. 45 (1 H, d, J = 7. 5 H z).

Example 2 1

N-[1-(3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one {4- [3- ((imidazo one Lu 4 one Irumechiru) Amino) Fuweniru] Chi § zone one Lou 2 Iruchio} Asetoami de synthesis of

From the product obtained 0. 93 g in Starting Material Synthesis Example 14, Ri by the same method as in Example 1 to give the title compound 0. 72 g as a pale yellow solid.

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

Example 22

N- [1 - (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one {4 one [3- ((imidazo one Lu 2 Irumechiru) Amino) Fuweniru] Chi § zone one Lou synthesis of 2-Iruchio} Asetoamido

From the product obtained 294mg in Starting Material Synthesis Example 15, Ri by the same method as in Example 1 to obtain 254 mg title compound as a slightly yellow solid.

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

Example 23

N-[1-(3, 4-dichlorobenzyl) Single 1 one year old Kiso piperidine one 4-I le] one {4 one [3- (imidazo Ichiru _ 4-I le carboxamide) phenyl] thiazolium, Ichiru -2-Iruchio} Asetoamido

From the product obtained 30 lmg in Starting Material Synthesis Example 16, Ri by the same method as in Example 1 to obtain 323 mg title compound as a slightly yellow solid.

One NMR (DMSO-d 6) 6 :. 1. 50- 1. 78 (2H, m), 2. 04 one 2. 18 (2H, m), 2. 60 -2 99 (2 H, m), . 3. 24-3 34 (2H, m), 3. 57 - 3. 78 (1 H, m), 4. 00 (2 H, s), 4. 3 2 (2H, s), 7. 30 . -8 01 (9H, m), 8. 25 -. 8. 38 (1H, m), 8. 42 -8 58 (1 H, m), 9. 90 (1 H, brs), 13. 0 (1 H, brs).

Example 24

{4 - [3- (L- Araniruamino) Fuweniru] thiazole one Roux 2 Iruchio} - N- [1 - (3, 4- dichloro port benzyl) one 1-O Kiso piperidin one 4-I le Synthesis of Asetoamido

From the product obtained 339 mg in Starting Material Synthesis Example 17, and more same manner as in Example 18 to give the title compound 174mg as a white powder.

^ - • NMR (DMSO- d 6 ) δ: 1 21 (3 H, d, J = 6. 8Hz), 1..

58- -. 1. 66 (2 H, m), 2 04 one 2. 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 (2 H, 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 (1 H, m), 7, 96 (1H, s), 8. 06-8 08 (1 H, m), 8. 32 (1 H, s), 8. 49 ( 1 H, d, J = 7. 6 H z) • experimental example 1: binding inhibition test of chemokine to human eosinophils

Human eosinophils were separated by CD 16 negative selector Chillon method from healthy human peripheral blood was anticoagulated (e.g., J. Immuno l. Methods, 14 5 Certificates, 105- 110 pp, 1991). Separated eosinophils (2 x 10 5 cells), 50 pmo 1 / L [ 125 I] - eot axin (2000 Ci / mmoL, Cane catcher Muhu Alma shear Bio Ltd. Tech) bond and 0. 1 mL of test compound use buffer (50 mmo l / L HEPES, 1 mmo l / L CaCl 2, 5 mmo 1 / L MgCl 2, 0. 5% © Shi serum albumin (BSA), 0. 1% sodium azide, pH 7. 6 mixed), 1 hour at 25 ° 〇, multiscreen pre - were incubated in preparative (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 1 / L MgCl 2, 0. 5 mo 1 / L NaCl, 0. 1% azide sodium, pH 7. after washing with 6) were measured radioactivity retained on the fill evening one. The compounds of the present invention had the binding inhibitory activity of chemokines in this test. IC 5 for some of the compounds of the present invention. Values (to human eosinophils [125 1] - concentration of eot ax in the test compound binds the required to reduce 50% of) were as follows. table 1

Experimental Example 2: effect on intracellular calcium concentration

The effect on the intracellular Cal Shiumu during CCL 11 stimulation in healthy human peripheral blood eosinophils of the compounds of the invention was studied by the following method.

Suspend the eosinophils isolated from the peripheral blood of healthy persons assay buffer (10 mmo l / L HE PES, and 0.5% © shea serum albumin hank s' ba 1 an ced sal tso lut i on) Nigoshi, 5 〃Mo 1 / L (manufactured by Dojin chemical Laboratory) of F ura- 2 AM presence, and incubated at 37 ° C 45 min.

After completion of the incubation, by washing three times with the assay buffer to remove Fu ra- 2 AM that was not incorporated into the cells.

Finally, cells were prepared in assay buffer such that 1 X 10 6 cells / mL, and stored in the dark to the measurement. The measurement of intracellular calcium was performed using FD SS 6000 manufactured by Hamamatsu Photonics Corporation. That is, after setting the FD SS 6000 put Fur a- 2 AM loading the cells suspension (0. 1 mL) in a 96-well plate for measurement, the fluorescence intensity due to excitation light having a wavelength of 340 11111 and 380 nm measured and calculated intracellular calcium concentration by determining the ratio of the fluorescence intensity to the excitation light of two wavelengths of this. Agonisuto uses a CCL 11 is a selective ligand to CCR3 (0. 3 nmo l / L), Ann evening agonist activity, were treated Agonisuto stimulus 5 minutes before eosinophils in the present invention compound at various concentrations It was determined as 50% inhibition rate of intracellular calcium concentration increases upon (IC 50 value). Table 2

Industrial Applicability

According to the present invention, the onset cells pathologies with chemokine receptors, progress, disease plays an Oite important role in the maintenance, for example, atherosclerosis, chronic 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 the reaction may be treated and / or prevention of human immunodeficiency syndrome.

Therefore, according to the present invention has an affinity to chemokine receptors, it is possible to provide a medicament for the treatment and Z or prevention of immune and inflammatory diseases. This application is No. filed in Japan 2 0 0 2 - 3 1 1 9 6 0 are the basis for, the contents of which are incorporated in full herein.

Also, references, including patents and patent applications cited in this specification are all the contents of which are incorporated herein to the extent that they have been disclosed by cited.

Claims

The scope of the claims
The general formula (1)
[In the formula,
Ring A represents an optionally substituted Ariru, substituted terrorist ring group to be or cycloalkyl which may have a substituent group,
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Te, may form a Okiso group, or R a and R b gar turned cord may form a ring together with them you bonded atoms,
p is an integer from 0 to 2,
m represents an integer of 0 5,
n represents an integer of 0 5,
V is a bond, may be substituted CI- e alkylene, single CO- or a S0 2 - indicates,
W is, - CH rather, - CH 2 -, - N rather, - NH-, an oxygen atom or a sulfur atom,
X is a bond, One NH-, -NR 1 - (. In the formula, R 1, represents an alkyl), One CO-, -CONR. (Wherein, R c represents a hydrogen atom or an alkyl.) One or one NH c CO-, -NR 2 CON 3 - (In the formula, R 2, R 3, which may be identical or different One, it shows it hydrogen atom or an alkyl. Alternatively, the R 2
It becomes R 3 Gar cord may form a ring together with the atoms to which they are attached. ), 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_ have a substituent may have also may CI- 6 alkylene mono- or monosubstituted group C i-6 alkylene - 0-, may have an S- substituent has a or a substituent - C i_ 6 Al Killen one or one which may have a substituent C doctor 6 alkylene one S-, one so- optionally substituted C i-e alkylene even though good C Bok 6 alkylene one S_〇 one one NRc- may have an optionally substituted C Bok 6 Al Killen one or monosubstituted group CI- e alkylene one NRc- (wherein, R c represents a hydrogen atom or alkyl.), one S0 2 - have but it may also have a substituent group C alkylene mono- or monosubstituted group Which may be C i-6 alkylene one S 0 2 -, -C (= N- C0 2 _ alkyl) one, - C (= N- S 0 2 - alkyl) -, - C (= N -S0 2 NH 2) Single, -C (= CH-N0 2 ) one or single C (= N- CN) - indicates,
Y is a bond, One NH-, -NR 4 - (wherein, R 4 represents an alkyl.), - CO-, one CONR d - or a NR d CO- (wherein, 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 Killen one or which may have one substituent (6 alkylene one S-,
-so- may have a substituent (^ -6 alkylene one or one which may have a substituent C Bok 6 alkylene _S 0_, _NR d - which may have a substituent
Ci-e alkylene one or alkylene one may have 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) mono-,
- 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 shows Le), one 0-CO- NR 8 -. or a NR 8 - C_〇 one 0- (wherein, R 8 represents a hydrogen atom or an alkyl), one -. substituted 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 Tei at best, it it a hydrogen atom or an alkyl. Alternatively, may form a ring together with the atoms connecting them become R 8 and R 9 gar together.)
_NR 8 S0 2 - or a S0 2 NR 8 _ (wherein, R 8 represents a hydrogen atom or alkyl Le.) Or single 0- CO- NR 8 - or single NR 8 - CO- 0- (wherein , R 8 represents a represents a hydrogen atom or alkyl.). It shows],
A is a bond, divalent which may have a substituent hydrocarbon ring group and a substituent may possess bivalent of groups selected from the heterocyclic group, 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 shows that group),
B represents a hydrogen atom, which may have a substituent Ariru, substituted heterocyclic group to be or cycloalkyl which may have a substituent group.
Provided that at least one nitrogen atom contained in the formula is that is Okishido of. Compounds, salts acceptable optical isomers thereof, or its pharmaceutically represented by].
2. The compound represented by the general formula (1) is, [In the formula,
Ar represents an optionally Ariru be substituted,
n represents an integer from 1 to 5,
Represents 0 or 1,
X is a bond, -NH-, -NR 1 -, (wherein, R 1 represents an alkyl.)
-CO-, - CONH-, - NHCO-, -NR 2 CONR 3 - ( wherein, R 2,
R 3 may be the same or different, shows the hydrogen atom or an alkyl, respectively. ), An oxygen atom, a sulfur atom, - SO_, - S0 2 - , one NHS 0 2 - or
- S0 2 NH- shows,
Y is a bond, -NH-, -NR 4 -, (wherein, R 4 represents an alkyl.)
- CO-, one CONH-, one NHCO-, -NR 5 CONR 6 - (wherein, R 5,
R 6, which may be the same or different, shows the it it hydrogen atom or an alkyl. ), An oxygen atom, a sulfur atom, - SO-, - S0 2 - , one NHS0 2 - or
Shows an 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 are shown.), an oxygen atom, a sulfur atom,
- SO- or a S0 2 - indicates, q is an integer of 1 to 4. It shows],
A represents bond, good § Li one alkylene which may have a substituent, Teroari one to but it may also have a substituent Len, or good cycloalkylene which may have a substituent group, B shows which may have a substituent Ariru, hetero Ariru to which may have a substituent, or a cycloalkyl which may have a substituent.
However,: For r = 0, at least one other nitrogen atom contained in the formula is O key Sid reduction. ]
In a compound of claim 1, wherein acceptable salts optical isomers thereof, or its pharmaceutically.
3. In the general formula (1),
n is an integer from 1 to 4,
A is a bond, compounds of claim 2 wherein Teroari an alkylene to may have a good § Li one Ren may have a substituent or substituents, the optical isomers or their on pharmaceutical acceptable salt thereof.
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, R 3, which may be the same or different, each represent a hydrogen atom or alkyl le.) , _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 to Teroari is one Ren,
Salts B is The compound of claim 2 or 3, wherein the heteroaryl may have also good Ariru or substituents have a substituent, acceptable optical isomers thereof, or its pharmaceutically.
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, R 3, which may be the same or different and is shown it hydrogen atom or alkyl Le. ), and,
Y is a bond, an oxygen atom or a sulfur atom,
There is a bond, A is a bond, a Teroari one Ren also to be have good § Li one Ren may have a substituent or substituents,
B is A compound according to any one of the four claims 2 is Te Roariru to may have a good Ariru or substituent may have a substituent, an optical isomer or is their pharmaceutically acceptable salt thereof.
6. (1) [4- (3-Shianofueniru) thiazole Ichiru one 2- Iruchio] _N_ [1-(3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] § cell Toami de,
(2) [4- (4-Shianofueniru) thiazole Ichiru one 2- Iruchio] _N- [1- (3, 4- dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] § cell Toami de,
(3) N- [1- (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] - (4-phenylene Ruchiazo one Lu 2 Iruchio) Asetoami de,
(4) N-[1 - (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4- (3-pyridyl) thiazole one Roux 2-^ T thio] Asetoami de,
(5) N-[1- (3, 4 Jikuro port benzyl) one 1-O Kiso piperidin one 4-I le] - [4- (4 one-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,
(6) N- [1 - (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] - [4 - (4-menu butoxycarbonyl phenylalanine) thiazole Ichiru - 2-I le Chio ] Asetoami de,
(7) N- [1- (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4 i (3 main butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio ' Asetoami de,
(8) [4 i (3 _ carboxymethyl phenylalanine) thiazole Ichiru - 2 Iruchio] one N one [1- (3, 4-dichloro port benzyl) one 1 over O Kiso piperidine one 4 one I le] § Setoami de,
(9) [4- (4 one carboxymethyl phenylalanine) thiazole one Roux 2- Iruchio] one N one [1 one (3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] § acetamide,
(10) N-[1 - (3, 4-dichlorobenzyl) piperidine one 4 one I le] one [4- (1 one Okisopirijin one 4 one I le) thiazole one Roux 2- Iruchio] Aseto Ami de,
(1 1) N-[1 one (3, 4-dichlorobenzyl) piperidine one 4 one I le] one [4- (1 one Okisopirijin one 3-I le) thiazole one Roux 2- Iruchio] Aseto amide,
(12) N-[1 - (3, 4-dichlorobenzyl) Single 1 one year old Kiso-4-I le] - [4- (2-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,
(13) N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] i (4 one Piraji two Ruchiazo one Lu 2 Iruchio) Asetoami de,
(14) (5-Amino one 1, 3, 4-thiadiazole 'Ichiru one 2- Iruchio) Single N one [1 - (3, 4 Jikuro port benzyl) _ 1 O Kiso piperidin one 4-I le] § Setoami de,
(15) N-[1- (3, 4-dichloro port benzyl) one 1-O Kiso-4-I le] - (5-phenyl - 1, 3, 4 Okisajiazo one Roux 2 Iruchi O) Asetoami de,
(16) N-[1-(3, 4-dichlorobenzyl) Single 1 over O Kiso piperidine one 4-I le] one [5- (4-pyridyl) one 1, 3, 4 _ Okisajiazo one Lou 2- Iruchio ] Asetoami de,
(17) N-[1 - (3, 4 Jikuro port benzyl) Single 1 one year old Kiso-4-I le] - [5- (4-pyridyl) one 1, 3, 4-thiadiazole one Lou 2- ^ Γ Lucio] Asetoami de, and
(18) (6-Amino base Nzochiazo one Lu 2 Iruchio) -N- claim 1 [1- (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4_ I le] Asetoami de, selected from compound or a pharmacologically acceptable salt thereof according to any one of 5 the.
7. (1) [4 - (3-Shianofuweniru) thiazole one Roux 2- Iruchio] one N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine one 4 one I le] § cell Toami de ,,
(4) N-[1 one (3, 4-dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] one [4- (3-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,
(5) N-[1 - (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le] - [4 i (4-pyridyl) thiazole one Roux 2- Iruchio] Asetoami de,
(7) N- [1 - (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] - [4 i (3 main butoxycarbonyl phenylalanine) thiazole one rule 2 I le Chio ' Asetoami de,
(9) [4 - (4 one carboxy off We sulfonyl) thiazole one Roux 2- Iruchio] -N one [1 - (3, 4-dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] § Setoami de , and
(10) N-[1 - (3, 4-dichlorobenzyl) piperidine one 4-I le] - [4- (1 one Okisopirijin one 4-I le) thiazole Ichiru one 2- Iruchio] Aseto Ami de,
Compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein is selected from.
8.
(1 9) [4 i (3-force Le Bamo Irufu We sulfonyl) thiazole one Roux 2- Iruchi O] - N- [1- (3, 4- dichlorobenzyl) one 1-O Kiso piperidin one 4 one I le ] Asetoami de,
(20) [4 - (4-Scarpa moil phenylpropyl) thiazole one Roux 2 Iruchio]-N-[1 - (3, 4 - dichlorobenzyl) one 1-O Kiso piperidin one 4-I le] Asetoami de,
(2 1) N- [1- (3, 4- dichlorobenzyl) Single 1 one year old Kiso piperidine one 4 one I le] one {4 one [3 - ((imidazol-_ 4 one Irumechiru) Amino) Hue sulfonyl] thiazole one Lou 2- Iruchio} Asetoami de,
(22) N- [1 - (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine
-4 one I le] - {4 one [3- ((Imida V- Lu 2 Irumechiru) Amino) off We sulfonyl] thiazole Ichiru one 2- Iruchio} Asetoami de,
(23) N- [1- (3, 4- dichlorobenzyl) Single 1 over O Kiso piperidine -4 one ^ T le] one {4 one [3- (imidazo one Lu 4-I Luca Lupo alkylcarboxamide) phenylene Le] thiazole one Roux 2- Iruchio} Asetoamido, and
5 (24) {4- [3- (L Araniruamino) phenyl] thiazole - Lu 2 Iruchio} -N- [1- (3, 4- dichloro port benzyl) one 1 over O Kiso piperidine one 4-I le] Asetoamido,
Compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from.
10 9. claimed compound according to any one of claim 1 to 8, a salt acceptable optical isomers thereof, or its pharmaceutically pharmaceutical composition comprising a pharmaceutically acceptable carrier.
10. chronic rheumatoid arthritis, asthma, allergic one rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative colitis or human immunodeficiency syndrome
9. The pharmaceutical composition according which is an agent for preventing or treating group 15.
1 1. A compound according to any one of claims 1 to 8, comprising a acceptable salts optical isomers thereof or a pharmaceutical, chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, ulcerative large
20 enteritis or agent for the prophylaxis or treatment of human immunodeficiency syndrome.
12. A compound according to any one of claims 1 to 8, which comprises administering a salt acceptable optical isomers thereof, or on the pharmaceuticals, chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic
Z5 flame, prevention and treatment methods for ulcerative colitis or human immunodeficiency syndrome.
13. chronic rheumatoid arthritis, asthma, allergic rhinitis, allergic conjunctivitis, allergic myelitis, atopic dermatitis, claims for the manufacture of an agent for the prophylaxis or treatment of ulcerative colitis or human immunodeficiency syndrome 1 8 a compound according to any one of the use of its optical isomers or a pharmaceutically acceptable salt thereof.
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US8999991B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8999990B2 (en) 2011-10-25 2015-04-07 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9139585B2 (en) 2011-10-31 2015-09-22 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9108947B2 (en) 2011-10-31 2015-08-18 Merck Sharp & Dohme Corp. Inhibitors of the Renal Outer Medullary Potassium channel
US9493474B2 (en) 2011-10-31 2016-11-15 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9206199B2 (en) 2011-12-16 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US8952166B2 (en) 2012-07-26 2015-02-10 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9206198B2 (en) 2012-07-26 2015-12-08 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9777002B2 (en) 2012-11-29 2017-10-03 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9573961B2 (en) 2012-12-19 2017-02-21 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9604998B2 (en) 2013-02-18 2017-03-28 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9765074B2 (en) 2013-03-15 2017-09-19 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US9751881B2 (en) 2013-07-31 2017-09-05 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel

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