JPH09124571A - Amide and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an unknown amide which has excellent preventive action against production and liberation of inflammatory cytokine such as interleukine-8 and tumor necrosis factor and is useful as a therapeutic and preventive medicine for inflammation diseases. SOLUTION: This amide is represented by formula I [R is a (lower alkyl) amino group; A<1> to A<3> are each a single bond, (substituted) alkylene; L is an arylene; Ra and Rb are each H, OH; X is O, S; M is an arylene; R<1> to R<4> are each H, OH, a halogen; R<5> is H, a (halogen-substituted) alkyl; R<6> is a benzene ring-condensed cycloalkyl], typically N- 3,5-dichloro-2-hydroxy-4-[4-(2- methylaminoethyl)benzoyloxy]benzoyl}-L-phenylalanine ethyl ester. The compound of formula I is prepared by using a compound of formula II (' means that amino group is protected, when necessary), a compound of formula III (R<19> is a protecting group; W is a halogen) and a compound of formula IV as main raw materials to carry out the reactions of condensation, reduction, deprotection and others.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to interleukin-8 (IL-8) and interleukin-1 (IL-).
1), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), GM-CSF and other so-called inflammatory cytokines that are directly or indirectly involved in inflammation. The present invention relates to a novel compound, and a medicine containing the compound, for example, an anti-inflammatory agent.

[0002]

2. Description of the Related Art Inflammation is one of the defensive reactions of the living body that is aimed at eliminating foreign substances, pathogenic bacteria, etc. and repairing damaged tissues. Upon receiving an inflammatory stimulus, first, a reaction of the microcirculatory system, particularly an increase in blood vessel permeability occurs. Chemical mediators and cytokines play an important role in this enhancement of blood vessel permeability. Subsequently, neutrophil migration, invasion, and activation occur, and the inflammatory reaction is triggered by the phagocytosis of foreign substances and pathogens and the release of chemical mediators in the local area of inflammation. Following neutrophils, migration and local accumulation of macrophages occur, and activated macrophages phagocytose foreign substances, pathogens, tissue breakdown products, etc., as with neutrophils, and produce various cytokines. Then, when the pathogenic bacteria, the foreign body, and the damaged tissue are removed and the tissue is reconstructed, the inflammation ends. Although the above is inflammation as a normal reaction, in allergies and autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), abnormal immune reactions result in prolonged inflammation or the appearance of strong systemic symptoms.

Many cytokines play an important role in each site of the inflammatory reaction. For example, leukocyte invasion into the inflammatory site requires leukocyte migration, adhesion to vascular endothelial cells, and passage through vascular wall. However, IL-1 and T
NF-α, IL-8, etc. are involved, and IL-1, TN
Neutrophils are activated by F-α and IL-8, release of lysosomal enzymes, production of active oxygen, prostaglandins, etc. occur, causing inflammation. IL-1, TNF-α, IL
When -6 and the like move into the circulation, they act on the liver to induce the production of acute-phase inflammatory proteins (CRP, SAA, etc.) and act on the bone marrow to cause an increase in neutrophils and platelets. In connective tissue inflammation such as rheumatoid arthritis (RA), IL-1,
It is said that TNF-α activates fibroblasts and osteoclasts and induces the production of prostaglandins and collagenases (Mebio, 11 (2), 18-23, 1994). in this way,
IL-1 and TNF-α play a central role in each phase of the inflammatory response.

By the way, taking IL-8 as an example, this IL
-8 is not only peripheral blood monocytes and tissue macrophages,
It is also produced by large granular lymphocytes (LGL) known as natural killer cells, T lymphocytes and various tissues / cells (fibroblasts, vascular endothelial cells, keratinized skin cells, etc.). At that time, as production stimulants, LPS, PHA, PSK (Coriolus ver.
Examples include mitogen lectins such as sicolor-derived protein-binding polysaccharide and krestin), and cytokines such as IL-1 and TNF-α. Many of these cells constitutively produce little IL-8, but I
When stimulated by an L-8 production stimulator, it produces 100 times more IL-8 within 24 hours than when it was not stimulated. For example, when human peripheral blood mononuclear cells are stimulated with PSK,
IL-8 mRNA is induced within 1 hour, and the amount of IL-8 mRNA reaches a peak after 3 hours, and then gradually decreases. With the induction of IL-8 mRNA, an IL-8 protein having a neutrophil migration ability was detected in the medium 3 hours after stimulation and gradually increased. The time course of IL-8 mRNA induction by IL-1, TNF-α stimulation is similar. IL
-8 is extremely stable against proteolytic enzymes produced by activated macrophages and the like.

[0008] Further, to describe the biological activity of IL-8, IL-8 has an in vitro effect on chemotaxis, degranulation inducing action, respiratory burst inducing action on neutrophils, It has an action of inducing lysosomal enzyme release, an action of inducing adhesion to unstimulated or stimulated vascular endothelial cells, an action of enhancing extravasation, an action of enhancing adhesion factor expression, an action of inducing leukotriene B ₄ -HETH release, etc. Has a chemotaxis-promoting action on B cells, an IgE production-suppressing action by IL-4 on B cells, a chemotaxis-promoting action on basophils, and a histamine / leukotriene release-inducing action. . In vivo, it has neutrophil / lymphocyte infiltration-inducing action, neutrophilia-inducing action, vascular permeability-enhancing action, and neutrophil-dependent synovial destruction. (Clinical immunity, 25 (8), 1013
-1020, 1993). As described above, IL-8 has various actions on neutrophils, but in addition to neutrophils, it also acts on T lymphocytes, basophils, monocytes, keratinocytes, melanoma cells and the like. It has been found to act, and its biological activity, target cells, as well as other cytokines, has been found to be truly diverse.

On the other hand, in vivo, IL-8 induces infiltration of neutrophils and lymphocytes into the injection site by intradermal injection, and also increases homing of T lymphocytes to local lymph nodes. It has been known. It is also known that the number of neutrophils in peripheral blood is remarkably increased by intravenous or intraperitoneal injection, and destruction of alveoli and the like is caused by large-scale administration. It is also known that intra-cavitary administration of IL-8 to rabbit knee joints causes destruction of joint synovium accompanied by a large amount of neutrophil infiltration. The above suggests that IL-8 has a strong inflammatory action in vivo.

As described above, IL-8 has various actions in addition to the neutrophil chemotactic action, and further, IL-8 is detected in the synovial fluid of gout and rheumatoid arthritis. In the case of dermatitis such as psoriasis, IL-8 is detected from the skin pieces, or in the case of asthma, the peripheral blood mononuclear cells produce IL-8-like chemotactic factor. And adult respiratory distress syndrome (adult r
In sepsis, which is considered to be one of the causes of espiratory distress syndrome (ARDS), IL-in the peripheral blood
From the fact that 8 has been detected, it is clear that IL-8 is involved in various diseases including inflammation.

Therefore, such IL-1, IL-6,
If substances that suppress cytokines involved in inflammation such as IL-8 and TNF-α can be obtained, these substances can be used for rheumatic diseases such as rheumatoid arthritis, arthritis due to gout, systemic lupus erythematosus, psoriasis, pustulosis, and atopic properties. Skin diseases such as dermatitis, respiratory diseases such as bronchial asthma, bronchitis, ARDS, and diffuse interstitial pneumonia, inflammatory bowel disease (ulcerative colitis, Crohn's disease), acute and chronic hepatitis including severe hepatitis , Acute / chronic glomerulonephritis, pyelonephritis, uveitis associated with Behcet's disease / vogt-Koyanagi / Harada disease, Mediterranean fever (multiple serositis), ischemic diseases such as myocardial infarction, systemic circulation associated with sepsis It is also extremely useful as a new type of therapeutic agent for non-infectious and infectious diseases accompanied by infiltration of neutrophils represented by insufficiency and multiple organ failure. In particular, it is expected that the novel mechanism of action will be effective as an anti-inflammatory agent.

Under such a technical background, recently, IL
Compounds having inflammatory cytokine inhibitory activity such as −8 have been reported. For example, special table HEI 7-503017
In the publication, 4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- is used as a cytokine inhibitor.
Imidazole derivatives such as (4-pyridyl) imidazole are disclosed in JP-A 7-503018 as pyridyl derivatives such as 1- (4-pyridyl) -2- (4-fluorophenyl) -4-phenylimidazole as cytokine inhibitors. As the substituted imidazole derivative, JP-A-3-34959 discloses a naphthalenemethanamino derivative having cytokine inhibitory activity. However, there is no description suggesting the compound of the present invention in these publications. In addition, a compound having a proteolytic enzyme inhibitory activity involved in inflammatory diseases has been reported. For example, JP-A-4-330
094 discloses a t-butyloxycarbonyl-trimethylsilyl-Ala-P as a serine protease inhibitor such as thrombin that induces proinflammatory changes such as IL-1.
ro-NH-CH [(CH _{2) 3} N _3] -B- pinanediol, Japanese Patent Publication No. Hei 5-279315, such as 4'-amidinophenyl 3-aminobenzoate as a proteolytic enzyme inhibitor benzoate amidino A phenyl ester derivative is disclosed in WO94 / 13631 as a proteolytic enzyme inhibitor such as 2- [4- (4-guanidinobenzoyloxy) phenyl] propionic acid benzyl ester as a propionic acid derivative. Discloses a phenylalanine derivative such as N- (trans-4-aminomethylcyclohexylcarbonyl) -L-phenylalanine 4-acetylanilide as a protease inhibitor. Further, JP-A-62-111963 discloses p-guanidinobenzoic acid thiophenyl ester derivatives such as p-guanidino-benzoic acid 4-ethoxycarboxymethylthiophenyl ester as an elastase inhibitor, and JP-A-63-165357 discloses. Is p-guanidinobenzoic acid 3-chloro- as an elastase inhibitor
Disclosed are p-guanidinobenzoic acid phenyl ester derivatives such as 5- {N- (4-sulfamoylphenyl) carbamoyl} phenyl ester. However,
There is no description suggesting the compound of the present invention in these publications.
Further, a compound that inhibits phospholipase A ₂ involved in inflammatory diseases has been reported. For example, Japanese Patent Application Laid-Open
286922 discloses guanidinophenol derivatives such as p- (N-benzyl-N-phenylcarbamoyl) benzoic acid p-guanidinophenyl ester as phospholipase A ₂ inhibitors.

The object of the present invention is to provide IL-8, IL-1, T
It is intended to provide a compound that can be a novel selective anti-inflammatory agent that suppresses the production and release of inflammatory cytokines such as NF-α and IL-6. Another object of the present invention is to provide a medicine containing the compound.

[0011]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have completed the present invention.

That is, the present invention is as follows.

(1) General formula (I):

[0014]

[Chemical 6]

[0015] {In the formula, R R _d; alkoxy group substituted with R _d; alkylthio group substituted with R _d; alkylamino group substituted with R _d; aminosulfonyl group; a halogen atom, a hydroxyl group, a mercapto Group; halogenated lower alkyl group; carboxyl group; or optionally substituted nitrogen-containing heterocyclic group [wherein R _d is amino group, guanidino group, amidino group, carbamoyl group, ureido group, thioureido group, hydrazino group] A hydrazinocarbonyl group or an imino group (these groups may be substituted with a substituent selected from a lower alkyl group, a halogenated lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or an amino protecting group) A], A ¹ , A ² and A ³ are the same or different and may be substituted, and one or more double bonds or A linear or branched alkylene group which may have a triple bond; or a single bond, L is an arylene group; a cycloalkylene group; or one or more hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom. A divalent aromatic heterocyclic group having an atom and optionally forming a condensed ring, wherein R _a and R _b are the same or different and each is a hydrogen atom;
Hydroxyl group; halogen atom; amino group which may be substituted with alkyl group or amino protecting group; alkyl group which may be substituted with halogen atom, hydroxyl group or amino group (wherein the amino group is an alkyl group or amino protecting group) An alkoxy group which may be substituted with a halogen atom, a hydroxyl group or an amino group (wherein the amino group may be substituted with an alkyl group or an amino protecting group); an alkylthio group; represents or alkylsulfonyl group, X is an oxygen atom; halogenated lower alkyl group; a cyano group; a nitro group; a carboxyl group; an alkoxycarbonyl group; aminosulfonyl group sulfur atom; -NR ⁷ -; - S
_{O -; - SO 2 -;} - CO -; - CR 8 R 9 -; - CH
= CH-;-C≡C-;-COO-;-OOC-;-N
^{R 7 CO -; - CONR 7} -; - NR 7 SO 2 -; - S
^{_{O 2 NR 7 -; - CS}} -; - COS -; - O-CO-O
^{-; - NR 7 -COO -;} - OOC-NR 7 -; - NH
-CO-NH-;-NH-CS-NH-;-NH-C
(= NH) -NH-; a divalent aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; or a cycloalkylene group [wherein R ⁷ is a hydrogen atom; An alkyl group; a cycloalkyl group; an aryl group; an aralkyl group; or an amino protecting group, and R ⁸ and R ⁹ are the same or different and represent a hydrogen atom; an alkyl group; a cycloalkyl group; an aryl group; or an aralkyl group]. Represents an arylene group; a cycloalkylene group; or a divalent heterocyclic group having one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom and which may form a condensed ring. ^{, R 1, R 2, R} 3, R 4 are the same or different, a hydrogen atom, a hydroxyl group, a halogen atom; a hydroxyl group may also be substituted with a substituent selected from a lower alkoxy group or a halogen atom Group; alkoxy group; mercapto group; alkylthio group; amino group which may be substituted with a substituent selected from alkyl group, aryl group, aralkyl group or amino protecting group; nitro group; cyano group; carboxyl group; alkoxycarbonyl group; an aryloxycarbonyl group; an acyl group; with or -O-CO-R ¹⁰ [wherein, R ¹⁰ is an amino group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyloxy group, an aryl group, an aryloxy group, an aryl An alkyl group which may be substituted with a substituent selected from an oxycarbonyl group, an aralkyloxy group, an aralkyloxycarbonyl group, an alkylthio group, an arylthio group, an acyl group or a halogen atom (wherein the amino group is a lower alkyl group or an amino group). May be substituted with a protecting group); Substitution An optionally substituted alkoxy group; an optionally substituted aryl group; an optionally substituted cycloalkyl group; an optionally substituted aryloxy group; an optionally substituted aralkyloxy group; a substituted Represents an optionally substituted alkylthio group; or an optionally substituted arylthio group], and R ⁵ represents a hydrogen atom; an alkyl group optionally substituted with a halogen atom; an optionally substituted aralkyl group; or amino Represents a protecting group, R ⁶ is a benzene ring-fused cycloalkyl group;

[0016]

Embedded image

[Wherein m is 0 or an integer selected from 1 to 6, n is an integer selected from 1 to 6 and R ¹¹ is an optionally substituted aryl group; Alkyl group; optionally substituted lower alkyl group;
Optionally substituted lower alkoxy group; optionally substituted lower alkylthio group; optionally substituted amino group with lower alkyl group, aryl group, aralkyl group or amino protecting group; substituted And a heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom;
OR ¹⁶ (wherein R ¹⁶ represents a hydrogen atom; a lower alkyl group; or an amino group which may be substituted with a lower alkyl group or an amino-protecting group), and R ¹² represents a hydrogen atom; Alkyl group; optionally substituted aryl group; optionally substituted aralkyl group; optionally substituted and aromatic having at least one hetero atom selected from nitrogen atom, sulfur atom or oxygen atom A heterocyclic group; or —CO (Y) _p R ¹⁷ (wherein Y is an oxygen atom;
Sulfur atom; -NR ¹⁸ -; or -NR ¹⁸ -SO ₂ - (R ¹⁸
Represents a hydrogen atom; an alkyl group; an aralkyl group; a hydroxyl group; an alkoxy group; an aryl group; or an amino protecting group),
p is 0 or 1, R ¹⁷ is a hydrogen atom; one or more selected from a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxycarbonyl group, an acyloxy group, a carboxyl group, an amino group, or a nitrogen atom, a sulfur atom or an oxygen atom. An alkyl group which may be substituted with a substituent selected from a heterocyclic group having a hetero atom (wherein the amino group is substituted with a substituent selected from an alkyl group, an aryl group, an aralkyl group or an amino protecting group). Optionally)); an optionally substituted alkenyl group; an optionally substituted alkynyl group; an optionally substituted cycloalkyl group;
Optionally substituted aryl group; optionally substituted aralkyl group; optionally substituted heterocyclic group having one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom; adamantyl Group; or a cycloalkylideneamino group), R ¹³ is a hydrogen atom; or a lower alkyl group, R ¹⁴ is a lower alkyl group; an aralkyl group; or an aryl group, R ¹⁵ is an aryl group; an aralkyl group; Atom, a sulfur atom or a heterocyclic group having one or more heteroatoms selected from oxygen atoms], or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

(2) In the general formula (I), R, A ¹ ,
A ² , A ³ , L, R _a , R _b , X, M, R ¹ , R ² , R
^At least one symbol selected from ³ , R ⁴ , R ⁵ and R ⁶ satisfies the following definition (1): the amide compound or a pharmaceutically acceptable salt thereof, or Prodrug. R is R _d1; R _d1 alkoxy group substituted with; R _d1 alkylthio group substituted with; alkylamino group substituted by R _d1; or which may nitrogen-containing substituted by a lower alkyl group or an amino protecting group Heterocyclic group [wherein R _d1 is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group or an imino group (these groups are lower alkyl groups, halogenated groups Which may be substituted with a substituent selected from a lower alkyl group or an amino protecting group). A ¹ , A ² ,
A ³ are the same or different and each represents a linear or branched alkylene group which may have one or more double or triple bonds in the chain; or a single bond. L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a , R _b
Are the same or different and are a hydrogen atom; a hydroxyl group; a halogen atom; an amino group which may be substituted with an alkyl group or an amino protecting group; an alkyl group which may be substituted with a halogen atom, a hydroxyl group or an amino group (wherein The amino group may be substituted with an alkyl group or an amino protecting group); a halogen atom, a hydroxyl group or an alkoxy group optionally substituted with an amino group (wherein the amino group is substituted with an alkyl group or an amino protecting group) Optionally)); an alkylthio group; or a halogenated lower alkyl group. X represents an oxygen atom; a sulfur ^{atom; -NR 7 '-; - SO} -; - SO 2 -;
^{-CO -; - CR 8 'R} 9'-; - CH = CH -; - C
≡C -; - COO -; - OOC -; - NR 7 'CO-;
^{-CONR 7 '-; - NR 7} ' SO 2 -; - SO 2 NR
⁷ '-;-CS-;-COS-;-O-CO-O-;-
^{NR 7 '-COO -; - OOC} -NR 7'-; - NH-
CO-NH-;-NH-CS-NH-;-NH-C (=
NH) -NH-; a divalent aromatic heterocyclic group having one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom; or a cycloalkylene group [wherein R ⁷ 'is a hydrogen atom; An alkyl group; an aralkyl group; or an amino protecting group, and R ⁸ ′ and R ⁹ ′ are the same or different and represent a hydrogen atom; an alkyl group; or an aralkyl group. M
Is an arylene group; a cycloalkylene group; or a nitrogen atom,
It represents a divalent heterocyclic group having one or more heteroatoms selected from a sulfur atom or an oxygen atom and which may form a condensed ring. R ¹ , R ² , R ³ and R ⁴ are the same or different,
Hydrogen atom; hydroxyl group; halogen atom; lower alkyl group optionally substituted by a substituent selected from hydroxyl group, lower alkoxy group or halogen atom; lower alkoxy group; mercapto group; lower alkylthio group; lower alkyl group, aralkyl group or An amino group which may be substituted with a substituent selected from an amino protecting group; or —O—CO—R ¹⁰ ′ [wherein R ¹⁰ ′ is an amino group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyloxy group. Group, aralkyloxy group, aralkyloxycarbonyl group or a lower alkyl group optionally substituted with a substituent selected from an acyl group (wherein, the amino group may be substituted with a lower alkyl group or an amino protecting group) Lower alkoxy group; lower alkyl group, carboxyl group or benzyloxycarbonyl group Optionally substituted aryl group;
Or represents a cycloalkyl group which may be substituted]. R ⁵ represents a hydrogen atom; an alkyl group which may be substituted with a halogen atom; an aralkyl group which may be substituted; or an amino protecting group. R ⁶ is a benzene ring-fused cycloalkyl group;

[0019]

Embedded image

[Where m is an integer selected from 0 or 1 to 6, n is an integer selected from 1 to 6 and R ¹¹ ′ is a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group or an amino group. An aryl group which may be substituted with a carboxyl group or a lower alkoxycarbonyl group; a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a cycloalkyl which may be substituted with a lower alkoxycarbonyl group Group; optionally substituted lower alkyl group; lower alkyl group, aryl group, aralkyl group, amino group optionally substituted with a substituent selected from amino-protecting group; lower alkyl group,
Halogen atom, hydroxyl group, lower alkoxy group, amino group,
A heterocyclic group which may be substituted with a carboxyl group or a lower alkoxycarbonyl group and has one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom; or —COOR ¹⁶ ′ (wherein R ¹⁶ 'Represents a hydrogen atom or a lower alkyl group) and R ¹² ' is a hydrogen atom; and may be substituted with a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group or an amino group. Lower alkyl group; aryl group; aralkyl group; aromatic heterocyclic group which may be substituted with lower alkyl group and has one or more hetero atoms selected from nitrogen atom, sulfur atom or oxygen atom; _{^{(Y 1) p R 17 '}} ( where, Y ¹ is an oxygen atom; a sulfur atom; -NR ^18' -; or -NR ¹⁸ '-SO
_2- (R ¹⁸ 'represents a hydrogen atom; a lower alkyl group; an aralkyl group; a hydroxyl group; an alkoxy group; or an amino protecting group)
, P is 0 or 1, R ¹⁷ ′ is a hydrogen atom; one selected from a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, a carboxyl group, an amino group, or a nitrogen atom, a sulfur atom or an oxygen atom. An alkyl group which may be substituted with a substituent selected from the above heterocyclic groups having a hetero atom (wherein the amino group is substituted with a substituent selected from a lower alkyl group, an aralkyl group or an amino protecting group). Or a cycloalkyl group which may be substituted with a lower alkyl group; an aryl group which may be substituted with a lower alkyl group, a halogen atom, an amino group, a carboxyl group, a hydroxyl group or a lower alkoxy group; an aralkyl group; or It may be substituted with a lower alkyl group, a halogen atom, an amino group, a carboxyl group, a hydroxyl group or a lower alkoxy group. And nitrogen atom, and shows a heterocyclic group) having one or more heteroatoms selected from sulfur or oxygen atom, R ¹³ is a hydrogen atom; or lower alkyl group, R ¹⁴ is a lower alkyl group; an aralkyl group; Or an aryl group and R ¹⁵ 'represents an aryl group or an aralkyl group]
Is shown.

(3) In the general formula (I), R, A ¹ ,
A ² , A ³ , L, R _a , R _b , X, M, R ¹ , R ² , R
^At least one symbol selected from ³ , R ⁴ , R ⁵ and R ⁶ satisfies the following definition (1): the amide compound or a pharmaceutically acceptable salt thereof, or Prodrug. R is R _d2; R _d2 alkoxy group substituted with; R _d2 alkyl amino group substituted by; or a lower alkyl group or an amino-protecting good nitrogen-containing Hajime Tamaki optionally substituted by a group [wherein, R _d2 Represents an amino group, a guanidino group, an amidino group or a carbamoyl group (these groups may be substituted with a lower alkyl group or an amino protecting group). A ¹ , A ² , A
³ are the same or different and each represents a linear alkylene group or a single bond. L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a and R _b are the same or different and each is a hydrogen atom; a hydroxyl group; an amino group which may be substituted with an alkyl group or an amino protecting group; an alkyl group which may be substituted with an amino group (wherein the amino group is Alkyl group or optionally substituted with amino protecting group); or alkoxy group optionally substituted with amino group (wherein the amino group may be substituted with alkyl group or amino protecting group) . X is an oxygen atom; a sulfur atom; -NR ⁷ ″
-; - CO -; - CH 2 -; - CH = CH -; - C≡C
-; - COO -; - OOC -; - NR 7 '' CO -; - C
^{ONR 7 ''-; - NR} 7 '' SO 2 -; - SO 2 NR 7 ''
-; -NH-CO-NH-; or a divalent aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom [wherein R ⁷ ″ is a hydrogen atom; A lower alkyl group; or an amino protecting group]. M represents an arylene group. R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom; a hydroxyl group; a halogen atom; a lower alkyl group which may be substituted with a substituent selected from a hydroxyl group, a lower alkoxy group or a halogen atom; or A lower alkoxy group is shown. R ⁵ represents a hydrogen atom; a lower alkyl group; an aralkyl group; or an amino protecting group. R ⁶ is a benzene ring-fused cycloalkyl group;

[0022]

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[Where m is an integer selected from 0 or 1 to 6, n is an integer selected from 1 to 6 and R ¹¹ ″ is an aryl group which may be substituted with a halogen atom or a hydroxyl group; A cycloalkyl group which may be substituted with a lower alkyl group or a hydroxyl group; a lower alkyl group; an amino group which may be substituted with a lower alkyl group or an amino-protecting group; or -COOR ¹⁶ '(wherein R ¹⁶ ' is R ¹² ″ is a hydrogen atom; a lower alkyl group which may be substituted with a hydroxyl group or a lower alkoxy group; an aryl group; an aralkyl group; and a lower alkyl group which may be substituted with a lower alkyl group. An aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; or —CO (Y ² ) _p R ¹⁷ ″ (wherein Y ² is an oxygen atom; Sulfur atom; NR ¹⁸ ''-; or -NR ¹⁸ '' -
SO ₂ — (R ¹⁸ ″ is a hydrogen atom; a lower alkyl group; an alkoxy group; or an amino-protecting group), and p is 0 or 1
R ¹⁷ ″ is a hydrogen atom; an alkyl group which may be substituted with an amino group (wherein the amino group may be substituted with a substituent selected from a lower alkyl group, an aralkyl group or an amino-protecting group). ); Cycloalkyl group; aryl group optionally substituted with halogen atom or hydroxyl group; aralkyl group; or optionally substituted with lower alkyl group,
And a heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom), R ¹³ is a hydrogen atom; or a lower alkyl group, and R ¹⁴ is a lower alkyl group; an aralkyl group; Or R ¹⁵ ′ represents an aryl group or an aralkyl group].

(4) In the general formula (I), R, A ¹ ,
A ² , A ³ , L, R _a , R _b , X, M, R ¹ , R ² , R
^At least one symbol selected from ³ , R ⁴ , R ⁵ and R ⁶ satisfies the following definition (1): the amide compound or a pharmaceutically acceptable salt thereof, or Prodrug. R is R _d2; alkoxy group substituted by R _d2; substituted with R _d2 alkylamino group; or piperazinyl group [wherein, R _d2 represents an amino group,
Represents a guanidino group, an amidino group or a carbamoyl group (these groups may be substituted with a lower alkyl group or an amino protecting group). A ¹ , A ² and A ³ are the same or different and each represents a linear alkylene group or a single bond.
L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a and R _b are the same or different and each is a hydrogen atom; a hydroxyl group; an amino group; a lower alkyl group which may be substituted with an amino group (wherein the amino group is substituted with a lower alkyl group or an amino protecting group. Or a lower alkoxy group. X is an oxygen atom; -NR ⁷ ″
-; -COO-; or -CONR ⁷ ″-[wherein
R ⁷ ″ represents a hydrogen atom; a lower alkyl group; or an amino protecting group]. M represents an arylene group. R ¹ ,
R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom; a hydroxyl group; a halogen atom; a lower alkyl group; or a lower alkoxy group. R ⁵ represents a hydrogen atom; a lower alkyl group; or an amino protecting group. R ⁶ is

[0025]

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[Where m ₁ is 1, R ¹¹ ′ ″ is a phenyl group or a cyclohexyl group, and R ¹² ′ ″ is —CO—Y ³
-R ¹⁷ '''(where Y ³ is an oxygen atom or -NR ¹⁸ '''
-(R ¹⁸ '''represents a hydrogen atom; a lower alkyl group; or an amino-protecting group), R ¹⁷ ''' represents a hydrogen atom; a lower alkyl group; an aralkyl group; phenyl optionally substituted with a halogen atom. Group; a cyclohexyl group; or a pyridyl group).

(5) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the amide compound described in (1) or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

(6) An inflammatory cytokine production inhibitor comprising the amide compound described in (1) or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.

(7) A therapeutic or prophylactic agent for inflammatory diseases, which comprises the amide compound described in (1) or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.

[0030]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the definition of each substituent is as follows. "Alkoxy group" has 1 carbon atom
To 6 linear or branched alkoxy groups, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyl. Oxy group,
Isopentyloxy group, neopentyloxy group, ter
Examples thereof include t-pentyloxy group, hexyloxy group, isohexyloxy group and neohexyloxy group. Preferably, it is a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert- It is a butoxy group.

The "lower alkoxy group" is one having 1 to 4 carbon atoms.
Means a linear or branched alkoxy group, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. .. Preferred are a methoxy group and an ethoxy group.

The term "alkylthio group" means a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyl. Thio group, s
ec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group,
Examples thereof include a tert-pentylthio group, a hexylthio group, an isohexylthio group, and a neohexylthio group.

The "lower alkylthio group" has 1 to 1 carbon atoms.
It means four linear or branched alkylthio groups, specifically, methylthio group, ethylthio group, propylthio group,
Examples thereof include an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group.

"Alkylamino group" means 1 to 6 carbon atoms.
Means a linear or branched monoalkylamino group or dialkylamino group, specifically, methylamino group, dimethylamino group, ethylamino group, diethylamino group, methylethylamino group, propylamino group, isopropylamino group. , Butylamino group, isobutylamino group, se
Examples thereof include a c-butylamino group, a tert-butylamino group, a pentylamino group, an isopentylamino group, a neopentylamino group, a tert-pentylamino group, a hexylamino group, an isohexylamino group and a neohexylamino group. Preferred is a linear alkylamino group, specifically, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group,
A butylamino group, a pentylamino group, and a hexylamino group. Particularly preferred is a linear alkylamino group having 1 to 4 carbon atoms, specifically, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, butylamino group and the like.

The "halogen atom" is specifically a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "halogenated lower alkyl group" is the above-mentioned lower alkyl group substituted with a halogen atom, and specifically includes fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group. Group, trifluoromethyl group, trichloromethyl group, difluoroethyl group, dichloroethyl group, pentatrifluoroethyl group, trichloroethyl group, fluoropropyl group and the like. Preferably, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group,
It is a trifluoromethyl group.

The "nitrogen-containing heterocyclic group" means at least 1
Means a 3- to 7-membered heterocyclic group containing nitrogen atoms and optionally having a sulfur atom or an oxygen atom. Specifically, aziridinyl group, thiazetidinyl group, azetidinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperazinyl group, piperidyl group,
Piperidino group, dioxazepinyl group, thiazepinyl group,
Diazepinyl group, perhydrodiazepinyl group, azepinyl group, perhydroazepinyl group, indolinyl group, isoindolinyl group, tetrazolyl group, triazolyl group, oxazolyl group, imidazolyl group, piperazolyl group, pyrrolyl group, triazinyl group, pyridyl group, etc. Is mentioned.
Preferably aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrazolidinyl group, morpholinyl group, morpholino group, piperazinyl group, piperidyl group, piperidino group,
It is a perhydroazepinyl group. Particularly preferred are pyrrolidinyl group, morpholino group, piperazinyl group, piperidyl group and piperidino group.

The term "alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group,
tert-pentyl group, hexyl group, isohexyl group,
Examples thereof include neohexyl group.

The "lower alkyl group" means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. Group, sec-butyl group, tert-butyl group and the like.

The "cycloalkyl group" means a carbon number of 3 to 7
And a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Preferred is a cycloalkyl group having 5 or 6 carbon atoms, and specifically, a cyclopentyl group and a cyclohexyl group.

The "aralkyl group" is an alkyl group substituted with an aryl group, and is specifically a benzyl group, a benzhydryl group, a trityl group, a phenethyl group, 3
-Phenylpropyl group, 2-phenylpropyl group, 4-
Examples thereof include a phenylbutyl group and a naphthylmethyl group.
Of these, a benzyl group and a phenethyl group are preferred.

The "aralkyloxy group" is an aralkyloxy group having an aralkyl group as described above, specifically, a benzyloxy group, a benzhydryloxy group,
Trityloxy group, phenethyloxy group, 3-phenylpropyloxy group, 2-phenylpropyloxy group, 4
Examples thereof include a phenylbutyloxy group and a naphthylmethoxy group. Of these, a benzyloxy group and a phenethyloxy group are preferable.

The term "aralkyloxycarbonyl group" means
An aralkyloxycarbonyl group having an aralkyl group as described above, specifically, a benzyloxycarbonyl group, a benzhydryloxycarbonyl group, a trityloxycarbonyl group, a phenethyloxycarbonyl group, 3
-Phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group, 4-phenylbutyloxycarbonyl group, naphthylmethoxycarbonyl group and the like can be mentioned. Preferred are a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

The "aryl group" means a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group and the like, preferably a phenyl group and a naphthyl group.

The "aryloxy group" is an aryloxy group having an aryl group as described above, and specific examples thereof include a phenoxy group and a naphthyloxy group.

The "aryloxycarbonyl group" is an aryloxycarbonyl group having an aryl group as described above, and specific examples thereof include a phenoxycarbonyl group and a naphthyloxycarbonyl group.

The "arylthio group" is an arylthio group having an aryl group as described above, and specific examples thereof include a phenylthio group and a naphthylthio group.

The "amino protecting group" is a commonly used protecting group and is not particularly limited as long as it protects the amino group from various reactions. Specifically, formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, pivaloyl group, 2-chloroacetyl group, 2-
Bromoacetyl group, 2-iodoacetyl group, 2,2-dichloroacetyl group, 2,2,2-trichloroacetyl group, 2,2,2-trifluoroacetyl group, phenylacetyl group, phenoxyacetyl group, benzoyl group, 4-
Chlorobenzoyl group, 4-methoxybenzoyl group, 4-
Acyl groups such as nitrobenzoyl group, naphthylcarbonyl group, adamantylcarbonyl group and phthaloyl group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-
Butoxycarbonyl group, pentyloxycarbonyl group,
Isopentyloxycarbonyl group, cyclohexyloxycarbonyl group, 2-chloroethoxycarbonyl group, 2
-Iodoethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2,2,2-trichloro-t
ert-butoxycarbonyl group, benzhydryloxycarbonyl group, bis- (4-methoxyphenyl) methoxycarbonyl group, phenacyloxycarbonyl group, 2-
Trimethylsilylethoxycarbonyl group, 2-triphenylsilylethoxycarbonyl group, fluorenyl-9-
Alkoxycarbonyl group such as methoxycarbonyl group; vinyloxycarbonyl group, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2- Alkenyloxycarbonyl groups such as propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group; benzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group, 2-chlorobenzyloxycarbonyl group, 3-chlorobenzyl Oxycarbonyl group, 3,
5-dimethoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 2-nitro-4,5-dimethoxybenzyloxycarbonyl group, 3,4 Aralkyloxycarbonyl groups such as 5-trimethoxybenzyloxycarbonyl group and phenethyloxycarbonyl group; trimethylsilyl group,
Lower alkylsilyl groups such as tert-butyldimethylsilyl group; alkylenebis (dialkylsilyl) groups such as ethylenebis (dimethylsilyl) group, propylenebis (dimethylsilyl) group, ethylenebis (diethylsilyl) group
Group; alkylthiocarbonyl group such as methylthiocarbonyl group, ethylthiocarbonyl group, butylthiocarbonyl group, tert-butylthiocarbonyl group; aralkylthiocarbonyl group such as benzylthiocarbonyl group; dicyclohexylphosphoryl group, diphenylphosphoryl group,
Dibenzylphosphoryl group, di- (4-nitrobenzyl)
Examples thereof include a phosphoryl group such as a phosphoryl group and a phenoxyphenylphosphoryl group; and a phosphinyl group such as a diethylphosphinyl group and a diphenylphosphinyl group.

The "linear or branched alkylene group which may have one or more double bonds or triple bonds in the chain" refers to a linear or branched chain having 1 to 10 carbon atoms. Means an alkylene group which may have one or more double or triple bonds, and specifically includes methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene. Group, octamethylene group, nonamethylene group, decamethylene group, dimethylmethylene group, diethylmethylene group, propylene group, methylethylene group, ethylethylene group, propylethylene group, isopropylethylene group, methylpentaethylene group, ethylhexamethylene group, dimethyl group Ethylene group, methyltriethylene group, dimethyltrimethylene group, vinylene group, propenylene group, butenile Group, butadienylene group, pentenylene group, pentadienylene group, hexenylene group, hexadienylene group, hexatrienylene group, heptenylene group, heptadienylene group, heptatrienylene group, octenylene group, octadienylene group, octatrienylene group, octatetraenylene group, Examples thereof include a propynylene group, a butynylene group, a pentynylene group, and a methylpropynylene group. Preferred is a linear alkylene group, specifically, a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group,
Heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, vinylene group, propenylene group, butenylene group, butadienylene group, pentenylene group, pentadienylene group, hexenylene group, hexadienylene group, hexatrienylene group, heptenylene group, heptadienylene group, heptap Trienylene group, octenylene group,
Octadienylene group, octatrienylene group, octatetraenylene group, propynylene group, butynylene group, pentynylene group. Particularly preferred is a linear alkylene group having 1 to 8 carbon atoms such as methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group and the like.

Specific examples of the "arylene group" include a phenylene group, a naphthylene group, an anthrylene group, a phenanthrylene group and a biphenylene group. Preferred are a phenylene group, a naphthylene group and a biphenylene group.

The "cycloalkylene group" has 3 to 10 carbon atoms.
7 cycloalkylene groups, that is, a divalent cycloalkyl group, specifically, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group,
Examples thereof include a cycloheptylene group. Preferably, it is a cycloalkylene group having 5 or 6 carbon atoms, specifically, a cyclopentylene group or a cyclohexylene group.

The "divalent aromatic heterocyclic group having at least one hetero atom selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring" is specifically mentioned. Tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine Ring, pyridazine ring, pyrimidine ring, pyridine ring, oxazolopyrimidine ring, oxazolopyridine ring, benzoxazole ring, benzothiazole ring, benzofuran ring, furopyridine ring, thienopyrimidine ring, benzothiophene ring, quinoline ring, quinazoline ring, naphthyridine ring Ring, isoindole ring, purine ring, ben Imidazole ring, indazole ring, divalent aromatic heterocyclic groups such as indole ring. It is preferably a 5- or 6-membered divalent aromatic heterocyclic group, specifically, a tetrazole ring, an oxadiazole ring,
Thiadiazole ring, triazole ring, oxazole ring,
Of isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, indazole ring, benzimidazole ring, benzoxazole ring, benzothiazole ring, benzofuran ring, quinoline ring It is a divalent aromatic heterocyclic group.

The "alkoxycarbonyl group" means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group. Group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert
-Butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, isohexyloxycarbonyl group, neohexyloxycarbonyl group and the like can be mentioned. Preferably, it is a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms, specifically, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group. , Sec-butoxycarbonyl group and tert-butoxycarbonyl group.

The "lower alkoxycarbonyl group" means a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms, specifically, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxy group. Carbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, te
rt-butoxycarbonyl group and the like. Of these, a methoxycarbonyl group and an ethoxycarbonyl group are preferred.

The "alkylsulfonyl group" has 1 carbon atom.
To 6 linear or branched alkylsulfonyl groups, specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, s
Examples thereof include an ec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, an isopentylsulfonyl group, a neopentylsulfonyl group, a tert-pentylsulfonyl group, a hexylsulfonyl group, an isohexylsulfonyl group, and a neohexylsulfonyl group.

The "divalent aromatic heterocyclic group having one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom" means one or more divalent aromatic heterocyclic groups selected from nitrogen atom, sulfur atom or oxygen atom. A 5- or 6-membered divalent aromatic heterocyclic group having a hetero atom, specifically a tetrazole ring,
Oxadiazole ring, thiadiazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring A divalent aromatic heterocyclic group such as a ring, a pyrimidine ring or a pyridine ring can be mentioned. Preferably, it is a 5-membered divalent aromatic heterocyclic group,
Specifically, tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring,
It is a divalent aromatic heterocyclic group having a thiophene ring. Particularly preferred is a divalent aromatic heterocyclic group having an oxadiazole ring, a thiadiazole ring or a triazole ring.

The "divalent heterocyclic group having at least one hetero atom selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring" is specifically a dioxolane ring. , Dithiol ring, pyrrolidine ring, morpholine ring,
Oxazine ring, piperazine ring, piperidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, thiatriazole ring, tetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring, isoxazole ring, oxazole ring, Thiazole ring, imidazole ring, pyrazole ring, pyrrole ring,
Furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring, furisoxazole ring, imidazothiazole ring, thienoisothiazole ring, thienothiazole ring, imidazopyrazole ring, cyclopentapyrazole ring , Pyrrolopyrrole ring, thienothiophene ring, thiadiazolopyrimidine ring, thiazolothiazine ring, thiazolopyrimidine ring, thiazolopyridine ring, oxazolopyrimidine ring, oxazolopyridine ring, benzoxazole ring, benzisothiazole ring, benzothiazole ring , Imidazopyrazine ring, purine ring, pyrazolopyrimidine ring, imidazopyridine ring, benzimidazole ring, indazole ring, benzooxathiol ring, benzodioxole ring, benzodithiol ring, indolidiene ring Ring, indoline ring, isoindoline ring, furopyrimidine ring, furopyridine ring, benzofuran ring, isobenzofuran ring, thieno pyrimidine ring,
Thienopyridine ring, benzothiophene ring, cyclopentaoxazine ring, cyclopentafuran ring, benzoxazine ring, benzothiazine ring, quinazoline ring, naphthyridine ring, quinoline ring, isoquinoline ring, benzopyran ring, pyridopyridazine ring, pyridopyrimidine ring, etc. A divalent heterocyclic group is mentioned. It is preferably a divalent heterocyclic group having a piperazine ring, a piperidine ring, a pyridine ring, a benzoxazole ring, a benzisothiazole ring, a benzothiazole ring or a benzimidazole ring.

The "acyl group" is specifically a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, caproyl group, isocaproyl group, acryloyl group, propioroyl group, Methacryloyl group, crotonoyl group, isocrotonoyl group, benzoyl group, naphthoyl group, toluoyl group, hydroatropoyl group, atropoyl group, cinnamoyl group, furoyl group, glyceroyl group,
Examples thereof include a tropoyl group, a benzyloyl group, a salicyloyl group, an anisoyl group, a vanilloyl group, a veratroyl group, a piperoniloyl group, a protocatechuyl group and a galloyl group. Preferred are formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, benzoyl group and naphthoyl group.

The "acyloxy group" is an acyloxy group having an acyl group as described above, specifically, a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, Isovaleryloxy group, pivaloyloxy group, caproyloxy group, isocaproyloxy group, acryloyloxy group, propioroyloxy group, methacryloyloxy group, crotonoyloxy group, isocrotonoyloxy group, benzoyloxy group, naphthoyloxy group Group, toluoyloxy group, hydroatropoyloxy group, atropoyloxy group, cinnamoyloxy group, furoyloxy group, glyceroyloxy group, tropoyloxy group, benzyloyloxy group, salicyloyloxy group, anisoyloxy group Group, Baniroiruokishi group, Bella Troy oxy group, piperazinyl Roni acryloyloxy group, pro solved Tech oil group, Garoiruokishi group and the like.
Preferred are formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, benzoyloxy group and naphthoyloxy group.

"Benzene ring-fused cycloalkyl" means
A condensed ring in which a benzene ring is condensed with a 4- to 8-membered cycloalkyl group, and specific examples thereof include a benzocyclobutane ring, an indane ring, a tetralin ring, a benzocycloheptane ring, and a benzocyclooctane ring. Preferred are indane ring and tetralin ring.

The "heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom" for R ¹¹ means at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom. A 3- to 7-membered heterocyclic group having
Oxadiazolyl group, thiadiazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group,
Furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiazinyl group, triazinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group,
Examples thereof include pyrimidinyl group, piperidyl group, piperidino group, pyridyl group, pyranyl group, thiopyranyl group, dioxazepinyl group, diazepinyl group and azepinyl group. It is preferably a 5- or 6-membered heterocyclic group, specifically, thiatriazolyl group, tetrazolyl group, dithiazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, Pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group,
Furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiazinyl group, triazinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group,
A pyrimidinyl group, a piperidyl group, a piperidino group, a pyridyl group, a pyranyl group and a thiopyranyl group are preferable, and a pyrrolyl group, a furanyl group, a thienyl group, a piperazinyl group, a piperidyl group, a piperidino group and a pyridyl group are particularly preferable.

The "aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom" for R ¹² means at least one selected from a nitrogen atom, a sulfur atom or an oxygen atom. A 5- or 6-membered aromatic heterocyclic group having a hetero atom, specifically, a tetrazolyl group,
Oxadiazolyl group, thiadiazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyrrolyl group, furanyl group, thienyl group, tetrazinyl group, triazinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group , Pyridyl groups and the like. It is preferably a 5-membered aromatic heterocyclic group, specifically, a tetrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group,
A thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a pyrrolyl group, a furanyl group and a thienyl group. Particularly preferred are oxadiazolyl group, thiadiazolyl group and triazolyl group.

The term "alkoxyalkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms and 1 carbon atom.
~ 6 means a straight or branched alkoxy group substituted, specifically, methoxymethoxy group, ethoxymethoxy group, propoxymethoxy group, isopropoxymethoxy group, butoxymethoxy group, isobutoxymethoxy group, sec-butoxymethoxy group, tert-butoxymethoxy group, pentyloxymethoxy group, isopentyloxymethoxy group, neopentyloxymethoxy group, t
ert-pentyloxymethoxy group, hexyloxymethoxy group, isohexyloxymethoxy group, neohexyloxymethoxy group, tert-hexyloxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, isopropoxyethoxy group, butoxyethoxy group Group, isobutoxyethoxy group, sec-butoxyethoxy group, tert-butoxyethoxy group, pentyloxyethoxy group, isopentyloxyethoxy group, neopentyloxyethoxy group, tert-pentyloxyethoxy group, hexyloxyethoxy group, isohexyl Oxyethoxy group, neohexyloxyethoxy group, tert-hexyloxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxypropoxy group, isopropoxy group Kishipuropokishi group, butoxy propoxy group, iso-butoxy propoxy group, sec- butoxy propoxy group, tert- butoxy propoxy group, pentyloxy propoxy group, iso-pentyloxy propoxy group, neopentyloxy propoxy group, tert-
Pentyloxypropoxy group, hexyloxypropoxy group, isohexyloxypropoxy group, neohexyloxypropoxy group, tert-hexyloxypropoxy group, methoxybutoxy group, ethoxybutoxy group, propoxybutoxy group, isopropoxybutoxy group, butoxybutoxy group, Isobutoxybutoxy group, sec-butoxybutoxy group, tert-butoxybutoxy group, pentyloxybutoxy group, isopentyloxybutoxy group, neopentyloxybutoxy group, tert-pentyloxybutoxy group, hexyloxybutoxy group, isohexyloxybutoxy group Group, neohexyloxybutoxy group, tert-hexyloxybutoxy group, methoxypentyloxy group, ethoxypentyloxy group, propoxypentyloxy group Group, iso-propoxy pentyloxy group, butoxy pentyloxy group, iso-butoxy pentyloxy group, sec- butoxy pentyloxy group, ter
t-butoxypentyloxy group, pentyloxypentyloxy group, isopentyloxypentyloxy group, neopentyloxypentyloxy group, tert-pentyloxypentyloxy group, hexyloxypentyloxy group, isohexyloxypentyloxy group, neohexyl Oxypentyloxy group, tert-hexyloxypentyloxy group, methoxyhexyloxy group, ethoxyhexyloxy group, propoxyhexyloxy group, isopropoxyhexyloxy group, butoxyhexyloxy group, isobutoxyhexyloxy group, sec-
Butoxyhexyloxy group, tert-butoxyhexyloxy group, pentyloxyhexyloxy group, isopentyloxyhexyloxy group, neopentyloxyhexyloxy group, tert-pentyloxyhexyloxy group, hexyloxyhexyloxy group, isohexyloxyhexyl Examples thereof include an oxy group, a neohexyloxyhexyloxy group and a tert-hexyloxyhexyloxy group. Preferably, a linear or branched alkoxy group having 1 to 4 carbon atoms is substituted with a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxymethoxy group or ethoxy. Methoxy group, propoxymethoxy group, isopropoxymethoxy group, butoxymethoxy group, isobutoxymethoxy group, sec-butoxymethoxy group, tert-butoxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, isopropoxyethoxy group, Butoxyethoxy group,
Isobutoxyethoxy group, sec-butoxyethoxy group, tert-butoxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxypropoxy group, isopropoxypropoxy group, butoxypropoxy group, isobutoxypropoxy group, sec-butoxypropoxy group, tert. -Butoxypropoxy group, methoxybutoxy group, ethoxybutoxy group, propoxybutoxy group, isopropoxybutoxy group, butoxybutoxy group,
An isobutoxybutoxy group, a sec-butoxybutoxy group, and a tert-butoxybutoxy group.

The "heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom" in R ¹⁵ and R ¹⁷ means at least one selected from a nitrogen atom, a sulfur atom or an oxygen atom. A heterocyclic group having from 3 to 7 members, specifically, an aziridinyl group, an oxiranyl group, an azetyl group, an azetidinyl group, an oxetanyl group, a thiatriazolyl group, a tetrazolyl group, a dithiazolyl group, an oxadiazolyl group, a thiadiazolyl group. , Triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group, furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiadinyl group, triazinyl group, morpholinyl group Group, mole Examples thereof include holino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, piperidyl group, piperidino group, pyridyl group, pyranyl group, thiopyranyl group, dioxazepinyl group, diazepinyl group and azepinyl group. It is preferably a 5- or 6-membered heterocyclic group, specifically, thiatriazolyl group, tetrazolyl group, dithiazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, Pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group, furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiazinyl group, triazinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group , A pyrimidinyl group, a piperidyl group, a piperidino group, a pyridyl group, a pyranyl group, a thiopyranyl group, particularly preferably a pyrrolyl group, a piperazinyl group, a piperidyl group,
A piperidino group and a pyridyl group.

The "alkenyl group" means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, an allyl group, a vinyl group, a propenyl group, an isopropenyl group,
1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-methyl-1-butenyl group, crotyl group,
1-methyl-3-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 1-methyl-2-pentenyl group, 4-pentenyl group, 1,3-pentadienyl group,
2,4-pentadienyl group, 1-hexenyl group, 3-hexenyl group, 4-hexenyl group, 1,3-hexadienyl group, 2,4-hexadienyl group and the like can be mentioned.

The "alkynyl group" means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, specifically, propargyl group, 2-butynyl group, 1-methyl-2-butynyl group, 2-pentynyl group, 1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 1,3-pentadiynyl group, 2,4-pentadiynyl group, 1-hexynyl group, 5-hexynyl group, 1,3 -Hexadiynyl group,
2,4-hexadiynyl group and the like can be mentioned.

Specific examples of the "cycloalkylidene amino group" include a cyclopropylidene amino group, a cyclobutylidene amino group, a cyclopentylidene amino group, a cyclohexylidene amino group, a cycloheptylidene amino group and the like. . Preferred are a cyclopentylideneamino group and a cyclohexylideneamino group.

The "alkoxy group" of the substituted alkoxy group in R means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, Isopropoxy group, butoxy group,
Examples include isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, isohexyloxy group, neohexyloxy group and the like. . A straight-chain alkoxy group is preferred, and specifically, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and a hexyloxy group. Particularly preferably, it is a linear alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group or a butoxy group.

The "alkylthio group" of the substituted alkylthio group in R means a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically, methylthio group, ethylthio group, propylthio group, Isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, hexylthio group, isohexylthio group,
Examples thereof include neohexylthio group. A linear alkylthio group is preferable, and specifically, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group are preferable. Particularly preferably, it has 1 carbon atom
To 4 linear alkylthio groups, specifically, a methylthio group, an ethylthio group, a propylthio group, and a butylthio group.

The "optionally substituted" of the "optionally substituted nitrogen-containing heterocyclic group" means that it may be substituted with 1 to 3 substituents. May be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specific examples include the above-mentioned lower alkyl group; the above-mentioned halogenated lower alkyl group; the above-mentioned cycloalkyl group; the above-mentioned aralkyl group; the above-mentioned aryl group; and the above-mentioned amino-protecting group.
A lower alkyl group and an amino protecting group are preferred.

"A straight-chain or branched alkylene group which may be substituted and may have one or more double or triple bonds in the chain" is "optionally substituted". Means that it may be substituted with one or more substituents, specifically, the above-mentioned halogen atom; hydroxyl group; the above-mentioned lower alkyl group, the above-mentioned halogenated lower alkyl group, the above-mentioned cycloalkyl group. An amino group which may be substituted with a substituent selected from the above aralkyl group, the above aryl group or the above amino protecting group; the above lower alkoxy group; the above aralkyl group; the above cycloalkyl group and the like. .

The “optionally substituted” of the “optionally substituted alkoxy group” and the “optionally substituted alkylthio group” in R ¹⁰ means that it is substituted with one or more substituents. The substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specifically, the above halogen atom; the above lower alkoxy group; the above alkylthio group; the amino group which may be substituted with the above lower alkyl group or the above acyl group; the carboxyl group;
The aforementioned alkoxycarbonyl group; the aforementioned acyl group; the aforementioned acyloxy group; the aforementioned aryl group; the aforementioned aryloxy group; the aforementioned arylthio group, the aforementioned aryloxycarbonyl group, the aforementioned aralkyloxy group, and the aforementioned aralkyloxycarbonyl. Group etc. Preferred are an amino group; a lower alkoxy group; a halogen atom; a carboxyl group; an alkoxycarbonyl group; and an aralkyloxycarbonyl group.

"An optionally substituted aryl group" for R ¹⁰ , "an optionally substituted cycloalkyl group", "an optionally substituted aryloxy group",
The "optionally substituted" of the "optionally substituted aralkyloxy group" and the "optionally substituted arylthio group" may have 1 to 3 substituents on the ring. This means that the substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specifically, the above lower alkyl group; the above halogen atom; the above lower alkoxy group; the above alkylthio group; the amino group which may be substituted with the above lower alkyl group or the above acyl group; the carboxyl group;
The aforementioned alkoxycarbonyl group; the aforementioned acyl group; the aforementioned acyloxy group; the aforementioned aryl group; the aforementioned aryloxy group; the aforementioned arylthio group, the aforementioned aryloxycarbonyl group, the aforementioned aralkyloxy group, and the aforementioned aralkyloxycarbonyl. Group etc. A lower alkyl group; an amino group; a lower alkoxy group; a halogen atom; a carboxyl group; an alkoxycarbonyl group; an aralkyloxycarbonyl group are preferred, and a lower alkyl group is particularly preferred.

The “optionally substituted” of the “optionally substituted aralkyl group” for R ⁵ means that the aryl group may have 1 to 3 substituents. The substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited.
Specifically, the above-mentioned lower alkyl group; the above-mentioned lower alkoxy group; the above-mentioned acyl group; the above-mentioned lower alkyl group or an amino group which may be substituted with the above-mentioned acyl group; the above-mentioned alkoxycarbonyl group; the above-mentioned aryl. An oxycarbonyl group; the above-mentioned aryloxy group; the above-mentioned alkylthio group; the above-mentioned arylthio group; the above-mentioned aryl group; the above-mentioned halogen atom and the like. It is preferably a lower alkyl group; a lower alkoxy group; a halogen atom, and particularly preferably a lower alkyl group.

"Optionally substituted lower alkyl group", "optionally substituted lower alkoxy group" and "optionally substituted lower alkylthio group" for R ¹¹
The “optionally substituted” means that it may be substituted with one or more substituents, the substituents may be the same or different, and the position of the substituents is arbitrary. There is no particular limitation. Specifically, the above-mentioned halogen atom; hydroxyl group; the above-mentioned alkoxy group; the above-mentioned aryloxy group; the above-mentioned lower alkyl or the amino group which may be substituted with the above-mentioned acyl group; the mercapto group; the above-mentioned alkylthio group; An arylthio group; a carboxyl group; the above-mentioned alkoxycarbonyl group; the above-mentioned aryloxycarbonyl group; a carbamoyl group; an alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, an isopropylsulfonyl group; a methylsulfinyl group,
Examples include an alkylsulfinyl group such as an ethylsulfinyl group and an isopropylsulfinyl group; an arylsulfonyl group such as a phenylsulfonyl group; the above halogenated lower alkyl group; a sulfamoyl group; a cyano group; a nitro group.
Preferred are a halogen atom; a hydroxyl group; an alkoxy group; an amino group; a carboxyl group; an alkoxycarbonyl group.

"An optionally substituted aryl group" and "an optionally substituted cycloalkyl group" for R ¹¹
And the “optionally substituted” of “heterocyclic group which may be substituted and has one or more hetero atoms selected from nitrogen atom, sulfur atom or oxygen atom” means one or more substitutions. Means that it may be substituted by a group,
The substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specifically, the above-mentioned lower alkyl group; the above-mentioned halogen atom; the hydroxyl group; the above-mentioned alkoxy group; the above-mentioned aryloxy group;
Amino group which may be substituted with the above lower alkyl group or the above acyl group; a mercapto group; the above alkylthio group; the above arylthio group; a carboxyl group; the above alkoxycarbonyl group; the above aryloxycarbonyl group; carbamoyl Group; alkylsulfonyl group such as methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group; alkylsulfinyl group such as methylsulfinyl group, ethylsulfinyl group, isopropylsulfinyl group; arylsulfonyl group such as phenylsulfonyl group; Alkyl group; sulfamoyl group; cyano group; nitro group and the like. Preferred are a lower alkyl group; a halogen atom; a hydroxyl group; an alkoxy group; an amino group; a carboxyl group; and an alkoxycarbonyl group.

The “optionally substituted” of the “optionally substituted alkyl group” for R ¹² means that it may be substituted with one or more substituents. They may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specifically, a hydroxyl group; the above lower alkoxy group; a mercapto group; the above lower alkylthio group; a carboxyl group; the above lower alkoxycarbonyl group; an amino group which may be substituted with the above lower alkyl group or the above acyl group. A halogen atom or the like. Preferred are a hydroxyl group; a halogen atom; and a lower alkoxy group.

"An optionally substituted aryl group" for R ¹² and "an optionally substituted nitrogen atom,
The "optionally substituted" of the "aromatic heterocyclic group having one or more hetero atoms selected from a sulfur atom or an oxygen atom" may have 1 to 3 substituents on the ring. This means that the substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specifically, a lower alkyl group described above; a hydroxyl group; a lower alkoxy group described above; a mercapto group; a lower alkylthio group described above; a carboxyl group; a lower alkoxycarbonyl group described above; a lower alkyl group described above or an acyl group described above. Optionally an amino group; a halogen atom and the like. Preferred are a hydroxyl group; a lower alkyl group; a halogen atom; and a lower alkoxy group.

The “optionally substituted” of the “optionally substituted aralkyl group” for R ¹² means that the aryl group may have 1 to 3 substituents. The substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited.
Specifically, the above-mentioned lower alkyl group; the above-mentioned lower alkoxy group; the above-mentioned acyl group; the above-mentioned lower alkyl group or an amino group which may be substituted with the above-mentioned acyl group; the above-mentioned alkoxycarbonyl group; the above-mentioned aryl. An oxycarbonyl group; the above-mentioned aryloxy group; the above-mentioned alkylthio group; the above-mentioned arylthio group; the above-mentioned aryl group; the above-mentioned halogen atom and the like. Preferred are a lower alkyl group; a lower alkoxy group; and a halogen atom.

"The optionally substituted alkenyl group" and the "optionally substituted alkynyl group" for R ¹⁷
The “optionally substituted” means that it may be substituted with one or more substituents, the substituents may be the same or different, and the position of the substituents is arbitrary. There is no particular limitation. Specifically, a hydroxyl group; an alkoxy group; a carboxyl group; an alkoxycarbonyl group; an acyloxy group; an alkyl group, an aryl group, an aralkyl group, or an amino-protecting group. And an amino group and the like. Preferred are a hydroxyl group; an alkoxy group; a carboxyl group; an alkoxycarbonyl group; and an acyloxy group.

"Optionally substituted cycloalkyl group" and "optionally substituted aryl group" for R ¹⁷
And the “optionally substituted” of “heterocyclic group which may be substituted and has one or more hetero atoms selected from nitrogen atom, sulfur atom or oxygen atom” means 1 to 1 on the ring. It means that it may have three substituents, and the substituents may be the same or different, and the position of the substituents is arbitrary and is not particularly limited. Specifically, a hydroxyl group; the above-mentioned lower alkoxy group; a mercapto group;
A lower alkylthio group described above; a carboxyl group; a lower alkoxycarbonyl group described above; a lower alkyl group described above; an amino group which may be substituted with a lower alkyl group described above;
The above halogen atom; a carbamoyl group; a cyano group; the above acyl group; a nitro group; an alkylsulfonyl group such as a methylsulfonyl group and an ethylsulfonyl group; an alkylsulfinyl group such as a methylsulfinyl group; a sulfamoyl group; the above lower alkyl group, An azomethine group optionally substituted with the above aryl group or the above aralkyl group;
Alkoxyamino group such as methoxyamino group and isopropoxyamino group; hydrazino group optionally substituted with the above lower alkyl group, the above aryl group or the above aralkyl group; alkoxythiocarbonyl group; the above lower alkyl group, An aminooxy group which may be substituted with the above aryl group or the above aralkyl group; a thioalkanoyl group and the like. Preferred are a hydroxyl group; a lower alkyl group; a halogen atom; a lower alkoxy group; an amino group; and a carboxyl group.

The “optionally substituted” of the “optionally substituted aralkyl group” for R ¹⁷ means that the aryl group may have 1 to 3 substituents. The substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited.
Specifically, the above-mentioned lower alkyl group; the above-mentioned lower alkoxy group; the above-mentioned acyl group; the above-mentioned lower alkyl group or an amino group which may be substituted with the above-mentioned acyl group; the above-mentioned alkoxycarbonyl group; the above-mentioned aryl. An oxycarbonyl group; the above-mentioned aryloxy group; the above-mentioned alkylthio group; the above-mentioned arylthio group; the above-mentioned aryl group; the above-mentioned halogen atom and the like. Preferred are a lower alkyl group; a lower alkoxy group; and a halogen atom.

The compound of the present invention represented by the general formula (I) is
For example, it can be synthesized by the following method, but the method for synthesizing the compound of the present invention is not limited thereto.

[0084]

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[0085]

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{In the formula, R'is an R group protected by an amino protecting group (however, when R is a dimethylamino group or the like, it is not necessary to protect R, so R'is R itself). Means R _a ', R _b ' is R _a ', R _b '
Is a group having an amino group, R _a and R _b each protected with an amino protecting group (provided that R _a ′ and R _b ′ are dimethylamino groups or the like, it is not necessary to protect them). R _a 'and R _b ' mean R _a and R _b respectively), and when R _a 'and R _b ' do not have an amino group, R _a 'and R _b ' respectively. R _a and R _b themselves and R ¹⁹ are methyl group, ethyl group, tert-butyl group, allyl group, phenyl group, benzyl group, trichloroethyl group, p-nitrobenzyl group, trimethylsilyl group, tert-butyldimethylsilyl group. , A methoxy protecting group such as a methoxymethyl group and a 2-trimethylsilylethyl group, W is a halogen atom, and W ¹ is —COW ³ ;
SO ₂ W ³ ; or —O—COW ³ (wherein W ³ represents a hydroxyl group or a halogen atom), W ² is a hydroxyl group; a mercapto group; or —NR ⁷ H (wherein R ⁷ is as defined above). A ² ′ represents a group lacking one methylene at the end of the A ² group, A ³ ′ represents a group lacking one methylene at the end of the A ³ group, and A ¹ , A ² , A ³ , L, X, M, R, _Ra ,
R _b , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above}

(Step 1) Compound (VIII) is prepared by converting compound (II) and compound (III) into triphenylphosphine, trimethylphosphine, triethylphosphine,
Triphenyl phosphite, trimethyl phosphite, triethyl phosphite and the like and diisopropyl azodicarboxylate, diethyl azodicarboxylate, in the presence of a condensing agent in combination with dicyclohexyl azodicarboxylate, ether, tetrahydrofuran, dioxane, dichloromethane, The reaction is carried out in an organic solvent such as chloroform, benzene, toluene, dimethylformamide or the like or a mixed solvent thereof under ice cooling or heating, or methanesulfonyl chloride, p-
In the presence of sulfonyl chlorides such as toluenesulfonyl chloride, benzenesulfonyl chloride and p-bromobenzenesulfonyl chloride and a base such as N, N-diisopropylethylamine, triethylamine and pyridine, benzene, toluene, dichloromethane, chloroform, ether, tetrahydrofuran and dioxane. ,
It can be synthesized by reacting in an organic solvent such as dimethylformamide or a mixed solvent thereof, or in the absence of a solvent under ice cooling or heating. This method is particularly suitable when X is an oxygen atom, a sulfur atom, or —NR ⁷ —.

(Step 2) Compound (VIII) is prepared by converting compound (II ′) and compound (III) into sodium hydride, potassium hydride, lithium hydride, potassium carbonate,
In the presence of a base such as sodium carbonate, potassium tert-butoxide, lithium diisopropylamide, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, dimethylformamide, methylene chloride, tetrahydrofuran, ether, benzene, toluene, etc. In an organic solvent or a mixed solvent thereof, −
It can be synthesized by reacting at 78 ° C to under heating. This method is particularly suitable when X is a sulfur atom or an oxygen atom. Further, X is -SO -, - SO ₂
In the case of −, the corresponding sulfide obtained in the above step 1 or 2 is oxidized with an oxidizing agent such as hydrogen peroxide, peracetic acid, metaperiodate, metachloroperbenzoic acid, acyl nitrate, or dinitrogen tetraoxide. Can be synthesized by.

(Step 3) For the compound (VIII), the compound (II ″) and the compound (III) are mixed with an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, ethyl acetate or a mixture thereof. Condensation in a solvent, catalytic reduction with hydrogen gas in the presence of a metal catalyst such as platinum black, platinum oxide, palladium black, palladium oxide, palladium carbon, Raney nickel, or sodium borohydride, sodium cyanoborohydride, trimethylsilane , Can be synthesized by treating with a reducing agent such as triethylsilane. This method is particularly suitable when X is —NR ⁷ —.

(Step 4) The compound (VIII) can be synthesized by using the compound (IIa) and the compound (IIIa) in the same manner as in the step 1. This method is particularly suitable when X is an oxygen atom, a sulfur atom, or —NR ⁷ —.

(Step 5) Compound (VIII) can be synthesized using compound (IIa) and compound (IIIa ') by the same method as in the above step 2. This method is particularly suitable when X is a sulfur atom or an oxygen atom. When X is —SO— or —SO ₂ —, the corresponding sulfide obtained in the above step 4 or 5 is hydrogen peroxide,
It can be synthesized by oxidizing with an oxidizing agent such as peracetic acid, metaperiodate, metachloroperbenzoic acid, acyl nitrate, and dinitrogen tetraoxide.

(Step 6) Compound (VIII) can be synthesized from compound (IIa) and compound (IIIa ″) by the same method as in step 3 above. This method is particularly suitable when X is —NR ⁷ —.

[0093] Further, X is -COO -; - CONR ⁷ -;
^{_{-SO 2 NR 7 -; - COS}} -; - O-CO-O -; -
OOC-NR ⁷ -; - in the case of NH-CO-NH- is
Compound (VIII) can also be synthesized by the following method. (Step 7) The compound (VIII) is prepared by converting the compound (IV) and the compound (V) into 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (WSC / HC).
l), 1-hydroxybenzotriazole (HOB
T), hydroxysuccinimide (HONSu), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), N-hydroxy-5-norbornene-
In the presence of a condensing agent such as 2,3-dicarboxylic acid imide (HONB) (these may be used in combination of two or more kinds), dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride. , An organic solvent such as toluene, or a mixed solvent thereof, under ice-cooling or heating (the reaction is triethylamine, N-methylmorpholine (NMM), pyridine, 4-dimethylaminopyridine (DMAP), N -May be carried out in the presence of a base such as methylpiperidine), or a hydroxide or carbonate of an alkali metal such as sodium, potassium, lithium, triethylamine, pyridine, N-methylmorpholine, N-
In the presence of a base such as methylpiperidine and 4-dimethylaminopyridine, in an organic solvent such as dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, dimethylsulfoxide, benzene and toluene, in water or a mixed solvent thereof, or without a solvent, under ice cooling. Alternatively, it can be synthesized by reacting under heating.

X is --OOC--; --NR ⁷ CO--; --NR
^{In the case of 7} SO ₂ —; —NR ⁷ —COO—, compound (VIII) can also be synthesized by the following method. (Step 8) Compound (VIII) can be synthesized using compound (VI) and compound (VII) in the same manner as in step 7 above.

Compound (I) can be synthesized by subjecting compound (VIII) obtained in any of the above steps 1 to 8 to the following steps 9 to 11. (Step 9) Compound (IX) is prepared by converting compound (VIII) into
Alkali metal hydroxides or carbonates such as sodium, potassium and lithium, 1,5-diazabicyclo [4.
3.0] Non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene and other bases, or hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, fluorinated Is it treated in the presence of an acid such as hydrogen, acetic acid or trifluoroacetic acid in an organic solvent such as methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, toluene, xylene, water or a mixed solvent thereof under ice cooling or heating? , Methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, in an organic solvent such as acetic acid or a mixed solvent thereof, platinum black, platinum oxide, palladium black, palladium oxide, palladium carbon, palladium carbon,
In the presence of a metal catalyst such as Raney nickel, catalytic reduction is carried out with hydrogen gas, or tetraethylammonium fluoride, tetra-n-butylammonium fluoride, etc.
It can be synthesized by treating in an organic solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide or the like or a mixed solvent thereof in the presence of a primary ammonium fluoride under ice cooling or heating. When the amino-protecting group protecting the amino group is eliminated by this step, the amino-group is protected by the conventional method.

(Step 10) Compound (I ') is prepared by converting compound (IX) and compound (X) into WSC.HCl, HOB.
T, HONSu, DCC, DPPA, CDI, HONB
Etc. in the presence of a condensing agent (these may be used in combination of two or more), an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride, toluene, or a mixture thereof. It can be synthesized by reacting in a solvent under ice cooling or under heating. However,
When compound (X) is, for example, a hydrochloride salt, this reaction may be carried out in the presence of a base such as triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like. In addition, R ¹² in R ⁶ is —CONHOH, —CH ₂ OH.
In the case of a group having a hydroxyl group such as, as the compound (X),
The one whose hydroxyl group is protected in advance is used.

(Step 11) A step of removing an amino-protecting group in R ′, R _a ′ and R _b ′, which may be appropriately selected from known methods. For example, when the amino protecting group in R ′, R _a ′ and R _b ′ is Boc (tert-butoxycarbonyl group), the compound (I ′) is converted into hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluene. In the presence of an acid such as sulfonic acid, methanesulfonic acid, hydrogen chloride-dioxane, hydrogen chloride-ether, dioxane, ether, dichloromethane, tetrahydrofuran, methanol, ethanol,
Compound (I) can be synthesized by reacting in an organic solvent such as chloroform, benzene, or toluene, water, a mixed solvent thereof, or no solvent. Further, for example, when the amino protecting group is a benzyloxycarbonyl group, in an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, acetic acid or a mixed solvent thereof, palladium carbon, platinum oxide, Raney nickel, etc. It can be synthesized by catalytic reduction with hydrogen gas in the presence of a metal catalyst. When R ¹² in R ⁶ is a hydroxyl group-protected group, the above steps may be carried out after elimination of the hydroxyl group-protecting group by a conventional method such as catalytic reduction. In the case of synthesizing the compound (I) in which R ¹² is a carboxyl group, for example, R
It can be synthesized by synthesizing the compound (I ′) in which ¹² is a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and then subjecting it to the above reaction. Furthermore, R ¹²
In the case of synthesizing a compound (I) in which R is a dimethylaminoethoxy group or the like, for example, a compound (I ′) in which R ¹² is a carboxyl group is synthesized, and a compound such as dimethylaminoethanol is reacted in the same manner as in Step 7 above. After the reaction, it can be synthesized by the above reaction.

The compound of the present invention represented by the general formula (I) can also be synthesized by the following method.

[0099]

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(Wherein A ¹ , A ² , A ² ', A ³ , L,
X, M, W, R ', R _a ', R _b ', R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above)

(Step 12) The compound (XI) can be prepared by using the compound (III ′) and the compound (X) in the step 10
Can be synthesized by a method similar to.

(Step 13) The compound (I ′) can be synthesized by using the compound (XI) and the compound (II) in the same manner as in the above step 1. This method is particularly suitable when X is an oxygen atom, a sulfur atom, or —NR ⁷ —.

(Step 14) The compound (I ′) can be synthesized by using the compound (XI) and the compound (II ′) in the same manner as in the above step 2. This method
It is particularly suitable when X is a sulfur atom or an oxygen atom.

(Step 15) The compound (I ′) can be synthesized by using the compound (XI) and the compound (II ″) in the same manner as in the above step 3. This method
It is particularly suitable when X is —NR ⁷ —.

[0105]

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(Wherein A ¹ , A ² , A ³ , L, X, M,
_{R ', R a', R} b ', R 1, R 2, R 3, R 4, R 5
And R ⁶ has the same meaning as above.)

(Step 16) The compound (XI a) can be prepared by using the compound (III _a1 ) and the compound (X) as described in the step 10
Can be synthesized by a method similar to.

(Step 17) The compound (I ′) was prepared by using the compound (XIa) and the compound (IIa) in the step 1
Can be synthesized by a method similar to. This method is particularly suitable when X is an oxygen atom, a sulfur atom, or —NR ⁷ —.

[0109]

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(Wherein A ¹ , A ² , A ³ , L, X, M,
_{W, R ', R a'} , R b ', R 1, R 2, R 3, R 4,
R ⁵ and R ⁶ are as defined above)

(Step 18) The compound (XIa ') is prepared by using the compound ( _IIIa1 ') and the compound (X) in the above-mentioned Step 1
It can be synthesized by the same method as for 0.

(Step 19) The compound (I ′) is prepared by using the compound (XIa ′) and the compound (IIa) in the step 2
Can be synthesized by a method similar to. This method is particularly suitable when X is a sulfur atom or an oxygen atom.

[0113]

Embedded image

(Wherein A ¹ , A ² , A ³ , L, X, M,
_{R ', R a', R} b ', R 1, R 2, R 3, R 4, R 5
And R ⁶ has the same meaning as above.)

(Step 20) Compound (XIa ″) can be synthesized using compound (III _a1 ″) and compound (X) by the same method as in Step 10 above.

(Step 21) The compound (I ') can be synthesized by using the compound (XIa'') and the compound (IIa) in the same manner as in the step 3. This method is particularly suitable when X is —NR ⁷ —.

[0117] Further, X is -COO -; - CONR ⁷ -;
^{_{-SO 2 NR 7 -; - COS}} -; - O-CO-O -; -
OOC-NR ⁷ -; - in the case of NH-CO-NH- is
Compound (I ′) can also be synthesized by the following method.

[0118]

Embedded image

(Wherein A ¹ , A ² , A ³ , L, X, M,
W ¹ , W ² , R ′, R _a ′, R _b ′, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above)

(Step 22) Compound (XIa ′ ″) can be synthesized using compound (V ′) and compound (X) in the same manner as in step 10 above.

(Step 23) The compound (I ′) can be prepared by using the compound (XIa ′ ″) and the compound (IV) in the step 7
Can be synthesized by a method similar to.

X is -OOC-; -NR ⁷ CO-; -NR
^{In the case of 7} SO ₂ —; —NR ⁷ —COO—, compound (I ′) can also be synthesized by the following method.

[0123]

Embedded image

(Wherein A ¹ , A ² , A ³ , L, X, M,
W ¹ , W ² , R ′, R _a ′, R _b ′, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above)

(Step 24) Compound (XIa ″ ″) can be synthesized using compound (VII ′) and compound (X) by the same method as in step 10 above.

(Step 25) Compound (I ′) can be synthesized by using compound (XIa ″ ″) and compound (VI) in the same manner as in Step 8 above.

Compound (I) can be produced by the steps 13 to 1 above.
The compound (I ′) obtained in 5, 17, 19, 21, 23 or 25 can be used for the synthesis in the same manner as in Step 11 above.

Further, when X is —CH═CH—, compound (VIII) can also be synthesized by the following method.

[0129]

Embedded image

(Wherein A ¹ , A ² , A ² ', A ³ , L,
X, M, W, R ', R _a ', R _b ', R ¹ , R ² ,
R ³ , R ⁴ and R ¹⁹ are as defined above)

(Step 26) Compound (VIII) is prepared by converting compound (IIIa ′) and compound (II ″) into triphenylphosphine, trimethylphosphine, triethylphosphine, triphenylphosphite, trimethylphosphite, Sodium hydride, potassium hydride, lithium hydride, potassium carbonate, sodium carbonate, potassium tert-butoxide, lithium diisopropylamide, methyl lithium, n-butyl lithium, triethyl phosphate, etc.
In the presence of a base such as sec-butyllithium and tert-butyllithium, dimethylformamide, methylene chloride,
It can be synthesized by reacting in an organic solvent such as tetrahydrofuran, ether, benzene, toluene or a mixed solvent thereof at -78 ° C to under heating. When R ¹ , R ² , R ³ , R ⁴ , R _a ′ and R _b ′ each represent a hydroxyl group, the above steps are carried out after previously protecting with a hydroxyl group-protecting group by a conventional method. In this case, the main product is a cis isomer when triphenylphosphine or the like is used, and a trans isomer when trimethyl phosphite is used.

[0132] X is ^{-CO -; - CR 8 R 9} -; - CH =
In the case of CH-;-CS-, the compound (VIIIa), compound (VIIIb), compound (V
IIIc) can be synthesized.

[0133]

Embedded image

(Wherein A ¹ , A ² , A ² ', A ³ ,
A ³ ', L, M, W, R', R _a ', R _b ', R ¹ , R
² , R ³ , R ⁴ and R ¹⁹ are as defined above)

(Step 27) The compound (XIII) is prepared by converting the corresponding Grignard reagent (XII) prepared by a conventional method from the compound (II ′) and the compound (IIIa ″) into an organic compound such as ether, tetrahydrofuran or dioxane. It can be synthesized by reacting in a solvent or a mixed solvent thereof at -78 ° C to under heating.

(Step 28) Compound (VIIIa) is prepared by reacting compound (XIII) with ether, tetrahydrofuran in the presence of an oxidizing agent such as chromic anhydride, pyridinium chlorochromate, manganese dioxide, sodium hypochlorite and ruthenium tetraoxide. It can be synthesized by reacting in an organic solvent such as dioxane, dioxane or the like or a mixed solvent thereof under ice cooling or heating. In addition, when X is -CS-,
The compound (VIIIa) obtained in the above step was treated with hydrogen sulfide, phosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,
It can be synthesized by reacting in the presence of 4-disulfide (Lawsson's reagent) or the like in an organic solvent such as benzene, toluene, methanol, ethanol or a mixed solvent thereof under ice cooling or heating.

(Step 29) Compound (VIIIb) was prepared by converting compound (XIII) into triethylsilane, lithium aluminum hydride-aluminum chloride, sodium borohydride-trifluoroborane, sodium cyanoborohydride-methyl iodide, triphenyl. It can be synthesized by reacting in the presence of a reducing agent such as phosphonium or the like in an organic solvent such as ether, tetrahydrofuran or dioxane or a mixed solvent thereof at -78 ° C to under heating.

(Step 30) Compound (VIIIc) is prepared by converting compound (XIII) into sulfuric acid, phosphoric acid, potassium hydrogensulfate,
Oxalic acid, p-toluenesulfonic acid, boron trifluoride-
Ether complex, thionyl chloride-pyridine, phosphorus oxychloride-pyridine, metasulfonyl chloride-pyridine,
It can be synthesized by reacting in the presence of p-toluenesulfonyl chloride-pyridine or the like in an organic solvent such as ether, tetrahydrofuran, dioxane or the like, or a mixed solvent thereof under ice cooling or heating. The compound (I) is synthesized by using the compound (VIII), (VIIIa), (VIIIb) or (VIIIc) obtained in the above steps 26, 28 to 30 by the same method as in the above steps 9 to 11. can do. In addition, for example -A ² -
When X—A ³ — is —CH ₂ —CH ₂ —, the compound (I ′) synthesized from the corresponding compound obtained in the above Step 26 or 30 is treated with platinum black, platinum oxide, palladium black, After the catalytic reduction with hydrogen gas in the presence of a metal catalyst such as palladium oxide, palladium carbon, Raney nickel, etc., the synthesis can be carried out by the same method as in the above step 11.

Further, when X is a divalent heterocyclic group having one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom, in particular, divalent group of oxadiazole ring, Compound (VIIId) can be synthesized by the method.

[0140]

Embedded image

(In the formula, A ¹ , A ² , A ³ , L, M and R ′
, R _a ′, R _b ′, R ¹ , R ² , R ³ , R ⁴ and R ¹⁹ are as defined above).

(Step 31) Compound (XVI) is prepared by converting compound (XIV) and compound (XV) into WSC.HCl, H
OBT, HONSu, DCC, DPPA, CDI, HO
In the presence of a condensing agent such as NB (these may be used in combination of two or more kinds), an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride, toluene or the like. It can be synthesized by reacting in a mixed solvent under ice cooling or under heating. This reaction may be carried out in the presence of a base such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, N-methylpiperidine.

(Step 32) The compound (VIIId) can be synthesized by heating the compound (XVI) in an organic solvent such as toluene, dioxane, tetrahydrofuran, benzene, xylene or a mixed solvent thereof.

When X is a divalent group of oxazole ring, compound (VIIIe) can be synthesized by the following method.

[0145]

Embedded image

(Wherein A ¹ , A ² , A ³ , L, M, W,
_{R ', R a', R} b ', R 1, R 2, R 3, R 4 and R
¹⁹ is as defined above)

(Step 33) Compound (XVIII) was prepared by converting compound (IIb) and compound (XVII) into tetrakis (triphenylphosphine) palladium (O), bis (dibenzylideneacetone) palladium (O) and bis (tri). Phenylphosphine) palladium (II) dichloride, etc., and in the presence of zinc, nickel, magnesium, etc., in an organic solvent such as dimethoxyethane, tetrahydrofuran, ether, methylene chloride, toluene, chloroform or a mixed solvent thereof, under ice cooling or heating. It can be synthesized by reacting below.

(Step 34) The compound (XIX) is synthesized by heating the compound (XVIII) in acetic acid in the presence of a complex such as lead tetraacetate and manganese acetate or, if necessary, with a solvent such as benzene. be able to.

(Step 35) Compound (VIIIe) is prepared by converting compound (XIX) into formic acid, acetic acid and propione in the presence of ammonium salt such as ammonium lower alkanecarboxylate such as ammonium acetate and ammonium formate or inorganic acid ammonium such as ammonium carbonate. It can be synthesized by heating in an acidic solvent such as an acid such as a lower alkanecarboxylic acid. The compound (I) is the compound (VIIId) or (VIIIe) obtained in the above step 32 or 35.
) Can be used to synthesize the compound in the same manner as in Steps 9 to 11 above.

When at least one of R ¹ , R ² , R ³ and R ⁴ of compound (I) is a halogen atom, it can be synthesized by the following method.

[0151]

Embedded image

[Wherein R ¹ ′, R ² ′, R ³ ′, R ⁴ ′]
Are at least one hydrogen atom; an alkyl group which may be substituted with a substituent selected from a hydroxyl group, a lower alkoxy group or a halogen atom; an alkoxy group; a mercapto group;
Alkylthio group; amino group which may be substituted with a substituent selected from alkyl group, aryl group, aralkyl group or amino protecting group; nitro group; cyano group; carboxyl group; alkoxycarbonyl group; aryloxycarbonyl group; acyl group ; or -O-CO-R ¹⁰ (wherein, R ¹⁰
Is the same as defined above, and at least one represents a hydrogen atom, and A ¹ , A ² , A ³ ,
L, X, M, R ' , R a', R b ', R 1, R 2,
R ³ , R ⁴ and R ¹⁹ are as defined above]

(Step 36) The compound (VIII) is prepared by converting the compound (VIII ') into tert-butyl hypochlorite, tert-butyl hypobromite, tert-butyl hypoiodite, sulfuryl chloride, sulfuryl bromide, Thionyl chloride,
Thionyl bromide, fluorine, chlorine, bromine, iodine, hydrogen fluoride, silver difluoride, in the presence of a halogenating agent such as xenon difluoride, dichloromethane, chloroform, acetonitrile, toluene, benzene, ether, tetrahydrofuran, dioxane, It can be synthesized by reacting in an organic solvent such as methanol, ethanol, carbon tetrachloride, ethyl acetate or the like, or a mixed solvent thereof, or in the absence of a solvent under ice cooling or under heating. In addition, this method may be performed after the synthesis of compound (I ′). Compound (I)
Can be synthesized in the same manner as in Steps 9 to 11 above, using the compound (VIII) obtained in Step 36 above.

When at least one of R ¹ , R ² , R ³ and R ⁴ of compound (I) is —O—CO—R ¹⁰ , it can be synthesized by the following method.

[0155]

Embedded image

[In the formula, R ¹ ″, R ² ″, R ³ ″, R ⁴ ″
Are the same or different and are a hydrogen atom group; a halogen atom; an alkyl group which may be substituted with a substituent selected from a hydroxyl group, a lower alkoxy group or a halogen atom; an alkoxy group; a mercapto group; an alkylthio group; an alkyl group, an aryl group. , An aralkyl group or an amino group which may be substituted with a substituent selected from an amino protecting group; a nitro group; a cyano group; a carboxyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; or an acyl group, and at least one of which is Represents a hydroxyl group, A ¹ , A ² , A ³ , L,
X, M, R ', R a', R b ', R 1, R 2, R 3, R
⁴ , R ¹⁰ and R ¹⁹ are as defined above]

(Step 37) Compound (I ′) is prepared by converting compound (I ″) into dichloromethane, chloroform, ether,
In an organic solvent such as tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, ethyl acetate, acetonitrile or a mixed solvent thereof, in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylpiperidine, N-dimethylaminopyridine. Can be synthesized by reacting with the compound (XX). The compound (I) can be synthesized using the compound (I ′) obtained in the above Step 37 in the same manner as in the above Step 11.

Further, the compound of the general formula (I) can be prepared according to a conventional method by an inorganic acid (eg hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid) or an organic acid (eg oxalic acid, maleic acid, fumaric acid). , Malic acid, tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, paratoluenesulfonic acid, benzoic acid, valeric acid, malonic acid, nicotinic acid, propionic acid) It can be a salt.

The compound thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization and chromatography.

The compounds of this invention include one or more stereoisomers based on asymmetric carbons, and all such isomers and mixtures thereof are included within the scope of this invention. The present invention also includes prodrugs and hydrates.

The prodrug of the amide compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof has a group capable of being chemically or metabolically decomposed, and may be obtained by solvolysis or physiologically. It is a derivative of the compound of the present invention which is pharmaceutically active under the conditions.

The compound of the present invention has an excellent inflammatory cytokine production inhibitory activity in mammals (eg, humans, rabbits, dogs, cats, monkeys, mice, rats, etc.), and rheumatic diseases such as rheumatoid arthritis. , Gouty arthritis, systemic lupus erythematosus, skin diseases such as psoriasis, pustulosis, atopic dermatitis, bronchial asthma, bronchitis, A
Respiratory diseases such as RDS / diffuse interstitial pneumonia, inflammatory bowel disease (ulcerative colitis, Crohn's disease), acute / chronic hepatitis including acute hepatitis, acute / chronic glomerulonephritis, nephrogenic nephritis, Behcet Disease-vogt-Uveitis associated with Koyanagi-Harada disease,
Prevention of non-infectious and infectious diseases with infiltration of neutrophils represented by Mediterranean fever (polyserosalitis), ischemic diseases such as myocardial infarction, systemic circulation failure associated with sepsis and multiple organ failure, or Useful for treatment. Further, it has been recognized that it also has an inhibitory effect on inflammatory cytokines such as IL-6 and GM-CSF.

When the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation containing an active ingredient, it is usually a pharmacologically acceptable carrier known per se. , Excipients, diluents, fillers, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, corrigents, solubilizers, other additives, Specifically, mixed with water, vegetable oil, alcohol such as ethanol or benzyl alcohol, carbohydrate such as polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, magnesium stearate, talc, lanolin, petrolatum, etc., tablets , Pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, suspensions, emulsions, A pharmaceutical composition in the form of drop agent, can be administered orally or parenterally.

The dose varies depending on the kind and degree of the disease, the compound to be administered, the route of administration, the age, sex, weight of the patient, etc., but when administered orally to an adult patient, it is usually 1
0.01-1000 mg per day, preferably 0.1-
It is selected from the range of about 100 mg, and i.
v. When administered, it is usually 0.01 to 1000 per day.
mg, preferably selected from the range of about 0.05 to 50 mg, which can be administered once or in several divided doses.

[0165]

EXAMPLES The present invention will be described more specifically below with reference to production examples and examples.

First, production examples of the intermediate compounds shown in Tables 1 to 4 will be shown. In the table, Me represents a methyl group, Ph represents a phenyl group, and Boc represents a tert-butoxycarbonyl group.

[0167]

[Table 1]

[0168]

[Table 2]

[0169]

[Table 3]

[0170]

[Table 4]

Production Example 1 5-Chloro-2,4-dihydroxy-3-methylbenzoic acid To a solution of methyl 2,4-dihydroxy-3-methylbenzoate (9.9 g) in ethyl acetate (100 ml) under ice cooling, Tert-Butyl hypochlorite (12.3 ml) was added. After stirring for 2 hours, add hexane (200 ml),
Crystals were precipitated by cooling with ice. The crystals were collected by filtration, dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (THF) (20 ml), 1M aqueous lithium hydroxide solution (40 ml) was added, and the mixture was heated under reflux for 18 hours. The reaction mixture was concentrated, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give the title compound (4.14 g, yield 37%).

Production Example 2 2,4-dihydroxy-5-fluorobenzoic acid 2,4-dihydroxybenzoic acid (1.22 g) and 1-
A solution of fluoro-2,6-dichloropyridinium triflate (5.0 g) in dioxane (50 ml) was added at 70 ° C.
For 5 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was filtered. The filtrate was extracted with ether, the organic layer was dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent:
The title compound (310 mg, yield 23%) was obtained by purification with ethyl acetate / ether = 1/2 v / v).

Production Example 3 (3-tert-butyldimethylsilyloxy-4-t)
ert-Butyldimethylsilyloxycarbonyl) benzyltriphenylphosphonium bromide (1) 3-tert-butyldimethylsilyloxy-4
-Tert-Butyldimethylsilyloxycarbonyltoluene A solution of 4-methylsalicylic acid (1.52 g) in methylene chloride (10 ml) was added at -78 ° C to triethylamine (2.53 g) and trifluoromethanesulfonic acid te.
rt-Butyldimethylsilyl (5.29 g) was added, and the reaction solution was gradually warmed to room temperature. The reaction solution is concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/9 v / v) to give the title compound (3.6 g, yield 95%).

(2) 3-tert-Butyldimethylsilyloxy-4-tert-butyldimethylsilyloxycarbonylbenzyl bromide 3-tert-butyldimethylsilyloxy-4-te
N-Bromosuccinimide (701 mg) and benzoyl peroxide (10 mg) were added to a solution of rt-butyldimethylsilyloxycarbonyltoluene (1.5 g) in carbon tetrachloride (50 ml), and the mixture was heated under reflux at 80 ° C for 2 hours under reflux. did. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/4 v / v) to give the title compound (1.63 g, yield 90%).

(3) (3-tert-Butyldimethylsilyloxy-4-tert-butyldimethylsilyloxycarbonyl) benzyltriphenylphosphonium bromide 3-tert-butyldimethylsilyloxy-4-te
Triphenylphosphine (571 mg) was added to a solution of rt-butyldimethylsilyloxycarbonylbenzyl bromide (1.00 g) in toluene (20 ml), and 2
Heated to reflux for an hour. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from toluene to give the title compound (467 mg,
Yield 30%) was obtained.

Production Example 4 4- (1,2-di-tert-butoxycarbonylguanidino) benzyl alcohol 4- (1,2-di-tert-butoxycarbonylguanidino) benzoic acid (11.38 g), 4-dimethylamino 1-Ethyl-3- (3-dimethylaminopropyl) was added to a solution of pyridine (DMAP) (4.03 g) and methanol (1.34 ml) in methylene chloride (150 ml).
Carbodiimide hydrochloride (WSC HCl) (6.33)
g) was added and the mixture was stirred for 15 hours at room temperature. Ethyl acetate was added to the reaction solution, which was washed successively with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and methylene chloride (150 ml) was added to the residue. 1 in this methylene chloride solution
M diisobutylaluminum hydride-toluene solution (1
00 ml) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hr, methanol (50 ml) was added, and then 10% aqueous citric acid solution was added. Further, chloroform was added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1 /
3 v / v) to give the title compound (5.15
g, yield 47%) was obtained.

Production Example 5 4- (2-tert-Butoxycarbonylmethylaminoethyl) benzoic acid (1) Methyl 4- (cyanomethyl) benzoate To a solution of potassium cyanide (3 g) in water (18 ml), 4 was added.
A solution of methyl-(bromomethyl) benzoate (10.9 g) in dimethyl sulfoxide (DMSO) (70 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1 v / v) to give the title compound (6.7 g, yield 87%).

(2) Methyl 4- (2-tert-butoxycarbonylaminoethyl) benzoate To a solution of methyl 4- (cyanomethyl) benzoate (2.8 g) in methanol (45 ml) was added di-tert-butyl dicarbonate ( 5.3 g) and Raney nickel (2.8
g) was added, and catalytic reduction was carried out in the presence of hydrogen gas at room temperature and 3 atm for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The precipitated crystals were washed with hexane and subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3
(1/93 v / v) to give the title compound (3.93
g, yield 87%).

(3) Methyl 4- (2-tert-butoxycarbonylmethylaminoethyl) benzoate Methyl 4- (2-tert-butoxycarbonylaminoethyl) benzoate (8.38 g) in dimethylformamide (DMF) (55 ml) ) Methyl iodide (3.74 ml) was added to the solution, and 60% oily sodium hydride (1.32 g) was added under ice cooling, and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 /
1 v / v) to give the title compound (7.32)
g, yield 83%).

(4) 4- (2-tert-Butoxycarbonylmethylaminoethyl) benzoic acid Methyl 4- (2-tert-butoxycarbonylmethylaminoethyl) benzoate (7.3 g) in methanol (3
5 ml) -THF (35 ml) mixed solution, 1N aqueous lithium hydroxide solution (75 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give the title compound (6.0 g, yield 86%).

Production Example 6 3- (1,2-Di-tert-butoxycarbonylguanidino) benzoic acid 3-Aminobenzoic acid (5 g) in ethanol (30 ml)
4N hydrogen chloride-dioxane solution (10 ml) and cyanamide (6.1 g) were added to the solution, and the mixture was heated with stirring at 90 ° C. for 6 hours under an argon gas stream. The reaction solution was concentrated under reduced pressure, and DMF (300 ml) was added to the residue. This DMF
Triethylamine (16.7 ml) was added to the solution, and chlorotrimethylsilane (5 ml) was gradually added at room temperature. After stirring for 1 hour, di-tert-butyl dicarbonate (23.8 g) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: toluene / ether = 1/1 v / v) to give the title compound (1.1 g, yield 14%). Got

Production Example 7 4- (2-tert-Butoxycarbonylmethylaminoethyl) -2-methylbenzoic acid (1) Ethyl 4-cyanomethyl-2-methylbenzoate Ethyl 2,4-dimethylbenzoate (8.91 g) ), N-
Carbon tetrachloride (2) of bromosuccinimide (NBS) (8.9 g) and benzoyl peroxide (BPO) (61 mg)
The solution was heated to reflux for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. DMF (60 ml) and water (25 ml) were added to the residue, and potassium cyanide (2.61 g) was added under ice cooling. After stirring at room temperature for 3 hours,
Ethyl acetate and water were added. Further, the mixture was neutralized with 5% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/15 to 1/4 v /
The title compound (2.95 g, yield 21%) was obtained by purification with v).

(2) Ethyl 4- (2-tert-butoxycarbonylaminoethyl) -2-methylbenzoate Ethyl 4-cyanomethyl-2-methylbenzoate (2.6
1 g) in ethanol (30 ml), di-tert
-Butyldicarbonate (4.21 g) and Raney nickel (1 g) were added, and catalytic reduction was carried out in the presence of hydrogen gas at room temperature and 3 atm for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1 v / v) to give the title compound (2.46 g, yield 62%).

(3) 4- (2-tert-Butoxycarbonylmethylaminoethyl) -2-methylbenzoic acid Ethyl 4- (2-tert-butoxycarbonylaminoethyl) -2-methylbenzoate (1.54 g) DM
Methyl iodide (1.42 g) was added to the F (15 ml) solution, and 60% oily sodium hydride (400 m) was added under ice cooling.
g) was added. After stirring for 3 hours, the reaction solution is poured into water,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the organic layer was concentrated under reduced pressure. The residue is ethanol (10 ml) and THF
It was dissolved in a mixed solvent of (10 ml), 1 M lithium hydroxide aqueous solution (10 ml) was added thereto, and the mixture was heated with stirring at 60 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the aqueous layer was washed with ether, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give the title compound (1.26 g, yield 86%).

Production Example 8 4- (2-tert-Butoxycarbonylaminoethyl) -2-methylbenzoic acid 4- (2-tert-Butoxycarbonylaminoethyl) -2-obtained in Production Example 7 (2) above Ethyl methylbenzoate (2.46 g) in ethanol (14 ml) and T
A 1 M aqueous lithium hydroxide solution (20 ml) was added to a mixed solution of HF (10 ml), and the mixture was heated with stirring at 60 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue to acidify it, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give the title compound (1.
92 g, yield 86%) was obtained.

Production Example 9 4- (2-tert-Butoxycarbonylmethylaminoethyl) -2,6-dimethylbenzoic acid Ethyl 2,4,6-trimethylbenzoate (7.5 g) was used, the same as Production Example 7. To give the title compound (1.3 g, yield 10%).

Production Example 10 3- (tert-Butoxycarbonylmethylaminomethyl) -2-methylbenzoic acid (1) Ethyl 3-amino-2-methylbenzoate / hydrochloride Ethyl 2-methyl-3-nitrobenzoate ( 5.02g)
Solution of ethanol (100 ml) in 1 st tin chloride (2
1.7 g) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, 5% aqueous potassium hydroxide solution and ethyl acetate were added to the residue, and the mixture was filtered. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the organic layer was concentrated under reduced pressure. Ether (100 ml) was added to the residue, 1 M hydrogen chloride-ether solution (30 ml) was further added, and the mixture was crystallized to give the title compound (4.6 g, yield 89%).

(2) Ethyl 3-cyano-2-methylbenzoate Ethyl 3-amino-2-methylbenzoate-hydrochloride (3.
To a mixed solution of 6 g) of water (83 ml) and concentrated sulfuric acid (10 ml), sodium nitrite (1.15 g) was gradually added under ice cooling. After 40 minutes, with saturated aqueous sodium carbonate solution,
It was brought to pH 6. The above aqueous solution was added to potassium cyanide (5.0
1 g) and copper (II) sulphate pentahydrate (7.83 g) were added slowly to a solution of water (70 ml). Reaction liquid at 70 ℃ 1
After heating and stirring for a period of time, ethyl acetate was added to the reaction solution and filtered. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9/1 v / v) to give the title compound (1.41 g, yield 45%).

(3) Ethyl 3- (tert-butoxycarbonylaminomethyl) -2-methylbenzoate To a solution of ethyl 3-cyano-2-methylbenzoate (1.4 g) in ethanol (20 ml) was added di-tert-. Butyl dicarbonate (4.84 g) and Raney nickel (2
g) was added, and catalytic reduction was performed in the presence of hydrogen gas at room temperature and 3 atm for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent:
The title compound (1.62 g, yield 75%) was obtained by purification with hexane / ethyl acetate = 9/1 v / v).

(4) 3- (tert-Butoxycarbonylmethylaminomethyl) -2-methylbenzoic acid 3- (tert-Butoxycarbonylaminomethyl)-
To a solution of ethyl 2-methylbenzoate (1.62 g) and methyl iodide (3.5 g) in DMF (30 ml) was added 60% oily sodium hydride (400 mg) under ice cooling, and the mixture was stirred at room temperature for 6 hours. did. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The residue was treated with ethanol (10 ml) and THF (10 ml).
ml) mixed solvent, 1M aqueous lithium hydroxide solution (10 ml) was added thereto, and the mixture was heated with stirring at 60 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The aqueous layer was washed with ether and acidified with 10% aqueous citric acid solution. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (1.31 g,
Yield 89%) was obtained.

Production Example 11 3,5-Di-tert-butoxycarbonylmethylaminomethylbenzoic acid (1) Ethyl 3,5-dibromomethylbenzoate 3,5-Dimethylbenzoic acid ethyl ester (6.5 g), NBS
A carbon tetrachloride (150 ml) solution of (13.0 g) and BPO (44 mg) was heated under reflux for 1 hour. The reaction solution was ice-cooled and filtered. The filtrate was concentrated under reduced pressure, methylene chloride (30 ml) and hexane (100 ml) were added to the residue,
Hexane was distilled off under normal pressure. The reaction solution was ice-cooled to give the title compound (3.89 g, yield 32%) as crystals.

(2) Ethyl 3,5-di-tert-butoxycarbonylaminomethyl benzoate Ethyl 3,5-dibromomethyl benzoate (3.89 g)
Was added to a solution of sodium azide (1.
66 g) was gradually added at room temperature. The reaction solution was stirred for 3 hours, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the organic layer was concentrated under reduced pressure. Ethanol (30 ml), di-tert-butyl dicarbonate (7.6 g) and 10% palladium on carbon (200 mg) were added to the residue.
Was added, and catalytic reduction was performed in the presence of hydrogen gas at room temperature and 3 atm for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/3 v / v) to give the title compound (3.45 g, yield 73%).

(3) 3,5-Di-tert-butoxycarbonylmethylaminomethylbenzoic acid Ethyl 3,5-di-tert-butoxycarbonylaminomethylbenzoate (3.45 g) and methyl iodide (6.0 g) In DMF (50 ml) solution of 6 under ice cooling.
0% oily sodium hydride (900 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the organic layer was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethanol (20 ml) and THF (20 ml), and 1M lithium hydroxide aqueous solution (2
0 ml) was added, and the mixture was heated with stirring at 60 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The aqueous layer was washed with ether and acidified with 10% aqueous citric acid solution. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (2.78 g, yield 81).
%).

Production Example 12 6- (2-tert-Butoxycarbonylaminoethylamino) nicotinic acid (1) Methyl 6- (2-tert-Butoxycarbonylaminoethylamino) nicotinate N-tert-Butoxycarbonylethylenediamine (801 mg) , Methyl 6-chloronicotinate (686
mg) and potassium carbonate (1.1 g) in DMF (7 m
l) The solution was heated and stirred at 130 ° C. for 2 hours. The reaction solution was allowed to cool, poured into water (70 ml), and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/2 v / v) to give the title compound (574 mg, yield 50%).

(2) 6- (2-tert-Butoxycarbonylaminoethylamino) nicotinic acid Methyl 6- (2-tert-butoxycarbonylaminoethylamino) nicotinate (550 mg) in methanol (3 ml) and THF (3 ml). 1M aqueous lithium hydroxide solution was added to the mixed solution of, and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue to acidify it, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (519 mg, yield 99%).

Production Example 13 3- (2-tert-Butoxycarbonylaminoethyl) benzaldehyde 3- (2-tert-Butoxycarbonylaminoethyl) benzyl alcohol (878 mg) and molecular sieves 3A (1 g) in methylene chloride (35 ml) To the above, pyridinium dichromate (2.02 g) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1 v / v) to give the title compound (435 mg, yield 50
%).

Production Example 14 4- (tert-Butoxycarbonylmethylaminomethyl) benzaldehyde 4- (tert-Butoxycarbonylmethylaminomethyl) benzyl alcohol (12 g) was used and Production Example 13 was used.
The title compound (8.87 g, yield 75%) was obtained in the same manner as.

Production Example 15 4- (3-tert-Butoxycarbonylaminopropyl) benzaldehyde 4- (3-tert-Butoxycarbonylaminopropyl) benzyl alcohol (624 mg) was used in the same manner as in Production Example 13 to give the title compound (400 mg , Yield 65
%).

Production Example 16 3- (tert-Butoxycarbonylaminomethyl) benzaldehyde 3- (tert-Butoxycarbonylaminomethyl) benzyl alcohol (675 mg) was used in the same manner as in Production Example 13 to give the title compound (498 mg, yield 75). %) Was obtained.

Production Example 17 3,5-di (tert-butoxycarbonylaminomethyl) benzaldehyde (1) 3,5-di (tert-butoxycarbonylaminomethyl) benzyl alcohol 3,5-di (tert-butoxycarbonylaminomethyl) ) Ethyl benzoate (1.63 g) in methylene chloride (5
Solution of diisobutylaluminum hydride in toluene (1.02M, 9.2m).
1) was gradually added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Further, methanol (16 ml) was added, and the mixture was stirred for 30 minutes. Then, 10% citric acid aqueous solution (32 ml) was added, and chloroform was added. The reaction solution was extracted with chloroform, the organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/2 v / v) to give the title compound (1.17 g, yield 80%).

(2) 3,5-di (tert-butoxycarbonylaminomethyl) benzaldehyde 3,5-di (tert-butoxycarbonylaminomethyl) benzyl alcohol (800 mg) in methylene chloride (35 ml) was added to dichromic acid. Pyridinium (820
mg) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2.
/ 1 v / v) to give the title compound (620 m
g, 78% yield).

Production Example 18 3,5-di (2-tert-butoxycarbonylaminoethyl) benzaldehyde Ethyl 3,5-di (2-tert-butoxycarbonylaminoethyl) benzoate (1 g) was used to give Production Example 17 and Similarly, the title compound (589 mg, yield 65%) was obtained.

Production Example 19 4- (2-tert-Butoxycarbonylmethylaminoethyl) benzaldehyde Methyl 4- (2-tert-butoxycarbonylmethylaminoethyl) benzoate (10.61 g) was used in the same manner as in Production Example 17. And the title compound (6.58 g, yield 69
%).

Production Example 20 4- (2-dimethylaminoethyl) benzaldehyde
Hydrochloride 4- (2-Dimethylaminoethyl) benzyl alcohol (810 mg), triethylamine (2.08 ml) and DMSO (3.21 ml) Toluene (5 ml) solution, 3-pyridinesulfonic acid (2.16 g) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography (developing solvent: methanol / chloroform = 15/85 v / v), and the 1M hydrogen chloride-ether solution was added to give the title compound (57 mg, yield 6
%).

Production Example 21 4- (2-tert-Butoxycarbonylaminoethyl) phenylacetaldehyde 4- (2-tert-Butoxycarbonylaminoethyl) phenyl-2-ethanol (1.00 g) in methylene chloride (10 ml), 2,2,6,6-Tetramethylpiperidine-N-oxide (TEMPO) (5.7 m
g), saturated aqueous sodium hydrogen carbonate (6.3 ml), potassium bromide (38
mg) and tetra-n-butylammonium chloride (50 mg) were added under ice cooling and stirred for 15 minutes. Sodium hypochlorite solution (2.5 ml), saturated aqueous sodium hydrogen carbonate (3.8 ml) and saturated brine (7.5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3.
/ 1v / v) to give the title compound (620m
g, yield 62%).

Production Example 22 4- (tert-Butoxycarbonylaminomethyl) phenylacetaldehyde 4- (tert-Butoxycarbonylaminomethyl) phenyl-2-ethanol (2.00 g) was used in the same manner as in Production Example 21 to give the title compound. (1742 mg, yield 37
%).

Production Example 23 L-phenylalanylmethylamino-4-fluorobenzene.hydrochloride N-tert-butoxycarbonyl-L-phenylalanine (1.06 g), p-fluoro-N-methylaniline.hydrochloride (646 mg) ) And hydroxybenzotriazole (HOBT) (541 mg) in methylene chloride (2
0 ml) solution, WSC.HCl (767 mg) and N
-Methylmorpholine (0.44 ml) was added and 1 at room temperature.
Stir for 6 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3/7 v /
Purification in v) gave N-tert-butoxycarbonyl-L-phenylalanylmethylamino-4-fluorobenzene. This was dissolved in a 4N hydrogen chloride-dioxane solution (10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue for crystallization to give the title compound (560 mg, yield 45
%).

Production Example 24 Methyl 2-hydroxybenzoate-4-carboxamide oxime Methyl 2-hydroxy-4-cyanobenzoate (2.00
g) in methanol (30 ml), water (6 ml),
Hydroxyamine hydrochloride (1.57 g) and sodium bicarbonate (1.9 g) were added, and the mixture was heated with stirring at 70 ° C. for 3 hours. The reaction solution is concentrated, 10% aqueous citric acid solution is added,
Filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/2 v / v) to give the title compound (82
3 mg, yield 35%) was obtained.

Production Example 25 4- [2- (4-tert-Butoxycarbonylaminomethylbenzoyl) ethyl] -2-hydroxybenzoic acid (1) 3-hydroxy-4-methoxycarbonyl-4 '
-Cyanochalcone 4-Cyanoacetophenone (1.01 g) and methyl 4-formyl-2-hydroxybenzoate (1.26 g) in methanol (30 ml) was added with potassium carbonate (100 ml).
mg) was added and the mixture was stirred at room temperature for 70 hours. 5% in the reaction solution
Hydrochloric acid (100 ml) was added, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and methylene chloride (20 ml) was added to the residue. Pyridine (3 ml) was added to this methylene chloride solution, and thionyl chloride (3 ml) was added under ice cooling. The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with a 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and methanol was added to the residue for crystallization to give the title compound (526 mg, yield 24%).
I got

(2) 4- [2- (4-tert-butoxycarbonylaminomethylbenzoyl) ethyl] -2-
Methyl hydroxybenzoate 3-hydroxy-4-methoxycarbonyl-4'-cyanochalcone (730 mg), di-tert-butyl dicarbonate (1.56 g) and Raney nickel (600).
mg) in methanol (20 ml) -dioxane (20 m
1) The mixed solution was catalytically reduced under hydrogen gas at 3 atm at room temperature for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/4 v / v) to give the title compound (624 mg, yield 64%).

(3) 4- [2- (4-tert-butoxycarbonylaminomethylbenzoyl) ethyl] -2-
Hydroxybenzoic acid 4- [2- (4-tert-butoxycarbonylaminomethylbenzoyl) ethyl] -2-hydroxybenzoic acid methyl (615 mg) in THF (5 ml) solution, 1M.
Lithium hydroxide aqueous solution (12 ml) was added, and at room temperature, 1
Stir for 8 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and methylene chloride and hexane were added to the residue for crystallization to give the title compound (4
26 mg, yield 72%) was obtained.

Example 1 N- [3,5-dichloro-2-hydroxy-4- [4-
(2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine ethyl ester-hydrochloride step 22) N- (3,5-dichloro-2,4-dihydroxybenzoyl) -L-phenylalanine ethyl ester (XIa '') ') 3,5-dichloro-2,4-dihydroxybenzoic acid (1.56 g), L-phenylalanine ethyl ester / hydrochloride (1.61 g) and HOBT (1.04 g) in DMF (15 ml) solution, ice. Under cooling, triethylamine (1.07 ml) and WSC · HCl (1.48 g) were added. After stirring at room temperature for 16 hours, ethyl acetate and water were added for extraction. The organic layer was washed successively with 10% citric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2 v / v) to give the title compound (1.97 g, yield 71%).

Step 23) N- [3,5-dichloro-2-
Hydroxy-4- [4- (2-tert-butoxycarbonylmethylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine ethyl ester (I ′) 4- (2-tert-butoxycarbonylmethylaminoethyl) benzoic acid (232 mg ) And the compound (398 mg) obtained in the above step 22) in methylene chloride (8 m
l) To the solution under ice cooling, DMAP (122 mg) and WS
C.HCl (192 mg) was added. After stirring at room temperature for 15 hours, water and ether were added to the reaction solution for extraction. The organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2 v / v) to give the title compound (49
8 mg, yield 91%) was obtained.

Step 11) N- [3,5-dichloro-2-
Hydroxy-4- [4- (2-methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine ethyl ester hydrochloride (I) In a solution of the compound (498 mg) obtained in the above step 23) in dioxane (4 ml). A 4N hydrogen chloride-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to obtain the title compound (414 mg, yield 92%) (see Table 5).

Example 1'N- [3,5-dichloro-2-hydroxy-4- [4-
(2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine ethyl ester / hydrochloride Step 11) N- [3,5-dichloro-2-hydroxy-
4- [4- (2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine ethyl ester hydrochloride (I) The compound (1.74) obtained in Step 23) of Example 1 above.
Trifluoroacetic acid (15 ml) was added to a solution of g) in methylene chloride (30 ml) at room temperature, and the mixture was stirred for 30 minutes.
Toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml), 1N hydrogen chloride-ether solution (8 ml) was added and crystallized to give the title compound (1.22 g, yield 81%).

Examples 2-137 The compounds of Examples 2-137 were prepared from the corresponding compounds in the same manner as in Example 1 (see Tables 5-74).

Example 138 N- [3,5-dichloro-2-hydroxy-4- [4-
(2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanylmethylamino-4-fluorobenzene-hydrochloride Step 22) N- (3,5-dichloro-2,4-dihydroxybenzoyl) -L- Phenylalanylmethylamino-4-fluorobenzene (XIa ''') 3,5-dichloro-2,4-dihydroxybenzoic acid (4
04 mg), L-phenylalanylmethylamino-4-
Fluorobenzene / hydrochloride (560mg) and HOBT
(245 mg) in DMF (8 ml) solution, WSC · H
Cl (348 mg) and N-methylmorpholine (0.2
ml) was added, and the mixture was stirred at room temperature for 22 hours. Ethyl acetate was added to the reaction solution, and the organic layer was added with 10% aqueous citric acid solution, water,
The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1 v / v) to give the title compound (461 mg, yield 53%).

Step 23) N- [3,5-dichloro-2-
Hydroxy-4- [4- (2-tert-butoxycarbonylmethylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanylmethylamino-4-fluorobenzene (I ′) 4- (2-tert-butoxycarbonylmethyl) Aminoethyl) benzoic acid (246 mg), the compound (451 mg) obtained in the above Step 22) and DMAP (115 m).
g) in a solution of methylene chloride (8 ml) under ice cooling under WSC
-HCl (181 mg) was added and it stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3/7 v / v) to give the title compound (173 mg, yield 25%).

Step 11) N- [3,5-dichloro-2-
Hydroxy-4- [4- (2-methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanylmethylamino-4-fluorobenzene-hydrochloride (I) Compound obtained in step 23) above (167 mg) 4N
A hydrogen chloride-dioxane (5 ml) solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to give the title compound (137 mg,
Yield 90%) was obtained (see Table 74).

Examples 139-147 The compounds of Examples 139-147 were prepared from the corresponding compounds analogously to Example 138 (see Tables 75-79).

Example 148 N- [3,5-dichloro-2-hydroxy-4- [4-
(2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine 2-dimethylaminoethyl ester dihydrochloride Step 11) N- [3,5-dichloro-2-hydroxy-
4- [4- (2-Methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine 2-dimethylaminoethyl ester dihydrochloride (I) (1) N- [3,5-dichloro-2-hydroxy- 4-
[4- (2-tert-Butoxycarbonylmethylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine N-obtained in the same manner as in Step 23) of Example 1 above.
[3,5-dichloro-2-hydroxy-4- [4- (2
-Tert-butoxycarbonylmethylaminoethyl)
Benzoyloxy] benzoyl] -L-phenylalanine benzyl ester (3.10 g) in ethyl acetate (30
ml) solution, 10% palladium carbon (300 mg) was added, and catalytic reduction was carried out in the presence of hydrogen gas at room temperature and normal pressure for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.62 g, yield 97%).

(2) N- [3,5-dichloro-2-hydroxy-4- [4- (2-tert-butoxycarbonylmethylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine 2-dimethylaminoethyl ester The compound (632 mg) obtained in the above (1), 2-dimethylaminoethanol (0.1 ml) and HOBT (1
62 mg) in DMF (4 ml) solution under ice-cooling, WSC
-HCl (230 mg) was added and it stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate /
The title compound (280 mg, yield 40%) was obtained by purification with ethanol = 4/1 v / v).

(3) N- [3,5-dichloro-2-hydroxy-4- [4- (2-methylaminoethyl) benzoyloxy] benzoyl] -L-phenylalanine 2
-Dimethylaminoethyl ester dihydrochloride (I) Trifluoroacetic acid (4 ml) was added to a solution of the compound (270 mg) obtained in (2) above in methylene chloride (4 ml), and the mixture was stirred at room temperature for 30 minutes. Toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Methylene chloride (5 ml) was added to the residue, and 1N hydrogen chloride-ether solution (4 ml) was further added. After stirring for 10 minutes, toluene was added to the reaction solution and concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (116 mg, yield 45%) (see Table 79).

Example 149 N- [4- (4-aminomethylbenzoyloxymethyl) -2-hydroxybenzoyl] -L-phenylalanine methyl ester.hydrochloride Step 22) N- (2-hydroxy-4-hydroxymethylbenzoyl) ) -L-Phenylalanine methyl ester (XIa ′ ″) 2-hydroxy-4-hydroxymethylbenzoic acid (1.
56 g), L-phenylalanine methyl ester · hydrochloride (2.00 g), WSC · HCl (1.78 g), H
OBT (1.25 g) and N-methylmorpholine (1.
A DMF (30 ml) solution of (33 ml) was stirred at room temperature for 2 hours. Then, ethyl acetate and water were added to the reaction solution,
Extracted. The organic layer was post-treated in the same manner as in Step 22) of Example 1 above to give the title compound (2.18 g, yield 72%).

Step 23) N- [4- (4-tert-butoxycarbonylaminomethylbenzoyloxymethyl) -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I ') 4-tert-butoxycarbonylamino Methylbenzoic acid (716 mg), compound (860 mg) obtained in the above step 22), WSC.HCl (600 mg) and D
A solution of MAP (383 mg) in methylene chloride (30 ml) was stirred at room temperature for 20 hours. Then, water and ether were added to the reaction solution for extraction. The organic layer was treated similarly to the step 23) in Example 1 above to give the title compound (567 mg, yield 40%).

Step 11) N- [4- (4-aminomethylbenzoyloxymethyl) -2-hydroxybenzoyl] -L-phenylalanine methyl ester.hydrochloride (I) Compound obtained in Step 23) above (430 mg) 4N
Hydrogen chloride-dioxane (5 ml) solution was added, and at room temperature,
Stir for 6 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the mixture was crystallized to give the title compound (369 m
g, yield 94%) (see Table 80).

Example 150 N- [4- (4-aminomethylbenzyloxy) -2-
Hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride Step 13) N- [4- (4-tert-butoxycarbonylaminomethylbenzyloxy) -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) 4- tert-Butoxycarbonylaminomethylbenzyl alcohol (1.30 g), step 2 of Example 1 above.
N- (2,4-dihydroxybenzoyl) -L-phenylalanine methyl ester (4.32 g) obtained in the same manner as 2) and triphenylphosphine (3.59).
To a solution of g) in THF (100 ml), diisopropyl azodicarboxylate (2.7 ml) was gradually added at room temperature. After stirring at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3/2 v / v) to give the title compound (2.22 g, Yield 76%) was obtained.

Step 11) N- [4- (4-aminomethylbenzyloxy) -2-hydroxybenzoyl] -L-
Phenylalanine methyl ester / hydrochloride (I) 4N of the compound (610 mg) obtained in the above step 13)
A hydrogen chloride-dioxane (10 ml) solution was added at room temperature to 5
Stirred for hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the mixture was crystallized to give the title compound (430 m
g, yield 80%) (see Table 80).

Examples 151 to 162 The compounds of Examples 151 to 162 were prepared from the corresponding compounds in the same manner as in Example 150 (see Tables 81 to 87).

Example 163 N- [4- [2- (4-aminomethylbenzoyl) ethyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride Step 10) N- [4- [2- ( 4-tert-butoxycarbonylaminomethylbenzoyl) ethyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) 4- [2- (4-tert-butoxycarbonylaminomethylbenzoyl) ethyl] -2-hydroxy Benzoic acid (420 mg), L-phenylalanine methyl ester.hydrochloride (249 mg) and HOBT (156 mg) in DMF (5 ml) was added with WSC.HCl (221 m).
g) and triethylamine (0.16 ml) were added and 1
Stir for 5 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with a 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2 v / v).
The title compound (498 mg, yield 8
4%).

Step 11) N- [4- [2- (4-aminomethylbenzoyl) ethyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I) Compound obtained in Step 10) (490 mg) of 4N
A hydrogen chloride-dioxane (8 ml) solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to give the title compound (360 mg,
A yield of 83%) was obtained (see Table 88).

Example 164 N- [4-[(E) -2- [4- (2-aminoethyl)]
Phenyl] vinyl] -2-hydroxybenzoyl] -L
-Phenylalanine methyl ester / hydrochloride step 26) 4-[(E) -2- [4- (2-tert-
Butoxycarbonylaminoethyl) phenyl] vinyl]
Methyl 2-methoxybenzoate (VIII) Methyl 4-bromomethyl-2-methoxybenzoate (25
A mixed solution of 0 mg) and trimethyl phosphite (239 mg) was heated with stirring at 180 ° C. for 11 hours. Toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Residual DMF (5 ml)
The solution was cooled with ice under potassium tert-butoxide (130
mg) was added and stirred for 30 minutes. 4- (2
A solution of -tert-butoxycarbonylaminoethyl) benzaldehyde (240 mg) in DMF (1 ml) was added at room temperature, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with a 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
(1/2 v / v) to give the title compound (241
mg, yield 61%).

Step 9) 4-[(E) -2- [4- (2-
tert-Butoxycarbonylaminoethyl) phenyl] vinyl] -2-hydroxybenzoic acid (IX) 25 of the compound (210 mg) obtained in step 26) above.
A% hydrogen bromide-acetic acid (2 ml) solution was heated with stirring at 100 ° C. for 1 hour. After air-cooling the reaction solution, toluene was added to the mixture to give -78
It was cooled to ° C, and hexane was added for crystallization. The crystals were collected by filtration and dissolved in DMF (4 ml). This DMF
The solution was triethylamine (129 mg) and di-ter.
t-Butyldicarbonate (279 mg) was added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, water and saturated saline, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was washed with ether and hexane to give the title compound (105 mg, yield 64%).

Step 10) N- [4-[(E) -2- [4
-(2-tert-butoxycarbonylaminoethyl)
Phenyl] vinyl] -2-hydroxybenzoyl] -L
-Phenylalanine methyl ester (I ') To a solution of the compound (50 mg) obtained in the above step 9), L-phenylalanine methyl ester / hydrochloride (31 mg) and HOBT (20 mg) in methylene chloride (5 ml) was added WSC / HCl (5 ml). 27 mg) and N-methylmorpholine (15 mg) were added under ice cooling, and the mixture was stirred for 16 hours at room temperature. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with a 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2 v / v) to give the title compound (65 mg, yield 92%).

Step 11) N- [4-[(E) -2- [4
-(2-Aminoethyl) phenyl] vinyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride (I) A solution of the compound (55 mg) obtained in the above step 10) in methylene chloride (1 ml) was added with triethyl alcohol. Fluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Toluene was added to the reaction mixture, the mixture was concentrated under reduced pressure, and methylene chloride (1 ml) was added to the residue. A 1N hydrogen chloride-ether solution (1 ml) was added to this, and ether was added for crystallization to obtain the title compound (34 mg, yield 70%) (see Table 88).

Examples 165 to 169 The compounds of Examples 165 to 169 were prepared from the corresponding compounds in the same manner as in Example 164 (see Tables 89 to 91).

Example 170 N- [4-[(Z) -2- (4-aminomethylphenyl) vinyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride Step 26) 4- [2- [4- (tert-Butoxycarbonylaminomethyl) phenyl] vinyl] -2-ter
t-Butyldimethylsilyloxybenzoic acid (VIII) 4-tert-butoxycarbonylaminomethylbenzaldehyde (98 mg) and (3-tert-butyldimethylsilyloxy-4-tert-butyldimethylsilyloxycarbonyl) benzyltriphenylphosphonium bromide ( To a solution of 300 mg) in DMF (10 ml), 60% oily sodium hydride (42 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was washed with ether and ethyl acetate. Water layer 10%
It was acidified with aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane /
The title compound (115 mg, yield 75%) was obtained by purification with acetic acid = 1/1 / 0.01 v / v / v).

Step 10) N- [4-[(Z) -2- [4
-(Tert-Butoxycarbonylaminomethyl) phenyl] vinyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) To a solution of the compound (50 mg) obtained in the above step 26) in methylene chloride (10 ml), Under ice cooling, L-phenylalanine methyl ester / hydrochloride (32 mg), triethylamine (15 mg), WSC / HCl (28.5 mg)
And HOBT (20 mg) were added, and the mixture was stirred at room temperature for 4 hours. Chloroform (100 ml) was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1 / 2.5.
(v / v) to give the title compound (25 mg, yield 35%).

Step 11) N- [4-[(Z) -2- (4
-Aminomethylphenyl) vinyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I) A 4N hydrogen chloride-dioxane (1 ml) solution of the compound (23 mg) obtained in the above step 10) was stirred at room temperature. Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ether to give the title compound (13 mg, yield 64%).
Was obtained (see Table 91).

Example 171 N- [4- [2- [4- (2-methylaminoethyl) phenyl] ethyl] -2-hydroxybenzoyl] -L-
Phenylalanine methyl ester / hydrochloride Step 11) N- [4- [2- [4- (2-methylaminoethyl) phenyl] ethyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride (I) ( 1) N- [4- [2- [4- (2-tert-butoxycarbonylmethylaminoethyl) phenyl] ethyl]
2-Hydroxybenzoyl] -L-phenylalanine methyl ester N obtained in the same manner as in Step 10) of Example 164 above.
-[4-[(E) -2- [4- (2-tert-butoxycarbonylmethylaminoethyl) phenyl] vinyl]
2-Hydroxybenzoyl] -L-phenylalanine methyl ester (42 mg) in methanol (10 ml)
10% Palladium on carbon (10 mg) was added to the solution, and the mixture was catalytically reduced for 1.5 hours in a hydrogen gas stream. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (39 m
g, yield 93%) was obtained.

(2) N- [4- [2- [4- (2-methylaminoethyl) phenyl] ethyl] -2-hydroxybenzoyl] -L-phenylalanine methyl ester.
Hydrochloride (I) A 4N hydrogen chloride-dioxane (2 ml) solution of the compound (39 mg) obtained in (1) above was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and ether was added for crystallization to give the title compound (30.5 mg, yield 91
%) Was obtained (see Table 92).

Examples 172 to 174 The compounds of Examples 172 to 174 were prepared from the corresponding compounds in the same manner as in Example 171 (see Tables 92 to 93).

Example 175 N- [4- (4-aminobenzoylamino) -2-hydroxybenzoyl] -L-phenylalanine methyl ester.hydrochloride Step 22) N- (4-amino-2-hydroxybenzoyl) -L -Phenylalanine methyl ester (XI
a ''') 4-amino-2-hydroxybenzoic acid (16 g), L-
Phenylalanine methyl ester / hydrochloride (24.9
g) and HOBT (15.6 g) DMF (130 m)
l) To the solution, N-methylmorpholine (12.6 ml) and WSC.HCl (22 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
Stir for 6 hours. Ethyl acetate and water were added to the reaction solution for extraction, and the organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and ether was further added for crystallization to give the title compound (26.27 g, yield 80%).

Step 23) N- [4- (4-tert-butoxycarbonylaminobenzoylamino) -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ') 4- (tert-butoxycarbonylamino) benzoic acid ( 237 mg), the compound (3
51 mg) and DMAP (244 mg) in DMF (10
ml) solution to which WSC.HCl (192 mg) was added,
The mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with water, 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane / chloroform = 3/4/3 v / v / v) to give the title compound (432 mg, yield 81%). Got

Step 11) N- [4- (4-Aminobenzoylamino) -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I) Chloride of the compound (404 mg) obtained in the above Step 23). To a solution of methylene (2 ml), trifluoroacetic acid (2 m
1) was added and stirred for 10 minutes. Toluene was added to the reaction solution and concentrated under reduced pressure. A 1 M hydrogen chloride-ether solution (5 ml) was added to the residue, and ether was added for crystallization to give the title compound (317 mg, yield 89%) (see Table 94).

Examples 176 to 192 The compounds of Examples 176 to 192 were prepared from the corresponding compounds in the same manner as in Example 175 (see Tables 94 to 102).

Example 193 N- [4- [N '-(4-aminomethylphenyl) ureido] -2-hydroxybenzoyl] -L-phenylalanine methyl ester / hydrochloride Step 23) N- [4- [N' -(4-Tert-butoxycarbonylaminomethylphenyl) ureido] -2-
Hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) 4- (tert-butoxycarbonylaminomethyl) benzoic acid (400 mg) in THF (10 ml) was added with triethylamine (0.246 ml) and diphenylphosphoryl azide (0.392 ml). ) Was added and the mixture was heated under reflux for 1 hour. N- (4-amino-2-hydroxybenzoyl) -L-phenylalanine methyl ester (40) obtained in the same manner as in Step 22) of Example 175 above was added to the reaction solution.
0 mg) was added and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, chloroform and water were added to the residue for extraction. The organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate.
The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1).
The title compound (89 mg, yield 10%) was obtained by purification with v / v).

Step 11) N- [4- [N '-(4-aminomethylphenyl) ureido] -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I) Obtained in Step 23) above. A 4N hydrogen chloride-dioxane (2 ml) solution of the compound (78 mg) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue for crystallization to give the title compound (61 mg, yield 8
8%) (see Table 103).

Example 194 N- [3,5-dichloro-2-hydroxy-4- (4-
Methylaminomethylbenzylamino) benzoyl] -D
L-phenylalanine N ', N'-dimethylamide-2
Hydrochloride Step 1) Methyl 4- (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -2-hydroxybenzoate (VIII ′) 4-tert-butoxycarbonylmethylaminomethylbenzyl alcohol (2.93 g) N, Methanesulfonyl chloride (994 μl) was added to an N-diisopropylethylamine (25 ml) solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. Further, methyl 4-amino-2-hydroxybenzoate (1.95 g) was added, and the mixture was added at 120 ° C. for 4 hours.
Stirred for hours. 10% aqueous citric acid solution was added to the reaction solution,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent:
The title compound (2.67 g, yield 57%) was obtained by purification with toluene / ether = 25/1 v / v).

Step 36) 4- (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -3,
Methyl 5-dichloro-2-hydroxybenzoate (VII
I) A solution of the compound (2.67 g) obtained in the above step 1) in methylene chloride (50 ml) was cooled to ice with terhypochlorous acid.
t-Butyl (1.66 ml) was added dropwise. After stirring at room temperature for 40 minutes, the reaction solution was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8/1 v / v) to give the title compound (2.28 g, yield). 73%).

Step 9) 4- (4-tert-butoxycarbonylmethylaminomethylmethylbenzylamino) -3,5
-Dichloro-2-hydroxybenzoic acid (IX) 1M aqueous lithium hydroxide solution (15 ml) was added dropwise to a solution of the compound (2.28 g) obtained in the above step 36) in ethanol (70 ml), and the mixture was added at 95 ° C for 3 hours. It was stirred. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and azeotroped with toluene to give the title compound (2.20 g, quantitative).

Step 10) N- [4- (4-tert-butoxycarbonylmethylaminomethylmethylbenzylamino)
-3,5-Dichloro-2-hydroxybenzoyl] -D
L-Phenylalanine N ′, N′-dimethylamide (I ′) Compound (455 mg) obtained in the above step 9) and DL
-Phenylalanine N ', N'-dimethylamide. Hydrochloride salt (251 mg) in DMF (7 ml) was added with WSC.
HCl (210 mg), HOBT (149 mg) and N
-Methylmorpholine (0.12 ml) was added, and at room temperature,
Stir for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1 v
/ v) to give the title compound (359 mg, yield 57%).

Step 11) N- [3,5-dichloro-2-
Hydroxy-4- (4-methylaminomethylbenzylamino) benzoyl] -DL-phenylalanine N ′,
N′-dimethylamide dihydrochloride (I) 4N of the compound (300 mg) obtained in the above step 10)
A hydrogen chloride-dioxane (10 ml) solution was added at room temperature to 5
The mixture was stirred for hours and concentrated under reduced pressure. Ether was added to the residue to crystallize the title compound (250 mg, yield 8
7%) (see Table 103).

Examples 195-202 The compounds of Examples 195-202 were prepared from the corresponding compounds analogously to Example 194 (see Tables 104-107).

Example 203 N- [3,5-dichloro-2-hydroxy-4- (4-
Methylaminomethylbenzylamino) benzoyl-N-
Methyl-2-phenethylamine dihydrochloride step 10) N- [4- (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -3,5-dichloro-2-hydroxybenzoyl-N-methyl-2-
Phenethylamine (I ′) 4 obtained in the same manner as in Step 9) of Example 194 above.
To a solution of (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -3,5-dichloro-2-hydroxybenzoic acid (455 mg) and N-methyl-2-phenethylamine (149 mg) in DMF (7 ml),
WSC · HCl (210 mg) and HOBT (149 m
g) was added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/2 v /
The title compound (360 mg, yield 63%) was obtained by purification with v).

Step 11) N- [3,5-dichloro-2-
Hydroxy-4- (4-methylaminomethylbenzylamino) benzoyl-N-methyl-2-phenethylamine dihydrochloride (I) 4N of the compound (360 mg) obtained in the above step 10)
A hydrogen chloride-dioxane (10 ml) solution was added at room temperature to 5
Stirred for hours. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue to give the title compound (284 mg, yield 83
%) Was obtained (see Table 108).

Examples 204-208 The compounds of Examples 204-208 were prepared from the corresponding compounds analogously to Example 203 (see Tables 108-110).

Example 209 N- [5-chloro-2-hydroxy-4- (4-methylaminomethylbenzylamino) benzoyl] -L-phenylalanine methyl ester dihydrochloride Step 1) 4- (4-tert- Butoxycarbonylmethylaminomethylbenzylamino) -5-chloro-2-hydroxybenzoic acid methyl (VIII) To a solution of 4-tert-butoxycarbonylmethylaminomethylbenzyl alcohol (576 mg) in N, N-diisopropylethylamine (1.5 ml). Methanesulfonyl chloride (0.2 ml) was added under ice cooling, and the mixture was stirred for 1 hour. Methyl 4-amino-5-chloro-2-hydroxybenzoate (461 mg) was added, and the mixture was heated with stirring at 100 ° C. for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 7/1 v / v) to give the title compound (35
0 mg, yield 35%) was obtained.

Step 9) 4- (4-tert-Butoxycarbonylmethylaminomethylbenzylamino) -5-chloro-2-hydroxybenzoic acid (IX) Ethanol (10 ml) of the compound (340 mg) obtained in the above Step 1) ) To the solution was added 1M aqueous lithium hydroxide solution (5 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (312 mg, yield 95%).

Step 10) N- [4- (4-tert-butoxycarbonylmethylaminomethylmethylbenzylamino)
-5-Chloro-2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ') DMF of the compound (340 mg) obtained in the above step 9)
(2 ml) solution, WSC.HCl (150 mg), H
OBT (105 mg), L-phenylalanine methyl ester / hydrochloride (168 mg) and triethylamine (0.11 ml) were added, and the mixture was stirred at room temperature for 16 hours.
Ethyl acetate was added to the reaction solution, 10% citric acid aqueous solution,
The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1 v / v) to give the title compound (284 mg, yield 62%).

Step 11) N- [5-chloro-2-hydroxy-4- (4-methylaminomethylbenzylamino)
Benzoyl] -L-phenylalanine methyl ester
Dihydrochloride (I) 4N of the compound (280 mg) obtained in the above step 10)
A hydrogen chloride-dioxane (5 ml) solution was stirred at room temperature for 5 hours, and concentrated under reduced pressure. Ether was added to the residue to crystallize the title compound (198 mg, yield 74
%) Was obtained (see Table 111).

Example 210 N- [4- [4- (2-aminoethyl) benzyl-N '
-Methylamino] -2-hydroxybenzoyl] -L-
Phenylalanine methyl ester / hydrochloride Step 1) 4- [4- (2-tert-butoxycarbonylaminoethyl) benzyl-N-methylamino] -2-
Methyl hydroxybenzoate (VIII) To a solution of 4- (2-tert-butoxycarbonylaminoethyl) benzyl alcohol (1.3 g) in N, N-diisopropylethylamine (10 ml) was added ice-cooled methanesulfonyl chloride (0.44 ml). ) Is added and 1
Stirred for hours. Methyl 2-hydroxy-4-methylaminobenzoate (937 mg) was added to the reaction solution, and the mixture was heated with stirring at 100 ° C. for 14 hours. Add 10% citric acid aqueous solution,
It was extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1 v / v) to give the title compound (1.08 g, yield 50%).

Step 9) 4- [4- (2-tert-Butoxycarbonylaminoethyl) benzyl-N-methylamino] -2-hydroxybenzoic acid (IX) Of the compound (700 mg) obtained in the above Step 1) A 1 M aqueous lithium hydroxide solution (5 ml) was added to a methanol (5 ml) -THF (5 ml) solution, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (649 mg, yield 9
6%) was obtained.

Step 10) N- [4- [4- (2-ter
t-butoxycarbonylaminoethyl) benzyl-N '
-Methylamino] -2-hydroxybenzoyl] -L-
Phenylalanine methyl ester (I ′) DMF of compound (500 mg) obtained in the above step 9)
(10 ml) solution, WSC.HCl (264 mg),
HOBT (211 mg), L-phenylalanine methyl ester / hydrochloride (297 mg) and N-methylmorpholine (0.153 ml) were added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1 v / v) to give the title compound (466 mg, yield 66%). Obtained.

Step 11) N- [4- [4- (2-aminoethyl) benzyl-N'-methylamino] -2-hydroxybenzoyl] -L-phenylalanine methyl ester hydrochloride (I) Step 11) above 4N of the compound (438 mg) obtained in
A hydrogen chloride-dioxane (6 ml) solution was stirred at room temperature for 6 hours, and concentrated under reduced pressure. Ether was added to the residue to crystallize the title compound (394 mg, yield 94
%) Was obtained (see Table 112).

Example 211 The compound of Example 211 was converted from the corresponding compound to Example 21.
It was prepared in the same manner as in No. 0 (see Table 112).

Example 212 N- [4- (4-aminomethylbenzylamino) -2-
Hydroxybenzoyl] -L-phenylalanine methyl ester dihydrochloride step 15) N- [4- (4-tert-butoxycarbonylaminomethylbenzylamino) -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) 4 -Tert-Butoxycarbonylaminomethylbenzaldehyde (1.53 g) and N- (4-amino-2-
A solution of hydroxybenzoyl) -L-phenylalanine methyl ester (2.04 g) in methanol (30 ml) was stirred at room temperature for 16 hours. 10% Palladium on carbon (200 mg) was added to this reaction solution, and catalytic reduction was carried out under normal pressure in the presence of hydrogen gas for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ether / toluene = 2/3 v / v) to give the title compound (2.05 g, yield 59).
%).

Step 11) N- [4- (4-aminomethylbenzylamino) -2-hydroxybenzoyl] -L-
Phenylalanine methyl ester dihydrochloride (I) 4N of the compound (2.05 g) obtained in the above step 15)
A hydrogen chloride-dioxane (20 ml) solution was added at room temperature to 6
Stirred for hours. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue for crystallization to give the title compound (1.82).
g, yield 94%) was obtained (see Table 113).

Examples 213 to 237 The compounds of Examples 213 to 237 were prepared from the corresponding compounds in the same manner as in Example 212 (see Tables 113 to 126).

Example 238 N- [5- [4- (2-aminoethyl) benzylamino] -2-hydroxybenzoyl] -L-phenylalanine methyl ester dihydrochloride Step 15) N- [5- [4- (2-tert-Butoxycarbonylaminoethyl) benzylamino] -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) 4- (2-tert-butoxycarbonylaminoethyl) benzaldehyde (634 mg) and N- (5 A solution of -amino-2-hydroxybenzoyl) -L-phenylalanine methyl ester (800 mg) in methanol was stirred at room temperature for 14 hours. 10% Palladium carbon (220 mg) was added to the reaction solution, and catalytic reduction was carried out at room temperature and normal pressure in the presence of hydrogen gas for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography of the residue (developing solvent: hexane / ethyl acetate = 4/1 v / v)
The title compound (572 mg, yield 4
1%).

Step 11) N- [5- [4- (2-aminoethyl) benzylamino] -2-hydroxybenzoyl] -L-phenylalanine methyl ester dihydrochloride (I) Obtained in Step 15) above. 4N of compound (550mg)
A hydrogen chloride-dioxane (6 ml) solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to give the title compound (468 mg,
Yield 89%) was obtained (see Table 127).

Example 239 The compound of Example 239 was prepared from the corresponding compound to Example 23.
It was prepared in the same manner as in Example 8 (see Table 127).

Example 240 N- [3,5-dichloro-2-hydroxy-4- (4-
Methylaminomethylbenzylamino) benzoyl] -L
-Phenylalanine isopropyl ester dihydrochloride step 36) 4- (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -3,5-dichloro-2-hydroxybenzoate methyl (VIII) Step 1 of Example 209 above). Obtained in the same manner as
To a solution of methyl (4-tert-butoxycarbonylmethylaminomethylbenzylamino) -2-hydroxybenzoate (2.67 g) in methylene chloride (50 ml) was added tert-butyl hypochlorite (1.66 ml) under ice cooling. In addition, the mixture was stirred at room temperature for 40 minutes. Add water to the reaction solution,
Extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8/1 v / v) to give the title compound (2.28 g, yield 73%).

Step 9) 4- (4-tert-butoxycarbonylmethylaminomethylmethylbenzylamino) -3,5
-Dichloro-2-hydroxybenzoic acid (IX) To a solution of the compound (2.28 g) obtained in the above Step 36) in ethanol (70 ml) was added 1M aqueous lithium hydroxide solution (15 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (2.19 g, yield 99%).

Step 10) N- [4- (4-tert-butoxycarbonylmethylaminomethylmethylbenzylamino)
-3,5-Dichloro-2-hydroxybenzoyl] -L
-Phenylalanine isopropyl ester (I ') DMF of the compound (400 mg) obtained in the above step 9)
(7 ml) solution, WSC.HCl (186 mg), H
OBT (131 mg), L-phenylalanine isopropyl ester / hydrochloride (236 mg) and N-methylmorpholine (0.11 ml) were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the reaction solution for extraction, and the organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1 v
/ v) to give the title compound (308 mg, yield 54%).

Step 11) N- [3,5-dichloro-2-
Hydroxy-4- (4-methylaminomethylbenzylamino) benzoyl] -L-phenylalanine isopropyl ester dihydrochloride (I) 4N of the compound (278 mg) obtained in the above step 10).
A hydrogen chloride-dioxane (5 ml) solution was stirred at room temperature for 6 hours, and the reaction solution was concentrated under reduced pressure. Ether was added to the residue and crystallized to give the title compound (206 mg, yield 77%) (see Table 128).

Examples 241 to 242 The compounds of Examples 241 to 242 were prepared from the corresponding compounds in the same manner as in Example 240 (see Tables 128 to 129).

Example 243 N- [4- (4-aminomethylanilino) methyl-2-
Hydroxybenzoyl] -L-phenylalanine methyl ester dihydrochloride step 6) Methyl 4- (4-tert-butoxycarbonylaminomethylanilino) methyl-2-hydroxybenzoate (VIII) 4- (tert-butoxycarbonylaminomethyl) ) Aniline (228 mg) and methyl 4-formyl-2-hydroxybenzoate (185 mg) in methanol (3 m
l) The solution was stirred at room temperature for 2 hours. 10% in the reaction solution
Palladium on carbon (35 mg) was added, and in the presence of hydrogen gas,
The catalytic reduction was carried out at room temperature and atmospheric pressure for 14 hours. Filter the reaction,
The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1).
v / v) to give the title compound (212 mg,
The yield was 53%).

Step 9) 4- (4-Tert-butoxycarbonylaminomethylanilino) methyl-2-hydroxybenzoic acid (IX) The compound (212 mg) obtained in Step 6) above in dioxane (0.5 ml), Sodium hydroxide (300 m) was added to a mixed solution of water (0.2 ml) and methanol (2 ml).
g) was added, and the mixture was heated with stirring at 60 ° C. for 5 hours. After allowing to cool, 10% aqueous citric acid solution was added to the reaction solution to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (193 mg, yield 94%).

Step 10) N- [4- (4-tert-butoxycarbonylaminomethylanilino) methyl-2-
Hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) In a methylene chloride solution of the compound (193 mg) obtained in the above step 9), L-phenylalanine methyl ester.
Hydrochloride (123 mg), WSC · HCl (120 m
g), HOBT (84 mg) and triethylamine (0.15 ml) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent:
The title compound (117 mg, yield 42%) was obtained by purification with hexane / ethyl acetate = 3/2 v / v).

Step 11) N- [4- (4-aminomethylanilino) methyl-2-hydroxybenzoyl] -L-
Phenylalanine methyl ester dihydrochloride (I) 4N of the compound (114 mg) obtained in the above step 10)
The hydrogen chloride-dioxane solution was stirred at room temperature for 5 hours.
The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to obtain the title compound (96 mg, yield 89%) (see Table 129).

Example 244 N- [4- (4-aminomethylbenzylaminomethyl)
2-Hydroxybenzoyl] -L-phenylalanine methyl ester dihydrochloride step 6) 4- (4-tert-butoxycarbonylaminomethylbenzyl-N′-tert-butoxycarbonylaminomethyl) -2-hydroxybenzoic acid methyl ( V
III) 4-tert-Butoxycarbonylaminomethylbenzylamine (351 mg) and methyl 4-formyl-2-hydroxybenzoate (268 mg) in methanol (5 m
l) The solution was stirred at room temperature for 1 hour. 10% in the reaction solution
Palladium on carbon (40 mg) was added, and under a hydrogen gas stream,
The catalytic reduction was carried out at room temperature and atmospheric pressure for 3 hours. The reaction was filtered and the filtrate was concentrated. Acetonitrile (10 ml) was added to the residue, and di-tert-butyl dicarbonate (486 m
g) was added. After stirring for 14 hours, the reaction solution was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1 v / v) to give the title compound (350 mg, yield 47%).

Step 9) 4- (4-tert-Butoxycarbonylaminomethylbenzyl-N′-tert-butoxycarbonylaminomethyl) -2-hydroxybenzoic acid (IX) Compound obtained in Step 6) above (417 mg) And sodium hydroxide (100 mg) in methanol (2 ml)-
The water (0.5 ml) mixed solution was stirred at room temperature for 16 hours. A 0.25N aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.

Step 10) N- [4- (4-tert-butoxycarbonylaminomethylbenzyl-N'-ter
t-butoxycarbonylaminomethyl) -2-hydroxybenzoyl] -L-phenylalanine methyl ester (I ′) The crude product obtained in the above step 9), methylene chloride (15
ml) -DMF (3 ml) mixed solution with WSC / HC
1 (175 mg), HOBT (123 mg), triethylamine (0.2 ml), L-phenylalanine methyl ester / hydrochloride (180 mg) were added, and 2.5 at room temperature.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1 v / v) to obtain the title compound (114 mg).

Step 11) N- [4- (4-aminomethylbenzylaminomethyl) -2-hydroxybenzoyl]
-L-Phenylalanine methyl ester dihydrochloride (I) A solution of the compound (114 mg) obtained in the above Step 10) in trifluoroacetic acid (4 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, hydrogen chloride-ether was added and the mixture was stirred, and the precipitated solid was collected by filtration and dried to give the title compound (79 mg, yield 18%) (see Table 130).

Example 245 N- [4- [4- (2-aminoethyl) benzenesulfonylamino] -2-hydroxybenzoyl] -L-phenylalanine ethyl ester / hydrochloride Step 7) 4- [4- (2- Methyl acetamidoethyl) benzenesulfonylamino] -2-hydroxybenzoate (VIII) 4- (2-acetamidoethyl) benzenesulfonyl chloride (1.57 g) and methyl 4-amino-2-hydroxybenzoate (1.00 g) Pyridine (10m
l) The solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue for extraction. The organic layer was washed successively with 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 10/1 v / v) to give the title compound (1.92 g, yield 82).
%).

Step 9) 4- [4- (2-tert-Butoxycarbonylaminoethyl) benzenesulfonylamino] -2-hydroxybenzoic acid (IX) 4N of the compound (1.92 g) obtained in Step 7) above. A hydrochloric acid-dioxane (50 ml) solution was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and ether and THF were added to the residue for crystallization to obtain a compound (1.57 g, yield 86%). Further, a solution of this compound (1.57 g) and di-tert-butyl dicarbonate (1.84 g) in dioxane (10 ml) was added with sodium hydroxide (3
(37 mg) and water (10 ml) were added to the aqueous sodium hydroxide solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate-ethyl acetate / acetic acid = 98).
/ 2 v / v) to give the title compound (848 m
g, yield 46%) was obtained.

Step 10) N- [4- [4- (2-ter
t-butoxycarbonylaminoethyl) benzenesulfonylamino] -2-hydroxybenzoyl] -L-phenylalanine ethyl ester (I ′) The compound (349 mg) obtained in the above step 9), L-phenylalanine ethyl ester / hydrochloride (184 mg). )
And HOBT (119 mg) in DMF (2 ml), triethylamine (0.12 ml) and WSC.H.
Cl (169 mg) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1 v / v) to give the title compound (418 mg, yield 85
%).

Step 11) N- [4- [4- (2-aminoethyl) benzenesulfonylamino] -2-hydroxybenzoyl] -L-phenylalanine ethyl ester.
Hydrochloride (I) 4N of the compound (418 mg) obtained in the above step 10)
A hydrogen chloride-dioxane (5 ml) solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the residue was crystallized to give the title compound (304 mg,
Yield 82%) was obtained (see Table 131).

Example 246 The compound of Example 246 was converted from the corresponding compound to Example 24.
It was produced in the same manner as in No. 5 (see Table 131).

Example 247 (2S) -3-phenyl-2- [4- [2-methyl-5]
-[4- (2-Methylaminoethyl) phenyl] oxazol-4-yl] benzoylamino] propionic acid ethyl ester / hydrochloride step 33) 4 '-(2-benzyloxycarbonylmethylaminoethyl) -4-methoxycarbonyl Deoxybenzoin (XVIII) 4- (2-benzyloxycarbonylmethylaminoethyl) benzyl bromide (3 g), 4-methoxycarbonylbenzoyl chloride (1.73 g), zinc dust (7
03 mg) and tetrakis (triphenylphosphine)
Palladium (95.7 mg) in dimethoxyethane (30
ml) solution was stirred at room temperature for 2 hours. The reaction solution was filtered, ethyl acetate was added to the filtrate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1 v / v) to give the title compound (1.34 g, yield 36).
%).

Step 34) α-acetoxy-4 ′-(2-
Benzyloxycarbonylmethylaminoethyl) -4-
Methoxycarbonyldeoxybenzoin (XIX) A solution of the compound (1.34 g) obtained in the above step 33) and lead tetraacetate (1.6 g) in acetic acid (11 ml) for 1 hour,
Heated to reflux. Ethyl acetate was added to the reaction solution, the organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2.
/ 1 v / v) to give the title compound (1.24
g, yield 83%).

Step 35) 4- (4-Methoxycarbonylphenyl) -2-methyl-5- [4- (2-benzyloxycarbonylmethylaminoethyl) phenyl] oxazole (VIIIe) Compound obtained in Step 34) above A solution of (1.2 g) and ammonium acetate (462 mg) in acetic acid (9 ml) was added to 2 parts.
Heated to reflux for an hour. Ethyl acetate was added to the reaction solution, the organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1 v / v) to give the title compound (89
0 mg, yield 77%) was obtained.

Step 9) 4- (4-carboxyphenyl)
2-Methyl-5- [4- (2-benzyloxycarbonylmethylaminoethyl) phenyl] oxazole (I
X) In a mixed solution of the compound (880 mg) obtained in the above step 35), methanol (6 ml) -THF (6 ml), 1
M lithium hydroxide aqueous solution (6 ml) was added, and the mixture was mixed at 50 ° C.
The mixture was heated and stirred for 0 minutes. Wash the reaction mixture with ethyl acetate and
It was acidified with 0% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (751 mg, yield 8
8%).

Step 10) (2S) -3-Phenyl-2-
[4- [5- [2-benzyloxycarbonylmethylaminoethyl) phenyl] -2-methyloxazole-4
-Yl] benzoylamino] propionic acid ethyl ester (I ') The compound (353 mg) obtained in the above step 9), L-phenylalanine ethyl ester / hydrochloride (172 m).
g), WSC.HCl (143 mg), HOBT (10
DM of 1 mg) and triethylamine (0.11 ml)
The F (4 ml) solution was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with a 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1 v / v) to obtain the title compound (420 mg, yield 87%).

Step 11) (2S) -3-phenyl-2-
[4- [2-Methyl-5- [4- (2-methylaminoethyl) phenyl] oxazol-4-yl] benzoylamino] propionic acid ethyl ester / hydrochloride (I) Compound obtained in Step 10) To a solution of (390 mg) in ethanol (8 ml) was added palladium hydroxide (100 m).
g) was added, and catalytic reduction was carried out at room temperature at 3 atm in the presence of hydrogen gas for 1 hour. The reaction solution is filtered, and the filtrate is 1N hydrogen chloride-
Ether solution (2 ml) was added, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (270 mg, yield 81%) (see Table 132).

Example 248 The compound of Example 248 was converted from the corresponding compound to Example 24.
It was produced in the same manner as 7 (see Table 132).

Example 249 (2S) -3-phenyl-2- [4- [5- [4- (2
-Methylaminoethyl) phenyl] -1,2,4-oxadiazol-3-yl] benzoylamino] propionic acid ethyl ester / hydrochloride Step 31) Ethyl benzoate-4-carboxamido-O- [4- (2- tert-Butoxycarbonylmethylaminoethyl) benzoyl] oxime (XVI) 4- (2-tert-butoxycarbonylmethylaminoethyl) benzoic acid (3.353 g) and 4-amidooxime ethyl benzoate (2.50 g) in methylene chloride. (5
DMAP (1.615 g) and WSC.HCl (2.534 g) were added to the solution (0 ml) at room temperature. At room temperature,
After stirring for 16 hours, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 7: 3 v / v) to give the title compound (4.9 g, yield 86%). Obtained.

Step 32) 4- [5- [4- (2-ter
Ethyl t-butoxycarbonylmethylaminoethyl) phenyl] -1,2,4-oxadiazol-3-yl] benzoate (VIIId) Dioxane (130 ml) of the compound (4.881 g) obtained in the above step 31). The solution was heated to reflux for 20 hours.
The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; hexane / ethyl acetate = 7: 3).
v / v) to give the title compound (3.142)
g, yield 67%) was obtained.

Step 9) 4- [5- [4- (2-tert
-Butoxycarbonylmethylaminoethyl) phenyl]
-1,2,4-Oxadiazol-3-yl] benzoic acid (IX) A solution of the compound (3.132 g) obtained in the above Step 32) in ethanol (40 ml) was added to a 2N aqueous sodium hydroxide solution at room temperature. (41 ml) was added, and the mixture was stirred at 50 ° C for 1 hr. The reaction mixture was concentrated under reduced pressure, 10% citric acid and ethyl acetate were added, and the mixture was extracted. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (3.232 g, yield 100%).
I got

Step 10) (2S) -3-Phenyl-2-
[4- [5- [4- (2-tert-Butoxycarbonylmethylaminoethyl) phenyl] -1,2,4-oxadiazol-3-yl] benzoylamino] propionic acid ethyl ester (I ′) The above steps 9) Compound (468 mg) obtained in 9), L-phenylalanine ethyl ester / hydrochloride (257 mg)
To a solution of HOBT and HOBT (150 mg) in DMF (5 ml) were added triethylamine (0.155 ml) and WSC.HCl (212 mg) under ice cooling. 16 at room temperature
After stirring for an hour, ethyl acetate and water were added for extraction. The organic layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; hexane / ethyl acetate =).
7: 3 v / v) to give the title compound (56 m
g, yield 8.4%) was obtained.

Step 11) (2S) -3-phenyl-2-
[4- [5- [4- (2-Methylaminoethyl) phenyl] -1,2,4-oxadiazol-3-yl] benzoylamino] propionic acid ethyl ester / hydrochloride (I) Step 10) A 4N hydrogen chloride-dioxane solution (2.5 ml) was added to a solution of the compound (55 mg) obtained in 1 above in dioxane (4 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the residue for crystallization to give the title compound (37 mg, yield 75
%) Was obtained (see Table 133).

Examples 250 to 253 The compounds of Examples 250 to 253 were prepared from the corresponding compounds in the same manner as in Example 249 (see Tables 133 to 135).

Structural formulas and physical properties of the compounds of the above Examples are shown in Tables 5 to 135. In the table, Me is a methyl group, E
t is an ethyl group, Pr is an n-propyl group, Bn is a benzyl group, Z is a benzyloxycarbonyl group, and Boc is ter.
Indicates a t-butoxycarbonyl group.

[0305]

[Table 5]

[0306]

[Table 6]

[0307]

[Table 7]

[0308]

[Table 8]

[0309]

[Table 9]

[0310]

[Table 10]

[0311]

[Table 11]

[0312]

[Table 12]

[0313]

[Table 13]

[0314]

[Table 14]

[0315]

[Table 15]

[0316]

[Table 16]

[0317]

[Table 17]

[0318]

[Table 18]

[0319]

[Table 19]

[0320]

[Table 20]

[0321]

[Table 21]

[0322]

[Table 22]

[0323]

[Table 23]

[0324]

[Table 24]

[0325]

[Table 25]

[0326]

[Table 26]

[0327]

[Table 27]

[0328]

[Table 28]

[0329]

[Table 29]

[0330]

[Table 30]

[0331]

[Table 31]

[0332]

[Table 32]

[0333]

[Table 33]

[0334]

[Table 34]

[0335]

[Table 35]

[0336]

[Table 36]

[0337]

[Table 37]

[0338]

[Table 38]

[0339]

[Table 39]

[0340]

[Table 40]

[0341]

[Table 41]

[0342]

[Table 42]

[0343]

[Table 43]

[0344]

[Table 44]

[0345]

[Table 45]

[0346]

[Table 46]

[0347]

[Table 47]

[0348]

[Table 48]

[0349]

[Table 49]

[0350]

[Table 50]

[0351]

[Table 51]

[0352]

[Table 52]

[0353]

[Table 53]

[0354]

[Table 54]

[0355]

[Table 55]

[0356]

[Table 56]

[0357]

[Table 57]

[0358]

[Table 58]

[0359]

[Table 59]

[0360]

[Table 60]

[0361]

[Table 61]

[0362]

[Table 62]

[0363]

[Table 63]

[0364]

[Table 64]

[0365]

[Table 65]

[0366]

[Table 66]

[0367]

[Table 67]

[0368]

[Table 68]

[0369]

[Table 69]

[0370]

[Table 70]

[0371]

[Table 71]

[0372]

[Table 72]

[0373]

[Table 73]

[0374]

[Table 74]

[0375]

[Table 75]

[0376]

[Table 76]

[0377]

[Table 77]

[0378]

[Table 78]

[0379]

[Table 79]

[0380]

[Table 80]

[0381]

[Table 81]

[0382]

[Table 82]

[0383]

[Table 83]

[0384]

[Table 84]

[0385]

[Table 85]

[0386]

[Table 86]

[0387]

[Table 87]

[0388]

[Table 88]

[0389]

[Table 89]

[0390]

[Table 90]

[0391]

[Table 91]

[0392]

[Table 92]

[0393]

[Table 93]

[0394]

[Table 94]

[0395]

[Table 95]

[0396]

[Table 96]

[0397]

[Table 97]

[0398]

[Table 98]

[0399]

[Table 99]

[0400]

[Table 100]

[0401]

[Table 101]

[0402]

[Table 102]

[0403]

[Table 103]

[0404]

[Table 104]

[0405]

[Table 105]

[0406]

[Table 106]

[0407]

[Table 107]

[0408]

[Table 108]

[0409]

[Table 109]

[0410]

[Table 110]

[0411]

[Table 111]

[0412]

[Table 112]

[0413]

[Table 113]

[0414]

[Table 114]

[0415]

[Table 115]

[0416]

[Table 116]

[0417]

[Table 117]

[0418]

[Table 118]

[0419]

[Table 119]

[0420]

[Table 120]

[0421]

[Table 121]

[0422]

[Table 122]

[0423]

[Table 123]

[0424]

[Table 124]

[0425]

[Table 125]

[0426]

[Table 126]

[0427]

[Table 127]

[0428]

[Table 128]

[0429]

[Table 129]

[0430]

[Table 130]

[0431]

[Table 131]

[0432]

[Table 132]

[0433]

[Table 133]

[0434]

[Table 134]

[0435]

[Table 135]

Next, formulation examples when the compound of the present invention is used as a drug are shown.

Formulation Example 1 (Production Example of Tablet) (1) Compound of Example 1 10 g (2) Lactose 50 g (3) Corn starch 15 g (4) Sodium carboxymethyl cellulose 44 g (5) Magnesium stearate 1 g (1), Knead the whole amount of (2), (3) and 30 g of (4) with water,
After vacuum drying, granulation was performed. 14 g of (4) and 1 g of (5) were mixed with the granulated powder, and the mixture was made into tablets by a tableting machine to produce 1000 tablets each containing 10 mg.

Formulation Example 2 (Production Example of Injection) 100 mg of the compound of Example 1 was dissolved in an aqueous solution prepared by dissolving 5 g of mannitol in 100 ml of water for injection to give 0.22 μm.
After filter sterilization with m filter, 1m in sterilized ampoule
By injecting 1 of each, an injection containing 1 mg per ampoule was obtained.

Next, the test results of the inhibitory effect of the compound of the present invention on the inflammatory cytokine production, LPS-induced peritonitis and LPS / D-galactosamine-induced hepatitis model will be shown.

Test Example 1: Cytokine production inhibitory effect Human peripheral blood collected with heparin was collected using Ficol-Paque (15 m
30 ml was added to 1) and the mixture was centrifuged at 400 G for 40 minutes at room temperature, and the obtained monocyte fraction layers were collected and washed 3 times with E-MEM medium. Finally, the cells are 0.5 × 10 ⁵ cells / 800
Prepared in RPMI-1640 medium containing 5% fetal bovine serum (2-mercaptoethanol) at a concentration of μl, and
800 μl was rolled up in a 4-well plate. Sample 100
μl was added, and 1 hour later, lipopolysaccharide (LPS: Lipopolysa
100 μl of ccharide) (100 μg / ml) was added. Supernatants 20 hours after LPS stimulation were collected and various cytokine amounts were measured by an ELISA kit. The concentration of the sample required for 50% inhibition (IC ₅₀ ) was determined by plotting the amount of cytokine at each concentration. The results are shown in Tables 136 to 145.

[0441]

[Table 136]

[0442]

[Table 137]

[0443]

[Table 138]

[0444]

[Table 139]

[0445]

[Table 140]

[0446]

[Table 141]

[0447]

[Table 142]

[0448]

[Table 143]

[0449]

[Table 144]

[0450]

[Table 145]

Test Example 2: Inhibitory effect on LPS-induced peritonitis Male Balb / c mice were intraperitoneally injected with LPS (30 μg / ml, 1 ml) prepared in physiological saline containing 0.5% CMC (carboxymethylcellulose). , Caused peritonitis. After 1 hour, the animals were sacrificed with carbon dioxide, and the amount of TNFα in the peritoneal fluid was measured with an ELISA kit. Sample is L
50 mg / kg was intravenously administered into the tail vein 60 minutes before PS administration, and the degree of inhibition was examined. The inhibitory effect of the sample was shown by the inhibitory rate with respect to the control group. Inhibition rate (%) = (TNF amount of sample treated group / TN of control group)
F amount) × 100 The results are shown in Tables 146 to 147. In the table, ** indicates a significant difference p <0.01 from the control group.

[0452]

[Table 146]

[0453]

[Table 147]

Test Example 3: Inhibitory effect on LPS / D-galactosamine-induced hepatitis model LPS (5 μg / kg) / in male C57BL / 6 mice.
D-galactosamine (500 mg / kg) saline solution was intraperitoneally administered to develop hepatitis. Six hours after the administration of the physiological saline solution of LPS / D-galactosamine, blood was collected from the orbital venous plexus of the mouse. Separating plasma from blood,
The blood ALT value was measured with a biochemical analyzer. Specimen is LPS / D-galactosamine physiological saline solution administration 1
It was administered intravenously in the tail vein before time, and the degree of suppression was examined. The inhibitory effect of the sample was shown by the inhibitory rate with respect to the control group. Suppression rate (%) = (ALT amount of sample treated group / AL of control group)
T amount) × 100 The results are shown in Table 148.

[0455]

[Table 148]

From the above results, the compound of the present invention has an inhibitory action on inflammatory cytokine production, and is effective in treating rheumatic diseases such as rheumatoid arthritis, arthritis due to gout, systemic lupus erythematosus, psoriasis, pustulosis and atopic dermatitis. Skin diseases, respiratory diseases such as bronchial asthma, bronchitis, ARDS, diffuse interstitial pneumonia, inflammatory bowel disease (ulcerative colitis, Crohn's disease), acute and chronic hepatitis including acute hepatitis, acute and chronic Uveitis associated with glomerulonephritis, nephrogenic nephritis, Behcet's disease, vogt-Koyanagi, Harada's disease, Mediterranean fever (multiple serositis), ischemic diseases such as myocardial infarction, systemic circulatory insufficiency and multiple organs associated with sepsis It can be seen that it is useful for the prevention or treatment of non-infectious and infectious diseases accompanied by infiltration of neutrophils represented by insufficiency and the like. Further, as a result of a test conducted on inflammatory cytokines such as IL-6 and GM-CSF, it was confirmed that these inflammatory cytokines were also suppressed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/415 A61K 31/415 31/425 AED 31/425 AED 31/44 31/44 31/495 31/495 C07C 235/60 9547-4H C07C 235/60 235/62 9547-4H 235/62 237/22 9547-4H 237/22 237/30 9547-4H 237/30 237/36 9547-4H 237/36 237/42 9547-4H 237/42 279/18 9451-4H 279/18 C07D 213/80 C07D 213/80 213/82 213/82 231/38 231/38 B 271/06 271/06 277/28 277 / 28 413/12 257 413/12 257

Claims (7)

[Claims] 1. A compound of the general formula (I): {Wherein R is R _d ; an alkoxy group substituted with R _d ; R
alkylamino group substituted with R _d;; substituted alkylthio group at _d aminosulfonyl group, a halogen atom, a hydroxyl group, a mercapto group, a halogenated lower alkyl group; a carboxyl group; or an unsubstituted or optionally nitrogen-containing optionally heterocyclic A group [wherein R _d is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group or an imino group (these groups are a lower alkyl group, a halogenated lower alkyl group); Group, a cycloalkyl group, an aralkyl group, an aryl group or an amino-protecting group) may be substituted), and A ¹ , A ² and A ³ are the same or different and are substituted. And a linear or branched alkylene group which may have one or more double or triple bonds in the chain; or a single Represents a bond, L is an arylene group;
A cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring;
_a and R _b are the same or different and each is a hydrogen atom; a hydroxyl group; a halogen atom; an amino group which may be substituted with an alkyl group or an amino protecting group; an alkyl group which may be substituted with a halogen atom, a hydroxyl group or an amino group. (Here, the amino group may be substituted with an alkyl group or an amino protecting group); a halogen atom, a hydroxyl group or an alkoxy group optionally substituted with an amino group (wherein the amino group is an alkyl group or an amino protecting group). Alkylthio group; halogenated lower alkyl group; cyano group; nitro group; carboxyl group; alkoxycarbonyl group; aminosulfonyl group; or alkylsulfonyl group, X
Sulfur atom; oxygen atom ^{-NR 7 -; - SO -;} - SO
_{2 -; - CO -; -} CR 8 R 9 -; - CH = CH -; -
C≡C -; - COO -; - OOC -; - NR 7 CO-;
^{-CONR 7 -; - NR 7 SO} 2 -; - SO 2 NR
⁷ -;-CS-;-COS-;-O-CO-O-;-N
^{R 7 -COO -; - OOC-} NR 7 -; - NH-CO-
NH-;-NH-CS-NH-;-NH-C (= NH)
-NH-; a divalent aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; or a cycloalkylene group [wherein R ⁷ is a hydrogen atom; an alkyl group; An alkyl group; an aryl group; an aralkyl group; or an amino protecting group, R ⁸ and R ⁹ are the same or different, and a hydrogen atom; an alkyl group; a cycloalkyl group;
Represents an aryl group; or an aralkyl group], M is an arylene group; a cycloalkylene group; or has one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom, and forms a condensed ring. And R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom; a hydroxyl group; a halogen atom; a substituent selected from a hydroxyl group, a lower alkoxy group or a halogen atom. Alkyl group which may be substituted; Alkoxy group; Mercapto group; Alkylthio group; Amino group which may be substituted with a substituent selected from alkyl group, aryl group, aralkyl group or amino protecting group; nitro group; cyano group A carboxyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; an acyl group; or —O—CO—R ¹⁰ [wherein R ¹⁰
Is an amino group, lower alkoxy group, carboxyl group, alkoxycarbonyl group, acyloxy group, aryl group, aryloxy group, aryloxycarbonyl group, aralkyloxy group, aralkyloxycarbonyl group, alkylthio group, arylthio group, acyl group or halogen atom. An alkyl group which may be substituted with a substituent selected from (wherein the amino group may be substituted with a lower alkyl group or an amino-protecting group); an optionally substituted alkoxy group; Optionally substituted aryl group; optionally substituted cycloalkyl group; optionally substituted aryloxy group; optionally substituted aralkyloxy group; optionally substituted alkylthio group; or optionally substituted Represents a good arylthio group], R
⁵ represents a hydrogen atom; an alkyl group which may be substituted with a halogen atom; an aralkyl group which may be substituted; or an amino protecting group, and R ⁶ is a benzene ring-fused cycloalkyl group; [Here, m is 0 or an integer selected from 1 to 6, n is an integer selected from 1 to 6, and R ¹¹ is an optionally substituted aryl group; an optionally substituted cycloalkyl group; Optionally substituted lower alkyl group; optionally substituted lower alkoxy group; optionally substituted lower alkylthio group; substituted with a substituent selected from lower alkyl group, aryl group, aralkyl group or amino protecting group An optionally substituted amino group; a heterocyclic group which may be substituted and has at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; or —COOR ¹⁶ (wherein R ¹⁶ is A hydrogen atom; a lower alkyl group; or a lower alkyl group or an amino group which may be substituted with an amino-protecting group), R ¹² represents a hydrogen atom; an optionally substituted alkyl group; Optionally substituted aryl group; optionally substituted aralkyl group; optionally substituted aromatic heterocyclic group having at least one hetero atom selected from nitrogen atom, sulfur atom or oxygen atom ; Or-
CO (Y) _p R ¹⁷ (where Y is an oxygen atom; a sulfur atom;
-NR ¹⁸ -; or -NR ¹⁸ -SO ₂ - (R ¹⁸ is a hydrogen atom; an alkyl group; an aralkyl group, a hydroxyl group, an alkoxy group, an aryl group; and or an amino protecting group) and, p is 0
Or 1, R ¹⁷ is a hydrogen atom; one or more hetero atoms selected from a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxycarbonyl group, an acyloxy group, a carboxyl group, an amino group, or a nitrogen atom, a sulfur atom or an oxygen atom. An alkyl group which may be substituted with a substituent selected from a heterocyclic group having (wherein the amino group may be substituted with a substituent selected from an alkyl group, an aryl group, an aralkyl group or an amino protecting group). ); An optionally substituted alkenyl group; an optionally substituted alkynyl group; an optionally substituted cycloalkyl group; an optionally substituted aryl group; an optionally substituted aralkyl group; And a heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; Or showing a cycloalkylidene amino group), R ¹³ is a hydrogen atom; Manchiru group or a lower alkyl group, R ¹⁴ is a lower alkyl group; or an aryl group, R ¹⁵ is an aryl group; an aralkyl group an aralkyl group; or A heterocyclic group having one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom], or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 2. In the general formula (I), R, A ¹ , A ² ,
A ³ , L, _Ra , R _b , X, M, R ¹ , R ² , R ³ , R
^At least one symbol selected from ⁴ , R ⁵ and R ⁶ satisfies the following definition: The amide compound according to claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof. . R is R _d1; R _d1 alkoxy group substituted with; R _d1 alkylthio group substituted with; alkylamino group substituted by R _d1; or which may nitrogen-containing substituted by a lower alkyl group or an amino protecting group Heterocyclic group [wherein R _d1 is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group or an imino group (these groups are lower alkyl groups, halogenated groups Which may be substituted with a substituent selected from a lower alkyl group or an amino protecting group). A ¹ , A ² ,
A ³ are the same or different and each represents a linear or branched alkylene group which may have one or more double or triple bonds in the chain; or a single bond. L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a , R _b
Are the same or different and are a hydrogen atom; a hydroxyl group; a halogen atom; an amino group which may be substituted with an alkyl group or an amino protecting group; an alkyl group which may be substituted with a halogen atom, a hydroxyl group or an amino group (wherein The amino group may be substituted with an alkyl group or an amino protecting group); a halogen atom, a hydroxyl group or an alkoxy group optionally substituted with an amino group (wherein the amino group is substituted with an alkyl group or an amino protecting group) Optionally)); an alkylthio group; or a halogenated lower alkyl group. X represents an oxygen atom; a sulfur ^{atom; -NR 7 '-; - SO} -; - SO 2 -;
^{-CO -; - CR 8 'R} 9'-; - CH = CH -; - C
≡C -; - COO -; - OOC -; - NR 7 'CO-;
^{-CONR 7 '-; - NR 7} ' SO 2 -; - SO 2 NR
⁷ '-;-CS-;-COS-;-O-CO-O-;-
^{NR 7 '-COO -; - OOC} -NR 7'-; - NH-
CO-NH-;-NH-CS-NH-;-NH-C (=
NH) -NH-; a divalent aromatic heterocyclic group having one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom; or a cycloalkylene group [wherein R ⁷ 'is a hydrogen atom; An alkyl group; an aralkyl group; or an amino protecting group, and R ⁸ ′ and R ⁹ ′ are the same or different and represent a hydrogen atom; an alkyl group; or an aralkyl group. M
Is an arylene group; a cycloalkylene group; or a nitrogen atom,
It represents a divalent heterocyclic group having one or more heteroatoms selected from a sulfur atom or an oxygen atom and which may form a condensed ring. R ¹ , R ² , R ³ and R ⁴ are the same or different,
Hydrogen atom; hydroxyl group; halogen atom; lower alkyl group optionally substituted by a substituent selected from hydroxyl group, lower alkoxy group or halogen atom; lower alkoxy group; mercapto group; lower alkylthio group; lower alkyl group, aralkyl group or An amino group which may be substituted with a substituent selected from an amino protecting group; or —O—CO—R ¹⁰ ′ [wherein R ¹⁰ ′ is an amino group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyloxy group. Group, aralkyloxy group, aralkyloxycarbonyl group or a lower alkyl group optionally substituted with a substituent selected from an acyl group (wherein, the amino group may be substituted with a lower alkyl group or an amino protecting group) Lower alkoxy group; lower alkyl group, carboxyl group or benzyloxycarbonyl group Optionally substituted aryl group;
Or represents a cycloalkyl group which may be substituted]. R ⁵ represents a hydrogen atom; an alkyl group which may be substituted with a halogen atom; an aralkyl group which may be substituted; or an amino protecting group. R ⁶ is a benzene ring-fused cycloalkyl group; [Where m is 0 or an integer selected from 1 to 6, n is an integer selected from 1 to 6, R ¹¹ ′ is a lower alkyl group,
Halogen atom, hydroxyl group, lower alkoxy group, amino group,
An aryl group which may be substituted with a carboxyl group or a lower alkoxycarbonyl group; a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a cycloalkyl group which may be substituted with a lower alkoxycarbonyl group An optionally substituted lower alkyl group; an amino group optionally substituted with a substituent selected from a lower alkyl group, an aryl group, an aralkyl group or an amino protecting group; a lower alkyl group, a halogen atom,
A heterocyclic group which may be substituted with a hydroxyl group, a lower alkoxy group, an amino group, a carboxyl group or a lower alkoxycarbonyl group and which has at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom; COO
R ¹⁶ ′ (wherein R ¹⁶ ′ represents a hydrogen atom or a lower alkyl group) and R ¹² ′ represents a hydrogen atom; a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group or Lower alkyl group optionally substituted with amino group; aryl group; aralkyl group; optionally substituted with lower alkyl group, and having one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom Aromatic heterocyclic group; or -CO (Y
¹ ) _p R ¹⁷ '(wherein Y ¹ is an oxygen atom; a sulfur atom;
NR ¹⁸ '-; or _{^{-NR 18' -SO 2 - (R}} 18 ' is hydrogen atom, lower alkyl group, an aralkyl group, a hydroxyl group, an alkoxy group; and or an amino protecting group) and, p is 0 or 1
R ¹⁷ 'is a hydrogen atom; a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, a carboxyl group, an amino group, or a hetero atom having one or more hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom. An alkyl group which may be substituted with a substituent selected from a ring group (wherein the amino group may be substituted with a substituent selected from a lower alkyl group, an aralkyl group or an amino protecting group); a lower alkyl group A cycloalkyl group which may be substituted with; a lower alkyl group, a halogen atom, an amino group, a carboxyl group, a hydroxyl group or an aryl group which may be substituted with a lower alkoxy group; an aralkyl group; or a lower alkyl group, a halogen atom, An amino group, a carboxyl group, a hydroxyl group or a lower alkoxy group may be substituted, and a nitrogen atom, The showing a heterocyclic group) having one or more heteroatoms selected from sulfur atom or an oxygen atom, R
¹³ is a hydrogen atom; or a lower alkyl group, R ¹⁴ is a lower alkyl group; an aralkyl group; or an aryl group, and R ¹⁵ ′ represents an aryl group or an aralkyl group]. 3. In the general formula (I), R, A ¹ , A ² ,
A ³ , L, _Ra , R _b , X, M, R ¹ , R ² , R ³ , R
^At least one symbol selected from ⁴ , R ⁵ and R ⁶ satisfies the following definition: The amide compound according to claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof. . R is R _d2; R _d2 alkoxy group substituted with; R _d2 alkyl amino group substituted by; or a lower alkyl group or an amino-protecting good nitrogen-containing Hajime Tamaki optionally substituted by a group [wherein, R _d2 Represents an amino group, a guanidino group, an amidino group or a carbamoyl group (these groups may be substituted with a lower alkyl group or an amino protecting group). A ¹ , A ² , A
³ are the same or different and each represents a linear alkylene group or a single bond. L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a and R _b are the same or different and each is a hydrogen atom; a hydroxyl group; an amino group which may be substituted with an alkyl group or an amino protecting group; an alkyl group which may be substituted with an amino group (wherein the amino group is Alkyl group or optionally substituted with amino protecting group); or alkoxy group optionally substituted with amino group (wherein the amino group may be substituted with alkyl group or amino protecting group) . X is an oxygen atom; a sulfur atom; -NR ⁷ ″
-; - CO -; - CH 2 -; - CH = CH -; - C≡C
-; - COO -; - OOC -; - NR 7 '' CO -; - C
^{ONR 7 ''-; - NR} 7 '' SO 2 -; - SO 2 NR 7 ''
-; -NH-CO-NH-; or a divalent aromatic heterocyclic group having at least one hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom [wherein R ⁷ ″ is a hydrogen atom; A lower alkyl group; or an amino protecting group]. M represents an arylene group. R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom; a hydroxyl group; a halogen atom; a lower alkyl group which may be substituted with a substituent selected from a hydroxyl group, a lower alkoxy group or a halogen atom; or A lower alkoxy group is shown. R ⁵ represents a hydrogen atom; a lower alkyl group; an aralkyl group; or an amino protecting group. R ⁶ is a benzene ring-fused cycloalkyl group; [Here, m is 0 or an integer selected from 1 to 6, n is an integer selected from 1 to 6, R ¹¹ ″ is an aryl group which may be substituted with a halogen atom or a hydroxyl group; a lower alkyl group or it may be substituted with a hydroxyl radical; lower alkyl; lower alkyl group or an amino-protecting amino group which may be substituted with a group; or -COOR ¹⁶ '
(Wherein R ¹⁶ ′ represents a hydrogen atom or a lower alkyl group), R ¹² ″ represents a hydrogen atom; a lower alkyl group optionally substituted with a hydroxyl group or a lower alkoxy group; an aryl group; an aralkyl group; a lower An aromatic heterocyclic group which may be substituted with an alkyl group and has one or more hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom; or —CO (Y ² ) _p R ¹⁷ ″ (here And Y ² is an oxygen atom; a sulfur atom; —NR ¹⁸ ″ —; or —NR ¹⁸ ″ —SO ₂ — (R
¹⁸ ″ represents a hydrogen atom; a lower alkyl group; an alkoxy group; or an amino-protecting group), p represents 0 or 1, and R ¹⁷ ″ represents a hydrogen atom; an alkyl group which may be substituted with an amino group ( Here, the amino group may be substituted with a substituent selected from a lower alkyl group, an aralkyl group or an amino protecting group); a cycloalkyl group; an aryl group which may be substituted with a halogen atom or a hydroxyl group; an aralkyl group Or a heterocyclic group which may be substituted with a lower alkyl group and has one or more heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom), R ¹³ is a hydrogen atom;
Or a lower alkyl group, R ¹⁴ is a lower alkyl group; an aralkyl group; or an aryl group, and R ¹⁵ ′ represents an aryl group or an aralkyl group]. 4. In the general formula (I), R, A ¹ , A ² ,
A ³ , L, _Ra , R _b , X, M, R ¹ , R ² , R ³ , R
^At least one symbol selected from ⁴ , R ⁵ and R ⁶ satisfies the following definition: The amide compound according to claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof. . R is R _d2; alkoxy group substituted by R _d2; substituted with R _d2 alkylamino group; or piperazinyl group [wherein, R _d2 represents an amino group,
Represents a guanidino group, an amidino group or a carbamoyl group (these groups may be substituted with a lower alkyl group or an amino protecting group). A ¹ , A ² and A ³ are the same or different and each represents a linear alkylene group or a single bond.
L represents an arylene group; a cycloalkylene group; or a divalent aromatic heterocyclic group which has one or more heteroatoms selected from nitrogen atom, sulfur atom or oxygen atom and which may form a condensed ring. . R _a and R _b are the same or different and each is a hydrogen atom; a hydroxyl group; an amino group; a lower alkyl group which may be substituted with an amino group (wherein the amino group is substituted with a lower alkyl group or an amino protecting group. Or a lower alkoxy group. X is an oxygen atom; -NR ⁷ ″
-; -COO-; or -CONR ⁷ ″-[wherein
R ⁷ ″ represents a hydrogen atom; a lower alkyl group; or an amino protecting group]. M represents an arylene group. R ¹ ,
R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom; a hydroxyl group; a halogen atom; a lower alkyl group; or a lower alkoxy group. R ⁵ represents a hydrogen atom; a lower alkyl group; or an amino protecting group. R ⁶ is [Here, m ₁ is 1, R ¹¹ ″ ″ is a phenyl group or a cyclohexyl group, and R ¹² ″ ″ is —CO—Y ³ —R ¹⁷ ″ ″.
(Here, Y ³ is an oxygen atom or -NR ¹⁸ '''-(R ¹⁸ '''
Represents a hydrogen atom; a lower alkyl group; or an amino-protecting group), and R ¹⁷ ′ ″ represents a hydrogen atom; a lower alkyl group; an aralkyl group; a phenyl group which may be substituted with a halogen atom; a cyclohexyl group; Group) is shown]. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof. 6. An inflammatory cytokine production inhibitor comprising the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient. 7. A therapeutic or prophylactic agent for inflammatory diseases, which comprises the amide compound according to claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient.