JP2003183283A - Condensed indole compound, method for producing the same and application of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a condensed indole derivative having IL-8 inhibitory activity, and to provide a pharmaceutical composition containing the same. <P>SOLUTION: This indole derivative (a salt thereof) is shown by the formula äwherein, ring A is a (substituted) benzene ring; Q is NR<SP>1</SP>(R<SP>1</SP>is H or the like) or the like; R is H or the like; and X and Y are each (1) H (except the case that X and Y are both hydrogen atoms), (2) a halogen atom, (3) OH, (4) -ZR<SP>2</SP>[Z is a binding bond, oxygen atom or the like; and R<SP>2</SP>is a (substituted) 1-6C alkyl, (substituted) 3-8C cycloalkyl or the like] or the like}. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused indole compound having an IL-8 inhibitory activity, a process for producing the same, and a use thereof.

[0002]

BACKGROUND OF THE INVENTION Chemokines are a group of endogenous basic low-molecular-weight proteins having a cell migration / activating effect on leukocytes. The existence of more than 40 kinds of chemokines has been revealed so far, and four subfamilies (CXC chemokines,
CC chemokines, C chemokines, CX3C chemokines). These chemokines are constitutively or inducibly expressed in the living body and play a very important role in both physiological function and pathological function. Its physiological functions include not only hematopoiesis and development such as angiogenesis, B lymphocyte generation, cerebellar granule cell layer formation, ventricular septal formation and lymphoid tissue formation, but also the localization of B lymphocytes to splenic follicles. Currently, it has been reported that T lymphocytes are involved in the immune response such as homing to lymph nodes and dendritic cells that have captured antigens to homing to lymph nodes. In addition, pathological functions have been shown to be involved in overall inflammatory reactions such as arteriosclerosis formation, pulmonary ischemia-reperfusion injury, inflammatory cell infiltration in virus infection, and invasion of AIDS virus into host cells. In particular, interleukin 8 (IL-8), one of the CXC chemokines, is neutrophil, macrophage, monocyte,
It has cell migration and activation effects on eosinophils and lymphocytes, and plays an important role in infiltration of inflammatory cells to the site of acute and chronic inflammation and its pathogenesis. Since IL-8 content in bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease (COPD) is increased, IL-8 is CO
It has attracted attention as a causative agent of neutrophil infiltration and activation in PD patients. On the other hand, 5H-pyrimido [5,4-
b] Indole derivatives include 1) 4-hydrazino-5H-pyrimido [5,4-b] indole and its related compounds in “Journal of Heterocyclic Chemistry”, Vol. 23, p. 647 (1986). Is described. 2) "Archief del Pharmacy" Volume 326,
On page 879 (1993), 4-amino-7,8-dimethoxy-5H-pyrimido [5,4-b] indole derivatives are described as phosphodiesterase inhibitors. 3) JP-A-6-220059 discloses a 5H-pyrimido [5,4-b] indole derivative having a substituent at the 2-position as a compound having a blood glucose lowering action. 4) "Journal of Pharmacy and Pharmacology", Vol. 47, p. 601 (1995), 4- (4'-n-butylanilino) -7,8 as a compound having a phosphodiesterase inhibitory action. -Dimethoxy-5H-pyrimido [5,4-b] indole is described. 5) JP-A-10-175977 discloses that a compound having an antibacterial activity is represented by the formula

[Chemical 8] Wherein, Y ¹ is a benzene ring which may be substituted, Y ²
Is a cyclic group which may be substituted, X is a divalent aliphatic hydrocarbon group which may be substituted, a divalent aromatic group which may be substituted, or a divalent group which may be substituted. In the alicyclic heterocyclic group of, X ¹ and X ² are each a lower alkylene having 1 or 2 atoms selected from a bond, oxygen and sulfur atom, or a lower alkylene optionally substituted with oxo. (Provided that X ¹ is a bond, X ² is a bond or methylene, and X is

[Chemical 9] When (1) Y ² is an optionally substituted phenyl, and 5H-pyrimido [5,4-b] indole is 7,
Having methoxy at both the 8-position, and (2) Y ² is 4
5H-pyrimido [5,4-b] indole derivative represented by phenyl which may have a chlorine atom or methoxy in the position and Y ¹ is an unsubstituted benzene ring). ing. 6) "Il Pharmaco" Vol. 54, p. 255 (199)
9) describes a 5H-pyrimido [5,4-b] indole derivative having a substituent at the 2-position as an HIV reverse transcriptase inhibitor. 7) "Journal of Medicinal Chemistry," Vol. 42, page 5464 (1999), contains EGF.
As a receptor tyrosine kinase inhibitor, the formula

[Chemical 10] Compounds represented by are described.

[0003]

[Problems to be Solved by the Invention] Chronic obstructive pulmonary disease (C
Chronic neutrophilic inflammation in the lung is observed in OPD patients, and it is considered that inflammatory mediators and proteases released by activated neutrophils cause sputum accumulation, airway obstruction, and alveolar destruction. Currently, bronchodilators such as anticholinergic agents and β ₂ stimulants, and expectorants are used as therapeutic agents, but all of them only improve the symptoms and do not suppress the progression of respiratory dysfunction. Also,
Although inhaled steroids have been shown to have an ameliorating effect on acute exacerbation of symptoms, they have not been found to have an inhibitory effect on the progression of respiratory dysfunction. Therefore, it is desired to develop a drug that suppresses the deterioration of respiratory function over time. On the other hand, a drug that suppresses the production or action of IL-8 may not only improve various symptoms based on neutrophilic inflammation but also suppress the deterioration of respiratory function due to alveolar destruction over time. Thought,
A high therapeutic effect can be expected in this disease. Therefore, the present invention provides a fused indole derivative which inhibits the production or action of IL-8, and a pharmaceutical composition containing the same.

[0004]

The present inventors have found that IL-8
As a result of diligent studies on a compound that inhibits the production or action of the above, in the 5H-pyrimido [5,4-b] indole derivative, a novel compound represented by the following general formula (I) or a salt thereof was specifically produced for the first time, The obtained compound is surprisingly excellent in its IL-8 based on its unique chemical structure.
The present invention was completed based on the finding that it has an inhibitory action, is useful as a medicine for preventing / treating agents of allergic diseases and / or inflammatory diseases, and has excellent oral absorbability. did. That is, the present invention provides the formula [1]

[Chemical 11] [In the formula, ring A is a benzene ring which may have a substituent.
, Q is NR¹(R¹Has a hydrogen atom or a substituent
May be C_1-6Represents alkyl), S (O)_n(N is not 0
And has an oxygen atom or a substituent.
Optionally methylene, R has a hydrogen atom or a substituent
May be C_1-6Alkyl, X and Y are independently
(1) Hydrogen atom (provided that X and Y are both hydrogen atoms
(2) halogen, (3) hydroxyl group, (4) amine
No, (5) -ZR²(Z is a bond, oxygen atom, sulfur atom or
Is -NR³-(R³Is a hydrogen atom, C_1-6Alkyl or C
_3-8Represents cycloalkyl), R²Has a substituent
May be C_1-6Alkyl, C which may have a substituent
_3-8Cycloalkyl, optionally substituted C_2-6A
Lucenyl or optionally substituted C_3-8Cyclo
Alkenyl), (6) C which may have a substituent
_6-14Aryl, (7) -NHCOR^Four(R^FourIs a hydrogen atom, C
_3-6Alkyl or C_3-8Cycloalkyl), (8)
-SO₂NR^FiveR⁶(R^FiveAnd R⁶Is a hydrogen atom, C_1-6Al
Kill or C_3-8Represents cycloalkyl or R^FiveOh
And R⁶Is a 3- to 8-membered ring with the adjacent nitrogen atom
Form amino)), (9) -COR⁷(R⁷Is water
Elementary atom, C_1-6Alkyl, C_3-8Cycloalkyl or C
_6-10Indicates aryl), (10) esterification or amidation
Optionally carboxyl, (11) nitro or (1
2) represents cyano, or X and Y taken together are C
_3-6Alkylene or C_1-4Indicates alkylenedioxy.
However, Q is NH, R is a hydrogen atom, and X and Y are both
When A is methoxy, Ring A is an unsubstituted benzene ring or
Except those having a benzene ring in which only the p-position is substituted]
Or a salt thereof, wherein [2] ring A is (1) (i)
C optionally having 1 to 3 halogen atoms_1-6
Alkyl, (ii) C _1-6Alkanoyl, (iii) C_6-10Ally
Lecarbonyl, (iv) C_1-6Alkylsulfonyl, (v) ami
Nosulfonyl, (vi) mono C_1-6Alkylaminosulfoni
Le, (vii) The C_1-6Alkylaminosulfonyl and (vii
i) selected from halogen atoms (hereinafter abbreviated as substituent group A)
C optionally having 1 to 3 substituents_1-10A
(2) The substituent selected from the above-mentioned Substituent group A is 1
C which may have 3 chairs_2-6Alkenyl, (3) above
Having 1 to 3 substituents selected from Group A
Good C_2-6Alkynyl, (4) selected from the above substituent group A
C optionally having 1 to 3 substituents_6-14Ants
(5) There is no 1 substituent selected from the above substituent group A.
C which may have 3_3-9Cycloalkyl, before (6)
Having 1 to 3 substituents selected from Substituent group A
May be C_3-6Cycloalkenyl, (7) oxygen atom, sulfur
1 to 3 kinds of iron selected from yellow atom and nitrogen atom
(B) aromatic or non-aromatic heterocycle containing 1 to 4 atoms
A group (this aromatic or non-aromatic heterocyclic group is
It may have 1 to 3 substituents selected from Group A
I), (8) even if it has 1 to 3 halogen atoms
Good C_1-6Alkylsulfonyl, (9) 1 to 3 halo
C which may have a gen atom_1-6Alkanoyl, (10)
C_6-10Aryl carbonyl, (11) carboxyl, (12) C
_1-6Alkoxycarbonyl, (13) selected from the above substituent group A
C optionally having 1 to 3 substituents_{6-1 0}A
Reel oxycarbonyl, (14) selected from the above substituent group A
C optionally having 1 to 3 substituents_{7-1 0}A
Aralkyloxycarbonyl, (15) (i) the above-mentioned substituent group A
C optionally having 1 to 3 substituents selected from
_1-10Alkyl, (ii) a substituent selected from the above substituent group A
C optionally having 1 to 3 groups_2-6Alkenyl,
(iii) 1 to 3 substituents selected from the above substituent group A
C which may have_6-14Aryl, (iv) the substituent A
It may have 1 to 3 substituents selected from the group
C_3-9Cycloalkyl, (v) selected from the above substituent group A
C which may have 1 to 3 substituents_3-6Cycloa
Lucenyl, (vi) having 1 to 3 halogen atoms
May be C_1-6Alkylsulfonyl, (vii) 1 to 3
C which may have a halogen atom_1-6Arcanoi
Le, (viii) C_6-14Arylcarbonyl, (ix) carboxy
Le, (x) C_1-6Alkoxycarbonyl, (xi) the substituent
It may have 1 to 3 substituents selected from Group A
I C_{6 -Ten}Aryloxycarbonyl and (xii)
Having 1 to 3 substituents selected from Group A
Good C_7-10Aralkyloxycarbonyl (hereinafter, substituted
1 or 2 substituents selected from group B)
Optionally having amino, selected from the group (16) substituent B
An optionally substituted imidoyl, (17) a substituent
It may have 1 to 3 substituents selected from Group B
Amidino, having a substituent selected from the group (18) substituent B
Optional hydroxyl group, selected from group (19) substituent B
A thiol which may have a substituent, (20) -CONR⁸
R⁹(R⁸Is (i) hydrogen atom, (ii) (i ') hydroxyl group, (ii') C
_1-6Alkyl, C_1-6From alkanoyl and benzoyl
Ami which may have 1 or 2 selected substituents
No, (iii ') halogen atom, (iv') nitro, (v ') cyan
No, (vi ') having 1 to 5 halogen atoms
Good C_1-6Alkyl and (vii ') 1 to 5 halogens
C which may have a hydrogen atom_1-6Chosen from alkoxy
C which may have 1 to 3 substituents_1-6Archi
Group, (iii) (i ') hydroxyl group, (ii') C_1-6Alkyl, C_1-6A
One substituent selected from lucanoyl and benzoyl
Or optionally two amino, (iii ') halogen source
Child, (iv ') nitro, (v') cyano, (vi ') 1 to 5
C which may have a halogen atom_1-6Alkyl and
(Vii ') having 1 to 5 halogen atoms
Good C_1-61 to 3 substituents selected from alkoxy
C which may have_3-6Cycloalkyl, (iv) (i ')
Hydroxyl group, (ii ') C_1-6Alkyl, C_1-6Alkanoyl and
And 1 or 2 substituents selected from benzoyl
Optional amino, (iii ') halogen atom, (iv') nit
B, (v ') cyano, (vi') 1 to 5 halogen atoms
May have C_1-6No alkyl and (vii ') 1
C which may have 5 halogen atoms_1-6Arco
May have 1 to 3 substituents selected from xy
I C_6-10Aryl, (v) (i ') hydroxyl group, (ii') C_1-6Al
Kill, C_1-6Selected from alkanoyl and benzoyl
An amino optionally having 1 or 2 substituents,
i ') halogen atom, (iv') nitro, (v ') cyano, (v
i ') C optionally having 1 to 5 halogen atoms
_1-6Alkyl and (vii ') 1 to 5 halogen atoms
May have C_1-6Substitution selected from alkoxy
C optionally having 1 to 3 groups_7-10Aralkyl,
Or (vi) selected from oxygen atom, sulfur atom and nitrogen atom.
Aroma containing 1 to 4 heteroatoms of 1 to 3 types
Aromatic or non-aromatic heterocyclic group (this aromatic or non-aromatic
Group heterocyclic groups include (i ') hydroxyl group, (ii') C_1-6Alkyl, C
_1-6Substituent selected from alkanoyl and benzoyl
An amino optionally having 1 or 2 of (iii ′) halo
No gen atom, (iv ') nitro, (v') cyano, (vi ') 1
C which may have 5 halogen atoms_1-6Archi
And (vii ') having 1 to 5 halogen atoms
May be C_1-6No substituents selected from alkoxy
You may have 3), R⁹Is a hydrogen atom, C_1-6A
Rukiru, C_3-6Cycloalkyl or C_7-10Aralkyl
(R⁸And R⁹Is 3 or with an adjacent nitrogen atom
8-membered cyclic amino may be formed)), (21)-
CSNR⁸R⁹(R⁸And R⁹Has the same meaning as above) (2
2) halogen atom, (23) cyano and (24) nitro (hereinafter,
And a substituent selected from the group C).
5 benzene rings, Q is NR¹(R¹Is water
No element selected from the group consisting of elementary atoms or the substituents A
C which may have 3 chairs_1-6Represents alkyl), S
(O)_n(N represents an integer of 0 to 2), an oxygen atom or
Has 1 or 2 substituents selected from the above Group A of substituents
Optionally methylene, R is a hydrogen atom or the above substitution
Having 1 to 3 substituents selected from Group A
Good C_1-6Alkyl, X and Y are independently (1) hydrogen source
Child, (2) halogen, (3) hydroxyl group, (4) amino, (5) -ZR²
(Z is a bond, oxygen atom, sulfur atom or -NR³−
(R³Is a hydrogen atom, C_1-6Alkyl or C_3-8Cycloa
Rukiru), R²Is (i) halogen, C_6-10Aryl and
C_1-6Has 1 to 3 substituents selected from alkoxy
C which may be_1-6Alkyl, (ii) halogen, C_6-10
Aryl and C_1-6A substituent selected from alkoxy
1 to 3 optionally have C_3-8Cycloalkyl,
(iii) halogen, C_6-10Aryl and C_1-6Alkoxy
C optionally having 1 to 3 substituents selected from
_2-6Alkenyl, (iv) halogen, C_6-10Aryl and
C_1-6Has 1 to 3 substituents selected from alkoxy
C which may be_3-8Cycloalkenyl), (6) before
Having 1 to 5 substituents selected from Group C
May be C_6-14Aryl, (7) -NHCOR^Four(R^FourIs
Hydrogen atom, C_3-6Alkyl or C_3-8Cycloalkyl
), (8) -SO₂NR^FiveR⁶(R^FiveAnd R⁶Is hydrogen
Child, C_1-6Alkyl or C_3-8Represents cycloalkyl,
R^FiveAnd R⁶Is 3 to 8 members with adjacent nitrogen atom
May form a cyclic amino), (9) -COR⁷(R⁷
Is a hydrogen atom, C_1-6Alkyl, C_3-8Cycloalkyl
Is C _6-10Aryl), (10) carboxyl, (11) C
_1-6Alkoxycarbonyl, (12) selected from the above substituent group A
C optionally having 1 to 3 substituents_{6-1 0}A
Reel oxycarbonyl, (13) selected from the above substituent group A
C optionally having 1 to 3 substituents_{7-1 0}A
Ralalkyloxycarbonyl, (14) -CONR⁸R⁹(R⁸
And R⁹Has the same meaning as above), (15) nitro, (16)
Cyano, (17) X and Y together are C_3-6Arche
Or (18) X and Y together are C_1-4Arche
[3] ring A, wherein the compound is [1]
May have 1 to 3 halogen atoms (1)
C_1-10Alkyl, (2) C_2-6Alkynyl, (3) C_6-14Ants
(4) C_1-6Alkanoyl, (5) C_{1- Ten}Alkyl and
And C_6-14May have a substituent selected from aryl
Selected from hydroxy group, (6) halogen atom and (7) cyano
A benzene ring optionally having 1 to 3 substituents,
Q is NR^1a(R^1aIs a hydrogen atom or C_1-6Alkyl),
S, SO, oxygen atom or methylene, R is hydrogen atom,
Is C_1-6Alkyl, X and Y are independently (1) a hydrogen atom,
(2) halogen, (3) hydroxyl group or (4) -Z^aR^2a(Z^aConcludes
A joint or an oxygen atom, R^2aIs (i) halogen, C_6-10A
Reel and C_1-6Substituent selected from alkoxy is 1
To C which may have 3 to 3_1-6Alkyl or (ii)
Halogen, C_6-10Aryl and C_1-6From alkoxy
C optionally having 1 to 3 substituents selected_3-8
Cycloalkyl) or X and Y together
C_1-4The above-mentioned [1] which is alkylenedioxy
Compound, [4] Ring A is C_2-6Alkynyl and halogen
May have 1 or 2 substituents selected from atoms
[5] X, wherein the compound is a benzene ring,
And Y are independently (1) hydrogen atom, (2) halogen, (3) water
Acid group or (4) -Z^aR^2a(Z^aIs a bond or oxygen atom
To R^2aIs (i) halogen, C_6-10Aryl and C_1-6A
Having 1 to 3 substituents selected from lucoxy,
Good C_1-6Alkyl or (ii) halogen, C_6-10Ants
And C_1-6No substituents selected from alkoxy
C which may have 3 chairs_3-8Indicates cycloalkyl
[6] R is hydrogen source
A compound according to the above [1] which is a child, [7] Q is NH,
The compound according to [1] above, which is S, an oxygen atom or methylene.
Compound [8] 4- (2,5-dichlorophenyl) amino
-7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
Ndol, 4- (4-chlorophenylsulfanyl)-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
Or benzyl or 4-benzyl-7,8-dimethoxy-5
The above is H-pyrimido [5,4-b] indole
A compound described in [1],

[9] A prodrug of the compound according to [1] or a salt thereof, [10] A pharmaceutical composition comprising the compound according to [1], a salt thereof or a prodrug thereof, and a formula [11].

[Chemical 12] [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
Alkylene or C _1-4 alkylenedioxy] or an IL-8 inhibitor comprising a compound represented by the formula [12], which is a preventive / therapeutic agent for IL-8-related diseases [11] [13] The agent according to [13], which is a preventive / therapeutic agent for allergic diseases and / or inflammatory diseases
[14] The agent according to [11] above, which is a prophylactic / therapeutic agent for chronic obstructive pulmonary disease (COPD), and [15] the above-mentioned agent [15] is a disease state progression inhibitor for chronic obstructive pulmonary disease (COPD). [11] The agent according to [11] above, which is a prophylactic / therapeutic agent for [16] rheumatism, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis and / or periosteitis.
Described agent, [17] formula

[Chemical 13] [In the formula, R is a hydrogen atom or C _1-6 alkyl which may have a substituent, and X and Y are independently (1) a hydrogen atom,
(2) halogen, (3) hydroxyl group, (4) amino, (5) -ZR ² (Z
Is a bond, oxygen atom, sulfur atom or —NR ³ — (R ³ is a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl)
The, R ² which may have a substituent C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally C _2-6 alkenyl optionally having substituent Or _C3-8 cycloalkenyl which may have a substituent), (6)
Optionally substituted C _6-14 aryl, (7) -NH
COR ⁴ (R ⁴ represents a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl), (8) -SO ₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ are C _1-6 alkyl or C _{3 -8} cycloalkyl, or R ⁵ and R ⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9)-
COR ⁷ (R ⁷ represents a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl), (10) an optionally esterified or amidated carboxyl, (1
1) nitro or (12) cyano, or X and Y
Together with C _3-6 alkylene or C _1-4 alkylenedioxy, and L represents a leaving group] or a salt thereof and a formula

[Chemical 14] [In the formula, Ring A is a benzene ring which may have a substituent, Q'is -NHR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent). , -SH, -O
H or -Q "-Zn-L '(Q is methylene which may have a substituent and L'is halogen)] or a salt thereof. Expression

[Chemical 15] [Wherein R, X and Y have the same meanings as described above, and Q is NR ¹
(R ¹ is a hydrogen atom or optionally substituted C _1-6
Alkyl), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent], or a salt thereof,
[18] For mammals, the formula

[Chemical 16] [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
Alkylene or C _1-4 alkylenedioxy] or a salt thereof is administered in an effective amount, [19] An IL-8 inhibitor for producing ,formula

[Chemical 17] [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
Alkylene or C _1-4 alkylenedioxy] or a salt thereof and the like.

Examples of the "substituent" in the "benzene ring which may have a substituent" represented by ring A include, for example,
Alkyl which may have a substituent, alkenyl which may have a substituent, alkynyl which may have a substituent, aryl which may have a substituent, and which has a substituent. Optionally cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic group, sulfonic acid-derived acyl, carboxylic acid-derived acyl, optionally esterified Carboxyl, amino optionally having substituent (s), imidoyl optionally having substituent (s), amidino optionally having substituent (s), hydroxyl group optionally having substituent (s), substituent having Optionally thiol, optionally substituted carbamoyl,
Examples thereof include thiocarbamoyl which may have a substituent, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), cyano, nitro and the like. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions.

Alkyl in "optionally substituted alkyl" as a substituent of ring A is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, n-
Pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl,
C such as n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl and the like.
_1-10 alkyl (preferably C _1-6 alkyl etc.) and the like can be mentioned. As the substituent that the “optionally substituted alkyl” as the substituent of ring A may have,
To lower alkyl optionally having 3 halogen atoms (for example, C _1-6 alkyl such as methyl, ethyl and propyl, mono-, di- or tri- such as trifluoromethyl and 1,1-difluoroethyl). Halogeno C _1-6 alkyl, etc.), acyl (for example, (i) C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, (ii) C _6-10 arylcarbonyl such as benzoyl, (iii) methylsulfonyl, C _1-6 alkylsulfonyl such as ethylsulfonyl, (iv) aminosulfonyl, (v) mono C _1-6 alkylaminosulfonyl such as methylaminosulfonyl and ethylaminosulfonyl, and di C _1- such as (vi) dimethylaminosulfonyl. ₆ alkylaminosulfonyl, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.) and the like. It may have 1 to 3 substituents selected from these at substitutable positions.

Examples of the alkenyl in the "alkenyl which may have a substituent (s)" as the substituent of ring A include, for example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl. 1
-Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
C _2-6 alkenyl such as 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like can be mentioned. Here, as the substituent of alkenyl, the same number of substituents as those in the above-mentioned “alkyl optionally having substituent (s)” can be mentioned.

Examples of the alkynyl in the "alkynyl which may have a substituent (s)" as the substituent (s) on ring A include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-.
Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. C _{2- 6} Examples include alkynyl. Here, as the substituent of alkynyl, the same number of the same substituents as those in the above-mentioned “alkyl optionally having substituent (s)” can be mentioned.

The aryl in the "optionally substituted aryl" as the substituent of the ring A includes monocyclic or condensed polycyclic aromatic hydrocarbons, for example, phenyl, naphthyl, anthryl, C such as phenanthryl, acenaphthylenyl, 4-indanyl, 5-indanyl
_6-14 aryl and the like. Here, as the substituent of aryl, the same number of substituents as those in the above-mentioned “alkyl optionally having substituent (s)” can be mentioned.

Cycloalkyl in the "optionally substituted cycloalkyl" as the substituent of ring A includes, for example, C ₃ such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. _{- 9} cycloalkyl (preferably C _3-8 cycloalkyl, etc.), etc., and 1-indanyl, and a condensed ring such as 2-indanyl. Here, as the substituent of cycloalkyl, the same number of substituents as those in the above-mentioned “alkyl optionally having substituent (s)” can be mentioned.

As a substituent of ring A, "having a substituent
Cycloalkenyl in "may be cycloalkenyl"
Are, for example, 2-cyclopenten-1-yl, 3-
Cyclopenten-1-yl, 2-cyclohexene-1-
Yl, 3-cyclohexen-1-yl, 1-cyclobute
C such as n-1-yl and 1-cyclopenten-1-yl
_3-6Examples thereof include cycloalkenyl. Where cyclo
The alkenyl substituent has the above-mentioned “having a substituent”.
Those similar to the substituents in "optionally alkyl"
The same number can be listed.

The heterocyclic group in the "heterocyclic group which may have a substituent (s)" as the substituent of ring A includes an oxygen atom, a sulfur atom and a nitrogen atom as atoms (ring atoms) constituting the ring system. 1 to 3 kinds (preferably 1) selected from atoms and the like
Or 2 kinds) an aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 or 2) heteroatoms, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocycle). Group) and the like. The "aromatic heterocyclic group" is an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2 , 4-Oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2 5- or 6-membered aromatic monocyclic heterocyclic groups such as 1,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and condensed aromatic heterocyclic groups [eg, benzofuranyl, isobenzofuranyl, benzothienyl] , Indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxa Zolyl, 1,2-benzisoxazolyl,
Benzothiazolyl, 1,2-benzisothiazolyl, 1
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-
Carborinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl, phenatridinyl, phenatrolinyl,
Indolizinyl, pyrrolo [1,2- b ] pyridazinyl,
Pyrazolo [1,5- a ] pyridyl, imidazo [1,2-
a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2-
a ] Pyrimidinyl, 1,2,4-triazolo [4,3-
a ]] Pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and other 8- to 12-membered fused aromatic heterocyclic groups (preferably the 5- or 6-membered aromatic monocyclic heterocycles described above). A heterocyclic group in which the group is condensed with a benzene ring, or a heterocyclic group in which two identical or different heterocycles of the above-mentioned 5- to 6-membered aromatic monocyclic heterocyclic group are condensed). The "non-aromatic heterocyclic group" is, for example, 3 to 8-membered (preferably 5
To 6 members) saturated or unsaturated (preferably saturated)
And the non-aromatic heterocyclic group (aliphatic heterocyclic group). Here, as the substituent of the heterocyclic group, the same number of substituents as those in the above-mentioned “alkyl optionally having substituent (s)” can be mentioned.

Examples of the "acyl derived from sulfonic acid" as a substituent of ring A include C _1-6 which may have 1 to 3 halogen atoms such as methanesulfonyl, trifluoromethanesulfonyl and ethanesulfonyl. Examples include acyl such as alkylsulfonyl.

The "acyl derived from a carboxylic acid" as a substituent of ring A is, for example, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl and the like C ₁ which may have 1 to 3 halogen atoms. _-6 alkanoyl include C _{6-1 0} aryl carbonyl benzoyl.

Examples of the "optionally esterified carboxyl" as a substituent of ring A include free carboxyl, lower alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl and the like.

Examples of the "lower alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,
C _1-6 alkoxy-, such as neopentyloxycarbonyl
Carbonyl and the like can be mentioned.

The "aryloxycarbonyl" is preferably C _6-10 aryloxy-carbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like.

Examples of the "aralkyloxycarbonyl" include C _7-10 aralkyloxy-carbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl (preferably C _6-10 aryl-C _1-4 alkoxy-).
Carbonyl) is preferred.

The "aryloxycarbonyl" and "aralkyloxycarbonyl" may have a substituent, and the substituent is, for example, a substituent of the benzene ring which may have the above-mentioned substituent. The same number of the same as those mentioned as the substituents of the “optionally substituted aryl” and the “optionally substituted aralkyl” are used.

As a substituent of ring A, "optionally substituted amino", "optionally substituted imidoyl", "optionally substituted amidino", " Examples of the substituent in the “hydroxyl group which may have a substituent” and the “thiol which may have a substituent” include, for example, “a substituent which may have a substituent of the ring A”. "Alkyl", "optionally substituted alkenyl", "optionally substituted aryl", "optionally substituted cycloalkyl", "optionally substituted" Examples of the same as “optionally cycloalkenyl”, “acyl derived from sulfonic acid”, “acyl derived from carboxylic acid”, and “optionally esterified carboxyl”, but having “substituent” "Amino" in "mayo amino" means Which may have a substituent imidoyl (e.g., C _1-6 alkyl imidoyl, formyl imidoyl, amidino, etc.) may be substituted with etc. Furthermore, with two substituents and the nitrogen atom In some cases, cyclic amino is formed, and examples of the cyclic amino in such a case include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and lower alkyl at the 4-position (for example, methyl, ethyl, propyl). , isopropyl, butyl, t- butyl, pentyl, C _1-6 alkyl such as hexyl, etc.), aralkyl (e.g. benzyl, C ₇ of phenethyl _-10 aralkyl, etc.), aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl _1-6 which may have a substituent selected from C _6-10 aryl etc.)
3- to 8-membered (preferably 5 to 6) such as piperazinyl
Member) cyclic amino and the like.

The "carbamoyl optionally having a substituent" as the substituent is, for example, -CONR ⁸ R ⁹ (R
⁸ is (i) hydrogen atom, (ii) optionally substituted C _1-6
Alkyl, (iii) optionally substituted C _3-6 cycloalkyl, (iv) optionally substituted C _6-10 aryl, (v) _optionally substituted Good C _7-10 aralkyl or (vi) an aromatic or non-aromatic heterocyclic group containing 1 to 4 1 to 3 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom (the aromatic or non-aromatic group). The heterocyclic group may have a substituent), R ⁹ is a hydrogen atom, C _1-6 alkyl, C _3-6 cycloalkyl or C
_7-10 aralkyl is shown (R ⁸ and R ⁹ may form a 3- to 8-membered cyclic amino together with the adjacent nitrogen atom) and the like.

The "C _1-6 alkyl" represented by "C _1-6 alkyl" and R ⁹ "optionally substituted C _1-6 alkyl" represented by R ⁸ is, For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-
Hexyl, isohexyl, 1,1-dimethylbutyl, 2,
2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-
Examples thereof include dimethylpropyl and 2-ethylbutyl.
Represented by R ⁸ and "C _3-6 cycloalkyl" represented by "C _3-6 cycloalkyl" and R ⁹ "optionally C _3-6 cycloalkyl optionally having substituent" Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The “C _6-10 aryl” of the “C _6-10 aryl which may have a substituent” represented by R ⁸ is, for example, phenyl, 1
-Naphthyl, 2-naphthyl and the like can be mentioned. Represented as "C _7-10 aralkyl" represented by "C _7-10 aralkyl" and R ⁹ "optionally C _7-10 aralkyl optionally having a substituent" at R ^8, for example, for example, Examples thereof include benzyl and phenethyl. The “aromatic or non-aromatic heterocyclic group containing 1 to 4 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom” represented by R ⁸ is a substituent of ring A. The same thing as the heterocyclic group in the "heterocyclic group which may have a substituent" of is mentioned.

"C _1-6 alkyl _optionally having substituent (s)" represented by R ⁸ , "C _{3-6 optionally} having substituent (s)"
“Cycloalkyl”, “C _{6-10 optionally} having substituent (s)
"Aryl", "C _7-10 aralkyl optionally having substituent (s)" and "aromatic or non-aromatic containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom" Examples of the substituent which the “group heterocyclic group” may have include (i) a hydroxyl group, (ii) C _1-6 alkyl, C _1-6
Substituent selected from alkanoyl and benzoyl is 1
Or optionally having 2 amino, (iii) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (iv) nitro, (v) cyano, (vi) having 1 to 5 halogen atoms. and optionally C _1-6 alkyl and (vii) 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.) a C _1-6 alkoxy such as optionally having. these It may have 1 to 3 substituents at the substitutable position.

The 3- to 8-membered cyclic amino formed by R ⁸ and R ⁹ together with the adjacent nitrogen atom is, for example, 1
-Azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and lower alkyl at the 4-position (for example, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl etc.), aralkyl (Eg, C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg, phenyl, 1
_-C6-10 aryl such as -naphthyl and 2-naphthyl) and the like, which may have a substituent selected from 1-piperazinyl and the like.

The substituent of "thiocarbamoyl which may have a substituent" as the substituent is, for example, -C.
SNR ⁸ R ⁹ (R ⁸ and R ⁹ have the same meanings as described above) and the like.

[0026] As C _1-6 alkyl in the "optionally substituted C _1-6 alkyl" represented by R ¹ and R
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-
Methylpropyl, n-hexyl, isohexyl, 1,1
Examples include C _1-6 alkyl such as dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl and 2-ethylbutyl. Where C _1-6
The substituent of alkyl is the same as the substituent of the “alkyl which may have a substituent” as the substituent of the “benzene ring which may have a substituent” represented by ring A described above. There are things.

The "halogen" represented by X and Y includes, for example, fluorine, chlorine, bromine, iodine and the like.

Z in "-ZR ² " represented by X and Y is a bond, an oxygen atom, a sulfur atom or -NR ^3- (R ³ is a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl). Indicates. Represented by R ³ "C _1-6 alkyl", R ^1, R
In the same as the C _1-6 alkyl "also C _1-6 alkyl optionally having substituent (s)" can be mentioned as shown. The “C _3-8 cycloalkyl” represented by R ³ includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

R ² of "-ZR ² " represented by X and Y is
(i) C optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy
_1-6 alkyl, (ii) halogen, C _6-10 aryl and C
C _3-8 cycloalkyl optionally having 1 to 3 substituents selected from _1-6 alkoxy, (iii) halogen,
C _6-10 aryl and C 1 to a substituent selected from _C1-6 alkoxy to 3 substituents optionally having C _2-6 alkenyl, the (iv) halogen, C _6-10 aryl and C _1-6 alkoxy C _3-8 cycloalkenyl and the like _optionally having 1 to 3 selected substituents are shown.

[0030] C _1-6 alkyl "halogen, C _6-10 aryl and C 1 to a substituent selected from _C1-6 alkoxy to three C _1-6 alkyl optionally having" represented by R ² _Examples of C _1-6 include the same as C _1-6 alkyl of “ _optionally substituted C _1-6 alkyl” represented by R ¹ and R. R ^{2 represents} a substituent selected from halogen, C _6-10 aryl and C _1-6 alkoxy in 1 to 3
And the halogen of “C _1-6 alkyl which may have one”,
Examples thereof include fluorine, chlorine, bromine and iodine. R
Represented by ² and C _6-10 aryl "halogen, C _6-10 aryl and C _1-6, 1 to substituents selected from alkoxy three optionally having C _1-6 alkyl", for example, Phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned. Represented by R ² and C _1-6 alkoxy "halogen, C _6-10 aryl and C _1-6, 1 to substituents selected from alkoxy three C _1-6 alkyl optionally having" are For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, se
Examples thereof include c-butoxy and tert-butoxy.

C _{3-8 of} "C _3-8 cycloalkyl optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy" represented by R ²
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. R ^{2 represents} “C which may have 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy.
“Halogen”, “C _6-10 aryl” and “C _1-6 alkoxy” of “ _3-8 cycloalkyl” are selected from “halogen, C _6-10 aryl and C _1-6 alkoxy represented by R ^2. C which may have 1 to 3 substituents
_{The same as} the "halogen", " _C6-10 aryl" and "C1-6 alkoxy" of " _1-6 alkyl" are mentioned.

C _2-6 alkenyl of "C _2-6 alkenyl optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy" represented by R ^2. And, for example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-
Butenyl, 2-ethyl-1-butenyl, 2-methyl-2
-Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
Hexenyl and the like can be mentioned. “Halogen” and “C _6- of“ C _2-6 alkenyl optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy ”represented by R ^2. " ₁₀ aryl" and "C
" _1-6 alkoxy" means "halogen, C" represented by R ^2.
“Halogen”, “C _6-10 aryl” and “C _1-6 ” of “C _1-6 alkyl optionally having 1 to 3 substituents selected from _6-10 aryl and C _1-6 alkoxy” The same thing as "alkoxy" is mentioned.

C of "C _3-8 cycloalkenyl optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy" represented by R ²
_3-8 cycloalkenyl means, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1 -Cyclopenten-1-yl and the like can be mentioned. “Halogen” and “C ₆ of“ C _3-8 cycloalkenyl optionally having 1 to 3 substituents selected from halogen, C _6-10 aryl and C _1-6 alkoxy ”represented by R ^2; _-10 aryl ”and“ C _1-6 alkoxy ”are the“ halogen ”for R ² .
C _6-10 aryl and C _1-6 C _1-6 alkyl also to 1 substituents have 3 selected from alkoxy "
And the same as the "C _6-10 aryl" and "C _1-6 alkoxy" of.

Examples of C _6-10 aryl in the “C _6-10 aryl _optionally having substituent (s)” represented by X and Y include phenyl, 1-naphthyl, 2-naphthyl and the like. Examples of the group include the same groups as the above-mentioned substituents in the “benzene ring which may have a substituent” represented by ring A.

"-NHCOR ⁴ " represented by X and Y
R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl. The “C _3-6 alkyl” represented by R ⁴ is
For example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2, 2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and the like can be mentioned. Examples of the “C _3-8 cycloalkyl” represented by R ⁴ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

"--SO ₂ NR represented by X and Y
⁵ R ⁶ ”, R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, and R ⁵ and R ⁶ together with the adjacent nitrogen atom form a 3- to 8-membered cyclic amino. May be. "C _1-6 alkyl" represented by R ⁵ and R ⁶
_Examples of C _1-6 include the same as the C _1-6 alkyl of “ _optionally substituted C _1-6 alkyl” represented by R ¹ and R. Examples of the “C _3-8 cycloalkyl” represented by R ⁵ and R ⁶ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Further, R ⁵ and R ⁶ may combine with the adjacent nitrogen atom to form a cyclic amino, and in such a case, the cyclic amino is, for example, 1
- azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 4-position a lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, C _1-6 alkyl hexyl, etc.), aralkyl (Eg, C _7-10 aralkyl such as benzyl and phenethyl), aryl (eg, phenyl,
3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as 1-piperazinyl which may have a substituent selected from C _6-10 aryl such as 1-naphthyl, 2-naphthyl, etc. Is mentioned.

R ^{7 of} "--COR ⁷ " represented by X and Y
_{Represents a} hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl. "C _1-6 alkyl" in the represented by R ⁷ wherein R ^1, "optionally substituted C _1-6 alkyl" represented by R as "C _1-6 alkyl"
The same thing as is mentioned. Examples of the “C _3-8 cycloalkyl” represented by R ⁷ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the “C _6-10 aryl” represented by R ⁷ include aryl such as phenyl, 1-naphthyl, 2-naphthyl and the like C _6-10.
Aryl etc. are mentioned.

The “optionally esterified or amidated carboxyl” represented by X and Y is carboxyl, and the substituent of the “optionally substituted benzene ring” represented by ring A above. “Lower alkoxycarbonyl”, “aryloxycarbonyl”, “aralkyloxycarbonyl” and “—CONR ⁸ R ⁹ (R
⁸ and R ⁹ have the same meanings as described above) "and the like.

C _3-6 formed by X and Y taken together
Alkylene, for _{example, - (CH 2) 3 -} , - (CH 2) 4 -, - (CH 2)
₅ -,-(CH ₂ ) _6- and the like. C _1-4 alkylenedioxy formed by X and Y taken together is, for example, —OCH ₂
O-, -O (CH ₂ ) ₂ O-, -O (CH ₂ ) ₃ O-,-O (CH ₂ ) ₄ O-
And so on.

As ring A, (1) C _1-10 alkyl _optionally having 1 to 3 halogen atoms, (2) C _2-6 alkynyl, (3) C _6-14 aryl, ( 4) a hydroxyl group which may have a substituent selected from C _1-6 alkanoyl, (5) C _1-10 alkyl and C _6-14 aryl, a substitution selected from (6) halogen atom and (7) cyano A benzene ring which may have 1 to 3 groups is preferable. Further, a benzene ring which may have 1 or 2 substituents selected from (1) C _2-6 alkynyl or (2) halogen atom is more preferable.

Q is NR ¹ (R ¹ is a hydrogen atom or C
_1-6 alkyl), S, SO, oxygen atom or methylene is preferable. Further, NH, S, oxygen atom or methylene is preferable.

R is preferably a hydrogen atom, methyl, ethyl or propyl. Further, a hydrogen atom is preferable.

X and Y are independently (1) hydrogen atom, (2) halogen, (3) hydroxyl group, or (4) -Z ^a R ^2a (Z
^a is a bond or an oxygen atom, R ^2a is (i) halogen, C
_6-10 aryl and C _1-6 1 without a substituent selected from alkoxy to 3 substituents optionally having C _1-6 alkyl or (ii) halogen, selected from C _6-10 aryl and C _1-6 alkoxy Preferred is a C _3-8 cycloalkyl optionally having 1 to 3 substituents), or those in which X and Y together are C _1-4 alkylenedioxy. Furthermore, X and Y are independently (1) a hydrogen atom,
(2) halogen, (3) hydroxyl group or (4) -Z ^a R ^2a (Z ^a is a bond or an oxygen atom, R ^2a is selected from (i) halogen, C _6-10 aryl and C _1-6 alkoxy. 1 substituent
To 3 C _1-6 alkyl or optionally having (ii)
Halogen, optionally C _6-10 has three, 1 to substituents selected from aryl and C _1-6 alkoxy C _3-8
Those which represent cycloalkyl) are preferred. Especially, X and Y are preferably independently a hydrogen atom, methyl, ethyl, methoxy, ethoxy or the like.

Preferred compounds as the compound (I) include, for example, 4- (3-chlorophenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indole, 4- (2,5-dichlorophenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indole, 7,8-dimethoxy-4- (3-ethynylphenyl) amino-5H-pyrimido [5,4-b] indole, 4- (3-chlorophenyl) ) Amino-8-methyl-
5H-pyrimido [5,4-b] indole, 4- (4-
Chlorophenylsulfanyl) -7,8-dimethoxy-
5H-pyrimido [5,4-b] indole, 8-ethyl-4- (4-fluorophenoxy) -5H-pyrimido [5,4-b] indole, 7,8-diethoxy-4-
Examples thereof include phenylamino-5H-pyrimido [5,4-b] indole, 4-benzyl-7,8-dimethoxy-5H-pyrimido [5,4-b] indole, and salts thereof. Among them, 4- (2,5-dichlorophenyl) amino-7,8-dimethoxy-5H-pyrimido [5,4-b] indole, 4- (4-chlorophenylsulfanyl) -7,8-dimethoxy-5H-pyrimido [5,4-b] indole or 4-benzyl-7,8
-Dimethoxy-5H-pyrimido [5,4-b] indole or salts thereof and the like are preferable.

The salt of compound (I) is an acid addition salt such as an inorganic acid salt (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), an organic acid salt (eg, acetate, tritium salt). Fluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.) Salts with bases (for example, alkali metal salts such as potassium salt, sodium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, trimethylamine salt, triethylamine salt, te
rt-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like) may be formed. The compound (I) or its salt may be a hydrate.

The prodrug of compound (I) is a compound which is converted into compound (I) having an IL-8 production inhibitory action in vivo by reaction with an enzyme, gastric acid or the like. As the prodrug of the compound (I), when the compound (I) has amino, the amino is acylated, alkylated, phosphorylated (eg, amino of the compound (I) is eicosanoylated, alanylated, Pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated When the compound (I) has a hydroxyl group, the compound having the hydroxyl group acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of the compound (I) is acetylated, palmitoylated, propanoylated, Pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); When (I) has a carboxyl, the compound obtained by esterifying or amidating the carboxyl (eg, carboxyl of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivalo) Iloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound and the like); and the like. These compounds can be produced by a method known per se. Further, the prodrug of compound (I) is a compound which is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, "Development of Pharmaceuticals", Volume 7, Molecular Design, pages 163 to 198. May be

The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. Examples of such salts include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc and iron) when the prodrug of compound (I) has an acidic group such as carboxyl. , Transition metals such as copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with organic amines such as diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, basic amino acids such as arginine, lysine, ornithine, and the like. When the prodrug of compound (I) has a basic group such as amino, an inorganic acid or organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid,
Trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), aspartic acid, glutamic acid and other acidic amino acids, etc. Of salt. Further, the prodrug of compound (I) may be either a hydrate or a non-hydrate.
The compound (I) may have one or more asymmetric carbons in the molecule, and the R configuration, S
Any of the configurations are included in the present invention. Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

The compound (I) is produced, for example, by the method shown below. Production Method 1 As shown in the following formula, compound (I) can be produced by reacting compound (II) with compound (III).

[Chemical 18] (In the formula, L is a leaving group (for example, a halogen atom or the like),
Q'is -NHR ¹ (R ¹ is a hydrogen atom, C _1-6 alkyl optionally having a substituent), -SH, -OH or -Q "-Zn-L '(Q" is a substituent) Methylene optionally having a group, L'represents a halogen atom), and other symbols have the same meanings as described above)

1) Q ′ is —NHR ¹ (R ¹ is a hydrogen atom,
Represents a C _1-6 alkyl which may have a substituent), -S
When H or —OH, this reaction is usually carried out in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxyethane,
Tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformylamide (DMF), N- Methylpyrrolidone (NMP), acetone, methyl ethyl ketone, dimethylsulfoxide (DMSO), water and the like can be used alone or in combination. Above all, DMF and NM
P, DMSO, dichloromethane, chloroform and the like are preferable. This reaction is usually carried out by reacting compound (III) with 1 to 5 equivalents, preferably 1 to 3 equivalents, with respect to compound (II). The reaction temperature is room temperature (about 15
To 25 ° C) to 150 ° C, and the reaction time is usually 5
Minutes to 100 hours. Moreover, in this reaction, the reaction may proceed more smoothly by allowing a base to coexist. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include alkali metal and alkaline earth metal hydroxides, hydrides, carbonates, hydrogen carbonates, organic acid salts, and the like, among which potassium carbonate, sodium carbonate, sodium hydroxide, and hydroxide. Preference is given to potassium, sodium hydrogen carbonate and potassium hydrogen carbonate. As the organic base, tertiary amines such as triethylamine are preferable. The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (II).

2) Q'is -Q "-Zn-L '(Q" is
Methylene optionally having a substituent, L'is a halogen atom
This reaction when a show) the is characterized in that to obtain compound (II) an organic zinc compound (III) was condensed in the presence of an organic palladium catalyst compound (I). This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether,
Dimethoxyethane, tetrahydrofuran, dioxane, etc., aromatic solvents (eg, toluene, chlorobenzene,
Xylene), N, N-dimethylformylamide (D
MF), N-methylpyrrolidone (NMP) and the like can be used alone or in combination. Above all, D
MF, tetrahydrofuran and the like are preferable. Organozinc compound (III) used in this reaction is a commercially available compound,
It is also possible to prepare from a halogenobenzyl derivative and zinc by a generally known method. This reaction is usually carried out by reacting compound (III) with 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (II). As the organic palladium catalyst, tetrakistriphenylphosphine palladium is preferable, and the amount used is 0.1 equivalent to 1.0 equivalent with respect to the compound (II). The reaction temperature is 0 ° C to 100 ° C, and the reaction time is generally 5 minutes to 100 hours.

Production Method 2 As shown by the following formula, the compound (IV) in which Q of the compound (I) is a sulfur atom can be converted into the compound (V) by subjecting it to an oxidation reaction.

[Chemical 19] (In the formula, each symbol has the same meaning as described above.) This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include alcohol solvents (eg, methanol, ethanol, isopropanol, etc.), halogenated solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, chlorobenzene, xylene, etc.), water. Etc. can be used alone or as a mixture thereof. Among them, methanol,
Water, dichloroethane and the like are preferred. The oxidizing agent used in this reaction is hydrogen peroxide, peracetic acid, perbenzoic acid,
Metachloroperbenzoic acid, sodium metaperiodate, hydroperoxide, iodine, bromine and the like can be mentioned. By adjusting the amount of these oxidizing agents to be used for compound (IV) (1 equivalent or 2 equivalents or more), sulfoxide or sulfone The conversion of is achieved. The reaction temperature is −20 ° C. to 100 ° C., preferably room temperature (about 15 to 2 ° C.).
5 ° C). The reaction time is usually 5 minutes to 100 hours.

Production Method 3 As shown in the following formula, the substituent X or Y of the compound (I)
Is halogen or aryl or C _1-6 alkoxy optionally having C _1-6 alkoxy or C _3-8 cycloalkoxy, the compound can be converted to compound (VI) and compound (VII). it can.

[Chemical 20] (Wherein, R ^11, R ¹² is aryl or C _1-6 which may have alkoxy C _{1 -6} alkyl or C _3-8 cycloalkyl, and the other symbols are as defined above) compound (VI) is optionally substituent X or Y is not a halogen or aryl, or C _1-6 alkoxy C _1-6
It is produced by heating compound (I) which is alkoxy or C _3-8 cycloalkoxy in pyridine hydrochloride, trifluoroacetic acid. The reaction temperature is 150 ° C to 190 ° C for pyridine hydrochloride, and room temperature (about 15 to 25 ° C) to 60 ° C for trifluoroacetic acid. The reaction time is usually 5 minutes to 2 hours. Compound (VII)
Is produced by reacting compound (VI) with an alkyl halide and a base. The reaction solvent is an ether solvent (eg, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.), a halogen solvent (eg, dichloromethane, dichloroethane, chloroform, etc.), an aromatic solvent (eg, toluene, chlorobenzene, xylene). Etc.), acetonitrile, N, N-
Dimethylformylamide (DMF), N-methylpyrrolidone (NMP), acetone, methylethylketone, dimethylsulfoxide (DMSO) and the like can be used alone or as a mixture thereof. Above all, DMF and NM
P, DMSO, tetrahydrofuran and the like are preferable. Examples of the base used in the reaction include sodium hydride, sodium hydroxide, potassium hydroxide, hydrogen carbonate and carbonate,
Triethylamine, diisopropylethylamine, 1,
Organic bases such as 8-diazabicyclo [5,4-b] undecene can also be used. This reaction is usually 1 to 5 equivalents of alkyl halide, preferably 1 to the compound (VI).
To 3 equivalents. The reaction temperature is room temperature (about 15 to 25 ° C.) to 500 ° C., and the reaction time is usually 5 minutes to 100 hours. In addition, in this reaction, the reaction may proceed more smoothly by coexisting sodium iodide and potassium iodide.

Compound (II) as shown in Production Method 1 to 3,
(III), (IV), (V), (VI) and (VII) may form a salt, and the salt is the same as the salt of compound (I). Further, the compounds (II), (III), (IV), (V), (VI) and (VII) may be hydrates. Compound (II), (II
I), (IV), (V), (VI) and (VII) are known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 which may have a substituent.
Alkylcarbonyl (eg acetyl, propionyl etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.), phenyloxycarbonyl (eg benzoxycarbonyl etc.) , C _7-10 aralkyloxycarbonyl (eg, benzyloxycarbonyl, etc.), trityl, phthaloyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl,
(Propionyl, butyryl, etc.), nitro group, etc. are used, and the number of substituents is about 1 to 3. As the carboxyl group-protecting group, for example, C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. To be As these substituents, a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc. are used, and the number of substituents is 1 to 3
It is about an individual.

Examples of the protective group for the hydroxy group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-alkyl).
Butyl, etc.), phenyl, C _7-10 aralkyl (eg,
Benzyl, etc.), C _1-6 alkylcarbonyl (eg,
Acetyl, propionyl etc.), formyl, phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), pyranyl, furanyl, silyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10
Aralkyl, nitro group, etc. are used, and the number of substituents is 1
Or about 4 pieces. In addition, as a method for introducing and removing a protecting group, a known method or a method similar thereto (for example,
The method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press Co.) is used. A method of treating with sodium methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

The thus-obtained compound (I) of the present invention or a salt thereof can be isolated and purified by an ordinary separation means such as recrystallization, distillation and chromatography. Thus, when the compound of the present invention is obtained as a free form, it can be converted into a salt by a known method or a method analogous thereto, and conversely, when it is obtained as a salt,
The free form or other salt can be converted by a known method or a method analogous thereto. Compound (I) or a salt thereof may have an asymmetric carbon, but when it is obtained as a mixture (racemate) of optically active substances, it should be separated into each optically active substance by a usual optical resolution means. You can

The compound (I) of the present invention or a salt thereof has an excellent IL-8 inhibitory action (in particular, an IL-8 production inhibitory action) and has low toxicity. Moreover, it is excellent in oral absorbability and duration of action, and also excellent in stability and pharmacokinetics. Therefore, the compound of the present invention is a mammal (eg, human, monkey,
Bovine, horse, dog, cat, rabbit, rat, mouse, etc.) as a prophylactic / therapeutic agent for IL-8-related diseases. Examples of IL-8-related diseases include allergic diseases (asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), etc.), inflammatory diseases (pain fever, retinopathy, nephropathy, neuropathy, large blood vessel). Diabetic complications such as disorders, rheumatism, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, arthritis such as periosteum, low back pain, gout, inflammation after surgery / trauma, remission of swelling,
Neuralgia, pharyngitis, cystitis, chronic hepatitis, acute pancreatitis, chronic pancreatitis, Crohn's disease, inflammatory bowel disease such as ulcerative colitis, meningitis, inflammatory eye disease, pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc. It is useful as a prophylactic / therapeutic agent for inflammatory lung diseases, etc.). Especially chronic obstructive pulmonary disease (COP
D) It is useful as a prophylactic / therapeutic agent, a prophylactic / therapeutic agent for rheumatism, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, and periosteum.

The pharmaceutical preparation of the present invention containing the compound (I) of the present invention has low toxicity, and the compound of the present invention can be used as it is or as a drug according to a method known per se generally used in the production method of pharmaceutical preparations. When mixed with a physically acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets),
Safely orally or parenterally (eg, topical, rectal, intravenous administration, etc.) as a pharmaceutical preparation such as powder, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained release agents, etc. Can be administered to. The content of the present compound in the preparation of the present invention is about 0.01 to about 10 based on the total preparation.
It is 0% by weight, preferably about 0.1 to about 50% by weight, more preferably about 0.5 to about 20% by weight. The dose varies depending on the administration subject, administration route, disease, symptom, etc., but as a prophylactic / therapeutic agent for chronic obstructive pulmonary disease, for example, for a patient (body weight of about 60 kg), the active ingredient [compound of the present invention (I)] as about 0.01 to about 30
mg / kg body weight, preferably about 0.1 to about 20 mg / kg body weight, more preferably about 1 to about 20 mg / kg body weight.
It may be administered orally in 1 to several divided doses daily. Examples of the pharmacologically acceptable carrier that may be used in the production of the formulation of the present invention include various organic or inorganic carrier substances that are commonly used as formulation materials, for example, an excipient in a solid formulation, a lubricant, Examples thereof include binders and disintegrants, or solvents for liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffering agents, soothing agents, and the like. Further, if necessary, conventional additives such as antiseptics, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be appropriately used in appropriate amounts. Examples of the excipient include lactose, sucrose, D-mannitol, starch,
Examples thereof include corn starch, crystalline cellulose, and light silicic acid anhydride. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. As a disintegrant,
Examples thereof include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, surface active agents such as polyvinyl alcohol, polyvinyl pyrrolidone, Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. As the buffer, for example, phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Examples of soothing agents include benzyl alcohol and the like. Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

[0059]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in more detail below with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured with a GEMINI 200 (200 MHz) type spectrometer manufactured by Varian using tetramethylsilane as an internal standard, and all δ values are shown in ppm. The mass spectrum was measured by PLATFORM2 manufactured by Micromass. "%" Indicates percent by weight unless otherwise specified. However, the yield shows mol / mol%. Other symbols in the present specification have the following meanings. s: singlet d: doublet t: triplet dt: double triplet m: multiplet br: wide room temperature refers to a range of about 15 to 25 ° C., but is not particularly limited.

[0060]

EXAMPLES Reference Example 1 [(6-Cyano-1,3-benzodioxol-5-ii
Ethyl) amino] ethyl acetate 6-amino-1,3-benzodioxole-5-carbonitrile (6.92 g) and ethyl bromoacetate (1
0.69 g), baking soda (6.45 g), ethanol (30
(mL) mixture was heated to reflux for 25 hours. The reaction mixture was poured into pure water (200 mL), and ethyl acetate (200 m
L). The organic layer was washed with saturated brine (50 mL), dried over magnesium sulfate, and concentrated to dryness to give a solid. This was ground in diethyl ether (50 mL) to give a powder. This powder was collected by filtration, washed three times with diethyl ether (10 mL), and dried under reduced pressure to give the title compound (6.80 g, yield 64%). ¹ H-NMR (CDCl ₃ ) δ 1.31 (3H, t, J = 7.0Hz), 3.93 (2H,
d, J = 5.8Hz), 4.26 (2H, q, J = 7.0Hz), 5.02 (1H, bt, J
= 5.8Hz), 5.95 (2H, s), 6.13 (1H, s), 6.81 (1H, s).

Reference Example 2 7-Amino-5H- [1,3] dioxolo [4,5-
f] A mixture of ethyl tert-butoxy potassium indole-6-carboxylate (3.05 g) and tetrahydrofuran (15 mL) was stirred for 1 hour under ice cooling, and then added to tetrahydrofuran of the compound of Reference Example 1 (6.80 g). The solution (50 mL) was added dropwise over 1 hour, and the obtained green-yellow suspension was further stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (400 mL), the obtained precipitate was collected by filtration, washed with pure water (5 mL) three times, and dried under reduced pressure to give the title compound (4.57 g, yield 67%). It was ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, t, J = 7.2Hz), 4.37 (2H,
q, J = 7.2Hz), 4.59 (2H, bs), 5.96 (2H, s), 6.68 (1H,
s), 6.86 (1H, s), 7.27 (1H, s), 7.75 (1H, bs).

Reference Example 3 7,9-Dihydro-8H- [1,3] dioxolo [4,4
5-f] pyrimido [5,4-b] indole-8-one The compound of Reference Example 2 (4.57 g) and formamide (7 m
The mixture with L) was heated with stirring in an oil bath at 140 ° C. for 2.5 hours. The brown powder produced was left to cool and collected by filtration to obtain N, N-
A 1: 3 mixture of dimethylformamide and isopropanol (4 mL), followed by 3% isopropanol (4 mL).
The extract was washed once with diethyl ether (4 mL) and dried under reduced pressure to give the title compound (3.84 g, yield 91%). ¹ H-NMR (DMSO-d ₆ ) δ 6.08 (2H, s), 6.95 (1H, s), 7.
34 (1H, s), 7.93 (1H, s), 11.95 (1H, s), 12.21 (1H,
bs).

Reference Example 4 8-Chloro-9H- [1,3] dioxolo [4,5-
f] pyrimido [5,4-b] indole The compound of Reference Example 3 (10 g) and phosphorus oxychloride (4 m
A mixture consisting of L) and N, N-diethylaniline (1 mL) was heated under reflux for 8 hours. Excess phosphorus oxychloride was distilled off under reduced pressure, and the residue was poured into ice water (150 mL). Ethyl acetate (100 mL) was added to this, and the deposited reference example 3
After removing the compound by filtration, the aqueous layer was washed with ethyl acetate (50
mL). The organic layers were combined and 1M citric acid (3
It was washed twice with 0 mL). The combined washing solution was extracted with ethyl acetate (25 mL). The combined organic layers were dried over magnesium sulfate, and the concentrated residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1: 3, v / v) to give the title compound (0.
34 g, yield 32%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 6.18 (2H, s), 7.13 (1H, s), 7.
61 (1H, s), 8.73 (1H, s), 12.25 (1H, bs).

Reference Example 5 [(7-Cyano-2,3-dihydro-1,4-benzodi
Oxyn-6-yl) amino] ethyl acetate Using 7-amino-2,3-dihydro-1,4-benzodioxin-6-carbonitrile, the same operation as in Reference Example 1 was performed to synthesize the title compound. Yield 72% ¹ H-NMR (CDCl ₃ ) δ 1.30 (3H, t, J = 7.2Hz), 3.89 (2H,
d, J = 5.1Hz), 4.15-4.30 (6H, m), 4.81 (1H, br), 6.05
(1H, s), 6.96 (1H, s). Reference Example 6 8-amino-2,3-dihydro-6H- [1,4] dio
Xino [2,3-f] indole-7-carboxylic acid ethi
Using the compounds of Le Reference Example 5, the procedure of Reference Example 2, the title compound was synthesized. Yield 49% ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, t, J = 7.4Hz), 4.20-4.45
(6H, m), 4.63 (2H, br), 6.71 (1H, s), 6.97 (1H,
s), 7.50 (1H, br). Reference Example 7 3,5,8,9-tetrahydro-4H- [1,4] dio
Xino [2,3-f] pyrimido [5,4-b] indole
Lu-4-one Using the compound of Reference Example 6, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 85% ¹ H-NMR (DMSO-d ₆ ) δ 4.20-4.35 (4H, m), 6.91 (1H,
s), 7.34 (1H, s), 7.92 (1H, s), 11.68 (1H, s), 12.2
2 (1H, s). Reference Example 8 4-chloro-8,9-dihydro-5H- [1,4] dio
Xino [2,3-f] pyrimido [5,4-b] indole
The title compound was synthesized in the same manner as in Reference Example 4 using the compound of Reference Example 7. Yield 59% ¹ H-NMR (DMSO-d ₆ ) δ 4.20-4.50 (4H, m), 7.07 (1H,
s), 7.63 (1H, s), 8.73 (1H, s), 12.00 (1H, s). Reference Example 9 [2-Cyano-4- (cyclopentyloxy) -5-me
Toxianilino] ethyl acetate 2-cyano-4-cyclopentyloxy-5-methoxyaniline was used to perform the same operation as in Reference Example 1 to synthesize the title compound. Yield 63% ¹ H-NMR (CDCl ₃ ) δ 1.30 (3H, t, J = 7.2Hz), 1.70-7.95
(8H, m), 3.85 (3H, s), 3.97 (2H, d, J = 5.4Hz), 4.26
(2H, q, J = 7.2Hz), 4.55-4.70 (1H, m), 4.80-4.95 (1
H, m), 6.06 (1H, s), 6.89 (1H, s). Reference Example 10 3-Amino-5- (cyclopentyloxy) -6-meth
Ethyl xy-1H-indole-2-carboxylate Using the compound of Reference Example 9, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 47% ¹ H-NMR (CDCl ₃ ) δ 1.40 (3H, t, J = 7.4Hz), 1.70-2.00
(8H, m), 3.88 (3H, s), 4.37 (2H, q, J = 7.4Hz), 4.50-
4.80 (2H, m), 4.80-4.85 (1H, m), 6.68 (1H, s), 6.91
(1H, s), 7.60-7.70 (1H, br).

Reference Example 11 8- (Cyclohexyloxy) -7-methoxy-3,5
-Dihydro-4H-pyrimido [5,4b] indole-
4-one Using the compound of Reference Example 10, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 83% ¹ H-NMR (DMSO-d ₆ ) δ 1.50-2.00 (8H, m), 3.84 (3H,
s), 4.80-4.86 (1H, m), 6.94 (1H, s), 7.33 (1H, s),
7.92 (1H, s), 8.00 (1H, br), 11.80 (1H, br). Reference Example 12 4-chloro-8- (cyclohexyloxy) -7-meth
Xy-5H-pyrimido [5,4-b] indole Using the compound of Reference Example 11, the same procedure as in Reference Example 4 was carried out to synthesize the title compound. Yield 94% ¹ H-NMR (DMSO-d ₆ ) δ 1.50-2.10 (8H, m), 3.92 (3H,
s), 4.85-5.00 (1H, m), 7.10 (1H, s), 7.59 (1H, s),
8.73 (1H, s), 12.12 (1H, s). Reference Example 13 [4- (benzyloxy) -2-cyano-5-methoxy
Anilino] ethyl 4-benzyloxy-2-cyano-5-methoxyaniline was used to perform the same operation as in Reference Example 1 to synthesize the title compound. Yield 100% ¹ H-NMR (CDCl ₃ ) δ 1.29 (3H, t, J = 7.2Hz), 3.89 (3H,
s), 3.97 (2H, d, J = 5.4Hz), 4.26 (2H, q, J = 7.2Hz),
4.92 (1H, t, J = 5.4Hz), 5.02 (2H, s), 6.07 (1H, s),
6.90 (1H, s), 7.25-7.50 (5H, m). Reference Example 14 3-Amino-5-benzyloxy-6-methoxy-1H
-Ethyl indole-2-carboxylate Using the compound of Reference Example 13, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 74% ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, t, J = 6.8Hz), 3.91 (3H,
s), 4.36 (2H, q, J = 6.8Hz), 4.40-4.70 (2H, br), 5.1
5 (2H, s), 6.71 (1H, s), 6.94 (1H, s), 7.30-7.50
(5H, m), 7.68 (1H, s). Reference Example 15 8-benzyloxy-7-methoxy-3,5-dihydro
-4H-Pyrimido [5,4b] indole-4-one Using the compound of Reference Example 14, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 75% ¹ H-NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 5.17 (2H, s), 6.
97 (1H, s), 7.30-7.55 (6H, m), 7.91 (1H, s), 11.83
(1H, s), 12.17 (1H, s).

Reference Example 16 8-Benzyloxy-4-chloro-7-methoxy-5H
-Pyrimido [5,4-b] indole Using the compound of Reference Example 15, the same operation as in Reference Example 4 was carried out to synthesize the title compound. Yield 31% ¹ H-NMR (DMSO-d ₆ ) δ 3.95 (3H, s), 5.23 (2H, s), 7.
13 (1H, s), 7.30-7.60 (5H, m), 7.72 (1H, s), 8.72
(1H, s), 12.12 (1H, s). Reference Example 17 (2-Cyano-4-ethylanilino) ethyl acetate 2-Cyano-4-ethylaniline was used and the same operation as in Reference Example 1 was carried out to give the title compound. Was synthesized. Yield 93% ¹ H-NMR (CDCl ₃ ) δ 1.18 (3H, t, J = 7.5Hz), 1.30 (3H,
t, J = 7.1Hz), 2.54 (2H, q, J = 7.5Hz), 3.97 (2H, d, J =
2.9Hz), 4.26 (2H, q, J = 7.1Hz), 5.00 (1H, bt, J = 2.
9Hz), 6.50 (1H, d, J = 9.6Hz), 7.21-7.27 (2H, m). Reference Example 18 3-Amino-5-ethyl-1H -indole -2-cal
Ethyl bonate Using the compound of Reference Example 17, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 61% ¹ H-NMR (CDCl ₃ ) δ 1.28 (3H, t, J = 7.6Hz), 1.41 (3H,
t, J = 7.1Hz), 2.73 (2H, q, J = 7.6Hz), 4.39 (2H, q, J =
7.1Hz), 4.72 (2H, bs), 7.18 (2H, m), 7.34 (1H, s),
7.72 (1H, bs). Reference Example 19 8-Ethyl-3,5-dihydro-4H-pyrimido [5,
4b] Indol-4-one Using the compound of Reference Example 18, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 71% ¹ H-NMR (DMSO-d ₆ ) δ 1.25 (3H, t, J = 7.6Hz), 2.75 (2
H, q, J = 7.6Hz), 7.33 (1H, d, J = 8.4Hz), 7.45 (1H,
d, J = 8.4Hz), 7.79 (1H, s), 7.98 (1H, s), 11.96 (1
H, bs), 12.31 (1H, bs). Reference Example 20 4-chloro-8-ethyl-5H-pyrimido [5,4-
b] Indole Using the compound of Reference Example 19, the same operation as in Reference Example 4 was carried out to synthesize the title compound. Yield 66% ¹ H-NMR (CDCl ₃ ) δ 1.34 (3H, t, J = 7.5Hz), 2.85 (2H,
q, J = 7.5Hz), 7.47-7.58 (2H, m), 8.18 (1H, s), 8.54
(1H, bs), 8.91 (1H, s).

Reference Example 21 (2-Cyano-4-isopropylanilino) ethyl acetate Using 2-cyano-4-isopropylaniline, the same operation as in Reference Example 1 was carried out to synthesize the title compound. Yield 9
6% ¹ H-NMR (CDCl ₃ ) δ 1.19 (6H, d, J = 6.6Hz), 1.28 (3H,
t, J = 7.5Hz), 2.75-2.90 (1H, m), 3.97 (2H, d, J = 5.4H
z), 4.23 (2H, q, J = 7.5Hz), 4.95-5.10 (1H, m), 6.50
(1H, d, J = 9.0Hz), 7.25-7.35 (2H, m). Reference Example 22 3-Amino-5-isopropyl-1H -indole -2
-Ethyl carboxylate Using the compound of Reference Example 21, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 41% ¹ H-NMR (CDCl ₃ ) δ 1.29 (6H, d, J = 7.0Hz), 1.41 (3H,
t, J = 6.8Hz), 2.90-3.10 (1H, m), 4.39 (2H, q, J = 6.8H
z), 4.50-4.85 (2H, br), 7.15-7.21 (2H, m), 7.36 (1
H, s), 7.60-7.85 (1H, br). Reference Example 23 8-isopropyl-3,5-dihydro-4H-pyrimido
[5,4b] Indol-4-one Using the compound of Reference Example 22, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 76% ¹ H-NMR (DMSO-d ₆ ) δ 1.28 (6H, d, J = 7.0Hz), 2.95-3.
20 (1H, m), 7.37 (1H, dd, J = 1.8, 8.8Hz), 7.46 (1H,
d, J = 8.8Hz), 7.81 (1H, d, J = 1.8Hz), 7.98 (1H, s),
11.90-12.40 (2H, br). Reference Example 24 8-isopropyl-4-chloro-5H-pyrimido [5,
4-b] Indole Using the compound of Reference Example 23, the same operation as in Reference Example 4 was performed to synthesize the title compound. Yield 77% ¹ H-NMR (DMSO-d ₆ ) δ 1.37 (6H, d, J = 6.6Hz), 3.00-3.
30 (1H, m), 7.50-7.80 (3H, m), 8.46 (1H, s), 9.02
(1H, s). Reference Example 25 (2-Cyano-4-trifluoromethoxyanilino) vinegar
Using ethyl 2-cyano-4-trifluoromethoxyaniline as an acid salt, the same operation as in Reference Example 1 was performed to synthesize the title compound. Yield 6% ¹ H-NMR (CDCl ₃ ) δ 1.32 (3H, t, J = 7.1Hz), 3.99 (2H,
d, J = 5.6Hz), 4.28 (2H, q, J = 7.1Hz), 5.00 (1H, bt, J
= 5.6Hz), 6.55 (1H, d, J = 8.8Hz), 7.26-7.32 (2H, m).

Reference Example 26 3-Amino-5-trifluoromethoxy-1H-indo
Ethyl-2-yl-2-carboxylate Using the compound of Reference Example 25, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 76% ¹ H-NMR (CDCl ₃ ) δ 1.42 (3H, t, J = 7.1Hz), 4.41 (2H,
q, J = 7.1Hz), 4.70 (2H, bs), 7.15-7.26 (2H, m), 7.41
(1H, s), 7.93 (1H, bs). Reference Example 27 8-trifluoromethoxy-3,5-dihydro-4H-
Pyrimido [5,4b] indole-4-one Using the compound of Reference Example 26, the title compound was synthesized in the same manner as in Reference Example 3. Yield 63% ¹ H-NMR (DMSO-d ₆ ) δ 7.46 (1H, d, J = 9.2Hz), 7.64 (1
H, d, J = 9.2Hz), 7.93 (1H, s), 8.05 (1H, s), 12.46
(1H, bs). Reference Example 28 4-chloro-8-trifluoromethoxy-5H-pyrimy
Dod [5,4-b] indole Using the compound of Reference Example 27, the same operation as in Reference Example 4 was carried out to synthesize the title compound. Yield 79% ¹ H-NMR (CDCl ₃ ) δ 7.53-7.66 (2H, m), 8.25 (1H, s),
8.63 (1H, bs), 8.97 (1H, s). Reference Example 29 (2-Cyano-4-trifluoromethylanilino) acetic acid
Using ethyl 2-cyano-4-trifluoromethylaniline,
The title compound was synthesized in the same manner as in Reference Example 1.
Yield 23% ¹ H-NMR (CDCl ₃ ) δ 1.32 (3H, t, J = 7.1Hz), 4.03 (2H,
d, J = 5.4Hz), 4.30 (2H, q, J = 7.1Hz), 5.52 (1H, bt, J
= 5.4Hz), 6.62 (1H, d, J = 8.8Hz), 7.63 (1H, d, J = 8.8)
Hz), 7.69 (1H, s). Reference Example 30 3-amino-5-trifluoromethyl-1H-indo-
Ethyl 2-carboxylate Using the compound of Reference Example 29, the same operation as in Reference Example 2 was carried out to synthesize the title compound. Yield 63% ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, t, J = 7.1Hz), 4.42 (2H,
q, J = 7.1Hz), 4.82 (2H, bs), 7.34 (1H, d, J = 8.7Hz),
7.53 (1H, d, J = 8.7Hz), 7.87 (1H, s), 8.06 (1H, b
s).

Reference Example 31 8-Trifluoromethyl-3,5-dihydro-4H-pi
Limid [5,4b] indole-4-one Using the compound of Reference Example 30, the same operation as in Reference Example 3 was carried out to synthesize the title compound. Yield 32% ¹ H-NMR (DMSO-d ₆ ) δ 7.45 (3H, m), 8.10 (1H, s), 8.
33 (1H, bs). Reference Example 32 4-chloro-8-trifluoromethyl-5H-pyrimido
[5,4-b] indole Using the compound of Reference Example 31, the same operation as in Reference Example 4 was performed to synthesize the title compound. Yield 36% ¹ H-NMR (CDCl ₃ ) δ 7.71 (1H, d, J = 8.6Hz), 7.93 (1H,
d, J = 8.6Hz), 8.71 (1H, s), 8.77 (1H, bs), 9.00 (1H,
s).

Reference Example 33 4-chloro-7,8-dimethoxy-5-methylpyrimide
[5,4-b] Indole 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole (150 mg), methyl iodide (0.071 mL), sodium hydride (46 mg).
The DMF (1 mL) solution of was stirred at 0 ° C. for 15 minutes,
It was added to water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure,
The title compound was obtained as a pale yellow solid (120 mg, yield 76%). ¹ H-NMR (DMSO-d ₆ ) δ 3.89 (3H, s), 3.99 (3H, s), 4.
19 (3H, s), 7.39 (1H, s), 7.65 (1H, s), 8.71 (1H,
s).

Reference Example 34 4-chloro-7,8-dimethoxy-5-ethylpyrimide
[5,4-b] indole The title compound was synthesized in the same manner as in Reference Example 33. MS m / z = 292 (M + 1). Reference Example 35 4-chloro-7,8-dimethoxy-5-propylpyrimy
Do [5,4-b] indole The title compound was synthesized in the same manner as in Reference Example 33. MS m / z = 306 (M + 1).

Example 1 7,8-Dimethoxy-4- (3-phenoxyphenyl)
Amino-5H-pyrimido [5,4-b] indole 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole (0.090 g) and 3-phenoxyaniline (0.278 g) A mixture of N-methylpyrrolidone (0.5 mL) was stirred at 140 ° C for 2 hours. The precipitated solid was collected by filtration and washed with isopropyl alcohol three times. The solid was neutralized by adding 5 mL of a 1N sodium hydroxide aqueous solution, the precipitated powder was collected by filtration, washed with pure water, and dried under reduced pressure to give the title compound (0.080
g, yield 65%) was obtained. MS m / z = 413 (M + 1).

Example 2 4- (3-chlorophenyl) amino-7,8-dimethoxy
The title compound was synthesized by the same procedure as in Example 1 using ci-5H-pyrimido [5,4-b] indole 3-chloroaniline. Yield 75% MS m / z = 355 (M + 1). Example 3 7,8-dimethoxy-4- (3-fluorophenyl) a
The title compound was synthesized by the same procedure as in Example 1 using mino-5H-pyrimido [5,4-b] indole 3-fluoroaniline. Yield 78% MS m / z = 339 (M + 1). Example 4 4- (2-chlorophenyl) amino-7,8-dimethoxy
The title compound was synthesized in the same manner as in Example 1 except that ci-5H-pyrimido [5,4-b] indole 2-chloroaniline was used. Yield 55% MS m / z = 355 (M + 1). Example 5 7,8-Dimethoxy-4- (2-fluorophenyl) a
The title compound was synthesized by the same procedure as in Example 1 using mino-5H-pyrimido [5,4-b] indole 2-fluoroaniline. Yield 54% MS m / z = 339 (M + 1).

Example 6 7,8-dimethoxy-4- (3-isopropylphenyl)
Ru) Amino-5H-pyrimido [5,4-b] indole Using 3-isopropylaniline, the title compound was synthesized in the same manner as in Example 1. Yield 49% MS m / z = 363 (M + 1). Example 7 7,8-Dimethoxy-4- (2-methylphenyl) ami
Using no-5H-pyrimido [5,4-b] indole o-toluidine, the same procedure as in Example 1 was carried out,
The title compound was synthesized. Yield 74% MS m / z = 335 (M + 1). Example 8 4-[(1,1'-biphenyl) -3-yl] amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 3- phenylaniline to synthesize the title compound. Yield 50% MS m / z = 397 (M + 1). Example 9 4-[(1,1'-biphenyl) -2-yl] amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 2- phenylaniline to synthesize the title compound. Yield 59% MS m / z = 397 (M + 1). Example 10 7,8-Dimethoxy-4-methylphenylamino-5H
Using -pyrimido [5,4-b] indole N-methylaniline, the title compound was synthesized in the same manner as in Example 1. Yield 27% MS m / z = 335 (M + 1).

Example 11 7,8-Dimethoxy-4- (3-methylphenyl) ami
Using no-5H-pyrimido [5,4-b] indole m-toluidine, the same procedure as in Example 1 was carried out,
The title compound was synthesized. Yield 90% MS m / z = 335 (M + 1). Example 12 4- (2,4-difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 2,4-difluoroaniline. Yield 80% MS m / z = 357 (M + 1). Example 13 4- (2,6-difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 2,6-difluoroaniline. Yield 54% MS m / z = 357 (M + 1). Example 14 4- (3,4-difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 3,4-difluoroaniline. Yield 100% MS m / z = 357 (M + 1). Example 15 4- (2,3-Difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 2,3-difluoroaniline. Yield 26% MS m / z = 357 (M + 1).

Example 16 4- (3,5-difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 3,5-difluoroaniline. Yield 60% MS m / z = 357 (M + 1). Example 17 4- (2-chloro-4-fluorophenyl) amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 2-chloro-4-fluoroaniline to synthesize the title compound. Yield 88% MS m / z = 373 (M + 1). Example 18 4- (4-chloro-2-fluorophenyl) amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 4-chloro-2-fluoroaniline to synthesize the title compound. Yield 84% MS m / z = 373 (M + 1). Example 19 4- (3-chloro-4-fluorophenyl) amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 3-chloro-4-fluoroaniline to synthesize the title compound. Yield 91% MS m / z = 373 (M + 1). Example 20 4- (5-Fluoro-2-methylphenyl) amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 5-fluoro-2-methylaniline to synthesize the title compound. Yield 74% MS m / z = 353 (M + 1).

Example 21 4- (2-Bromophenyl) amino-7,8-dimethoxy
The title compound was synthesized by the same procedure as in Example 1 using ci-5H-pyrimido [5,4-b] indole 2-bromoaniline. Yield 34% MS m / z = 401 (M + 2). Example 22 4- (3-Bromophenyl) amino-7,8-dimethoxy
The title compound was synthesized by the same procedure as in Example 1 using ci-5H-pyrimido [5,4-b] indole 3-bromoaniline. Yield 77% MS m / z = 401 (M + 2). Example 237,8-dimethoxy-4- (2,3,4-trichlorophle
Phenyl) amino-5H-pyrimido [5,4-b] indo
Using Lumpur 2,3,4-trichloroaniline, the procedure of Example 1, the title compound was synthesized. Yield 43% MS m / z = 423 (M + 1). Example 24 4- (2,5-dibromophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,5-dibromoaniline. Yield 42% MS m / z = 477 (M + 1). Example 25 4- (2-Fluoro-4-methylphenyl) amino-
7,8-Dimethoxy-5H-pyrimido [5,4-b] ii
The same operation as in Example 1 was carried out using ndol 2-fluoro-4-methylaniline to synthesize the title compound. Yield 80% MS m / z = 353 (M + 1).

Example 26 4- (4-bromo-2-methylphenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indo
Using Lumpur 4-bromo-2-methylaniline, following the procedure of Example 1, the title compound was synthesized. Yield 82% MS m / z = 413 (M + 1). Example 27 4- (2,5-difluorophenyl) amino-7,8-
The title compound was synthesized by the same procedure as in Example 1 using dimethoxy-5H-pyrimido [5,4-b] indole 2,5-difluoroaniline. Yield 93% MS m / z = 357 (M + 1). Example 28 7,8-Dimethoxy-4- (2-methoxyphenyl) a
The title compound was synthesized in the same manner as in Example 1 using mino-5H-pyrimido [5,4-b] indole 2-methoxyaniline. Yield 77% MS m / z = 351 (M + 1). Example 29 7,8-Dimethoxy-4- (3-methoxyphenyl) a
The title compound was synthesized by the same procedure as in Example 1 using mino-5H-pyrimido [5,4-b] indole 3-methoxyaniline. Yield 92% MS m / z = 351 (M + 1). Example 30 4- (3-Cyanophenyl) amino-7,8-dimethoxy
Using si-5H-pyrimido [5,4-b] indole 3-cyanoaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 64% MS m / z = 346 (M + 1).

Example 31 1- {3-[(7,8-dimethoxy-5H-pyrimido
[5,4-b] Indol-4-yl) amino] pheny
Using Le} ethanone 3-aminophenyl-ethanone was obtained in the same manner as in Example 1, the title compound was synthesized. Yield 77% MS m / z = 363 (M + 1). Example 32 7,8-Dimethoxy-4- (3-trifluoromethylphenyl)
Phenyl) amino-5H-pyrimido [5,4-b] indo
The title compound was synthesized in the same manner as in Example 1 by using benzyl 3-trifluoromethylaniline. Yield 89% MS m / z = 389 (M + 1). Example 33 7,8-Dimethoxy-4- (2-trifluoromethylphenyl)
Phenyl) amino-5H-pyrimido [5,4-b] indo
Using Lumpur 2-trifluoromethyl aniline was obtained in the same manner as in Example 1, the title compound was synthesized. Yield 55% MS m / z = 389 (M + 1). Example 34 4- (2,3-dichlorophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,3-dichloroaniline. Yield 25% MS m / z = 389 (M + 1). Example 35 4- (2,4-dichlorophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,4-dichloroaniline. Yield 31% MS m / z = 389 (M + 1).

Example 36 4- (2,5-dichlorophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,5-dichloroaniline. Yield 23% MS m / z = 389 (M + 1). Example 37 4- (3,4-dichlorophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 3,4-dichloroaniline. Yield 45% MS m / z = 389 (M + 1). Example 38 4- (3,5-dichlorophenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 3,5-dichloroaniline. Yield 39% MS m / z = 389 (M + 1). Example 39 4- (3-chloro-2-methylphenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indo
Using 3-chloro-2-methylaniline, the title compound was synthesized in the same manner as in Example 1. Yield 42% MS m / z = 369 (M + 1). Example 40 4- (3-chloro-4-methylphenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indo
Using 3-chloro-4-methylaniline, the title compound was synthesized in the same manner as in Example 1. Yield 45% MS m / z = 369 (M + 1).

Example 41 4- (5-chloro-2-methylphenyl) amino-7,
8-dimethoxy-5H-pyrimido [5,4-b] indo
Using Lumpur 5-chloro-2-methylaniline, following the procedure of Example 1, the title compound was synthesized. Yield 34% MS m / z = 369 (M + 1). Example 42 4- (2,3-Dimethylphenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 using methoxy-5H-pyrimido [5,4-b] indole 2,3-dimethylaniline. Yield 44% MS m / z = 349 (M + 1). Example 43 4- (2,4-Dimethylphenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,4-dimethylaniline. Yield 16% MS m / z = 349 (M + 1). Example 44 4- (2,5-Dimethylphenyl) amino-7,8-di
The title compound was synthesized by the same procedure as in Example 1 using methoxy-5H-pyrimido [5,4-b] indole 2,5-dimethylaniline. Yield 45% MS m / z = 349 (M + 1). Example 45 4- (2,6-Dimethylphenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 2,6-dimethylaniline. Yield 11% MS m / z = 349 (M + 1).

Example 46 4- (3,4-dimethylphenyl) amino-7,8-di
The title compound was synthesized in the same manner as in Example 1 by using methoxy-5H-pyrimido [5,4-b] indole 3,4-dimethylaniline. Yield 52% MS m / z = 349 (M + 1). Example 47 7,8-Dimethoxy-4- (2-ethylphenyl) ami
The title compound was synthesized in the same manner as in Example 1 except that no-5H-pyrimido [5,4-b] indole 2-ethylaniline was used. Yield 33% MS m / z = 349 (M + 1). Example 48 7,8-Dimethoxy-4- (3-ethylphenyl) ami
The title compound was synthesized in the same manner as in Example 1 except that no-5H-pyrimido [5,4-b] indole 3-ethylaniline was used. Yield 55% MS m / z = 349 (M + 1). Example 49 7,8-Dimethoxy-4- (3-ethynylphenyl) a
Using mino-5H-pyrimido [5,4-b] indole 3-ethynylaniline, the title compound was synthesized in the same manner as in Example 1. Yield 53% MS m / z = 345 (M + 1). Example 50 8-Benzyloxy-4-phenylamino-7-methoxy
Si-5H-pyrimido [5,4-b] indole Using the compound of Reference Example 16 and aniline, the same procedure as in Example 1 was carried out to synthesize the title compound. Yield 93% ¹ H-NMR (DMSO-d ₆ ) δ 3.97 (3H, s), 5.19 (2H, s), 7.
17 (1H, t, J = 7.6Hz), 7.33 (1H, s), 7.30-7.60 (7H,
m), 7.72 (1H, s), 7.93 (2H, d, J = 7.6Hz), 8.75 (1H,
s), 10.60 (1H, s), 12.02 (1H, s).

Example 51 8,9-Dihydro-4-phenylamino-5H- [1,
4] Dioxino [2,3-f] pyrimido [5,4-b]
The title compound was synthesized by the same procedure as in Example 1 using the compound of Indole Reference Example 8 and aniline. Yield 62% MS m / z = 319 (M + 1). Example 52 8-Phenylamino-9H- [1,3] dioxolo
[4,5-f] Pyrimido [5,4-b] indole Using the compound of Reference Example 4 and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 77% MS m / z = 305 (M + 1). Example 53 8-Chloro-4-phenylamino-5H-pyrimido
Using [5,4-b] indole 4,8-dichloro-5H-pyrimido [5,4-b] indole and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 23% MS m / z = 2
95 (M + 1). Example 54 8-Chloro-4- (3-chlorophenyl) amino-5H
-Pyrimido [5,4-b] indole 4,8-dichloro-5H-pyrimido [5,4-b] indole and 3-chloroaniline were subjected to the same operations as in Example 1 to synthesize the title compound. . Yield 33% MS m / z = 329 (M + 1). Example 55 8-Chloro-4- (4-chlorophenyl) amino-5H
-Pyrimido [5,4-b] indole 4,8-dichloro-5H-pyrimido [5,4-b] indole and 4-chloroaniline were subjected to the same operations as in Example 1 to synthesize the title compound. .. Yield 48% MS m / z = 329 (M + 1).

Example 56 8-Methyl-4-phenylamino-5H-pyrimido
[5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] Using indole and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 40% MS m / z = 275 (M + 1). Example 57 4- (2-chlorophenyl) amino-8-methyl-5H
-Pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] Example 1 using indole and 2-chloroaniline
The title compound was synthesized in the same manner as in. Yield 69
% MS m / z = 309 (M + 1). Example 58 4- (3-chlorophenyl) amino-8-methyl-5H
-Pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] Example 1 using indole and 3-chloroaniline
The title compound was synthesized in the same manner as in. Yield 34
% ¹ H-NMR (DMSO-d ₆ ) δ 2.50 (3H, s), 7.11 (1H, d, J =
7.6Hz), 7.38-7.46 (2H, m), 7.65-7.69 (2H, m), 7.93
(1H, m), 8.29 (1H, bs), 8.60 (1H, s), 9.51 (1H, b
s), 11.06 (1H, bs). Example 59 4- (4-chlorophenyl) amino-8-methyl-5H
-Pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] Example 1 using indole and 4-chloroaniline
The title compound was synthesized in the same manner as in. Yield 87
% MS m / z = 309 (M + 1). Example 60 4- (2,5-Dichlorophenyl) amino-8-methyl
-5H-pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] Using indole and 2,5-dichloroaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 64% MS m / z = 345 (M + 2).

Example 61 8-Ethyl-4-phenylamino-5H-pyrimido
[5,4-b] indole Using the compound of Reference Example 20 and aniline, the same procedure as in Example 1 was carried out to synthesize the title compound. Yield 75% MS m / z = 289 (M + 1). Example 62 4- (2-chlorophenyl) amino-8-ethyl-5H
-Pyrimido [5,4-b] indole The title compound was synthesized by the same procedure as in Example 1 using the compound of Reference Example 20 and 2-chloroaniline. Yield 67% MS m / z = 323 (M + 1). Example 63 4- (3-chlorophenyl) amino-8-ethyl-5H
-Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 3-chloroaniline, the title compound was synthesized in the same manner as in Example 1. Yield 79% MS m / z = 323 (M + 1). Example 64 4- (4-chlorophenyl) amino-8-ethyl-5H
-Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 4-chloroaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 84% MS m / z = 323 (M + 1). Example 65 4- (2,5-Dichlorophenyl) amino-8-ethyl
-5H-Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 2,5-dichloroaniline, the title compound was synthesized in the same manner as in Example 1. Yield 58% MS m / z = 357 (M).

Example 66 4- (5-chloro-2-fluorophenyl) amino-8
-Ethyl-5H-pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 5-chloro-2-fluoroaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 68% MS m / z = 341 (M + 1). Example 67 4-Phenylamino-8-isopropyl-5H-pyrimyi
Do [5,4-b] indole Using the compound of Reference Example 24 and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 34% ¹ H-NMR (DMSO-d ₆ ) δ 1.31 (6H, d, J = 6.9Hz), 3.00-3.
20 (1H, m), 7.05 (1H, t, J = 7.5Hz), 7.39 (2H, t, J =
7.5Hz), 7.47 (1H, d, J = 8.7Hz), 7.66 (1H, d, J = 8.7H)
z), 7.95 (2H, d, J = 7.5Hz), 7.97 (1H, s), 8.53 (1H,
s), 9.52 (1H, s), 11.42 (1H, s). Example 68 4- (3-chlorophenyl) amino-8-isopropyl
-5H-pyrimido [5,4-b] indole Using the compound of Reference Example 24 and 3-chloroaniline, the title compound was synthesized in the same manner as in Example 1. Yield 28% ¹ H-NMR (DMSO-d ₆ ) δ 1.31 (6H, d, J = 6.6Hz), 3.00-3.
20 (1H, m), 7.10 (1H, dd, J = 1.2, 7.8Hz), 7.40 (1H,
d, J = 8.0Hz), 7.50 (1H, dd, J = 2.0, 8.8Hz), 7.65-7.7
5 (2H, m), 7.97 (1H, d, J = 1.2Hz), 8.29 (1H, d, J =
2.0Hz), 8.60 (1H, s), 9.53 (1H, s), 11.08 (1H, s). Example 69 8-Methoxy-4-phenylamino-5H-pyrimido
[5,4-b] indole 4-chloro-8-methoxy-5H-pyrimido [5,4-
b] Using indole and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 76% ¹ H-NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 7.06 (1H, t, J =
7.5Hz), 7.20 (1H, dd, J = 2.6, 8.8Hz), 7.40 (2H, t,
J = 7.5Hz), 7.56 (1H, d, J = 2.6Hz), 7.68 (1H, d, J = 8.8
Hz), 7.92 (2H, d, J = 7.5Hz), 8.52 (1H, s), 9.34 (1
H, s), 11.08 (1H, s). Example 70 4- (2,5-Dichlorophenyl) amino-8-methoxy
Ci-5H -pyrimido [5,4-b] indole 4-chloro-8-methoxy-5H-pyrimido [5,4-
b] Using indole and 2,5-dichloroaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 32% ¹ H-NMR (DMSO-d ₆ ) δ 3.88 (3H, s), 7.20-7.40 (2H,
m), 7.60-7.75 (3H, m), 8.21 (1H, d, J = 1.4Hz), 8.62
(1H, s), 9.43 (1H, s), 11.76 (1H, s).

Example 71 4- (2-chlorophenyl) amino-8-ethoxy-5
H-pyrimido [5,4-b] indole 4-chloro-8-ethoxy-5H-pyrimido [5,4-
b] Example 1 using indole and 2-chloroaniline
The title compound was synthesized in the same manner as in. Yield 60
% ¹ H-NMR (DMSO-d ₆ ) δ 1.40 (3H, t, J = 7.0Hz), 4.14 (2
H, q, J = 7.0Hz), 7.20-7.35 (2H, m), 7.43 (1H, t, J =
8.0Hz), 7.55-7.75 (3H, m), 7.97 (1H, dd, J = 1.6, 8.
0Hz), 8.54 (1H, s), 9.45 (1H, s), 11.69 (1H, s). Example 72 4- (3-chlorophenyl) amino-8-ethoxy-5
H-pyrimido [5,4-b] indole 4-chloro-8-ethoxy-5H-pyrimido [5,4-
b] Example 1 using indole and 3-chloroaniline
The title compound was synthesized in the same manner as in. Yield 59
% ¹ H-NMR (DMSO-d ₆ ) δ 1.41 (3H, t, J = 7.0Hz), 4.13 (2
H, q, J = 7.0Hz), 7.15-7.30 (2H, m), 7.46 (1H, t, J =
8.0Hz), 7.62 (1H, s), 7.69-7.80 (2H, m), 8.28 (1H,
s), 8.74 (1H, s), 10.26 (1H, s), 11.63 (1H, s). Example 73 4- (4-chlorophenyl) amino-8-ethoxy-5
H-pyrimido [5,4-b] indole 4-chloro-8-ethoxy-5H-pyrimido [5,4-
b] Example 1 using indole and 4-chloroaniline
The title compound was synthesized in the same manner as in. Yield 62
% ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (3H, t, J = 7.0Hz), 4.13 (2
H, q, J = 7.0Hz), 7.22 (1H, dd, J = 2.6, 7.2Hz), 7.46
(2H, d, J = 9.0Hz), 7.56 (1H, d, J = 2.6Hz), 7.68 (1H,
d, J = 7.2Hz), 7.97 (2H, d, J = 9.0Hz), 8.58 (1H, s),
9.67 (1H, s), 11.19 (1H, s). Example 74 4-Phenylamino-8-trifluoromethoxy-5H
-Pyrimido [5,4-b] indole Using the compound of Reference Example 28 and aniline, the title compound was synthesized in the same manner as in Example 1. Yield 78% MS m / z = 345 (M + 1). Example 75 4- (3-chlorophenyl) amino-8-trifluoro
Methoxy-5H-pyrimido [5,4-b] indole Using the compound of Reference Example 28 and 3-chloroaniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 33% ¹ H-NMR (DMSO-d ₆ ) δ 7.10 (1H, m), 7.37-7.55 (2H,
m), 7.77 (1H, m), 7.85 (1H, d, J = 9.2Hz), 8.03 (1H,
s), 8.34 (1H, m), 8.60 (1H, s).

Example 76 4-Phenylamino-8-trifluoromethyl-5H-
Pyrimido [5,4-b] indole Using the compound of Reference Example 32 and aniline, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 82% MS m / z = 329 (M + 1). Example 77 7-Chloro-4-phenylamino-5H-pyrimido
Using [5,4-b] indole 4,7-dichloro-5H-pyrimido [5,4-b] indole and aniline, the title compound was synthesized in the same manner as in Example 1. Yield 23% ¹ H-NMR (DMSO-d ₆ ) δ 7.08 (1H, t, J = 7.4Hz), 7.31 (1
H, dd, J = 8.4Hz, J = 0.9Hz), 7.41 (2H, dd, J = 8.4Hz, J
= 7.4Hz), 7.91 (2H, d, J = 8.4Hz), 7.95 (1H, s), 8.1
4 (1H, d, J = 8.4Hz), 8.57 (1H, s), 9.47 (1H, s), 1
1.33 (1H, s).

Example 78 7,8-Dimethoxy-4-phenylsulfanyl-5H
-Pyrimido [5,4-b] indole 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole (100 mg) in N-methylpyrrolidone (1.0 mL) was added to thiophenol (40 mg).
mg) was added and the mixture was stirred at 60 ° C. for 18 hours. The reaction solution was added to water and extracted with ethyl acetate-tetrahydrofuran (1: 1). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give the title compound as a colorless solid (83 mg, yield 67%). ¹ H-NMR (DMSO-d ₆ ) δ 3.88 (3H, s), 3.92 (3H, s), 7.
09 (1H, s), 7.40-7.70 (6H, m), 8.62 (1H, s).

Example 79 4- (2-chlorophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 2-chlorothiophenol, the same procedure as in Example 78 was performed. Was performed to synthesize the title compound. Yield 47% MS m / z = 372 (M + 1). Example 80 4- (3-chlorophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 3-chlorothiophenol, the same procedure as in Example 78 was performed. Was performed to synthesize the title compound. Yield 53% MS m / z = 372 (M + 1).

Example 81 4- (4-chlorophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 4-chlorothiophenol, the same procedure as in Example 78 was performed. Was performed to synthesize the title compound. Yield 47% MS m / z = 372 (M + 1). Example 82 4- (2-Bromophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 2-bromothiophenol, the same procedure as in Example 78 was performed. Was performed to synthesize the title compound. Yield 40% MS m / z = 417 (M + 1). Example 83 4- (3-Bromophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 3-bromothiophenol, the same procedure as in Example 78 was performed. Was performed to synthesize the title compound. Yield 44% MS m / z = 417 (M + 1). Example 84 4- (4-Bromophenylsulfanyl) -7,8-di
Methoxy-5H-pyrimido [5,4-b] indole Using 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole and 4-bromothiophenol, the same procedure as in Example 78. Was performed to synthesize the title compound. Yield 42% MS m / z = 417 (M + 1). Example 85 8-Ethyl-4-phenylsulfanyl-5H-pyrimyi
[5,4-b] indole Example 7 using the compound of Reference Example 20 and thiophenol
The same operation as in 8 was performed to synthesize the title compound. Yield 5
2% MS m / z = 306 (M + 1).

Example 86 4- (2,4-difluorophenylsulfanyl) -8
-Ethyl-5H-pyrimido [5,4-b] indole The title compound was synthesized by the same procedure as in Example 78 using the compound of Reference Example 20 and 2,4-difluorothiophenol. Yield 46% MS m / z = 342 (M + 1). Example 87 4- (2-chlorophenylsulfanyl) -8-ethyl
-5H-Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 2-chlorothiophenol, the same procedure as in Example 78 was carried out to synthesize the title compound. Yield 28% MS m / z = 340 (M + 1). Example 88 4- (3-chlorophenylsulfanyl) -8-ethyl
-5H-Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 3-chlorothiophenol, the same operation as in Example 78 was carried out to synthesize the title compound. Yield 47% MS m / z = 340 (M + 1). Example 89 8-Methyl-4-phenylsulfanyl-5H-pyrimyi
De [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] The title compound was synthesized by the same procedure as in Example 78 using indole and thiophenol. Yield 72% MS m / z = 292 (M + 1). Example 90 4- (2-chlorophenylsulfanyl) -8-methyl
-5H-pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] The title compound was synthesized by the same procedure as in Example 78 using indole and 2-chlorothiophenol.
Yield 59% MS m / z = 326 (M + 1).

Example 91 4- (3-chlorophenylsulfanyl) -8-methyl
-5H-pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] The title compound was synthesized by the same procedure as in Example 78 using indole and 3-chlorothiophenol.
Yield 79% MS m / z = 326 (M + 1). Example 92 4- (4-chlorophenylsulfanyl) -8-methyl
-5H-pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] The title compound was synthesized by the same procedure as in Example 78 using indole and 4-chlorothiophenol.
Yield 59% MS m / z = 326 (M + 1). Example 93 4- (2,4-difluorophenylsulfanyl) -8
-Methyl -5H-pyrimido [5,4-b] indole 4-chloro-8-methyl-5H-pyrimido [5,4-
b] The title compound was synthesized by the same procedure as in Example 78 using indole and 2,4-difluorothiophenol. Yield 51% MS m / z = 328 (M + 1).

Example 94 7,8-Dimethoxy-4-phenylsulfinyl-5H
-Pyrimido [5,4-b] indole A solution of the compound of Example 78 (50 mg) in N-methylpyrrolidone (0.5 mL) was cooled to 0 ° C, and m-chloroperbenzoic acid (37 mg) was added. The reaction mixture was stirred at room temperature for 1 hr, and then ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10
(mL) and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound as a pale yellow solid (25 mg, yield 47).
%). ¹ H-NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 3.92 (3H, s), 7.
38 (1H, s), 7.50-7.70 (3H, m), 7.62 (1H, s), 7.90-
8.15 (2H, m), 8.87 (1H, s), 11.80-11.90 (1H, br).

Example 95 7,8-Dimethoxy-4-phenoxy-5H-pyrimide
[5,4-b] indole 4-chloro-7,8-dimethoxy-5H-pyrimido [5,4-b] indole (60 mg), phenol (108 mg), potassium carbonate (63 mg) in N, N-.
Dimethylformamide solution (0.5 mL) at 60 ° C for 1
Stir for 8 hours. The reaction mixture was extracted with ethyl acetate-water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as a colorless solid (37 mg, yield 50%). ¹ H-NMR (DMSO-d ₆ ) δ 3.89 (3H, s), 3.92 (3H, s), 7.
08 (1H, s), 7.30-7.40 (3H, m), 7.45-7.60 (2H, m),
7.60 (1H, s), 8.44 (1H, s), 12.03 (1H, s).

Example 96 7,8-Dimethoxy-4- (4-fluorophenoxy)-
Using 5H-pyrimido [5,4-b] indole 4-fluorophenol, the title compound was synthesized in the same manner as in Example 95. Yield 64% MS m / z = 340 (M + 1). Example 97 8-Cyclohexyloxy-4- (4-fluoropheno
Xy) -7-methoxy-5H-pyrimido [5,4-b]
Using the compound of Indole Reference Example 12 and 4-fluorophenol,
The title compound was synthesized in the same manner as in Example 95. Yield 28% ¹ H-NMR (DMSO-d ₆ ) δ 1.60-2.10 (8H, m), 3.98 (3H,
s), 4.80-4.95 (1H, m), 6.99 (1H, s), 7.10-7.30 (4H,
m), 7.71 (1H, s), 8.39 (1H, s), 8.62 (1H, s). Example 98 8-Ethyl-4-phenoxy-5H-pyrimido [5,4
-B] Indole Using the compound of Reference Example 20 and phenol, the same operation as in Example 95 was carried out to synthesize the title compound. Yield 58% ¹ H-NMR (DMSO-d ₆ ) δ 1.29 (3H, t, J = 7.6Hz), 2.81 (2
H, q, J = 7.6Hz), 7.25-7.40 (3H, m), 7.45-7.60 (4H,
m), 8.02 (1H, s), 8.51 (1H, s), 12.17 (1H, s). Example 99 8-Ethyl-4- (4-fluorophenoxy) -5H-
Pyrimido [5,4-b] indole Using the compound of Reference Example 20 and 4-fluorophenol,
The title compound was synthesized in the same manner as in Example 95. Yield 71% ¹ H-NMR (DMSO-d ₆ ) δ 1.29 (3H, t, J = 7.8Hz), 2.81 (2
H, q, J = 7.8Hz), 7.30-7.60 (6H, m), 8.01 (1H, s),
8.51 (1H, s), 12.18 (1H, s).

Example 100 7,8-Dihydroxy-4-phenylamino-5H-pi
A mixture of rimido [5,4-b] indole 7,8-dimethoxy-4-phenylamino-5H-pyrimido [5,4-b] indole (470 mg) and pyridine hydrochloride (3.4 g) at 190 ° C. Stir for hours. The reaction mixture was allowed to cool to room temperature, water (20 mL) was added, the precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound as a brown solid (340 mg, yield 76%). ¹ H-NMR (DMSO-d ₆ ) δ 7.06 (1H, s), 7.21 (1H, t, J =
8.4Hz), 7.46 (2H, t, J = 8.4Hz), 7.55 (1H, s), 7.95
(2H, d, J = 8.4Hz), 8.83 (1H, s), 9.40-9.60 (1H, b
r), 10.10-10.30 (1H, br), 11.19 (1H, s), 12.40 (1
H, s).

Example 101 4- (3-chlorophenyl) amino-7,8-dihydro
Xy-5H-pyrimido [5,4-b] indole Using the compound of Example 2, the same operation as in Example 100 was carried out to synthesize the title compound. Yield 43% ¹ H-NMR (DMSO-d ₆ ) δ 7.05 (1H, s), 7.25 (1H, d, J =
7.6Hz), 7.48 (1H, t, J = 7.6Hz), 7.54 (1H, s), 7.86
(1H, d, J = 7.6Hz), 8.24 (1H, s), 8.90 (1H, s), 9.51
(1H, br), 10.23 (1H, br), 11.31 (1H, br), 12.46 (1
H, br). Example 102 8-Hydroxy-4-phenylamino-5H-pyrimido
[5,4-b] indole Using the compound of Example 69, the same operation as in Example 100 was carried out to synthesize the title compound. Yield 97% ¹ H-NMR (DMSO-d ₆ ) δ 7.20-7.30 (2H, m), 7.40-7.80
(5H, m), 7.99 (2H, d, J = 7.8Hz), 8.91 (1H, s), 9.65
(1H, br), 11.39 (1H, br).

Example 103 8-Hydroxy-7-methoxy-4-phenylamino-
5H-pyrimido [5,4-b] indole The compound of Example 50 (20 mg) was dissolved in trifluoroacetic acid (0.2 mL), and the mixture was stirred at 90 ° C for 2 hr. The reaction mixture was concentrated under reduced pressure, the residual solid was washed with ethyl acetate, and dried under reduced pressure to give the title compound as a yellow solid (10 mg,
Yield 67%). ¹ H-NMR (DMSO-d ₆ ) δ 3.96 (3H, s), 7.22 (1H, t, J =
8.0Hz), 7.35 (1H, s), 7.46 (2H, d, J = 8.0Hz), 7.50
(1H, s), 7.84 (2H, d, J = 8.0Hz), 8.81 (1H, s), 9.35
(1H, s), 10.32 (1H, s), 11.48 (1H, s).

Example 104 7,8-Diethoxy-4-phenylamino-5H-pyri
Mido [5,4-b] indole Ethyl bromide (111 mg) and potassium carbonate (187 mg) were added to a solution of the compound of Example 100 (100 mg) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the residue was extracted with a tetrahydrofuran-ethyl acetate (1: 1) mixed solution (20 mL) and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give the title compound as a brown solid (10 mg, yield 8.5%).
Got as. ¹ H-NMR (DMSO-d ₆ ) δ 1.30-1.50 (6H, m), 4.00-4.25
(4H, m), 7.04 (1H, t, J = 7.6Hz), 7.26 (1H, s), 7.38
(2H, t, J = 7.6Hz), 7.51 (1H, s), 7.90 (2H, d, J = 7.6
Hz), 8.46 (1H, s), 9.28 (1H, s), 10.95 (1H, s).

Example 105 7,8-dipropoxy-4-phenylamino-5H-pi
Limid [5,4-b] indole Using the compound of Example 100 and iodopropane, the title compound was synthesized in the same manner as in Example 104. Yield 16% ¹ H-NMR (DMSO-d ₆ ) δ 1.00-1.20 (6H, m), 1.70-1.95
(4H, m), 3.95-4.15 (4H, m), 7.08 (1H, t, J = 6.6Hz),
7.27 (1H, s), 7.39 (2H, t, J = 6.6Hz), 7.52 (1H, s),
7.90 (2H, d, J = 6.6Hz), 8.47 (1H, s), 9.28 (1H,
s), 10.92 (1H, s). Example 106 8-Ethoxy-4-phenylamino-5H-pyrimido
[5,4-b] indole Using the compound of Example 102 and iodoethane, Example 1
The same operation as in 04 was performed to synthesize the title compound. Yield 50% ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (3H, t, J = 7.0Hz), 4.13 (2
H, q, J = 7.0Hz), 7.06 (1H, t, J = 7.2Hz), 7.20 (1H, d
d, J = 2.6, 8.8Hz), 7.40 (2H, t, J = 7.2Hz), 7.56 (1H,
d, J = 2.6Hz), 7.67 (1H, d, J = 8.8Hz), 7.92 (2H, d,
J = 8.8Hz), 8.52 (1H, s), 9.34 (1H, s), 11.08 (1H,
s). Example 107 4-phenylamino-8-propoxy-5H-pyrimido
[5,4-b] indole Using the compound of Example 102 and iodopropane, the same procedure as in Example 104 was carried out to synthesize the title compound. Yield 25% ¹ H-NMR (DMSO-d ₆ ) δ 1.03 (3H, t, J = 7.2Hz), 1.70-1.
90 (2H, m), 4.04 (2H, t, J = 6.6Hz), 7.10 (1H, t, J =
7.0Hz), 7.21 (1H, dd, J = 3.0, 8.8Hz), 7.40 (2H, t,
J = 7.0Hz), 7.54 (1H, d, J = 3.0Hz), 7.67 (1H, d, J = 8.
8Hz), 7.93 (2H, d, J = 7.0Hz), 8.52 (1H, s), 9.39 (1
H, s), 11.15 (1H, s). Example 108 8-isopropoxy-4-phenylamino-5H-pyri
Mido [5,4-b] indole The title compound was synthesized by the same procedure as in Example 104 using the compound of Example 102 and iodoisopropane. Yield 25% ¹ H-NMR (DMSO-d ₆ ) δ 1.32 (6H, d, J = 6.2Hz), 4.60-4.
80 (1H, m), 7.06 (1H, t, J = 7.2Hz), 7.18 (1H, dd, J =
2.6, 9.0Hz), 7.40 (2H, t, J = 7.2Hz), 7.55 (1H, d, J
= 2.6Hz), 7.66 (1H, d, J = 9.0Hz), 7.92 (2H, d, J = 7.2
Hz), 8.52 (1H, s), 9.32 (1H, s), 11.04 (1H, s). Example 109 8-Cyclopentyloxy-4-phenylamino-5H
-Pyrimido [5,4-b] indole using the compound of Example 102 and iodocyclopentane,
The title compound was synthesized in the same manner as in Example 104. Yield 22% ¹ H-NMR (DMSO-d ₆ ) δ 1.50-2.10 (8H, m), 4.85-5.00
(1H, m), 7.06 (1H, t, J = 7.2Hz), 7.17 (1H, dd, J = 2.
6, 8.8Hz), 7.40 (2H, t, J = 7.2Hz), 7.52 (1H, d, J =
2.6Hz), 7.66 (1H, d, J = 8.8Hz), 7.92 (2H, d, J = 7.2H
z), 8.52 (1H, s), 9.32 (1H, s), 11.04 (1H, s). Example 110 8-Cyclopentyloxy-7-methoxy-4-phenyl
Luamino-5H-pyrimido [5,4-b] indole Using the compound of Example 103 and iodocyclopentane,
The title compound was synthesized in the same manner as in Example 104. Yield 20% ¹ H-NMR (DMSO-d ₆ ) δ 1.45-2.00 (8H, m), 3.91 (3H,
s), 4.80-4.95 (1H, m), 7.05 (1H, t, J = 8.8Hz), 7.27
(1H, s), 7.40 (2H, t, J = 8.8Hz), 7.49 (1H, s), 7.90
(2H, d, J = 8.8Hz), 8.48 (1H, s), 9.30 (1H, s), 10.
93 (1H, s).

Example 111 7-methoxy-8-methoxyethoxy-4-phenyla
Mino-5H-pyrimido [5,4-b] indole The compound of Example 103 (60 mg), bromoethyl methyl ether (0.037 mL), 1,8-diazabicyclo [5,4,0] -7-undecene (0 (0.059 mL)
N, N-dimethylformamide (0.5 mL) solution of was stirred at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 2: 1) to give the title compound as a colorless solid (15 m
g, 21% yield). ¹ H-NMR (DMSO-d ₆ ) δ 3.35 (3H, s), 3.70-3.80 (2H,
m), 3.93 (3H, s), 4.15-4.20 (2H, m), 7.05 (1H, t,
J = 7.4Hz), 7.28 (1H, s), 7.39 (2H, t, J = 7.4Hz), 7.5
4 (1H, s), 7.90 (2H, d, J = 7.4Hz), 8.47 (1H, .s),
9.27 (1H, s), 10.94 (1H, s).

Example 112 4-Benzyl-7,8-dimethoxy-5H-pyrimido
After stirring a solution of [5,4-b] indole zinc powder (196 mg) and 1,2-dibromoethane (0.01 mL) in N, N-dimethylformamide (3.0 mL) at 70 ° C. for 10 minutes, trimethylsilyl chloride was added. (0.01 mL) was added, and the mixture was further stirred for 30 minutes. The reaction solution was cooled to 0 ° C., benzyl bromide was added, and the mixture was stirred at room temperature for 2 hours. Tetrakistriphenylphosphine palladium (155 mg) and 4-
Chloro-7,8-dimethoxy-5H-pyrimido [5,4
-B] Add indole (200 mg) and add 30 at 60 ° C.
Stir for minutes. The reaction solution was extracted with ethyl acetate and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: acetic acid) to give the title compound as a colorless solid (110 mg, yield 45%). ¹ H-NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 3.93 (3H, s), 4.
40 (2H, s), 7.11 (1H, s), 7.15-7.50 (5H, m), 7.61
(1H, s), 8.82 (1H, s), 11.75 (1H, s).

Example 113 4-Benzyl-8-ethyl-5H-pyrimido [5,4-
b] Indole Using the compound of Reference Example 20, the same operation as in Example 112 was carried out to synthesize the title compound. Yield 20% ¹ H-NMR (DMSO-d ₆ ) δ 1.28 (3H, t, J = 7.6Hz), 2.80 (2
H, q, J = 7.6Hz), 4.44 (2H, s), 7.10-7.70 (7H, m),
8.04 (1H, s), 8.91 (1H, s), 11.91 (1H, s). Example 114 7,8-dimethoxy-5-methyl-4-phenylamino
Pyrimido [5,4-b] indole Using the compound of Reference Example 33, the same operation as in Example 1 was carried out to synthesize the title compound. Yield 42% ¹ H-NMR (DMSO-d ₆ ) δ 3.87 (3H, s), 3.95 (3H, s), 4.
11 (3H, s), 7.03 (1H, t, J = 7.2Hz), 7.33 (1H, s), 7.
34 (2H, t, J = 7.2Hz), 7.55 (1H, s), 7.61 (2H, d, J =
7.2 Hz), 8.42 (1H, s), 8.74 (1H, s). Example 115 7,8-Dimethoxy-5-ethyl-4-phenylamino
Pyrimido [5,4-b] indole Using the compound of Reference Example 34, the title compound was synthesized in the same manner as in Example 1. Yield 59% MS m / z = 349 (M + 1). Example 116 7,8-dimethoxy-4-phenylamino-5-propyi
Rupyrimido [5,4-b] indole Using the compound of Reference Example 35, the title compound was synthesized in the same manner as in Example 1. Yield 63% MS m / z = 363 (M + 1).

Tables 1, 2 and 3 show the compounds synthesized in the examples.

[0106]

[Table 1]

[0107]

[Table 2]

[0108]

[Table 3]

Experimental Example 1 IL-8 production system using NCI-H292 cells NCI-H292 (ATCC) strain with 10% fetal calf serum (Nichirei), 100
U / ml penicillin, M containing 100 μg / ml streptavidin
Cultured in EM-α medium (GIBCO BRL), 2x10^Fiveto cells / ml
Was prepared in a culture medium. 96-well microplate (F
alcon), LPS (SIG
MA) or 100 μl of TNF-α (genzyme) adjusted to 4 ng / ml
/ well was dispensed. Then, add 100 μl / well of cells, and
℃, 5% CO ₂Culture supernatant after 1-day culture in incubator 5
The amount of IL-8 in 0 μl was measured using the ELISA method.

Experimental Example 2 Measurement of amount of produced IL-8 (ELISA) A 96-well immunoplate (Nunc) was prepared with anti-human IL-8 monoclonal antibody (ENDOGEN) at a concentration of 0.5 μg / ml in PBS and 100 μl Each well was dispensed and left at room temperature overnight. After removal of the antibody, 25% Block Ace was dispensed at 200 μl / well, and left still at room temperature for 1 hour to block the plate. After removing the blocking solution, 50 mM TRIS-HCl containing 0.2% Tween-20 (pH 8.
0) The plate was washed once with a buffer solution, and PBS containing 10% Block Ace was dispensed at 50 μl / well, and the culture supernatant was 50 μl / well.
The mixture was added and left standing for 1 hour at room temperature. After removing the supernatant, 0.2% Tween-2
The plate was washed twice with 50 mM TRIS-HCl (pH 8.0) buffer containing 0, and the anti-human IL-8 monoclonal biotin-labeled antibody (E
NDOGEN) was prepared in PBS containing 10% Block Ace to a concentration of 0.1 μg / ml, 100 μl / well was dispensed, and the mixture was allowed to stand at room temperature for 1 hour. After antibody removal, 50 mM TRIS- containing 0.2% Tween-20
Wash the plate twice with HCl (pH8.0) buffer and use HRP-Strep
200% tavidin (Vector) in PBS containing 10% Block Ace
It was diluted 100 times and dispensed at 100 μl / well, and left still at room temperature for 30 minutes. 50 mM containing 0.2% Tween-20 after HRP-Streptavidin removal
Wash the plate 3 times with TRIS-HCl (pH 8.0) buffer and
Microwell Peroxidase Substrate (KPL) 100 μl / well
The mixture was dispensed and allowed to stand at room temperature for 30 minutes to develop the color of the plate. TMB
Stop the reaction by adding 100 μl / well of Stop Solution (KPL), and then use a plate reader (Labsystems) to measure the absorbance A (450-
540) nm was measured. Human IL is the standard for IL-8
-8 ELISA Standard (ENDOGEN) was used.

Experimental Example 3 Evaluation of compound based on suppression of IL-8 production NCI-H292 (ATCC) strain was treated with 10% fetal calf serum (Nichirei), 100
U / ml penicillin, M containing 100 μg / ml streptavidin
The cells were cultured in EM-α medium (GIBCO BRL), and the medium was adjusted to 2 × 10 ⁵ cells / ml. 96-well microplate (F
alcon), LPS (SIG
MA) or 4 μg / ml of TNF-α (genzyme) at 90 μl /
Dispense well, add 10 μl / well of compound prepared to a final concentration of 0.3 μM in the medium, and then prepare 100 cells.
μl / well was added, and the amount of IL-8 in 50 μl of the culture supernatant after 1-day culture at 37 ° C. and 5% CO ₂ incubator was measured by the ELISA method. IL-8 is produced without stimulating cells
When the amount of IL-8 produced after stimulation with LPS or TNF-α is 100%, the compound's IL-8 production inhibitory activity (IC ₅₀ : μ
M) was calculated (Table 4).

[Table 4]

[0112]

INDUSTRIAL APPLICABILITY Since the compound (I) of the present invention or a salt thereof has an excellent IL-8 inhibitory effect, it can be effectively used as a preventive / therapeutic agent for allergic diseases and / or immune diseases.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 19/06 A61P 19/06 19/08 19/08 29/00 29/00 101 101 37 37/08 37 / 08 43/00 111 43/00 111 C07D 491/147 C07D 491/147 (72) Inventor ▲ Zaki ▼ Hironobu 5-6-7 Honmachi, Toyonaka City, Osaka Prefecture Takeda Toyonaka Heim 206 206 F-term (reference) 4C050 AA01 AA07 AA08 BB04 CC08 DD07 DD08 EE03 FF01 GG04 GG05 HH01 4C086 AA01 AA02 AA03 AA04 CB05 CB22 MA01 MA04 NA14 ZA59 ZA96 ZB11 ZB13 ZB15 ZC02

Claims (19)

[Claims] 1. The formula: [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) Hydrogen atom (provided that both X and Y are hydrogen atoms), (2) halogen, (3) hydroxyl group, (4) amino, (5) -ZR ² (Z is a bond, oxygen Atom, sulfur atom or --NR ^3- (R ³ is a hydrogen atom, C _1-6 alkyl or C
_3-8 cycloalkyl), R ² is optionally substituted C _1-6 alkyl, optionally substituted C
_3-8 cycloalkyl, C _2-6 alkenyl which may have a substituent or C _3-8 cycloalkenyl which may have a substituent), (6) having a substituent Good C
_6-14 aryl, (7) -NHCOR ⁴ (R ⁴ is a hydrogen atom, C
_3-6 alkyl or C _3-8 cycloalkyl), (8)
—SO ₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R ⁶ together with the adjacent nitrogen atom have 3 to 8 membered members; Cyclic amino may be formed), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C
_6-10 aryl), (10) optionally esterified or amidated carboxyl, (11) nitro or (1
2) represents cyano, or X and Y together represent C _3-6 alkylene or C _1-4 alkylenedioxy. However, when Q is NH, R is a hydrogen atom, and X and Y are both methoxy, ring A is an unsubstituted benzene ring or a benzene ring substituted only at the p-position. Or a salt thereof. 2. Ring A is (1) (i) 1 to 3 halogen atoms
C which may have children_1-6Alkyl, (ii) C _1-6Arca
Noil, (iii) C_6-10Arylcarbonyl, (iv) C_1-6A
Rukyisulfonyl, (v) aminosulfonyl, (vi) mono C
_1-6Alkylaminosulfonyl, (vii) diC_1-6Alkyl
Aminosulfonyl and (viii) halogen atom (hereinafter,
The substituent selected from the group A) is 1 to 3
C which may have_1-10Alkyl, (2) the substituent A
It may have 1 to 3 substituents selected from the group
C_2-6Alkenyl, (3) a substituent selected from the above substituent group A
C optionally having 1 to 3 groups_2-6Alkynyl,
(4) 1 to 3 substituents selected from the above substituent group A
C which may have_6-14Aryl, (5) the substituent group A
C optionally having 1 to 3 substituents selected from
_3-9Cycloalkyl, (6) selected from the above substituent group A
C which may have 1 to 3 substituents_3-6Cycloa
From lukenyl, (7) oxygen atom, sulfur atom and nitrogen atom
Contains 1 to 4 heteroatoms of 1 to 3 types selected
Aromatic or non-aromatic heterocyclic group (this aromatic or non-aromatic
The aromatic heterocyclic group has a substituent selected from the above substituent group A.
1 to 3), (8) 1 to 3
C which may have a halogen atom_1-6Alkyl sulfo
Nyl, (9) even if it has 1 to 3 halogen atoms
Good C_1-6Alkanoyl, (10) C_6-10Aryl Carboni
(11) Carboxyl, (12) C_1-6Alkoxy Carboni
(13) There is no 1 substituent selected from the above substituent group A
C which may have 3_{6-1 0}Aryloxycarboni
(14) There is no 1 substituent selected from the above substituent group A.
C which may have 3_{7-1 0}Aralkyl oxycarbo
Nil, (15) (i) a substituent selected from the above substituent group A is 1
To C which may have 3 to 3 _1-10Alkyl, (ii) before
Having 1 to 3 substituents selected from Substituent group A
May be C_2-6Alkenyl, (iii) from the above substituent group A
C optionally having 1 to 3 substituents selected_6-14
Aryl, (iv) a substituent selected from the above-mentioned substituent group A is 1
To C which may have 3 to 3_3-9Cycloalkyl, (v)
Having 1 to 3 substituents selected from the above-mentioned substituent group A
May be C_3-6Cycloalkenyl, (vi) 1 to 3
C optionally having 4 halogen atoms_1-6Alkyls
Rufonyl, (vii) having 1 to 3 halogen atoms
May be C_1-6Alkanoyl, (viii) C_6-14Aryl
Carbonyl, (ix) carboxyl, (x) C_1-6Alkoxyca
Rubonyl, (xi) a substituent selected from the above-mentioned substituent group A
1 to 3 optionally have C_{6 -Ten}Aryl oxyca
Rubonyl and (xii) a substituent selected from the above substituent group A
C optionally having 1 to 3 groups_7-10Aralkillo
Xycarbonyl (hereinafter abbreviated as Substituent Group B)
An amino optionally having 1 or 2 substituents,
(16) Substituent may have a substituent selected from Group B
Imidoyl, a substituent selected from the group (17) substituent B
1 to 3 optionally amidino, (18) substituent
A hydroxyl group which may have a substituent selected from Group B, (1
9) Substituent may have a substituent selected from Group B
Thiol, (20) -CONR⁸R⁹(R⁸Is (i) hydrogen atom, (i
i) (i ') hydroxyl group, (ii') C_1-6Alkyl, C_1-6Alkano
1 or 2 substituents selected from
Optionally have amino, (iii ') halogen atom, (i
v ') nitro, (v') cyano, (vi ') 1-5 halo
C which may have a gen atom_1-6Alkyl and (vi
i ') C optionally having 1 to 5 halogen atoms
_1-6Having 1 to 3 substituents selected from alkoxy
May be C_1-6Alkyl, (iii) (i ') hydroxyl group, (i
i ’) C_1-6Alkyl, C_1-6Alkanoyl and benzoi
May have 1 or 2 substituents selected from
Amino, (iii ') halogen atom, (iv') nitro, (v ')
Ano, (vi ') having 1 to 5 halogen atoms
Good C_1-6Alkyl and (vii ') 1-5 halo
C which may have a gen atom_1-6Choose from alkoxy
C optionally having 1 to 3 substituents_3-6Shiku
Low alkyl, (iv) (i ') hydroxyl group, (ii') C_1-6Archi
Le, C_1-6Selected from alkanoyl and benzoyl
An amino optionally having 1 or 2 substituents, (ii
i ') halogen atom, (iv') nitro, (v ') cyano, (v
i ') C optionally having 1 to 5 halogen atoms
_1-6Alkyl and (vii ') 1 to 5 halogen atoms
May have C_1-6Substitution selected from alkoxy
C optionally having 1 to 3 groups_6-10Aryl,
(v) (i ') hydroxyl group, (ii') C_1-6Alkyl, C_1-6Arca
1 or 2 substituents selected from noyl and benzoyl
2 optionally have amino, (iii ') halogen atom,
(iv ') nitro, (v') cyano, (vi ') 1 to 5 ha
C which may have a rogen atom_1-6Alkyl and (vi
i ') C optionally having 1 to 5 halogen atoms
_1-6Having 1 to 3 substituents selected from alkoxy
May be C_7-10Aralkyl, or (vi) oxygen source
1 to 3 kinds selected from a child, a sulfur atom and a nitrogen atom
Aromatic or non-aromatic containing 1 to 4 heteroatoms
Heterocyclic group (This aromatic or non-aromatic heterocyclic group is (i ')
Hydroxyl group, (ii ') C_1-6Alkyl, C_1-6Alkanoyl and
And 1 or 2 substituents selected from benzoyl
Optional amino, (iii ') halogen atom, (iv') nit
B, (v ') cyano, (vi') 1 to 5 halogen atoms
May have C_1-6No alkyl and (vii ') 1
C which may have 5 halogen atoms_1-6Arco
May have 1 to 3 substituents selected from xy
I), R⁹Is a hydrogen atom, C_1-6Alkyl, C_3-6Cycloal
Kill or C_7-10Aralkyl (R⁸And R⁹Are adjacent
Forming a 3- to 8-membered cyclic amino with a nitrogen atom
, (21) -CSNR⁸R⁹(R⁸And R
⁹Has the same meaning as above) (22) halogen atom, (23) sia
No and (24) nitro (hereinafter abbreviated as substituent C group)
Benzo which may have 1 to 5 substituents selected from
Zen ring, Q is NR¹(R¹Is a hydrogen atom or the substituent A
It may have 1 to 3 substituents selected from the group
C_1-6Represents alkyl), S (O)_n(N is an integer from 0 to 2
Selected from the oxygen group or the substituent group A.
Methylene optionally having 1 or 2 substituents, R
Is a hydrogen atom or a substituent selected from the above substituent group A.
1 to 3 optionally have C_1-6Alkyl, X and
And Y are independently (1) hydrogen atom, (2) halogen, (3) hydroxide
Group, (4) amino, (5) -ZR²(Z is a bond, oxygen atom,
Sulfur atom or -NR³-(R³Is a hydrogen atom, C_1-6Al
Kill or C_3-8Cycloalkyl), R²Is (i) halo
N, C_6-10Aryl and C_1-6Chosen from alkoxy
C which may have 1 to 3 substituents_1-6Archi
(Ii) halogen, C_6-10Aryl and C_1-6Arco
May have 1 to 3 substituents selected from xy
I C_3-8Cycloalkyl, (iii) halogen, C_6-10Ally
Le and C_1-6There is no 1 substituent selected from alkoxy
C which may have 3_2-6Alkenyl, (iv) halogen
N, C_6-10Aryl and C_1-6Chosen from alkoxy
C which may have 1 to 3 substituents_3-8Cyclo
Alkenyl), (6) selected from the above substituent group C
C optionally having 1 to 5 substituents_6-14Ally
Le, (7) -NHCOR^Four(R^FourIs a hydrogen atom, C_3-6Alkyl
Or C_3-8Cycloalkyl), (8) -SO₂NR^Five
R⁶(R^FiveAnd R⁶Is a hydrogen atom, C_1-6Alkyl or C
_3-8Represents cycloalkyl, R^FiveAnd R⁶Is adjacent to
Forming a 3- to 8-membered cyclic amino with an elementary atom
Good), (9) -COR⁷(R⁷Is a hydrogen atom, C_1-6Archi
Le, C_3-8Cycloalkyl or C _6-10Show aryl
), (10) Carboxyl, (11) C_1-6Alkoxy carbo
Nil, (12) The substituent selected from Group A above is 1
C which may have 3 chairs_{6-1 0}Aryloxycarbo
Nil, (13) The substituent selected from Group A above is 1
C which may have 3 chairs_{7-1 0}Aralkyl oxycal
Bonyl, (14) -CONR⁸R⁹(R⁸And R⁹Is the same as above
(Significant) (15) nitro, (16) cyano, (17) X and Y
Together C_3-6Alkylene or (18) X and Y
Together C_1-4An alkylenedioxy.
The compound according to 1. 3. Ring A (1) C _1-10 alkyl _optionally having 1 to 3 halogen atoms, (2) C _2-6 alkynyl, (3) C _6-14 aryl, ( 4) C _1-6 alkanoyl, (5) C
_A hydroxyl group which may have a substituent selected from _1-10 alkyl and C _6-14 aryl, (6) a halogen atom and (7)
A benzene ring which may have 1 to 3 substituents selected from cyano, Q is NR ^1a (R ^1a is a hydrogen atom or C
_1-6 alkyl), S, SO, oxygen atom or methylene,
R is a hydrogen atom or C _1-6 alkyl, X and Y are independently (1) hydrogen atom, (2) halogen, (3) hydroxyl group or (4)-
Z ^a R ^2a (Z ^a may have a bond or an oxygen atom, and R ^2a may have 1 to 3 substituents selected from (i) halogen, C _6-10 aryl and C _1-6 alkoxy. C _1-6 alkyl or (ii) halogen, C _6-10 aryl and C
_1-6 alkoxy represents C _3-8 cycloalkyl optionally having 1 to 3 substituents), or X
The compound of claim 1 wherein Y and Y together are C _1-4 alkylenedioxy. 4. The compound according to claim 1, wherein ring A is a benzene ring optionally having 1 or 2 substituents selected from C _2-6 alkynyl and a halogen atom. 5. X and Y are independently (1) hydrogen atom, (2) halogen, (3) hydroxyl group or (4) -Z ^a R ^2a (Z ^a is a bond or an oxygen atom, and R ^2a is (i) halogen, C _6-10 aryl and C _1-6 1 without a substituent selected from alkoxy to 3 substituents optionally having C _1-6 alkyl or (ii) halogen, C _6-10 aryl and C The compound according to claim 1, which is C _3-8 cycloalkyl which may have 1 to 3 substituents selected from _1-6 alkoxy). 6. The compound according to claim 1, wherein R is a hydrogen atom. 7. The compound according to claim 1, wherein Q is NH, S, an oxygen atom or methylene. 8. 4- (2,5-Dichlorophenyl) amino-7,8-dimethoxy-5H-pyrimido [5,4-b] indole, 4- (4-chlorophenylsulfanyl)-
7,8-Dimethoxy-5H-pyrimido [5,4-b] indole or 4-benzyl-7,8-dimethoxy-5
H-pyrimido [5,4-b] indole.
The described compound. 9. A prodrug of the compound according to claim 1 or a salt thereof. 10. A pharmaceutical composition comprising the compound according to claim 1, a salt thereof or a prodrug thereof. 11. The formula: [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
An alkylene or C _1-4 alkylenedioxy] or an IL-8 inhibitor comprising a salt thereof. 12. The agent according to claim 11, which is a prophylactic / therapeutic agent for IL-8-related diseases. 13. The agent according to claim 11, which is a preventive / therapeutic agent for allergic diseases and / or inflammatory diseases. 14. The agent according to claim 11, which is a prophylactic / therapeutic agent for chronic obstructive pulmonary disease. 15. The agent according to claim 11, which is an agent for suppressing the progression of the disease state of chronic obstructive pulmonary disease. 16. The agent according to claim 11, which is a prophylactic / therapeutic agent for rheumatism, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis and / or periosteitis. 17. The formula: [In the formula, R is a hydrogen atom or C _1-6 alkyl which may have a substituent, and X and Y are independently (1) a hydrogen atom,
(2) halogen, (3) hydroxyl group, (4) amino, (5) -ZR ² (Z
Is a bond, oxygen atom, sulfur atom or —NR ³ — (R ³ is a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl)
The, R ² which may have a substituent C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally C _2-6 alkenyl optionally having substituent Or _C3-8 cycloalkenyl which may have a substituent), (6)
Optionally substituted C _6-14 aryl, (7) -NH
COR ⁴ (R ⁴ represents a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl), (8) -SO ₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ are C _1-6 alkyl or C _{3 -8} cycloalkyl, or R ⁵ and R ⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9)-
COR ⁷ (R ⁷ represents a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl), (10) an optionally esterified or amidated carboxyl, (1
1) nitro or (12) cyano, or X and Y
Together with C _3-6 alkylene or C _1-4 alkylenedioxy, L represents a leaving group] or a salt thereof and a compound of the formula: [In the formula, Ring A is a benzene ring which may have a substituent, Q'is -NHR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent). , -SH, -O
H or -Q "-Zn-L '(Q" represents methylene which may have a substituent and L'represents a halogen)] or a salt thereof. The formula [Chemical formula 5] [Wherein R, X and Y have the same meanings as described above, and Q is NR ¹
(R ¹ is a hydrogen atom or optionally substituted C _1-6
Alkyl), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent], or a salt thereof. 18. For mammals, the formula: [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
Alkylene or C _1-4 alkylenedioxy] or an effective amount of a salt thereof. 19. A compound of formula ## STR7 ## for preparing an IL-8 inhibitor. [In the formula, ring A is a benzene ring which may have a substituent, Q is NR ¹ (R ¹ represents a hydrogen atom or C _1-6 alkyl which may have a substituent), S (O) _n (n represents an integer of 0 to 2), an oxygen atom or methylene which may have a substituent, and R represents a hydrogen atom or a C _1-6 alkyl which may have a substituent. , X and Y are independently
(1) hydrogen atom, (2) halogen, (3) hydroxyl group, (4) amino,
(5) -ZR ² (Z is a bond, an oxygen atom, a sulfur atom or-
NR ³ - (R ³ is a hydrogen atom, C _1-6 an alkyl or C _3-8 cycloalkyl) a, R ² which may have a substituent C _1-6 alkyl, substituted _{Optionally represents} C _3-8 cycloalkyl, optionally substituted C _2-6 alkenyl or optionally substituted C _3-8 cycloalkenyl), and (6) substituent _Optionally having C _6-14
Aryl, (7) -NHCOR ⁴ (R ⁴ represents a hydrogen atom, C _3-6 alkyl or C _3-8 cycloalkyl), (8) -SO
₂ NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom, C _1-6 alkyl or C _3-8 cycloalkyl, or R ⁵ and R 6
⁶ may form a 3- to 8-membered cyclic amino with an adjacent nitrogen atom), (9) -COR ⁷ (R ⁷ is a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl or C _{6 -Ten}
Represents aryl), (10) represents an optionally esterified or amidated carboxyl, (11) nitro or (12) cyano, or X and Y together represent C _3-6
Alkylene or C _1-4 alkylenedioxy] or a salt thereof.