JP2003192591A - Medicine composed of 5-membered ring compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine effective for inhibiting the infiltration of leukocyte such as acidophilic leukocyte and lymphocyte and useful for the treatment of various inflammatory diseases. <P>SOLUTION: The medicine contains a 5-membered ring compound or its salt expressed by formula [X is O or S; R<SP>1</SP>is H, a substituted or unsubstituted alkyl or the like; R<SP>2</SP>is H, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or the like; Y<SP>1</SP>is single bond, a substituted or unsubstituted alkylene, CO(CH<SB>2</SB>)<SB>n</SB>or the like; the wavy line is (E) or (Z) configuration; R<SP>3</SP>is a substituted or unsubstituted aryl or the like; Y<SP>2</SP>is a substituted or unsubstituted alkylene or the like; R<SP>4</SP>is H, a substituted or unsubstituted alkanoyl, a substituted or unsubstituted alkyl or the like; R<SP>5</SP>is H or the like). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 5-membered ring compound or a salt thereof for pharmaceutical use. More specifically, the present invention provides L-threo-3- (3,4-dihydroxyphenyl)
-N- [3- (4-Fluorophenyl) propyl] serine Pyrrolidineamide binds to a specific binding site in vivo and inhibits infiltration of leukocytes such as eosinophils and lymphocytes, thereby treating various inflammations. The present invention relates to a pharmaceutical composition comprising a novel 5-membered ring compound or a salt thereof which is effective for

[0002]

2. Description of the Related Art As an experimental model of dyspnea in bronchial asthma, a patient with atopic asthma is inhaled with an allergen and an immediate asthmatic response (IA) is performed.
R) is caused. That is, when an allergen is inhaled by an atopic asthma patient, an asthma reaction (bronchospasm) occurs after about 20 minutes, and the original state is restored after about 2 hours. After that, when we continued to observe the patients who had the immediate asthmatic reaction, it was found that bronchospasm was caused again in 6 to 10 hours in about half of the cases, and it was considered that a late asthmatic response (LAR) was observed. Named (Booji-Noord, H. et al., J. Allergy Clin. Immuno
l., 48, 344-354, 1971). In late-onset asthma, the bronchospasm reaction is long-lasting and accompanied by lung hyperinflation, which is strongly suppressed by steroids. From this, it is recognized that the above-mentioned allergen-induced bronchial asthma is important as a clinical model for dyspnea of steroid-dependent and severe bronchial asthma. It has been recognized that the immediate reaction is type I allergy resulting from activation of mast cells by IgE antibody, and the delayed reaction is T lymphocyte and eosinophilic allergy (eosinophil inflammation). It was It has been revealed that these immediate and delayed reactions also occur in allergic rhinitis and dermatitis (Okuhira, Hirokazu, medi
cina, 34, 200-203 (1997)). In addition, it has been reported that when a delayed asthmatic reaction is induced by an allergen in a patient with bronchial asthma, eosinophil accumulation occurs in the lung (De Monchy, J.
G., et al., Am. Rev. Respir. Dis., 131, 373-376 (1
985)). Evidence for eosinophilia in the blood and sputum of many patients with bronchial asthma, a significant number of eosinophil infiltrates in the lung tissue of patients with asthma, bronchial walls and mucus slings of patients. Since the deposition of major basic protein (MBP), a tissue-damaging protein derived from eosinophils, is observed in the lungs, eosinophil-derived products are important for the injury of the respiratory epithelium associated with late-onset asthma attack. It is said to have a role (Filley, WV, et al., Lancet. 2 (828
8), 11-6 (1982)).

[0003] At present, the concept of the development of bronchial asthma has come to be regarded as a chronic inflammatory disease from mere reversible bronchospasm, and the treatment method has changed accordingly. 1995 United States National Heart Lung Blood Institute (NIH /
(NHLBI) and WHO are the Global Initiative for Asthm
a: GINA), which has become an international therapeutic guideline for treating patients with bronchial asthma. As described above, until relatively recently, bronchial asthma is a type I allergic disease in which IgE antibodies are involved, and the development of therapeutic agents has been advanced with a focus on the pathogenic mechanism centered on the role of mast cells. However, as seen in the NIH / NHLBI view, bronchial asthma is currently positioned as an inflammatory disease of the respiratory tract, and bronchial asthma is referred to as "chronic epithelial exfoliating eosinophil-infiltrating bronchitis". / It is considered to be inflammation of the respiratory tract formed by inflammatory cells centering on T lymphocytes (Mizawa Misawa, Jpn Pharmacol., 111, 193-194 (1998). In the above GINA,
The Western treatment policies so far have been mainly adopted, and inhaled steroids, which are anti-inflammatory agents, are used as the first-line drug. In Japan, in line with this guideline, we have set guidelines that consider inhaled steroids as the basis of asthma treatment (supervised by Sohei Makino, Japanese Society of Allergology, Guidelines for Treatment of Allergic Diseases, p3-65, Life Science Medica (1995). ). Although steroids are positioned as the only specific medicine for severe bronchial asthma and atopic dermatitis, they have strong effects and side effects (hypertension, diabetes, obesity, immunosuppression, cataracts, mental disorders, skin atrophy, etc.). Also has. Inhaled steroids have been developed with the aim of reducing these systemic side effects.
It is difficult to prove that steroids administered by inhalation do not circulate throughout the body, and concerns about side effects specific to steroids have not been dispelled. Recently, side effects of inhaled steroids have been reported in Europe and the United States, and the US FDA has issued a warning document regarding the risk of side effects of inhaled steroids for the treatment of bronchial asthma and nasal steroids for the treatment of allergic rhinitis. He is instructing him to hang in (Konig, P., Allergol. Int., 49, 1-6 (2000)).

[0004] As described above, the infiltration of eosinophils into the lesion site plays a major role not only in bronchial asthma but also in the development and deterioration of delayed reaction of allergic dermatitis and rhinitis. But,
Steroids are the only specific medicine for treating allergic diseases such as bronchial asthma by suppressing the infiltration and activation of eosinophils, and orally administrable anti-inflammatory agents with few side effects that can replace steroids are available in the medical field. I want it. For example, in an attempt to develop a drug that suppresses eosinophilic inflammation, an antibody that neutralizes interleukin 5 that causes proliferation / differentiation of eosinophil progenitor cells and prolongation of survival of mature eosinophils (in anti-IL-5 Japanese antibody) (Garlisi, CG, Pulm.Pha
rmacol.Ther., 12, 81-85 (1999)), a small molecule inhibitor of the adhesion factor Very Late Antigen 4 (VLA-4) specific for eosinophils (Haworth, D., et al., Br. J. Pharmacol., 126, 17
51-1760 (1999)), a small molecule antagonist to CCR3, a receptor for eotaxin, which is a chemokine specific for eosinophils that causes eosinophil migration (Wells, T. et al.
NC, et al., Inflammation Res., 48, 353-62, (199
9)) has been studied, but it has not replaced steroids.

[0005] On the other hand, L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serinepyrrolidineamide may have an effect of suppressing eosinophil migration. Known (Sugasawa, T. and Mo
rooka, S., Recent Advancesin Cellular and Molecula
r Biology, 3, 223-227, Peeters Press, Leuven, Belg
ium (1992), Sugasawa, T. et al., J. Biol. Chem., 2
72, 21244-21252 (1997), WO 98/26065). The L-threo-3- (3,4-dihydroxyphenyl) -N- [3-
The specific binding site of (4-fluorophenyl) propyl] serine pyrrolidine amide in vivo is a receptor-like membrane protein, also called SMBS protein (SMBP) (Sugasawa, T. et al., J. Biol. Che
m., 267, 21244-21252 (1997), WO 98/26065). Therefore, if eosinophil migration is suppressed by binding to this SMBS protein, it is possible to treat allergic diseases such as asthma.

[0006]

An object of the present invention is to provide a pharmaceutical composition comprising a compound which suppresses infiltration of leukocytes such as eosinophils and lymphocytes and is effective as a therapeutic agent for various inflammations.

[0007]

[Means for Solving the Problems] The inventors of the present invention have found that SMBS is also expressed in rat lung membranes while conducting extensive studies in order to solve the above problems. -Threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine pyrrolidine amide binding property with [ ¹²⁵ I] iodocyanopindolol (Sugasawa, T. et al. ., J. Biol. C
hem., 272, 21244-21252 (1997), WO 98/26065), and a new test method for suppressing the onset of delayed reaction was constructed, and various compounds were prepared using the method. The present inventors have found that a certain five-membered ring compound binds to SMBS and suppresses infiltration of leukocytes such as eosinophils and lymphocytes by screening S.

[0008] That is, the present invention is: (1) Formula (1)

[Chemical 5] [X represents an oxygen atom or a sulfur atom. R¹Is hydrogen
Atom, substituted or unsubstituted alkyl, substituted or unsubstituted
Substituted aryl, or substituted or unsubstituted monocyclic or
Represents a bicyclic heterocyclic group. R^TwoIs a hydrogen atom,
Or unsubstituted alkyl, substituted or unsubstituted aryl,
Substituted or unsubstituted monocyclic or bicyclic heterocycle
Group, or -CON (R ⁶) R⁷Represents R⁶Is the hydrogen source
Represents a child or substituted or unsubstituted alkyl. R⁷Is
Substituted or unsubstituted aryl, substituted or unsubstituted monocycle
Formula represents a heterocyclic group, or substituted or unsubstituted alkyl
You Or, -N (R⁶) R⁷Represents a cyclic imino group
Good. Y¹Is a single bond, a substituted or unsubstituted alkylate
-CO (CH_Two)_n-, -SO _Two(CH_Two)_n-, -C
ONH (CH_Two)_n-, -CSNH (CH_Two)_n-Or
-COO (CH_Two)_nRepresents-. n represents an integer from 0 to 5
You Wavy lines mean (E) or (Z) coordination. R^ThreeIs
Hydrogen atom, substituted or unsubstituted aryl, substituted or
Unsubstituted monocyclic heterocyclic group, substituted or unsubstituted bicyclic
Telocyclic group, or substituted or unsubstituted cycloalkyl
Represent Y^TwoIs a substituted or unsubstituted alkylene, or
Represents alkenylene. R^FourIs a hydrogen atom, substituted or
Unsubstituted alkanoyl, substituted or unsubstituted alkyl,-
COOR⁸, -SO_TwoR⁹, -COR¹⁰, -CON
(R¹¹) R¹², -CSN (R^Thirteen) R¹⁴, Cycloal
Kill, substituted or unsubstituted aryl, substituted or unsubstituted
A substituted monocyclic heterocyclic group, -C (= NH) N (R¹⁵) R¹⁶To
Represent R⁵Is a hydrogen atom, or a substituted or unsubstituted
Represents Luquil. Or, -N (R^Four) R⁵Is a cyclic imino group
May be represented. R⁸Is a substituted or unsubstituted alkyl
Group, cycloalkyl, substituted or unsubstituted aryl, or
Or represents a substituted or unsubstituted monocyclic heterocyclic group. R⁹
Is substituted or unsubstituted alkyl, substituted or unsubstituted
Aryl, or substituted or unsubstituted monocyclic heterocyclic group
Represents R¹⁰Is cycloalkyl, substituted or non-substituted
Substituted aryl, or substituted or unsubstituted monocyclic heterocycle
Represents a group. R¹¹Represents a hydrogen atom or alkyl.
R¹²Is a hydrogen atom, substituted or unsubstituted alkyl,
Chloroalkyl, substituted or unsubstituted aryl, substituted if
Or unsubstituted arylcarbonyl, or substituted or non-substituted
Represents a substituted monocyclic heterocyclic group. Or, -N (R ¹¹) R
¹²May represent a cyclic imino group. R^ThirteenIs the hydrogen source
Represents a child or alkyl. R¹⁴Is a hydrogen atom,
Or unsubstituted alkyl, cycloalkyl, substituted or
Unsubstituted aryl, substituted or unsubstituted aryl carbonyl
Or a substituted or unsubstituted monocyclic heterocyclic group.
You Or, -N (R^Thirteen) R¹⁴Represents a cyclic imino group
May be. R¹⁵Represents a hydrogen atom or alkyl.
R¹⁶Is a hydrogen atom or substituted or unsubstituted alkyl
Represent Or, -N (R¹⁵) R¹⁶Represents a cyclic imino group
May be used] or a five-membered ring compound represented by
Contains the above acceptable salts or their prodrugs
Medicine.

(2) When Y ¹ is a single bond, —N
The 5-membered ring compound according to claim 1, wherein (R ⁴ ) R ⁵ is not amino, dialkylamino or acetylamino, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. (3) Formula (2)

[Chemical 6] [X represents an oxygen atom or a sulfur atom. R¹Is hydrogen
Atom, substituted or unsubstituted alkyl, substituted or unsubstituted
Substituted aryl, or substituted or unsubstituted bicyclic heterocycle
Represents a group. R^TwoIs a hydrogen atom, substituted or unsubstituted
Kill, substituted or unsubstituted aryl, substituted or unsubstituted
Represents a substituted bicyclic heterocyclic group. Y¹Is a single bond or substitution
Or unsubstituted alkylene, -CO (CH_Two)_n-Or-
SO_Two(CH_Two)_nRepresents- (n represents an integer from 0 to 5)
). The wavy line means (E) or (Z) coordination. R^ThreeIs
Substituted or unsubstituted aryl, substituted or unsubstituted monocyclic
5- or 6-membered heterocyclic group, or substituted or non-substituted
Represents a substituted bicyclic heterocyclic group. Y^TwoReplaces or does not
It represents a substituted alkylene or alkenylene. R^FourIs water
Elementary atom, alkanoyl, aroyl, substituted or unsubstituted
Alkyl, alkylcarbamoyl, alkoxycarbonyl
Alkylaminothiocarbonyl, alkylsulfoni
Or a substituted or unsubstituted arylsulfonyl group
You R ⁵Is a hydrogen atom or a substituted or unsubstituted
And a 5-membered ring compound according to claim 1
Or a pharmaceutically acceptable salt thereof or a prod thereof.
A drug containing rag.

(4) Formula (3)

[Chemical 7] [X represents an oxygen atom or a sulfur atom. R ¹ is a hydrogen atom; alkyl; alkyl substituted with a hydroxyl group, halogen atom or amino; aryl; alkoxy, alkoxy substituted with a halogen atom, hydroxyl group, halogen atom,
Cyano, amino, mono- or di- (alkyl) amino,
5-membered or 6-membered cyclic imino group which may further contain oxygen atom or nitrogen atom as a ring-forming hetero atom, nitro, alkyl, halogen atom or alkyl group substituted with halogen atom or hydroxyl group, substituted with cycloalkyl, cycloalkyl Alkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
Nitrogen substituted with one or more of groups selected from the group consisting of sulfamoyl, alkylsulfamoyl, di (alkyl) sulfamoyl, aryl, and alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group; nitrogen 5 members or 6 containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms
Membered heterocycle and benzene ring fused bicyclic heterocycle group;
Alternatively, a two-membered ring formed by condensing a benzene ring with a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom substituted with a group selected from alkyl, alkoxy, halogen atom and hydroxyl group. Represents a cyclic heterocyclic group. R ² is a hydrogen atom; alkyl; an alkyl substituted with a group selected from a hydroxyl group, a halogen atom or amino; an aryl; an alkoxy, an alkoxy substituted with a halogen atom, a hydroxyl group, a halogen atom, cyano, amino, mono- or di- -(Alkyl) amino, 5-membered or 6-membered cyclic imino which may further contain an oxygen atom or a nitrogen atom as a ring-forming hetero atom, nitro, alkyl, an alkyl substituted with a halogen atom or a hydroxyl group, cycloalkyl, cyclo Alkyl substituted with alkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, di ( Alkyl, sulfamoyl, aryl, and aryl substituted with one or more groups selected from the group consisting of alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group; selected from nitrogen atom, oxygen atom and sulfur atom A bicyclic heterocyclic group condensed with a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms and a benzene ring; or a nitrogen atom or oxygen substituted with a group selected from alkyl, alkoxy, halogen atom or hydroxyl group. It represents a bicyclic heterocyclic group in which a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from atoms and sulfur atoms and a benzene ring are condensed. Y ¹ is a single bond; straight chain or branched chain C ₁
-C ₅ alkylene; linear or branched C ₁ -C ₅ alkylene substituted with a hydroxyl group, a halogen atom or an amino group; -CO (CH ₂ ) _n- ; -SO ₂ (CH ₂ ) _n- n represents an integer of 0 to 5). R ³ is aryl; alkoxy, alkoxy substituted with a halogen atom, hydroxyl group, halogen atom, cyano, amino, mono- or di- (alkyl) amino, nitro, alkyl, alkyl substituted with a halogen atom or hydroxyl group, cyclo Alkyl, alkyl substituted with cycloalkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di
(Alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, di (alkyl) sulfamoyl, aryl, and a group selected from the group consisting of alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group. An aryl substituted with one or two or more kinds; a monocyclic 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
A monocyclic 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom substituted with a group selected from alkyl, alkoxy, a halogen atom and a hydroxyl group; a nitrogen atom; Bicyclic heterocyclic group in which a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from oxygen atom and sulfur atom and a benzene ring are condensed; or a group selected from alkyl, alkoxy, halogen atom and hydroxyl group Represents a bicyclic heterocyclic group in which a 5-membered or 6-membered heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom substituted with and a benzene ring are condensed. Y ² is a linear or branched C
_2- C ₅ alkylene; linear or branched C ₂ -C ₅ alkylene substituted with a group selected from hydroxyl group, alkoxy, halogen atom, amino, and alkanoylamino; or linear or branched C ₃ -C ₅ represents alkenylene. R ⁴ is a hydrogen atom; alkanoyl; aroyl; alkyl; alkyl substituted with a group selected from a hydroxyl group, an alkoxy, a halogen atom and an amino group; alkylcarbamoyl; alkoxycarbonyl; alkylaminothiocarbonyl; alkylsulfonyl; arylsulfonyl; or alkyl Represents an arylsulfonyl substituted with. R ⁵ is a hydrogen atom; alkyl; or a hydroxyl group,
Represents an alkyl substituted with a group selected from a halogen atom and amino], and a pharmaceutical containing the 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

(5) X is a sulfur atom, a 5-membered ring compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a drug containing a prodrug thereof. (6) The five-membered ring compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ¹ is a hydrogen atom.
Alternatively, a drug containing a prodrug thereof. (7) R ² is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted monocyclic or bicyclic heterocyclic group, —CON (R ⁶ ) R ⁷ or a substituted or unsubstituted heterocycle. The group carbonyl.
7. A drug containing the 5-membered ring compound according to any one of to 6 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. (8) A 5-membered ring compound according to any one of claims 1 to 6, wherein R ² is substituted or unsubstituted aryl, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0012] (9) Y¹Is a substituted or unsubstituted alkylate
-CO (CH_Two)_n-, -SO _Two(CH_Two)_n-, -C
ONH (CH_Two)_n-, -CSNH (CH_Two)_n-Or
-COO (CH_Two)_n-Is any one of (1) to (8)
A 5-membered ring compound or a pharmaceutically acceptable salt thereof,
Is a drug containing a prodrug thereof. (10) Y¹Is a single bond, -CO-, -SO_Two-,-
CONH- or -COO-, any one of claims 1 to 8.
The 5-membered ring compound described therein or a pharmaceutically acceptable compound thereof
A drug containing a salt or a prodrug thereof. (11) Y¹Is a single bond or -CO-.
A 5-membered ring compound according to any one of 1 to 8 or a pharmaceutical thereof
Contains the above acceptable salts or their prodrugs
Medicine. (12) R^ThreeIs a substituted or unsubstituted aryl,
Is a substituted or non-substituted single A cyclic heterocyclic group according to any one of claims 1 to 11.
5-membered ring compound or a pharmaceutically acceptable salt thereof, or
A medicament containing the prodrug thereof. (13) The wavy line means a (Z) configuration,
Any of the five-membered ring compounds or pharmaceutically acceptable thereof
A salt or a prodrug thereof. (14) Y^TwoIs ethylene or trimethylene
The five-membered ring compound according to any one of claims 1 to 13 or
A pharmaceutically acceptable salt of
Pharmaceuticals contained.

(15) R ⁴ is a substituted or unsubstituted alkanoyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkylcarbamoyl, a substituted or unsubstituted alkylaminothiocarbonyl, or a substituted or unsubstituted alkoxycarbonyl. A pharmaceutical composition containing the 5-membered ring compound according to any one of 1 to 14 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. (16) R ⁴ is a substituted or unsubstituted alkanoyl,
A 5-membered ring compound according to any one of claims 1 to 14, which is a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkylcarbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. (17) A 5-membered ring compound according to any one of claims 1 to 15, wherein R ⁵ is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

(18) Formula (4):

[Chemical 8] [Ring A represents a benzene ring or a pyridine ring. m is 2
Or 3 is represented. Y^ThreeRepresents a single bond or carbonyl
You R¹⁷Is 1 or 2 and is a halogen atom, C₁
-C_FourAlkoxy, trifluoromethoxy, morpholino
And methylenedioxy are independently selected. R
¹⁸Is 1 or 2 and is a halogen atom, C₁-C_Four
Independent from alkoxy, trifluoromethoxy and hydroxyl
Standing and selected. R¹⁹Is C₁-C_FourAlkyl; water
Acid group, C₁-C_FourAlkoxy, mono or di (C₁−
C_FourAlkyl) amino, morpholino or carboxy
C replaced by ₁-C_FourAlkyl; C₁-C_FourAlkyl
Amino; or hydroxyl group, C₁-C_FourAlkoxy, mono
Shiji (C₁-C_FourAlkyl) amino, morpholino
C substituted with carboxy₁-C_FourAlkylamino
Or a five-membered ring compound according to claim 1
Is its pharmaceutically acceptable salt, or their prodrugs.
A drug containing guar.

(19) When Y ³ is a single bond, R ¹⁹
19. A 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof, according to claim 18, wherein is not methyl. (20) whether ring A is a benzene ring, (i) Y ³ is a single bond, and R ¹⁹ is C ₁ -C ₄ alkylamino,
Or (ii) Y ³ is carbonyl and R ¹⁹ is C _1-.
The 5-membered ring compound according to claim 8, which is C ₄ alkyl, or a pharmaceutically acceptable salt thereof, or a drug containing a prodrug thereof. (21) A medicine comprising a leukocyte infiltration inhibitor. (22) The medicine according to any one of claims 1 to 20, which is a therapeutic agent for inflammation. (23) The medicament according to any one of claims 1 to 20, which is a therapeutic agent for autoimmune disease-related inflammation or allergic inflammation.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Throughout this specification, the terms of each substituent have the following meanings. Examples of the “alkyl” include straight chain or branched chain C ₁ -C ₆ alkyl, and specifically, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, 3-. Methyl-2-propyl, 1,1-dimethylethyl, n-pentyl, n-hexyl and the like can be mentioned. Examples of the substituent in the “substituted alkyl” include a hydroxyl group, a halogen atom, amino, mono- or di (alkyl) amino, carboxy, alkoxycarbonyl, alkoxy, carbamoyl, mono- or di-.
(Alkyl) carbamoyl, cyclic imino group, alkoxyalkoxy, hydroxyalkoxy, carboxyalkoxy, alkanoyloxy, aryloxy, aryl,
Arylcarbonylamino, arylamino, arylalkylamino, alkanoylamino, alkylthio,
Examples include cycloalkyl, arylalkoxy, arylalkyl (alkyl) amino, arylsulfonyl, alkylsulfonyl, carbamoylalkoxy, mono- or di (alkyl) carbamoylalkoxy, arylsulfonylamino, arylcarbamoylamino and the like.
(The alkyl mentioned here may be substituted with alkoxy, alkoxycarbonyl, carboxy, dialkylamino or hydroxyl group.

[0017] The aryl mentioned here may be substituted with alkyl, alkoxy, halogen atom, or hydroxyl group).
One of these or two or more of the same or different is selected. For example, 1 to 3 of the same or different substituents described above
Alkyl, preferably 1 to 2 substituted. As the substituted alkyl for R ⁴ , particularly preferable substituents include hydroxyl group, alkoxy, mono- or di (alkyl) amino, morpholino, carboxy, alkoxyalkoxy, hydroxyalkoxy, carboxyalkoxy and the like. Examples of the “alkyl substituted with a halogen atom or a hydroxyl group” include fluorine, chlorine,
Examples thereof include linear or branched C ₁ -C ₆ alkyl substituted with 1 to 3 halogen atoms or hydroxyl groups such as bromine and iodine, and specifically, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl. , Bromomethyl, fluoroethyl, 2,2,2-trifluoroethyl,
3-fluoro-1-propyl, 3-fluoro-2-propyl, 4-fluoro-1-butyl, 4-fluoro-2-
Butyl, 3-fluoromethyl-2-propyl, 1,1-
Di (fluoromethyl) ethyl, 5-fluoro-1-pentyl, 6-fluoro-1-hexyl, hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxy-1-propyl, 2,3-dihydroxy-1-
Propyl, 4-hydroxy-1-butyl, 5-hydroxy-1-pentyl, 6-hydroxy-1-hexyl and the like can be mentioned. Examples of the “alkoxy” include linear or branched C ₁ -C ₆ alkoxy, and specifically, methoxy, ethoxy, n-propoxy, 2-propoxy, n-butoxy, 1,1-dimethylethoxy. , N-
Examples include pentyloxy and n-hexyloxy.

[0018] As the substituent in the "substituted alkoxy",
For example, the substituent in substituted alkyl is mentioned.
Examples of the “halogen-substituted alkoxy” include linear or branched C ₁ -C ₆ alkoxy substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom, bromine atom, and the like. Is fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,
Bromomethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy and the like can be mentioned.
“Alkylamino” includes, for example, amino substituted with straight or branched chain C ₁ -C ₆ alkyl,
Specifically, methylamino, ethylamino, n-propylamino, 2-propylamino, n-butylamino, 2
-Butylamino, 1-methylpropylamino, 1,1-
Dimethylethylamino, n-pentylamino, n-hexylamino and the like can be mentioned. “Dialkylamino” includes, for example, straight chain or branched chain C ₁ -C ₆ alkyl 2
Examples thereof include amino substituted with an individual, and specific examples thereof include dimethylamino, diethylamino, ethylmethylamino, di-n-propylamino, di-n-butylamino and the like.

[0019] Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine, and preferable examples include fluorine, chlorine and bromine. Examples of the “cycloalkyl” include C ₃ -C ₈ cycloalkyl, and specifically include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the substituent of the “substituted cycloalkyl” include alkyl, alkoxy, hydroxyl group and the like. Examples of the “cycloalkylalkyl” include linear or branched C ₁ -C ₆ alkyl substituted with C ₃ -C ₈ cycloalkyl, and specifically,
Examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and the like. Examples of the “alkoxycarbonyl” include straight chain or branched chain C ₁ -C ₆ alkoxycarbonyl, and specifically, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl, n-butoxycarbonyl. , 2-butoxycarbonyl, 1-methylpropoxycarbonyl, 1,1-dimethylethoxycarbonyl, n-
Examples include pentyloxycarbonyl and n-hexyloxycarbonyl.

[0020] Examples of "alkanoyl" include straight chain or branched chain C ₁ -C ₇ alkanoyl, and specifically, formyl, acetyl, propanoyl, butanoyl,
Pentanoyl, pivaloyl, hexanoyl, heptanoyl and the like can be mentioned. Examples of the substituent in the "substituted alkanoyl" include a substituent in the substituted alkyl, and preferably a hydroxyl group, an alkoxy, a cyclic imino group, carboxy, alkoxyalkoxy, carboxyalkoxy, alkoxycarbonyl, alkanoyloxy, aryloxy, aryl. , Arylcarbonylamino, arylamino, amino, mono- or di (alkyl) amino, arylalkylamino, aroylamino, alkanoylamino, alkylthio, halogen atom and the like. Particularly preferred substituents include hydroxyl group, alkoxy, dialkylamino, morpholino, carboxy and the like. 1 to be arbitrarily selected from these
It can be substituted with 3 substituents, preferably 1-2
Can be substituted with one substituent. “Alkylcarbamoyl” includes, for example, straight chain or branched chain C ₁ -C
₆ alkyl-substituted carbamoyl may be mentioned, and specifically,
Methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, 2-propylcarbamoyl, n-butylcarbamoyl, 2-butylcarbamoyl, 3-methyl-2-propylcarbamoyl, 1,1-dimethylethylcarbamoyl, n-pentylcarbamoyl, n- Hexylcarbamoyl and the like can be mentioned.

[0021] Examples of the "dialkylcarbamoyl" include carbamoyl substituted with two linear or branched C ₁ -C ₆ alkyls, and specific examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and dialkylcarbamoyl. Examples include -n-propylcarbamoyl and di-n-butylcarbamoyl. Examples of the “alkylthio” include straight chain or branched chain C ₁ -C ₆ alkylthio, specifically, methylthio, ethylthio,
n-propylthio, 2-propylthio, n-butylthio, 2-butylthio, 1-methylpropylthio, 1,1
-Dimethylethylthio, n-pentylthio, n-hexylthio and the like can be mentioned. Examples of the “alkylsulfinyl” include straight chain or branched chain C ₁ -C ₆ alkylsulfinyl, specifically, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,
2-propylsulfinyl, n-butylsulfinyl,
2-Butylsulfinyl, 1-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl and the like can be mentioned.

[0022] Examples of the "alkylsulfonyl" include straight chain or branched chain C ₁ -C ₆ alkylsulfonyl, specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 2-propylsulfonyl, n. -Butylsulfonyl, 2-butylsulfonyl, 1
-Methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl and the like can be mentioned. "Alkylsulfamoyl"
Examples thereof include straight chain or branched chain C ₁ -C ₆ alkylsulfamoyl, and specifically, methylsulfamoyl, ethylsulfamoyl, n-propylsulfamoyl, 2-propylsulfamoyl. Moyl, n-butylsulfamoyl, 2-butylsulfamoyl, 1-methylpropylsulfamoyl, 1,1-dimethylethylsulfamoyl, n-pentylsulfamoyl, n-hexylsulfamoyl and the like. To be “Dialkylsulfamoyl” includes, for example, straight chain or branched chain C ₁
-C ₆ sulfamoyl substituted are exemplified by two alkyl, specifically, dimethylsulfamoyl, diethylsulfamoyl, ethyl methylsulfamoyl, di -n
-Propylsulfamoyl, di-n-butylsulfamoyl and the like can be mentioned. Examples of the “alkylaminothiocarbonyl” include linear or branched C ₁ -C ₆ alkyl-substituted aminothiocarbonyl, and specifically, methylaminothiocarbonyl, ethylaminothiocarbonyl, n-propylaminothiocarbonyl. , N-butylaminothiocarbonyl, n-pentylaminothiocarbonyl, n-hexylaminothiocarbonyl and the like.

[0023] Examples of "alkylene" include straight chain or branched chain C ₁ -C ₆ alkylene, and specifically,
Methylene, ethylene, trimethylene, tetramethylene,
Examples include pentamethylene, methylethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, hexamethylene and the like. Preferred examples of "alkylene" for Y ² include straight chain or branched chain C ₂ -C ₆ alkylene, more preferably straight chain or branched chain C ₂ -C ₄ alkylene, and particularly preferred. Examples include ethylene and trimethylene. Examples of the substituent in the “substituted alkylene” include hydroxyl group, alkoxy, halogen atom, amino, alkanoylamino and the like, which can be substituted with 1 to 3 substituents arbitrarily selected from these, preferably 1 It can be substituted with ~ 2 substituents. Specific examples of the substituted alkylene include 2-hydroxytrimethylene and the like.

[0024] As "alkenylene" include straight-chain or branched C ₃ -C ₆ alkenylene and the like, specifically mentioned propenylene, butenylene, 2-butenylene, pentenylene, 2-pentenylene, 3-pentenylene and the like To be Examples of the "aryl" include C ₆ -C ₁₀ aryl, specifically, phenyl, naphthyl, etc., preferably phenyl. Examples of the substituent in the “substituted aryl” include alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic imino group, monocyclic heterocyclic group, halogen atom, carboxy, cyano, amino, mono- or di (alkyl) amino, nitro. , Alkyl substituted with a halogen atom or a hydroxyl group, cycloalkyl, cycloalkylalkyl,
Methylenedioxy, ethylenedioxy, alkoxycarbonyl, carbamoyl, mono- or di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, aryl, alkyl as a substituent, alkoxy, Examples thereof include aryl substituted with a group selected from a halogen atom and a hydroxyl group.
Preferred substituents include alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic imino group, monocyclic heterocyclic group, halogen atom, alkyl substituted with halogen atom or hydroxyl group, methylenedioxy, and the like.
Particularly preferred are alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic imino group, halogen atom, methylenedioxy and the like. R ¹ , R ² and R ³
Preferred examples of the substituent of the substituted aryl in are:
Alkoxy, di (alkyl) amino, halogen-substituted alkoxy, cyclic imino group, halogen atom, alkyl substituted with a halogen atom or a hydroxyl group, methylenedioxy and the like can be mentioned, and particularly preferably C ₁ -C ₄ alkoxy,
Examples include trifluoromethoxy, morpholino, halogen atoms, methylenedioxy and the like. These substituents may be the same or different and, for example, 1 to 3 may be substituted with aryl, and preferably 1 to 2 may be substituted.

[0025] "As a substituent, alkyl, alkoxy, halogen
Ant substituted with a group selected from a hydrogen atom or a hydroxyl group
Examples of the “alkyl” include methyl, ethyl, n-propy
2-propyl, n-butyl, 2-butyl, 1-methyl
Rupropyl, 1,1-dimethylethyl, n-pentyl,
Straight-chain or branched-chain C such as n-hexyl₁-C₆Archi
, Methoxy, ethoxy, propoxy, 2-propoxy
Ci, n-butoxy, 1,1-dimethylethoxy, n-pe
Straight-chain or straight-chain such as ntyloxy and n-hexyloxy
Branch C₁-C₆Alkoxy, fluorine, chlorine, bromine, iodine
Substituents selected from halogen atoms such as oxygen and hydroxyl groups
1 or 2 or more, preferably the same or different 1
To 3 and more preferably 1 to 2
C₆-C ₁₀Aryl (eg phenyl, naphthyl)
Get it. Specifically, 4-methylphenyl, 2-methyl
Phenyl, 4- (n-propyl) phenyl, 4- (2-propyl
Ropyl) phenyl, 4- (n-butyl) phenyl, 4-me
Toxyphenyl, 3,4-dimethoxyphenyl, 3,4,
5-trimethoxyphenyl, 4-ethoxyphenyl, 4
-(N-propoxy) phenyl, 4- (n-butoxy) phen
Nil, 4-bromophenyl, 4-fluorophenyl,
3,4-difluorophenyl, 4-chlorophenyl, 4
-Hydroxyphenyl, 2-hydroxyphenyl, etc.
You can

[0026] Examples of the "cyclic imino group" include a 5-membered or 6-membered cyclic imino group which may further contain an oxygen atom or a nitrogen atom as a ring-forming heteroatom, and specifically, pyrrolidino. , Piperidino, morpholino and the like. In the cyclic imino group in —N (R ⁶ ) R ⁷ ,
The benzene ring may be condensed with a 5- or 6-membered cyclic imino group which may further contain an oxygen atom or a nitrogen atom as a ring-forming hetero atom. Examples of such cyclic imino groups include, for example, benzopiperidino, benzopyrrolidinyl, benzomorpholino and the like. The “monocyclic heterocyclic group” includes, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (however, an oxygen atom and a sulfur atom are not simultaneously contained), a 5-membered or 6-membered heterocyclic groups, specifically, aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, dioxolanyl, pyranyl, dioxanyl. And other non-aromatic heterocyclic groups. An aromatic heterocyclic group is preferred, and pyridyl is particularly preferred.

[0027] The "bicyclic heterocyclic group" includes, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (however, the oxygen atom and the sulfur atom are not included at the same time. ) A condensed heterocyclic group in which a 5- or 6-membered heterocyclic ring and a benzene ring are condensed. Specific examples include benzofuryl, benzothienyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, phthalazinyl and quinoxalinyl.
Examples of the substituent in the “substituted monocyclic heterocyclic group” and the “substituted bicyclic heterocyclic group” include alkyl, alkoxy, halogen atom, hydroxyl group and the like. With regard to such substituents, 1 to 3 of the same or different can be substituted on the monocyclic heterocyclic group, and preferably 1 to 2 can be substituted. The "aroyl", for example, _{C 7} -
C ₁₁ aroyl may be mentioned, and specifically, benzoyl,
Examples include naphthoyl. “Prodrug” refers to a compound that is hydrolyzed in vivo to regenerate the 5-membered ring compound of the present invention. Prodrugs of the present invention include compounds prepared by all means of prodrug formation known to those of skill in the art. For example, when the 5-membered ring compound of the present invention has a carboxyl group, an amino group or the like, a compound in which those groups are easily hydrolyzed into an ester group or an amide group corresponds to a prodrug. .
When the 5-membered ring compound has a carboxyl group, the carboxyl group may be a methyl group such as alkyl such as methyl and ethyl, methyloxymethyl, ethyloxymethyl, 2-methyloxyethyl, 2-methyloxyethyloxymethyl and the like. Acyloxymethyl such as alkyloxyalkyl, pivaloyloxymethyl, acetyloxymethyl, cyclohexylacetyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl, etc., alkoxycarbonylalkyl such as ethyloxycarbonyloxy-1-ethyl, cyclohexyloxycarbonyloxy- Examples thereof include compounds derived from cycloalkyloxycarbonylalkyl such as 1-ethyl. When the 5-membered ring compound has an amino group, a compound in which the amino group is derivatized to acetamide or the like can be mentioned.

[0028] The 5-membered ring compound of the formula (1) of the present invention may be a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include an acid addition salt and a base addition salt. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide and sulfate, citrate, oxalate, malate, tartrate, fumarate, maleate and other organic acids. Examples of the base addition salt include inorganic base salts such as sodium salt and calcium salt, and organic base salts such as meglumine salt and trishydroxymethylaminomethane salt. The compound included in the present invention may have asymmetry or a substituent having an asymmetric carbon, and optical isomers may exist. The present invention includes a mixture of each of these isomers and an isolated one. The present invention also includes solvates such as hydrates of 5-membered ring compounds or pharmaceutically acceptable salts thereof. The 5-membered ring compound of the formula (1) of the present invention can be produced by the following method and methods analogous thereto.

[0029]Manufacturing method 1 Compound (1) in which X is a sulfur atom is produced by the following method.
To be done.

[Chemical 9] [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Y
² has the same meaning as above. X ¹ represents a halogen atom such as a chlorine atom or a bromine atom] thiourea compound (3) and α
By reacting the -haloketone compound (4) in a solvent in the presence or absence of a base, a compound (1) in which X is a sulfur atom can be obtained. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, diethyl ether, and tetrahydrofuran (THF).
Ether solvent such as dichloromethane, dichloroethane,
Examples thereof include halogenated hydrocarbon solvents such as chloroform, aprotic solvents such as dimethylformamide, and aromatic solvents such as toluene. Examples of the base include organic amines such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as potassium carbonate and sodium carbonate. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0030]Manufacturing method 2 Compound (1) in which X is a sulfur atom can also be prepared by the following method.
Manufactured. This manufacturing method uses R^Four, R⁵When introducing
This is effective when protection is required. Usually as a protecting group
Although a commonly used amino-protecting group can be used,
Below, 2-methyl-2-propyloxycarbonyl
Will be explained.

[Chemical 10] [In the formula, R ¹ , R ² , R ³ , Y ¹ , Y ² and X ¹ have the same meanings as described above. R ²⁰ is a substituted or unsubstituted alkanoyl group, substituted or unsubstituted alkyl, —CO
_{^{OR 8, -SO 2 R 9,}} -COR 10, -CON (R
^{11) R} 12, represents -CSN ^{(R 13) R 14,} cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclic group, a ^{-C (= NH) N (R} 15) R 16 , etc. . R ²¹ represents substituted or unsubstituted alkyl or the like.
Boc represents 2-methyl-2-propyloxycarbonyl. R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² ,
R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ have the same meanings as described above]

[0031] Thiourea compound (5) and α-haloketone compound
Compound (6) is obtained by reacting (4) in a solvent in the presence or absence of a base. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide and toluene. And the like. Examples of the base include organic amines such as triethylamine, pyridine and 4-dimethylaminopyridine,
Inorganic bases such as potassium carbonate and sodium carbonate can be mentioned. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent. Then, the compound (6) is deprotected in the presence of an acid in a solvent to obtain the compound (7). As an acid,
Examples thereof include inorganic acids such as hydrochloric acid and organic acids such as trifluoroacetic acid. Examples of the solvent include ether solvents such as diethyl ether, THF and dioxane, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform. The reaction temperature is selected in the range of about 0 ° C. to the boiling point of the solvent.

[0032] The corresponding alkyl halide corresponding to compound (7),
A compound such as an ester, an acid chloride, an acid anhydride, a chloroformate, a sulfonyl chloride, a sulfonate, an isocyanate or an isothiocyanate is reacted in a solvent in the presence or absence of a base to give a compound (8 ) Can be obtained. Specific examples of such a compound include, for example, a substituted or unsubstituted alkanoyl halide, a substituted or unsubstituted aroyl halide, a substituted or unsubstituted alkyl halide, an alkylcarbamoyl halide, a halogenated formic acid alkyl ester, an alkylsulfonyl halide, a substituted or unsubstituted. Arylsulfonyl halide, alkylcarboxylic acid anhydride, arylcarboxylic acid anhydride, alkylcarboxylic acid alkyl ester,
Examples thereof include arylcarboxylic acid alkyl esters, alkyl isocyanates, and alkyl isothiocyanates. Examples of the solvent include diethyl ether and THF
Ether solvent such as dichloromethane, dichloroethane,
Examples thereof include halogenated hydrocarbon solvents such as chloroform, aprotic solvents such as dimethylformamide, and aromatic solvents such as toluene. Examples of the base include organic amines such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as potassium carbonate and sodium carbonate. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent. R ²¹ —X ² (R ²¹ has the same meaning as described above) in the presence of a base in the solvent of the compound (8).
X ² represents a halogen atom such as a chlorine atom and a bromine atom) to give a compound (9).
Examples of the solvent include ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, and aromatic solvents such as toluene. Examples of the base include organic amines such as triethylamine, pyridine and 4-dimethylaminopyridine,
Examples thereof include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, and lithium diisopropylamide. The reaction temperature is selected in the range of about 0 ° C. to the boiling point of the solvent. In the reaction with the compound (7) and the compound (8),
Carboxylic acid can also be used as a reaction reagent. In that case, N, N′-dicyclohexylcarbodiimide,
A condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide can be used.

[0033]Manufacturing method 3 Compound (1) in which X is a sulfur atom can also be prepared by the following method.
Manufactured.

[Chemical 11] [In the formula, R ¹ , R ² , R ³ , R ²¹ , Y ¹ , Y ² and Boc are as defined above] Compound (6) in a solvent in the presence of a base, R ²¹ -X
² (R ²¹ has the same meaning as above. X ² represents a halogen atom such as a chlorine atom or a bromine atom) to give a compound (10). Examples of the solvent include ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, and aromatic solvents such as toluene. Examples of the base include metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide and the like. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0034] The compound (11) is obtained by deprotecting the compound (10) in the presence of an acid in a solvent. Examples of the acid include inorganic acids such as hydrochloric acid and organic acids such as trifluoroacetic acid. Examples of the solvent include ether solvents such as diethyl ether, THF and dioxane, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform. The reaction temperature is selected in the range of about 0 ° C. to the boiling point of the solvent. Manufacturing method 1 to 3 above
The raw material compound used in is produced by the following method.

[Chemical 12] [In the formula, R ³ , R ⁴ , R ⁵ , Y ¹ and Y ² are as defined above. R ²² represents alkyl] The amine compound (12) and the isocyanate compound (13) or the dithiocarbamic acid ester (14) in a solvent,
The thiourea compound (3) can be obtained by the reaction.
As the solvent, for example, methanol, ethanol, 2-
Alcohol solvent such as propanol, diethyl ether,
Examples thereof include ether solvents such as THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatic solvents such as toluene. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0035]

[Chemical 13] [Wherein R ³ , R ⁴ , R ⁵ , R ²² , Y ¹ and Y ² have the same meanings as described above] The amine compound (15) and the isocyanate compound (16) or the dithiocarbamic acid ester (17) The thiourea compound (3) can be obtained by reacting in a solvent. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, diethyl ether and T.
Examples thereof include ether solvents such as HF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatic solvents such as toluene. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent. The thiourea compound (5) protected with 2-methyl-2-propyloxycarbonyl or the like can be obtained by the following method.

[0036]

[Chemical 14] [Wherein R ³ , R ²² , Y ¹ , Y ² and Boc are as defined above] The amine compound (18) and the isocyanate compound (13) or dithiocarbamic acid ester (14) in a solvent The thiourea compound (5) can be obtained by the reaction. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, diethyl ether and T.
Examples thereof include ether solvents such as HF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatic solvents such as toluene. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0037]

[Chemical 15] [Wherein R ³ , R ²² , Y ¹ , Y ² and Boc are as defined above] The amine compound (15) and the isocyanate compound (19) or the dithiocarbamic acid ester (20) are mixed in a solvent. The thiourea compound (5) can be obtained by the reaction. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, diethyl ether and T.
Examples thereof include ether solvents such as HF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatic solvents such as toluene. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0038] Isothiocyanate compounds (13), (16),
(19) is commercially available, or is obtained from the corresponding amino compound, for example, Synlett. 1997, 773-774,
J. Org. Chem., 1997, 62, 4539-4540, or J. Me
It can be synthesized according to the method described in the literature of d. Chem., 1984, 27, 1570-1574. Further, from the corresponding carboxylic acid, for example, Synth. Commun. 1997, 27,
751-756, or Indian, J. Chem., 1998, 1153-115
It can be synthesized according to the method described in literatures such as 6. Dithiocarbamic acid ester compound (1
4), (17) and (20) are commercially available, or can be obtained from the corresponding amino compounds by, for example, J. Chem. So.
c.1956, 1644-1649, or Syn. Commun. 1984, 537-
It can be synthesized according to the method described in the literature such as 546.

[0039] The α-haloketone compound (4) may be commercially available, or may be prepared from a corresponding ketone body, for example,
J. Med. Chem. 1987, 1497-1502, Tetrahedoron Lett.
1998, 4987-4990, or Acta Chim. Scand. 1986, B
It can be synthesized according to the method described in the literature such as 40, 700-702.

[0040]Manufacturing method 4 Compound (1) in which X is an oxygen atom is produced by the following method.
To be done.

[Chemical 16] [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Y
² has the same meaning as defined above] In the presence of a base in a solvent, a compound of the formula:
⁴ (R ⁵ ) N—Y ² —X ³ (R ⁴ , R ⁵ , and Y ² have the same meanings as above. X ³ represents a halogen atom such as chlorine atom or bromine atom) Thus, the compound (22) is obtained. Examples of the solvent include diethyl ether,
Examples thereof include ether solvents such as THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatic solvents such as toluene. Examples of the base include metal hydrides such as sodium hydride and potassium hydride. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0041] Compound (23) is obtained by reacting compound (22) with a sulfurizing reagent such as phosphorus pentasulfide. Examples of the solvent include ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, and aromatic solvents such as toluene. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent. Then, the compound (23) was added to a solvent of R ³ —Y ¹ —NH ₂ (R
³ and Y ¹ have the same meanings as defined above) to give compound (24). As a solvent,
For example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as dimethylformamide, aromatics such as toluene. A solvent etc. are mentioned. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent.

[0042]Manufacturing method 5 Compound (1) in which X is a sulfur atom is produced by the following method.
To be done.

[Chemical 17] [Where R¹, R^Two, R^Three, R^Four, R⁵And Y^TwoIs before
It is synonymous with the description. Y^FourIs a substituted or unsubstituted alkylate
-CO (CH_Two)_n-, -SO_Two(CH_Two)_n-, -C
ONH (CH_Two)_n-, -CSNH (CH_Two)_n-Or
-COO (CH_Two) _nRepresents-] An alkyl halide corresponding to the imine compound (25),
Ester, acid chloride, acid anhydride, chloroformic acid ester
, Sulfonyl chloride, sulfonic acid ester, isocyanate
A compound such as anate or isothiocyanate can be used as a base.
By reacting in a solvent in the presence or absence,
Compound (26) is obtained by reacting with a carboxylic acid.
You can This reaction is the same as the method for synthesizing compound (8).
It can be implemented in this way.

[0043]

[Chemical 18] [Wherein R ¹ , R ² , R ⁴ , R ⁵ , Y ² and X ¹ have the same meanings as described above] In the above reaction, a thiourea compound (27) protected with a diphenylmethyl group was used as a protecting group. An example of a method for producing the compound (25) will be shown. In the same manner as in Production Method 1, protected thiourea compound (27) and α-haloketone compound
Compound (28) can be obtained by reacting (4). The protecting group of compound (28) is deprotected by applying an acid catalyst in a solvent to give compound (25). Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and sulfonic acids such as methanesulfonic acid. Examples of the solvent include ether solvents such as ether and THF, alcohol solvents such as methanol, ethanol and 2-propanol, acetic acid and water. The reaction temperature is selected from the range of room temperature to the boiling point of the solvent. In carrying out the above reaction, if necessary, a technique of protection or deprotection can be used. For protection and deprotection technologies, see Green et al. (TW Greene and PGM Wuts, "Pr
otecting Groups in Organic Synthesis ", 1991, JOHN
WILEY & SONS, INC.).

[0044] Further, after forming the 5-membered ring compound, the functional group can be converted into another functional group. In this transformation, the methods usually used in organic chemistry can be used. These methods are described, for example, in the following books. "Experimental Chemistry" Volume 19-26 (1992, Maruzen) "Precision Organic Synthesis" (1983, Nankodo) Compendium of Organic Synthetic Methods, Vol. 1-9
(John Wiley & Sons) Comprehensive Organic Synthesis, Vol. 1-9 (1991, P
ergamon Press) Comprehensive Organic Transformations (1989, VCH P
ublishers) Survey of Organic Syntheses, Vol. 1-2 (1970, 197
7, John Wiley & Sons) Specifically, ester group, carboxyl group, amide group,
A hydroxyl group, an ether group and the like can be mutually converted, and a halogen atom can be changed to an amino group and an amino group can be changed to a urea group.

[0045] The 5-membered ring compound (1) of the present invention or an intermediate for producing the same can be purified by a conventional method. Further, when an isomer exists in the 5-membered ring compound (1) of the present invention or an intermediate for producing the same, it can be purified in the same manner. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene and ketones such as acetone. System solvent,
Examples thereof include hydrocarbon solvents such as hexane and the like, or mixed solvents thereof. Examples of the method for purely obtaining the optical isomer include an optical resolution method. As the optical resolution method, when the compound of the present invention or an intermediate thereof has a basic substituent such as an amino group, for example, the compound of the present invention or an intermediate thereof is in an inert solvent (e.g., methanol, ethanol, 2-propanol). Alcohol-based solvents such as, ether-based solvents such as diethyl ether, ester-based solvents such as ethyl acetate, aromatic hydrocarbon-based solvents such as toluene, acetonitrile and their mixed solvents), optically active acids (for example, mandelic acid) , N-benzyloxyalanine, lactic acid and other monocarboxylic acids, tartaric acid, o-diisopropylidene tartaric acid, malic acid and other dicarboxylic acids, camphor sulfonic acid, bromocamphor sulfonic acid and other sulfonic acids) is there. When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, it forms a salt with an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, and strychnine). The method can also be adopted. The temperature for forming a salt in the above optical resolution method may be in the range of room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to around the boiling point of the solvent. The precipitated salt can be cooled, if necessary, before being collected by filtration to improve the yield. The amount of the optically active acid or amine used is appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. Crystals in an inert solvent if necessary (for example, methanol, ethanol, alcohol solvent such as 2-propanol, ether solvent such as diethyl ether, ester solvent such as ethyl acetate, aromatic hydrocarbon solvent such as toluene, It is also possible to obtain a highly pure optically active salt by recrystallization from acetonitrile or the like and a mixed solvent thereof. If necessary, the obtained salt can be treated with an acid or a base by a usual method to give a free form.

[0046] The 5-membered ring compound of the formula (1) of the present invention or a salt thereof or a prodrug thereof is useful as a medicine and particularly has an action of suppressing infiltration of leukocytes such as eosinophils and lymphocytes. Therefore, it is useful as a therapeutic agent for autoimmune disease-related inflammation, allergic inflammation, acute inflammation, and other inflammatory diseases having cell infiltration. Here, examples of the autoimmune disease-induced inflammation include rheumatism, multiple sclerosis, inflammatory bowel disease, and type I diabetes. Examples of allergic inflammation include bronchial asthma, inflammatory bowel disease, allergic rhinitis, atopic dermatitis, urticaria, and allergic conjunctivitis. In bronchial asthma, the present 5-membered ring compound and the like are particularly useful for late-onset asthma. Examples of acute inflammation include inflammatory lung disease and the like. Examples of other inflammatory diseases include eosinophilia, eosinophilic vasculitis, eosinophilic granuloma, transplant rejection, and tumor metastasis. When used as an anti-inflammatory agent, it can be used in combination with a steroid agent used as a therapeutic agent for inflammatory diseases, and its therapeutic effect is enhanced, and it is possible to reduce or eliminate steroid agents with strong side effects. Becomes Antiallergic agent when used as a therapeutic agent for allergic diseases
(Chemical transmitter release inhibitors, antihistamines, antileukotrienes, antithromboxanes, etc.) and bronchodilators (xanthine-based agents such as theophylline, β-stimulants) and bronchodilators in bronchial asthma can be used in combination. Is. When used as a therapeutic agent for autoimmune diseases such as rheumatism, it can be used in combination with a non-steroidal anti-inflammatory agent such as a cyclooxygenase (COX) inhibitor.

The 5-membered ring compound of the present invention or a salt thereof or a prodrug thereof can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of a topical agent, injection, transdermal agent, nasal agent and the like. As an oral agent or a rectal administration agent, for example, capsules, tablets, pills, powders, cachets, suppositories,
Examples include liquid agents. Examples of the injection include a sterile solution or suspension. Examples of the topical agent include creams, ointments, lotions, transdermal agents (ordinary patch agents, matrix agents) and the like. The above-mentioned dosage forms are formulated by a conventional method using pharmaceutically acceptable excipients and additives. A pharmaceutically acceptable excipient,
Examples of the additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents and preservatives.

[0048] Examples of the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc,
Examples thereof include sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting point wax and cocoa butter. A capsule can be prepared by putting the compound of the present invention in a capsule together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or encapsulated without excipients. The cachet can be manufactured in the same manner. The powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents and the like. Examples of the injectable solution include solutions, suspensions and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution may also be prepared in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water. A solution suitable for oral administration can be produced by adding the compound of the present invention to water, and optionally adding a colorant, a flavor, a stabilizer, a sweetener, a solubilizer, a thickener, and the like. A liquid suitable for oral administration can also be produced by adding the compound of the present invention to water together with a dispersant and increasing the viscosity. Examples of the thickener include pharmaceutically acceptable natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, known suspending agents, and the like. Examples of the topical administration agent include the above liquid agents, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned topical administration agent can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier that are commonly used. Ointments and creams
For example, it can be obtained by adding a thickening agent and / or a gelling agent to an aqueous or oily base and formulating it. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like. Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin and beeswax.

[0049] A lotion is prepared by adding one or more kinds of pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, perfumes and the like to an aqueous or oily base. be able to. The topical agent may optionally contain a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, and benzalkonium chloride, and a bacterial growth inhibitor. The compounds of the present invention may also be administered nasally in liquid spray, powder or lozenge formulations. The dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 1000 mg, preferably about 2 to about 500 mg per day for an adult. The range, particularly preferably the range of about 5 to about 100 mg, can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of about 0.1 to about 300 mg, preferably the range of about 1 to about 200 mg, once or in several divided doses.

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 N- {4- (4-bromophenyl) -3- [3- (dimethylamino) propyl] thiazole-2 (3H) -ylidene} aniline

[Chemical 19] N- [3- (dimethylamino) propyl] -N'-phenylthiourea (800 mg) obtained in Reference Example 3 below, 2-
A mixture of bromo-4′-bromoacetophenone (1.09 g) and ethanol (30 ml) was heated under reflux under a nitrogen atmosphere. After 9 hours, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol (50:
Purified in 1)). Crystallization from isopropyl alcohol gave the title compound (830 mg). Melting point: 110-111 ° C ¹ H-NMR (CDCl ₃ ): δ 1.79 (2H, m), 2.11 (6H, s), 2.52
(2H, t, J = 7.0), 3.92 (2H, t, J = 7.0), 5.74 (1H, s),
7.02-7.09 (3H, m), 7.26-7.37 (4H, m), 7.58 (2H, d,
(J = 8.4)

Example 2 N- {3- [3- (dimethylamino) propyl] -5-phenylthiazole-2 (3H) -ylidene} aniline

[Chemical 20] N- [3- (dimethylamino) propyl] -N′-phenylthiourea (650 mg) obtained in Reference Example 3 below, 2-
Bromo-2-phenylacetaldehyde (600 mg) and N, N-dimethylformamide (11 ml) were reacted in the same manner as in Example 1 to obtain the title compound (497 mg). Melting point: 84-86 ° C ¹ H-NMR (CDCl ₃ ): δ2.01 (2H, m), 2.26 (6H, s), 2.37
(2H, t, J = 6.8), 3.98 (2H, t, J = 6.8), 6.97 (1s, s),
7.03-7.38 (10H, m)

Examples 3 to 7 By the same method as in Example 1, various α-bromoketones were reacted with thiourea to obtain the compounds shown in Table 1. Table 1

[Chemical 21] Example 8 N- [3- (2-Aminoethyl) -4- (4-bromophenyl) thiazole-2 (3H) -ylidene] aniline (1) t-butyl 2- [4- (4-bromophenyl) -2-
(Phenylimino) thiazol-3 (2H) -yl] ethyl carbamate

[Chemical 22] T-butyl 2-[(anilinocarbothioyl) amino] ethyl carbamate (1.5 g) obtained in Reference Example 1, 2-bromo-4′-bromoacetophenone (1.55 g), potassium carbonate (772 mg) N, N-dimethylformamide (3
8 ml) of the mixture was heated and stirred at 80 ° C. under a nitrogen atmosphere. After 2 hours, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography [n-hexane-ethyl acetate (9:
1)]. Crystallization from isopropyl alcohol gave the title compound (2.41 g). ¹ H-NMR (CDCl ₃ ): δ1.43 (9H, s), 3.38 (2H, m), 3.94
(2H, t, J = 5.5), 5.77 (1H, s), 5.91 (1H, m), 7.05-
7.12 (3H, m), 7.28-7.38 (4H, m), 7.59 (2H, d, J = 8.
Four)

(2) N- [3- (2-aminoethyl) -4- (4-
Bromophenyl) thiazole-2 (3H) -ylidene] aniline

[Chemical 23] t-Butyl 2- [4- (4-bromophenyl) -2- (phenylimino) thiazol-3 (2H) -yl] ethyl carbamate (1.5 g), trifluoroacetic acid (10 ml) and water (5
ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Crystallization was performed by adding n-hexane to give the title compound (93
7 mg) was obtained. Melting point: 58-61 ° C ¹ H-NMR (CDCl ₃ ): δ2.93 (2H, t, J = 6.6), 3.87 (2H, t,
J = 6.6), 5.76 (1H, s), 7.04-7.08 (3H, m), 7.26-7.37
(4H, m), 7.59 (2H, d, J = 8.4)

Example 9 N- [3- (3-Aminopropyl) -4- (4-methoxyphenyl) -thiazole-2 (3H) -ylidene] aniline (1) t-butyl 3- [4- (4 -Methoxyphenyl) -2-
(Phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 24] T-Butyl 3-[(anilinocarbothioyl) amino] propylcarbamate (309 mg) obtained in Reference Example 4, 2
-Bromo-4'-methoxyacetophenone (252m
g), potassium carbonate (339 mg) and ethanol (8 ml) were reacted in the same manner as in Example 8 (1) to give the title compound (4
29 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ1.41 (9H, s), 1.64 (2H, m), 3.07
(2H, m), 3.86 (3H, s), 3.95 (2H, t, J = 6.6), 5.74 (1
H, s), 5.87 (1H, m), 6.97-7.37 (9H, m)

(2) N- [3- (3-aminopropyl) -4- (4
-Methoxyphenyl) -thiazole-2 (3H) -ylidene] aniline

[Chemical 25] A mixture of t-butyl 3- [4- (4-methoxyphenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate (400 mg) and 4N hydrogen chloride dioxane solution (8 ml) at room temperature. Stir for 2 hours. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue, and the insoluble salt was filtered off to give the title compound (379 mg) as a hydrochloride salt. Melting point: 215-218 ° C ¹ H-NMR (CDCl ₃ , free amino form): δ 1.70 (2H, m), 2.6
4 (2H, t, J = 6.6), 3.85 (3H, s), 3.94 (2H, t, J = 6.6),
5.70 (1H, s), 6.94-7.10 (5H, m), 7.26-7.36 (4H, m)

Example 10 N- [3- (3-aminopropyl) -5-methyl-4-phenylthiazole-2 (3H) -ylidene] aniline (1) t-butyl 3- [5-methyl-4- Phenyl-2-
(Phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 26] T-Butyl 3-[(anilinocarbothioyl) amino] propylcarbamate (300 mg) obtained in Reference Example 4, 2
-Bromo-propiophenone (227 mg) and ethanol
The mixture (8 ml) was heated to reflux under a nitrogen atmosphere. After 2 hours, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate (8: 2)) to give the title compound (389 mg). ¹ H-NMR (CDCl ₃ ): δ 1.40 (9H, s), 1.54 (2H, m), 1.91
(3H, s), 3.06 (2H, m), 3.84 (2H, t, J = 6.4), 6.04 (1
H, m), 7.02-7.49 (10H, m)

(2) N- [3- (3-aminopropyl) -5-methyl-4-phenylthiazole-2 (3H) -ylidene]
Aniline

[Chemical 27] t-Butyl 3- [5-methyl-4-phenyl-2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate (370 mg) and 4N hydrogen chloride dioxane solution
(4 ml) was used and the reaction was carried out in the same manner as in Example 9 (2) to give the title compound (327 mg) as a hydrochloride salt. Melting point: 240-243 ° C

Example 11 N- [3- (3-aminopropyl) -4- (1,1′-biphenyl-4-yl) thiazol-2 (3H) -ylidene] aniline (1) t-butyl 3- [4- (1,1'-biphenyl-4-yl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 28] T-Butyl 3- (anilinocarbothioylamino) propylcarbamate (200 mg) obtained in Reference Example 4, 2
Using -bromo-4'-phenylacetophenone (197 mg) and ethanol (4 ml), the reaction was carried out in the same manner as in Example 10 (1) to obtain the title compound (275 mg). ¹ H-NMR (CDCl ₃ ): δ 1.39 (9H, s), 1.69 (2H, m), 3.11
(2H, m), 4.02 (2H, t, J = 6.4), 5.84 (1s, s), 5.87 (1
H, m), 7.04-7.18 (3H, m), 7.33-7.48 (7H, m), 7.50-
7.70 (4H, m)

(2) N- [3- (3-aminopropyl) -4-
(1,1'-biphenyl-4-yl) thiazole-2 (3H)
-Yliden] Aniline

[Chemical 29] t-Butyl 3- [4- (1,1'-biphenyl-4-yl)-
A mixture of 2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate (233 mg) and 4N-hydrogen chloride dioxane solution (2 ml) was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (185 mg). Melting point: 50-54 ° C ¹ H-NMR (CDCl ₃ ): δ 1.74 (2H, m), 2.69 (2H, t, J = 6.
6), 4.02 (2H, t, J = 6.6), 5.81 (1H, s), 7.04-7.11 (3
H, m), 7.33-7.47 (7H, m), 7.48-7.69 (4H, m)

Examples 12 to 149 By the same method as in Examples 8 to 10 or 11, various α
By reacting bromoketone with thiourea
The compound shown in was obtained. Table 2

[Chemical 30]

[0062] Table 3

[Chemical 31]

[0063] Table 4

[Chemical 32] Table 5

[Chemical 33]

[0064] Table 6

[Chemical 34] Table 7

[Chemical 35]

Table 8

[Chemical 36]

[0066] Table 9

[Chemical 37]

[0067] Table 10

[Chemical 38]

[0068] Table 11

[Chemical 39]

Table 12

[Chemical 40]

Example 150 N- {4- (4-bromophenyl) -3-[(3-methylamino) propyl] thiazole-2 (3H) -ylidene} aniline (1) t-butyl 3- [4- (4-bromophenyl) -2
-(Phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 41] T-Butyl 3- (anilinocarbothioylamino) propylcarbamate (3 g) obtained in Reference Example 4, 2-bromo-4′-bromoacetophenone (2.97 g), potassium carbonate (2.01 g) and N, N-dimethylformamide (75
The reaction was performed in the same manner as in Example 8 (1) to give the title compound (2.90 g). ¹ H-NMR (CDCl ₃ ): δ1.41 (9H, s), 1.65 (2H, m), 3.08
(2H, m), 3.93 (2H, t, J = 6.6), 5.73 (1H, m), 5.79 (1
H, s), 7.04-7.14 (3H, m), 7.24-7.37 (4H, m), 7.60
(2H, d, J = 8.4)

(2) t-Butyl 3- [4- (4-bromophenyl) -2- (phenylimino) thiazole-3 (2H)-
Il] propyl (methyl) carbamate

[Chemical 42] t-Butyl 3- [4- (4-bromophenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate (250 mg) was dissolved in N, N-dimethylformamide (2 ml), and nitrogen was added. Sodium hydride (26 mg, 60% oil dispersion) was added in an ice bath under an atmosphere and stirred for 15 minutes. Methyl iodide (41 μl) was added to the reaction mixture, and the mixture was returned to room temperature and stirred for 6 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate (10: 1)) to give the title compound (249 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ): δ 1.40 (9H, s), 1.86 (2H, m), 2.72
(3H, s), 3.16 (2H, m), 3.81 (2H, t, J = 7.5), 5.76 (1
H, s), 7.03-7.08 (3H, m), 7.25 (2H, d, J = 8.4), 7.3
4 (2H, m), 7.59 (2H, d, J = 8.4)

(3) N- {4- (4-bromophenyl) -3-
[3- (methylamino) propyl] thiazole-2 (3H)-
Yliden} aniline

[Chemical 43] Using t-butyl 3- [4- (4-bromophenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propyl (methyl) carbamate (200 mg), Example 8 (2)
The reaction was performed in the same manner as in to give the title compound (149 mg). Melting point: 143-148 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.84 (2H, m), 2.38 (3H, s), 2.61
(2H, t, J = 6.8), 3.92 (2H, t, J = 6.8), 5.80 (1H, s),
7.05-7.10 (3H, m), 7.26 (2H, d, J = 8.4), 7.36 (2H,
m), 7.60 (2H, d, J = 8.4)

Example 151 N- {4- (4-bromophenyl) -3- [4- (methylamino) butyl] thiazole-2 (3H) -ylidene} aniline (1) t-butyl 4- [4- (4-bromophenyl) -2
-(Phenylimino) thiazol-3 (2H) -yl] butyl carbamate

[Chemical 44] T-Butyl 4- (anilinocarbothioylamino) butyl carbamate (1.5 g) obtained in Reference Example 21, 2-bromo-4′-bromoacetophenone (1.42 g), potassium carbonate (962 mg) and N, N-dimethylformamide (3
The reaction was performed in the same manner as in Example 8 (1) using 5 ml) to obtain the title compound (2.1 g) as an amorphous substance. ¹ H-NMR (CDCl ₃ ): δ1.36-1.40 (11H, m), 1.67 (2H, m),
3.09 (2H, m), 3.80 (2H, t, J = 7.5), 4.90 (1H, m),
5.75 (1H, s), 7.03-7.09 (3H, m), 7.25 (2H, d, J = 8.
4), 7.34 (2H, m), 7.59 (2H, d, J = 8.4)

(2) t-butyl 4- [4- (4-bromophenyl) -2- (phenylimino) thiazole-3 (2H)-
Il] butyl (methyl) carbamate

[Chemical 45] t-Butyl 4- [4- (4-bromophenyl) -2- (phenylimino) thiazol-3 (2H) -yl] butylcarbamate (250 mg) was used and the reaction was carried out in the same manner as in Example 150 (2). The title compound (205 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ): δ1.29-1.50 (11H, m), 1.59 (2H, m),
2.77 (3H, s), 3.11 (2H, m), 3.84 (2H, t, J = 6.8),
5.75 (1H, s), 7.03-7.07 (3H, m), 7.25 (2H, d, J = 8.
4), 7.35 (2H, m), 7.59 (2H, d, J = 8.4) (3) N- {4- (4-bromophenyl) -3- [4- (methylamino) butyl] thiazole-2 ( 3H) -Ylidene} aniline

[0075]

[Chemical 46] Using the compound (205 mg) obtained in (2) above, the reaction was carried out in the same manner as in Example 8 (2) to obtain the title compound (158 mg). Melting point: 56-57 ° C ¹ H-NMR (CDCl ₃ ): δ 1.46 (2H, m), 1.70 (2H, m), 2.37
(3H, s), 2.56 (2H, t, J = 7.0), 3.82 (2H, t, J = 7.5),
5.76 (1H, s), 7.05-7.09 (3H, m), 7.26 (2H, d, J = 8.
4), 7.35 (2H, m), 7.59 (2H, d, J = 8.4)

Example 152 N- {4- (4-methoxyphenyl) -3- [3- (methylamino) propyl] thiazole-2 (3H) -ylidene} aniline (1) 3- [4- (4- Methoxyphenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propyl (methyl) carbamate

[Chemical 47] T-Butyl 3- [4- (4) obtained by the method of Example 9 (1)
-Methoxyphenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate (1.4 g) was reacted in the same manner as in Example 150 (2) to give the title compound (740 mg) as a colorless liquid. Obtained as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.39 (9H, s), 1.86 (2H, m), 2.71
(3H, s), 3.14 (2H, m), 3.82 (2H, t, J = 7.5), 3.86 (3
H, s), 5.69 (1H, s), 6.96 (2H, d, J = 8.8), 7.04-7.0
9 (3H, m), 7.26-7.37 (4H, m)

(2) N- {4- (4-methoxyphenyl) -3-
[3- (methylamino) propyl] thiazole-2 (3H)-
Yliden} aniline

[Chemical 48] Example 9 using the compound (74 mg) obtained in the above (1)
The reaction was performed in the same manner as in (2) to obtain the title compound (750 mg) as a hydrochloride salt. Melting point: 143-146 ° C. ¹ H-NMR (CDCl ₃ , free form): δ 1.77 (2H, m), 2.32 (3
H, s), 2.48 (2H, t, J = 6.8), 3.86 (3H, s), 3.92 (2
H, t, J = 7.0), 5.69 (1H, s), 6.96 (2H, d, J = 8.8),
7.02-7.09 (3H, m), 7.26-7.37 (4H, m)

Example 153 N- {3- [4- (4-bromophenyl) -2-phenyliminothiazol-3 (2H) -yl] propyl} acetamide

[Chemical 49] N- [3- (3-aminopropyl) -4- (4-bromophenyl) -thiazole-2 (3 obtained in Example 132
H) -ylidene] aniline hydrochloride (730 mg) and triethylamine (0.77 ml) were added to N, N-dimethylformamide.
(5 ml), and acetic anhydride was added dropwise in an ice bath under a nitrogen atmosphere. After stirring at the same temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (580 mg). Melting point: 155-157 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.66 (2H, m), 1.86 (3H, s), 3.24
(2H, m), 3.90 (2H, t, J = 6.4), 5.81 (1H, s), 7.05-7.
12 (3H, m), 7.12-7.40 (5H, m), 7.61 (2H, d, J = 8.4)

Examples 154 to 167 By the same method as in Example 153, various amino compounds were reacted with acetic anhydride to obtain amide compounds shown in Table 13. Table 13

[Chemical 50]

Example 168 2-({3- [4- (4-bromophenyl) -2- (phenylimino) -thiazol-3 (2H) -yl] propyl} amino) -2-oxoethyl acetate

[Chemical 51] The amino compound (1.21 g) obtained in Example 132 and triethylamine (800 mg) were mixed with tetrahydrofuran (1
5 ml), and acetoxyacetyl chloride (466 mg) was added dropwise at room temperature under a nitrogen atmosphere. After stirring for 30 minutes at the same temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue
Purification with [chloroform-methanol (97: 3)] gave the title compound (1.1 g). Melting point: 156-159 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.56 (2H, m), 1.64 (3H, s), 3.35
(2H, m), 3.90 (2H, t, J = 6.1), 4.46 (2H, s), 5.79
(1H, s), 7.00-7.10 (3H, m), 7.24 (2H, d, J = 8.4),
7.34 (2H, m), 7.58 (2H, d, J = 8.4), 8.01 (1H, t, J =
5.9) Example 169 N- {3- [4- (4-bromophenyl) -2- (phenylimino) -thiazol-3 (2H) -yl] propyl} -2
-Hydroxyacetamide

[Chemical 52] The compound obtained in Example 168 (1.1 g), 5% aqueous sodium hydroxide solution (2 ml) and methanol (15 ml)
The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: methanol (99: 1))
The title compound (923 mg) was obtained. Melting point: 185-186 ° C ¹ H-NMR (CDCl ₃ ): δ 1.70 (2H, m), 2.52 (1H, m), 3.32
(2H, m), 3.88-3.95 (4H, m), 5.81 (1H, s), 7.04-7.
12 (3H, m), 7.26 (2H, d, J = 8.4), 7.34 (2H, m), 7.6
1 (2H, d, J = 8.4), 7.68 (1H, m)

Example 170 2-Hydroxy-N- {3- [4- (4-methoxyphenyl) -2- (phenylimino) -thiazole-3 (2H)-
Ill] propyl} acetamide

[Chemical 53] N- [3- (3-aminopropyl) -4- (4-methoxyphenyl) -thiazole-2 (3 obtained by the method of Example 9)
H) -Ylidene] aniline Hydrochloride (1.2 g) was used and the reaction was carried out according to the methods of Example 168 and Example 169 to give the title compound (1.1 g) as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.69 (2H, m), 2.74 (1H, t, J = 5.
5), 3.31 (2H, m), 3.87 (3H, s), 3.89-3.94 (4H, m),
5.75 (1H, s), 6.98 (2H, d, J = 8.8), 7.05-7.11 (3H,
m), 7.26-7.38 (4H, m), 7.74 (1H, m)

Example 171 N- {3- [4- (4-bromophenyl) -2-phenyliminothiazol-3 (2H) -yl] propyl} methanesulfonamide

[Chemical 54] The amino compound (1.21 g) obtained in Example 132 and triethylamine (800 mg) were mixed with tetrahydrofuran (1
5 ml), and methanesulfonyl chloride (391 mg) was added dropwise at room temperature under a nitrogen atmosphere. 3 at the same temperature
After stirring for 0 minutes, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol (97: 3)) to give the title compound (1.04 g). Melting point: 128-134 ° C ¹ H-NMR (CDCl ₃ ): δ 1.69 (2H, m), 2.77 (3H, s), 3.13 (2
H, m), 3.96 (2H, t, J = 6.0), 5.84 (1H, s), 6.66 (1
H, m), 7.06-7.13 (3H, m), 7.24 (2H, d, J = 8.2), 7.36
(2H, m), 7.61 (2H, d, J = 8.2)

Examples 172-174 By the same method as in Example 171, the amino compound obtained by the method of Example 132 or Example 9 is reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride, and the results are shown in Table 14. A sulfonamide compound was obtained. Table 14

[Chemical 55] Ts represents a tosyl group.

Example 175 Methyl 3- [4- (4-bromophenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 56] The amino compound (1.21 g) obtained in Example 132 and triethylamine (800 mg) were mixed with tetrahydrofuran (1
5 ml), and methyl chloroformate (322 mg) was added dropwise at room temperature under a nitrogen atmosphere. 30 at the same temperature
After stirring for minutes, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol (95: 5)) to give the title compound (1.05 g). Melting point: 132-134 ° C ¹ H-NMR (CDCl ₃ ): δ1.62 (2H, m), 3.13 (2H, m), 3.60
(3H, s), 3.90 (2H, t, J = 6.4), 5.77 (1H, s), 6.02
(1H, m), 7.03-7.10 (3H, m), 7.21-7.37 (4H, m), 7.56
(2H, d, J = 8.4)

Example 176 Methyl 3- [4- (4-methoxyphenyl) -2- (phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 57] By using the amino compound (1.2 g) obtained by the method of Example 9 and by a method similar to that of Example 175, the title compound (69
8 mg) was obtained. Melting point: 106-108 ° C ¹ H-NMR (CDCl ₃ ): δ1.61 (2H, m), 3.16 (2H, m), 3.61
(3H, s), 3.86 (3H, s), 3.93 (2H, t, J = 6.3), 5.73 (1
H, s), 6.11 (1H, m), 6.97 (2H, d, J = 8.6), 7.04-7.1
2 (3H, m), 7.26-7.38 (4H, m)

Example 177 N- {3- [2- (2-methoxyphenyl) -4- (3,4-
Methylenedioxyphenyl) iminothiazole-3 (2
H) -yl] propyl} -N′-ethylurea

[Chemical 58] The amino compound (200 mg) obtained in Example 67 and triethylamine (0.13 ml) were dissolved in N, N-dimethylformamide (4 ml), and ethyl isocyanate (38 μl) was added dropwise in an ice bath under a nitrogen atmosphere. After stirring at the same temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (147 mg). Melting point: 134-136 ° C ¹ H-NMR (CDCl ₃ ): δ 1.02 (3H, t, J = 7.2), 1.54 (2H,
m), 3.09-3.16 (4H, m), 3.84 (3H, s), 4.04 (2H, t, J
= 6.1), 4.29 (1H, m), 5.75 (1H, s), 6.05 (2H, s), 6.
44 (1H, m), 6.83-6,86 (3H, m), 6.99-7.26 (4H, m)

Examples 178 to 183 By the same method as in Example 177, Examples 9 and 7
9 or the amino compound obtained by the method of Example 108 was reacted with ethyl isocyanate or ethyl isothiocyanate to obtain the urea and thiourea compounds shown in Table 15. Table 15

[Chemical 59]

Example 184 (1) t-butyl 3- [4- (4-nitrophenyl) -2
-(Phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 60] A mixture of t-butyl 3- (anilinocarbothioylamino) propylcarbamate (6.2 g), 2-bromo-4′-nitroacetophenone (4.9 g) and ethanol (50 ml) obtained in Reference Example 4 was added with nitrogen. The mixture was heated under reflux in the atmosphere. 1
After the lapse of time, the reaction mixture was allowed to cool, and the resulting crystals were filtered off to obtain the title compound (8.84 g) as a hydrobromide salt. (2) t-butyl 3- [4- (4-aminophenyl) -2
-(Phenylimino) thiazol-3 (2H) -yl] propylcarbamate

[Chemical 61] Compound (1 g) obtained in (1) above, 10% palladium /
A mixture of activated carbon (200 mg) and methanol (50 ml) was hydrogenated at room temperature and atmospheric pressure. After 3 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol (98:
2)) and the title compound (640 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.40 (9H, s), 1.63 (2H, m), 3.06
(2H, m), 3.86 (2H, brs), 3.94 (2H, t, J = 6.6), 5.70
(1H, s), 5.96 (1H, m), 6.71 (2H, d, J = 8.6), 7.02-
7.36 (7H, m)

(3) 4- [4- (aminophenyl) -3- (3-
Aminopropyl) -thiazole-2-ylidene] aniline

[Chemical 62] The compound (640 mg) obtained in the above (2) was used in Example 9 (2).
The title compound (550 mg) was obtained as a hydrochloride by a reaction similar to the above. Melting point: 254-257 ° C

Example 185 (1) Methyl 4- {3- [3- (t-butoxycarbonyl) amino] propyl-2- (phenylimino) -2,3-
Dihydrothiazol-4-yl} benzoate

[Chemical 63] T-Butyl 3- (anilinocarbothioylamino) propylcarbamate (6.19 g) obtained in Reference Example 4, 2-
Bromo-4 '-(methoxycarbonyl) acetophenone
Example 1 using (5.14 g) and methanol (51 ml)
The reaction was performed in the same manner as 0 (1) to obtain the title compound (8.84 g). ¹ H-NMR (CDCl ₃ ): δ 1.40 (9H, s), 1.62-1.66 (2H, m),
3.08 (2H, m), 3.96-4.00 (5H, m), 5.71 (1H, m), 5.8
7 (1H, s), 7.05-7.38 (5H, m), 7.47 (2H, d, J = 8.3),
8.13 (2H, d, J = 8.3)

(2) 4- {3- [3- (t-butoxycarbonyl) amino] propyl-2- (phenylimino) -2,3
-Dihydrothiazol-4-yl} benzoic acid

[Chemical 64] A mixture of the compound (4.68 g) obtained in (1) above, 1N-sodium hydroxide aqueous solution (15 ml) and methanol (30 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the resulting solid was filtered off to obtain the title compound (3.85 g).

(3) 4- [3- (3-aminopropyl) -2-
(Phenylimino) -2,3-dihydrothiazole-4-
Ill] benzoic acid

[Chemical 65] Using the compound (300 mg) obtained in (2) above, the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (250 mg) as a hydrochloride salt. Melting point: 248-252 ° C

[0093] In the following examples, the structure was confirmed by NMR and L
It was performed by C / MS. The equipment and conditions of LC / MS are as follows. API 150EX (PE SCIEX), Ionization method: ESI, Voltage: 40 eV Column: Mightysil RP-18 GP (Kanto Kagaku), Flow rate: 3.5 ml / min, Detection wavelength: 220 nm Analytical conditions (A solution: 0.05%) Trifluoroacetic acid aqueous solution, B
Liquid: 0.035% trifluoroacetic acid acetonitrile solution): Method A: 0.0 min (B liquid concentration: 10%) → 0.5 min
(B solution concentration: 10%) → 4.2 min (B solution concentration: 99
%), Method B: 0.0 min (concentration of liquid B: 40%) → 0.5 min
(B solution concentration: 40%) → 4.2 min (B solution concentration: 99%)

Examples 186 to 207 In the same manner as in Example 10 or 11, various α-bromoketones were reacted with thiourea to obtain the compounds shown in Table 16. Table 16 (1)

[0095] Table 16 (Part 2)

[0096] Table 16 (Part 3)

[0097] Table 16 (Part 4)

Table 16 (No. 5)

[0099]

Example 208 N- [3- (3-aminopropyl) -4-[(benzyloxy) methyl] thiazole-2 (3H) -ylidene] -4- (trifluoromethoxy) aniline (1) tyl 3 -{3-[(tert-Butoxycarbonyl) amino] propyl} -2-{[4- (trifluoromethoxy) phenyl] imino} -2,3-dihydrothiazole-4
-Carboxylate

[Chemical 66] T-Butyl 3-{[4- (trifluoromethoxy) anilinocarbothioyl] amino} propylcarbamate (10.0 g) obtained in Reference Example 40, ethyl 2-bromopyruvate (3.29 ml) and ethanol. (50 ml), the reaction was carried out in the same manner as in Example 10 (1), and the product was purified by silica gel column chromatography [n-hexane-ethyl acetate (5: 1)] to give the title compound (7.71 g) as a white solid. Got as.

(2) tert-Butyl 3- [4- (hydroxymethyl) -2-{[4- (trifluoromethoxy) phenyl] imino} thiazol-3 (2H) -yl] propylcarbamate

[Chemical 67] Lithium aluminum hydride (1.0 g) was suspended in tetrahydrofuran (200 ml), and a solution of the compound (3.0 g) obtained in (2) above in tetrahydrofuran (100 ml) was added dropwise in an ice bath under a nitrogen atmosphere. After 1 hour, water was added to the reaction mixture to crush excess lithium aluminum hydride, and 10N aqueous sodium hydroxide solution was added. The resulting slurry was dried over sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title compound (2.61 g).

(3) tert-Butyl 3- [4-[(benzyloxy) methyl] -2-{[4- (trifluoromethoxy) phenyl] imino} thiazol-3 (2H) -yl] propyl carbamate

[Chemical 68] The compound (313 mg) obtained in the above (2) was dissolved in N, N-dimethylformamide (3 ml), and sodium hydride (56 mg, 60% oil dispersion) was added thereto in an ice bath under a nitrogen atmosphere. Stir for minutes. Benzyl bromide (179 mg) was added to the reaction mixture, and the temperature was returned to room temperature.
Stir for hours. The reaction mixture was poured into a 10% aqueous citric acid solution under ice cooling and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography [n
-Hexane-ethyl acetate (5: 1)] to give the title compound (137 mg) as an oil.

(4) N- [3- (3-aminopropyl) -4-
[(Benzyloxy) methyl] thiazole-2 (3H) -ylidene] -4- (trifluoromethoxy) aniline

[Chemical 69] Using the compound (137 mg) obtained in (3) above, a reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (133 mg) as a hydrochloride salt. LC / MS: 438 (MH ⁺ ), retention time 3.52 min
(Condition A)

Example 209 N- [3- (3-aminopropyl) -4-{[(4-chlorobenzyl) oxy] methyl} thiazole-2 (3H) -ylidene] -4- (trifluoromethoxy) aniline

[Chemical 70] The compound (313 mg) obtained in Example 208 (2) and 4-
Using chlorobenzyl bromide (216 mg), the reaction was carried out in the same manner as in Example 208 (3) and (4) to give the title compound (1
52 mg) was obtained as the hydrochloride salt. LC / MS: m / z = 472 (MH ⁺ ), retention time 3.7
2 min (condition A)

Example 210 N- [3- (3-aminopropyl) -4-[(benzyloxy) methyl] thiazole-2 (3H) -ylidene] -5-methoxy-2-pyridinamine (1) tert- Butyl 3- [4- (hydroxymethyl)
-2-[(5-methoxy-2-pyridyl) imino] thiazol-3 (2H) -yl] propyl carbamate

[Chemical 71] T-Butyl 3-[(5-methoxy-, obtained in Reference Example 62)
2-Pyridylaminocarbothioyl) amino] propylcarbamate (10.0 g) was used, Example 208 (1),
The reaction was performed in the same manner as in (2) to obtain the title compound (4 g) as a pale yellow solid.

(2) N- [3- (3-aminopropyl) -4-
[(Benzyloxy) methyl] thiazole-2 (3H) -ylidene] -5-methoxy-2-pyridinamine

[Chemical 72] Using the compound (283 mg) obtained in (1) above, the reaction was carried out in the same manner as in Example 208 (3) and (4) to give the title compound (1
28 mg) was obtained as the hydrochloride salt. LC / MS: m / z = 385 (MH ⁺ ), retention time 2.9.
9 min (condition A)

Example 211 N- [3- (3-aminopropyl) -4-{[(4-chlorobenzyl) oxy] methyl} thiazole-2 (3H) -ylidene] -5-methoxy-2-pyridinamine

[Chemical 73] The compound (276 mg) obtained in Example 210 (1) was used for the same reaction as in Examples 208 (3) and (4) to give the title compound (92 mg) as a hydrochloride salt. LC / MS: m / z = 419 (MH ⁺ ), retention time 3.2
1 min (condition A)

Example 212 N- [3- (3-aminopropyl) -4-{[(4-chlorobenzyl) (methyl) amino] methyl} thiazole-2 (3H)
-Ylidene] -4- (trifluoromethoxy) aniline (1) tert-butyl 3- [4-{[(4-chlorobenzyl) (methyl) amino] methyl} -2-{[4- (trifluoromethoxy) Phenyl] imino} thiazole-3 (2H)-
Il] propyl carbamate

[Chemical 74] The compound (300 mg) obtained in Example 208 (2) and triethylamine (101 mg) were dissolved in tetrahydrofuran (30 ml).
And dissolved in water, and methanesulfonyl chloride (115 mg) was added dropwise under ice cooling. After stirring at the same temperature for 1.5 hours, the reaction mixture was mixed with N-methyl-4-chlorobenzylamine (1.04 g).
Was added dropwise and the mixture was further stirred for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (2: 1)] to give the title compound (83 m
g) was obtained as an oil.

(2) N- [3- (3-aminopropyl) -4-
{[(4-chlorobenzyl) (methyl) amino] methyl} thiazole-2 (3H) -ylidene] -4- (trifluoromethoxy) aniline

[Chemical 75] Example 9 using the compound (80 mg) obtained in the above (1)
The reaction was performed in the same manner as in (2) to obtain the title compound (83 mg) as a hydrochloride salt. LC / MS: m / z = 485 (MH ⁺ ), retention time 3.4.
3 min (condition A)

Example 213 N- [3- (3-aminopropyl) -4-{[(4-chlorobenzyl) (methyl) amino] methyl} thiazole-2 (3H)
-Ylidene] -5-methoxy-2-pyridinamine

[Chemical 76] Using the compound (200 mg) obtained in Example 210 (1), a reaction was carried out in the same manner as in Example 212 to give the title compound (145 m
g) was obtained as the hydrochloride salt. LC / MS: m / z = 432 (MH ⁺ ), retention time 2.83
min (condition A)

Example 214 N-methyl-N ′-{2- [2-[(4-fluorophenyl)
Imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] ethyl} urea

[Chemical 77] Using the amino compound obtained in Example 194 (25 g, hydrochloride), methylisocyanate (3.1 g) and triethylamine (50 ml), the reaction was carried out in the same manner as in Example 177 to crystallize from methanol to give the title compound (12.93 g). )
Got Melting point: 191-194 ° C ¹ H-NMR (CDCl ₃ ): δ 2.66 (3H, d, J = 4.7), 3.24 (4H,
t, J = 4.8), 3.43 (2H, m), 3.86-3.89 (6H, m), 5.10-
5.60 (2H, m), 5.73 (1H, s), 6.95 (2H, d, J = 8.8),
7.03-7.05 (4H, m), 7.27 (2H, dd, J = 1.9, J = 8.2).

Example 215 Ethyl N- {3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl} glycine- To

[Chemical 78] The compound obtained in Example 106 (25 g, free amino compound) and triethylamine (9.78 ml) were dissolved in tetrahydrofuran (250 ml), and ethyl bromoacetate (7.21 ml) in tetrahydrofuran (60 m) was added over 40 minutes under ice cooling.
l) The solution was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-methanol (30: 1)] to give the title compound (24.7 g) as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.23 (3H, t, J = 7.2), 1.77 (2H,
m), 2.54 (2H, t, J = 6.8), 3.26 (2H, s), 3.83 (3H,
s), 3.94 (2H, t, J = 7.2), 4.13 (2H, q, J = 7.2), 5.75
(1H, s), 6.90-6.98 (3H, m), 7.14 (2H, dd, J = 8.4, J
= 8.6), 7.37 (2H, dd, J = 5.3, J = 8.6) LC / MS: m / z = 478 (MH ⁺ ), retention time 3.6.
1 min (condition A)

Example 216 Ethyl N- {3- [2-[(4-chloro-2-methoxyphenylimino)]-4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl} -β -Alaninet

[Chemical 79] The compound obtained in Example 106 (1.74 g, free amino compound) was dissolved in ethanol (10 ml), and ethyl acrylate (0.48 ml) in ethanol (3 ml) was added thereto under ice cooling for 15 minutes.
0 ml) solution was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue [chloroform-methanol (30: 1)]
The title compound (1.87 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.23 (3H, t, J = 7.2), 1.77 (2H,
m), 2.40 (2H, t, J = 6.8), 2.57 (2H, t, J = 6.8), 2.77
(2H, t, J = 6.8), 3.83 (3H, s), 3.93 (2H, t, J = 7.2),
4.09 (2H, q, J = 7.2), 5.76 (1H, s), 6.90-6.97 (3H,
m), 7.14 (2H, dd, J = 8.6, J = 8.6), 7.36 (2H, dd, J =
5.3, J = 8.6). LC / MS: m / z = 492 (MH ⁺ ), retention time 3.6.
0 min (condition A)

Example 217 N- {3- [4- (4-fluorophenyl) -2-[(4-fluorophenyl) imino] thiazol-3 (2H) -yl]
Propyl} guanidine (1) N, N "-di-tert-butoxycarbonyl-N '-{3- [4- (4-fluorophenyl) -2-[(4
-Fluorophenyl) imino] thiazol-3 (2H) -yl] propyl} guanidine

[Chemical 80] The compound (837 mg, free amino body) obtained in Example 116 was dissolved in ethanol (10 ml), and 1,3-bis (ter-butoxycarbonyl) -2-methylisothiourea (639 mg) was dissolved at room temperature under a nitrogen atmosphere. Was added and stirred for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (5: 1)] to give the title compound (1.12 g).

(2) N- {3- [4- (4-fluorophenyl)
-2-[(4-fluorophenyl) imino] thiazole-3
(2H) -yl] propyl} guanidine

[Chemical 81] Using the compound (1.12 g) obtained in (1) above, the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (905 mg) as a hydrochloride salt. LC / MS: m / z = 388 (MH ⁺ ), retention time 2.8
1 min (condition A)

Example 218 N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (Morpholino) phenyl] thiazol-3 (2H) -yl] propyl} -4-morpholinecarboxoxyimidamide (1) tert-butyl 3- [2-[(4-fluorophenyl) imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl [imino (morpholino) methyl] carbamate

[Chemical 82] The compound (522 mg, hydrochloride salt) obtained in Example 195 was suspended in tetrahydrofuran (30 ml), and the method of Katritzky, AR et al.
1- (1H-1,2,3-benzotriazol-1-yl) synthesized by (J. Org. Chem., 2000, 65, 8080-8082)
-1-Morpholinomethanimine (1.16 g) was added and the mixture was stirred overnight. A 10% aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml), and di-t-butyl dicarbonate (240 m) was added at room temperature under a nitrogen atmosphere.
g) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform-methanol (95: 5)],
The title compound (540 mg) was obtained as an amorphous.

(2) N- {3- [2-[(4-fluorophenyl) imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} -4-morpholinecarbo Oxyimidamide

[Chemical 83] Using the compound (535 mg) obtained in (1) above, a reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (467 mg) as a hydrochloride salt. LC / MS: m / z = 525 (MH ⁺ ), retention time 2.9
8 min (Condition A) Example 219 N- {3- [4- (1,3-benzodioxol-5-yl) -2-{[4- (trifluoromethoxy) phenyl] imino} thiazole-3 ( 2H) -yl] propyl} -2-hydroxyacetamide

[Chemical 84] The compound obtained in Example 77 (600 mg, free amino compound), 2-hydroxyacetic acid (156 mg), 1-hydroxybenzotriazole monohydrate (315 mg) and N, N
To a mixture of dimethylformamide (10 ml), hydrochloric acid 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (394 mg) was added and stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (458 mg). ¹ H-NMR (DMSO-d ₆ ): δ 1.67 (2H, m), 3.00 (2H, m), 3.
71 (2H, d, J = 5.7), 3.81 (2H, t, J = 7.9), 5.41 (1H,
t, J = 5.7), 6.11 (2H, s), 6.18 (1H, s), 6.93 (1H, d,
J = 8.1), 7.01-7.11 (4H, m), 7.30 (2H, d, J = 8.4), 7.
71 (1H, m) LC / MS: m / z = 496 (MH ⁺ ), retention time 3.4.
9 min (condition A)

Example 220 N ′-{3- [2-[(4-fluorophenyl) imino] -4
-[4- (morpholino) phenyl] thiazole-3 (2H)-
Ill] propyl} -N, N-dimethylurea

[Chemical 85] It was synthesized by a combinatorial method. That is, 1 ml of a tetrahydrofuran solution (45.3 μmol / ml) of the compound (free amino compound) obtained in Example 195 was added to a tetrahydrofuran solution of triethylamine (118 μmol).
/ Ml) (500 μl) and a solution of N, N-dimethylcarbamoyl chloride in tetrahydrofuran (58.9 μmol /
1 ml) was added, and the mixture was stirred at room temperature for 6 hours. Approximately 10 m of tris-amine resin (Argonaut) in the reaction mixture
g and isocyanate resin (Argonaut) about 20 m
g, and the mixture was stirred at room temperature overnight. The reaction mixture is filtered,
The filtrate was washed twice with chloroform (1 ml), and the filtrate was saturated aqueous sodium hydrogen carbonate solution (2 ml), followed by water (2 m
It was washed twice with l). The organic layer was passed through a filter containing magnesium sulfate, washed twice with chloroform (1 ml), and the filtrate was concentrated to give the title compound (18 mg). LC / MS: m / z = 484 (MH ⁺ ), retention time 3.2
9 min (condition A)

Example 221 N-butyl-N ′-{3- [2-[(4-fluorophenyl)
Imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} urea

[Chemical 86] It was synthesized by a combinatorial method. That is, 1 ml of a tetrahydrofuran solution (45.3 μmol / ml) of the compound (free amino compound) obtained in Example 195 was added to a tetrahydrofuran solution (58.9) of n-butyl isocyanate.
μmol / ml) 1 ml was added, and the mixture was stirred at room temperature for 6 hours. Add tris-amine resin (Argonau) to the reaction mixture.
Company t) about 10 mg and isocyanate resin (Argonau
About 20 mg was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, the filtrate was washed twice with chloroform (1 ml), and the filtrate was saturated aqueous sodium hydrogen carbonate solution (2 ml),
Subsequently, it was washed twice with water (2 ml). The organic layer was passed through a filter containing magnesium sulfate, and chloroform (1 m
l), washed twice, and the filtrate was concentrated to give the title compound (22 m
g) was obtained. LC / MS: m / z = 512 (MH ⁺ ), retention time 3.6.
49 min (condition A)

Example 222 N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} benzamide

[Chemical 87] It was synthesized by a combinatorial method. That is, 1 ml of a tetrahydrofuran solution (45.3 μmol / ml) of the compound (free amino compound) obtained in Example 195 was added to a tetrahydrofuran solution of benzoic acid (58.9 μmol / ml).
1 ml of a tetrahydrofuran solution of 1-hydroxybenzotriazole monohydrate (118 μmol / ml) 500
μl and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in tetrahydrofuran (11
(8 μmol / ml) (500 μl) was added, and the mixture was stirred at room temperature overnight. Chloroform (2.5 ml) was added to the reaction mixture,
Saturated aqueous sodium hydrogen carbonate solution (2 ml), followed by water (2 ml)
ml) and washed twice. The organic layer was passed through a filter containing magnesium sulfate, washed twice with chloroform (1 ml), and the filtrate was concentrated to give the title compound (23 mg). LC / MS: m / z = 517 (MH ⁺ ), retention time 3.5.
5 min (condition A)

Examples 223 to 312 In the following, a reaction was carried out using the corresponding amino compound and Table 1
The compound shown in 7 was obtained. Table 17 (Part 1)

Table 17 (No. 2)

[0123] Table 17 (Part 3)

[0124] Table 17 (Part 4)

Table 17 (No. 5)

[0126] Table 17 (No. 6)

[0127] Table 17 (No. 7)

Table 17 (Part 8)

Table 17 (No. 9)

Table 17 (No. 10)

[0131] Table 17 (Part 11)

Table 17 (12)

Table 17 (No. 13)

Table 17 (14)

Table 17 (No. 15)

Table 17 (No. 16)

Table 17 (No. 17)

Table 17 (No. 18)

Table 17 (No. 19)

Table 17 (20)

Examples 313 to 319 In the following, the compounds shown in Table 18 were obtained by the same reaction as in Example 150 using the corresponding Boc-protected amino compound. Table 18 (1)

[0142] Table 18 (Part 2)

Example 320 4-chloro-N- [4- (4-fluorophenyl) -3-
{3-[(2,2,2-Trifluoroethyl) amino] propyl} thiazole-2 (3H) -ylidene] -2-methoxyaniline

[Chemical 88] To the mixture of the compound obtained in Example 106 (1.0 g, free amino compound), triethylamine (0.72 ml) and tetrahydrofuran (5 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (592 mg). After refluxing for 2 hours under a nitrogen atmosphere, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (85:15)] to give the title compound (8
00 mg) was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.72 (2H, m), 2.64 (2H, t, J = 6.
6), 3.04 (2H, q, J = 9.5), 3.82 (3H, s), 3.95 (2H,
t, J = 6.8), 5.77 (1H, s), 6.90-6.98 (3H, m), 7.15
(2H, dd, J = 8.8, J = 8.6), 7.36 (2H, dd, J = 5.3, J = 8.
8). LC / MS: m / z = 474 (MH ⁺ ), retention time 3.6.
8 min (condition A)

Example 321 2-({3- [2-[(4-chloro-2-methoxyphenyl)
Imino] -4- (4-fluorophenyl) thiazole-3
(2H) -yl] propyl} amino) ethanol (1) tyl N- (tert-butoxycarbonyl) -N
-{3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-3 (2
H) -yl] propyl} glycine

[Chemical 89] A solution of the compound (24.6 g) obtained in Example 215 in tetrahydrofuran (150 ml) was diluted with di-t-butyl dicarbonate (1).
1.26 g) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (27.7 g) as an oil.

(2) tert-Butyl 3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl (2
-Hydroxyethyl) carbamate

[Chemical 90] Tetrahydrofuran of compound (3g) obtained in (1) above
Lithium borohydride (170 mg) was added to the solution (20 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (1: 1)] to give the title compound (2.
14 g) was obtained as an amorphous.

(3) 2-({3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl)
Thiazol-3 (2H) -yl] propyl} amino) ethanol

[Chemical 91] Using the compound (850 mg) obtained in (2) above, the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (758 mg) as a hydrochloride salt. ¹ H-NMR (DMSO-d ₆ ): δ 2.02 (2H, m), 2.89 (4H, m), 3.
63 (2H, t, J = 5.3), 3.89 (3H, s), 4.20 (2H, m), 6.9
3 (1H, s), 7.16 (1H, dd, J = 2.2, J = 8.4), 7.35-7.44
(4H, m), 7.67 (2H, dd, J = 8.6, J = 5.3), 9.10 (2H, br
LC / MS: m / z = 436 (MH ⁺ ), retention time 3.1.
8 min (condition A)

Example 322 3-({3- [2-[(4-chloro-2-methoxyphenyl)
Imino] -4- (4-fluorophenyl) thiazole-3
(2H) -yl] propyl} amino) -1-propanol (1) ethyl N- (tert-butoxycarbonyl) -N
-{3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-3 (2
H) -yl] propyl} -β-alaninate

[Chemical 92] The amino compound (1.87 g) obtained in Example 216 was used and the title compound was obtained in the same manner as in Example 321 (1).
(2.16 g) was obtained as an oil.

(2) 3-({3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl)
Thiazol-3 (2H) -yl] propyl} amino) -1-
Propanol

[Chemical 93] Example 3 using the compound (1.3 g) obtained in the above (1)
21 (2) and (3) were carried out to give the title compound (88
9 mg) was obtained as the hydrochloride salt. LC / MS: m / z = 450 (MH ⁺ ), retention time 3.2
1 min (condition A)

Examples 323 to 326 Hereinafter, using the corresponding ester compound, Example 321 is performed.
By the same reaction as in (2), the compounds shown in Table 19 were obtained. Table 19

Example 327 N- {3- [2-[(4-chloro-2-methoxyphenyl)
Imino] -4- (4-fluorophenyl) thiazole-3
(2H) -yl] propyl} glycine (1) N- (tert-butoxycarbonyl) -N- {3
-[2-[(4-chloro-2-methoxyphenyl) imino]
-4- (4-fluorophenyl) thiazole-3 (2H)-
Ill] propyl} glycine

[Chemical 94] Ethanol of compound (3 g) obtained in Example 321 (1)
(5 ml) solution with 4N-sodium hydroxide aqueous solution (5 ml)
Was added dropwise, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was then acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the title compound (2.
92 g) was obtained as a foam.

(2) N- {3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl} glycine

[Chemical 95] Using the compound (665 mg) obtained in (1) above, the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (577 mg) as a hydrochloride salt. LC / MS: m / z = 450 (MH ⁺ ), retention time 3.2
0 min (condition A).

Example 328 N- {3- [2-[(4-chloro-2-methoxyphenyl)
Imino] -4- (4-fluorophenyl) thiazole-3
(2H) -yl] propyl} -β-alanine (1) N- (tert-butoxycarbonyl) -N- {3
-[2-[(4-chloro-2-methoxyphenyl) imino]
-4- (4-fluorophenyl) thiazole-3 (2H)-
Ill] propyl} -β-alanine

[Chemical 96] The ester compound (850 m) obtained in Example 322 (1)
g) was used and the reaction was carried out in the same manner as in Example 327 (1) to obtain the title compound (715 mg) as a foamy substance.

(2) N- {3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl} -β- Alanine

[Chemical 97] Using the compound (700 mg) obtained in (1) above, the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (588 mg) as a hydrochloride salt. LC / MS: m / z = 464 (MH ⁺ ), retention time 3.2
6 min (condition A).

Example 329 N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} glycine (1) ethyl N- (tert-butoxycarbonyl)-
N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} glycineate

[Chemical 98] The title compound was prepared in the same manner as in Example 321 (1), using the amino compound (3.3 g) obtained in Example 252.
(4.1 g) was obtained as an oil.

(2) N- (tert-butoxycarbonyl)-
N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] -1,3-thiazole-3
(2H) -yl] propyl} glycine

[Chemical 99] Example 3 using the compound (4.1 g) obtained in the above (1)
The reaction was performed in the same manner as in 27 (1) to obtain the title compound (3.0 g) as a foamy substance. (3) N- {3- [2-[(4-fluorophenyl) imino]
-4- [4- (morpholino) phenyl] thiazole-3 (2
H) -yl] propyl} glycine

[Chemical 100] Example 9 using the compound (30 mg) obtained in the above (2)
The reaction was performed in the same manner as (2) to obtain the title compound (31 mg) as a hydrochloride salt. LC / MS: m / z = 471 (MH ⁺ ), retention time 2.9
2 min (condition A)

Example 330 N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] -1,3-thiazole-3
(2H) -yl] propyl} -β-alanine (1) ethyl N- (tert-butoxycarbonyl)-
N- {3-[-2-[(4-fluorophenyl) imino] -4
-[4- (morpholino) phenyl] thiazole-3 (2H)-
Ill] propyl} -β-alanate

[Chemical 101] Using the amino compound (900 mg) obtained in Example 253 and in the same manner as in Example 321 (1), the title compound was obtained.
(1.08 g) was obtained as an oil. (2) N- (tert-butoxycarbonyl) -N- {3
-[(2-[(4-fluorophenyl) imino] -4- [4-
(Morpholino) phenyl] thiazol-3 (2H) -yl) propyl] -β-alanine

[Chemical 102] Using the compound (1.08 g) obtained in (1) above, a reaction was carried out in the same manner as in Example 327 (1) to give the title compound (800 m
g) was obtained as a foam.

(3) N- {3- [2-[(4-fluorophenyl) imino] -4- [4- (morpholino) phenyl] -1,3
-Thiazol-3 (2H) -yl] propyl} -β-alanine

[Chemical 103] Using the compound (300 mg) obtained in (2) above, the reaction was performed in the same manner as in Example 9 (2) to obtain the title compound (310 mg) as a hydrochloride salt. LC / MS: m / z = 485 (MH ⁺ ), retention time 3.1
3 min (condition A)

Example 331 N-[({3- [4- (1,3-benzodioxol-5-yl) -2-{[4- (trifluoromethoxy) phenyl] imino} thiazole-3 ( 2H) -yl] propyl} amino) carbonyl] glycine

[Chemical 104] The compound (800 mg) obtained in Example 277 was used for the same reaction as in Example 327 (1) to crystallize from ethyl acetate to obtain the title compound (726 mg). LC / MS: m / z = 539 (MH ⁺ ), retention time 3.5
0 min (condition A)

Example 332 3-({3- [4- (1,3-benzodioxol-5-yl) -2-{[4- (trifluoromethoxy) phenyl] imino} thiazole-3 (2H ) -Yl] propyl} amino) -3
-Oxopropanoic acid

[Chemical 105] The compound (800 mg) obtained in Example 234 was used for the same reaction as in Example 327 (1) to crystallize from ethyl acetate to give the title compound (726 mg). LC / MS: m / z = 524 (MH ⁺ ), retention time 3.5.
5 min (condition A)

Example 333 [2-({3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-
3 (2H) -yl] propyl} amino) ethoxy] acetic acid (1) ethyl [2-((tert-butoxycarbonyl)
{3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-3 (2
H) -yl] propyl} amino) ethoxy] acetate

[Chemical 106] The compound (1.1 g) obtained in Example 321 (2) was dissolved in tetrahydrofuran (20 ml), and sodium hydride (410 mg, 60% oil dispersion) was divided into several portions in an ice bath under a nitrogen atmosphere. And added and stirred for 30 minutes. Ethyl bromoacetate (0.45 ml) in the reaction mixture
Was added and the mixture was returned to room temperature and stirred for 6 hours. The reaction mixture was poured into a 5% aqueous citric acid solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (8: 2)] to give the title compound (980 mg) as a colorless oil.

[0161] (2) [2-((tert-butoxycarbonyl)
{3- [2-[(4-chloro-2-methoxyphenyl 1) imino] -4- (4-fluorophenyl) thiazole-3 (2
H) -yl] propyl} amino) ethoxy] acetic acid

[Chemical 107] Using the compound (950 mg) obtained in (1) above, a reaction was carried out in the same manner as in Example 327 (1) to give the title compound (762 m
g) was obtained as a foam.

(3) [2-({3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazol-3 (2H) -yl] propyl} amino ) Ethoxy]
Acetic acid

[Chemical 108] Using the compound (750 mg) obtained in the above (2), the reaction was carried out in the same manner as in Example 9 (2) to obtain the title compound (579 mg) as a hydrochloride salt. LC / MS: m / z = 494 (MH ⁺ ), retention time 3.2
7 min (condition A)

Example 334 N ² — {3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-
3 (2H) -yl] propyl} -N ¹ -ethylglycinamide (1) N ^2- (tert-butoxycarbonyl) -N ² —
{3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl) thiazole-3 (2
H) -yl] propyl} -N ¹ -ethylglycinamide

[Chemical 109] Carboxylic acid compound (1.0) obtained in Example 327 (1)
g), ethylamine hydrochloride (297 mg), 1-hydroxybenzotriazole monohydrate (418 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (394 mg) and N, N-dimethylformamide (7 m
l) to the mixture of N, N-diisopropylethylamine
(1.27 ml) was added dropwise and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (1: 1)] to give the title compound (929 mg) as a foamy substance.

(2) N ^2- {3- [2-[(4-chloro-2-methoxyphenyl) imino] -4- (4-fluorophenyl)
Thiazol-3 (2H) -yl] propyl} -N ¹ -ethylglycinamide

[Chemical 110] Using the compound (900 mg) obtained in (1) above, the reaction was performed in the same manner as in Example 9 (2) to obtain the title compound (850 mg) as a hydrochloride salt. LC / MS: m / z = 477 (MH ⁺ ), retention time 3.3.
6 min (condition A)

[0165] Example 335 ^{N 1} - ethyl ^{-N 2 - {3- [2 -} [(4- fluorophenyl) imino] -4- [4- (morpholino) phenyl] thiazole -3 (2H) - yl] propyl } Glycinamide

[Chemical 111] It was synthesized by a combinatorial method. That is, a solution of the compound obtained in Example 329 (2) in dichloromethane (4
3.8 μmol / ml) in 1 ml of N, N-dimethylformamide solution of ethylamine hydrochloride (35.0 μmol / ml)
ml), a dichloromethane solution of diisopropylethylamine (35.0 μmol / ml) and a carbodiimide resin suspension in dichloromethane (79.2 mg / ml).
1 ml of Argonaut) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was washed with dichloromethane (1
After washing twice with (ml), the filtrate was washed twice with saturated aqueous sodium hydrogen carbonate solution (2 ml), and then with water (2 ml) twice. The organic layer was passed through a filter containing magnesium sulfate, washed twice with dichloromethane (1 ml), and the filtrate was concentrated.
90% trifluoroacetic acid (2 ml) was added to the residue, and the mixture was stirred at room temperature for 2 hours.
After stirring for an hour, the mixture was concentrated. The residue was dissolved in dichloromethane (2 ml) and the excess amount of ion exchange resin (Dow
ex1-X8, OH type) was added and stirred at room temperature for 1 hour.
The reaction mixture was filtered and the filtrate was dichloromethane (1 ml).
After washing twice with, the filtrate was concentrated to give the title compound (6 mg). LC / MS: m / z = 498 (MH ⁺ ), retention time 3.0
1 min (condition A)

Examples 336 to 347 Hereinafter, the corresponding carboxylic acid compound and various amines were reacted in the same manner as in Example 334 or Example 335 to obtain the compounds shown in Table 20. Table 20 (1)

Table 20 (Part 2)

Table 20 (Part 3)

Example 348 4-Nitrophenyl 3- [2-[(4-fluorophenyl) imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propylcarbamate

[Chemical 112] The compound obtained in Example 195 (3.0 g, hydrochloride) was suspended in tetrahydrofuran (36 ml), and the suspension was stirred under a nitrogen atmosphere.
Diisopropylethylamine (5 ml) was added dropwise in an ice bath and the mixture was stirred for 30 minutes. Chloroformic acid in the reaction mixture 4
-Nitrophenyl (1.19 g) was added and the mixture was stirred for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from n-hexane-ethyl acetate to give the title compound
(2.57 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.72 (2H, m), 3.23-3.30 (6H,
m), 3.88 (4H, t, J = 4.9), 3.99 (2H, t, J = 6.2), 5.78
(1H, s), 6.96 (2H, d, J = 8.8), 7.02-7.10 (4H, m), 7.
22-7.29 (5H, m), 8.21 (2H, dd, J = 7.1, J = 2.0).

Example 349 N- [2- (dimethylamino) ethyl] -N ′-{3- [2-
[(4-Fluorophenyl) imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} urea

[Chemical 113] The compound (108 mg) obtained in Example 348 was dissolved in dichloromethane (3 ml), and N, N-dimethylethylenediamine (33 mg) was added at room temperature under a nitrogen atmosphere to give 1
Stir for hours. A 1% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (84 mg) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ): δ 1.66 (2H, m), 2.13 (6H, s), 2.2
2 (2H, t, J = 7.2), 3.09-3.19 (4H, m), 3.24 (4H, t,
J = 4.8), 3.87-3.94 (6H, m), 4.68 (1H, t, J = 4.9), 5.
71 (1H, s), 5.94 (1H, m), 6.94 (2H, d, J = 8.8), 6.9
8-7.06 (4H, m), 7.26 (2H, dd, J = 7.0, J = 1.9). LC / MS: m / z = 527 (MH ⁺ ), retention time 2.9.
4 min (condition A)

[0171] Examples 350 to 355 Table 2 below shows the same reaction as in Examples 348 and 349.
The compound shown in 1 was obtained. Table 21 (1)

[0172] Table 21 (Part 2)

Example 356 2-Bromo-N- {3- [2-[(4-phenylolophenyl) imino] -4- [4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} Acetamide

[Chemical 114] Using the compound obtained in Example 195 (2.0 g, hydrochloride) and bromoacetyl chloride (663 mg), Example 1
The reaction was performed in the same manner as in 68 to obtain the title compound (1.2 g) as an amorphous. Example 357 N- {3- [2-[(4-fluorophenyl) imino] -4-
[4- (morpholino) phenyl] thiazol-3 (2H) -yl] propyl} -2- (1-pyrrolidinyl) acetamide

[Chemical 115] The compound (200 mg) obtained in Example 356, pyrrolidine (0.32 ml) and N, N-dimethylformamide (2 m
The mixture of l) was stirred at room temperature for 8 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-methanol (97: 3)] to give the title compound (123 mg) as an oil. ¹ H-NMR (CDCl ₃ ): δ 1.56-1.60 (4H, m), 1.70 (2H,
m), 2.48 (4H, t, J = 5.3), 3.07 (2H, s), 3.15-3.30 (6
H, m), 3.86-3.92 (6H, m), 5.69 (1H, s), 6.92-7.06
(6H, m), 7.25 (2H, d, J = 7.7), 7.85 (1H, t, J = 6.1). LC / MS: m / z = 524 (MH ⁺ ), retention time 2.9.
5 min (condition A)

Examples 358 to 361 [0174] Hereinafter, the same reaction as in Example 357 was carried out to give Example 356.
The compound shown in Table 22 was obtained by reacting the compound obtained in 3 above with various amines. Table 22

Example 362 3- [2-[(2,4-dimethoxybenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] -1-propanamine

[Chemical 116] A solution of thiourea (3.40 g) obtained in Reference Example 90 and 4- (trifluoromethoxy) phenacyl bromide (2.76 g) in ethanol (90 ml) was stirred at room temperature for 22 hours, and then the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (4: 1)] to give a cyclized product (1.32).
g) was obtained. 4N Hydrochloric acid / dioxane (12 ml) was added to the obtained cyclized product (1.20 g), the mixture was stirred at room temperature for 0.5 hr, ether was added, and the title compound (0.87 g) was collected by filtration.
Was obtained as the hydrochloride salt. ¹ H-NMR (DMSO-d ₆ ): δ 1.86 (2H, m), 2.74 (2H, m), 3.
78 (3H, s), 3.87 (3H, s), 4.15 (2H, t, J = 7.2), 4.52
(2H, d, J = 5.0), 6.57 (1H, dd, J = 2.4, J = 8.4), 6.64
(1H, d, J = 2.4), 7.09 (1H, s), 7.36 (1H, d, J = 8.
4), 7.55 (2H, d, J = 8.6), 7.71 (2H, d, J = 8.6), 8.96
(3H, brs), 11.13 (1H, m). LC / MS: m / z = 468 (MH ⁺ ), retention time 3.1.
8 min (condition A) Examples 363 to 372 By the same method as in Example 362 or 373, Table 23
The compound shown in was obtained.

Table 23 (No. 1)

Table 23 (Part 2)

Example 373 N- {3- [2-[(2,4-dimethoxybenzyl) imino]
-4- [4- (trifluoromethoxy) phenyl] -1,3
-Thiazol-3 (2H) -yl] propyl} acetamide

[Chemical 117]

[0179] The compound obtained in Example 362 (250 mg,
Hydrochloride), triethylamine (0.22 ml) and tetrahydrofuran (3 ml) in a mixture of acetic anhydride (48 μl) under ice cooling.
Was added and stirred for 2 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [2% methanol-chloroform] to give the title compound (230 mg). ¹ H-NMR (CDCl ₃ ): δ 1.48 (2H, m), 1.53 (3H, s), 3.12
(2H, m), 3.78-3.83 (8H, m), 4.21 (2H, s), 5.84 (1
H, s), 6.46-6.48 (2H, m), 7.27-7.40 (6H, m). LC / MS: m / z = 510 (MH ⁺ ), retention time 3.5.
9 min (condition A) Examples 374 to 381 By the same method as in Example 373 or 382, Table 24
The compound shown in was obtained.

[0180] Table 24

[0181] Table 24 (Part 2)

Example 382 N- {3- [2-[(4-chlorobenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} -2-methoxyacetamide

[Chemical 118] It was synthesized by a combinatorial method. That is, 1 ml of a tetrahydrofuran solution (45.3 μmol / ml) of the compound (free amino compound) obtained in Example 364 was added to a tetrahydrofuran solution of methoxyacetic acid (58.9 μmol / ml).
1 ml, tetrahydrofuran solution of 1-hydroxybenzotriazole monohydrate (118 μmol / ml)
500 μl and 500 μl of a 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride tetrahydrofuran suspension (118 μmol / ml) were added, and the mixture was stirred at room temperature overnight. Chloroform (2.5 ml) was added to the reaction mixture, and the mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution (2 ml) and then with water (2 ml) twice. Pass the organic layer through a filter containing magnesium sulfate, and add 2 ml of chloroform (1 ml).
After washing twice, the filtrate was concentrated to obtain the title compound. LC / MS: m / z = 514 (MH ⁺ ), retention time 3.
76 min (condition A)

Example 383 N- {3- [2-[(2,4-dimethoxybenzyl) imino]
-4- [4- (trifluoromethoxy) phenyl] -1,3
-Thiazol-3 (2H) -yl] propyl} -2-methoxyacetamide

[Chemical 119] The compound obtained in Example 362 (960 mg, hydrochloride),
And 2-methoxyacetyl chloride (0.2 ml) were reacted in the same manner as in Example 373 to give the title compound (260
mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.64 (2H, m), 3.16-3.26 (5H,
m), 3.70 (2H, s), 3.76-3.89 (8H, m), 4.29 (2H, s),
5.79 (1H, s), 6.46-6.50 (2H, m), 7.26-7.33 (4H,
m), 7.39 (1H, d, J = 8.8), 7.48 (1H, m). LC / MS: m / z = 540 (MH ⁺ ), retention time 3.
69 min (condition A)

Example 384 N- {3- [2-[(4-chlorobenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} -2- (1-pyrrolidinyl) acetamide

[Chemical 120] The compound obtained in Example 364 (100 mg, hydrochloride salt),
Triethylamine (108 μl) and tetrahydrofuran
2-bromoacetyl chloride (3
(0 mg) was added, the mixture was stirred for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-ethyl acetate (1: 1)], and the reaction intermediate (82 m
g) was obtained. Pyrrolidine (0.119 ml) was added to a mixture of the obtained reaction intermediate (80 mg), triethylamine (20 μl) and tetrahydrofuran (5 ml), the mixture was stirred for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [3% methanol-chloroform] and then chlorinated to give the title compound (56 mg) as a hydrochloride salt. LC / MS: m / z = 553 (MH ⁺ ), retention time 3.3.
3 min (condition A) Example 385-401 The compound shown in Table 25 was obtained by the method similar to Example 384 or 402. Table 25 (Part 1)

[0185] Table 25 (Part 2)

[0186] Table 25 (Part 3)

Example 402 N- {3- [2-[(4-chloro-2-methoxybenzyl)
Imino] -4- (4-fluorophenyl) -1,3-thiazol-3 (2H) -yl] propyl} -N′-ethylurea

[Chemical 121] Ethyl isocyanate (0.16 ml) was added to a tetrahydrofuran (5 ml) solution of the compound (800 mg, free amine) obtained in Example 363, and the mixture was stirred for 2 hours, and then the solvent was evaporated under reduced pressure. Isopropyl alcohol was added to the residue and collected by filtration to give the title compound (453 mg). ¹ H-NMR (CDCl ₃ ): δ 0.94 (3H, t, J = 7.2), 1.43 (2H,
m), 2.93-3.06 (4H, m), 3.33 (1H, m), 3.81 (2H, t, J =
6.2), 3.85 (3H, s), 4.18 (2H, s), 5.82 (1H, s), 6.0
6 (1H, m), 6.91 (1H, s), 6.97 (1H, d, J = 8.1), 7.13
(2H, dd, J = 8.6, J = 8.4), 7.33 (2H, dd, J = 8.6, J = 5.
3), 7.44 (1H, d, J = 8.1). LC / MS: m / z = 477 (MH ⁺ ), retention time 3.6.
0 min (Condition A) Examples 403 to 408 By a method similar to that in Example 373, 402 or 409, the compounds shown in Table 26 were obtained.

Table 26

Example 409 N- {3- [2-[(4-chlorobenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} -N ′-(2-methoxyethyl) urea

[Chemical 122] The compound obtained in Example 364 (1.54 g, hydrochloride),
4-Nitrophenyl chloroformate (1.21 g) was added to a mixture of diisopropylethylamine (1.94 g) and tetrahydrofuran (30 ml) under ice-cooling and the mixture was stirred for 2 hours, then saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was diluted with ethyl acetate. Extracted. The organic layer was washed with saturated brine and dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the reaction intermediate (1.
73 g) was obtained. 2-methoxyethylamine was added to a solution of the obtained reaction intermediate (100 mg) in dichloromethane (5 ml).
(25 mg) was added and the mixture was stirred for 2 hours.
Aqueous sodium hydroxide solution was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was added with n-hexane-ethyl acetate (1: 1) and collected by filtration to give the title compound (60 mg). LC / MS: m / z = 543 (MH ⁺ ), retention time 3.7
3 min (condition A)

Example 410 {3- [2-[(4-chlorobenzyl) imino] -4- [4-
(Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl}-(2-hydroxyethyl)
Urea

[Chemical 123] [1160] By a method similar to that in Example 409, the title compound was obtained. LC / MS: m / z = 529 (MH ⁺ ), retention time 3.5.
6 min (condition A)

Example 411 3- [2-[(4-chloro-2-methoxybenzyl) imino] -4- (4-fluorophenyl) -1,3-thiazol-3 (2H) -yl]-(2 -Methoxyethyl) -1-propanamine

[Chemical 124] The compound obtained in Example 363 was Boc-modified according to a conventional method to obtain the compound (1.00 g), sodium hydride.
The mixture of (0.24 g) and dimethylformamide (5 ml) was stirred for 0.5 hours, 2-methoxyethyl bromide was added, and the mixture was stirred for 6 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (4: 1), 4N hydrochloric acid / dioxane (2 ml) was added, the mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. Aqueous ammonia was added to the residue and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (185 m
g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.73 (2H, m), 2.49 (2H, t, J = 6.
8), 2.61 (2H, t, J = 5.1), 3.28 (3H, s), 3.35 (2H,
t, J = 5.1), 3.82-3.86 (5H, m), 4.26 (2H, s), 5.75
(1H, s), 6.85 (1H, d, J = 1.8), 6.93 (1H, dd, J = 1.8,
J = 8.1), 7.12 (2H, dd, J = 8.6, J = 8.4), 7.35 (2H, dd,
J = 8.6, J = 5.3), 7.46 (1H, d, J = 8.1). LC / MS: m / z = 465 (MH ⁺ ), retention time 3.1
3 min (Condition A) Examples 412 to 416 By a method similar to that in Example 411, the compounds shown in Table 27 were obtained.

[0192] Table 27

Example 417 N ² — {3- [2-[(4-chlorobenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} -N ¹ -ethylglycinamide

[Chemical 125] It was synthesized by a combinatorial method. That is, the compound obtained in Example 427 was Boc-modified according to a conventional method, and a dichloromethane solution of the obtained compound (43.8 μmol / m
1), a solution of ethylamine hydrochloride in N, N-dimethylformamide (35.0 μmol / ml) (1 ml) and diisopropylethylamine in dichloromethane (35.0 μmol)
/ Ml) and carbodiimide resin in dichloromethane (79.2 mg / ml Argonaut) 1 ml
Was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was washed twice with dichloromethane (1 ml), and the filtrate was saturated aqueous sodium hydrogen carbonate solution (2 ml), followed by water (2 m).
It was washed twice with l). The organic layer was passed through a filter containing magnesium sulfate, washed twice with dichloromethane (1 ml), and the filtrate was concentrated. 90% Trifluoroacetic acid (2 ml) was added to the residue and the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated. The residue was dissolved in dichloromethane (2 ml), an excess amount of ion exchange resin (Dowex 1-X8, OH type) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filtrate was washed twice with dichloromethane (1 ml), and the filtrate was concentrated,
The title compound was obtained. LC / MS: m / z = 527 (MH ⁺ ), retention time 3.3.
4 min (condition A) Examples 418 to 426 By the same method as in Example 417 or 427, Table 28
The compound shown in was obtained.

[0194] Table 28 (No. 1)

[0195] Table 28 (Part 2)

Example 427 N- {3- [2-[(4-chlorobenzyl) imino] -4-
[4- (trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} glycine

[Chemical 126] The compound obtained in Example 415 was Boc-modified according to a conventional method, and a mixture of the obtained compound (1.23 g), 2N aqueous sodium hydroxide solution (6 ml) and ethanol (6 ml) was stirred for 2 hours, and then the solvent was distilled off under reduced pressure. I left. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4N hydrochloric acid / dioxane (2 ml), the mixture was stirred at room temperature for 3 hours, ether was added, and the mixture was collected by filtration.
The title compound (148 mg) was obtained as the hydrochloride salt. LC / MS: m / z = 500 (MH ⁺ ), retention time 3.3
1 min (condition A)

Example 428 By a method similar to that in Example 427, the following compound was obtained.

[Chemical 127] LC / MS: m / z = 514 (MH ⁺ ), retention time 3.3.
0 min (condition A)

Example 429 N ′-{3- [2-[(4-chloro-2-methoxybenzyl) imino] -4- (4-fluorophenyl) -1,3-thiazol-3 (2H) -yl ] Propyl} guanidine

[Chemical 128] The compound obtained in Example 363 (800 mg, free amine), 1,3-bis (ter-butoxycarbonyl) -2
A mixture of -methylisothiourea (576 mg) and tetrahydrofuran (5 ml) was refluxed for 3 hours, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue
Purification with [n-hexane-ethyl acetate (4: 1) gave a reaction intermediate (529 mg). The obtained reaction intermediate (100
4N hydrochloric acid / dioxane (20 ml) was added to 0 mg) and the mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. Aqueous ammonia was added to the residue and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography [1
0% methanol-chloroform] to give the title compound
(278 mg) was obtained. LC / MS: m / z = 448 (MH ⁺ ), retention time 3.0
8 min (condition A)

Example 430 N ′-{3- [2-[(4-chlorobenzyl) imino] -4-
[4- (Trifluoromethoxy) phenyl] -1,3-thiazol-3 (2H) -yl] propyl} ethanesulfonamide

[Chemical formula 129] It was synthesized by a combinatorial method. That is, 1 ml of a tetrahydrofuran solution (45.3 μmol / ml) of the compound (free amino compound) obtained in Example 364 was added to a tetrahydrofuran solution of triethylamine (118 μmol).
/ Ml) (500 μl) and ethanesulfonyl chloride in tetrahydrofuran (58.9 μmol / ml) 1
ml was added, and the mixture was stirred at room temperature for 6 hours. About 10 mg of tris-amine resin (Argonaut) and about 20 mg of isocyanate resin (Argonaut) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was washed twice with chloroform (1 ml), and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution (2 ml) and then with water (2 ml).
Washed twice. The organic layer was passed through a filter containing magnesium sulfate, washed twice with chloroform (1 ml), and the filtrate was concentrated to give the title compound. LC / MS: m / z = 534 (MH ⁺ ), retention time 3.8
8 min (condition A)

Example 431 3- (3-aminopropyl) -N- (4-chlorophenyl)
-2-[(2,4-dimethoxybenzoyl) imino] -2,3
-Dihydro-1,3-thiazole-4-carboxamide (1) 3- {3-[(tert-butoxycarbonyl) amino] propyl} -2-[(2,4-dimethoxyphenyl) imino] -2,3 -Dihydro-1,3-thiazole-4-carboxylic acid

[Chemical 130] Thiourea (5.00 g) obtained in Reference Example 71, ethyl 2-bromopyruvate (1.74 ml) and ethanol (13
The mixture (0 ml) was heated and stirred at 60 ° C., and then Boc was formed according to a conventional method, and the obtained ester compound (2.46 g) was hydrolyzed according to a conventional method to obtain the title compound.

(2) 3- (3-aminopropyl) -N- (4-
Chlorophenyl) -2-[(2,4-dimethoxybenzoyl) imino] -2,3-dihydro-1,3-thiazole-4
-Carboxamide

[Chemical 131] It was synthesized by a combinatorial method. That is, (1) above
A solution of the compound obtained in 1. in dichloromethane (43.8 μmo
l / ml), 4-chlorophenylamine in dichloromethane (35.0 μmol / ml) (1 ml), diisopropylethylamine in dichloromethane (35.0 μmo).
1 ml of carbodiimide resin in dichloromethane (79.2 mg / ml Argonaut) 1 m
1 was added, and the mixture was stirred overnight at room temperature. The reaction mixture is filtered,
After washing the filtrate twice with dichloromethane (1 ml), the filtrate was saturated aqueous sodium hydrogen carbonate solution (2 ml), followed by water (2 ml).
ml) and washed twice. The organic layer was passed through a filter containing magnesium sulfate, washed twice with dichloromethane (1 ml), and the filtrate was concentrated. 90% Trifluoroacetic acid (2 ml) was added to the residue, the mixture was stirred at room temperature for 2 hr, and the mixture was concentrated to give the title compound as a trifluoroacetic acid salt. LC / MS: m / z = 475 (MH ⁺ ), retention time 3.4.
0 min (Condition A) Examples 432 to 445 By a method similar to that in Example 431, 362 or 373, the compounds shown in Table 29 were obtained.

[0202] Table 29 (No. 1)

[0203] Table 29 (Part 2)

[0204] Table 29 (Part 3)

Example 446 N- [3- [3- (acetamino) propyl] -4- [4-
(Trifluoromethoxy) phenyl] -1,3-thiazole-2 (3H) -ylidene] -2,4-dimethoxybenzamide

[Chemical 132] Thiourea (1.00 g) obtained in Reference Example 80, 2-bromo-4 ′-(trifluoromethoxy) acetophenone
A mixture of (0.87g) and isopropanol (10ml) was stirred at 70 ° C for 1 hour and then allowed to cool to a solid (1.32g).
Was collected by filtration. 25% Hydrobromic acid-acetic acid (9 ml) was added to the obtained solid (3.00 g), the mixture was stirred for 4 hours, the solvent was evaporated under reduced pressure, and the residue was diluted with acetone to give a solid (1.88 g).
g) was collected by filtration. The obtained solid (1.00 g), triethylamine (0.70 ml), 2,4-dimethoxybenzoyl chloride (0.50 g) and a mixture of tetrahydrofuran (7 ml) were stirred under ice cooling for 0.5 hours, and then reacted. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was crystallized from toluene to give the title compound (0.93 g). Melting point: 131-132 ° C ¹ H-NMR (CDCl ₃ ): δ 1.61-1.65 (5H, m), 3.07 (2H,
m), 3.86 (3H, s), 3.93 (3H, s), 4.33 (2H, t, J = 6.
2), 6.54-6.57 (3H, m), 6.79 (1H, m), 7.35 (2H, d, J
= 8.1), 7.43-7.46 (2H, m), 8.11 (1H, dd, J = 7.0, J =
LC / MS: m / z = 524 (MH ⁺ ), retention time 3.7.
2 min (Condition A) Examples 447 to 472 By a method similar to that in Example 373, 446 or 431, the compounds shown in Table 30 were obtained.

Table 30 (No. 1)

Table 30 (Part 2)

Table 30 (Part 3)

Table 30 (Part 4)

Example 473 N- [3- [3- (acetylamino) propyl] -4-
({[(4-Methylphenyl) sulfonyl] amino} methyl) thiazole-2 (3H) -ylidene] -2,4-dimethoxybenzamido (1) ethyl 3- [3- (acetylamino) propyl]-
2-[(2,4-dimethoxybenzoyl) imino] -2,3-
Dihydrothiazole-4-carboxylate

[Chemical 133] A mixture of thiourea (24.64 g) obtained in Reference Example 93, ethyl bromopyruvate (10 ml) and ethanol (700 ml) was heated with stirring at 70 ° C. under a nitrogen atmosphere. 5
After time, the reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (29.36 g) as a hydrobromide salt.

(2) N- [3- [3- (acetylamino) propyl] -4- (hydroxymethyl) thiazole-2 (3H)-
Ylidene] -2,4-dimethoxybenzamide

[Chemical 134] Lithium borohydride (2.0 g) was added to a solution of the hydrobromide-free ester compound (10 g) obtained in (1) above in tetrahydrofuran (300 ml), and the mixture was stirred at room temperature under a nitrogen atmosphere at room temperature. Stir overnight. To the reaction mixture was added 10% aqueous citric acid under ice cooling to destroy excess lithium borohydride, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.3 g).

(3) N- [3- [3- (acetylamino) propyl] -4- (azidomethyl) thiazole-2 (3H) -ylidene] -2,4-dimethoxybenzamide

[Chemical 135] Compound (3.45 g) obtained in the above (2) and triethylamine
(976 mg) was dissolved in DMF (35 ml), and methanesulfonyl chloride (0.75 ml) was added dropwise under ice cooling. After stirring at the same temperature for 1 hour, the reaction mixture was mixed with sodium azide (6
27 mg) was added and the mixture was further stirred for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-methanol (98: 2)] to give the title compound (3.48 g) as an oil.

(4) N- [3- [3- (acetylamino) propyl] -4- (aminoethyl) thiazole-2 (3H) -ylidene] -2,4-dimethoxybenzamide

[Chemical 136] Ethanol (46 m) of the compound (2.3 g) obtained in (3) above
l) in a solution of 10% palladium / carbon catalyst (230 m
g) was added and hydrogenated at normal pressure. After 4 hours, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in a 10% aqueous citric acid solution, washed with chloroform, the aqueous layer was made basic with aqueous ammonia and extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4
8 g) was obtained as an oil.

[0214] (5) N- [3- [3- (acetylamino) propyl] -4-({[(4-methylphenyl) sulfonyl] amino}
Methyl) thiazole-2 (3H) -ylidene] -2,4-dimethoxybenzamide

[Chemical 137] Compound (200 mg) obtained in the above (4) and triethylamine
(100 mg) was dissolved in tetrahydrofuran (5 ml) and p-toluenesulfonyl chloride was added at room temperature under a nitrogen atmosphere.
(117 mg) was added. After 2 hours, add 10 to the reaction mixture.
% Aqueous citric acid solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-methanol (97:32)] to give the title compound (240 mg) as an amorphous substance. LC / MS: m / z = 547 (MH ⁺ ), retention time 3.4.
3 min (condition A) Examples 474 to 542 Examples 321, 373, 382, 402, 409, 41
By a method similar to 1,427, 417, 429, 430 or 446, the compounds shown in Table 31 were obtained.

[0215] Table 31 (1)

[0216] Table 31 (Part 2)

[0217] Table 31 (Part 3)

Table 31 (No. 4)

[0219] Table 31 (Part 5)

[0220] Table 31 (Part 6)

[0221] Table 31 (No. 7)

[0222] Table 31 (Part 8)

[0223] Table 31 (No. 9)

[0224] Table 31 (Part 10)

[0225] Table 31 (Part 11)

[0226] Table 31 (Part 12)

Table 31 (No. 13)

Table 31 (14)

Table 31 (15)

Table 31 (16)

Table 31 (No. 17)

[0232] Table 31 (No. 18)

[0233] Table 31 (No. 19)

[0234] Table 31 (20)

[0235] The crystals of the compounds obtained in Examples 157 and 480 were subjected to structural analysis by X-ray, and as a result, it was confirmed to be the (Z) form. Preferred examples of the compound (1) in which X is an oxygen atom are shown below.

[0236]

[Chemical 138]

Reference Example 1 t-butyl 2-[(anilinocarbothioyl) amino] ethyl carbamate

[Chemical 139] t-Butyl 2-aminoethylcarbamate (1.76m
Phenyl isothiocyanate (1.5 g) was added dropwise to an ethanol (22 ml) solution containing 1) and heated at 75 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and crystallized from n-hexane to give the title compound (3.25 g). ¹ H-NMR (CDCl ₃ ): δ 1.35 (9H, s), 3.33 (2H, m), 3.75
(2H, m), 4.89 (1H, m), 6.86 (1H, m), 7.21-7.46 (5H,
m), 7.72 (1H, brs) Reference Examples 2 to 24 In the same manner as in Reference Example 1, various isothiocyanates were reacted with amine compounds to give thiourea compounds shown in Table 32.

Table 32

Reference Example 25 t-Butyl 3-{[4- (trifluoromethyl) anilinocarbothioyl] amino} propyl carbamate (1) 4- (trifluoromethyl) phenyl isothiocyanate

[Chemical 140] 4- (trifluoromethyl) aniline (1.34 g), thiophosgene (0.73 ml), sodium hydrogen carbonate (5.1
g), chloroform (70 ml) and water (140 ml), using the literature (Burke, TR, Jr .; Bajwa, BS; Jacobso
n, AE; Rice, KC; Streaty, RA; Klee, WA
J. Med. Chem., 1984, 27, 1570-1574) to carry out the reaction to obtain the title compound (1.62 g). ¹ H-NMR (CDCl ₃ ): δ7.33 (2H, d, J = 8.4), 7.62 (2H, d,
(J = 8.4)

(2) t-Butyl 3-({[4- (trifluoromethyl) anilino] carbothioyl} amino) propyl carbamate

[Chemical 141] In the same manner as in Reference Example 1, 4- (trifluoromethyl) phenyl isothiocyanate (1.62 g) was reacted with t-butyl 3- (aminopropyl) carbamate (1.39 g) to give the title compound (2.33 g). ) Was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ): δ1.35 (9H, s), 1.74 (2H, m), 3.11
(2H, m), 3.70 (2H, m), 4.69 (1H, m), 7.38 (2H, d, J
= 8.4), 7.56-7.68 (4H, m)

[0241] Reference Examples 26 to 32 In the same manner as in Reference Example 25, various anilines were reacted with thiophosgene to form isothiocyanate, and then t
-Butyl 3- (aminopropyl) carbamate was reacted to obtain the thiourea compounds shown in Table 33. Table 33

Reference Example 33 t-Butyl 3-({[2- (trifluoromethoxy) anilino] carbothioyl} amino) propyl carbamate

[Chemical 142] Tetrahydrofuran (1 containing 2- (trifluoromethoxy) aniline (1.8 g) and triethylamine (2.9 ml)
To the solution, thiophosgene (0.8 ml) was added dropwise in an ice bath under a nitrogen atmosphere. Then return to room temperature, 2
Stir for hours. T-Butyl 3- (aminopropyl) carbamate (1.39 g) was added to the reaction mixture, and the mixture was further stirred for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform] to give the title compound
(2.9 g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ): δ 1.36 (9H, s), 1.72 (2H, m), 3.11
(2H, m), 3.70 (2H, m), 4.78 (1H, t, J = 6.4), 7.27-
7.54 (6H, m)

Reference Example 34 t-butyl 3-{[(2,4,6-trifluoroanilino)
Carboti oil] amino} propyl carbamate

[Chemical 143] Using 2,4,6-trifluoroaniline (1.5 g),
The title compound (1.1 g) was obtained by the same method as in Reference Example 33. ¹ H-NMR (CDCl ₃ ): δ 1.36 (9H, s), 1.59 (2H, m), 2.91
(2H, m), 3.40 (2H, m), 6.83 (1H, m), 7.24 (2H, t,
J = 9.0), 7.90 (1H, brs), 8.90 (1H, brs)

Reference Example 35 t-butyl 3-{[(2,4 dichloro-6-methoxyanilino) carbothioyl] amino} propylcarbamate

[Chemical 144] Using 2,4-dichloro-6-methoxyaniline (1.0 g) and in the same manner as in Reference Example 33, the title compound (99
7 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.33 (9H, s), 1.67 (2H, m), 3.10
(2H, m), 3.65 (2H, m), 3.84 (3H, s), 4.71 (1H,
m), 6.88 (1H, d, J = 2.2), 6.97 (1H, brs), 7.06 (1H,
m), 7.11 (1H, d, J = 2.2)

Reference Example 36 (1) t-Butyl 3-isothiocyanatopropylcarbamate

[Chemical 145] t-Butyl 3-aminopropyl carbamate (17.4
g), triethylamine (1.4 ml), carbon disulfide (30.
2 ml) and tetrahydrofuran (100 ml), and used in a literature (Li, G. Tajima; H., Ohtani, TJ Org. Chem., 19
97, 62, 4539-4540) to give a title compound (15.2 g). ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.89 (2H, m), 3.25
(2H, m), 3.60 (2H, t, J = 6.6), 4.64 (1H, brs)

(2) t-butyl-{[(2,3-methylenedioxyphenylamino) carbothioyl] amino} propylcarbamate

[Chemical 146] Neville et al. (Neville, CF et al, J. Chem. Soc.
2,3-methylenedioxyphenylamine (698) obtained by the method described in Perkin Trans. 1, 1991, 259-262).
A mixture of (mg), t-butyl 3-isothiocyanatopropylcarbamate (1.1 g) and dioxane (10 ml) was heated under reflux under a nitrogen atmosphere. After 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether-n-hexane to give the title compound (803 mg). ¹ H-NMR (CDCl ₃ ): δ 1.37 (9H, s), 1.73 (2H, m), 3.14
(2H, m), 3.71 (2H, m), 4.79 (1H, m), 6.03 (2H,
s), 6.71-6.88 (3H, m), 7.12 (1H, m), 7.35 (1H, brs)

Reference Examples 37 to 57 In the same manner as in Reference Example 36 (2), various anilines were reacted with t-butyl 3-isothiocyanatopropylcarbamate to obtain the thiourea compounds shown in Table 34.

[0248] Table 34

Reference Example 58 N- [3- (dimethylamino) propyl] -N ′-(2-pyridyl) thiourea

[Chemical 147] Ethyl 2-pyridyldithiocarbamate (600m
g), 3- (dimethylamino) propylamine (0.38 m
A mixture of 1) and ethanol (6 ml) was heated to reflux under a nitrogen atmosphere. After 1.5 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (786 mg) as a crude oil. ¹ H-NMR (CDCl ₃ ): δ 1.89 (2H, m), 2.23 (6H, s), 2.40
(2H, t, J = 7.0), 3.76 (2H, m), 6.73 (2H, d, J = 8.3),
6.96 (1H, m), 7.64 (1H, m), 8.18 (1H, m), 8.44 (1
H, brs), 11.72 (1H, brs)

Reference Example 59 t-butyl 3-{[(2-pyridyl ruamino) carbothioyl] amino} propyl carbamate

[Chemical 148] In the same manner as in Reference Example 58, ethyl 2-pyridyldithiocarbamate (1.98 g) and t-butyl 3-aminopropylcarbamate (1.74 g) were reacted and crystallized from n-hexane-diethyl ether to give the title compound ( 2.7
8 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.89 (2H, m), 3.25
(2H, m), 3.84 (2H, m), 5.04 (1H, brs), 6.75 (1H, d,
J = 8.2), 6.97 (1H, m), 7.65 (1H, m), 8.21 (1H, m),
8.54 (1H, brs), 11.81 (1H, brs)

Reference Example 60 t-butyl 4-{[(2-pyridyl ruamino) carbothioyl] amino} butyl carbamate

[Chemical 149] In the same manner as in Reference Example 58, ethyl 2-pyridyldithiocarbamate (500 mg) and t-butyl 4-aminobutylcarbamate (474 mg) were reacted and crystallized from n-hexane-diethyl ether to give the title compound (2.7
8 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ1.44 (9H, s), 1.59-1.80 (4H, m),
3.20 (2H, m), 3.76 (2H, m), 4.63 (1H, brs), 6.73
(1H, d, J = 8.4), 6.96 (1H, m), 7.65 (1H, m), 8.19
(1H, m), 8.43 (1H, brs), 11.72 (1H, brs)

Reference Example 61 t-butyl 3-{[(4-pyridylamino) carbothioyl] amino} propylcarbamate

[Chemical 150] Hansen et al. (Hansen, ET; Peterson, HJ Sy
nthetic Commun., 1984, 14, 537-546), methyl 4-pyridyldithiocarbamate (35
0 mg), t-butyl 3-aminopropyl carbamate
(364 mg) was reacted in the same manner as in Reference Example 58 to obtain the title compound (2.78 g). ¹ H-NMR (CDCl ₃ ): δ1.42 (9H, s), 1.78 (2H, m), 3.18
(2H, m), 3.75 (2H, m), 4.83 (1H, brs), 7.30 (2H, d,
J = 4.8), 7.97 (1H, brs), 8.52 (2H, d, J = 4.8)

Reference Example 62 t-butyl 3-({[(5-methoxy-2-pyridyllu) amino] carbothioyl} amino) propylcarbamate (1) methyl 5-methoxy-2-pyridyldithiocarbamate

[Chemical 151] Lombardino, JGJ Med. Che
m. 1981, 24, 39-42), and tetrahydrofuran (5 m containing 2-amino-5-methoxypyridine (1.26 g) and triethylamine (1.48 ml).
Carbon disulfide (0.61 ml) was added dropwise to 1). After stirring overnight at room temperature, diethyl ether was added to the reaction mixture, and a yellow solid was collected by filtration. Methyl iodide (0.35 m) was added to a suspension of methanol (6 ml) containing the obtained solid (1.7 g).
l) was added dropwise. The mixture was stirred at room temperature for an hour, and the generated crystals were filtered off to give the title compound (993 mg). ¹ H-NMR (CDCl ₃ ): δ 2.68 (3H, s), 3.87 (3H, s), 7.28
(1H, dd, J = 8.2, J = 3.1), 8.08 (1H, d, J = 3.1), 8.44
(1H, m), 9.69 (1H, brs)

(2) t-butyl 3-({[(5-methoxy-2
-Pyridylul) amino] carbothioyl} amino) propylcarbamate

[Chemical 152] By a method similar to that in Reference Example 58, methyl 5-methoxy-2-pyridyldithiocarbamate (950 mg) and t-
Butyl 3-aminopropyl carbamate (772 mg)
And crystallized from n-hexane-ethanol,
The title compound (1.51 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.88 (2H, m), 3.24
(2H, m), 3.79-3.85 (5H, m), 5.05 (1H, brs), 6.68
(1H, d, J = 8.8), 7,26 (1H, dd, J = 8.8, J = 2.8), 7.88
(1H, d, J = 2.8), 8.27 (1H, brs), 11.53 (1H, brs)

Reference Example 63 t-butyl 3-({[(5-methyl-2-pyridyl) amino]
Carbothioyl oil} amino) propyl carbamate

[Chemical 153] In the same manner as in Reference Example 62, the reaction was performed using 5-methyl-2-aminopyridine (4 g) to give the title compound (1.
47 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.88 (2H, m), 2.28
(3H, s), 3.24 (2H, m), 3.82 (2H, m), 5.05 (1H, br
s), 6.64 (1H, brs), 7.48 (1H, d, J = 7.3), 8.01 (1H,
s), 8.27 (1H, m), 11.70 (1H, brs)

Reference Example 64 t-butyl 3-{[(3,4,5-trimethoxyanilino)
Carbothioyl] amino} propylcarbamate (1) t-butyl 3-{[(methylsulfanyl) carbothioyl] amino} propylcarbamate

[Chemical 154] Carbon disulfide (2.07 ml) was added dropwise to tetrahydrofuran (10 ml) containing t-butyl 3-aminopropylcarbamate (6 g) and triethylamine (5.03 ml),
Stir at room temperature for 2.5 hours. Methyl iodide (2.14 ml) was added dropwise to the reaction mixture at room temperature to 0.5.
Stir for hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (11 g) as a crude oil. ¹ H-NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.78 (2H, m), 2.63
(3H, s), 3.21 (2H, m), 3.83 (2H, m), 4.80 (1H, br
s), 8.30 (1H, brs) (2) t-butyl 3-{[(3,4,5-trimethoxyanilino) carbothioyl] amino} propylcarbamate

[0257]

[Chemical 155] t-Butyl 3-{[(methylsulfamoyl) carbothionyl] amino} propylcarbamate (3 g) 3,4,5-
Trimethoxyaniline (2.07g) and xylene (20m
The mixture of l) was heated to reflux under a nitrogen atmosphere. After 9 hours, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [chloroform-ethyl acetate (19:
1)] to obtain the title compound (1.46 g). Amorphous ¹ H-NMR (CDCl ₃ ): δ 1.37 (9H, s), 1.73 (2H, m), 3.12
(2H, m), 3.69 (2H, m), 3.84 (3H, s), 3.85 (6H,
s), 4.79 (1H, brs), 6.48 (2H, s), 7.09 (1H, brs),
7.62 (1H, brs)

Reference Example 65 t-Butyl 3-[({[2- (4-pyridyl) ethyl] amino} carbothioyl) amino] propyl carbamate

[Chemical 156] t-Butyl 3-{[(methylsulfamoyl) carbothionyl] amino} propylcarbamate (1 g), 4- (2-
Aminoethyl) pyridine (462 mg) and ethanol (10
ml) and react in the same manner as in Reference Example 64.
(977 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.42 (9H, s), 1.70 (2H, m), 3.92
(2H, m), 3.17 (2H, m), 3.61-3.76 (4H, m), 5.03 (1
H, m), 6.61 (1H, m), 7.18 (2H, d, J = 5.6), 7.19 (1
H, m), 8.43 (2H, d, J = 5.6) Reference Examples 66 to 80 and 93 In the same manner as in Reference Example 1, various isothiocyanates were reacted with amine compounds to synthesize the thioureas shown in Table 35. did.

Table 35

[Chemical 157]

Reference Examples 81 to 92 Various amine compounds were reacted with t-butyl 3-isothiocyanatopropylcarbamate in the same manner as in Reference Example 36 (2) to synthesize the thioureas shown in Table 36. Reference Example 93 N- (2-aminoethyl) -N '-(4-fluorophenyl)
Thiourea hydrochloride

[Chemical 158] 4N hydrochloric acid-dioxane (30 ml) was added to t-butyl 2-[(fluoroanilinocarbothioyl) amino] ethyl carbamate (4.27 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. Toluene was added to the residue and the solvent was evaporated under reduced pressure to give the title compound (3.4 g). ¹ H-NMR (d-DMSO): δ 3.01 (2H, m), 3.78 (2H, m), 7.
16 (2H, m), 7.43 (2H, m), 7.98 (2H, br), 8.08 (1H,
t, J = 5.8), 10.12 (1H, br)

[0261]

[Chemical 159] N- [2-[[[(4-Fluorophenyl) amino] carbonothioyl] amino] ethyl] -N'-methylurea N- (2-aminoethyl) -N '-(4-fluorophenyl)
Thiourea hydrochloride (3.4g), triethylamine (5m
Methyl isocyanate (1.01 g) was added to a mixed solution of l) and tetrahydrofuran (50 ml), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue for extraction, and the organic layer was washed with saturated brine.
After liquid separation, the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (3.6 g) was obtained as crystals. ¹ H-NMR (CDCl ₃ ): δ 2.73 (3H, δ, J = 4.9), 3.39 (2H,
m), 3.73 (2H, m), 4.39 (1H, br), 4.84 (1H, m), 7.00
(1H, br), 7.12 (2H, dd, J = 8.7, J-2.3), 7.24 (2H,
m), 7.52 (1H, br)

[0262] Table 36

[Chemical 160]

[0263] Pharmacological testTest example 1 Receptor binding evaluation test of compounds using rat lung membrane Sugazawa et al. (Sugasawa, T. et al., J. Biol. Che
m., 272, 21244-21252 (1997)).
It was.

[0264]Preparation of rat lung membrane SD male rats (7 weeks old at the time of testing, Charles River Japan
ー) Remove the trachea and blood vessels from the isolated lung, shred, and
Squirrel-Saline buffer (10 mM Tris-HCl-154
It was washed with mM sodium chloride, pH 7.4). This
Buffer for Modification (1mM Ethylenediaminetetraacetic acid (E
DTA), 1 mM 4- (2-aminoethyl) benzenesulfate
Honyl fluoride (AEBSF), 5 μg / ml apro
-Tins containing 5 μg / ml leupeptin)
Saline homogenize with a Hiscotron while cooling with ice in a buffer solution.
It was tuned (maximum speed: 1 minute). Low speed centrifugation (1500 xg,
After 20 minutes at 4 ° C, the supernatant was ultracentrifuged (100,000 xg, 2
0 minutes, 4 ° C), and the pellet is Tris-saline buffer solution.
And stored at -80 ° C. Protein concentration is bovine blood
Clear albumin (BSA) as standard Bio-Rad
It was measured with a protein assay kit manufactured by.

[0265]Ligand binding test 96-well non-protein-adsorbing round-bottomed assay plate (Iwashiro Glass
1nM in each well (purchased from a subsidiary)¹²⁵I] -Iodine
Cyanopindolol (purchased from Amersham) 10 μM
Serotonin, 20 μm dl-propranol, 10 μM
Entramine, 1.1 mM ascorbic acid and 100
200 μl of Tris-saline buffer containing μg lung membrane
Add, mix by pipetting and mix at 37 ° C for 3
Incubated for 0 minutes. Test compound is 100%
Dissolve in tyl sulfoxide solution and add 2 μl (final DMSO
Concentration: 1%). Also, determine the amount of non-specific binding
Instead of the test compound, a final concentration of 100 μM L
-Threo-3- (3,4-dihydroxyphenyl) -N-
[3- (4-Fluorophenyl) propyl] serine pyrrolidi
Namide was added. During this time, multi-screen play
G (96 hole B fiberglass, Millipore Cat. No. MA
FB NOB10) with 0.3% polyethyleneimine (PEI) / tri
30 minutes or more after adding 100 μl of physiological saline buffer
Incubated. Suction filtration washing (200 μl ice-cold
Squirrel-saline buffer was added and aspirated), and the 96-well
The reaction solution on the assay plate is a multi-screen plate.
Suction filter wash four times above. Multi screen plate
Punch the B glass fiber filter paper at the bottom and place it on the filter paper.
Wrapped [¹²⁵I] -of iodocyanopindolol
The γ-dose was measured and used as the binding amount. DMSO (final
Concentration: 1%) The total amount of binding in the presence of 100 μ
ML-threo-3- (3,4-dihydroxyphenyl)-
N- [3- (4-fluorophenyl) propyl] serine pyro
The binding amount in the presence of lysine amide was defined as the non-specific binding amount. Total
The value obtained by subtracting the non-specific binding amount from the binding amount is the specific binding.
Is the amount. The compound binding activity is calculated according to the following formula
The test compound is¹²⁵I] -Iodocyanopine
Inhibits specific binding of drol to rat lung membrane SMBS
It is shown as a percentage.

[0266] The results are shown in Tables 37 to 45. Table 37 Binding activity of Example compounds (test concentration 30 μM)

[0267]

[0268] Table 38 Binding activity of Example compounds (test concentration 30 μM)

[Chemical 161]

Table 39 Binding activity of Example compounds (test concentration 30 μM)

[Chemical 162]

Table 40 Binding activity of example compounds (test concentration 1 μM)

Table 41 Binding activity of Example compounds (test concentration 1 μM)

Table 42 Binding activity of Example compounds (test concentration 1 μM)

Table 43 Binding activity of Example compounds (test concentration 1 μM)

Table 44 Binding activity of Example compounds (test concentration 1 μM)

Table 45 Binding activity of Example compounds (test concentration 1 μM)

[0276]Test example 2 Evaluation of compounds in the guinea pig late-onset asthma model An evaluation test was conducted using the compound obtained in Example 1. Hart
Enter the ley male guinea pig (purchased from Japan SLC)
After preliminarily breeding after loading for about 1 week, 2% (w / v) egg white al
Bumin (OA) physiological saline is ultrasonic nebulizer (OM
RON NE-U12, conditions: maximum atomization amount, maximum air volume)
Use in a plastic box (4 / box)
It was exposed by inhalation for 5 minutes and sensitized (day 0). Similar operation
I went on the 7th day. Each one on the 14th or 15th day,
2% OA was inhaled for 5 minutes to induce the reaction (Charen
Di). One hour before this challenge, the antihistamine
Pyrilamine Leinate (dissolved in physiological saline, 10 mg / 2
(ml / kg) was administered intraperitoneally. Test compound is 0.5%
Suspended in methylcellulose (MC) at 2 o'clock for antigen challenge
2 times before and 6 hours later, 100 mg / 5 ml / kg
It was administered intraperitoneally. The control group was also 0.5% M
C was administered. Hutson et al. For measuring and analyzing respiratory function
Law (Penny A. Hutson et al. Am Rev Respir Dis 1988 1
37, 548-557). Before antigen challenge (drug
Before administration) and antigen challenge 5 minutes, 3, 17, 20 o'clock
After a while, the respiratory function was measured and the waveform was recorded in MacLab Chart v3.4 (AD
 Instruments) and use it later to solve
Was analyzed. Specific airway conductanc
e; sGaw), and using this as an index, the degree of improvement in respiratory function
Was evaluated. The results are shown in Table 46.

[0277] Table 46 As shown in Table 46 above, a significant reduction in sGaw was observed in the control group 5 minutes after the antigen challenge.
(Immediate asthmatic reaction: IAR), and a significant decrease in sGaw was observed after 17 and 20 hours (delayed asthmatic reaction:
LAR). The test compound showed a tendency to suppress the IAR that occurred immediately after the reaction was initiated. 20 expressing LAR
At the time value, the test compound showed a tendency to suppress LAR (the rate of change of sGaw was the control group: −36.7 ±).
4.6%, test compound group: -14.2 ± 15.0%, about 60% of inhibition).

[0278]Test example 3 Evaluation of compounds in guinea pig leukocyte infiltration model
Value Sensitization, challenge, pyrilamine maleate and drugs
The administration was performed in the same manner as in Test Example 2. Bronchoalveolar lavage fluid
(BALF) recovery was performed 24 hours after challenge.
That is, pentobarbital (50 mg / ml) was added to 0.5
ml / mouse, intraperitoneally administered for anesthesia
The abdomen is opened and the abdominal descending abdominal aorta is cut and exsanguinated.
Let it die. Make an incision in the diaphragm and then an incision in the neck.
After exposing the tube and inserting the cannula after tracheotomy, 5 ml
5 ml of ice-cold saline was injected using a syringe.
After injection, repeat injection and suction three times using the same recovery solution
After filtering with a stainless mesh, turn it into a tube on ice.
I got it. Do this twice and collect the collected liquid in the same tube
(If the amount of collected liquid is less than 7 ml, do not use as data.
I). 1500 after reading the collected amount by visual inspection after collection
Centrifugation at rpm, 4 ℃ for 3 minutes, discard the supernatant, and perform hypotonic hemolysis
I went. Centrifuge at 1500 rpm for 3 minutes at 4 ℃
Discard, phosphate buffer containing 0.5% BSA (PBS (-))
The cells were suspended in 1 ml. Automatic white with this suspension
The total cell number was measured with a blood cell counter. After measurement, the site
Prepare slides using spin and stain with Diff Quick
Stained using the kit. Smear slide with an optical microscope
Observed, eosinophils, neutrophils, macrophores in 300 cells
Di and lymphocytes were measured. The results are shown in Table 47.

Table 47 As shown in Table 41 above, a significant increase in the total cell number was observed between the saline-administered group and the control group. Compared with this control group, the test compound administration group suppressed the total cell number by 82%. Regarding eosinophils, a significant increase was observed between the saline-administered group and the control group. Compared with this control group, the test compound administration group suppressed the number of eosinophils by 79%. Regarding lymphocytes, a significant increase was observed between the saline-administered group and the control group. Compared with this control group, the test compound administration group suppressed the lymphocyte count by 70%.

Test Example 4 By the same method as in Test Example 1, a receptor binding evaluation test using a synthetic compound of rat lung membrane was performed. The results are shown in Tables 48-51. Table 48

[0281] Table 49

[0282] Table 50

[0283] Table 51

The 5-membered ring compound of the present invention or a salt thereof,
Alternatively, their prodrugs inhibit the infiltration of leukocytes such as eosinophils and lymphocytes, and are thus useful for the treatment of various inflammations.

[0284]

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/506 A61K 31/506 31/5375 31/5375 A61P 29/00 A61P 29/00 37/02 37/02 37 / 08 37/08 43/00 105 43/00 105 C07D 277/42 C07D 277/42 417/14 417/14 // C07D 417/04 417/04 417/12 417/12 (72) Inventor Fujio Ande Osaka City Konohana-ku, 3-1,98 Kasugade, Sumitomo Pharmaceutical Co., Ltd. (72) Inventor, Toshinari Sugasawa, 3-3-198, Kasuga, Konohana-ku, Osaka, Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hajime Kawakami Sumitomo Pharma Co., Ltd. F-Terms (Reference) 4C033 AD09 AD13 AD20 4C063 AA01 AA03 BB01 BB09 CC62 CC75 CC81 CC92 DD12 DD15 DD25 DD29 DD34 DD62 EE01 4C086 AA01 AA02 BC73 BC82 GA02 GA04 GA07 GA08 GA10 GA12 MA01 MA04 ZB07 ZB11 ZB13 ZB21

Claims (23)

[Claims] 1. The formula (1) [Chemical 1] [X represents an oxygen atom or a sulfur atom. R¹Is hydrogen
Atom, substituted or unsubstituted alkyl, substituted or unsubstituted
Substituted aryl, or substituted or unsubstituted monocyclic or
Represents a bicyclic heterocyclic group. R^TwoIs a hydrogen atom,
Or unsubstituted alkyl, substituted or unsubstituted aryl,
Substituted or unsubstituted monocyclic or bicyclic heterocycle
Group, or -CON (R ⁶) R⁷Represents R⁶Is the hydrogen source
Represents a child or substituted or unsubstituted alkyl. R⁷Is
Substituted or unsubstituted aryl, substituted or unsubstituted monocycle
Formula represents a heterocyclic group, or substituted or unsubstituted alkyl
You Or, -N (R⁶) R⁷Represents a cyclic imino group
Good. Y¹Is a single bond, a substituted or unsubstituted alkylate
-CO (CH_Two)_n-, -SO _Two(CH_Two)_n-, -C
ONH (CH_Two)_n-, -CSNH (CH_Two)_n-Or
-COO (CH_Two)_nRepresents-. n represents an integer from 0 to 5
You Wavy lines mean (E) or (Z) coordination. R^ThreeIs
Hydrogen atom, substituted or unsubstituted aryl, substituted or
Unsubstituted monocyclic heterocyclic group, substituted or unsubstituted bicyclic
Telocyclic group, or substituted or unsubstituted cycloalkyl
Represent Y^TwoIs a substituted or unsubstituted alkylene, or
Represents alkenylene. R^FourIs a hydrogen atom, substituted or
Unsubstituted alkanoyl, substituted or unsubstituted alkyl,-
COOR⁸, -SO_TwoR⁹, -COR¹⁰, -CON
(R¹¹) R¹², -CSN (R^Thirteen) R¹⁴, Cycloal
Kill, substituted or unsubstituted aryl, substituted or unsubstituted
A substituted monocyclic heterocyclic group, -C (= NH) N (R¹⁵) R¹⁶To
Represent R⁵Is a hydrogen atom, or a substituted or unsubstituted
Represents Luquil. Or, -N (R^Four) R⁵Is a cyclic imino group
May be represented. R⁸Is a substituted or unsubstituted alkyl
Group, cycloalkyl, substituted or unsubstituted aryl, or
Or represents a substituted or unsubstituted monocyclic heterocyclic group. R⁹
Is substituted or unsubstituted alkyl, substituted or unsubstituted
Aryl, or substituted or unsubstituted monocyclic heterocyclic group
Represents R¹⁰Is cycloalkyl, substituted or non-substituted
Substituted aryl, or substituted or unsubstituted monocyclic heterocycle
Represents a group. R¹¹Represents a hydrogen atom or alkyl.
R¹²Is a hydrogen atom, substituted or unsubstituted alkyl,
Chloroalkyl, substituted or unsubstituted aryl, substituted if
Or unsubstituted arylcarbonyl, or substituted or non-substituted
Represents a substituted monocyclic heterocyclic group. Or, -N (R ¹¹) R
¹²May represent a cyclic imino group. R^ThirteenIs the hydrogen source
Represents a child or alkyl. R¹⁴Is a hydrogen atom,
Or unsubstituted alkyl, cycloalkyl, substituted or
Unsubstituted aryl, substituted or unsubstituted aryl carbonyl
Or a substituted or unsubstituted monocyclic heterocyclic group.
You Or, -N (R^Thirteen) R¹⁴Represents a cyclic imino group
May be. R¹⁵Represents a hydrogen atom or alkyl.
R¹⁶Is a hydrogen atom or substituted or unsubstituted alkyl
Represent Or, -N (R¹⁵) R¹⁶Represents a cyclic imino group
May be used] or a five-membered ring compound represented by
Contains the above acceptable salts or their prodrugs
Medicine. 2. When Y ¹ is a single bond, —N (R ⁴ ).
The 5-membered ring compound according to claim 1, wherein R ⁵ is not amino, dialkylamino or acetylamino, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 3. The formula (2) [Chemical 2] [X represents an oxygen atom or a sulfur atom. R¹Is hydrogen
Atom, substituted or unsubstituted alkyl, substituted or unsubstituted
Substituted aryl, or substituted or unsubstituted bicyclic heterocycle
Represents a group. R^TwoIs a hydrogen atom, substituted or unsubstituted
Kill, substituted or unsubstituted aryl, substituted or unsubstituted
Represents a substituted bicyclic heterocyclic group. Y¹Is a single bond or substitution
Or unsubstituted alkylene, -CO (CH_Two)_n-Or-
SO_Two(CH_Two)_nRepresents- (n represents an integer from 0 to 5)
). The wavy line means (E) or (Z) coordination. R^ThreeIs
Substituted or unsubstituted aryl, substituted or unsubstituted monocyclic
5- or 6-membered heterocyclic group, or substituted or non-substituted
Represents a substituted bicyclic heterocyclic group. Y^TwoReplaces or does not
It represents a substituted alkylene or alkenylene. R^FourIs water
Elementary atom, alkanoyl, aroyl, substituted or unsubstituted
Alkyl, alkylcarbamoyl, alkoxycarbonyl
Alkylaminothiocarbonyl, alkylsulfoni
Or a substituted or unsubstituted arylsulfonyl group
You R ⁵Is a hydrogen atom or a substituted or unsubstituted
And a 5-membered ring compound according to claim 1
Or a pharmaceutically acceptable salt thereof or a prod thereof.
A drug containing rag. 4. The formula (3): [X represents an oxygen atom or a sulfur atom. R ¹ is a hydrogen atom; alkyl; alkyl substituted with a hydroxyl group, halogen atom or amino; aryl; alkoxy, alkoxy substituted with a halogen atom, hydroxyl group, halogen atom,
Cyano, amino, mono- or di- (alkyl) amino,
5-membered or 6-membered cyclic imino group which may further contain oxygen atom or nitrogen atom as a ring-forming hetero atom, nitro, alkyl, halogen atom or alkyl group substituted with halogen atom or hydroxyl group, substituted with cycloalkyl, cycloalkyl Alkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
Nitrogen substituted with one or more of groups selected from the group consisting of sulfamoyl, alkylsulfamoyl, di (alkyl) sulfamoyl, aryl, and alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group; nitrogen 5 members or 6 containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms
Membered heterocycle and benzene ring fused bicyclic heterocycle group;
Alternatively, a two-membered ring formed by condensing a benzene ring with a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom substituted with a group selected from alkyl, alkoxy, halogen atom and hydroxyl group. Represents a cyclic heterocyclic group. R ² is a hydrogen atom; alkyl; an alkyl substituted with a group selected from a hydroxyl group, a halogen atom or amino; an aryl; an alkoxy, an alkoxy substituted with a halogen atom, a hydroxyl group, a halogen atom, cyano, amino, mono- or di- -(Alkyl) amino, 5-membered or 6-membered cyclic imino which may further contain an oxygen atom or a nitrogen atom as a ring-forming hetero atom, nitro, alkyl, an alkyl substituted with a halogen atom or a hydroxyl group, cycloalkyl, cyclo Alkyl substituted with alkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, di ( Alkyl, sulfamoyl, aryl, and aryl substituted with one or more groups selected from the group consisting of alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group; selected from nitrogen atom, oxygen atom and sulfur atom A bicyclic heterocyclic group condensed with a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms and a benzene ring; or a nitrogen atom or oxygen substituted with a group selected from alkyl, alkoxy, halogen atom or hydroxyl group. It represents a bicyclic heterocyclic group in which a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from atoms and sulfur atoms and a benzene ring are condensed. Y ¹ is a single bond; straight chain or branched chain C ₁
-C ₅ alkylene; linear or branched C ₁ -C ₅ alkylene substituted with a hydroxyl group, a halogen atom or an amino group; -CO (CH ₂ ) _n- ; -SO ₂ (CH ₂ ) _n- n represents an integer of 0 to 5). R ³ is aryl; alkoxy, alkoxy substituted with a halogen atom, hydroxyl group, halogen atom, cyano, amino, mono- or di- (alkyl) amino, nitro, alkyl, alkyl substituted with a halogen atom or hydroxyl group, cyclo Alkyl, alkyl substituted with cycloalkyl, methylenedioxy, ethylenedioxy, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, di
(Alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, di (alkyl) sulfamoyl, aryl, and a group selected from the group consisting of alkyl, alkoxy, aryl substituted with a halogen atom or a hydroxyl group. An aryl substituted with one or two or more kinds; a monocyclic 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom;
A monocyclic 5-membered or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom substituted with a group selected from alkyl, alkoxy, a halogen atom and a hydroxyl group; a nitrogen atom; Bicyclic heterocyclic group in which a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from oxygen atom and sulfur atom and a benzene ring are condensed; or a group selected from alkyl, alkoxy, halogen atom and hydroxyl group Represents a bicyclic heterocyclic group in which a 5-membered or 6-membered heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom substituted with and a benzene ring are condensed. Y ² is a linear or branched C
_2- C ₅ alkylene; linear or branched C ₂ -C ₅ alkylene substituted with a group selected from hydroxyl group, alkoxy, halogen atom, amino, and alkanoylamino; or linear or branched C ₃ -C ₅ represents alkenylene. R ⁴ is a hydrogen atom; alkanoyl; aroyl; alkyl; alkyl substituted with a group selected from a hydroxyl group, an alkoxy, a halogen atom and an amino group; alkylcarbamoyl; alkoxycarbonyl; alkylaminothiocarbonyl; alkylsulfonyl; arylsulfonyl; or alkyl Represents an arylsulfonyl substituted with. R ⁵ is a hydrogen atom; alkyl; or a hydroxyl group,
Represents an alkyl substituted with a group selected from a halogen atom and amino], and a pharmaceutical containing the 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 5. A 5-membered ring compound according to any one of claims 1 to 4, wherein X is a sulfur atom, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 6. A 5-membered ring compound according to any one of claims 1 to 5, wherein R ¹ is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 7. R ² is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic or bicyclic heterocyclic group, —CON (R ⁶ ) R ⁷ , or substituted or unsubstituted A 5-membered ring compound according to any one of claims 1 to 6, which is a heterocyclic group carbonyl, or a pharmaceutically acceptable salt thereof, or a drug containing a prodrug thereof. 8. A 5-membered ring compound according to any one of claims 1 to 6, wherein R ² is substituted or unsubstituted aryl, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 9. Y ¹ is a substituted or unsubstituted alkylene,
_{-CO (CH 2) n -,} - SO 2 (CH 2) n -, - CON
_{H (CH 2) n -,} - CSNH (CH 2) n -, or -C
5 as described in any one of (1) to (8), which is OO (CH ₂ ) _n −.
A pharmaceutical containing a membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 10. Y ¹ is a single bond, —CO—, —SO ₂ —,
9. A 5-membered ring compound according to any one of claims 1 to 8 which is -CONH- or -COO-, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 11. The 5-membered ring compound according to claim 1, wherein Y ¹ is a single bond or —CO—, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 12. The 5-membered ring compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is a substituted or unsubstituted aryl, or a substituted or unsubstituted monocyclic heterocyclic group. Or a drug containing a prodrug thereof. 13. A wavy line means a (Z) configuration.
A pharmaceutical containing the 5-membered ring compound or the pharmaceutically acceptable salt thereof, or a prodrug thereof. 14. The 5-membered ring compound according to any one of claims 1 to 13, Y ² is ethylene or trimethylene, or a pharmaceutically acceptable salt thereof, or a drug containing a prodrug thereof. 15. R ⁴ is a substituted or unsubstituted alkanoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbamoyl, a substituted or unsubstituted alkylaminothiocarbonyl, or a substituted or claim 1 is unsubstituted alkoxycarbonyl, 15. A drug containing the 5-membered ring compound according to any of 14 or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 16. The 5-membered ring compound according to any one of claims 1 to 14 or a pharmaceutically acceptable compound thereof, wherein R ⁴ is a substituted or unsubstituted alkanoyl, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkylcarbamoyl. A drug containing a salt or a prodrug thereof. 17. The 5-membered ring compound according to any one of claims 1 to 15, wherein R ⁵ is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 18. The formula (4): [Chemical 4] [Ring A represents a benzene ring or a pyridine ring. m is 2
Or 3 is represented. Y^ThreeRepresents a single bond or carbonyl
You R¹⁷Is 1 or 2 and is a halogen atom, C₁
-C_FourAlkoxy, trifluoromethoxy, morpholino
And methylenedioxy are independently selected. R
¹⁸Is 1 or 2 and is a halogen atom, C₁-C_Four
Independent from alkoxy, trifluoromethoxy and hydroxyl
Standing and selected. R¹⁹Is C₁-C_FourAlkyl; water
Acid group, C₁-C_FourAlkoxy, mono or di (C₁−
C_FourAlkyl) amino, morpholino or carboxy
C replaced by ₁-C_FourAlkyl; C₁-C_FourAlkyl
Amino; or hydroxyl group, C₁-C_FourAlkoxy, mono
Shiji (C₁-C_FourAlkyl) amino, morpholino
C substituted with carboxy₁-C_FourAlkylamino
Or a five-membered ring compound according to claim 1
Is its pharmaceutically acceptable salt, or their prodrugs.
A drug containing guar. 19. The 5-membered ring compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein R ¹⁹ is not methyl, when Y ³ is a single bond, or a medicament containing a prodrug thereof. 20. Ring A is a benzene ring, (i) Y ³ is a single bond, R ¹⁹ is C ₁ -C ₄ alkylamino, or (ii) Y ³ is carbonyl and R ¹⁹ is C
A 5-membered ring compound according to claim 8, which is _1- C ₄ alkyl, or a pharmaceutically acceptable salt thereof, or a drug containing a prodrug thereof. 21. The pharmaceutical agent according to claim 1, which is a leukocyte infiltration inhibitor. 22. The medicine according to claim 1, which is a therapeutic agent for inflammation. 23. The pharmaceutical agent according to claim 1, which is a therapeutic agent for autoimmune disease-induced inflammation or allergic inflammation.