JPH11228576A - Apoptosis inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor useful for the prophylaxis or therapy of diseases caused by excessive apoptosis such as viral diseases, e.g. AIDS, organ disorders, e.g. hepatitis or autoimmune diseases by including a specific compound having inhibiting actions on both the production of an Fas ligand and the production of a tumor necrosis factor-α. SOLUTION: This inhibitor is obtained by including a condensed ring compound of a 7-membered ring comprising a triazepine or a diazepine and a 5 membered ring containing 2-4 nitrogen atoms having inhibiting actions on both the production of an Fas ligand and the production of a tumor necrosis factor-α.6-(4-Bromophenyl)-4-(4-methoxybenzyl)-1-methyl-4H-2,3,4,5,10b- pentaazabenzo[e]azulene, etc., are cited as the condensed ring compound. The inhibitor is usually systemically or locally and orally or parenterally administered and the dose thereof is usually 0.01-1,000 mg for an adult administered once to several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an apoptosis inhibitor containing a triazepine compound or a diazepine compound as an active ingredient, and more specifically to a Fas antagonist and an antiviral agent. The present invention also relates to a novel triazepine compound having a Fas antagonistic action and an antiviral action.

[0002]

2. Description of the Related Art In a multicellular organism, many cells are removed by cell death during the ontogeny process. It is speculated that this cell death is caused by a predetermined program. Also in adult,
On the one hand, when the cell number increases due to cell division, cell death occurs on the other hand, and it is thought that the total cell number is maintained in balance. Wyllie and colleagues observed the morphology of dying cells under an electron microscope and classified cell death into two morphologies: necrosis and apoptosis [In
t. Cytol., 68, 251-306 (1980)].

[0003] In the case of necrosis, the permeability of cell membranes increases at an early stage, intracellular organelles such as nuclei and mitochondria swell, and eventually lysosomes are destroyed.
The cells are destroyed by the released protease. On the other hand, in the case of apoptosis, no major changes are observed in the structures of mitochondria and lysosomes, and chromosomes condense in the nucleus and cytoplasm shrink in the early stages. At the same time, the nucleus (DNA) may be fragmented into several parts, or a bubble-like structure may be formed on the cell surface, and then divided into mini-cells called apoptotic bodies. It is believed that passive death caused by external causes, so to speak, is mainly caused by necrosis, whereas pre-programmed cell death seen during development, differentiation or tissue turnover is caused by apoptosis.

[0004] Tumor necrosis factor-α is a substance that transmits an apoptotic signal from outside the cell.
α; TNF-α) and Fas ligand (FasL) are known [Science, 267, 1449-
1456 (1995) [Science, 267 (5203), 1449-
1456 (1995)]]. FasL and TNF-α are specific receptors such as Fas (also called APO-1 and CD95) and TNF receptor 1 (TNF-R1, TNF
Receptor p55), TNF receptor 2
(TNF-R2, also called TNF receptor p75). These receptors are T
Called the NF-R superfamily, it exhibits several specific structural features. FasL and TNF-α are secreted as ligands for trimers, and when bound to the receptor, promote the formation of the receptor trimer. Then, a signal of cell death is transmitted from the receptor complex to the nucleus to induce cell death.

The time required to induce cell death differs between FasL and TNF-α, and FasL induces cell death more rapidly than TNF-α. However, these cell death inducing mechanisms are based on interleukin 1β converting enzyme (interleuki
It is thought that n-1β converting enzyme (ICE) or ICE-like protease may be a common effector of receptor-mediated apoptosis of these substances.

[0006] Hitherto, Fas / FasL-mediated immune reactions have been associated with organ damage due to viral infection, viral diseases such as hepatitis and AIDS, graft-versus-host disease (GVHD), autoimmune diseases, and ulcerative colitis. It has been pointed out that it is involved in the onset and the like. It is said that most of the various TNF-α actions, such as cytotoxic activity, antiviral activity, antiparasitic activity, septic shock, and multiple organ failure, are mediated by p55. In case of AIDS, CD4 positive T
Attention has been focused on cell-induced cell death via Fas / FasL. Fas is strongly expressed in peripheral T cells of a person infected with human immunodeficiency virus (HIV), and anti-Fas
It has been reported that the antibody has high sensitivity to s antibody [Brad, 83, 5624-5628 (1994)].
[Blood, 83 , 5624-5628 (1994)]. In addition, TNF-α increases in the blood with the onset of AIDS from HIV infection [American Journal of Medicine, 85, 28
9-291 (1988) [Am. J. Med., 85 , 289-29]
1 (1988)]]. Furthermore, it has been suggested that stimulation of lymphocytes isolated from HIV-infected individuals with TNF-α increases HIV production [Lancet, 1206-1207 (1989) [Lancet, 1206-1207 (1989)].

[0007] Normally, there are about 1000 CD4-positive cells per 1 µl in the peripheral blood of a healthy subject, but in AIDS patients, the number of CD4-positive cells is reduced to several, and the immune system is destroyed. However, HIV-infected cells are at most 1% of peripheral blood lymphocyte cells even in AIDS patients whose disease state has progressed the most.
It has been found that it is usually about 0.01%. Thus, apoptosis is considered as a cause of death of CD4 + T cells.

[0008] Ameisen and Capro
n) proposes that HIV infection may cause activation of CD4-positive T cells, which may lead to apoptotic death of CD4-positive cells. HIV-uninfected CD4-positive cells may also be activated by the binding of free gp120 protein released from infected cells to the CD4 molecule and die without HIV infection. In addition, T cell apoptosis of HIV-infected patients is IL
There is also a report [Clinical Immunity, Vol. 29, No. 1, p. 78] that it is inhibited by the addition of -2.

From the above, if a compound capable of suppressing excessive apoptosis can be prepared, diseases caused by such excessive apoptosis, for example, viral diseases such as AIDS, and organ damage such as hepatitis due to viral infection, etc. , GVHD, autoimmune diseases, or diseases such as septic shock and multiple organ failure.

Compounds having apoptosis inhibitory activity are described in International Publication WO 97/07805, which has a general formula

Embedded image (R ¹ is hydrogen, alkoxy or halogen; R ² is carbamoyl; R ³ and R ⁴ are hydrogen, acyloxy, arylthio,
Heterocyclic thio, sulfinyl, sulfonyl or bromine; m
Represents 1 or 2. The compound represented by the general formula is described in International Publication WO97 / 08174.

Embedded image (R ¹ is hydrogen, alkoxy or halogen; R ² is alkoxy or aryloxy; R ³ is hydrogen, acyloxy, arylthio, heterocyclic thio; m represents 1 or 2). , These publications,
There is no disclosure of triazepine or diazepine compounds as in the present invention.

On the other hand, as a triazepine compound, International Publication WO96 / 16062 (JP-A-8-225)
546), the general formula

Embedded image Wherein R ¹ is aryl or heteroaryl; R ² is H,
Hydroxyl, halogen or lower alkyl; R ⁴ forms H or halogen, or R ² and R ⁴ form carbonyl;
R ³ is H, lower alkyl, lower alkoxy, cycloalkyl, aryl, heteroaryl, -XY ｛X is-
_{(CH 2) m -, -CO-} , -COCH 2 -, -N
HCH _2- , -CH ₂ NH-, -OCH ₂ -,-
(CH ₂ ) _n O— and the like; Y represents a halogen atom, cycloalkyl, aryl or heteroaryl, and the like; A represents a benzene ring or a thiophene ring. Are described as therapeutic agents for osteoporosis.

It has also been reported that certain compounds having a triazepine skeleton have anticonvulsant, muscle relaxant, sedative, anxiolytic, and tranquilizing effects [US Pat. No. 4,144,233; Patent Specification No. 5091381, U.S. Patent Specification No. 3891666
No. 3,880,878].

However, these publications do not disclose that the triazepine compound of the present invention has an apoptosis-suppressing action and an antiviral action,
The compounds of the present invention represented by the following general formulas [II] and [III] are not described.

Further, diazepine compounds are described in International Publication WO 93/07129 (US Pat. No. 559).
No. 3988, EP 628560), a compound of the general formula

Embedded image Wherein Ar is aryl or heteroaryl; X is an oxygen or sulfur atom, or Y is bonded to = NN-C
^{(R 6) -, = N} -C (R 5) = C (R 6) -, = C
^{(R 5) -N = C (} R 6) -, = N-O-CO- or ^{= N-N (R 5)} -CO- to form; ring Q is

Embedded image Represents Are described as therapeutic agents for osteoporosis.

Certain triazolodiazepine compounds have a cell adhesion inhibitory action (JP-A-7-179417) and a PAF antagonistic action (JP-A-5-86067,
JP-A-2-49787, JP-A-2-256681
Japanese Patent Application Laid-Open No. 64-79185 or coronary vasodilatory action
Has been reported.

However, these publications do not disclose that the diazepine compound of the present invention has an apoptosis-suppressing action and an antiviral action, and the compounds are represented by the following general formulas (II) and (III). Are not described.

[0017]

An object of the present invention is to provide a novel apoptosis inhibitor, for example, an antiviral drug, especially an anti-HIV drug. Another object of the present invention is to provide a novel compound useful as an active ingredient of the apoptosis inhibitor. Furthermore, the present invention provides a method for preventing or treating various diseases caused by excessive apoptosis, for example, organ disorders such as hepatitis, GVHD, autoimmune diseases, ulcerative colitis, and the like, and preventing or treating diseases caused by viruses, particularly HIV. The aim is to provide a method. Still another object of the present invention is to provide a novel use of a triazepine compound or a diazepine compound.

[0018]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies in search of a useful apoptosis inhibitor. As a result, a triazepine compound or a diazepine compound represented by the following general formula [I] was obtained. The present inventors have found that the compound has a remarkable inhibitory effect on apoptosis, and completed the present invention.

The present invention relates to an apoptosis inhibitor, for example, an antiviral agent, particularly an anti-HIV agent, comprising a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a novel triazepine compound having the apoptosis-suppressing action, for example, an antiviral action, particularly an anti-HIV action. The present invention still further provides a method for preventing or treating various diseases caused by excessive apoptosis comprising administering a compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof, or a disease caused by a virus: In particular, it relates to a method for preventing or treating AIDS.

The compounds represented by the following general formula [I] in the present invention have excellent inhibitory effects on Fas ligand production and Fas ligand mR as apparent from the test examples described later.
NA increase inhibitory action, TNF-α production inhibitory action, IFN-
IL- which has a γ production inhibitory action, an HIV-1 proliferation inhibitory action, a hepatitis inhibitory action, and an apoptosis inhibitory action.
2. Has little adverse effect on production. Therefore, these compounds are useful as antiviral agents against various diseases associated with apoptosis, for example, HIV, etc., or therapeutic agents for organ disorders such as hepatitis, GVHD, autoimmune diseases, ulcerative colitis, etc. is there. More particularly, the compounds of the present invention not only inhibit apoptosis but also
It is to directly suppress the growth of V. More specifically, it is as shown in the following (1) to (7).

(1) An apoptosis inhibitor comprising a compound having a Fas ligand production inhibitory activity and a TNF-α production inhibitory activity, wherein the compound comprises a seven-membered ring composed of triazepine or diazepine and 2 to 4 An apoptosis inhibitor characterized by being a fused ring compound with a five-membered ring containing a nitrogen atom.

(2) General formula [I]

Embedded image Wherein R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group; R ² represents a hydroxyl group, a lower alkoxy group, an aralkyloxy group or

Embedded image [Where R ³ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkynyl group, a cyano group, an acyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, -CR ⁶ ＣＲCR ⁷ R ⁸ (where R ⁶ , R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl group), —CR ⁹ ＮN—R ¹⁰ (Here, R ⁹ represents a hydrogen atom or a lower alkyl group, and R ¹⁰ represents a lower alkyl group, a hydroxyl group or a lower alkoxy group.),-(CH ₂ ) _j-
OR ¹¹ (where R ¹¹ represents a lower alkyl group or an aryl group which may be substituted, j represents 0 or an integer of 1 to 5), — (CH ₂ ) _j —CO ₂ R ¹² (here, And R
¹² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group, and j has the same meaning as described above. ), -CONR ²⁵ R ²⁶ <where R ²⁵ , R
²⁶ is the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or R ²⁵ and R ²⁶ together Become-(CH
_{2) p -Z- (CH 2)} r - { wherein, Z is an oxygen atom, N
-Ak (Ak represents the same meaning as described above) or a single bond, and p and r are the same or different and represent an integer of 1 to 3. ). Represents｝. >,-CONHNHCHO
,

Embedded image (Where R ¹³ and R ¹⁴ are the same or different and each represent a hydrogen atom,
Represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group, Ak represents a lower alkyl group, and R ¹² has the same meaning as described above. ) Or -X
-Y {wherein, X is _{- (CH 2) k -,} -CO-,
_{-COCH 2 -, -NH -, -} NHCH 2 -, -CH
_{2 NH-, -CH 2 NHCO-, -OCH} 2 -, -
(CH ₂ ) _k O— or —CH ₂ S— (where k represents an integer of 1 to 4), Y represents a halogen atom,
Cycloalkyl group, an amino group, a mono- or di-substituted amino group, an optionally substituted aryl group, an optionally substituted heteroaryl group or -N _2. And R ⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, R ⁵ represents a hydrogen atom or a halogen atom, or a carbon atom to which R ⁴ and R ⁵ are bonded together. Together form a carbonyl group. Or B represents a CH group,

Embedded image (Where R _a and R _b are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, A heteroarylalkyl group or an acyl group, R _c and R _c ′ being the same or different and each representing a hydrogen atom, a lower alkyl group or an aralkyl group, and R _d being a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group; A cycloalkylalkyl group, an aralkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or a heteroarylalkyl group; U represents an oxygen atom or a sulfur atom;
Represents 0, 1 or 2, and m represents 0 or an integer of 1 to 6. Ring A is

Embedded image Wherein R ¹⁵ and R ¹⁶ are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxy group,
It may be substituted by a cyano group, a nitro group, an amino group, a mono- or di-substituted amino group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted aminocarbonyl group or an acyloxy group. ), A cycloalkyl group, an aralkyl group, an aralkyl group substituted with a lower alkyl group, a lower alkenyl group,
Lower alkynyl group, hydroxyl group, lower alkoxy group, carboxy group, cyano group, nitro group, amino group, mono- or disubstituted amino group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, mono- or disubstituted aminocarbonyl group, Represents an acyl group or an acyloxy group. Represents B; a nitrogen atom or C—R ^17, wherein R ¹⁷ is a hydrogen atom or —CO ₂ R ¹⁸ (here, R ¹⁸
Represents a hydrogen atom, a lower alkyl group, an optionally substituted aryl group or an aralkyl group. ) Or together with R ² together with the carbon atom to which they are attached

Embedded image (Where R ¹⁹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group,
Optionally substituted aryl group, an optionally substituted heteroaryl group or heteroarylalkyl group, R ²⁰
Represents a hydrogen atom, a lower alkyl group or an aralkyl group,
n represents 0 or 1. ). V represents a nitrogen atom or C—R ²¹ (where R ²¹ represents a hydrogen atom or a lower alkyl group); W represents a nitrogen atom or a CH group. ] Or a pharmaceutically acceptable salt thereof.

(3) The apoptosis inhibitor according to the above (2), which comprises a compound of the formula [I] wherein B is a nitrogen atom or a pharmaceutically acceptable salt thereof.

(4) An antiviral agent comprising a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof.

(5) The antiviral agent according to the above (4), wherein the virus is HIV.

(6) General formula [II]

Embedded image Wherein R ²¹ ′ represents a hydrogen atom or a lower alkyl group;
R ²² and R ²³ are the same or different and represent a hydrogen atom, a lower alkyl group or an aryl group, or R ²² and R ²³ together

Embedded image (Where Z, p, and r each have the same meaning as described above); R ² , rings A, B, V, and W each have the same meaning as described above. Or a pharmaceutically acceptable salt thereof.

(7) General formula [III]

Embedded image [Wherein R ³ ′ is

Embedded image [Wherein, R _e is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, isoxazolyl group, an optionally substituted triazolyl group with a lower alkyl group, [1,3,4] oxadiazolyl group, [1,2,3] thiadiazolyl group , Imidazolinyl group, oxazolinyl group, 2-oxoimidazolidinyl group, benzimidazolyl group, phthalimide group, maleimide group or

Embedded image (Wherein R ²⁵ and R ²⁶ each represent the same meaning as described above), and R _f and R _g each represent a hydrogen atom or R _f and R _g together represent a carbonyl group. , T represents an oxygen atom, a sulfur atom or an NH group. ]. Or a pharmaceutically acceptable salt thereof.

The definition of each substituent used in the present specification is as follows. The "aryl group" represents a phenyl group having 6 to 12 carbon atoms, a naphthyl group or a biphenyl group, and is preferably a phenyl group.

The "optionally substituted aryl group" refers to an aryl group represented by the above "aryl group" which may have 1 to 3 substituents on the ring. Examples of the substituent include a halogen atom, a lower alkyl group, a haloalkyl group, an aralkyl group, a hydroxyl group, a lower alkoxy group, a methylenedioxy group, a haloalkyloxy group, an aralkyloxy group, a lower alkylthio group, a cyano group, a carboxy group, and a lower alkoxycarbonyl. Group, acyl group, nitro group, amino group, mono- or di-substituted amino group, carbamoyl group, mono- or di-substituted aminocarbonyl group, imide group, lower alkylsulfonyl group, cyclic aminosulfonyl group, amidino group, acyloxy group, dialkylamino Alkoxy group, dialkylaminomethylimino group (for example, -N = CH-NMe
_Second magnitude. ), Pyrrolyl group, 2-oxooxazolidinyl group, dihydroimidazolyl group, imidazolyl group, 2-mercaptoimidazolyl group, pyrazolyl group, dihydrooxazolyl group, isoxazolyl group, triazolyl group, alkyltriazolyl group, oxadiazolyl group , A tetrazolyl group, an alkyltetrazolyl group, a benzimidazolyl group or a ureido group. Further, two or more substituents may be substituted at the same time, but it is preferably mono-substitution, and the substitution position is not particularly limited as long as it is chemically permissible.

The substituent is preferably a halogen atom, lower alkyl group, haloalkyl group, hydroxyl group, lower alkoxy group, methylenedioxy group, haloalkyloxy group, aralkyloxy group, lower alkylthio group, cyano group, carboxy group, lower alkoxycarbonyl. Group, acyl group,
Nitro group, amino group, mono- or di-substituted amino group (especially amino group substituted with lower alkyl, acylamino group,
An alkoxycarbonylamino group, an N-alkyl-N-alkoxycarbonylamino group, an N-alkyl-N-acylamino group, a lower alkylsulfonylamino group or a bis-lower alkylsulfonylamino group. ), A carbamoyl group, a mono- or disubstituted aminocarbonyl group (especially an aminocarbonyl group substituted with a lower alkyl, an N-alkyl-N-alkoxyaminocarbonyl group, a cyclic aminocarbonyl group or a hydrazinocarbonyl group), an imide group,
Alkylsulfonyl group, cyclic aminosulfonyl group, amidino group, dialkylaminoalkoxy group, -N = CH-
NMe ₂ , 1-pyrrolyl group, 2-oxo-1-oxazolidinyl group, 1-imidazolyl group, 2-imidazolyl group, 4,5-dihydro-2-imidazolyl group, 2-mercapto-1-imidazolyl group, 3-pyrazolyl Group, 4,
5-dihydro-2-oxazolyl group, 5-isoxazolyl group, 3-triazolyl group, 5-methyl-3-triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group, alkyltetrazolyl group, 2-benzimidazolyl Or a ureido group.

Particularly preferably, the substituent is a fluorine atom,
Chlorine atom, bromine atom, methyl group, methoxy group, methylenedioxy group, methylthio group, cyano group, carboxy group,
Methoxycarbonyl group, tert-butoxycarbonyl group, nitro group, N-acetyl-N-methylamino group, methylaminocarbonyl group, propylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, azetidinii Carbonyl, pyrrolidinylcarbonyl, hydrazinocarbonyl, methylsulfonyl, pyrrolidinylsulfonyl, amidino, 2-oxo-1-oxazolidinyl, 2-imidazolyl, 4,5-dihydro-2
-Imidazolyl group, 4,5-dihydro-2-oxazolyl group, 3-triazolyl group, 5-methyl-3-triazolyl group, 1,3,4-oxadiazolyl group, 3-ethyl-1-ureido group, 3,3 -Dimethyl-1-ureido group, 3,3-diethyl-1-ureido group, 3-methyl-
A 3-phenyl-1-ureido group, a pyrrolidinylcarbonylamino group or a morpholinocarbonylamino group.

The substituent of the aryl group which may be substituted in R ¹ is preferably a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, an amino group, a mono- or di-substituted amino group. (Particularly an alkoxycarbonylamino group) or a ureido group, and the substituent of the optionally substituted aryl group in R ³ is preferably a halogen atom, a lower alkyl group, a haloalkyl group, a hydroxyl group, a lower alkoxy group, a methylenedioxy group. Group, haloalkyloxy group, aralkyloxy group, lower alkylthio group, cyano group, carboxy group, lower alkoxycarbonyl group, acyl group, nitro group, amino group, mono- or di-substituted amino group (especially amino group substituted with lower alkyl) , Acylamino group, alkoxycarbonyl Amino group, N-alkyl-N-alkoxycarbonylamino group, N-alkyl-N-acylamino group, lower alkylsulfonylamino group or bis-lower alkylsulfonylamino group), carbamoyl group,
A mono- or di-substituted aminocarbonyl group (especially an aminocarbonyl group substituted by lower alkyl, N-alkyl-N
An alkoxyaminocarbonyl group, a cyclic aminocarbonyl group or a hydrazinocarbonyl group. ), Imide group, alkylsulfonyl group, cyclic aminosulfonyl group, amidino group, dialkylaminoalkoxy group, -N = CH-NM
e ₂ , 1-pyrrolyl group, 2-oxo-1-oxazolidinyl group, 1-imidazolyl group, 2-imidazolyl group,
4,5-dihydro-2-imidazolyl group, 2-mercapto-1-imidazolyl group, 3-pyrazolyl group, 4,5-
Dihydro-2-oxazolyl group, 5-isoxazolyl group, 3-triazolyl group, 5-alkyl-3-triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group, alkyltetrazolyl group or 2-benzimidazolyl group It is.

Particularly preferred substituents of the aryl group which may be substituted in R ¹ are chlorine atom, bromine atom, methyl group, methoxy group, carboxy group, methoxycarbonyl group, tert-butoxycarbonyl group, nitro group and amino group. Tert-butoxycarbonylamino group, 3-
Ethyl-1-ureido group, 3,3-dimethyl-1-ureido group, 3,3-diethyl-1-ureido group, 3-methyl-3-phenyl-1-ureido group, pyrrolidinylcarbonylamino group or morpholino a carbonylamino group, etc., particularly preferably a fluorine atom as a substituent group of the aryl group which may be substituted in R ^3, a chlorine atom, a bromine atom, a methyl group, tert- butyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group , Ethoxy group, methylenedioxy group, trifluoromethoxy group, benzyloxy group,
Methylthio, cyano, carboxy, methoxycarbonyl, acetyl, nitro, amino, dimethylamino, formylamino, acetylamino, methoxycarbonylamino, N-methoxycarbonyl-N
-Methylamino group, N-acetyl-N-methylamino group, methanesulfonylamino group, bismethanesulfonylamino group, carbamoyl group, methylaminocarbonyl group, propylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropyl Aminocarbonyl group, N-methoxy-N-methylaminocarbonyl group, azetidinylcarbonyl group, pyrrolidinylcarbonyl group, 4-methylpiperazinylcarbonyl group,
Hydrazinocarbonyl group, succinimide group, maleinimide group, a phthalimide group, methylsulfonyl group, pyrrolidinylsulfonyl group, amidino group, 2-dimethylaminoethoxy _{group, -N = CH-NMe 2,} 1- pyrrolyl group, 2- Oxo-1-oxazolidinyl group, 1-imidazolyl group, 2-imidazolyl group, 4,5-dihydro-2
-Imidazolyl group, 2-mercapto-1-imidazolyl group, 3-pyrazolyl group, 5-isoxazolyl group, 5-
Examples thereof include a methyl-3-triazolyl group, a 1,3,4-oxadiazolyl group, a tetrazolyl group, a 1-methyltetrazolyl group, a 2-methyltetrazolyl group and a 2-benzimidazolyl group.

The term "heteroaryl group" means a 5- or 6-membered unsaturated ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and may be a condensed ring. It may be partially saturated. For example, pyridyl group, pyridine-1-oxide group, thienyl group, thiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, indolyl group, quinolyl group, furyl group,
Examples include a benzofuryl group, a 1H-benzimidazol-2-yl group and a 2-benzothiazolyl group. Preferred are a pyridyl group, a pyridine-1-oxide group, a thienyl group, a thiazolyl group, an isoxazolyl group, an indolyl group and the like.

"Pyridine-1-oxide group" means

Embedded image Represents

The "optionally substituted heteroaryl group" means one of the above-mentioned "heteroaryl group" on the ring.
Represents a group which may have from 3 to 3 substituents. As the substituent, a halogen atom, a lower alkyl group, a haloalkyl group, an aralkyl group, a hydroxyl group, a lower alkoxy group,
Methylenedioxy, haloalkyloxy, aralkyloxy, lower alkylthio, cyano, carboxy, lower alkoxycarbonyl, acyl, nitro, amino, mono- or disubstituted amino, carbamoyl, one or two Substituted aminocarbonyl group, imide group, lower alkylsulfonyl group, cyclic aminosulfonyl group, amidino group, acyloxy group, dialkylaminoalkoxy group, pyrrolyl group, 2-oxooxazolidinyl group, dihydroimidazolyl group, imidazolyl group, 2- Examples include mercaptoimidazolyl group, pyrazolyl group, dihydrooxazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, alkyltetrazolyl group, benzimidazolyl group or ureido group. Also, two or more may be substituted at the same time,
It is preferably mono-substituted, and the substitution position is not particularly limited as long as it is chemically permissible.

As the substituent, a halogen atom,
Lower alkyl group, haloalkyl group, hydroxyl group, lower alkoxy group, aralkyloxy group, haloalkyloxy group,
A cyano group, a nitro group, an amino group, a mono- or di-substituted amino group and an acyloxy group.

When the heteroaryl group is a pyridyl group or a thienyl group, the substituent is particularly preferably a fluorine atom,
Chlorine atom, methyl group, hydroxyl group, methoxy group, cyano group,
When the heteroaryl group is an isoxazolyl group or a thiazolyl group, the substituent is particularly preferably a chlorine atom or a methyl group.

The "halogen atom" is chlorine, bromine, fluorine or iodine, preferably chlorine or bromine.

"Lower alkyl group" refers to a group having 1 to 6 carbon atoms.
Represents a straight or branched chain alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group,
a tert-pentyl group or a hexyl group, preferably a methyl group having 1 to 4 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a te
and an rt-butyl group.

The term "haloalkyl group" means a group represented by the above "lower alkyl group" substituted by a group represented by the above "halogen atom", for example, a fluoromethyl group, a chloromethyl group and a bromomethyl group. , Trifluoromethyl group, trichloromethyl group, trifluoroethyl group,
A trichloroethyl group, a pentafluoropropyl group or a chlorobutyl group, preferably a fluoromethyl group,
A chloromethyl group, a bromomethyl group, a trifluoromethyl group or a trichloromethyl group.

"Cycloalkyl group" refers to an alkyl group having a cyclic alkyl moiety having 3 to 10 carbon atoms.
For example, a cyclopropyl group, a 2,3-dimethylcyclopropyl group, a cyclobutyl group, a 3-methylcyclobutyl group,
Cyclopentyl group, 3,4-dimethylcyclopentyl group, cyclohexyl group, 4-methylcyclohexyl group,
Cycloheptyl group, cyclooctyl group, norbornyl group, adamantyl group, bicyclo [3.3.0] octan-1-yl group or bicyclo [3.3.1] nonane-9-
Il group and the like. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

The "cycloalkylalkyl group" means a group represented by the above "lower alkyl group" substituted by a group represented by the above "cycloalkyl group". 3-dimethylcyclopropylmethyl group, cyclobutylmethyl group, 3-methylcyclobutylmethyl group, cyclopentylmethyl group, 3,4-
Dimethylcyclopentylmethyl group, cyclohexylmethyl group, 4-methylcyclohexylmethyl group, cycloheptylmethyl group, cyclooctylmethyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl group, norbornylmethyl group, 1-adamantylmethyl group, Bicyclo [3.3.0] octan-1-ylmethyl group, bicyclo [3.3.1] nonan-9-ylmethyl group and the like.

The "aralkyl group" is an arylalkyl group in which the aryl part is represented by the above "aryl group" and the alkyl part is represented by the above "lower alkyl group". A phenethyl group, a phenylpropyl group, a phenylbutyl group or a phenylhexyl group; a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, an acyloxy group on the aryl group; It may have 1 to 3 substituents selected from groups and the like.
Further, two or more substituents may be substituted at the same time, but it is preferably mono-substitution, and the substitution position is not particularly limited as long as it is chemically permissible.

Preferably, the phenyl group or a phenyl group having a halogen atom, a lower alkyl group, a haloalkyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group or an amino group as a substituent and the alkyl moiety have 1 carbon atom.
An aralkyl group having from 4 to 4 alkyl groups.

The term "aralkyl group substituted with a lower alkyl group" refers to the group obtained by substituting the group represented by the above "aralkyl group" with the group represented by the above "lower alkyl group". Group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-isopropylbenzyl group, 4-methylphenylethyl group, 4-ethylphenylethyl group or 4-propylphenylethyl group, preferably 4-methylbenzyl Group, 4-ethylbenzyl group or 4-isopropylbenzyl group.

The term "heteroarylalkyl group" means a group represented by the above "lower alkyl group" substituted by the above "heteroaryl group". The heteroaryl group is a halogen atom, a lower alkyl group, It may have 1 to 3 substituents selected from a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group and an amino group, and the heteroatoms constituting the ring may be nitrogen, oxygen or sulfur. It is something that is. The alkyl moiety has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. For example, pyridylmethyl group (2-pyridylmethyl group, 3-pyridylmethyl group or 4-pyridylmethyl group), quinolylmethyl group (such as 2-quinolylmethyl group or 3-quinolylmethyl group), indolylmethyl group (2-indolylmethyl group) Or a 3-indolylmethyl group), a thienylmethyl group (2
-Thienylmethyl group or 3-thienylmethyl group), furylmethyl group (2-furylmethyl group or 3-furylmethyl group), benzofurylmethyl group (such as 2-benzofurylmethyl group or 3-benzofurylmethyl group), 1H-benzimidazol-2-ylmethyl group, 2-benzothiazolylmethyl group, 2- (2-thienyl) ethyl group, 2- (2-
Furyl) ethyl and the like.

The term "lower alkenyl group" means an alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl -1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group,
1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-1-pentenyl group,
4-methyl-1-pentenyl group, 2,3-dimethyl-1
-Butenyl group or 3,3-dimethyl-1-butenyl group, preferably an ethenyl group having 2 to 4 carbon atoms;
-Propenyl group, 1-butenyl group, 2-butenyl group, 3
-Butenyl group or 2-methyl-1-propenyl group.

The "lower alkynyl group" means an alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-
Butynyl group, 3-butynyl group, 1-pentynyl group, 2-
Pentynyl group, 3-pentynyl group, 3-methyl-1-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-
Hexynyl group, 4-hexynyl group, 5-hexynyl group,
A 3-methyl-1-pentynyl group, a 4-methyl-1-pentynyl group or a 3,3-dimethyl-1-butynyl group, preferably an ethynyl group having 2 to 4 carbon atoms, a 1-propynyl group, -Propynyl group, 1-butynyl group, 2-
Butynyl group or 3-butynyl group.

The term "lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy. , A pentyloxy group, a tert-pentyloxy group or a hexyloxy group, preferably a methoxy group having 1 to 4 carbon atoms, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group. .

The "aralkyloxy group" is an arylalkoxy group in which the aryl moiety is represented by the above "aryl group" and the alkoxy moiety is represented by the above "lower alkoxy group". Group,
Phenethyloxy group, phenylpropoxy group, phenylbutoxy group or phenylhexyloxy group and the like, a halogen atom, a lower alkyl group on the aryl group,
It may have one to three substituents selected from a hydroxyl group, a lower alkoxy group, a haloalkyl group, a cyano group, a nitro group, an amino group, an acyloxy group and the like. Further, two or more substituents may be substituted at the same time, but it is preferably mono-substitution, and the substitution position is not particularly limited as long as it is chemically permissible.

The term "lower alkylthio group" means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group. Pentylthio, tert-pentylthio, hexylthio, and the like, preferably a methylthio group having 1 to 4 carbon atoms, ethylthio, propylthiosi, isopropylthio, butylthio, or tert-butylthio. Particularly preferred are a methylthio group, an ethylthio group, a propylthio group and a butylthio group.

The term "lower alkoxycarbonyl group" refers to the lower alkoxy moiety represented by the above "lower alkoxy group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl. , An isobutoxycarbonyl group or a tert-butoxycarbonyl group. Preferred are a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.

The “aralkyloxycarbonyl group” is
The aralkyl moiety represents the aralkyl group described above, such as a benzyloxycarbonyl group, a 2-phenylethoxycarbonyl group or a 3-phenylpropoxycarbonyl group, and a halogen atom, a nitro group, an alkyl group, or an alkoxy group as a substituent. Or a trifluoromethyl group.

The term "acyl group" means a formyl group; an alkanoyl group having 2 to 6 carbon atoms such as an acetyl group, a propionyl group, a butyryl group or a pivaloyl group; or an aryl group having one to three substituents. And an aroyl group such as a benzoyl group, a 4-chlorobenzoyl group, a 4-methylbenzoyl group or a 4-methoxybenzoyl group. Preferred are a formyl group, an acetyl group, a pivaloyl group and a benzoyl group.

The "lower alkylsulfonyl group" refers to a sulfonyl group substituted with the above-mentioned "lower alkyl group", such as a methylsulfonyl group, an ethylsulfonyl group or a propylsulfonyl group.

The term "mono- or di-substituted amino group" means an amino group substituted with lower alkyl, an alkoxycarbonylamino group, an acylamino group, an N-alkyl-N-alkoxyamino group, an N-alkyl-N-alkoxycarbonylamino. Group, N-alkyl-N-acylamino group, lower alkylsulfonylamino group, bis-lower alkylsulfonylamino group or cyclic amino group

"Amino group substituted by lower alkyl group"
Represents a mono- or di-substituted amino group represented by the above-mentioned "lower alkyl group", for example, a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group,
And a diethylamino group or a dipropylamino group. Preferred are a methylamino group, an ethylamino group, a dimethylamino group and a diethylamino group.

The “alkoxycarbonylamino group” is
Represents an amino group substituted by the above “alkoxy group”, for example, methoxycarbonylamino group, ethoxycarbonylamino group, propyloxycarbonylamino group, isopropyloxycarbonylamino group or te
rt-butoxycarbonylamino group and the like.

The term "acylamino group" refers to an amino group substituted with the above-mentioned "acyl group" and has 2 to 6 carbon atoms such as a formylamino group; an acetylamino group, a propionylamino group or a pivaloylamino group. Or an aroylamino group such as a benzoylamino group, 4-chlorobenzoylamino group or 4-methylbenzoylamino group which may have 1 to 3 substituents on the aryl group. Preferred are a formylamino group, an acetylamino group and a benzoylamino group.

The term "N-alkyl-N-alkoxyamino group" refers to an amino group substituted by one represented by the above "lower alkyl group" or "lower alkoxy group". Methoxy-N-methylamino group, N-ethyl-N-methoxyamino group, N-ethoxy-N-methylamino group, N-ethoxy-N-ethylamino group and the like.

The term "N-alkyl-N-alkoxycarbonylamino group" refers to an amino group substituted by one represented by the above "lower alkyl group" and one represented by the above "lower alkoxycarbonyl group". N-methoxycarbonyl-N-methylamino group, N-ethyl-N-methoxycarbonylamino group, N-ethoxycarbonyl-N
-Methylamino group, N-ethoxycarbonyl-N-ethylamino group and the like.

The term "N-alkyl-N-acylamino group" refers to an amino group substituted with one of the above-mentioned "lower alkyl group" and one of the above-mentioned "lower acyl group", for example, N-formyl. -N-methylamino group, N-formyl-N-methylamino group, N-acetyl-N-methylamino group, N-acetyl-N-ethylamino group, N-
Acetyl-N-benzoylamino group and the like.

The term "lower alkylsulfonylamino group" refers to an amino group substituted by the same groups as those described above for the "lower alkylsulfonylamino group", for example, a methylsulfonylamino group, an ethylsulfonylamino group or a propylsulfonylamino group. is there.

"Bis lower alkylsulfonylamino group"
Represents an amino group disubstituted by the above-mentioned "lower alkylsulfonyl group", such as a bis (methylsulfonyl) amino group or a bis (ethylsulfonyl) amino group.

"Cyclic amino group" refers to an azetidinyl group,
A pyrrolidinyl group, a piperidino group, a morpholino group having an oxygen, sulfur, or nitrogen atom as a heteroatom, a thiomorpholino group, a piperazinyl group, or the like, and a lower alkyl group or an aralkyl group is substituted at the 4-position nitrogen atom of the piperazinyl group. May be.

"Mono- or disubstituted aminocarbonyl group"
Is an aminocarbonyl group substituted with lower alkyl,
N-alkyl-N-alkoxyaminocarbonyl group, cyclic aminocarbonyl group, hydrazinocarbonyl group, etc.

The term "aminocarbonyl group substituted with a lower alkyl group" refers to an aminocarbonyl group which is mono- or di-substituted in the above-mentioned "lower alkyl group", for example, a methylaminocarbonyl group, an ethylaminocarbonyl group. Group, propylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group or dipropylaminocarbonyl group. Preferred are a methylaminocarbonyl group, an ethylaminocarbonyl group, a dimethylaminocarbonyl group and a diethylaminocarbonyl group.

The term "N-alkyl-N-alkoxyaminocarbonyl group" refers to an aminocarbonyl group substituted by one of the above-mentioned "lower alkyl group" and one of the above-mentioned "lower alkoxy group". N-methoxy-
N-methylaminocarbonyl group, N-ethyl-N-methoxyaminocarbonyl group, N-ethoxy-N-ethylaminocarbonyl group, N-ethoxy-N-ethylaminocarbonyl group and the like.

"Cyclic aminocarbonyl group" means those whose cyclic amino moiety is represented by the above "cyclic amino group", for example, azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinocarbonyl group, morpholinocarbonyl A thiomorpholinocarbonyl group, a piperazinylcarbonyl group or a 4-methyl-1-piperazinylcarbonyl group. Preferred are a pyrrolidinylcarbonyl group, a piperidinocarbonyl group, a morpholinocarbonyl group and a piperazinylcarbonyl group.

The term "cyclic aminosulfonyl group" refers to a sulfonyl group substituted by the above-mentioned "cyclic amino group", such as an azetidinylsulfonyl group, a pyrrolidinylsulfonyl group or a piperidinosulfonyl group. It is.

The "imide group" represents a succinimide group, a maleimide group or a phthalimide group.

The term "acyloxy group" means a formyloxy group; an alkanoyloxy group having 2 to 6 carbon atoms such as an acetyloxy group, a propionyloxy group, a butyryloxy group or a pivaloyloxy group; A benzoyloxy group which may have a substituent,
An aroyloxy group such as a 4-chlorobenzoyloxy group, a 4-methylbenzoyloxy group or a 4-methoxybenzoyloxy group. Preferred are an acetyloxy group, a propionyloxy group, a pivaloyloxy group and a benzoyloxy group.

The "alkyltetrazolyl group" is a 1-methyl-1H-tetrazolyl group or a 2-methyl-2H-tetrazolyl group.

The “dialkylaminoalkoxy group” is
The amino group disubstituted with the one shown in the above "lower alkyl group" represents a group substituted by the "lower alkoxy group", for example, dimethylaminomethoxy group, diethylaminomethoxy group, dimethylaminoethoxy group, diethylaminoethoxy group And the like.

The “ureido group” is

Embedded image (R ²¹ ′, R ²² and R ²³ each have the same meaning as described above).

“Pharmaceutically acceptable salt” refers to hydrochloride,
Inorganic acid addition salts such as hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate; Organic acid addition salts such as citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate; amino acid addition salts such as aspartate or glutamate Inorganic base salts such as sodium, potassium, calcium or magnesium; organic base salts such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, trishydroxymethylaminomethane, dicyclohexylamine, ethylenediamine, quinine and guanidine; Asparagine, glutamine, arginine, Including but basic salts of amino acids such as Suchijin or lysine, but not limited thereto. Further, depending on the case, it may be a hydrate or a hydrate.

[0078]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention is described in International Publication WO9.
No. 6/16062 (JP-A-8-225546) and WO 93/07129 (U.S. Pat. No. 5,593,988, European Patent 638).
560) can be produced by the method described in US Pat. No. 560, which is described in more detail below. In addition, in each production process, a protective group may be introduced into a functional group as necessary, and then deprotection may be performed for production.

Production Method 1 In the production method described here, of the compounds represented by the general formula [I], B is a nitrogen atom, and V is C—R ²¹ (R ²¹
Represents the same meaning as described above. ), And is suitable for producing a compound in which W is a nitrogen atom.

[0080]

Embedded image

First Step Known or disclosed in JP-A-53-121791, JP-A-53-121791
4-85978, JP-A-2-256681, U.S. Pat. No. 4,144,233, Synthesis,
677 (1980) [Synthesis, 677 (1980)] and references cited therein, Journal of Organometallic Chemistry, 215, 139-150 (198).
1 year) [J. Organomet. Chem., 215, 139-150 (1981)],
Heterocycles, 31, 1241 (1990)
[Heterocycles, 31, 1241 (1990)], Journal of Organic Chemistry, Vol. 56, p. 3750 (1991) [J. Org. Chem., 56, 3750 (1991)], etc. (Iii) (R ¹ , ring A
Represents the same meaning as described above. ) Is a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone, acetonitrile, toluene, water or the like; By reacting with thiophosgene, thiocarbonyldiimidazole, di-2-pyridylthiocarbonate, diethylthiocarbamyl chloride or carbon disulfide in a mixed solvent, the compound represented by the general formula (iv) (R ¹ and ring A are each as defined above) A compound having the same meaning is obtained. In addition to the above, a commonly used isothiocyanate synthesis method can be used for this reaction.

Second Step The compound represented by the general formula (iv) obtained in the first step is converted into dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, In a solvent such as acetone, ethyl acetate, water or a mixture thereof, a hydrazine compound represented by the general formula (v) (R ² has the same meaning as described above) or a salt thereof under ice-cooling or heating. The reaction is carried out preferably under ice cooling to room temperature to obtain a compound represented by the general formula (vi) (R ¹ , R ² and ring A each have the same meaning as described above). When a salt of a hydrazine compound is used, it is desirable to add an organic base such as triethylamine or N, N-diisopropylethylamine or an inorganic base such as sodium hydrogen carbonate.

Third Step The compound represented by the general formula (vi) obtained in the second step is converted into a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, benzene, toluene or a mixture thereof. In a solvent, an inorganic acid such as hydrochloric acid, sulfuric acid or hydrobromic acid or p-
By heating in the presence of an organic acid such as toluenesulfonic acid or trifluoroacetic acid, the compound represented by the general formula (vii)
(Wherein R ¹ , R ² and ring A have the same meanings as described above) or a salt thereof.

Fourth Step The compound represented by the general formula (vii) obtained in the third step is dissolved or suspended in a solvent such as N, N-dimethylformamide or tetrahydrofuran, and reacted with a base such as sodium hydride. By reacting with an alkyl halide represented by the general formula (viii) (Ak represents a lower alkyl group and Hal represents a halogen atom),
(R ¹ , R ² , ring A and Ak each have the same meaning as described above). Alternatively, the compound represented by the general formula (vii) is prepared by adding a compound such as acetone, methyl ethyl ketone, toluene, methanol, ethanol, water or a mixture thereof in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. You may make it react with the compound shown by general formula (viii).

Fifth Step The compound represented by the general formula (ix) obtained in the fourth step is
Ethanol, n-propanol, isopropanol, n
-Dissolve or suspend in a solvent such as butanol and toluene, add an acylhydrazine compound represented by the general formula (x) (R ²¹ has the same meaning as described above), and heat, preferably 90 to 110 ° C. Or at a temperature higher than that, the compound (R ¹ ) represented by the compound [I-2] wherein B is a nitrogen atom and V is C—R ²¹ among the compounds represented by the general formula [I] , R ² , R ²¹ and ring A each have the same meaning as described above.). In this case, hydrochloric acid,
It is preferable to add an acid such as acetic acid, p-toluenesulfonic acid or trifluoroacetic acid. Further, when one or more equivalents of these acids are added to the compound represented by the general formula (ix), a salt of the compound represented by the general formula [I-2] can be directly obtained.

Production Method 2 The production method described here is suitable for producing a compound of the formula [I] wherein B is a nitrogen atom.

Embedded image

Step 6 Among the compounds represented by the general formula [I], the compound [I] wherein R ² is a 4-methoxybenzyl group and B is a nitrogen atom
-3] (R ¹ , rings A, V and W have the same meanings as described above) in a solvent such as chloroform, 1,4-dioxane, acetic acid, trifluoroacetic acid or a mixed solvent thereof in methane. By reacting in the presence of a strong acid such as sulfonic acid, sulfuric acid, hydrochloric acid or hydrobromic acid, the compound represented by the general formula (xi)
(R ¹ , rings A, V, and W each have the same meaning as described above). In some cases, the acid used may itself be used as the solvent. In this reaction, it may be preferable to add a benzyl cation scavenger such as phenol, anisole or thioanisole. In this step, the acid-labile protecting group can be removed at the same time. For example, carboxylic acid tert
A -butyl ester compound (a compound in which R ¹ is a tert-butoxycarbonylphenyl group) can be converted to a carboxylic acid compound (a compound in which R ¹ is a carboxyphenyl group). Further, in this case, by adding an alcohol, the obtained carboxylic acid compound can be converted into an ester with the alcohol used in the reaction.

Seventh Step The compound represented by the general formula (xi) obtained in the sixth step is converted to N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetone, methyl ethyl ketone, dichloromethane, chloroform, 1,2-dichloroethane, water and the like. Sodium hydride, potassium hydride, sodium hydroxide,
Potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine,
In the presence of a base such as pyridine, N, N-dimethylaminopyridine, lithium bis (trimethylsilyl) amide, lithium diisopropylamide or sodium amide,
By reacting with a halogeno compound represented by the general formula (xii) (R ² and Hal each have the same meaning as described above) under ice cooling or heating, preferably under ice cooling to room temperature, the compound represented by the general formula [ Of the compounds represented by I], compounds represented by the following compound [I-4] wherein B is a nitrogen atom (R ¹ , R ² , rings A, V and W each have the same meaning as described above) can get. In this reaction, the general formula (xi
The base to be used may be appropriately selected depending on the reactivity and stability of the compound represented by i), and in some cases, these bases may be used in an appropriate combination.

Production method 3 The production method described here is based on the following formula: wherein R ¹ is an aryl group or a heteroaryl group in the compound represented by the general formula [I], and the aryl group or the heteroaryl group is substituted with a substituent. It is suitable for producing a compound having a carboxy group, an alkoxycarbonylamino group, an amino group or a nitro group.

Embedded image

Eighth Step Of the compounds represented by the general formula [I], the aryl or heteroaryl group in R ¹ is substituted with an alkoxycarbonyl group, a benzyloxycarbonyl group,
Compound having a methoxybenzyloxycarbonyl group or a 3,4-dimethoxybenzyloxycarbonyl group [I
-5] (R ²⁴ ′ represents a lower alkyl group, a benzyl group, a 4-methoxybenzyl group or a 3,4-dimethoxybenzyl group, ring C represents an aryl group or a heteroaryl group,
R ² , rings A, B, V and W each have the same meaning as described above. ) With methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-
The reaction is carried out using a base such as sodium hydride or potassium hydroxide in dioxane, water or a mixed solvent thereof (when R ²⁴ ′ is a lower alkyl group). Alternatively, the reaction is carried out using an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, trifluoroacetic acid or methanesulfonic acid (R ²⁴ ′ is a lower alkyl group, a 4-methoxybenzyl group or a 3,4-dimethoxybenzyl group. in the case of.). Alternatively, a catalytic reduction reaction with hydrogen is performed in the presence of a catalyst such as palladium carbon, palladium black or palladium hydroxide carbon (R
²⁴ 'is benzyl, 4-methoxybenzyl or 3,4
In the case of a dimethoxybenzyl group. ), The compound [I-6] (R ² , ring A, B, ring A) having a carboxy group as a substituent on the aryl group or heteroaryl group in R ¹ among the compounds represented by the general formula [I] C,
V and W each have the same meaning as described above. ) Is obtained. In some cases, the acid itself used as a reagent may be used as the solvent.

Ninth Step The compound represented by the general formula [I-6] obtained in the eighth step is treated with benzene, toluene, acetone, methyl ethyl ketone or a mixture thereof in the presence of diphenylphosphoric azide in the presence of a compound of the general formula (I-6). xiii) (R ²⁴ is a lower alkyl group,
Represents a benzyl group, a 4-methoxybenzyl group or a 3,4-dimethoxybenzyl group. Is reacted with an alcohol represented by the formula (I) to give, in the compound represented by the general formula [I], an arylcarbonyl group or a heteroaryl group represented by R ¹ as an alkoxycarbonylamino group, benzyloxycarbonylamino group or 4 Compound having a -methoxybenzyloxycarbonylamino group [I-7]
(R ² , R ²⁴ , rings A and B, rings C, V and W each have the same meaning as described above). In this reaction, it may be preferable to add a base such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium hydroxide or potassium hydroxide. In some cases, the alcohol used may itself be used as the solvent.

Tenth Step Among the compounds represented by the general formula [I-7] obtained in the ninth step, compounds wherein R ²⁴ is a lower alkyl group, a 4-methoxybenzyl group or a 3,4-dimethoxybenzyl group The reaction is carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane in the presence of an acid such as hydrogen chloride, hydrogen bromide, trifluoroacetic acid or methanesulfonic acid, or methanol, The presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide in ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water or a mixture thereof. By performing the reaction below, the compound represented by the general formula [I] Compounds having an amino group as a substituent on the aryl or heteroaryl group in R ¹ [I-
8] (R ² , rings A and B, rings C, V and W each have the same meaning as described above) or a salt thereof. Further, among the compounds represented by the general formula [I-7], a compound in which R ²⁴ is a benzyl group, a 4-methoxybenzyl group or a 3,4-dimethoxybenzyl group is converted to methanol, ethanol, n-
By performing catalytic reduction with hydrogen in the presence of a catalyst such as palladium carbon, palladium black or palladium hydroxide carbon in propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof, the general formula [I- 8] is obtained.

Eleventh Step The compound represented by the general formula [I-8] obtained in the tenth step is treated with sodium perborate or its water in dichloromethane, acetone, acetic acid, trifluoroacetic acid, water or a mixture thereof. Hydrate, hydrogen peroxide, m-chloroperbenzoic acid or monopersulfate compound
d; potassium peroxymonosulfate) to perform a reaction using an oxidizing agent such as a compound having a nitro group as a substituent on the aryl group or heteroaryl group in R ¹ among the compounds represented by the general formula [I] [ I-9]
(R ² , rings A and B, rings C, V and W each have the same meaning as described above).

Production Method 4 The production method described here is suitable for producing the compound represented by the general formula [II] among the compounds represented by the general formula [I].

Embedded image

Twelfth Step Of the compounds represented by the general formula [I], a compound [I-8] (R ² , rings A and B) having an amino group as a substituent on the aryl or heteroaryl group in R ³ , Ring C,
V, W and Ak each have the same meaning as described above. ) Or a salt thereof, dichloromethane, 1,2-dichloroethane,
In a solvent such as chloroform or pyridine, in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine, the general formula (xiv) (R ²² , R ²³ and Hal have the same meanings as described above, respectively) With the compound represented by the general formula [II] to obtain a compound [II-2] wherein R ²¹ ′ is a hydrogen atom among the compounds represented by the general formula [II]. . Alternatively, the compound represented by the general formula [II-2] can be reacted with a compound represented by the general formula (xv) (R ²² and R ²³ each have the same meaning as described above) in the above solvent. Is obtained. At this time, when a salt of the compound represented by the general formula [I-8] is used, it is preferable to add the above base. Then, in a solvent such as dimethylformamide or tetrahydrofuran, in the presence of a base such as sodium hydride, sodium hydroxide or potassium hydroxide, Ak-Hal
(Ak and Hal have the same meanings as described above), respectively, to give a compound of the general formula [II]
And the compound [II-3] wherein R ²¹ ′ is a lower alkyl group (R ² , R ²² , R ²³ , ring A, B, ring C, V, W, and Ak are the same as those described above). Represents the meaning of.)
Is obtained.

Production Method 5 The production method described here is based on the compound represented by the general formula [I] in which R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group has, as a substituent, a carboxy group, a carbamoyl group or an aminocarbonyl group mono- or di-substituted with a lower alkyl group. Suitable for preparing compounds.

Embedded image

Thirteenth Step Among the compounds represented by the general formula [I], the compound [I-10] (R ¹ , R ² ) having an alkoxycarbonyl group as a substituent in the aryl group or heteroaryl group in R ³ .
R ⁴ , R ⁵ , ring A, B, ring C, V, W, and Ak each have the same meaning as described above. ) Was performed in the same manner as in the eighth step to obtain a compound represented by the general formula [I]:
Compound [I-11] having a carboxy group as a substituent on the aryl group or heteroaryl group in R ³ (R
¹ , R ⁴ , R ⁵ , ring A, B, ring C, V, and W each have the same meaning as described above. ) Is obtained.

Fourteenth Step The compound represented by the general formula [I-11] obtained in the thirteenth step is treated with dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,
In a solvent such as N, N-dimethylformamide or dimethylsulfoxide, in the presence of a base such as triethylamine, N, N-diisopropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium carbonate, ethyl chlorocarbonate or isobutyl chlorocarbonate To give a mixed acid anhydride. Alternatively, it is reacted with a halogenating agent such as thionyl chloride or oxalyl chloride in the above solvent to obtain an acid halide. In this case, the catalyst amount of N, N
-It may be preferable to add dimethylformamide. The resulting carboxylic acid derivative such as a mixed acid anhydride or acid halide may or may not be isolated and purified. Next, in the above-mentioned solvent in the presence of the above-mentioned base, a compound represented by the general formula (xvi)
²⁵ and R ²⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or R ²⁵ and R ²⁶ Together

Embedded image (Z, p, and r each have the same meaning as described above.) By reacting with the amine compound represented by｝, among the compounds represented by the general formula [I], the aryl group or the heteroaryl group in R ³ is mono- or disubstituted with a carbamoyl group or a lower alkyl group as a substituent. Compound having an aminocarbonyl group [I-12]
(R ¹ , R ⁴ , R ⁵ , R ²⁵ , R ²⁶ , ring A, B, ring C, V,
W represents the same meaning as described above. ) Is obtained.

Alternatively, a compound represented by the general formula [I-11] can be prepared by dicyclohexylcarbodiimide (DC) in a solvent such as N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or 1,4-dioxane.
C), diisopropylcarbodiimide, 1-ethyl-3
By reacting with a compound represented by the general formula (xvi) in the presence of a condensing agent such as-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) or diphenylphosphoryl azide, the compound represented by the general formula [I- 12] is obtained. In this case, it may be preferable to add a reaction auxiliary such as 1-hydroxybenzotriazole or 4-dimethylaminopyridine. or,
A known amide bond formation reaction such as the method described in “Basic and Experimental Peptide Synthesis”, Nobuo Izumiya, Maruzen Co., Ltd. (1985) can be used.

[0100] Production methods described herein manufacturing process 6, among the compounds represented by the general formula [I], R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group is suitable for producing a compound having an acyl group, a 3-pyrazolyl group, or a 5-isoxazolyl group as a substituent.

Embedded image

Fifteenth Step Among the compounds of the general formula [I-12] obtained in the fourteenth step, the compound [I-13] (Ak ′) wherein R ²⁵ is a lower alkoxy group and R ²⁶ is a lower alkyl group , Ak ″ are the same or different and each represents a lower alkyl group, and R ¹ , R ⁴ ,
R ⁵ , rings A and B, rings C, V and W each have the same meaning as described above. ) In a solvent such as diethyl ether or tetrahydrofuran, with a Grignard reagent represented by the general formula (xvii) (Ak and Hal each have the same meaning as described above) to obtain a compound represented by the general formula [I]: Among the compounds represented by the formula (I-1), a compound having an acyl group as a substituent on the aryl group or heteroaryl group in R ³ .
4] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, W, and Ak each have the same meaning as described above).

Sixteenth Step Among the compounds of the general formula [I-14] obtained in the fifteenth step, the compound [I-15] wherein Ak is a methyl group
(R ¹ , R ⁴ , R ⁵ , ring A, B, ring C, V, and W each have the same meaning as described above) in N, N-dimethylformamide dimethyl acetal under heating, preferably 10
The reaction is performed at 0 ° C to 130 ° C. Then, by reacting with hydrazine or a salt thereof or a hydrate thereof in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane under heating, the compound represented by the general formula [I] is obtained. Among the compounds, the aryl group or the heteroaryl group for R ³ includes:
Compound having a 3-pyrazolyl group as a substituent [I-1
6] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above).

Step 17 The compound represented by the general formula [I-15] is reacted in the same manner as in Step 16 using hydroxylamine or a salt thereof instead of hydrazine or a salt or hydrate thereof. Thereby, among the compounds represented by the general formula [I], the aryl group or the heteroaryl group in R ³ is
Compound [I-17] having a 5-isoxazolyl group as a substituent (R ¹ , R ⁴ , R ⁵ , ring A, B, ring C, V,
W represents the same meaning as described above. ) Is obtained.

[0104] Production methods described herein manufacturing method 7 Among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group has a hydrazinocarbonyl group or a 1,3,4-oxadiazolyl group as a substituent. Suitable.

Embedded image

Eighteenth Step The compound represented by the general formula [I-10] is converted to methanol, ethanol, n-propanol, isopropanol, N,
By reacting with hydrazine or a hydrate thereof in a solvent such as N-dimethylformamide or dimethylsulfoxide, of the compound represented by the general formula [I], the aryl group or heteroaryl group represented by R ³ is substituted as a substituent. Compound having a hydrazinocarbonyl group [I-18]
(R ¹ , R ⁴ , R ⁵ , ring A, B, ring C, V, W each have the same meaning as described above).

Step 19 The compound of the formula [I-18] obtained in the step 18 is dissolved in a solvent such as benzene, toluene, N, N-dimethylformamide or dimethylsulfoxide in a solvent such as triethyl orthoformate or triethyl orthoacetate. Of the compound represented by the general formula [I], the aryl group or heteroaryl group represented by R ³ is substituted with a 1,3,4-oxadiazolyl group or 5-alkyl-1,5 Compound [I-19] having a 3,4-oxadiazolyl group (R ²⁷ represents a hydrogen atom or a lower alkyl group, and R ¹ , R ⁴ , R ⁵ , ring A, B, ring C,
V and W each have the same meaning as described above. ) Is obtained.

[0107] Production methods described herein manufacturing method 8 Among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group is suitable for producing a compound having a benzimidazolyl group as a substituent.

Embedded image

Step 20 The compound represented by the general formula [I-10] is prepared in a solvent such as benzene or toluene in the presence of trimethylaluminum.
By reacting o-phenylenediamine, a compound [I-20] (R ¹ ) having a benzimidazolyl group as a substituent on the aryl group or heteroaryl group in R ³ among the compounds represented by the general formula [I] , R ⁴ , R
⁵ , Rings A and B, Rings C, V and W each have the same meaning as described above. ) Is obtained.

Production Method 9 The production method described here is based on the compound represented by the general formula [I] in which R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, a compound having an alkoxycarbonylamino group or an N-alkyl-N-alkoxycarbonylamino group as a substituent on the aryl group or the heteroaryl group is produced. Suitable for

Embedded image

Step 21 The compound of the formula (I-11) obtained in the step 13 is treated with the compound of the formula (xviii) (A
k represents the same meaning as described above. A) a compound having an alkoxycarbonylamino group as a substituent on the aryl group or heteroaryl group in R ³ among the compounds represented by the general formula [I] by reacting with an alcohol represented by the formula [I-21]; (R ¹ , R ⁴ , R ⁵ , ring A, B,
Rings C, V, W and Ak each have the same meaning as described above. ) Is obtained.

Step 22 The compound of the formula [I-21] obtained in the step 21 is treated with the compound of the formula (xix) (A
k ′ and Hal each have the same meaning as described above. By reacting with the compound represented by the formula (I), the aryl group or the heteroaryl group in R ³ has an N-alkyl-N-alkoxycarbonylamino group as a substituent among the compounds represented by the general formula [I]. Compound [I-22]
(R ¹ , R ⁴ , R ⁵ , rings A, B, V, W, Ak, and Ak ′ each have the same meaning as described above).

[0112] Production methods described herein manufacturing method 10, among the compounds represented by formula (I), R ² is

Embedded image In the formula, R ³ is an aryl group or a heteroaryl group, which is suitable for producing a compound having a 3-triazolyl group as a substituent on the aryl group or the heteroaryl group.

Embedded image

[0113] Among the compounds represented by the general formula obtained in the first 23 step 14 step [I-12], compound R ^25, R ²⁶ are both hydrogen atoms [I-23] (R ^1, R ^4, R ⁵ , ring A, B, ring C, V,
W represents the same meaning as described above. ) Is converted to N, N-dimethylformamide dimethyl acetal or N, N-
Dimethylacetamide The reaction is performed in dimethylacetal. The compound obtained by this reaction need not be isolated and purified. Then with hydrazine in acetic acid, preferably by reaction under heating, among the compounds represented by formula (I), the aryl group or heteroaryl group in R ^3, the substituent 3-triazolyl or 5 Compound having an alkyl-3-triazolyl group [I-24]
(R ¹ , R ⁴ , R ⁵ , R ²⁷ , ring A, B, ring C, V, and W each have the same meaning as described above).

[0114] Production method 11 Production method described here, among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group is suitable for producing a compound having an amidino group as a substituent.

Embedded image

Twenty-fourth Step Of the compounds represented by the general formula [I], a compound [I-25] (R ¹ , R ⁴ , R 3) having a cyano group as a substituent on the aryl or heteroaryl group in R ^{3 5} , ring A, B, ring C, V, and W each have the same meaning as described above) in a solvent such as tetrahydrofuran or 1,4-dioxane, and an alcohol represented by the general formula (xviii) and hydrogen chloride or The reaction is performed in the presence of an acid such as hydrogen bromide. In some cases, the alcohol used may itself be used as the solvent. The obtained alkoxyimino compound need not be isolated and purified. Next, by reacting ammonia in a solvent such as methanol, ethanol, n-propanol or isopropanol, among the compounds represented by the general formula [I], the aryl group or heteroaryl group in R ³ is substituted with amidino as a substituent. Compounds having a group [I-
26] (R ¹ , R ⁴ , R ⁵ , rings A and B, rings C, V and W each have the same meaning as described above).

[0116] Production method 12 Production method described here, among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl or heteroaryl group, the aryl or heteroaryl group is suitable for producing a compound having a dihydro-2-imidazolyl group or a 2-imidazolyl group as a substituent.

Embedded image

Twenty-fifth Step An alcohol such as methanol, ethanol, n-propanol or isopropanol and tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform or a compound thereof represented by the following general formula [I-25]: In the presence of an acid such as hydrogen chloride or hydrogen bromide. The obtained alkoxyimino compound need not be isolated and purified. Then, by reacting with ethylenediamine in a solvent such as methanol, ethanol, n-propanol or isopropanol, among the compounds represented by the general formula [I], the aryl group or heteroaryl group in R ³ is substituted with dihydro- as a substituent. Compound having a 2-imidazolyl group [I-2
7] (R ¹ , R ⁴ , R ⁵ , rings A and B, rings C, V and W each have the same meaning as described above).

Step 26 The compound of the formula [I-27] obtained in the step 25 is dissolved in a solvent such as tetrahydrofuran or 1,4-dioxane in potassium permanganate, chromium trioxide or potassium dichromate. By performing an oxidation reaction in the presence of an oxidizing agent and a base such as sodium acetate or potassium acetate, preferably under heating, an aryl group or a heteroaryl group in R ³ among the compounds represented by the general formula [I],
Compound having a 2-imidazolyl group as a substituent [I-
28] (R ¹ , R ⁴ , R ⁵ , rings A and B, rings C, V and W each have the same meaning as described above).

Production Method 13 The production method described here relates to a method for producing a compound represented by the general formula [I] wherein R ² is

Embedded image wherein R ³ is an aryl group or a heteroaryl group, and is suitable for producing a compound having a tetrazolyl group or an alkyltetrazolyl group as a substituent on the aryl group or the heteroaryl group. .

Embedded image

Twenty-seventh Step The compound represented by the general formula [I-25] is converted into tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, chloroform, benzene, toluene, N, N-dimethylformamide, methanol, ethanol, An azide such as sodium azide or trimethylsilyl azide in a solvent such as n-propanol, isopropanol or n-butanol in the presence of an acid such as ammonium chloride, hydrochloric acid, acetic acid, trifluoroacetic acid or methanesulfonic acid or aluminum chloride To form a compound [I-29] (R ¹ , R ⁴ , R ⁴ ) having a tetrazolyl group as a substituent on the aryl group or heteroaryl group in R ³ among the compounds represented by the general formula [I]. ^5, ring a, B, ring C, V, W are the same meanings, respectively Represents.) Is obtained.

Step 28 The compound represented by the general formula [I-29] obtained in the step 27 is treated with methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane or a mixture thereof. among, by reaction with a diazo alkane diazomethane, among the compounds represented by formula (I), the aryl group or heteroaryl group in R ^3, compound having an alkyl tetrazolyl group as a substituent [I- 30]
(R ¹ , R ⁴ , R ⁵ , ring A, B, ring C, V, W, and Ak each have the same meaning as described above). At this time,
In some cases, a mixture of different alkyl groups may be obtained, but silica gel column chromatography,
Separation can be performed using a known separation means such as thin layer chromatography, high performance liquid chromatography or crystallization.

Manufacturing Method 14 The manufacturing method described here is based on the assumption that R ² is

Embedded image When R ³ is an aryl or heteroaryl group, the aryl or heteroaryl group is suitable for producing a compound having a dialkylaminoalkoxy group as a substituent.

Embedded image

Twenty-ninth Step Among the compounds represented by the general formula [I], the compound [I-31] (R ¹ , R ⁴ , R 3) having a hydroxyl group as a substituent in the aryl group or the heteroaryl group in R ^{3 5} , ring A,
B, V, and W each have the same meaning as described above. ) In a solvent such as tetrahydrofuran or 1,4-dioxane,
Dialkylamino represented by the general formula (xx) (s represents an integer of 1 to 6, and Ak and Ak 'each have the same meaning as described above) in the presence of triphenylphosphine and diisopropylazodicarboxylate. By reacting with an alcohol, among the compounds represented by the general formula [I], an aryl group or a heteroaryl group in R ³ is
Compound [I-32] having a dialkylaminoalkoxy group as a substituent (R ¹ , R ⁴ , R ⁵ , ring A, B, ring C,
V, W, Ak, Ak ', and s each have the same meaning as described above. ) Is obtained.

[0124] Production method 15 Production method described here, among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl or heteroaryl group, the aryl or heteroaryl group is suitable for producing a compound having —N ＝ CH—NMe ₂ as a substituent.

Embedded image

[0125] Of the 30th step the compound represented by formula (I), the aryl group or heteroaryl group in R ^3, a compound having an amino group as a substituent [I-33] (R ^1, R ^4, R ⁵ , rings A, B, rings C, V, and W have the same meanings as described above) in a solvent such as tetrahydrofuran or 1,4-dioxane in the presence of thionyl chloride with N, N-dimethylformamide. By reacting, a compound [I-34] (R ¹ , R ² ) having, as a substituent, —N ＝ CH—NMe ₂ as a substituent on the aryl group or the heteroaryl group in R ³ among the compounds represented by the general formula [I] R ⁴ , R ⁵ , ring A,
B, rings C, V and W each have the same meaning as described above. ) Is obtained.

Production Method 16 The production method described here is based on the compound represented by the general formula [I] in which R ² is

Embedded image In the formula, R ³ is an aryl group or a heteroaryl group, and is suitable for producing a compound having a 2-oxo-3-oxazolidinyl group as a substituent on the aryl group or the heteroaryl group.

Embedded image

Step 31 The compound represented by the general formula [I-33] is dissolved in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide or dimethylsulfoxide. 2-Chloroethyl chloroformate is reacted in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate. The resulting carbamate compound need not be isolated and purified. Then, the reaction is carried out using a base such as sodium hydride in a solvent such as tetrahydrofuran or N, N-dimethylformamide to obtain an aryl group or a heteroaryl group for R ³ among the compounds represented by the general formula [I]. And a compound [I-35] having a 2-oxo-3-oxazolidinyl group as a substituent (R ¹ , R ⁴ , R
⁵ , Rings A and B, Rings C, V and W each have the same meaning as described above. ) Is obtained. In this case, it may be preferable to add a reaction auxiliary such as potassium iodide.

[0128] Production methods described herein manufacturing method 17, among the compounds represented by formula (I), R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the compound is suitable for producing a compound having an imide group as a substituent on the aryl group or the heteroaryl group.

Embedded image

Step 32 The compound represented by the formula [I-33] is treated with a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylsulfoxide or pyridine. Wherein, in the general formula (xxi), R ²⁸ and R ²⁹ each represent a hydrogen atom or represent a benzene ring together with the carbon atom to which they are bonded;

Embedded image Represents a single bond or a double bond. ) Is reacted. The obtained acyl compound need not be isolated and purified. Then, acetic anhydride is used as a solvent and a reagent, and further reacted under heating, preferably at 90 ° C. to 120 ° C., in the presence of a base such as sodium acetate, potassium acetate, sodium hydrogen carbonate or potassium hydrogen carbonate, to obtain a compound of the general formula Among the compounds represented by I], the compound [I-36] (R ¹ , R ⁴ , R ⁵ , R ²⁸ , R ³ ) having an imide group as a substituent on the aryl group or heteroaryl group in R ³
R ²⁹ , ring A, B, ring C, V, W,

Embedded image Represents the same meaning as described above. ) Is obtained.

Manufacturing Method 18 The manufacturing method described here is based on the assumption that R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group is suitable for producing a compound having a 1-pyrrolyl group as a substituent.

Embedded image

Thirty-third step: The compound of the formula [I-33] is reacted with 2,5-dimethoxytetrahydrofuran in a solvent such as acetic acid or propionic acid at room temperature or under heating, preferably at 90 ° C. to 110 ° C. In the compound represented by the general formula [I], a compound having a 1-pyrrolyl group as a substituent on the aryl group or the heteroaryl group in R ³ [I-
37] (R ¹ , R ⁴ , R ⁵ , rings A, B, rings C, V, and W each have the same meaning as described above).

Production Method 19 The production method described here relates to a method for producing a compound represented by the general formula [I] wherein R ² is

Embedded image When R ³ is an aryl group or a heteroaryl group, the aryl group or the heteroaryl group has a 2-mercapto-1-imidazolyl group or a 1-imidazolyl group as a substituent. Suitable.

Embedded image

Step 34 The compound represented by the general formula [I-33] is dissolved in a solvent such as N, N-dimethylformamide or dimethyl sulfoxide.
By reacting with 1,1′-thiocarbonyldiimidazole and aminoacetaldehyde dimethyl acetal, among the compounds represented by the general formula [I], the aryl group or heteroaryl group in R ³ is substituted with 2-mercapto- Compound [I-38] having a 1-imidazolyl group (R ¹ , R ⁴ , R ⁵ , ring A, B, ring C, V,
W represents the same meaning as described above. ) Is obtained.

Step 35 The compound represented by the general formula [I-38] obtained in the step 34 was treated with Raney nickel in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane. By performing the reduction reaction, among the compounds represented by the general formula [I], the aryl group or the heteroaryl group in R ³ is
Compound having a 1-imidazolyl group as a substituent [I-
39] (R ¹ , R ⁴ , R ⁵ , rings A and B, rings C, V and W each have the same meaning as described above).

[0135] Production methods described herein manufacturing method 20, among the compounds represented by formula (I), R ² is

Embedded image Where R ³ is a pyridine-1-oxide group.

Embedded image

Step 36 Among the compounds represented by the general formula [I], the compound [I-40] wherein R ³ is a pyridyl group (R ¹ , R ⁴ , R ⁵ , ring A,
B, V, and W each have the same meaning as described above. M) -chlorobenzoic acid or peracetic acid in dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, 1,4-dioxane, ethyl acetate, n-hexane or a mixture thereof. The compound [I-41] (R ¹ , wherein R ³ is a pyridine-1-oxide group among the compounds represented by the general formula [I] by performing an oxidation reaction using a peracid or hydrogen peroxide of
R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above. Is obtained.

Production Method 21 The production method shown here is a method of preparing a compound represented by the general formula [I] wherein R ² is

Embedded image When R ³ is a formyl group or —CHＮN—R ¹⁰
(R ¹⁰ has the same meaning as described above.)

Embedded image

Step 37 Among the compounds represented by the general formula [I], the compound [I-42] wherein R ³ is a dimethoxymethyl group (R ¹ , R ⁴ ,
R ⁵ and rings A, B, V and W each have the same meaning as described above. ) In dichloromethane, chloroform, tetrahydrofuran, acetone, methanol, ethanol, n-propanol, isopropanol, water or a mixture thereof in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid. The compound [I-43] (R ¹ , R ⁴ , R ^{3) wherein} R ³ is a formyl group among the compounds represented by the general formula [I]
R ⁵ and rings A, B, V and W each have the same meaning as described above. ) Is obtained. In some cases, the acid used may itself be the solvent.

[0139] shown in a solvent such as pyridine compound represented by the general formula obtained in the first 38 step 37 step [I-43], general formula (xxii) (R ¹⁰ have the same meanings as defined above.) By reacting with an amine compound represented by the general formula [I], the compound [I-4] wherein R ³ is —CH ＝ NR ¹⁰
4] (R ¹ , R ⁴ , R ⁵ , R ¹⁰ , rings A, B, V, and W each have the same meaning as described above).

Production Method 22 The production method shown here is based on the formula (I) in which R ² is

Embedded image When R ³ is

Embedded image (R ²⁵ and R ²⁶ each have the same meaning as described above.),
An acyl group or

Embedded image (R ¹⁰ and Ak each have the same meaning as described above.)

Embedded image

Step 39 Of the compounds represented by the general formula [I], compounds [I-45] wherein R ³ is a carboxy group (R ¹ , R ⁴ , R ⁵ , rings A, B, V and W are Each has the same meaning as above.)
Is reacted with an amine compound represented by the general formula (xvi) in the same manner as in the fourteenth step, so that, of the compounds represented by the general formula [I], R ³ is

Embedded image [I-46] (R ¹ , R ⁴ , R ⁵ , R ²⁵ , R
²⁶ , rings A, B, V, and W each have the same meaning as described above. ) Is obtained.

Step 40 Of the compounds represented by the general formula [I-46] obtained in Step 39, compounds [I-47] (R ¹ ) wherein R ²⁵ is a lower alkoxy group and R ²⁶ is a lower alkyl group , R ⁴ , R ⁵ , rings A, B, V, W, Ak ′ and Ak ″ each have the same meaning as described above), by performing the same method as in the fifteenth step to obtain a compound of the general formula [I] [I-48] wherein R ³ is an acyl group (R ¹ , R ⁴ , R ⁵ , rings A, B, V, W, and Ak have the same meanings as described above). ) Is obtained.

Step 41 The compound represented by the general formula [I-48] obtained in the step 40 is reacted with an amine compound represented by the general formula (xxii) in a solvent such as pyridine to obtain a compound represented by the general formula [xxii]: I] wherein R ³ is

Embedded image (R ¹ , R ⁴ , R ⁵ , R ¹⁰ , rings A, B, V, W, and Ak each have the same meaning as described above).

Production Method 23 The production method described here is based on the compound represented by the general formula [I] in which R ² is

Embedded image When R ³ is a formylhydrazino group or 1,3,
Suitable for producing compounds that are 4-oxadiazolyl groups.

Embedded image

Step 42 The compound of the formula [I] is reacted with a formic hydrazide in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, benzene or toluene to give the compound of the formula [I-45]. Of the compounds shown, R
³ is a formylhydrazinocarbonyl group [I
-50] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above). Or the fourteenth
The compound represented by the general formula [I-50] can be obtained by the same method as in the step.

Step 43 The compound represented by the general formula [I-50] obtained in the step 42 is dissolved in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform or acetonitrile using phosphorus oxychloride, preferably under heating. By reacting with
Among the compounds represented by the general formula [I], R ³ is 1,3
Compound [I-51] which is a 4-oxadiazolyl group (R
¹ , R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above. ) Is obtained. In this case, phosphorus oxychloride itself used as a reagent may be used as a solvent.

[0147] Production methods described herein manufacturing method 24, among the compounds represented by formula (I), R ² is

Embedded image Is suitable for producing a compound in which R ³ is a 2-hydroxyethylaminocarbonyl group or a 4,5-dihydro-2-oxazolyl group.

Embedded image

Step 44 The compound of the formula [I] is reacted with 2-aminoethanol in the same manner as in the method of the step 14 to give the compound of the formula [I-45] Of the compounds [I-52] wherein R ³ is a 2-hydroxyethylaminocarbonyl group (R ¹ , R ⁴ , R ⁵ , rings A, B,
V and W each have the same meaning as described above. ) Is obtained.

Step 45 The compound of the formula [I-52] obtained in the step 44 is treated with triethylamine, N, N-dimethylformamide or the like in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran or N, N-dimethylformamide. , Sulfonylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride or thionyl chloride in the presence of a base such as N, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine. The reaction is carried out with a halogenating agent at a temperature from room temperature to room temperature. Then, this is reacted under heating, preferably at 40 ° C. to 100 ° C., to obtain a compound [I-I] of the compound represented by the general formula [I] wherein R ³ is a 4,5-dihydro-2-oxazolyl group. 53] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above).

[0150] Production method 25 Production method described here, among the compounds represented by formula (I), R ² is

Embedded image Where R ³ is a carbamoylmethylaminocarbonyl group or a 4,5-dihydro-4-oxoimidazolyl group.

Embedded image

Step 46 The compound of the formula [I] is reacted with glycinamide or a salt thereof in the same manner as in the step 14 to give the compound of the formula [I-45]. [I-54] wherein R ³ is a carbamoylmethylaminocarbonyl group (R ¹ , R ⁴ , R ⁵ , ring A,
B, V, and W each have the same meaning as described above. ) Is obtained.

Step 47 The compound represented by the general formula [I-54] obtained in the step 46 is treated with phosphorus oxychloride in a solvent such as pyridine.
Preferably, the reaction is carried out under heating to obtain a compound represented by the formula [I] wherein R ³ is a 4,5-dihydro-4-oxoimidazolyl group [I-5
5] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, and W each have the same meaning as described above).

Production Method 26 The production method described here is based on the compound represented by the general formula [I] in which R ² is

Embedded image Is suitable for producing a compound in which R ³ is a diazomethylcarbonyl group, a halogenomethylcarbonyl group, a 2-amino-4-thiazolyl group or a 2-acylamino-4-thiazolyl group.

Embedded image

Forty-eighth Step The compound represented by the general formula [I-45] is reacted with isobutyl chloroformate at -10 ° C. to room temperature in a solvent such as tetrahydrofuran in the presence of a base such as triethylamine or N, N-diisopropylethylamine. . Then, by reacting with diazomethane at 0 ° C. to room temperature, compounds [I-56] (R ¹ , R ⁴ , R ³ ) in which R ³ is a diazomethylcarbonyl group among the compounds represented by the general formula [I]
R ⁵ and rings A, B, V and W each have the same meaning as described above. ) Is obtained.

Step 49 The compound represented by the general formula [I-56] obtained in Step 48 is treated with hydrogen chloride or odor in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran or 1,4-dioxane. By reacting a hydrogen halide such as hydrogen halide at 0 ° C. to room temperature, the compound represented by the general formula [I]
Wherein R ³ is a halogenomethylcarbonyl group [I-57] (R ¹ , R ⁴ , R ⁵ , rings A, B, V, W, and Hal have the same meanings as described above, respectively) ) Is obtained.

Step 50 The compound of the formula [I-57] obtained in the step 49 is treated with thiourea under heating in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or 1,4-dioxane. Preferably, the reaction is carried out under heating to reflux to obtain a compound [I-58] (R ¹ , R ⁴ ) wherein R ³ is a 2-amino-4-thiazolyl group among the compounds represented by the general formula [I]. , R ⁵ , ring A,
B, V, and W each have the same meaning as described above. ) Is obtained.

Step 51 The compound represented by the general formula [I-58] obtained in the step 50 is treated with dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane,
Formula (xxii) in a solvent such as N, N-dimethylformamide or pyridine in the presence of a base such as triethylamine, N, N-diisopropylethylamine or pyridine.
i) An acyl halide represented by (Hal ′ represents a halogen atom, Ak represents the same meaning as described above) or a general formula (xxiv) (Ak represents the same meaning as described above). The compound [I-59] (R ¹ , R ⁴ , R ⁵ ) wherein R ³ is a 2-acylamino-4-thiazolyl group among the compounds represented by the general formula [I] ,
Rings A, B, V, W and Ak each have the same meaning as described above. ) Is obtained.

Production Method 27 The production method described here is based on the following formula: wherein R ¹ is an aryl group or a heteroaryl group in the compound represented by the general formula [I], and the aryl group or the heteroaryl group is substituted with a substituent. A compound having a methylamino group, and a compound represented by the general formula (II):
It is suitable for producing a compound in which R ²¹ ′ is a methyl group among the compounds represented by

Embedded image

Step 52 The compound of the formula [I-7] obtained in the ninth step is subjected to a reduction reaction using a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran or 1,4-dioxane. To obtain a compound [I] in which R ¹ is an aryl group or a heteroaryl group and the aryl group or the heteroaryl group has a methylamino group as a substituent among the compounds represented by the general formula [I]. -60] (R
² , Rings A and B, Rings C, V and W each have the same meaning as described above. ) Is obtained.

Step 53 The compound represented by the general formula [I-60] obtained in Step 52 is treated with phosgene, chloroform in a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane or chloroform. React with phosgene equivalents such as trichloromethyl carbonate or triphosgene. Then, by reacting with an amine compound represented by the general formula (xxv) (R ²² and R ²³ have the same meanings as described above), the compound represented by the general formula [II-4] (R ² , R ²² , R ²³ ,
Rings A, B, C, V, and W each have the same meaning as described above. Is obtained.

The compound of the present invention represented by the general formula [I] thus obtained has an inhibitory action on Fas ligand production, an inhibitory action on Fas ligand mRNA increase, an inhibitory action on TNF-α production, an inhibitory action on IFN-γ production, an inhibitory action on apoptosis,
It has an HIV proliferation inhibitory action and a hepatitis inhibitory action. When the compound of the present invention is used as an apoptosis inhibitor, an antiviral agent such as an anti-HIV agent, a therapeutic agent for hepatitis, a therapeutic agent for GVHD, or a therapeutic agent for an autoimmune disease, it is usually administered orally or parenterally, systemically or locally. You.

The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like, but is generally in the range of 0.01 mg to 1 g per adult, once or several times a day orally or parenterally. Is done.

When the compound of the present invention is made into a solid composition for oral administration, it can be in the form of tablets, pills, powders, granules and the like. In such a solid composition, the one or more active substances include at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol,
It is mixed with grape or the like, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylhydrin, magnesium aluminate metasilicate or anhydrous silicate powder.
Further, the composition may be mixed with additives other than the diluent according to a conventional method.

When preparing tablets or pills, they may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or with two or more layers. May be. In addition, the capsule may be made of a substance such as gelatin or ethyl cellulose.

When a liquid composition for oral administration is prepared, it can be in the form of a pharmaceutically acceptable emulsion, solubilizer, suspension, syrup or elixir. The diluent used includes, for example, purified water, ethanol, vegetable oil and emulsifier. In addition, the composition may contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances, preservatives and the like in addition to the diluent.

When preparing parenteral injections,
Sterile aqueous or non-aqueous solutions, solubilisers, suspending agents or emulsifiers are used. Examples of aqueous solutions, solubilizing agents, and suspending agents include distilled water for injection, physiological saline cyclodextrin and derivatives thereof, and organic amines such as triethanolamine, diethanolamine, monoethanolamine, and triethylamine, or inorganic alkali solutions. Etc.

In the case of preparing a water-soluble solution, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and the like may be used. As the solubilizer, for example, a surfactant such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester (mixed micelle formation), or lecithin or hydrogenated lecithin (liposome formation) is also used. or,
An emulsion formulation comprising a water-insoluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol can also be used.

Other compositions for parenteral administration include external solutions, ointments and other suppositories, suppositories or pessaries containing one or more active substances and formulated according to methods known per se. And so on.

[0169]

The compounds represented by the general formula [I] according to the present invention and the method for producing the same will be specifically described with reference to the following Reference Examples and Examples. However, it goes without saying that the present invention is not limited to these examples.

Reference Example 1 (first step) 2- (4-bromobenzoyl) phenylisothiocyanate

Embedded image According to the method described in U.S. Pat. No. 4,144,233, thiophosgene (1.67 ml) and 2-aminophenyl 4
-Bromophenyl ketone (5.52 g) to give the title compound (5.
2g) was obtained as a pale yellow solid. FAB (+) MS (low resolution) 319

Reference Examples 2 to 4 (First Step) In the same manner as in Reference Example 1, the compounds of Reference Examples 2 to 4 were obtained. These are shown in Table 1.

[Table 1]

Reference Example 5 (second step) N- [2- (4-bromobenzoyl) phenyl] -1-
(4-methoxybenzyl) hydrazinecarbothioamide

Embedded image 4-Methoxybenzylhydrazine hydrochloride (4.15 g) was dissolved in methanol (50 ml), and after cooling with ice, triethylamine
(3.38 ml) was added dropwise over 5 minutes. To this reaction mixture was added 2- (4-bromobenzoyl) phenylisothiocyanate (5.2 g) obtained in Reference Example 1 in tetrahydrofuran (100 m
l) The solution was added with ice cooling, and the mixture was stirred under ice cooling for 15 minutes and at room temperature for 40 minutes. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in ethyl acetate (200 ml), and washed twice with water.
The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the residue obtained by concentrating the filtrate under reduced pressure was crystallized from diethyl ether to give the title compound (5.1 g) as pale-yellow crystals. . Melting point 173.0-174.5 ℃

Reference Examples 6 to 8 (Second Step) In the same manner as in Reference Example 5, the compounds of Reference Examples 6 to 8 were obtained. These are shown in Table 2.

[Table 2]

Reference Example 9 (3rd step) 5- (4-bromophenyl) -3- (4-methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4]
Triazepine-2-thione

Embedded image N- [2- (4-bromobenzoyl) phenyl] -1- (4-methoxybenzyl) hydrazinecarbothioamide (5.0 g) obtained in Reference Example 5 was suspended in ethanol (50 ml), and p-toluenesulfone was added. Acid monohydrate (190 mg) was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in chloroform (50 ml), and washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated. The precipitated crystals were collected by filtration to give the title compound (4.6 g) as yellow crystals. Melting point 158.0-159.5 ℃

Reference Examples 10 to 12 (Third Step) In the same manner as in Reference Example 9, the compounds of Reference Examples 10 to 12 were obtained. These are shown in Table 3.

[Table 3]

Reference Example 13 (Fourth step) 5- (4-bromophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,
2,4] triazepine

Embedded image 5- (4-bromophenyl) -3- obtained in Reference Example 9
(4-Methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione (4.5 g)
Was dissolved in acetone (45 ml), potassium carbonate (13.8 g) was added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere.
After cooling with ice, methyl iodide (0.74 ml) was added, and the mixture was stirred under ice cooling for 3 hours and at room temperature for 30 minutes. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether, and washed sequentially with a 5% aqueous citric acid solution and water. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.4 g) as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.53 (3H, s), 3.78 (3H,
s), 4.69 (2H, s), 6.82 (2H, d, J = 8.7Hz), 6.93-6.97 (2H,
m), 7.13-7.25 (5H, m), 7.41-7.44 (3H, m)

Reference Examples 14 to 16 (Fourth Step) In the same manner as in Reference Example 13, the compounds of Reference Examples 14 to 16 were obtained. These are shown in Table 4.

[Table 4]

Example 1 (fifth step) 6- (4-bromophenyl) -4- (4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Embedded image 5- (4-bromophenyl) -3 obtained in Reference Example 13
-(4-methoxybenzyl) -2-methylthio-3H-
Benzo [e] [1,2,4] triazepine (4.3 g), acetylhydrazine (1.3 g) and p-toluenesulfonic acid monohydrate (175 mg) were dissolved in n-butanol (50 ml).
The mixture was heated and stirred at 0 ° C. for 18 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in ethyl acetate, and washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate, and water. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the residue obtained by concentrating the filtrate under reduced pressure was crystallized from ethyl acetate-n-hexane to give the title compound (3.3 g) as crystals. Obtained. Melting point 204.5-205.5 ℃

Examples 2 to 4 (Fifth Step) The 4- [3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,2,4] obtained in Reference Example 14
4] Triazepin-5-yl] benzoic acid tert-
Butyl ester, 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -8-methyl-2-methylthio-3H-benzo [e] [1,2, obtained in Reference Example 15.
4] Triazepine, 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -2- obtained in Reference Example 16
Methylthio-3H-pyrido [2,3-e] [1,2,
4] The compounds of Examples 2 to 4 were obtained from triazepine in the same manner as in Example 1. These are shown in Table 5. Example 2 4- [4- (4-methoxybenzyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
[Azulen-6-yl] benzoic acid tert-butyl ester ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.59 (9H, s), 2.61 (3H,
s), 3.80 (3H, s), 4.85-5.12 (2H, m), 6.85 (2H, d, J = 8.7H
z), 7.14 (1H, d, J = 8.0Hz), 7.31-7.36 (4H, m), 7.44 (2H,
d, J = 8.5 Hz), 7.60-7.63 (1H, m), 7.94 (2H, d, J = 8.5 Hz) Example 3 6- (4-chlorophenyl) -4- (4-methoxybenzyl) -1, 9-dimethyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene Melting point 213.5-216.5 ° C (recrystallization solvent: chloroform-diethyl ether) Example 4 6- (4-Chlorophenyl) -4- (4-methoxybenzyl) -1-methyl-4H- 2,3,4,5,10,1
0b-hexaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.72 (3H, s), 3.80 (3H,
s), 4.99 (2H, s), 6.86 (2H, d, J = 8.7Hz), 7.27-7.35 (7H,
m), 7.50-7.53 (1H, m), 8.61-8.63 (1H, m)

[0180]

[Table 5]

Reference Example 17 (sixth step) 4- (1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl) benzoic acid
Methyl ester

Embedded image 4- [4- (4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid obtained in Example 2
tert-butyl ester (300 mg) methanesulfonic acid
(0.6 ml) The solution was stirred at 70 ° C. for 1 hour. Methanol (1 ml) was added to the reaction mixture, and the mixture was heated under reflux for 1 hour. After cooling, a saturated aqueous sodium hydrogen carbonate solution (25 ml) and chloroform (25 ml) were added to the reaction mixture. The separated organic layer was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the residue obtained was crystallized from chloroform-diethyl ether to give the title compound (134 mg) as colorless crystals. 245.5-247 ° C

Reference Examples 18 to 20 (Sixth Step) In the same manner as in Reference Example 17, the compounds of Reference Examples 18 to 20 were obtained. These are shown in Table 6.

[Table 6]

Example 5 (seventh step) 4- [4- (N-acetyl-N-methylamino) benzyl] -6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,1 described in JP-A-8-225546.
Ob-pentaazabenzo [e] azulene (270 mg) was treated with N,
After dissolving in N-dimethylformamide (5 ml) and cooling with ice, sodium hydride (60% oily, 38 mg) was added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Cool on ice again, chloride 4
-(N-acetyl-N-methylamino) benzyl (190m
g) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and extracted three times with chloroform. Wash the organic layer five times with water,
Dry over anhydrous magnesium sulfate. The desiccant is filtered off,
The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol =
The residue obtained from the 25: 1 eluate was crystallized from chloroform-diethyl ether to give the title compound (330
mg) as crystals. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.87 (3H, s), 2.62 (3H,
s), 3.25 (3H, s), 4.80-5.35 (2H, m), 7.12 (2H, d, J = 8.1H
z), 7.20-7.55 (9H, m), 7.65 (1H, t, J = 6.0Hz)

Example 6 (seventh step) 6- (4-chlorophenyl) -1-methyl-4- (4-
Methylsulfonylbenzyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,1 described in JP-A-8-225546.
Ob-pentaazabenzo [e] azulene (400 mg) was added to N,
After dissolving in N-dimethylformamide (8 ml) and cooling with ice, sodium hydride (60% oily, 62 mg) was added, and the mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Cool on ice again, chloride 4
-Methylsulfonylbenzyl (291 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was ice-cooled, citric acid and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography.
The residue obtained from a chloroform: methanol = 25: 1 eluate was recrystallized from ethyl acetate-diethyl ether to give the title compound (395 mg) as crystals. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 3.04 (3H,
s), 4.90-5.40 (2H, m), 7.20-7.50 (7H, m), 7.59 (2H, d, J =
8.4Hz), 7.67 (1H, t, J = 7.6Hz), 7.87 (2H, d, J = 8.4Hz)

Examples 7 to 18 (seventh step) In the same manner as in Example 5 or 6, the compounds of Examples 7 to 18 were obtained. These are shown in Tables 7 and 8. Example 7 6- (4-chlorophenyl) -4- (4-dimethylaminocarbonylbenzyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 2.80-3.20
(6H, m), 4.80-5.30 (2H, m), 7.20-7.50 (11H, m), 7.60-7.
Example 8 6- (4-Chlorophenyl) -4- (4-diethylaminocarbonylbenzyl) -1-methyl-4H-2,3,70 (1H, m)
4,5,10b-Pentazaazabenzo [e] azulene Melting point 175.5-176.5 ° C (recrystallization solvent: ethyl acetate) Example 9 6- (4-chlorophenyl) -4- (4-dipropylaminocarbonylbenzyl) -1 -Methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 0.60-1.10 (6H, m), 1.40-
1.90 (4H, m), 2.62 (3H, s), 3.10-3.60 (4H, m), 4.80-5.30
(2H, m), 7.10-7.80 (12H, m) Example 10 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] benzoic acid methyl ester Melting point 137-139 ° C (recrystallization solvent: diethyl ether) Example 11 6- (4-chlorophenyl) -1-methyl-4- (4-
Methylthiobenzyl) -4H-2,3,4,5,10b
-Pentazabenzo [e] azulene Melting point 171.5-173.0 ° C (recrystallization solvent: methanol-diethyl ether)

Example 12 6- (4-Chlorophenyl) -1-methyl-4- [4-
(Pyrrolidin-1-ylcarbonyl) benzyl] -4H
-2,3,4,5,10b-Pentazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.08-2.00 (4H, m), 2.62
(3H, s), 3.43 (2H, t, J = 6.6Hz), 3.64 (2H, t, J = 6.6Hz), 4.
97 (1H, d, J = 15.0Hz), 5.15 (1H, d, J = 15.0Hz), 7.20-7.49
(12H, m), 7.63 (1H, t, J = 7.8Hz) Example 13 6- (4-Chlorophenyl) -1-methyl-4- (4-
Pyrrolidin-1-ylsulfonylbenzyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene Melting point 245.9-247.6 ° C (recrystallization solvent: chloroform-diethyl ether) Example 14 6- (4-chlorophenyl) -4- [3- (4 , 5-Dihydrooxazol-2-yl) benzyl] -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H , s), 4.05 (2H, t,
J = 9.3Hz), 4.16 (2H, t, J = 9.3Hz), 4.80-5.30 (2H, m), 7.1
0-8.10 (12H, m) Example 15 6- (4-Chlorophenyl) -1-methyl-4- (2-
Propinyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.25-2.35 (1H, m), 2.61
(3H, s), 4.50-4.75 (2H, m), 7.20-7.75 (8H, m) Example 16 4- (2-butynyl) -6- (4-chlorophenyl)-
1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Melting point 226.5-229.5 ° C (recrystallization solvent: dichloromethane-
Diethyl ether)

Example 17 6- (4-Chlorophenyl) -4-cyanomethyl-1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 4.55-4.80
(2H, m), 7.30-7.60 (7H, m), 7.68 (1H, dt, J = 8.0Hz, 1.5Hz) Example 18 6- (4-chlorophenyl) -4- (2,2-dimethoxyethyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 3.20-3.50
(6H, m), 3.80-4.30 (2H, m), 4.76 (1H, t, J = 5.4Hz), 7.20-
7.70 (8H, m)

[0188]

[Table 7]

[0189]

[Table 8]

Examples 19 to 30 (seventh step) 1-methyl-6 described in JP-A-8-225546
-Phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, obtained in Reference Example 18
(4-bromophenyl) -1-methyl-4H-2,3,
4,5,10b-Pentazaazabenzo [e] azulene, 1-methyl-6 described in JP-A-8-225546
(4-methylphenyl) -4H-2,3,4,5,10
b-Pentazaazabenzo [e] azulene, 4- (1-methyl-4H-2,3,4,5,10 obtained in Reference Example 17
b-pentaazabenzo [e] azulen-6-yl) benzoic acid methyl ester, 1,9-dimethyl-6-phenyl-4H-2, described in JP-A-8-225546
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) obtained in Reference Example 19
-1,9-dimethyl-4H-2,3,4,5,10b-
The compounds of Examples 19 to 30 were obtained from pentaazabenzo [e] azulene in the same manner as in Example 5 or Example 6. These are shown in Tables 9 and 10.

Example 19 4- (4-cyanobenzyl) -1-methyl-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Melting point: 215-216.5 ° C. (recrystallization) Solvent: chloroform-diethyl ether) Example 20 4- (4-bromobenzyl) -6- (4-bromophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] Azulene Melting point 248.5-249.5 ° C (recrystallization solvent: chloroform-methanol) Example 21 4- [4- (N-acetyl-N-methylamino) benzyl] -1-methyl-6- (4-methylphenyl) -4H
-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.87 (3H, s), 2.37 (3H,
s), 2.62 (3H, s), 3.25 (3H, s), 4.80-5.30 (2H, m), 7.00-
7.70 (12H, m) Example 22 1-methyl-6- (4-methylphenyl) -4- (4-
Methylsulfonylbenzyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.36 (3H, s), 2.63 (3H,
s), 3.06 (3H, s), 4.90-5.40 (2H, m), 7.10-8.00 (12H, m) Example 23 4- [1-Methyl-6- (4-methylphenyl) -4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] benzoic acid methyl ester ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.35 (3H, s), 2.65 (3H,
s), 3.90 (3H, s), 4.90-5.30 (2H, m), 7.00-8.10 (12H, m)

Example 24 1-methyl-6- (4-methylphenyl) -4- [4-
(Pyrrolidin-1-ylcarbonyl) benzyl] -4H
-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.80-2.00 (4H, m), 2.36
(3H, s), 2.62 (3H, s), 3.43 (2H, t, J = 6.6Hz), 3.64 (2H, t,
J = 6.6Hz), 4.95 (1H, d, J = 15.0Hz), 5.14 (1H, d, J = 15.0H
z), 7.12 (2H, d, J = 7.8Hz), 7.20-7.48 (9H, m), 7.62 (1H,
(t, J = 7.8 Hz) Example 25 4- [4- (4-chlorobenzyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] benzoic acid methyl ester Melting point 186-187.5 ° C (recrystallization solvent: ethyl acetate) Example 26 4- [4- (4 -Cyanobenzyl) -1-methyl-4H
-2,3,4,5,10b-Pentazaazabenzo [e] azulen-6-yl] benzoic acid methyl ester Melting point 239.5-241 ° C (recrystallization solvent: ethyl acetate) Example 27 4- (3,4- Example 284 Dichlorobenzyl) -1,9-dimethyl-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Melting point 158-159 ° C (recrystallization solvent: diethyl ether) -(4-cyanobenzyl) -1,9-dimethyl-6-
Phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Melting point 214-216 ° C (recrystallization solvent: ethyl acetate-n-hexane)

Example 29 6- (4-Chlorophenyl) -4- (4-cyanobenzyl) -1,9-dimethyl-4H-2,3,4,5,10
b-Pentazabenzo [e] azulene Melting point 206.5-208.0 ° C (recrystallization solvent: chloroform-diethyl ether) Example 30 6- (4-Chlorophenyl) -4- (4-diethylaminocarbonylbenzyl) -1,9-dimethyl -4H-
2,3,4,5,10b-Pentazaazabenzo [e] azulene Melting point 195-196 ° C (recrystallization solvent: chloroform-diethylether-n-hexane)

[0194]

[Table 9]

[0195]

[Table 10]

Examples 31 to 36 (seventh step) 2,9-dimethyl-4-phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3] described in JP-A-8-225546 -E] azulene, 4- (4-chlorophenyl) -2-ethyl-9-methyl-6H-5,
6,7,8,9a-pentaazathieno [2,3-e] azulene, 4- (4-chlorophenyl) -2,3,9-trimethyl-6H-5,6,7,8,9a-pentaazathieno [2 3-e] azulene, 4- (4-methoxyphenyl) -2,3,9-trimethyl-6H-5,6,7,
The compounds of Examples 31 to 36 were obtained from 8,9a-pentaazathieno [2,3-e] azulene in the same manner as in Example 5 or Example 6. These are shown in Table 11.

Example 31 6- (4-Chlorobenzyl) -2,9-dimethyl-4-
Phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene Melting point 128-130 ° C (recrystallization solvent: diethyl ether-n-
Hexane) Example 32 6- (4-cyanobenzyl) -2,9-dimethyl-4-
Phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene Melting point 192-195 ° C (recrystallization solvent: ethyl acetate-diethyl ether) Example 33 4- (4-chlorophenyl)- 6- (4-cyanobenzyl) -2-ethyl-9-methyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene Melting point 199-200 ° C (recrystallization solvent: ethyl acetate-diethyl ether) Example 34 4- (4-chlorophenyl) -6- (3,4-difluorobenzyl) -2,3,9-trimethyl-6H-5,
6,7,8,9a-pentaazathieno [2,3-e] azulene Melting point 189-191 ° C (recrystallization solvent: ethyl acetate-diethyl ether) Example 35 4- (4-chlorophenyl) -6- (4-cyano Benzyl) -2,3,9-trimethyl-6H-5,6,7,
8,9a-Pentazaazathieno [2,3-e] azulene Melting point 210 to 211 ° C (recrystallization solvent: ethyl acetate-diethyl ether) Example 36 6- (4-cyanobenzyl) -4- (4-methoxyphenyl)- 2,3,9-trimethyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene Melting point 171-172 ° C (recrystallization solvent: ethyl acetate-diethyl ether)

[0198]

[Table 11]

Example 37 (seventh step) 6- (4-chlorophenyl) -4- (3,4-dichlorobenzyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Embedded image In the same manner as in Example 5 or 6, the title compound (128 m
g) was obtained. However, potassium hydroxide (88 mg) was used instead of sodium hydride (60% oily), and 3,4-dichlorobenzyl chloride (44%) was used instead of 4-methylsulfonylbenzyl chloride.
μl) was used. Melting point: 181 to 183 ° C (recrystallization solvent: diethyl ether-n-
Hexane)

Examples 38 to 41 (Seventh Step) The compounds of Examples 38 to 41 were obtained in the same manner as in Example 37. These are shown in Table 12. Example 38 4- (4-chlorophenyl) -6- (3,4-dichlorobenzyl) -2-ethyl-9-methyl-6H-5,6,
7,8,9a-Pentazaazathieno [2,3-e] azulene Melting point 151-153 ° C (recrystallization solvent: diethyl ether) Example 39 4- (4-chlorophenyl) -6- (4-fluorobenzyl) -2, 3,9-trimethyl-6H-5,6,7,
8,9a-Pentazaazathieno [2,3-e] azulene Melting point 242 to 243 ° C (recrystallization solvent: diethyl ether) Example 40 6- (4-chlorobenzyl) -4- (4-chlorophenyl) -2,3 9-trimethyl-6H-5,6,7,
8,9a-Pentazaazathieno [2,3-e] azulene Melting point 230-231 ° C (recrystallization solvent: diethyl ether) Example 41 4- (4-chlorophenyl) -6- (3,4-dichlorobenzyl) -2, 3,9-trimethyl-6H-5,6,
7,8,9a-pentaazathieno [2,3-e] azulene Melting point 191 ° -193 ° C. (recrystallization solvent: diethyl ether)

[0201]

[Table 12]

Example 42 (seventh step) 4- [1-methyl-4- (4-nitrobenzyl) -4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] benzoic acid methyl ester

Embedded image 4- (1-methyl-4H-2, obtained in Reference Example 17
From 3,4,5,10b-pentaazabenzo [e] azulen-6-yl) benzoic acid methyl ester (1.20 g),
In the same manner as in Example 5, the title compound (1.22 g) was obtained as pale yellow crystals. However, instead of sodium hydride (60% oily), lithium bis (trimethylsilyl) amide 1
M tetrahydrofuran solution (3.78 ml) was replaced with p-nitrobenzyl bromide instead of 4-methylsulfonylbenzyl chloride.
(855 mg) was used. 205-206 ° C (recrystallization solvent: ethyl acetate-diethyl ether)

Example 43 (seventh step) 6- (4-chlorophenyl) -1-methyl-4- (4-
Nitrobenzyl) -4H-2,3,4,5,10,10
b-Hexazabenzo [e] azulene

Embedded image 6- (4-chlorophenyl) -1 obtained in Reference Example 20
Example 42 from -methyl-4H-2,3,4,5,10,10b-hexaazabenzo [e] azulene (150 mg)
In the same manner as in the above, the title compound (152 mg) was obtained. 224-226 ° C (recrystallization solvent: ethyl acetate-diethyl ether)

Example 44 (8th step) 4- [4- (4-chlorobenzyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] benzoic acid

Embedded image 4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid obtained in Example 25
To a suspension of methyl ester (2.24 g) in methanol (45 ml)
An aqueous solution of N sodium hydroxide (9.8 ml) was added. The mixture was stirred at 50 ° C. for 1.5 hours. After allowing the reaction mixture to cool, it was concentrated under reduced pressure. Diethyl ether and water were added to the residue, and the aqueous layer was separated. The obtained aqueous layer was made acidic with a 5% aqueous potassium hydrogen sulfate solution (50 ml), and the precipitate was extracted twice with chloroform. The chloroform layer was washed three times with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
After the drying agent was filtered off, the residue obtained by concentration under reduced pressure was crystallized from chloroform-diethyl ether to give the title compound (2.09 g) as colorless crystals. 247-248 ° C

Example 45 (8th step) [4- (4-cyanobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid

Embedded image 4- [4- (4-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid obtained in Example 26
From the methyl ester (630 mg), the title compound (446 mg) was obtained in the same manner as in Example 44. 190-192 ° C (recrystallization solvent: chloroform-diethyl ether)

Example 46 (8th step) 4- [1-methyl-4- (4-nitrobenzyl) -4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] benzoic acid

Embedded image Methyl 4- [1-methyl-4- (4-nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoate obtained in Example 42 The ester (97.1 mg) was dissolved in 1,4-dioxane (0.5 ml), and concentrated hydrochloric acid (0.8 ml) was added thereto.
Warmed for hours. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide was added to the residue to make a basic aqueous solution, and the mixture was washed with ethyl acetate. The basic solution was acidified with 1N hydrochloric acid to produce an insoluble solid product. By recrystallizing this material with methanol-ethyl acetate-diethyl ether,
The title compound (79.4 mg) was obtained as pale yellow crystals. 290 ° C

Example 47 (ninth step) 4- [4- (4-chlorobenzyl) -1-methyl-4H
Tert- 2,2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid
Butyl ester

Embedded image 4- [4- (4-chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid obtained in Example 44 ( Three
50mg), diphenylphosphoryl a
zide; DPPA, 0.18 ml), triethylamine (0.12 ml)
A solution of tert-butyl alcohol (7 ml) was heated to reflux for 18 hours. After allowing the reaction solution to cool, it was concentrated under reduced pressure. A 5% aqueous solution of potassium hydrogen sulfate and ethyl acetate were added to the obtained residue, and the organic layer was separated. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel chromatography, and the title compound (3
95 mg) was obtained as a pale yellow amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.52 (9H, s), 2.61 (3H,
s), 4,86-5.09 (2H, m), 6.63 (1H, s), 7.24-7.38 (11H, m),
7.59-7.62 (1H, m)

Examples 48 to 49 (9th step) [4- (4-Cyanobenzyl)-obtained in Example 45
1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid, 4- [1-methyl-4- (4- Nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid to give the compounds of Examples 48 to 49 in the same manner as in Example 47. Obtained. These are shown in Table 13. Example 48 4- [4- (4-cyanobenzyl) -1-methyl-4H
Tert- 2,2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid
Butyl ester ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.52 (9 H, s), 2.62 (3 H,
s), 4.95-5.19 (2H, m), 6.59 (1H, s), 7.27-7.40 (7H, m),
7.48 (2H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.7Hz), 7.62-7.67
Example 49 4- [1-Methyl-4- (4-nitrobenzyl) -4H
Tert- 2,2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid
Butyl ester ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.51 (9 H, s), 2.63 (3 H,
s), 5.03 (1H, d, J = 14.0Hz), 5.15 (1H, d, J = 14.0Hz), 6.61
(1H, s), 7.20-7.42 (7H, m), 7.54 (2H, d, J = 8.7Hz), 7.60-
7.69 (1H, m), 8.16 (2H, d, J = 8.7Hz)

[0209]

[Table 13]

Example 50 (10th step) 4- [4- (4-chlorobenzyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylamine hydrochloride

Embedded image 4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid obtained in Example 47 tert-butyl ester (100 mg) in 4N
It was dissolved in a hydrogen chloride-1,4-dioxane solution (1.5 ml) and stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was crystallized from ethanol to give the title compound (62 m
g) was obtained as pale yellow crystals. Melting point 183-185 ° C

Examples 51 to 52 (tenth step) 4- [4- (4-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaaza obtained in Example 48 Benzo [e] azulen-6-yl] phenylcarbamic acid tert-butyl ester, 4- [1-methyl-4- (4-nitrobenzyl) -4H-2,3,4,5 obtained in Example 49 , 10b-Pentazaazabenzo [e] azulen-6-yl] phenylcarbamic acid
The compounds of Examples 51 to 52 were obtained from tert-butyl ester in the same manner as in Example 50. These are shown in Table 14. Example 51 4- [4- (4-cyanobenzyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] phenylamine hydrochloride Melting point 180-190 ° C (solvent for decomposition and recrystallization: ethanol-isopropanol) Example 52 4- [1 -Methyl-4- (4-nitrobenzyl) -4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-6-yl] phenylamine hydrochloride Melting point 236-237 ° C (recrystallization solvent: methanol-diethyl ether)

[0212]

[Table 14]

Example 53 (11th step) 4- (4-chlorobenzyl) -1-methyl-6- (4-
Nitrophenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylamine obtained in Example 50 Hydrochloric acid The salt (135 mg) was partitioned between a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give a residue (100
mg) was dissolved in acetic acid (2 ml). Add sodium perboboratetetrahydrate (185m
g) was added and stirred at 50 ° C. for 7 hours. The reaction mixture was allowed to cool, and water (20 ml) and chloroform (20 ml) were added. The separated organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol = 9.
The residue obtained from the 8: 2 eluate was crystallized from ethyl acetate to give the title compound (68 mg) as a pale-yellow solid. 240-242 ° C

Example 54 (Twelfth Step) 3- [4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene- 6-yl] phenyl] -1,1-dimethylthiourea

Embedded image 4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylamine obtained in Example 50 Hydrochloric acid To a solution of the salt (500 mg) in pyridine (1 ml) was added N,
N-Dimethylcarbamoyl (143 mg) was added and at room temperature.
The mixture was stirred at 70 ° C for 1.5 hours for 1.5 hours. The reaction solution was allowed to cool, poured into a 5% aqueous potassium hydrogen sulfate solution (30 ml), and extracted with ethyl acetate (100 ml). Twice with 5% aqueous potassium hydrogen sulfate solution (30 ml) and saturated aqueous sodium hydrogen carbonate solution (30 m
l), washed successively with a saturated aqueous sodium chloride solution (30 ml), and dried over anhydrous sodium sulfate. After the drying agent was separated by filtration, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and the residue obtained from a 97: 3 eluate of chloroform: methanol was crystallized with chloroform-diethyl ether to give the residue. The compound (491 mg) was obtained as pale yellow crystals. 262-263 ° C

Examples 55 to 62 (Twelfth Step) 4- [4- (4-chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaaza obtained in Example 50 Benzo [e] azulen-6-yl] phenylamine hydrochloride, 4- [1-methyl-4- (4-nitrobenzyl) -4H-2,3,4,5,10b- obtained in Example 52 Example 55 to Example 55 from pentaazabenzo [e] azulen-6-yl] phenylamine hydrochloride in the same manner as in Example 54
The compound of Example 62 was obtained. These are shown in Table 15. Example 55 1,1-Dimethyl-3- [4- [1-methyl-4- (4
-Nitrobenzyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulen-6-yl] phenyl] urea ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 3.04 (6H,
s), 5.03 (1H, d, J = 15.5Hz), 5.21 (1H, d, J = 15.5Hz), 6.42
(1H, s), 7.26-7.43 (7H, m), 7.54 (2H, d, J = 8.8Hz), 7.65 (1
H, dt, J = 7.7, 2.1 Hz), 8.16 (2H, d, J = 8.8 Hz) Example 56 1,1-Diethyl-3- [4- [4- (4-chlorobenzyl) -1-methyl -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulen-6-yl] phenyl] urea ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.23 (6H, t, J = 7.3 Hz), 2.
61 (3H, s), 3.38 (4H, q, J = 7.3Hz), 4.86-5.09 (2H, m), 6.3
9 (1H, s), 7.18-7.39 (11H, m), 7.63 (1H, m) Example 57 1-methyl-3- [4- [4- (4-chlorobenzyl)
-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenyl] -1
-Phenylurea Melting point 243.5 to 245.0 ° C (recrystallization solvent: ethyl acetate-diethyl ether) Example 58 1-Methyl-3- [4- [1-methyl-4- (4-nitrobenzyl) -4H-2,3] , 4,5,10b-Pentazaazabenzo [e] azulen-6-yl] phenyl] -1
-Phenylurea ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 3.34 (3H,
s), 5.01 (1H, d, J = 13.9Hz), 5.19 (1H, d, J = 13.9Hz), 6.34
(1H, s), 7.21-7.42 (11H, m), 7.47-7.54 (3H, m), 7.64 (1
H, dt, J = 7.7, 1.5 Hz), 8.14 (2H, d, J = 8.4 Hz) Example 59 4- (4-chlorobenzyl) -1-methyl-6- [4-
(Pyrrolidin-1-ylcarbonylamino) phenyl]
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Melting point 158 to 161 ° C (recrystallization solvent: ethyl acetate-diethyl ether)

Example 60 1-methyl-4- (4-nitrobenzyl) -6- [4-
(Pyrrolidin-1-ylcarbonylamino) phenyl]
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.92-2.00 (4H, m), 2.62
(3H, s), 3.47 (4H, t, J = 6.6Hz), 5.00 (1H, d, J = 15.5Hz),
5.21 (1H, d, J = 15.5Hz), 6.29 (1H, s), 7.20-7.45 (7H, m),
7.53 (2H, d, J = 8.4Hz), 7.65 (1H, t, J = 8.4Hz), 8.16 (2H, d, J
J = 8.4 Hz) Example 61 4- (4-chlorobenzyl) -1-methyl-6- (4-
Morpholinocarbonylaminophenyl) -4H-2,
3,4,5,10b-Pentazaazabenzo [e] azulene Melting point 175-176 ° C (recrystallization solvent: chloroform-diethyl ether) Example 62 1-methyl-4- (4-nitrobenzyl) -6- (4 −
Morpholinocarbonylaminophenyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 3.49 (4H, t,
J = 5.1Hz), 3.75 (4H, t, J = 5.1Hz), 5.03 (1H, d, J = 15.5Hz),
5.21 (1H, d, J = 15.5Hz), 6.52 (1H, s), 8.20-8.42 (7H, m),
7.53 (2H, d, J = 8.4Hz), 7.66 (1H, t, J = 7.7Hz), 8.16 (2H,
d, J = 8.4Hz)

[0219]

[Table 15]

Example 63 (12th step) 1-ethyl-3- [4- [4- (4-chlorobenzyl)
-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenyl] urea

Embedded image 4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylamine obtained in Example 50 Hydrochloric acid Ethyl isocyanate (40 mg) was added to a solution of the salt (90 mg) and triethylamine (20 mg) in chloroform (1 ml), and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 4 hours. The reaction solution was allowed to cool, and chloroform (20 ml) was added. 5% potassium hydrogen sulfate aqueous solution, saturated sodium hydrogen carbonate aqueous solution (10 ml),
After sequentially washing with a saturated aqueous sodium chloride solution (10 ml), the mixture was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and the residue obtained from the chloroform: methanol = 96: 4 eluate was crystallized with chloroform-diethyl ether to give the residue. The compound (85 mg) was obtained as pale yellow crystals. 179-180 ° C

Example 64 (Twelfth Step) 1-ethyl-3- [4- [1-methyl-4- (4-nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [ e] azulen-6-yl] phenyl] urea

Embedded image 4- [1-Methyl-4- (4-nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylamine obtained in Example 52 Hydrochloric acid The title compound (67 mg) was obtained from the salt (90 mg) in the same manner as in Example 63. 261.2-261.8 ° C (recrystallization solvent: chloroform)

Example 65 (13th step) 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] benzoic acid

Embedded image 4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid methyl ester obtained in Example 10 To a solution of (171 mg) in ethanol (1 ml) was added a 1N aqueous sodium hydroxide solution (0.37 ml).
And further stirred at 45 ° C. for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The aqueous layer was separated and adjusted to pH 3 with 1N hydrochloric acid under ice cooling. The precipitated residue was extracted with ethyl acetate, and the organic layer was washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was crystallized from a mixed solvent of chloroform-ethyl acetate to give the title compound (105.6 mg) as colorless crystals. 190-193 ° C

Example 66 (13th step) 4- [1-methyl-6- (4-methylphenyl) -4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] benzoic acid

Embedded image Methyl 4- [1-methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl) benzoate obtained in Example 23 To a solution of the ester (2.25 g) in ethanol (22 ml) was added 2N
An aqueous sodium hydroxide solution (5.14 ml) was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water (12.1 ml) and 4N hydrochloric acid (3.50 ml) were added to the residue under ice-cooling.
Stirred for 0 minutes. The precipitated solid was collected by filtration and washed with water to give the title compound (1.96 g) as colorless crystals. ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.33 (3H, s), 2.55 (3H,
s), 4.86 (1H, d, J = 14.1Hz), 5.06 (1H, d, J = 14.1Hz), 7.15
-7.30 (4H, m), 7.40-7.50 (3H, m), 7.68-7.80 (2H, m), 7.8
8 (2H, d, J = 8.2Hz)

Example 67 (14th step) N-methyl-4- [1-methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene -4-ylmethyl] benzamide

Embedded image 4- [1-Methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid obtained in Example 66 ( 250 mg) and 1-hydroxybenzotriazole monohydrate (108 mg) were dissolved in N, N-dimethylformamide (5 ml). Under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC-HC
1, 136 mg), triethylamine (286 μl) and methylamine hydrochloride (100 mg) were sequentially added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform. This was washed three times with a 0.5N aqueous sodium hydroxide solution and further four times with water, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by concentration under reduced pressure was crystallized from chloroform-diethyl ether to give the title compound (228 mg) as crystals. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.35 (3H, s), 2.61 (3H,
s), 3.00 (3H, d, J = 3.3Hz), 4.80-5.30 (2H, m), 6.10-6.30
(1H, m), 7.00-7.80 (12H, m)

Examples 68 to 73 (14th step) 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo obtained in Example 65 From [e] azulen-4-ylmethyl] benzoic acid, the compounds of Examples 68 to 73 were obtained in the same manner as in Example 67. These are shown in Table 16. Example 68 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] benzamide ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.51 (3H, s), 4.75-5.1
0 (2H, m), 7.10-8.00 (14H, m) Example 69 N-methyl-4- [6- (4-chlorophenyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzamide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 3.00 (3H, d ,
J = 4.9Hz), 4.80-5.30 (2H, m), 6.10-6.30 (1H, m), 7.10-
7.80 (12H, m) Example 70 N-propyl-4- [6- (4-chlorophenyl) -1
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzamide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 0.98 (3H, t, J = 7.4 Hz) , 1.
54-1.78 (2H, m), 2.62 (3H, s), 3.38-3.45 (2H, m), 4.97 (1
H, d, J = 12.4Hz), 5.16 (1H, d, J = 12.4Hz), 6.05-6.20 (1H,
m), 7.15-7.80 (12H, m) Example 71 6- (4-Chlorophenyl) -1-methyl-4- (4-
Methylpiperazinocarbonylbenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.32 (3H, s), 2.35-2.50
(4H, m), 2.62 (3H, s), 3.40-3.55 (2H, m), 3.70-3.85 (2H,
m), 4.90-5.20 (2H, m), 7.20-7.45 (11H, m), 7.60-7.70 (1
H, m) Example 72 N, N-Dimethyl-4- [1-methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene-4 -Ylmethyl] benzamide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.36 (3H, s), 2.62 (3H,
s), 2.80-3.20 (6H, m), 4.80-5.30 (2H, m), 7.00-7.70 (12
H, m) Example 73 N, N-Diethyl-4- [1-methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene-4 -Ylmethyl] benzamide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.00-1.40 (6H, m), 2.36
(3H, s), 2.62 (3H, s), 3.10-3.70 (4H, m), 4.80-5.30 (2H,
m), 7.00-7.70 (12H, m)

[0224]

[Table 16]

Example 74 (14th step) N-methoxy-N-methyl-4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulen-4-ylmethyl]
Benzamide

Embedded image 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid obtained in Example 65 (500 mg) ) Was added to a chloroform (5 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 50 ° C for 20 minutes. The reaction solution was concentrated under reduced pressure, chloroform (5 ml) was added to the obtained residue, and N, O-dimethylhydroxylamine hydrochloride (130 mg) and triethylamine (0.31 ml) were added under ice-cooling.
ml) and stirred at room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol =
The title compound (533 mg) was obtained from the 19: 1 eluate. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 3.35 (3H,
s), 3.56 (3H, s), 4.80-5.30 (2H, m), 7.15-7.70 (12H, m)

Example 75 6- (4-Chlorophenyl) -1-methyl-4- (azetidin-1-ylcarbonylbenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Embedded image In the same manner as in Example 74, the title compound (31.9 mg) was obtained.
However, azetidine hydrochloride (28 mg) was used instead of N, O-dimethylhydroxylamine, and dichloromethane was used instead of chloroform. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.20-2.50 (2H, m), 2.62
(3H, s), 4.16-4.40 (4H, m), 4.96 (1H, m), 5.16 (1H, m),
7.20-7.42 (9H, m), 7.57 (2H, d, J = 7.8Hz), 7.64 (1H, t, J =
(7.8Hz)

Example 76 (15th step) 4- (4-acetylbenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Embedded image N-methoxy-N-methyl-4- obtained in Example 74
[6- (4-chlorophenyl) -1-methyl-4H-
A solution of 2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzamide (300 mg) in tetrahydrofuran (3 ml) was added to an argon atmosphere at −30 ° C.
A 1M methylmagnesium bromide-toluene solution (2 ml) was added thereto, and the temperature was slowly raised to room temperature. Citric acid in the reaction solution
(150 mg) and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography to obtain the title compound (150 mg) from a chloroform: methanol 19: 1 eluate. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.59 (3H, s), 2.62 (3H,
s), 4.90-5.30 (2H, m), 7.20-8.00 (12H, m)

Example 77 (16th step) 6- (4-Chlorophenyl) -1-methyl- [4- (pyrazol-3-yl) benzyl] -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Embedded image 4- (4-acetylbenzyl)-obtained in Example 76
6- (4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene
(150 mg) was dissolved in N, N-dimethylformamide dimethyl acetal (1 ml) and stirred at 120 ° C. for 12 hours. Chloroform (5 ml) was added to the reaction solution, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and ethanol (5 ml) and hydrazine (200 μl) were added to the residue, followed by stirring at 110 ° C. for 2 hours. Chloroform was added to the reaction solution, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from chloroform-diethyl ether to give the title compound (82 mg) as crystals. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.62 (3H, s), 4.93-5.17
(2H, m), 6.59 (1H, d, J = 2.5Hz), 7.19-7.44 (9H, m), 7.60-
7.71 (4H, m)

Example 78 (17th step) 6- (4-Chlorophenyl) -4- [4- (isoxazol-5-yl) benzyl] -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- (4-acetylbenzyl)-obtained in Example 76
6- (4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene
(150 mg) was dissolved in N, N-dimethylformamide dimethyl acetal (1.5 ml) and stirred at 110 ° C. for 8 hours. Chloroform (5 ml) was added to the reaction solution, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and ethanol (5 ml) and hydroxylamine hydrochloride (35 mg) were added to the residue, followed by stirring at 110 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate.
Washed sequentially with water and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and chloroform: methanol = 1.
From the 9: 1 eluate, the title compound (57 mg) was obtained as an amorphous solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.61 (3H, s), 4.90-5.25
(2H, m), 6.49 (1H, s), 7.21-7.75 (12H, m), 8.24 (1H, s)

Example 79 (18th step) 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoylhydrazine

Embedded image 4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid methyl ester obtained in Example 10 (70 mg) was dissolved in N, N-dimethylformamide (0.5 ml), and hydrazine monohydrate (73 μl) was dissolved.
Was added and stirred at room temperature for 23 hours. Chloroform was added to the reaction solution, washed with water and a saturated aqueous solution of sodium chloride in that order, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated by azeotropic distillation with toluene to give the title compound (67 mg) as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.90-2.40 (3H, br s), 2.
62 (3H, s), 4.90-5.20 (2H, m), 7.20-7.50 (9H, m), 7.60-
7.70 (3H, m)

Example 80 (19th step) 6- (4-Chlorophenyl) -1-methyl-4- [4-
(1,3,4-oxadiazol-2-yl) benzyl] -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoylhydrazine obtained in Example 79 (100 mg ) Was dissolved in toluene (5 ml),
Triethyl orthoformate (1 ml) was added, and the mixture was heated under reflux at 110 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and the residue obtained from a chloroform: methanol = 19: 1 eluate was crystallized from ethyl acetate-diethyl ether to give the title compound (85 mg). ) Was obtained as colorless crystals. Melting point 198 ~ 200 ℃

Example 81 (20th step) 4- [4- (1H-benzimidazol-2-yl) benzyl] -6- (4-chlorophenyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image Under an argon atmosphere, a 1.8 M trimethylaluminum-toluene solution (1.4 ml) was added to toluene (5 ml), and the mixture was cooled with ice. Then, o-phenylenediamine (81 mg) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 1.5 hours. To this was added 4- [6- (4-chlorophenyl) -1 obtained in Example 10.
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid methyl ester (220 mg) was added, and the mixture was heated under reflux for 2 hours.
The reaction solution was ice-cooled, water (1 ml) and methanol (5 ml) were added,
The insolubles were collected by filtration. The insoluble material collected by filtration was dissolved in a mixed solvent of chloroform / methanol, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride.
It was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol = 96: 4.
The residue obtained from the eluate was crystallized from isopropanol to give the title compound (182 mg) as crystals. ^{1 H NMR (300MHz, δppm,} DMSO-d 6) 2.53 (3H, s), 3.31 (3H,
s), 4.75-5.20 (2H, m), 7.10-8.25 (16H, m), 12.83 (1H, s)

Example 82 (21st step) 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] phenylcarbamic acid methyl ester

Embedded image 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzoic acid obtained in Example 65 (177 mg) ) In toluene (3 ml)
(60.6 μl) and diphenylphosphate azide (121 mg) were added,
After stirring at 100 ° C. for 1.5 hours and at 120 ° C. for 30 minutes, methanol (0.5 ml) was added and the mixture was further stirred for 30 minutes. The reaction solution was allowed to cool, washed sequentially with a 5% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After the drying agent is filtered off, the filtrate is concentrated under reduced pressure, the residue obtained is subjected to silica gel column chromatography, and the crude product obtained from a 20: 1 chloroform: methanol eluate is crystallized from chloroform-methanol. By
The title compound (57 mg) was obtained. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 3.75 (3H,
s), 4.80-5.10 (2H, m), 6.69 (1H, s), 7.18-7.38 (11H, m),
7.63 (1H, m)

Example 83 (Step 22) N- [4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene-4 -Ylmethyl] phenyl] -N-methylcarbamic acid methyl ester

Embedded image Methyl 4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] phenylcarbamate obtained in Example 82 Ester (330 mg) was added to N, N-
After dissolving in dimethylformamide (5 ml) and adding sodium hydride (60% oily, 28 mg) under ice-cooling, the mixture was stirred at room temperature for 30 minutes. Then add 20 μl of methyl iodide every hour
Were added twice each. The reaction mixture was ice-cooled again, sodium hydride (60% oily, 14 mg) was added, and the mixture was stirred at room temperature for 30 minutes, and then methyl iodide was added twice, 20 μl / hour. The reaction mixture was ice-cooled again, sodium hydride (60% oily, 7 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography, and the crude product obtained with the ethyl acetate eluate was again subjected to silica gel column chromatography, and acetone: n-hexane = 1: 1 was used. The title compound (140 mg) was obtained as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 3.28 (3H,
s), 3.70 (3H, s), 4.85-5.20 (2H, m), 7.15-7.50 (10H, m),
7.60-7.70 (2H, m)

Example 84 (23rd step) 6- (4-chlorophenyl) -1-methyl-4- [4-
(5-Methyl-4H- [1,2,4] triazole-3
-Yl) benzyl] -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Embedded image 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] benzamide obtained in Example 68 (50 mg) N, N-dimethylacetamide dimethyl acetal (0.90 ml) was added to the mixture under argon atmosphere.
Stirred at 0 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, acetic acid (0.40 ml) and anhydrous hydrazine (7.4 μl) were added to the obtained residue, and the mixture was stirred at 90 ° C. for 4.5 hours under an argon atmosphere. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol = 9.
The crude product obtained from the 8: 2 to 94: 6 eluate was crystallized from chloroform-n-hexane to give the title compound (32.5 mg) as pale yellow crystals. 205-206 ° C

Example 85 (24th step) 3- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] phenylamidine

Embedded image 6- (4-chlorophenyl) -4- (3-cyanobenzyl) -1-methyl-4H described in Example 163 described later.
-2,3,4,5,10b-Pentazaazabenzo [e] azulene (1.5 g) was dissolved in chloroform (15 ml), and ethanol (620 ml) and 4N hydrogen chloride-1,4-dioxane solution (18 m
l) was added and the mixture was stirred at room temperature for 3 days. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methanol (15 ml), and 2.0 M
An ammonia-methanol solution (3.5 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 2N hydrochloric acid, and washed twice with ethyl acetate. Water layer is 2N under ice cooling
After basification with an aqueous sodium hydroxide solution, the mixture was extracted with n-butanol. The organic layer was washed twice with water, the solvent was distilled off under reduced pressure, and the obtained residue was triturated with methanol-diethyl ether to give the title compound (125 mg) as an amorphous solid. ^{1 H NMR (300MHz, δppm,} DMSO-d 6) 2.53 (3H, s), 4.70-5.1
0 (2H, m), 6.20-6.50 (1H, m), 7.10-7.90 (12H, m), 8.31 (3
H, s)

Example 86 (24th step) 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] phenylamidine

Embedded image 6- (4-Chlorophenyl) -4- (4-cyanobenzyl) -1-methyl-4H described in Example 164 described below.
The title compound (184 mg) was obtained as an amorphous solid from -2,3,4,5,10b-pentaazabenzo [e] azulene (1.20 g) in the same manner as in Example 85. ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.54 (3 H, s), 4.91 (1 H,
d, J = 14.7Hz), 5.14 (1H, d, J = 14.7Hz), 7.00-7.90 (12H,
m), 9.15 (1.5H, s), 9.35 (1.5H, s)

Example 87 (25th step) 6- (4-Chlorophenyl) -4- [4- (4,5-dihydro-1H-imidazo-2-yl) benzyl] -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl) -4- (4-cyanobenzyl) -1-methyl-4H described in Example 164 described below.
-2,3,4,5,10b-pentaazabenzo [e] azulene (1.20 g) was added to ethanol (12 ml) and chloroform (12 ml).
4N hydrogen chloride-1,4-dioxane (73 ml)
Was added and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. 600 mg of the obtained residue was dissolved in methanol (16 ml), ethylenediamine (71.1 mg) was added, and the mixture was refluxed for 4.5 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained residue was methanol-ethyl acetate,
Then, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (225 mg) as colorless crystals. Melting point 253.5-254.5 ℃

Example 88 (Step 26) 6- (4-Chlorophenyl) -4- [4- (1H-imidazo-2-yl) benzyl] -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl) -4 obtained in Example 87
-[4- (4,5-dihydro-1H-imidazo-2-yl) benzyl] -1-methyl-4H-2,3,4,5
10b-Pentazabenzo [e] azulene (200 mg), sodium acetate (73.6 mg) and anhydrous 1,4-dioxane (15 ml)
, And potassium permanganate (195 mg) was added little by little, and the mixture was refluxed for 15 hours under an argon atmosphere. The insolubles in the reaction solution were separated by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography. From a chloroform: methanol = 96: 4 to 90:10 eluate, a yellow oil (22.3 mg) was obtained. ). This was crystallized from chloroform-n-hexane to give the title compound (15.
1 mg) were obtained as pale pink crystals. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 4.42-5.00
(1H, m), 5.00-5.10 (1H, m), 7.14 (2H, s), 7.19-7.79 (12
H, m)

Example 89 (27th step) 2,9-dimethyl-4-phenyl-6- [4- (1H-
Tetrazol-5-yl) benzyl] -6H-5,6,
7,8,9a-pentaazathieno [2,3-e] azulene

Embedded image 6- (4-cyanobenzyl)-obtained in Example 32
2,9-dimethyl-4-phenyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene (2
43 mg), sodium azide (116 mg), ammonium chloride (9
7 mg) in N, N-dimethylformamide (2.4 ml).
And heated at 150 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 ml).
The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and then crystallized by adding ethyl acetate to give the title compound (2
42 mg) were obtained as yellow crystals. 264-265 ℃ (decomposition)

Examples 90 and 91 (28th step) 2,9-dimethyl-4-phenyl-6- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -6
H-5,6,7,8,9a-pentaazathieno [2,3
-E] Azulene (Example 90)

Embedded image And 2,9-dimethyl-4-phenyl-6- [4- (2
-Methyl-2H-tetrazol-5-yl) benzyl]
-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene (Example 91)

Embedded image 2,9-dimethyl-4-phenyl-6- [4- (1H-tetrazol-5-yl) benzyl] -6H-5,6,7,8,9a-pentaazathieno [2, obtained in Example 89 3-e] Azulene (183mg) in tetrahydrofuran
(5 ml) and a mixed solvent of methanol (1 ml) and cooled on ice. To this was added a diethyl ether solution of diazomethane until the reaction solution turned yellow. The reaction solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography (elution solvent: chloroform: acetone = 10: 1). The low polar fraction was collected and concentrated, and the obtained residue was crystallized from a mixed solvent of diethyl ether-ethyl acetate to give
2,9-dimethyl-4-phenyl-6- [4- (1-methyl-1H-tetrazol-5-yl) benzyl] -6
H-5,6,7,8,9a-pentaazathieno [2,3
-E] Azulene (123 mg) was obtained as pale yellow crystals. Melting point 199.5-200.5 ℃

Next, the highly polar fraction was collected and concentrated, and the obtained residue was crystallized from a mixed solvent of diethyl ether-ethyl acetate to give 2,9-dimethyl-4-phenyl-6- [4- (2-Methyl-2H-tetrazol-5-yl) benzyl] -6H-5,6,7,8,9a
-Pentazaazathieno [2,3-e] azulene (17 mg) was obtained as yellow crystals. 180-182 ° C

Example 92 (29th step) 6- (4-Chlorophenyl) -4- [4- (2-dimethylaminoethoxy) benzyl] -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 6- (4-chlorophenyl) -4- (4-hydroxybenzyl) -1-methyl- described in Example 167 described below.
4H-2,3,4,5,10b-pentaazabenzo [e] azulene (350 mg) and triphenylphosphine (24
3 mg) was dissolved in tetrahydrofuran (7 ml), and a solution of diisopropylazodicarboxylate (182 μl) in tetrahydrofuran (500 μl) was added dropwise. Then, N, N-dimethylaminoethanol (85 μl) in tetrahydrofuran (500
μl) and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography, and chloroform: methanol = 40: 1 to 1 was used.
From the 0: 1 eluate, the title compound (188 mg) was obtained as an amorphous solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.32 (6H, s), 2.60 (3H,
s), 2.71 (2H, t, J = 6.0Hz), 4.05 (2H, t, J = 6.0Hz), 4.70-
5.20 (2H, m), 6.86 (2H, d, J = 8.4Hz), 7.10-7.70 (10H, m)

Example 93 (30th step) 6- (4-chlorophenyl) -4- (4-dimethylaminomethylideneaminobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene hydrochloride

Embedded image Anhydrous N, N-dimethylformamide (22 μl) was charged into a reaction vessel under a nitrogen atmosphere, and anhydrous tetrahydrofuran (2.
0 ml) and cooled on ice. Thionyl chloride is added to this solution.
(24 μl), and the mixture was stirred at room temperature for 1 hour. This was followed by 4- (4-aminobenzyl) described in Example 170 below.
-6- (4-chlorophenyl) -1-methyl-4H-
A solution of 2,3,4,5,10b-pentaazabenzo [e] azulene (83 mg) in tetrahydrofuran (3.0 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (74 mg). 64 mg of this was dissolved in ethyl acetate (10 ml) and 4N
A few drops of a hydrogen chloride-ethyl acetate solution (0.10 ml) and methanol were added, and the mixture was stirred at 80 ° C for 1 hour. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (37 mg) as crystals. ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.56 (3H, s), 3.26 (3H,
s), 3.32 (3H, s), 4.75-4.85 (1H, m), 4.95-5.50 (1H, m),
7.20 (1H, d, J = 7.8Hz), 7.35-7.55 (8H, m), 7.70-7.75 (2H,
m), 8.69 (1H, d, J = 12.9Hz), 11.41 (1H, d, J = 12.9Hz)

Example 94 (Step 31) 6- (4-Chlorophenyl) -1-methyl-4- [4-
(2-oxooxazolidin-3-yl) benzyl]-
4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H described in Example 170 below.
-2,3,4,5,10b-pentaazabenzo [e] azulene (207 mg) was suspended in tetrahydrofuran (3 ml),
Potassium carbonate (138mg) and 2-chloroethyl chloroformate
(62 μl) in dichloromethane (1 ml) was added and
Stirred for 0 minutes. Chloroform (30 ml) was added to the reaction solution,
The organic layer was washed twice with water (10 ml) and saturated aqueous sodium chloride solution (1
0 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a residue (311 mg).
Was obtained as a colorless oil. Of these, 211 mg was dissolved in N, N-dimethylformamide (15 ml) and potassium iodide was dissolved.
(66 mg) and sodium hydride (60% oily, 32 mg) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated by azeotropic distillation with toluene, and the obtained residue was subjected to silica gel column chromatography. The residue obtained from the ethyl acetate eluate was crystallized from ethyl acetate to give the title compound (114 m
l) was obtained as crystals. Melting point 242.5 ~ 244.0 ℃

Example 95 (Step 32) 1- [4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene-4 -Ylmethyl] phenyl] pyrrole-2,5-dione

Embedded image 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H described in Example 170 below.
2,2,3,4,5,10b-Pentazabenzo [e] azulene (120 mg) and maleic anhydride (31.2 mg) were dissolved in chloroform (2.4 ml), and the mixture was stirred at room temperature under an argon atmosphere for 4 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in acetic anhydride (2.4 ml), sodium acetate (119 mg) was added, and the mixture was stirred at 100 ° C for 15 minutes under an argon atmosphere. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The drying agent is filtered off, and the residue obtained by concentrating the filtrate under reduced pressure is subjected to preparative thin-layer chromatography (developing solvent; chloroform: methanol = 9: 1).
Then, the residue was crystallized from chloroform-n-hexane to give the title compound (20.1 mg) as pale-yellow crystals. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.62 (3H, s), 4.95 (1H, d,
J = 13.8Hz), 5.18 (1H, d, J = 13.8Hz), 6.85 (2H, s), 7.15-
7.70 (12H, m)

Examples 96 to 97 (32nd step) The compounds of Examples 96 to 97 were obtained in the same manner as in Example 95. These are shown in Table 17. Example 96 1- [4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] phenyl] pyrrolidine-2 , 5-dione ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 2.89 (4H,
s), 4.95 (1H, d, J = 13.5Hz), 5.19 (1H, d, J = 13.5Hz), 7.15
-7.40 (9H, m), 7.50 (2H, d, J = 8.4Hz), 7.64 (1H, t, J = 8.4H
z) Example 97 2- [4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] phenyl] iso Indole-1,3-dione ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 4.98 (1H, d,
J = 12.8Hz), 5.21 (1H, d, J = 12.8Hz), 7.20-7.48 (9H, m),
7.53 (2H, d, J = 8.4Hz), 7.65 (1H, t, J = 8.4Hz), 7.73-7.84
(2H, m), 7.90-8.00 (2H, m)

[0248]

[Table 17]

Example 98 (Step 33) 6- (4-Chlorophenyl) -1-methyl-4- [4-
(Pyrrole-1-yl) benzyl] -4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H described in Example 170 below.
2,2-Dimethoxytetrahydrofuran (32 mg) was added to a solution of 2,3,4,5,10b-pentaazabenzo [e] azulene (100 mg) in acetic acid (20 ml), and the mixture was added at room temperature for 3 hours.
The mixture was stirred at 00 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from chloroform-diethyl ether to give the title compound (75 mg) as crystals. 219.5-220.5 ° C

Example 99 (Step 34) 6- (4-Chlorophenyl) -4- [4- (1-mercaptoimidazol-2-yl) benzyl] -1-methyl-4H-2,3,4,5 , 10b-Pentazaazabenzo [e] azulene

Embedded image N, of 1,1-thiocarbonyldiimidazole (106 mg) and aminoacetaldehyde dimethyl acetal (63 mg)
The N-dimethylformamide (2 ml) solution was stirred under ice cooling for 1 hour and at room temperature overnight. This was combined with 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10 described in Example 170 below.
N, N of b-pentaazabenzo [e] azulene (225 mg)
-Dimethylformamide (1 ml) solution at room temperature for 15 minutes.
The mixture was stirred at 60 ° C. for 3 minutes. The reaction solution was allowed to cool, and water (1
ml), adjusted to pH 3 with sulfuric acid, and heated to 100 ° C.
For 3 hours. The reaction was allowed to cool and extracted with chloroform. Wash the organic layer with saturated aqueous sodium chloride,
Dry over anhydrous magnesium sulfate. The desiccant is filtered off,
The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography. The residue obtained from the chloroform: methanol = 19: 1 eluate was crystallized from chloroform-diethyl ether to give the title compound (1).
25 mg) were obtained as crystals. ^{1 H NMR (300MHz, δppm,} DMSO-d 6) 2.53 (3H, s), 4.80-5.1
0 (2H, m), 7.01-7.03 (1H, m), 7.21-7.24 (2H, m), 7.43-7.
49 (7H, m), 7.57-7.60 (2H, m), 7.70-7.73 (2H, m), 12.33
(1H, br s)

Example 100 (35th step) 6- (4-Chlorophenyl) -4- [4- (imidazol-1-yl) benzyl] -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 6- (4-chlorophenyl) -4 obtained in Example 99
-[4- (1-Mercaptoimidazol-2-yl) benzyl] -1-methyl-4H-2,3,4,5,10b
-Dissolve pentaazabenzo [e] azulene (150 mg) in ethanol (3 ml), add a small amount of Raney nickel,
The mixture was heated to reflux for 7.5 hours. The reaction solution was filtered through celite,
The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography. The residue obtained from the chloroform: methanol = 19: 1 eluate was crystallized from chloroform-diethyl ether to give the title compound (8
0 mg) were obtained as crystals. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.62 (3H, s), 4.80-5.26
(2H, m), 7.19-7.84 (15H, m)

Example 101 (Step 36) 3- [6- (4-Chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] -pyridine-1-oxide

Embedded image 6- (4-chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) described in Example 180 described later.
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (20.06 g) was added to anhydrous dichloromethane (300 ml).
Under ice cooling, and m-chloroperbenzoic acid (9.07 g) was added thereto, followed by stirring at room temperature for 1 hour. After cooling the reaction solution on ice,
m-Chloroperbenzoic acid was further added twice (1.5 g and 0.8 g) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure,
The obtained residue was extracted with ethyl acetate. The organic layer was sequentially washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography. Chloroform: methanol = 50: 1
The residue obtained from the 20: 1 eluate was ethanol (50 ml)
The title compound (7.94 g) was obtained by crystallization by adding diethyl ether (50 ml) gradually in two portions.
Was obtained as colorless needles. 239-240 ° C

Embodiments 102 to 105 (Thirty-Sixth Step) Embodiments 102 to 10 were carried out in the same manner as in Embodiment 101.
Compound 3 was obtained. These are shown in Table 18. Example 102 3- [8-chloro-6- (2-chlorophenyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] -pyridine-1
-Oxide Melting point 196-197 ° C (crystallization solvent: ethyl acetate-diethyl ether) Example 103 4- [2,9-dimethyl-4-phenyl-6H-5,
6,7,8,9a-pentaazathieno [2,3-e] azulen-6-ylmethyl] -pyridin- ¹ -oxide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.50 (3H, s), 2.63 (3H,
s), 6.47 (1H, s), 7.32-7.44 (7H, m), 8.20 (2H, d, J = 4.8H
z) Example 104 4- [4- (4-chlorophenyl) -2-ethyl-9-
Methyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulen-6-ylmethyl] -pyridin-1-oxide Melting point 147-150 ° C (crystallization solvent: ethyl acetate-diethyl ether) Example 105 4- [4- (4-Chlorophenyl) -2,3,9-trimethyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulen-6-ylmethyl] -pyridine -1-oxide Melting point 159-162 ° C (crystallization solvent: ethyl acetate-diethyl ether)

[0254]

[Table 18]

Example 106 (Step 37) [6- (4-Chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] ethanal

Embedded image 6- (4-Chlorophenyl) -4 obtained in Example 18
-(2,2-dimethoxyethyl) -1-methyl-4H-
To 2,3,4,5,10b-pentaazabenzo [e] azulene (2.76 g) was added a 50% aqueous trifluoroacetic acid solution (30 ml), and the mixture was stirred at room temperature for 6 hours. Trifluoroacetic acid (15ml)
Was added and stirred at room temperature overnight. Water was added to the reaction solution, and extracted with chloroform. The organic layer was sequentially washed twice with water and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography,
The title compound (1.1 g) was obtained as an amorphous solid from a chloroform: methanol = 25: 1 eluate. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.63 (3H, s), 4.40-4.70
(2H, m), 7.20-7.60 (7H, m), 7.60-7.80 (1H, m), 9.95 (1H, m
s)

Example 107 (Step 38) 6- (4-Chlorophenyl) -4- [2- (N-methoxyimino) ethyl] -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Embedded image [6- (4-Chlorophenyl) obtained in Example 106
-1-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] ethanal (250
mg) in pyridine (5 ml) and methoxylamine hydrochloride
(89 mg) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography.From the ethyl acetate eluate, the title compound (100 mg)
Was obtained as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 3.89 (1.5H,
s), 3.94 (1.5H, s), 4.50-4.90 (2H, m), 6.90-7.10 (0.5H,
m), 7.20-7.70 (8.5H, m)

Examples 108 to 109 (Step 39) [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo] described in Example 210 described later. e] Azulen-4-yl] acetic acid,
Example 108 to Example 109 in the same manner as Example 67.
Was obtained. These are shown in Table 19. Example 108 [6- (4-chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] -N-methoxy-N-methylacetamide ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 3.22 (3H,
s), 3.79 (3H, s), 4.70-5.10 (2H, br s), 7.25-7.62 (8H,
m) Example 109 [6- (4-chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetamide ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.53 (3H, s), 4.10-4.5
0 (2H, m), 7.00-7.20 (1H, m), 7.22 (1H, d, J = 7.2Hz), 7.30
-7.60 (6H, m), 7.65-7.80 (2H, m)

[0258]

[Table 19]

Example 110 (40th step) 6- (4-chlorophenyl) -1-methyl-4- (2-
Oxopropyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image [6- (4-Chlorophenyl) obtained in Example 108
-1-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] -N-methoxy-N-methylacetamide (1.6 g) is dissolved in anhydrous tetrahydrofuran (20 ml). After cooling to -78 ° C, methylmagnesium bromide (12.7 ml) was added, and the mixture was stirred under ice cooling for 1.5 hours. 1N hydrochloric acid (15 ml) was added dropwise to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was sequentially washed twice with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and the chloroform: methanol = 50: 1 eluate was used to elute the title compound.
(956 mg) was obtained as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.22 (3H, s), 2.61 (3H,
s), 4.50-4.90 (2H, m), 7.20-7.50 (7H, m), 7.60-7.70 (1
H, m)

Example 111 (Step 41) 6- (4-Chlorophenyl) -4- [2- (N-methoxyimino) propyl] -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl)-obtained in Example 110
1-methyl-4- (2-oxopropyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene
(190 mg) was dissolved in pyridine (5 ml), methoxylamine hydrochloride (52 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and chloroform was added to the obtained residue. This was sequentially washed twice with a saturated aqueous solution of sodium hydrogen carbonate and water, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain the title compound (135 mg) as an amorphous solid from an ethyl acetate eluate. ¹ H NMR (300 MHz, δppm, CDCl ₃ ) 1.81 (3H, s), 2.61 (3H,
s), 3.87 (1.5H, s), 3.91 (1.5H, s), 4.50-5.10 (2H, m),
7.20-7.70 (8H, m)

Example 112 (Step 42) 2- [6- (4-Chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethylcarbonyl] hydrazinocarbaldehyde

Embedded image [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetic acid (300 m) described in Example 210 described later.
g), in the same manner as in Example 67, the title compound (313 mg)
Was obtained as an amorphous solid. However, formic hydrazide (54 mg) was used instead of methylamine hydrochloride and triethylamine. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 4.40-4.80
(2H, m), 7.10-7.80 (8H, m), 8.07 (1H, s), 8.90-9.20 (1H,
m), 9.30-9.60 (1H, m)

Example 113 (Step 43) 6- (4-Chlorophenyl) -1-methyl-4- (1,
3,4-oxadiazol-2-ylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 2- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethylcarbonyl] hydrazino obtained in Example 112 Carboxaldehyde (313 mg) was dissolved in acetonitrile (5 ml), phosphorus oxychloride (570 μl) was added, and the mixture was heated under reflux for 1.5 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was sequentially washed twice with a saturated aqueous solution of sodium hydrogen carbonate and twice with water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to obtain the title compound (75 mg) as an amorphous solid from a chloroform: methanol = 25: 1 eluate. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.63 (3H, s), 5.20-5.45
(2H, m), 7.20-7.50 (7H, m), 7.60-7.75 (1H, m), 8.41 (1H,
s)

Example 114 (Step 44) 4- [6- (4-Chlorophenyl) -1-methyl-4H
-2,3,5,10b-Tetraazabenzo [e] azulen-4-yl] -N- (2-hydroxyethyl) acetamide

Embedded image 4- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,5,10b-Tetraazabenzo [e] azulen-4-yl] acetic acid (from 350 mg). In the same manner as in Example 67, the title compound (290 mg) was obtained as colorless crystals. However, 2-aminoethanol (69.9 mg) was used instead of methylamine hydrochloride and triethylamine. In addition, ethanol-n-hexane was used as a crystallization solvent. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.65 (3H, s), 3.38-3.60
(4H, m), 3.70-3.80 (2H, m), 4.67 (1H, t, J = 5.3Hz), 7.20-
7.45 (7H, m), 7.70 (1H, dt, J = 6.0,1.2Hz)

Example 115 (Step 45) 6- (4-Chlorophenyl) -4- (4,5-dihydrooxazol-2-ylmethyl) -1-methyl-4H-
2,3,5,10b-tetraazabenzo [e] azulene

Embedded image 6- (4-Chlorophenyl)-obtained in Example 114
1-methyl-4H-2,3,5,10b-tetraazabenzo [e] azulen-4-yl] -N- (2-hydroxyethyl) acetamide (250 mg), methanesulfonyl chloride (140 mg) and triethylamine (0.43 ml) was dissolved in chloroform (10 ml), and the mixture was stirred at room temperature for 2 hours under an argon atmosphere, and heated under reflux for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform.
The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-n-hexane to give the title compound (191 mg) as colorless crystals. Melting point 208 ~ 209 ℃

Example 116 (Step 46) 6- (4-Chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethylcarbonylaminoglycinamide

Embedded image [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetic acid described in Example 210 described below (500 m
g) and glycinamide hydrochloride (165 mg) from Example 67
In the same manner as in the above, the title compound (494 mg) was obtained. ^{1 H NMR (300MHz, δppm,} DMSO-d 6) 2.53 (3H, s), 3.50-3.8
0 (2H, m), 4.10-4.70 (2H, m), 7.00-8.20 (11H, m)

Example 117 (Step 47) 2- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-ylmethyl] imidazol-4-one

Embedded image 6- (4-Chlorophenyl)-obtained in Example 116
1-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] -N- (2-hydroxyethyl) acetamide (253 mg) was dissolved in pyridine (5 ml), Phosphorus oxychloride (70 μl) was added, and the mixture was stirred at 80 ° C. for 15 minutes. The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography. From a chloroform: methanol = 20: 1 eluate,
The title compound (75 mg) was obtained as an amorphous solid. ^{1 H NMR (300MHz, δppm,} DMSO-d 6) 2.54 (3H, s), 4.17 (2H,
d, J = 5.4Hz), 4.20-4.60 (2H, m), 7.10-7.80 (8H, m), 8.74
(1H, t, J = 5.4Hz)

Example 118 (48th step) 3- [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] diazopropan-2-one

Embedded image [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetic acid (4.0 g) described in Example 210 described later.
Was suspended in tetrahydrofuran (80 ml), cooled to -5 ° C, triethylamine (2.3 ml) and isobutyl chloroformate (1.55 ml) were added, and the mixture was stirred at -5 ° C for 30 minutes. Next, a large excess of diazomethane-diethyl ether solution was added thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure,
Chloroform and water were added to the obtained residue to carry out liquid separation.
The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give the title compound (3.81 g) as an amorphous solid from a chloroform: methanol = 10: 1 eluate. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.61 (3H, s), 4.40-4.90
(2H, m), 5.30-5.60 (1H, m), 7.20-7.80 (8H, m)

Example 119 (50th step) 1-chloro-3- [6- (4-chlorophenyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] propan-2-one

Embedded image 3- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] diazopropane-2 obtained in Example 118 -One (1.03 g) was dissolved in chloroform (20 ml), and 4N hydrogen chloride-1,4-dioxane solution (1.3 ml) was added under ice cooling.
Was added dropwise and stirred at room temperature for 2 hours. Add water to the reaction solution,
Extracted with chloroform. The organic layer was washed successively twice with water and a saturated aqueous solution of sodium hydrogen carbonate and then with water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give the title compound (753 mg) as an amorphous solid from a chloroform: methanol = 10: 1 eluate. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.61 (3H, s), 4.27 (2H,
s), 4.60-5.20 (2H, m), 7.20-7.80 (8H, m)

Example 120 (51st step) 4- (2-aminothiazol-4-ylmethyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene

Embedded image The 1-chloro-3- [6- (4-
(Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-Pentazabenzo [e] azulen-4-yl] propan-2-one (753 mg) was dissolved in ethanol (20 ml), thiourea (286 mg) was added, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted twice with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography. The chloroform: methanol = 10: 1 eluate was used to elute the title compound.
(450 mg) was obtained as an amorphous solid. ¹ H NMR (300 MHz, δp
pm, DMSO-d ₆ ) 2.53 (3H, s), 4.40-4.90 (2H, m), 6.29 (1H,
s), 6.85 (2H, s), 7.23 (1H, d, J = 7.8Hz), 7.40-7.80 (7H,
m)

Example 121 (Step 52) 4- (2-acetamidothiazol-4-ylmethyl)
-6- (4-chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- (2-aminothiazole- obtained in Example 120
4-ylmethyl) -6- (4-chlorophenyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (250 mg) was dissolved in chloroform (10 ml), and triethylamine (164 μl) and acetyl chloride (6 ml) were dissolved.
3 μl) and heated to reflux for 30 minutes and 1.5 hours at room temperature. The reaction solution was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography to obtain the title compound (90 mg) from a chloroform: methanol = 10: 1 eluate. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.19 (3H, s), 2.60 (3H,
s), 4.80-5.40 (2H, m), 6.84 (1H, s), 7.10-7.70 (8H, m),
9.91 (1H, s)

Examples 122 to 282 The compounds of Examples 122 to 282 were obtained in the same manner as in the method described in JP-A-8-225546. These are shown in Tables 20 to 35.

[Table 20]

[0272]

[Table 21]

Example 138 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 5.03 (1H,
m), 5.11 (1H, m), 7.24-7.43 (7H, m), 7.54 (2H, d, J = 8.8H
z), 7.68 (1H, m), 8.17 (2H, d, J = 8.8 Hz) Example 139 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 5.15 (1H,
m), 5.28 (1H, m), 7.20-7.47 (6H, m), 7.68 (1H, m), 8.63
(1H, d, J = 2.2Hz), 8.95 (1H, t, J = 2.2Hz)

[0274]

[Table 22]

[0275]

[Table 23]

[0276]

[Table 24]

Example 166 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 4.81-4.85
(1H, m), 5.02-5.05 (1H, m), 5.06 (2H, s), 5.13 (2H, s),
6.72-7.00 (3H, m), 7.17-7.44 (17H, m), 7.60-7.66 (1H, m) Example ^{168 1 H NMR (300MHz, δppm} , CDCl 3) 2.60 (3H, s), 4.56-4.60
(1H, m), 4.81-4.85 (1H, m), 6.59-6.66 (2H, m), 6.74-6.7
5 (1H, m), 7.18-7.20 (1H, d, J = 7.4Hz), 7.42-7.51 (5H, m),
7.68-7.75 (2H, m) Example 169 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.40 (3 H, t, J = 7.2 Hz), 2.
60 (3H, s), 4.02 (2H, q, J = 7.2Hz), 4.88-5.03 (2H, m), 6.8
3 (2H, d, J = 9.0Hz), 7.18-7.64 (10H, m)

[0278]

[Table 25]

[0279]

[Table 26]

Example 185 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 4.92 (1H,
m), 5.09 (1H, m), 7.26-7.47 (9H, m), 7.70 (1H, dt, J = 7.8,
1.6Hz)

[0281]

[Table 27]

Example 198 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 4.65 (2H,
s), 5.38 (1H, m), 5.49 (1H, m), 7.18-7.41 (10H, m), 7.52
(2H, d, J = 8.6Hz), 7.63 (1H, dt, J = 7.6,1.4Hz)

[0283]

[Table 28]

Example 208 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 4.54 (2H, d,
J = 6.6Hz), 6.27 (1H, t, J = 6.6Hz), 7.25-7.41 (5H, m), 7.4
7-7.52 (2H, m), 7.60-7.67 (1H, m)

[0285]

[Table 29]

Example 221 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.70 (3H, s), 4.23-4.42
(2H, m), 7.36-7.52 (5H, m), 7.62-7.65 (2H, m), 7.72-7.7
8 (1H, m)

[0287]

[Table 30]

Example 223 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.68 (3H, s), 4.25-4.40
(2H, m), 6.16-6.20 (1H, m), 6.28-6.37 (2H, m), 6.97-7.0
5 (1H, m), 7.32-7.47 (5H, m), 7.61-7.70 (3H, m) Example ^{224 1 H NMR (300MHz, δppm} , CDCl 3) 2.19 (3H, s), 2.67 (3H,
s), 4.25-4.39 (2H, m), 6.42 (2H, d, J = 8.2Hz), 6.71 (1H, m
s), 6.87 (2H, d, J = 8.2Hz), 7.31-7.44 (5H, m), 7.61-7.66
(3H, m) Example 225 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.67 (3H, s), 3.82 (3H,
s), 4.35 (2H, m), 6.37 (1H, m), 6.60-6.72 (3H, m), 7.29-
7.43 (6H, m), 7.61-7.64 (3H, m) Example ^{226 1 H NMR (300MHz, δppm} , CDCl 3) 2.67 (3H, s), 3.63 (3H,
s), 3.77 (3H, s), 4.31 (2H, m), 5.98 (1H, m), 6.07-6.11
(1H, m), 6.60-6.62 (1H, d, J = 6.0Hz), 7.31-7.43 (6H, m),
7.60-7.64 (3H, m) Example 227 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.69 (3H, s), 3.96-4.12
(2H, m), 7.03-7.76 ( 13m) Example ^{232 1 H NMR (300MHz, δppm} , CDCl 3) 2.61 (3H, s), 4.08 (2H,
m), 5.34 (1H, m), 7.27-7.72 (13H, m)

[0289]

[Table 31]

Example 233 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 5.40 (2H,
s), 7.28-7.67 (11H, m), 8.03-8.07 (2H, m) Example 237 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 3.77 (3H, m)
s), 3.89 (3H, s), 5.34 (2H, br s), 6.88 (1H, d, J = 6.0Hz),
7.04 (1H, dd, J = 3.0,9.0Hz), 7.23-7.47 (8H, m), 7.59-7.
65 (1H, m) Example ^{238 1 H NMR (300MHz, δppm} , CDCl 3) 2.59 (3H, s), 2.73-2.88
(2H, m), 3.81-3.98 (2H, m), 4.44-4.61 (1H, m), 7.22-7.4
Example 239 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 0.96-1.66 (7 H, m), 2.57
(3H, s), 2.88-3.47 (3H, m), 3.95-4.78 (4H, m), 7.13-7.6
5 (13H, m) Example ^{240 1 H NMR (300MHz, δppm} , CDCl 3) 1.10-1.71 (5H, m), 2.57
(3H, s), 3.20 (1H, m), 3.54 (1H, m), 3.74-3.83 (4H, m),
4.04-4.08 (2H, m), 4.52-4.59 (1H, m), 5.42 (1H, m), 6.80
-7.59 (12H, m) Example 242 ¹ H NMR (300 MHz, δppm, CDCl ₃ ) 2.60 (3H, s), 3.74 (2H,
s), 3.83 (3H, s), 3.85 (2H, s), 6.71-6.80 (3H, m), 7.25-
7.41 (7H, m), 7.60-7.66 (1H, m)

[0291]

[Table 32]

Example 243 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 3.72-3.74
(8H, m), 4.78 (2H, s), 6.71-6.77 (3H, m), 7.24-7.64 (8H, m
m) Example 245 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.36 (3H, s), 2.62 (3H,
s), 5.07 (2H, m ), 7.16 (2H, d, J = 9Hz), 7.25-7.68 (10H, m) Example ^{248 1 H NMR (300MHz, δppm} , CDCl 3) 2.60 (3H, s), 4.98 (1H,
m), 5.11 (1H, m), 7.21 (1H, d, J = 2.4Hz), 7.25-7.31 (2H,
m), 7.35-7.38 (3H, m), 7.42-7.48 (1H, m), 7.59 (1H, dd, J
= 8.7, 2.4Hz), 7.74 (1H, dt, J = 8.0, 1.8Hz), 8.53 (1H, d
Example 249 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3 H, s), 4.98 ( ¹ H, d, J = 4.8, 1.6 Hz), 8.67 (1 H, d, J = 1.8 Hz)
m), 5.12 (1H, m), 7.26-7.47 (9H, m), 7.62 (1H, dd, J = 8.8,
2.4Hz), 8.55 (1H, m ), 8.56 (1H, m) Example ^{250 1 H NMR (300MHz, δppm} , CDCl 3) 2.57 (3H, s), 5.12 (1H,
m), 5.28 (1H, m), 7.22 (1H, d, J = 2.0Hz), 7.38-7.54 (5H,
m), 7.80-7.89 (2H, m), 7.94 (2H, d, J = 6.5Hz), 8.82 (2H, m
d, J = 5.6Hz)

Example 251 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.27 (3H, s), 2.55 (3H,
s), 5.15 (1H, m), 5.30 (1H, m), 7.10 (2H, d, J = 8.0Hz), 7.
21 (1H, d, J = 2.5Hz), 7.38-7.52 (7H, m), 7.79-7.88 (2H,
m), 7.95 (2H, d , J = 6.5Hz), 8.82 (2H, d, J = 6.5Hz) Example ^{254 1 H NMR (300MHz, δppm} , CDCl 3) 2.61 (3H, s), 4.98 (1H ,
m), 5.15 (1H, m), 7.27-7.46 (9H, m), 7.63 (1H, dd, J = 8.9,
4.0Hz), 8.55 (2H, dd, J = 4.5, 2.0Hz)

[0294]

[Table 33]

Example 262 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.47 (3 H, d, J = 1.1 Hz), 2.
61 (3H, s), 3.81 (3H, s), 4.97 (2H, s), 6.42 (1H, q, J = 1.1H
z), 6.85-6.90 (2H, m ), 7.32-7.49 (7H, m) Example ^{263 1 H NMR (300MHz, δppm} , CDCl 3) 2.48 (3H, d, J = 1.5Hz), 2.
63 (3H, s), 5.05 (2H, s), 6.43 (1H, q, J = 1.5Hz), 7.25-7.4
5 (6H, m), 7.79 (1H, dt, J = 7.5,2.0Hz), 8.53 (1H, dd, J = 5.
0, 2.0Hz), 8.72 (1H, d, J = 2.0Hz)

[0296]

[Table 34]

[0297]

[Table 35]

Example 282 ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 3.79 (3H, s), 4.92 (2H,
s), 6.83-6.87 (2H, m), 6.97 (1H, d, J = 1.8Hz), 7.06-7.41
(9H, m), 7.51-7.57 (1H, m)

Examples 283 to 298 The compounds of Examples 283 to 298 were obtained in the same manner as in the method described in International Publication WO 93/07129. These are shown in Tables 36 to 37.

[Table 36]

[0300]

[Table 37]

Example 299 (Step 44) 4- [6- (4-Chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulen-4-yl] -N- (2-hydroxyethyl) acetamide

Embedded image 4- [6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetic acid described in Example 210 (1.06 g)
) And ethanolamine (209 µl) to give the title compound (940 mg) in the same manner as in Example 67. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.61 (3H, s), 3.20-3.80
(5H, m), 4.54 (2H, s), 7.10-7.80 (9H, m)

Example 300 (Step 45) 6- (4-Chlorophenyl) -4- (4,5-dihydrooxazol-2-ylmethyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Embedded image 4- [6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] -N- (obtained in Example 299 2
From -hydroxyethyl) acetamide (250 mg), the title compound (189 mg) was obtained in the same manner as in Example 115. However, purification was performed using silica gel column chromatography (elution solvent; chloroform: methanol = 10: 1). ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.59 (3H, s), 3.88 (2H, t,
J = 9.4Hz), 4.28 (2H, t, J = 9.4Hz), 7.20-7.80 (8H, m)

Example 301 (ninth step) 4- [4- (4-chlorobenzyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid ethyl ester

Embedded image 4- [4- (4-chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] benzoic acid obtained in Example 44
(4.0 g), and in the same manner as in Example 47, the title compound (3.4
8g) was obtained. However, ethanol (20 ml) was used instead of tert-butyl alcohol. ^{1 H NMR (300MHz, δppm,} CDCl 3) 1.31 (3H, t, J = 7.2Hz), 2.
61 (2H, s), 4,23 (2H, q, J = 7.2Hz), 4.87-5.10 (2H, m), 6.8
3 (1H, s), 7.24-7.39 (11H, m), 7.60-7.65 (1H, m)

Example 302 (52nd step) 4- (4-Chlorobenzyl) -1-methyl-6- (4-
Methylaminophenyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Embedded image 4- [4- (4-chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulen-6-yl] phenylcarbamic acid obtained in Example 301 A solution of ethyl ester (1.50 g) in tetrahydrofuran (15 ml) was added under ice-cooling to lithium aluminum hydride.
(140 mg) was added dropwise over 5 minutes to a suspension of tetrahydrofuran, followed by stirring at room temperature for 3 hours. The reaction solution was cooled on ice, and water (0.1
4 ml) and a mixture of tetrahydrofuran (3 ml), and then a 4N aqueous sodium hydroxide solution (0.14 ml), water (0.42 ml)
Were sequentially added. After stirring at room temperature for 20 minutes, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform, washed with a saturated aqueous sodium chloride solution (20 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography. From the eluate of chloroform: methanol = 98: 2 to 97: 3, the title compound (874m
g) was obtained as a pale yellow amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 2.85 (3H,
s), 4,01 (1H, br s), 4.86-5.06 (2H, m), 6.50 (2H, d, J = 8.
7Hz), 7.21-7.36 (9H, m), 7.58-7.63 (1H, m)

Example 303 (53rd step) 3- [4- [4- (4-Chlorobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene- 6-yl] phenyl] -1,1,3-
Trimethylurea

Embedded image 4- (4-chlorobenzyl)-obtained in Example 302
1-methyl-6- (4-methylaminophenyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
To a solution of azulene (824 mg) and triethylamine (583 mg) in tetrahydrofuran (10 ml) was added triphosgene (228
mg) and stirred at room temperature for 1 hour. After ice cooling again,
2M dimethylamine-tetrahydrofuran solution (4.80 ml)
Was added and stirred at room temperature for 1 hour. 0.3N hydrochloric acid
(50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution (30 ml) and a saturated aqueous sodium chloride solution (30 ml), and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography. From the eluate of ethyl acetate: methanol = 96: 4 to chloroform: methanol = 95: 5, the title compound (292) was obtained.
mg) was obtained as a pale yellow amorphous solid. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.61 (3H, s), 2.72 (6H,
s), 3.22 (3H, s), 4.88-5.10 (2H, m), 6.97 (2H, d, J = 7.2H
z), 7.25-7.42 (9H, m), 7.61-7.67 (1H, m)

Test Example Next, the biological activity of the compound of the present invention was tested. Test Example 1 Inhibition of Fas Ligand Production of Human T Cell Line (HPB-ALL) HPB-ALL was established from a human leukemia patient by CD
4 positive, constitutive and functional Fas positive human T cell line. HPB-ALL is a Fas ligand-like CH-11 antibody [Yonehara et al., Journal of Experimental
Medicine, 169, 1747-1756 (198
9 years) The addition of [J. Exp. Med., 169 , 1747-1756 (1989)] causes apoptotic cell death. When PMA (4-α-Phorbol-12-myristate-13-acetate) and ionomycin are simultaneously added to these cells, remarkable production of Fas ligand and apoptosis are caused. Detection of human Fas ligand HPB-ALL cells were transformed with 10% FCS (fetal bovine serum) /
The cells were cultured in RPMI1640 medium. Thereafter, the test compound was added to a final concentration of 0.01 to 10 μM, and PMA and ionomycin were added to a final concentration of 10 ng / ml and 2 μg / ml, respectively. Add metalloprotease inhibitor to final concentration
10 μM was added. After 5 hours of culture, cell surface Fas ligand was stained with a human Fas ligand-specific mouse monoclonal antibody and a fluorescently labeled anti-mouse antibody. Detection was performed using a flow cytometer (Becton Dickinson).
inson). The results are shown in Table 38 as IC ₅₀
Indicated by value.

[0307]

[Table 38]

Test Example 2 Apoptosis Inhibitory Activity of Human T Cell Line (HPB-ALL) HPB was added to a test compound at a final concentration of 0.01 to 10 μM.
-In addition to ALL, PMA and ionomycin at each final concentration
10 ng / ml and 2 μg / ml were added. After 15 hours of culture, live cells were detected. Detection of live cells Apoptosis inhibitory activity was measured using cell survival as an index.
That is, MTT [3- (4,5-Dimethylthiazol-2-yl) -2,5-diphe
NST with the same function as nyltetrazolium bromide]
-1 [4- [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-t
etrazolio] -1,3-benzenedisulfonate, Boehringer Mannheim].
The cells were cultured for 4 hours after the addition of WST-1, and detected by measuring absorbance at an absorption wavelength of 450 nm. The results are shown in Table 39 as IC ₅₀ values.

[0309]

[Table 39]

Test Example 3 Human peripheral blood mononuclear cell (PBMC; Peripheral Blood M)
onnuclear Cell) TNF-α production inhibitory activity Isolation and culture of human PBMC Ficoll-Paque [trade name, Pharmacia Biotech (P)
harmacia Biotech) was used to separate the PBMC fraction. The cells (PBMC) were cultured in 10% FCS (fetal calf serum) / RPMI1640 medium. Thereafter, the test compound was added to a final concentration of 0.01 to 10 μM, and LP was added.
S (lipopolysaccharide; lipopolysaccaride) was added to a final concentration of 10 μg / ml. The supernatant cultured for 24 hours was separated and stored frozen at -80 ° C. Measurement of TNF-α On the day of measurement, the culture supernatant was thawed, and the TNF-α content was determined by EL
Quantification was performed using ISA (Amersham). The method followed the measurement method of the ELISA kit. The results are shown in Table 40 as IC ₅₀ values.

[0311]

[Table 40]

Test Example 4 Human peripheral blood mononuclear cell (PBMC; Peripheral Blood M)
Separation and Culture of Human PBMC from Ononuclear Cell) A PBMC fraction was separated from healthy human blood collected using a heparin-containing transfusion bag using Ficoll-Paque (trade name). The cells (PBMC) were cultured in 10% FCS (fetal calf serum) / RPMI1640 medium. Thereafter, the test compound was added to a final concentration of 0.01 to 10 μM, and co
nA (concanavalin A) was added to a final concentration of 10 μg / ml. The supernatant cultured for 15 hours was separated and stored frozen at -80 ° C. Measurement of IL-2 On the day of measurement, the culture supernatant was thawed, and the IL-2 content was determined by ELI.
Quantification was performed using SA (CAYMAN). The method followed the measurement method of the ELISA kit. Table 41 shows the results.
The IC ₅₀ value is shown in FIG.

[0313]

[Table 41]

Test Example 5 Inhibitory Activity of Human PBMC on HIV-1 Proliferation PBMC isolated from peripheral blood of a healthy subject was subjected to 2 μg / ml of PH.
A (Phytohemagglutinin; Phytohemagglutinin) was stimulated. Three days later, the test compound was added to a final concentration of 0.001 to 20 μM, and HIV-1 was added to moi (mulitiplicity o).
f infection) = 0.1. After culturing for 7 days, H
The growth of IV-1 is based on the amount of HIV-1 antigen p24 in the supernatant.
It was measured and detected by gen capture ELISA (Cellular). The method followed the measurement method of the ELISA kit, and the results are shown in Table 42 as IC ₅₀ values.

[0315]

[Table 42]

Test Example 6 Inhibitory Activity of In-vivo Fas Ligand mRNA Increase by Con A Stimulation When mouse spleen cells were stimulated with con A (concanavalin A), the amount of Fas ligand mRNA in the cells increased [Journal of Immunology, 154, 3
806-3813 (1995) [J. Immunol., 154 ,
3806-3813 (1995)]. Also, when con A is intravenously administered to mice, blood levels of TNF-α, INF-γ and the like increase [Journal of Experimental Medicine, Vol. 179, pp. 1529-1537 (1994)].
Year) [J. Exp. Med., 179 , 1529-1537 (1994)]. At this time, the present inventors have found that the amount of Fas ligand mRNA in the liver and spleen increases. Mice express Fas at a high frequency on the liver cell membrane even in a normal body [Nature, 364, pp. 806 to 809 (1993) [Nat
ure, 364 , 806-809 (1993)], suggesting that the Fas-Fas ligand system may contribute to liver damage [Nature Medicine, 3, 409-41].
3 (1997) [Nature med., 3 , 409-413 (199)
7)].

A 7 week old female C57BL / 6 mouse was
The test compound suspended in 0.5% CMC-Na (sodium carboxymethylcellulose) was orally administered at a dose of 10 mg / kg. One hour later, the con prepared in saline
A was administered intravenously at a dose of 15 mg / kg. One hour later, the spleen was removed, rapidly frozen in liquid nitrogen, and stored at -80 ° C. MRNA was extracted from the spleen according to a conventional method, and mouse Fas ligand mRNA was obtained by ³² P-labeled RT-PCR.
Was amplified. For detection, after Northern blotting, ³² P counts of dots were counted using BAS2000 (Fuji Film Co., Ltd.).
This was performed using a densitometer. HPRT (hypoxanthine phosphoribosyltransferase; Hypo
Xantinephosphoribosyltransferaze) was used as a control, and compensation was performed. The inhibition rate (inhibition%) of the test compound administration group with respect to the mouse Fas ligand mRNA increase in the spleen of the 0.5% CMC-Na administration group was calculated, and the results are shown in Table 43.

[0318]

[Table 43]

Test Example 7 Inhibitory activity of mouse con A hepatitis 7 weeks old, female C57BL / 6 mice were treated with 0.5% CMC-
The test compound suspended in Na (sodium carboxymethylcellulose) was orally administered at a dose of 10 mg / kg. Immediately, con A prepared with physiological saline (concanavalin
A) was administered intravenously at a dose of 10 mg / kg. 24 hours later,
Blood was collected from the fundus and centrifuged. ALT (alanine aminotransferase; Alan)
ine aminotransferase) (GPT), 0.5%
The inhibition rate (inhibition%) of the test compound administration group with respect to the increase in blood GPT of the CMC-Na administration group was calculated, and the results are shown in Table 4.
The results are shown in FIG.

[0320]

[Table 44]

[0321]

EFFECTS OF THE INVENTION The compound represented by the above general formula [I] according to the present invention has an activity of inhibiting the production of Fas ligand, inhibiting the production of TNF-α, and inhibiting the elevation of the mRNA of Fas ligand, as is clear from the above Test Examples. It has excellent apoptosis-suppressing activity based thereon, and also has HIV proliferation-suppressing activity, hepatitis-suppressing activity and the like. Moreover, it shows only a very weak inhibitory activity on the production of IL-2 having T cell proliferation activity and apoptosis inhibitory activity. Therefore,
The compound represented by the general formula [I] according to the present invention is selected from HIV
It also has an antiviral action against the like. Therefore, these compounds are considered to be effective in preventing and treating diseases caused by excessive apoptosis, such as AIDS, hepatitis, GVHD, autoimmune diseases, and ulcerative colitis. Since the compound of the present invention has an antiviral effect,
It is expected to be a very useful antiviral drug.

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 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Masanori Baba 3-54-19, Kotokujidai, Kagoshima City, Kagoshima Prefecture

Claims (7)

[Claims] 1. An inhibitory action on Fas ligand production and TNF
An apoptosis inhibitor comprising a compound having an inhibitory action on α production, wherein the compound is a condensed ring compound of a seven-membered ring composed of triazepine or diazepine and a five-membered ring containing 2 to 4 nitrogen atoms. An apoptosis inhibitor characterized by the following. 2. A compound of the general formula [I] [Wherein, R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group; R ² represents a hydroxyl group, a lower alkoxy group, an aralkyloxy group or [Where R ³ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkynyl group, a cyano group, an acyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, -CR ⁶ ＣＲCR ⁷ R ⁸ (where R ⁶ , R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl group), —CR ⁹ ＮN—R ¹⁰ (Here, R ⁹ represents a hydrogen atom or a lower alkyl group, and R ¹⁰ represents a lower alkyl group, a hydroxyl group or a lower alkoxy group.),-(CH ₂ ) _j-
OR ¹¹ (where R ¹¹ represents a lower alkyl group or an aryl group which may be substituted, j represents 0 or an integer of 1 to 5), — (CH ₂ ) _j —CO ₂ R ¹² (here, And R
¹² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group, and j has the same meaning as described above. ), -CONR ²⁵ R ²⁶ <where R ²⁵ , R
²⁶ is the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or R ²⁵ and R ²⁶ together Become-(CH
_{2) p -Z- (CH 2)} r - { wherein, Z is an oxygen atom, N
-Ak (Ak represents the same meaning as described above) or a single bond, and p and r are the same or different and represent an integer of 1 to 3. ). Represents｝. >,-CONHNHCHO
, (Where R ¹³ and R ¹⁴ are the same or different and each represent a hydrogen atom,
Represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group, Ak represents a lower alkyl group, and R ¹² has the same meaning as described above. ) Or -X
-Y {wherein, X is _{- (CH 2) k -,} -CO-,
_{-COCH 2 -, -NH -, -} NHCH 2 -, -CH
_{2 NH-, -CH 2 NHCO-, -OCH} 2 -, -
(CH ₂ ) _k O— or —CH ₂ S— (where k represents an integer of 1 to 4), Y represents a halogen atom,
Cycloalkyl group, an amino group, a mono- or di-substituted amino group, an optionally substituted aryl group, an optionally substituted heteroaryl group or -N _2. And R ⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, R ⁵ represents a hydrogen atom or a halogen atom, or a carbon atom to which R ⁴ and R ⁵ are bonded together. Together form a carbonyl group. Or when B represents a CH group, (Where R _a and R _b are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, A heteroarylalkyl group or an acyl group, R _c and R _c ′ being the same or different and each representing a hydrogen atom, a lower alkyl group or an aralkyl group, and R _d being a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group; A cycloalkylalkyl group, an aralkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or a heteroarylalkyl group; U represents an oxygen atom or a sulfur atom;
Represents 0, 1 or 2, and m represents 0 or an integer of 1 to 6. A ring A is Wherein R ¹⁵ and R ¹⁶ are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxy group,
It may be substituted by a cyano group, a nitro group, an amino group, a mono- or di-substituted amino group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted aminocarbonyl group or an acyloxy group. ), A cycloalkyl group, an aralkyl group, an aralkyl group substituted with a lower alkyl group, a lower alkenyl group,
Lower alkynyl group, hydroxyl group, lower alkoxy group, carboxy group, cyano group, nitro group, amino group, mono- or disubstituted amino group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, mono- or disubstituted aminocarbonyl group, Represents an acyl group or an acyloxy group. Represents B; a nitrogen atom or C—R ^17, wherein R ¹⁷ is a hydrogen atom or —CO ₂ R ¹⁸ (here, R ¹⁸
Represents a hydrogen atom, a lower alkyl group, an optionally substituted aryl group or an aralkyl group. ) Or together with R ² together with the carbon atom to which they are attached (Where R ¹⁹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group,
Optionally substituted aryl group, an optionally substituted heteroaryl group or heteroarylalkyl group, R ²⁰
Represents a hydrogen atom, a lower alkyl group or an aralkyl group,
n represents 0 or 1. ). V represents a nitrogen atom or C—R ²¹ (where R ²¹ represents a hydrogen atom or a lower alkyl group); W represents a nitrogen atom or a CH group. ] Or a pharmaceutically acceptable salt thereof. 3. The apoptosis inhibitor according to claim 2, comprising a compound of the formula [I] wherein B is a nitrogen atom or a pharmaceutically acceptable salt thereof. 4. An antiviral agent comprising a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof. 5. The antiviral agent according to claim 4, wherein the virus is HIV. 6. A compound of the general formula [II] Wherein R ²¹ ′ represents a hydrogen atom or a lower alkyl group;
R ²² and R ²³ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aryl group, or R ²² and R ²³ together represent (Where Z, p, and r each have the same meaning as described above); R ² , rings A, B, V, and W each have the same meaning as described above. Or a pharmaceutically acceptable salt thereof. 7. A compound of the general formula [III] [Wherein R ³ ′ is [Wherein, R _e is a pyrrolyl group, an imidazolyl group, a pyrazolyl group, isoxazolyl group, an optionally substituted triazolyl group with a lower alkyl group, [1,3,4] oxadiazolyl group, [1,2,3] thiadiazolyl group , An imidazolinyl group, an oxazolinyl group, a 2-oxoimidazolidinyl group, a benzimidazolyl group, a phthalimide group, a maleimide group or (Wherein R ²⁵ and R ²⁶ each represent the same meaning as described above), and R _f and R _g each represent a hydrogen atom or R _f and R _g together represent a carbonyl group. , T represents an oxygen atom, a sulfur atom or an NH group. ]. Or a pharmaceutically acceptable salt thereof.