JP2000319278A - Condensed pyrazine compound and drug containing the compound as active ingredient - Google Patents

Abstract

(57) Abstract: An adhesion molecule expression inhibitor represented by the general formula (I). Embedded image (Wherein, R ¹ and R ² are H, alkyl, alkenyl, etc., or together, formula (Z); R ³ is H, alkyl, alkenyl, etc .; Ring A is a carbocycle, heterocycle; J is alkyl ,
Halogen-substituted alkyl, OH, SH, alkoxy, etc .; E
Is a single bond, O, S, etc .; G is (substituted) alkyl, alkenyl, alkynyl, carbocycle, etc. [Effect] The compound represented by the general formula (I) has an inhibitory effect on the expression of an adhesion molecule, and has various inflammatory diseases, rheumatoid arthritis, allergy, bronchial asthma, atopic dermatitis, psoriasis, ischemia-reperfusion injury Suppression, nephritis, hepatitis, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, suppression of transplant organ rejection, sepsis, diabetes, autoimmune disease, cancer metastasis,
It is useful for the prevention and treatment of arteriosclerosis and AIDS.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a condensed pyrazine compound and an adhesion molecule expression inhibitor containing the condensed pyrazine compound as an active ingredient. More specifically, general formula (I)

Embedded image (Wherein all symbols have the same meanings as described below), a non-toxic salt thereof, a non-toxic salt thereof, a production method thereof, and an adhesion molecule expression inhibitor containing them as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Cell-cell adhesion is a fundamental reaction in living organisms and is deeply involved in various life phenomena. There are many cases in which this overreaction or abnormal reaction is considered to be the cause of disease. The inflammatory reaction is one of the biological defense reactions that protect the host from foreign substances that have originally entered the living body. In this reaction, enhanced adhesion between leukocytes and vascular endothelial cells is considered as an important process in the initial stage. I have. Leukocytes are one of the main cells responsible for the inflammatory response, and infiltrate the local area of the inflammation and release various chemical mediators, cytokines, enzymes and the like to enhance the inflammatory response. Therefore, infiltration of leukocytes into inflamed areas is important for the development of an inflammatory response, and it is considered that a process in which leukocytes flowing in blood vessels adhere to vascular endothelial cells is essential as an initial reaction of this infiltration.

The process of cell infiltration is as follows: 1) capture of leukocytes on vascular endothelial cells, 2) rolling of leukocytes, 3) strong adhesion of leukocytes to endothelial cells, 4) migration of leukocytes out of blood vessels. Divided into stages.

In recent years, it has been shown that these various cell-cell adhesions are mediated by a group of molecules called adhesion molecules expressed on each cell membrane. It has been revealed that they play an important role in a stage-specific manner. That is,
The process of capture and rolling is triggered by the binding of selectin molecules such as E-selectin to the carbohydrate antigen, and the subsequent processes of strong adhesion and extravasation out of the blood vessel involve integrin molecules on leukocytes and endothelium. ICAM-1 on cells
(Intercellular Adhesion Molecule-1) and VCA
It has been clarified that it depends on binding to immunoglobulin superfamily molecules such as M-1 (Vascular Cell Adhesion Molecule-1). E-selectin, VCA
Both M-1 and ICAM-1 are adhesion molecules whose expression is induced in vascular endothelial cells by stimulation of inflammatory cytokines such as TNF and IL-1, and the expression of these molecules is actually enhanced in various lesions Have been reported. That is, it is considered that the enhanced expression of these adhesion molecules enhances cell-cell adhesion and is involved in the formation of pathological conditions such as chronic inflammation.

Further, it has been suggested that such adhesion to vascular endothelial cells is involved not only in inflammatory reactions but also in metastasis of cancer cells, and progress of allergic reactions or immune reactions accompanied by cell infiltration. In addition, VCAM in HIV-infected patients
-1 and increased ICAM-1 concentration [Clinical Immunology and Immunopathology, 8
1 , 16-21 (1996)] suggests a relationship between expression of adhesion molecules and HIV infection. From the above viewpoint, the adhesion molecule E
Inhibition of expression of -selectin, VCAM-1 and ICAM-1 suppresses cell-cell adhesion and is expected to have an effect of improving various disease states.

The present invention provides a useful novel therapeutic agent having an unprecedented mechanism by suppressing the expression of these molecules. The clinical application of the present invention can be applied to diseases in which cell adhesion or invasion is considered to be involved in the etiology and exacerbation of the disease state [The Hand Book of Immonopharmacology, Adhesio
n Molecule, Academic Press, (1994), Trends in Phar
macologial Sience Vol. 16, 418-423 (1995), Molecula
r Medicine Today, Vol. 3, 418-423 (1997), Molecula
r Medicine Today, Vol. 3, 310-321 (1997), Inflammation Vo
l. 17, 459-467 (1997)], for example, various inflammatory diseases,
Rheumatoid arthritis, allergy, bronchial asthma, atopic dermatitis, psoriasis, suppression of ischemia-reperfusion injury, nephritis, hepatitis,
Prevention and / or treatment of multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, suppression of transplant rejection, sepsis, diabetes, autoimmune disease, cancer metastasis, arteriosclerosis, AIDS (AIDS).

[0007]

2. Description of the Related Art For example, in the specification of British Patent No. 1235910, a compound represented by the general formula (X)

Embedded image

[0008] British Patent No. 1146770 discloses that
General formula (Y)

Embedded image It is disclosed that the 1,2,4-triazolo- [4,3-a] pyrazine derivative represented by is effective for the treatment of bronchial disease.

Further, WO9535296 discloses a compound represented by the general formula (Z)

Embedded image It has been disclosed that the condensed imidazole derivative represented by the formula (1) has an inhibitory action on the expression of an adhesion protein.

[0010]

OBJECTS OF THE INVENTION The present inventors have conducted intensive studies to find a compound having an inhibitory effect on the expression of adhesion molecules. As a result, they have found that the condensed pyrazine compound of the present invention achieves the object.

[0011]

DISCLOSURE OF THE INVENTION The present invention provides a compound represented by the following general formula (1):

Embedded image[Wherein, R¹And R^TwoAre independently (i) hydrogen sources
(Ii) a C1-8 alkyl group, (iii) a C2-8 alkyl
Kenyl group, (iv) C2-8 alkynyl group, (v) C1
8 alkoxy group, (vi) C1-8 alkylthio group, (vi
i) Cyc1, (viii) cyano group, (ix) formyl group,
(X) -COOR¹⁴Group (in the group, R¹⁴Is a hydrogen atom or C
Represents a 1-8 alkyl group. ), (Xi) -CONR¹⁵R
¹⁶Group (in the group, R ¹⁵And R¹⁶Are independently hydrogen sources
, A C1-8 alkyl group or a phenyl group
You. ), (Xii) a hydroxyl group, a C1-4 alkoxy group,
Nonoxy group, halogen atom, cyano group, C2-5 acyl
Group, -COOR¹⁴Group, -CONR¹⁵R¹⁶Group, -NR¹⁷R
¹⁸Group (in the group, R¹⁷And R¹⁸Are independently hydrogen sources
, A C1-8 alkyl group or an acetyl group. )
C1-8 substituted with one or two groups selected from
Alkyl group, C2-8 alkenyl group or C2-8 alkyl
Quinyl group, (xiii) C1-8 alkyl substituted with Cyc1
Group, C1-8 alkoxy group or C1-8 alkyl group
Represents an o group, or R¹And R^TwoAre connected
Together with the merging carbon atoms

Embedded imageWherein Cyc1 is a C3-15 monocyclic, bicyclic, tricyclic
Cyclic carbocycle or 1-4 nitrogen atoms, 1-2 oxygen
5-18 membered atoms containing atoms and / or one sulfur atom
Represents a monocyclic, bicyclic or tricyclic heterocyclic ring,
The prime ring or hetero ring is one or more of (i) C1
-8 alkyl group, (ii) C1-8 alkoxy group, (ii
i) nitro group, (iv) halogen atom, (v) cyano group,
(Vi) hydroxyl group, (vii) benzyloxy group, (viii)-
NR¹⁰¹R¹⁰²Group (in the group, R¹⁰¹And R¹⁰²Is German
Stands for a hydrogen atom or a C1-8 alkyl group
You. ), (Ix) -COOR^{Ten Three}Group (in the group, R¹⁰³Is hydrogen field
Or a C1-8 alkyl group. ), (X) bird
Halomethyl group, (xi) trihalomethoxy group, (xii)
Phenyl, (xiii) phenyloxy, (xiv) phenyl
Group, phenyloxy group, hydroxyl group, -NR¹⁰¹R ¹⁰²And
And -COOR¹⁰³C1-8 substituted with a group selected from
Substituted with an alkyl group or a C1-8 alkoxy group
May be

Embedded imageIs a C3-7 monocyclic carbocycle or 1-4 nitrogen atoms
, One or two oxygen atoms and / or one sulfur atom
A 3- to 7-membered monocyclic heterocyclic ring containing^ThreeIs 1) hydrogen atom, 2) C1-8 alkyl group, 3) C2-8 alkenyl group, 4) C2-8 alkynyl group, 5) C1-8 alkoxy group, 6) C1-8 alkylthio group, 7) halogen atom 8) nitro group, 9) cyano group, 10) hydroxyl group, 11) formyl group, 12) C2-5 acyl group, 13) -NR^FourR^FiveGroup (in the group, R^FourAnd R^FiveRespectively
Independently a hydrogen atom, a C1-8 alkyl group or acetyl
Represents a group. ), 14) -COOR⁶Group (in the group, R⁶Is a hydrogen atom or C1
Represents a -8 alkyl group. ), 15) -CONR¹⁹R²⁰Group (in the group, R¹⁹And R²⁰Haso
Each independently represents a hydrogen atom, a C1-8 alkyl group,
Or hydroxyl group, 1-2 nitrogen atoms or 1
5- to 7-membered monocyclic ring containing a nitrogen atom and one oxygen atom
C1-4 alkyl group substituted by a group selected from heterocycle
Or together form = CH-NR^{twenty one}R^{twenty two}Group (group
Medium, R^{twenty one}And R^{twenty two}Are each independently a hydrogen atom or
Represents a C1-4 alkyl group. )), 16) trihalomethyl group, 17) trihalomethoxy group, 18) phenyl group, 19) phenyloxy group, 20) phenylthio group, or 21) phenyl group-substituted C1-8 alkyl group, C1
-8 alkoxy group, C1-8 alkylthio group, or C
1-8 alkylamino group, 22) hydroxyl group, C1-4 alkoxy group, phenoxy group,
Halogen atom, cyano group, C2-5 acyl group, -COO
R⁶Group, -CONR¹⁹R²⁰Group, -NR^FourR^FiveSelected from groups
C1-8 alkyl substituted by one or two groups
Group, C2-8 alkenyl group or C2-8 alkynyl group
And n represents an integer of 1 to 5, and J represents J^aOr
J^bAnd J^aIs 1) C1-8 alkyl group, 2) Cyc2, 3) C1-8 alkyl group substituted with Cyc2, 4) C1-8 alkyl substituted with 1 to 17 halogen atoms.
5) a halogen atom or a C1-8 alkoxy group, or 5) a halogen atom;
Monocyclic, bicyclic, tricyclic carbocyclic or 1 to 4 nitrogen atoms
, One or two oxygen atoms and / or one sulfur atom
A 5- to 18-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing
Represents one or more of these carbocycles or heterocycles.
(I) a C1-8 alkyl group, (ii) a C1-8
Alkoxy group, (iii) nitro group, (iv) halogen atom,
(V) cyano group, (vi) hydroxyl group, (vii) benzyloxy
Group, (viii) -NR²⁰¹R²⁰²Group (in the group, R²⁰¹And R
²⁰²Are each independently a hydrogen atom or a C1-8 alkyl
Represents a radical. ), (Ix) -COOR^{20 Three}Group (in the group, R
²⁰³Represents a hydrogen atom or a C1-8 alkyl group.
You. ), (X) trihalomethyl group, (xi) trihalometo
Xy group, (xii) phenyl group, (xiii) phenyloxy
Group, (xiv) phenyl group, phenyloxy group, hydroxyl group,
-NR²⁰¹R ²⁰²Or -COOR²⁰³Replaced by
Substituted with C1-8 alkyl group or C1-8 alkoxy group
The J^bIs the hydroxyl group, mercapto
Group, C1-4 alkoxy group, C1-4 alkylthio group,
C1-4 alkylsulfinyl group, C1-4 alkyls
Rufonyl group, carboxyl group, C1-4 alkoxycal
Bonyl, hydroxymethyl, formyl,
Represents an ano group, E is a single bond, an oxygen atom, a sulfur atom,-
SO-, -SO_Two-, C1-4 alkylene-M- (only
And the alkylene group is bonded to the ring, and the M group is bonded to the G group.
You. And M represents an oxygen atom, a sulfur atom, -SO-,
-SO_TwoAnd G represents 1) a C1-8 alkyl group, 2) a C2-8 alkenyl group, 3) a C2-8 alkynyl group 4) -OR⁷, -SR⁸, -NR⁹R^TenOr -COR¹¹
A C1-8 alkyl group substituted with a group selected from the group consisting of: 5) Cyc3, 6) a C1-8 alkyl group substituted with Cyc3.
And C1-8 alkyl groups, C2 to C2 in the above 1) to 4).
8 alkenyl groups and C2-8 alkynyl groups are represented by the following (i)
-(Xi) may be substituted with: (i) a halogen atom, (ii) a cyano group, (iii) a sulfonyl group,
(iv) -SO- (C1-4 alkyl) group, (v) -SO_Two−
(C1-4 alkyl) group, (vi) -SO_TwoNR^{twenty four}R^{twenty five}Base
(In the group, R^{twenty four}And R^{twenty five}Are each independently a hydrogen atom
Or a C1-4 alkyl group. ), (Vii) -NR
²⁶SO_Two-(C1-4 alkyl) group (in the group, R²⁶Is hydrogen
Represents an atom or a C1-4 alkyl group. ), (Viii) water
An amidino group optionally substituted with an acid group, (ix) formyl
Amino group, (x) C1-4 alkoxycarbonylamino
Group, (xi) di (C1-4 alkyl) amine (N-oxy
Cyc3 is a C3-15 monocyclic, bicyclic, or tricyclic ring
Formula carbocycle or 1-4 nitrogen atoms, 1-2 oxygen atoms
And a 5-18 membered unit containing one sulfur atom
Represents a ring, bicyclic or tricyclic heterocyclic ring,
The ring or heterocycle may comprise one or more (i) C1
8 alkyl groups, (ii) C1-8 alkoxy groups, (iii)
Nitro group, (iv) halogen atom, (v) cyano group, (v
i) hydroxyl group, (vii) benzyloxy group, (viii) -NR
¹⁰¹R¹⁰²Group (in the group, R¹⁰¹And R¹⁰²Are independent
Represents a hydrogen atom or a C1-8 alkyl group. ),
(Ix) -COOR^{Ten Three}Group (in the group, R¹⁰³Is a hydrogen atom or
Represents a C1-8 alkyl group. ), (X) trihalometh
Group, (xi) trihalomethoxy group, (xii) phenyl
Group, (xiii) phenyloxy group, (xiv) phenyl group,
Phenyloxy group, hydroxyl group, -NR¹⁰¹R ¹⁰²And -C
OOR¹⁰³C1-8 alkyl substituted with a group selected from
Or a C1-8 alkoxy group or an (xv) oxo group
(However, (1) J is J^aWhen
G represents a C1-8 alkyl group in 1) -4), C2-8
An alkenyl group and a C2-8 alkynyl group have at least one
(2) J
Is J^a, Cyc3 in 5) to 6) indicated by G is small.
Is substituted with at least one oxo group, and (3)
The carbon atom in the C1-8 alkyl group of (i) is (i) a carbon atom
3 to 7-membered cycloalkyl, one of which is a ring constituent atom
Or (ii) two adjacent carbon sources
With 3 to 7 membered cycloalkyl
May be represented. ), R⁷Is a hydrogen atom, C1-8 alkyl
Group, C2-8 alkenyl group, or phenyl group or
Is a C1-8 alkyl substituted by a C1-8 alkoxy group
Or a C2-5 acyl group;⁸Is hydrogen field
, A C1-8 alkyl group, a C2-8 alkenyl group,
Or phenyl or C1-8 alkoxy substituted
A C1-8 alkyl group, or -S- (C1-8 alkylene)
N) -OR^{twenty three}Group (in the group, R^{twenty three}Is a hydrogen atom or C1-8
Represents an alkyl group, and a carbon atom in C1-8 alkylene
Is (i) 3 to 7 with one carbon atom as a ring constituting atom.
Or (ii) next to
3 to 7 members, with the two carbon atoms in combination as ring constituent atoms
May represent cycloalkyl. ) And R⁹
Is a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl
Group, or a phenyl group or a C1-8 alkoxy group
Represents a substituted C1-8 alkyl group,^TenIs hydrogen field
C1-8 alkyl group, C2-8 alkenyl group,
A C1-8 alkyl group or a C2-5
Represents a sil group;¹¹Is (i) a C1-8 alkyl group, (i
i) a C1-8 alkoxy group, (iii) a hydroxyl group, (iv)
A C1-8 alkyl group or a C1-8
Lucoxy group or (v) -NR¹²R¹³Group (in the group, R¹²You
And R¹³Are each independently a hydrogen atom or C1-8
C1-8 alkyl substituted by alkyl or phenyl group
Represents a group. )

Embedded image Represents a single bond or a double bond. Or a non-toxic salt thereof,

[2] A method for producing the compound represented by the general formula (1), [3] A cell adhesion molecule expression inhibitor comprising the compound represented by the general formula (1) as an active ingredient.

In the present invention, the C1-4 alkyl group is a methyl, ethyl, propyl, butyl group and isomers thereof. The C1-8 alkyl group is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof. C1-4
Alkoxy groups are methoxy, ethoxy, propoxy,
Butoxy groups and isomers thereof. The C1-8 alkoxy group is a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.

The C1-8 alkylthio group is a methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio group and isomers thereof. C1-8 alkylamino group means methylamino, ethylamino, propylamino,
Butylamino, pentylamino, hexylamino, heptylamino, octylamino groups and isomers thereof.

Halogen atoms include chlorine, bromine, fluorine,
It means an iodine atom. A trihalomethyl group is chlorine,
A methyl group tri-substituted by bromine, fluorine and iodine atoms. A trihalomethoxy group is a methoxy group trisubstituted by chlorine, bromine, fluorine, and iodine atoms. A C1-8 alkyl group in which 1 to 17 halogen atoms are substituted means chlorine, bromine, fluorine, iodine atoms 1 to 17
Substituted by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof. The C1-8 alkoxy group in which 1 to 17 halogen atoms are substituted is chlorine, bromine, fluorine,
Methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy groups substituted by 1 to 17 iodine atoms and isomers thereof.

The C1-4 alkylene group includes a methylene, ethylene, trimethylene, tetramethylene group and isomers thereof. The C1-8 alkylene group is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group and isomers thereof. The C2-8 alkenyl group is a vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl group and isomers thereof. C2-8 alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,
Octynyl group and isomers thereof. The C2-5 acyl group includes an acetyl group, a propionyl group, a butyryl group, a pentanoyl group and isomers thereof.

Examples of the C3-7 monocyclic carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene,
And a benzene ring. 1 to 4 nitrogen atoms, 1 to
3 containing two oxygen atoms and / or one sulfur atom
A 7-membered monocyclic heterocycle is defined as 1-4 nitrogen atoms, 1-
3 containing two oxygen atoms and / or one sulfur atom
It includes a monocyclic heterocyclic aryl having 7 to 7 members or a partially or entirely saturated monocyclic heterocyclic aryl.

The 3- to 7-membered monocyclic heterocyclic aryl having 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom includes pyrrole, imidazole, triazole, Tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,
Diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (thiopyran), tiepin,
Oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine ring and the like.

The aforementioned 3 to 7 containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom
Examples of those partially or wholly saturated with a membered monocyclic heterocycle include oxirane, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, Tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole , Tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroiso Azole, tetrahydroisoquinoline, benzothiazole, morpholine, thiomorpholine, oxolane, oxane ring, and the like.

Examples of C3-15 monocyclic, bicyclic and tricyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene , Naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene,
Perhydroacenaphthylene, perhydrobiphenylene ring and the like can be mentioned.

A 5- to 18-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom is defined as 1 to 4 5 to 18-membered monocyclic, bicyclic or tricyclic heterocyclic aryl containing at least one nitrogen atom, one or two oxygen atoms and / or one sulfur atom, or a partially or wholly saturated one thereof included.

5 to 18 containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom described above.
As membered monocyclic, bicyclic or tricyclic heterocyclic aryl,
Pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiane (thiopyran), tiepin, oxazole, isoxazole, thiazole, isothiazole, oxa Diazole,
Oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,
Thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, carbazole, acridine ring And the like.

5 to 1 containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom
Examples of those partially or wholly saturated with an 8-membered monocyclic, bicyclic or tricyclic heterocyclic ring include pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine. , Tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,
Tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,
Dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine,
Thiomorpholine, oxolane, oxane, indoline,
Isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,
Perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydro Naphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzo Thiazole, perhydrobenzothiazole, di Drobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiaazepine, benzothiadiazepine, benzazepine, benzodiazepine, indolooxoazepine, indolotetrahydrooxazepine, indoloxadiazepine , Indolotetrahydrooxadiazepine, indolothiaazepine, indolotetrahydrothiaazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, Benzofurazan, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole,
Tetrahydrocarbazole, perhydrocarbazole,
Examples include dihydroacridine, tetrahydroacridine, perhydroacridine ring and the like.

The term "one or two nitrogen atoms or a 5- to 7-membered monocyclic heterocycle containing one nitrogen atom and one oxygen atom" means pyrrole, pyrroline, pyrrolidine, imidazole,
Pyrazole, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, oxazole, isoxazole, oxazine, morpholine ring and the like.

Examples of the 3- to 7-membered cycloalkyl in which one carbon atom in the C1-8 alkyl group or the C1-8 alkylene group is a ring-constituting atom include, for example, a C2 alkyl group or an alkylene group. If

Embedded image In the case of a C3 alkyl group or an alkylene group,

Embedded image And the like.

Examples of the 3- to 7-membered cycloalkyl in the C1-8 alkyl group or the C1-8 alkylene group in which two adjacent carbon atoms are a ring constituting atom include, for example, a C4 alkyl group or a C4 alkyl group. In the case of an alkylene group,

Embedded image And the like.

In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Further, isomers (E, Z, cis, trans) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , An optically active substance having optical activity (D, L, d, l-form), polar forms (high-polarity forms, low-polarity forms) by chromatographic separation, equilibrium compounds, mixtures of any ratio thereof, and racemic mixtures All are included in the present invention.

[0028]

[Salts] The present invention includes all non-toxic salts.
For example, common salts, acid addition salts, hydrate salts and the like can be mentioned. The compound of the present invention represented by the general formula (I) is converted into a corresponding salt by a known method. The salt is preferably a non-toxic, water-soluble salt. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine and the like.

The compound of the present invention represented by the general formula (I)
It is converted to the corresponding acid addition salt by known methods. The acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate Like, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Organic acid salts.
Further, the compound of the present invention represented by the general formula (I) or a salt thereof can be converted into a hydrate by a known method.

[0030]

Specific Compounds Among the compounds of the present invention represented by the general formula (I), preferred compounds are those represented by the general formula (IA)

Embedded image (In the formula, J ^ab represents a trifluoromethyl group, a methylsulfinyl group, a formyl group, a cyano group, and other symbols have the same meanings as described above.)

Formula (IB)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (IC)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (ID)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (IE)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (IF)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (IG)

Embedded image (In the formula, all symbols have the same meanings as described above.)

Formula (IH)

Embedded image (Wherein, R ^1G and R ^2G each independently represent (i) a hydrogen atom, (ii) a C1-8 alkyl group, (iii) a C2-8 alkenyl group, (iv) a C2-8 alkynyl group, (v) C1
-8 alkoxy group, (vi) C1-8 alkylthio group,
(Vii) Cyc1, (viii) cyano group, (ix) a formyl group, (x) -COOR ¹⁴ group (representing the radical, R ¹⁴ is a hydrogen atom or a C1~8 alkyl group.), (Xi) -CONR
¹⁵ R ¹⁶ groups (wherein R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a C1-8 alkyl group or a phenyl group), (xii) a hydroxyl group, a C1-4 alkoxy group, a phenoxy group, a halogen atom , cyano group, C2-5 acyl group, -COOR ¹⁴ group, -CONR ¹⁵ R ¹⁶ groups, -NR ¹⁷ R
¹⁸ groups (in the groups, R ¹⁷ and R ¹⁸ each independently represent a hydrogen atom, a C1-8 alkyl group or an acetyl group)
C1-8 substituted with one or two groups selected from
An alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, (xiii) a C1-8 alkyl group substituted with Cyc1, a C1-8 alkoxy group or a C1-8 alkylthio group, and other symbols have the same meanings as described above. Represents ). Specifically, Table 1 shown below
To the compounds described in Table 16 and the compounds described in the Examples, or non-toxic salts thereof.

[0038]

[Table 1]

[0039]

[Table 2]

[0040]

[Table 3]

[0041]

[Table 4]

[0042]

[Table 5]

[0043]

[Table 6]

[0044]

[Table 7]

[0045]

[Table 8]

[0046]

[Table 9]

[0047]

[Table 10]

[0048]

[Table 11]

[0049]

[Table 12]

[0050]

[Table 13]

[0051]

[Table 14]

[0052]

[Table 15]

[0053]

[Table 16]

[0054]

[Table 17]

[0055]

[Table 18]

[0056]

[Table 19]

[0057]

[Table 20]

[0058]

[Table 21]

[0059]

[Table 22]

[0060]

[Table 23]

[0061]

[Table 24]

[0062]

[Table 25]

[0063]

[Table 26]

[0064]

[Table 27]

[0065]

[Table 28]

[0066]

[Table 29]

[0067]

[Table 30]

[0068]

[Table 31]

[0069]

[Table 32]

[0070]

[Production Method of the Compound of the Present Invention] The compound of the present invention represented by the general formula (I) can be produced by the following methods or the methods described in Examples. [1] Among the compounds of the present invention represented by the general formula (I), R
³ is a compound having no —NH ₂ group, that is, a compound of the general formula (I
-1)

Embedded image (Wherein R ^1-1 and R ^2-1 independently represent the same meaning as R ¹ and R ² , provided that R ^1-1 and R ^2-1
The R ³ group in the group does not represent the —NH ₂ group, and the other symbols have the same meanings as described above. ) Is a compound represented by
It can be manufactured by the following methods (a) to (c).

(A) When the E group is an oxygen atom, a sulfur atom,-(C
A compound representing 1-4 alkylene) -O- or-(C1-4 alkylene) -S-, that is, a compound represented by the general formula (I-1-a)

Embedded image (Wherein, E ^a is an oxygen atom, a sulfur atom,-(C1-4 alkylene) -O- or-(C1-4 alkylene) -S
Represents-, and the other symbols have the same meanings as described above. The compound represented by the general formula (II-a-1)

Embedded image (Wherein XX represents a general leaving group (for example, represents a chlorine atom, a bromine atom, an iodine atom, a mesyl group or a tosyl group, and other symbols have the same meanings as described above)). Or the general formula (II-a-2)

Embedded image (Wherein L represents a C1-4 alkylene group, and other symbols have the same meanings as described above) and a compound represented by the general formula (III-a)

Embedded image (Wherein, E ^a-1 represents an oxygen atom or a sulfur atom, and other symbols have the same meanings as described above).

The compound represented by the general formula (II-a-1) or (II-a
-2) and the compound represented by the general formula (III-a) are known. For example, in an organic solvent (dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, acetone, etc.), an alkali metal Hydrides (such as sodium hydride), alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), alkaline earth metal hydroxides (such as barium hydroxide and calcium hydroxide), Using an alkali metal carbonate (eg, sodium carbonate, potassium carbonate), an aqueous solution thereof, or a mixture thereof, an alcohol or thiol represented by the general formula (III-a) is reacted at a temperature of −20 to 40 ° C. Formula (II-a-1) or Formula (II-a-
The reaction is carried out by reacting the compound shown in 2) at -20 to 40 ° C. This reaction is desirably performed under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

[0073] Also, a halogen atom J groups in J ^a group or J ^b group, i.e. a hydroxyl group, a mercapto group, C1 -4 alkoxy, C1 -4 alkylthio, C1 -4 alkylsulfinyl group, C1 -4 alkyl When it is a sulfonyl group, a carboxyl group, a C1-4 alkoxycarbonyl group, a hydroxymethyl group, a formyl group, or a cyano group, it can also be produced by the methods shown in the following Reaction Schemes A to D. In the reaction scheme, Z represents an oxygen atom or a sulfur atom, p-TsOH represents p-toluenesulfonic acid, TFAA represents trifluoroacetic anhydride, and alkyl represents an alkyl group. All the reactions in the reaction scheme are known.

[0074]

Embedded image

[0075]

Embedded image

[0076]

Embedded image

[0077]

Embedded image

(B) a compound wherein the E group represents a single bond, that is, a compound of the general formula (I-1-b)

Embedded image (Wherein E ^b represents a single bond, and other symbols have the same meanings as described above).
b)

Embedded image (Wherein all symbols have the same meanings as described above) and a compound represented by the general formula (III-b-1)

Embedded image (Wherein all symbols have the same meanings as described above), a compound represented by the general formula (III-b-2)

Embedded image (Wherein all symbols have the same meanings as described above) or a compound represented by the general formula (III-b-3)

Embedded image (Wherein T represents a C1-8 alkyl group, and other symbols have the same meanings as described above).

The compound represented by the general formula (II-b) and the general formula (III-b-1), the general formula (III-b-2) or the general formula (II-b)
The reaction with the compound represented by Ib-3) is known (J. Me
d. Chem., 33 , 2240 (1990), J. Heterocyclic Chem.,
31 , 549 (1994)), for example, using an organic solvent (pyridine, toluene, benzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol) or
Or without using, the general formula (III-b-1), the general formula (III-b
-2) or by reacting the compound represented by the general formula (III-b-3) with the compound represented by the general formula (II-b) at 20 to 150 ° C.

(C) The group E is a —SO— group, a —SO ₂ — group,
-(C1-4 alkylene) -SO- group or-(C1
4 alkylene) -SO ₂ - compound representing the group, namely the general formula (I-1-c)

Embedded image (Wherein, E ^C is -SO- group, -SO ₂ - group, - (C1 -4
Alkylene) -SO- group or - (C1 -4 alkylene) -SO ₂ - represents a group and the other symbols have the same meanings as described above. The compound represented by the general formula (I-1-)
In the compounds a), the group E represents a sulfur atom or a-(C1-4 alkylene) -S- group, that is, a compound represented by the general formula (I-1-a-
1)

Embedded image (Wherein E ^a-2 represents a sulfur atom or ^a- (C1-4 alkylene) -S- group, and the other symbols have the same meanings as described above). can do.

This oxidation reaction is known. For example, in an organic solvent (dichloromethane, chloroform, benzene, hexane, t-butyl alcohol, acetone, etc.), one equivalent or an excess of an oxidizing agent (hydrogen peroxide, sodium periodate) is used. , In the presence of acyl nitrite, sodium perborate, peracid (eg, m-chloroperbenzoic acid, peracetic acid, Oxone (registered trademark), etc.) at a temperature of -78 to 40 ° C. Done.

[2] Among the compounds of the present invention represented by the general formula (I), compounds wherein R ³ represents a —NH ₂ group, ie, a compound of the general formula (I-2)

Embedded image (Wherein, R ^1-2 and R ^2-2 independently represent the same meaning as R ¹ and R ² , provided that R ^1-2 and R ^2-2
The R ³ group in the group represents a —NH ₂ group, and the other symbols have the same meanings as described above. The compound represented by the formula (I-1) is a compound wherein the R ³ group represents a nitro group in the formula (I-1), that is, the compound represented by the formula (I-1-1)

Embedded image (Wherein R ^1-1-2 and R ^2-1-2 are each independently R ¹
And represent the same meaning as R ^2. However, it is assumed that R ³ in R ^1-1-2 and R ^2-1-2 represents a nitro group, and other symbols have the same meanings as described above. ) Can be produced by subjecting the compound to the reduction reaction.

The reduction reaction of this nitro group is known, and is carried out, for example, by a hydrogenolysis reaction and a reduction reaction using an organic metal. The hydrogenolysis reaction is known and includes, for example, organic solvents [ether-based (eg, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (eg, methanol, ethanol, etc.), benzene-based (eg, benzene, toluene, etc.) ),
Hydrogenation in ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), amides (eg, dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof. Catalyst (e.g., palladium-carbon, palladium black,
In the presence of palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, etc., an inorganic acid (eg, hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or an organic acid (eg, acetic acid, p -Toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid or the like), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate at a temperature of 0 to 200 ° C. When an acid is used, its salt may be used.
A reduction reaction using an organic metal is known. For example, in an organic solvent (ethanol, methanol, etc.) miscible with water, in the presence or absence of an aqueous hydrochloric acid solution, an organic metal (zinc, iron,
Using tin, tin chloride, iron chloride)
C. at a temperature of .degree.

[3] Among the compounds of the present invention represented by the general formula (I), R ³ is a —NR ^4-3 R ^5-3 group (wherein R ^4-3 and R ^5-3 are each independently Have the same meaning as R ⁴ and R ⁵ , provided that they do not represent hydrogen at the same time), that is, a compound represented by the general formula (I-3)

Embedded image (Wherein R ^1-3 and R ^2-2 independently represent the same meaning as R ¹ and R ² , provided that R ^1-3 and R ^2-3
The R ³ group in the group represents a —NR ^4-3 R ^5-3 group, and other symbols have the same meanings as described above. ) Can also be produced by subjecting the compound represented by the general formula (I-2) to an alkylation reaction or an acetylation reaction.

The alkylation reaction is known. For example, an alkylation reaction is carried out using an alkyl iodide (such as methyl iodide) in an organic solvent (such as tetrahydrofuran, dimethylformamide or a mixed solvent thereof) in the presence of sodium hydride. ~
It is performed at a temperature of 40 ° C. The acetylation reaction is known, for example, in the presence of a tertiary amine or pyridine,
The reaction is performed at a temperature of 0 to 80 ° C. using acetic anhydride.

[4] R¹Group is (i) COOH group, (ii) CON
R¹⁵R¹⁶Group, (iii) formyl group, (iv) nitrile group, (v) C
2-8 alkenyl groups, (vi) halogen atoms, hydroxyl groups,
A methyl group substituted with a group selected from a nonoxy group, (v
ii) COOR^14aGroup (in the group, R ^14aIs a C1-8 alkyl group
Represents ), Nitrile group, halogen atom, acetyl
Group, C1-6 alkyl group, C2-6 alkenyl group
An ethenyl group substituted with a^TwoBut water
The compound which is an elemental atom is obtained by the following reaction scheme 1 (1) and
It can also be manufactured by the method shown in 1 (2).
You.

In the reaction scheme, X is a halogen atom, Ph is a phenyl group, s is 0 or an integer of 1 to 6, R ^X
Represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, C2
-6 represents an alkenyl group, a COOR ^14a group, a nitrile group, or an acetyl group, ^RY represents a hydrogen atom, a C1-6 alkyl group, a halogen atom or a nitrile group, and the other symbols have the same meanings as described above. In the reaction schemes, each reaction is all known.

[0088]

Embedded image

[0089]

Embedded image

[5] n is 1, and R ³ is (i) a formyl group, (ii) a C1-8 alkanoyl group, (iii) a C2-8 alkenyl group, (iv) a halogen atom or —NR ⁴ R Methyl group substituted with ⁵ groups, (v) C1 substituted with a hydroxyl group
C8 substituted by a group selected from an alkyl group of 8 to 8 (vi) a COOR ⁶ group, a hydroxyl group, a halogen atom and a nitrile group.
Compounds having from 8 to 8 alkenyl groups are prepared according to the following reaction scheme 2.
It can also be manufactured by the methods shown in (1) and 2 (2). In Scheme, t represents an integer of 0 or 1 to 6, R ^W is a hydrogen atom, Cl to 6 alkyl groups,
C2-6 alkenyl group, halogen atom, nitrile group, C
OOR ^6a group (R ^6a group represents a C1-8 alkyl group)
Wherein R ^Z represents a hydrogen atom, a C1-6 alkyl group, a halogen atom or a nitrile group, and the other symbols have the same meanings as described above. All the reactions in the reaction scheme are known.

[0091]

Embedded image

[0092]

Embedded image

Formula (II-a), Formula (III-a), Formula (II-b), Formula (III-b-1) or Formula (III-b-
The compound represented by 2) is known per se or can be easily produced by a known method (J.
Med. Chem., 33 , 2240 (1990) or J. Med. Chem., 3
5 , 3323 (1992)).

In each reaction in the present specification, the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography,
Alternatively, it can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions.

[0095]

[Pharmacological activity] The following experiment proved that the compound of the present invention represented by the general formula (I) has the activity of inhibiting the expression of adhesion molecules. (1) Inhibition of expression of adhesion molecules from vascular endothelial cells [Experimental method] Human umbilical vein endothelial cells were treated with antibiotics (100
5% bovine containing U / ml penicillin and 100 μg / ml streptomycin: Gibco, 0.01 mg / ml heparin (Nissui Pharmaceutical) and 0.005 mg / ml endothelial cell growth factor (Nissui Pharmaceutical) MCD with fetal serum
Gelatin coat 96 with B104 medium (Nissui Pharmaceutical Co., Ltd.)
The cells were cultured in a well-plated plastic plate until they reached confluence. The compound is dissolved in dimethyl sulfoxide,
The medium was adjusted to a final concentration of 0.2%, and 50 μl was added. Furthermore, human TNFα (genzyme) was added at 10 ng /
ml (for E-selectin, ICAM-1 quantification), or 10 ng / ml of human TNFα and human IL-4.
(Genzyme) was added in an amount of 50 μl at 1 ng / ml (for VCAM-1 quantification) to stimulate vascular endothelial cells. After stimulation for 6 hours, the cells were washed once with PBS (-) and fixed with 0.3% hydrogen peroxide / methanol for 10 minutes at room temperature. P
After washing three times with BS (-), anti-ICA was used as a primary antibody.
M-1 antibody (BBA4), anti-E-selectin antibody (BBA
2) or anti-VCAM-1 antibody (BBA6) (both mouse IgG1, 1.25 μg / ml: R & D) 100
μl was added and incubated for 30 minutes at 37 ° C. Thereafter, the plate was washed three times with PBS (-), and a secondary antibody (peroxidase-labeled goat anti-mouse IgG antibody: 40
0-fold dilution: Nordic Immunological laboratories) 1
00 μl was added and incubated for 30 minutes at room temperature. After washing four times with PBS (-), the substrate solution (1 mg / ml ortho-phenylene-diamine-2HC)
l and 0.1% hydrogen peroxide) and incubated for 4 minutes at room temperature. 8N sulfuric acid 50μl
In addition, the reaction was stopped, and the absorbance at 490 nm was measured with a microplate reader. The inhibition rate was calculated by the following formula, and the 50% expression inhibitory concentration (IC ₅₀ ) was determined from the percentage relative to the control group.

[0096]

## EQU1 ## Inhibition rate (%) = [(CS) / (CB)] × 100 C: Absorbance under cytokine stimulation S: Absorbance in the presence of cytokine-stimulated drug B: Absorbance under non-stimulation The results are shown in Table 17.

[0097]

[Table 33]

In the above evaluation system, MTT [3- (4,5-dimethyl-2) was used as a cytotoxicity test to confirm that the action of the compound was not due to cytotoxicity.
-Thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide] assay was performed to determine the number of viable cells.

(2) Cytotoxicity test by MTT assay [Experimental method] After adding and culturing a sample under the same conditions as in the above test, washing was performed once with PBS (-), and 1 mg / ml of MT was added.
100 μl of T solution was added, and the cells were cultured for 3 hours. After cultivation,
The supernatant was removed, 100 μl of methanol was added, the mixture was stirred well, and the absorbance at 570 nm / 690 nm was measured with a microplate reader. The inhibition rate was calculated by the following formula.

[0100]

## EQU2 ## Inhibition rate (%) = [(CS) / C] × 100 C: Absorbance under cytokine stimulation S: Absorbance in the presence of cytokine-stimulated drug

As a result, the inhibition rate of the compound of Example 2 (52) was 8.4%.

[0102]

[Toxicity] As described above, the toxicity of the compound of the present invention is extremely low, and it can be judged that the compound is sufficiently safe for use as a medicament.

[0103]

[Application to pharmaceuticals] In animals including humans, particularly humans, inhibiting the expression of adhesion molecules can be used, for example, for various inflammatory diseases, rheumatoid arthritis, allergy, bronchial asthma, atopic dermatitis, psoriasis, and ischemic disease. Suppression of perfusion injury, nephritis,
Useful for prevention and / or treatment of hepatitis, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, suppression of transplant rejection, sepsis, diabetes, autoimmune disease, cancer metastasis, arteriosclerosis, AIDS (AIDS) It is.

In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt, an acid addition salt, or a hydrate thereof for the above-mentioned purpose, it is usually required to be orally or systemically or locally. It is administered in parenteral form. Dosage should be based on age, weight,
Depending on symptoms, therapeutic effect, administration method, treatment time, etc., it is usually 1 mg to 10 mg per adult.
Orally in the range of 00 mg once to several times a day,
Or 1 mg to 100 per adult
The parenteral administration (preferably, intravenous administration) is performed once to several times a day in the range of mg, or 1 hour to 24 hours a day.
It is continuously administered intravenously for a time range. Of course, as described above, the dose varies depending on various conditions, so that a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range. When the compound of the present invention is administered, it is used as a solid preparation for oral administration, a liquid preparation for oral administration, and an injection, an external preparation, a suppository and the like for parenteral administration.

The solid preparation for oral administration for oral administration includes tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. In such solid dosage forms for internal use, the one or more active substances can be as such or excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, Disintegrator (calcium cellulose glycolate, etc.), lubricant (magnesium stearate, etc.),
It is mixed with a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.) and the like, and is formulated and used according to a conventional method. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin. Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances may be converted to a commonly used diluent (purified water,
Dissolved, suspended or emulsified in ethanol or a mixture thereof). Further, the liquid preparation may contain a humectant, a suspending agent, an emulsifier, a sweetener, a flavor, a fragrance, a preservative, a buffer and the like.

Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections which are dissolved or suspended in a solvent before use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent. As a solvent, for example, distilled water for injection,
Physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used. Further, this injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. . These are manufactured and prepared by sterilization or aseptic operation in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be manufactured and then sterilized or dissolved in sterile distilled water for injection or other solvents before use.

Other preparations for parenteral administration include external solutions, ointments, liniments, inhalants, sprays, suppositories and vagina which contain one or more active substances and are formulated in a conventional manner. Pessaries for internal administration, etc. are included. Sprays may contain, in addition to the commonly used diluents, buffers such as sodium bisulfite, which provide isotonicity with stabilizers such as sodium chloride, sodium citrate, or citric acid. It may be. For example, US Patent No.
The details are described in 2,868,691 and 3,095,355.

[0108]

EXAMPLES The present invention will now be described in detail with reference to Examples and Examples, but the present invention is not limited thereto. Chromatographic separation point and TLC
The solvent in parentheses shown in the above indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. The solvent in parentheses shown in the NMR section indicates the solvent used for the measurement. The names of the condensed rings and the numbers of the atoms around the rings are given as follows.

[0109]

Embedded image 1,2,4-triazolo [4,3-a] quinoxaline

[0110]

Embedded image 1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine

Example 1 Sodium 2- (1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxalin-4-yl) thioethylsulfonate

Embedded image

Sodium (2-mercaptoethane) sulfonate (790 mg) in dimethylformamide (30 m
l) Add 60% sodium hydride (168m
g) was added. After the mixture was stirred at room temperature for 30 minutes,
4-chloro-1-trifluoromethyl-1,2,4
-Triazolo [4,3-a] quinoxaline (J. Med.Che
m., 33 , 2240 (1990)) (1.09 g). The mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the precipitate was collected by filtration. The precipitate was washed with water and hexane to give the title compound (907 mg) having the following physical data.
I got TLC: Rf 0.18 (chloroform: methanol = 3: 1); NMR (300 MHz, DMSO-d ₆ ): δ 8.10-
7.97 (m, 2H), 7.82-7.74 (m, 2H), 3.66-3.56 (m, 2H), 2.93
-2.85 (m, 2H).

Reference Example 1 (1) to 1 (2) A method described in J. Med. Chem., 33 , 2240 (1990) using a corresponding compound instead of 2,3-dichlorobenzopyrazine. The following operation was performed to obtain the following compound.

Reference Example 1 (1) 4-chloro-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.60 (hexane: ethyl acetate = 1:
1); NMR (CDCl ₃ ): δ 8.87 (1H, dd, J = 1.6, 4.6 Hz), 8.50 (1
H, dd, J = 1.6,8.0Hz), 7.81 (1H, dd, J = 4.6,8.0Hz).

Reference Example 1 (2) 4-chloro-8-fluoro-1-trifluoromethyl-
1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.42 (hexane: ethyl acetate = 1:
1).

Examples 2 (1) to 2 (56) 4-Chloro-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline or, alternatively, Reference Example 1 (1) Alternatively, the following compound was obtained by performing the same operation as in Example 1 using the compound produced in Reference Example 1 (2) and the corresponding compound instead of sodium (2-mercaptoethane) sulfonate.

Example 2 (1) 4- (2-chloroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] Pyrazine

Embedded image TLC: Rf 0.42 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.67 (dd, J = 4.4, 1.6 Hz, 1)
H), 8.25 (dd, J = 8.4,1.6Hz, 1H), 7.67 (dd, J = 8.4,4.4Hz, 1H
H), 5.00 (t, J = 6.0 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H).

Example 2 (2) 4- (3-chloropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4]
Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.42 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.65 (dd, J = 4.6, 1.6 Hz, 1)
H), 8.25 (dd, J = 8.0,1.6Hz, 1H), 7.66 (dd, J = 8.0,4.6Hz, 1H)
H), 4.90 (t, J = 6.2Hz, 2H), 3.84 (t, J = 6.2Hz, 2H), 2.52-
2.40 (m, 2H).

Example 2 (3) 4- (2-cyanoethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] Pyrazine

Embedded image TLC: Rf 0.26 (toluene: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.5, 1.5 Hz, 1)
H), 8.27 (dd, J = 8.1,1.5Hz, 1H), 7.70 (dd, J = 8.1,4.5Hz, 1H
H), 5.00 (t, J = 6.9 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H).

Example 2 (4) 4- (2-Chloro-2-propenyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4':
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.42 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.67 (dd, J = 4.8, 1.6 Hz, 1)
H), 8.25 (dd, J = 8.4,1.6Hz, 1H), 7.67 (dd, J = 8.4,4.8Hz, 1H
H), 5.75 (m, 1H), 5.55 (m, 1H), 5.32 (m, 2H).

Example 2 (5) 4- (2-Fluoroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4]
Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.53 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.67 (dd, J = 4.8, 1.6 Hz, 1)
H), 8.24 (dd, J = 8.2,1.6Hz, 1H), 7.67 (dd, J = 8.2,4.8Hz, 1H)
H), 5.07 (m, 2H), 4.96-4.92 (m, 1H), 4.85-4.80 (m, 1H).

Example 2 (6) 4- [2- (Nt-butoxycarbonylamino) ethylthio] -1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.41 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.18-8.06 (m, 2H), 7.77-
7.61 (m, 2H), 5.12 (brs, 1H), 3.65-3.57 (m, 4H), 1.44 (s,
9H).

Example 2 (7) 4- (2-methylsulfinylethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.35 (chloroform: methanol = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.67 (dd, J = 4.8, 1.6 Hz, 1)
H), 8.27 (dd, J = 8.4,1.6Hz, 1H), 7.68 (dd, J = 8.4,4.8Hz, 1H)
H), 5.25 (ddd, J = 12.0,8.4,4.4Hz, 1H), 5.14 (ddd, J = 12.
0,5.2,5.0Hz, 1H), 3.45 (ddd, J = 13.6,5.2,4.4Hz, 1H), 3.
24 (ddd, J = 13.6, 8.4, 5.0 Hz, 1H), 2.79 (s, 3H).

Example 2 (8) 4- (2-methylsulfonylethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4':
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.63 (chloroform: methanol = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.69 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.27 (dd, J = 8.0,1.8Hz, 1H), 7.70 (dd, J = 8.0,4.8Hz, 1H
H), 5.16 (t, J = 5.6Hz, 2H), 3.66 (t, J = 5.6Hz, 2H), 3.26
(s, 3H).

Example 2 (9) 4- (2-oxo-4-methyloxazolidin-4-yl) methyloxy-1-trifluoromethyl-1,2,2
4-triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine

Embedded image TLC: Rf 0.41 (chloroform: methanol = 9:
1); NMR (300 MHz, CDCl ₃ ): δ 8.69 (dd, J = 4.5, 1.5 Hz, 1)
H), 8.24 (dd, J = 8.4,1.5Hz, 1H), 7.69 (dd, J = 8.4,4.5Hz, 1H
H), 5.98 (brs, 1H), 4.74 (d, J = 11.1Hz, 1H), 4.64 (d, J = 1
1.1Hz, 1H), 4.47 (d, J = 9.0Hz, 1H), 4.24 (d, J = 9.0Hz, 1H),
1.65 (s, 3H).

Example 2 (10) 4- [2- (2-oxopyrrolidin-1-yl) ethyl] oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3 4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.58 (chloroform: methanol = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.66 (dd, J = 4.4, 1.6 Hz, 1)
H), 8.24 (dd, J = 8.4,1.6Hz, 1H), 7.67 (dd, J = 8.4,4.4Hz, 1H
H), 4.88 (t, J = 5.2Hz, 2H), 3.88 (t, J = 5.2Hz, 2H), 3.72
(t, J = 7.0Hz, 2H), 2.40 (dd, J = 8.0,7.8Hz, 2H), 2.16-1.98
(m, 2H).

Example 2 (11) 4- (1-oxothian-4-yl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4':
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.44 & 0.38 (chloroform: methanol = 9: 1); NMR (200 MHz, CDCl ₃ ): δ 8.66 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.24 (dd, J = 8.0,1.8Hz, 7 / 10H), 8.21 (dd, J = 8.0,1.8H
z, 3 / 10H), 7.67 (dd, J = 8.0,4.8Hz, 7 / 10H), 7.66 (dd, J = 8.
0,4.8Hz, 3 / 10H), 5.92-5.84 (m, 7 / 10H), 5.64-5.52 (m, 3 /
10H), 3.36-2.76 (m, 6H), 2.39-2.20 (m, 2H).

Example 2 (12) 4- (1,1-dioxothian-4-yl) oxy-1
-Trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.52 (chloroform: methanol = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.69 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.23 (dd, J = 8.0,1.8Hz, 1H), 7.68 (dd, J = 8.0,4.8Hz, 1H)
H), 5.90-5.81 (m, 1H), 3.64-3.48 (m, 2H), 3.16-3.00 (m,
2H), 2.81-2.52 (m, 4H).

Example 2 (13) N- [2- (1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine-4 -Yl) oxoethyl] -N, N-dimethylamine N-oxide

Embedded image TLC: Rf 0.09 (chloroform: methanol = 3:
1); NMR (200 MHz, CDCl ₃ ): δ 8.68 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.29 (dd, J = 8.0,1.8Hz, 1H), 7.69 (dd, J = 8.0,4.8Hz, 1H
H), 5.41-5.34 (m, 2H), 3.93-3.85 (m, 2H), 3.41 (s, 6H).

Example 2 (14) 4- (2-Sulfamoylethyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.56 (chloroform: methanol = 9:
1); NMR (300 MHz, CDCl ₃ ): δ 8.17-8.10 (m, 2H), 7.76-
7.69 (m, 2H), 4.74 (brs, 2H), 3.91-3.86 (m, 2H), 3.72-3.
67 (m, 2H).

Example 2 (15) 4- (2-cyanoethyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.54 (hexane: ethyl acetate = 1:
1); NMR (300 MHz, CDCl ₃ ): δ 8.17-8.10 (m, 2H), 7.77-
7.67 (m, 2H), 3.72 (t, J = 7.2Hz, 2H), 3.00 (t, J = 7.2Hz, 2
H).

Example 2 (16) 4- (2,2,2-trifluoroethyl) oxy-1-
Trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.26 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.72 (dd, J = 4.5, 1.8 Hz, 1)
H), 8.28 (dd, J = 8.1,1.8Hz, 1H), 7.71 (dd, J = 8.1,4.5Hz, 1
H), 5.17 (q, J = 8.1 Hz, 2H).

Example 2 (17) 4- (2,2,3,3,3-pentafluoropropyl)
Oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.32 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.72 (dd, J = 4.5, 1.8 Hz, 1)
H), 8.29 (dd, J = 8.1,1.8Hz, 1H), 7.72 (dd, J = 8.1,4.5Hz, 1H
H), 5.24 (brt, J = 12.6Hz, 2H).

Example 2 (18) 4- (1,3-Difluoropropan-2-yl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.61 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.69 (dd, J = 4.4, 1.8 Hz, 1)
H), 8.24 (dd, J = 8.2,1.8Hz, 1H), 7.68 (dd, J = 8.2,4.4Hz, 1
H), 6.23-5.98 (m, 1H), 4.91 (dd, J = 47.6, 4.8 Hz, 4H).

Example 2 (19) 4- (2,2-Difluoroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′:
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.19 (hexane: ethyl acetate = 2:
1); NMR (200 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.8, 1.6 Hz, 1)
H), 8.28 (dd, J = 8.4,1.6Hz, 1H), 7.71 (dd, J = 8.4,4.8Hz, 1H
H), 6.35 (tt, J = 55.2,4.4Hz, 1H), 4.95 (dt, J = 4.4,12.8H
z, 2H).

Example 2 (20) 4- (2,2,3,3-tetrafluoropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.27 (hexane: ethyl acetate = 2:
1); NMR (200 MHz, CDCl ₃ ): δ 8.72 (dd, J = 4.8, 1.6 Hz, 1)
H), 8.29 (dd, J = 8.4,1.6Hz, 1H), 7.72 (dd, J = 8.4,4.8Hz, 1H)
H), 6.20 (tt, J = 52.9,4.4Hz, 1H), 5.14 (tt, J = 12.0,1.2H
z, 2H).

Example 2 (21) 4- (2,2-Dichloroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3
4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.42 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.5, 1.8 Hz, 1)
H), 8.27 (dd, J = 8.1,1.8Hz, 1H), 7.70 (dd, J = 8.1,4.5Hz, 1H
H), 6.25 (t, J = 6.3 Hz, 1H), 5.12 (d, J = 6.3 Hz, 2H).

Example 2 (22) 4- (4,4,4-trifluorobutyl) oxy-1-
Trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.67 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.66 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.24 (dd, J = 8.4,1.8Hz, 1H), 7.67 (dd, J = 8.4,4.8Hz, 1H)
H), 4.81 (t, J = 6.2 Hz, 2H), 2.57-2.21 (m, 4H).

Example 2 (23) 4- (1,1,1-trifluoropropan-2-yl)
Oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.72 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.26 (dd, J = 8.0,1.8Hz, 1H), 7.70 (dd, J = 8.0,4.8Hz, 1H)
H), 6.25-6.12 (m, 1H), 1.75-1.71 (m, 3H).

Example 2 (24) 4- (4-chlorobutyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] Pyrazine

Embedded image TLC: Rf 0.46 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.65 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.23 (dd, J = 8.0,1.8Hz, 1H), 7.66 (dd, J = 8.0,4.8Hz, 1H)
H), 4.79 (t, J = 6.0Hz, 2H), 3.67 (t, J = 6.0Hz, 2H), 2.24-
2.00 (m, 4H).

Example 2 (25) 4- (2,2,3,4,4,4-hexafluorobutyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.54 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.73 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.30 (dd, J = 8.0,1.8Hz, 1H), 7.72 (dd, J = 8.0,4.8Hz, 1H
H), 5.60-4.97 (m, 3H).

Example 2 (26) 4- (2 (R) -chloropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4':
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.35 (toluene: ethyl acetate = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.67 (dd, J = 4.4, 1.8 Hz, 1)
H), 8.25 (dd, J = 8.4,1.8Hz, 1H), 7.67 (dd, J = 8.4,4.4Hz, 1H
H), 4.95 (dd, J = 11.4,6.6Hz, 1H), 4.73 (dd, J = 11.4,6.6H
z, 1H), 4.55 (sextet, J = 6.6Hz, 1H), 1.73 (d, J = 6.6Hz, 3
H).

Example 2 (27) 4- (2,3-Dichloropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4':
3,4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.38 (toluene: ethyl acetate = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.68 (dd, J = 4.4, 1.8 Hz, 1)
H), 8.27 (dd, J = 8.4,1.8Hz, 1H), 7.68 (dd, J = 8.4,4.4Hz, 1H)
H), 5.09 (dd, J = 11.8,5.6Hz, 1H), 5.02 (dd, J = 11.8,5.6H
z, 1H), 4.63 (quintet, J = 5.6Hz, 1H), 4.04 (d, J = 5.6Hz, 3
H).

Example 2 (28) 4- (2-methylsulfonylaminoethyl) thio-1-
Trifluoromethyl-1,2,4-triazolo [4,3
-A] Quinoxaline

Embedded image TLC: Rf 0.40 (chloroform: ethyl acetate = 1:
1); NMR (300 MHz, DMSO-d ₆ ) 8.12-7.99 (m, 2H), 7.84-7.76
(m, 2H), 7.43 (t, J = 6.0Hz, 1H), 3.55 (t, J = 6.0Hz, 2H), 3.
39 (q, J = 6.0Hz, 2H), 2.98 (s, 3H).

Example 2 (29) 4- (Cyanomethyl) thio-1-trifluoromethyl-
1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.33 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.22-8.17 (m, 2H), 7.78-
7.74 (m, 2H), 4.22 (s, 2H).

Example 2 (30) 4- (3,3,3-trifluoro-2-hydroxypropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.27 (hexane: ethyl acetate = 4:
1); NMR (300 MHz, CDCl ₃ ): δ 8.17 (brd, J = 9.0 Hz, 1H),
8.10-8.05 (m, 1H), 7.79-7.69 (m, 2H), 4.62 (d, J = 5.7Hz, 1
H), 4.48-4.38 (m, 1H), 3.78 (dd, J = 14.7,3.3Hz, 1H), 3.7
0 (dd, J = 14.7, 9.3Hz, 1H).

Example 2 (31) 4- (2-acetyloxy-3,3,3-trifluoropropyl) thio-1-trifluoromethyl-1,2,4
-Triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.48 (hexane: ethyl acetate = 4:
1); NMR (300 MHz, CDCl ₃ ): δ 8.15 (brd, J = 9.6 Hz, 1H),
8.10 (dd, J = 7.5,2.4Hz, 1H), 7.78-7.65 (m, 2H), 5.90-5.7
9 (m, 1H), 4.25 (dd, J = 14.4,3.0Hz, 1H), 3.32 (dd, J = 14.4,
9.9Hz, 1H), 2.17 (s, 3H).

Example 2 (32) 4- (N-hydroxyamidinomethyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-
a] Quinoxaline

Embedded image TLC: Rf 0.46 (chloroform: methanol = 9:
1); NMR (300 MHz, DMSO-d ₆ ): δ 9.30 (s, 1H), 8.10-8.0
2 (m, 2H), 7.83-7.76 (m, 2H), 5.69 (s, 2H), 4.12 (s, 2H).

Example 2 (33) 4- [2- (N-hydroxyamidino) ethyl] thio-
1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.45 (chloroform: methanol = 9:
1); NMR (300 MHz, DMSO-d ₆ ): δ 9.60 (s, 1H), 8.40 (s, 1)
H), 8.15 (s, 1H), 8.09-8.01 (m, 2H), 7.80-7.76 (m, 2H),
3.63 (t, J = 7.2Hz, 2H), 2.76 (t, J = 7.2Hz, 2H).

Example 2 (34) 4- (4,4,4-trifluoro-3-hydroxybutyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.24 (hexane: ethyl acetate = 7:
3); NMR (200 MHz, CDCl ₃ ): δ 8.20-8.03 (m, 2H), 7.79-
7.65 (m, 2H), 4.32-4.11 (m, 1H), 3.97 (d, J = 5.0Hz, 1H),
3.81-3.59 (m, 2H), 2.34-2.20 (m, 2H).

Example 2 (35) 4- [2- (N-formylamino) ethyl] thio-1-
Trifluoromethyl-1,2,4-triazolo [4,3
-A] Quinoxaline

Embedded image TLC: Rf 0.36 (chloroform: methanol = 9:
1); NMR (300 MHz, CDCl ₃ ): δ 8.23 (s, 1H), 8.16-8.06
(m, 2H), 7.76-7.65 (m, 2H), 6.18 (brs, 1H), 3.85-3.75
(m, 2H), 3.72-3.60 (m, 2H).

Example 2 (36) 4- (3-Fluoropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3
4] pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.15 (toluene: ethyl acetate = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.65 (dd, J = 4.6, 1.6 Hz, 1)
H), 8.24 (dd, J = 8.4,1.6Hz, 1H), 7.66 (dd, J = 8.4,4.6Hz, 1H
H), 4.88 (t, J = 6.2Hz, 2H), 4.74 (dt, J = 47.2,5.8Hz, 2H),
2.40 (m, 2H).

Example 2 (37) 4- (4-Fluorobutyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4]
Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.18 (toluene: ethyl acetate = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.64 (dd, J = 4.6, 1.6 Hz, 1)
H), 8.23 (dd, J = 8.4,1.6Hz, 1H), 7.66 (dd, J = 8.4,4.6Hz, 1H)
H), 4.80 (t, J = 6.4Hz, 2H), 4.57 (dt, J = 47.4,5.8Hz, 2H),
2.24-1.84 (m, 4H).

Example 2 (38) 4- (cyanomethylthio) -8-fluoro-1-trifluoromethyl-1,2,4-triazolo [4,3-a]
Quinoxaline

Embedded image TLC: Rf 0.34 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.22 (dd, J = 9.0, 5.7 Hz, 1)
H), 7.88 (dd, J = 9.0,2.7Hz, 1H), 7.52 (ddd, J = 9.0,7.8,2.
7Hz, 1H), 4.19 (s, 2H).

Example 2 (39) 4- (2-Cyanoethyl) thio-8-fluoro-1-trifluoromethyl-1,2,4-triazolo [4,3-
a] Quinoxaline

Embedded image TLC: Rf 0.28 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.13 (dd, J = 9.3, 6.0 Hz, 1)
H), 7.86 (dd, J = 9.0,2.7Hz, 1H), 7.49 (ddd, J = 9.3,7.8,2.
7Hz, 1H), 3.70 (t, J = 7.8Hz, 2H), 2.98 (t, J = 7.8Hz, 2H).

Example 2 (40) 4- (2-cyanoethyl) oxy-8-fluoro-1-
Trifluoromethyl-1,2,4-triazolo [4,3
-A] Quinoxaline

Embedded image TLC: Rf 0.42 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 7.97 (dd, J = 9.2, 6.0 Hz, 1)
H), 7.87 (dd, J = 9.6,2.6Hz, 1H), 7.46 (ddd, J = 9.2,7.4,2.
6 Hz, 1 H), 4.97 (t, J = 6.6 Hz, 2 H), 3.09 (t, J = 6.6 Hz, 2 H).

Example 2 (41) 4- (3-cyanopropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.37 (toluene: ethyl acetate = 2:
1); NMR (200 MHz, CDCl ₃ ): δ 8.14 (m, 1H), 7.97 (m, 1)
H), 7.75-7.58 (m, 2H), 4.87 (t, J = 6.0Hz, 2H), 3.07 (t, J =
7.2Hz, 2H), 2.37 (m, 2H).

Example 2 (42) 4- (2-cyanoethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.44 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.18-8.12 (m, 1H), 8.01-
7.94 (m, 1H), 7.80-7.62 (m, 2H), 4.99 (t, J = 6.6Hz, 2H),
3.10 (t, J = 6.6Hz, 2H).

Example 2 (43) 4- (2-cyanopropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4]
Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.45 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.69 (dd, J = 4.6, 1.8 Hz, 1)
H), 8.26 (dd, J = 8.0,1.8Hz, 1H), 7.69 (dd, J = 8.0,4.6Hz, 1H
H), 4.98 (dd, J = 11.0,6.6Hz, 1H), 4.74 (dd, J = 11.0,6.6H
z, 1H), 3.49-3.32 (m, 1H), 1.59 (d, J = 7.4Hz, 3H).

Example 2 (44) 4- (4-cyanobutyl) oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.43 (toluene: ethyl acetate = 2:
1); NMR (200 MHz, CDCl ₃ ): δ 8.13 (m, 1H), 7.95 (m, 1)
H), 7.73-7.56 (m, 2H), 4.79 (t, J = 6.0Hz, 2H), 2.52 (t, J =
6.8Hz, 2H), 2.30-1.80 (m, 4H).

Example 2 (45) 4- (2-cyanopropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.59 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.18-8.11 (m, 1H), 7.99-
7.94 (m, 1H), 7.76-7.60 (m, 2H), 4.97 (dd, J = 11.0,6.8Hz,
1H), 4.74 (dd, J = 11.0,6.6Hz, 1H), 3.50-3.33 (m, 1H), 1.
58 (d, J = 7.2 Hz, 3H).

Example 2 (46) 4- (2-Fluoropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.62 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.18-8.05 (m, 2H), 7.77-
7.62 (m, 2H), 5.21-4.88 (m, 1H), 3.74 (dd, J = 18.0,6.2Hz,
1H), 3.73 (dd, J = 20.2,5.4Hz, 1H), 1.56 (dd, J = 23.4,6.2H
z, 3H).

Example 2 (47) 4- (3-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.34 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.19-8.11 (m, 2H), 7.78-
7.63 (m, 2H), 3.62 (t, J = 7.0Hz, 2H), 2.61 (t, J = 6.6Hz, 2
H), 2.26 (m, 2H).

Example 2 (48) 4- (3-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b ] Pyrazine

Embedded image TLC: Rf 0.26 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.71 (dd, J = 4.4, 1.6 Hz, 1)
H), 8.45 (dd, J = 8.0,1.6Hz, 1H), 7.71 (dd, J = 8.0,4.4Hz, 1H
H), 3.63 (t, J = 7.0Hz, 2H), 2.60 (t, J = 6.6Hz, 2H), 2.25
(m, 2H).

Example 2 (49) 4- (3-chloropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b ] Pyrazine

Embedded image TLC: Rf 0.63 (hexane: ethyl acetate = 1:
1); NMR (300 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.37 (dd, J = 8.1,1.8Hz, 1H), 7.70 (dd, J = 8.1,4.8Hz, 1H)
H), 3.75 (t, J = 6.0Hz, 2H), 3.64 (d, J = 6.9Hz, 2H), 2.35 (t
t, J = 6.9,6.0Hz, 2H).

Example 2 (50) 4- (4-cyanobutyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.37 (toluene: ethyl acetate = 6:
1); NMR (200 MHz, CDCl ₃ ): δ 8.17-8.05 (m, 2H), 7.77-
7.61 (m, 2H), 3.51 (t, J = 7.0Hz, 2H), 2.48 (t, J = 6.6Hz, 2
H), 2.16-1.84 (m, 4H).

Example 2 (51) 4- (4-cyanobutyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] Pyrazine

Embedded image TLC: Rf 0.23 (toluene: ethyl acetate = 6:
1); NMR (200 MHz, CDCl ₃ ): δ 8.70 (dd, J = 4.6, 1.8 Hz, 1)
H), 8.38 (dd, J = 8.0,1.8Hz, 1H), 7.70 (dd, J = 8.0,4.6Hz, 1
H), 3.51 (t, J = 7.0Hz, 2H), 2.48 (t, J = 6.6Hz, 2H), 2.17-
1.83 (m, 4H).

Example 2 (52) 4- (2-Fluoropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4]
Pyrido [2,3-b] pyrazine

Embedded image TLC: Rf 0.46 (toluene: ethyl acetate = 9:
1); NMR (200 MHz, CDCl ₃ ): δ 8.71 (dd, J = 4.6, 1.6 Hz, 1)
H), 8.36 (dd, J = 8.0,1.6Hz, 1H), 7.71 (dd, J = 8.0,4.6Hz, 1
H), 5.04 (m, 1H), 3.74 (dd, J = 18.4,6.2Hz, 1H), 3.73 (dd,
J = 20.2,5.6Hz, 1H), 1.56 (dd, J = 23.4,6.2Hz, 3H).

Example 2 (53) 4- (2-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.45 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.19-8.08 (m, 2H), 7.78-
7.75 (m, 2H), 3.81 (dd, J = 14.0,7.0Hz, 1H), 3.60 (dd, J = 1
4.0,7.0Hz, 1H), 3.35-3.17 (m, 1H), 1.57 (d, J = 7.0Hz, 3
H).

Example 2 (54) 4- (2-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b ] Pyrazine

Embedded image TLC: Rf 0.37 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 8.73 (dd, J = 4.8, 1.8 Hz, 1)
H), 8.39 (dd, J = 8.0,1.8Hz, 1H), 7.73 (dd, J = 8.0,4.8Hz, 1H
H), 3.83 (dd, J = 14.0,7.0Hz, 1H), 3.61 (dd, J = 14.0,7.0H
z, 1H), 3.33-3.15 (m, 1H), 1.57 (d, J = 7.0Hz, 3H).

Example 2 (55) 4- (2-chloroethyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] Pyrazine

Embedded image TLC: Rf 0.82 (toluene: ethyl acetate = 1:
1); NMR (200 MHz, CDCl ₃ ): δ 8.72 (dd, J = 4.4, 1.8 Hz, 1)
H), 8.40 (dd, J = 8.0,1.8Hz, 1H), 7.72 (dd, J = 8.0,4.4Hz, 1
H), 3.96-3.77 (m, 4H).

Example 2 (56) 4- (2-cyanopropyl) oxy-8-fluoro-1
-Trifluoromethyl-1,2,4-triazolo [4,
3-a] Quinoxaline

Embedded image TLC: Rf 0.33 (toluene: ethyl acetate = 4:
1); NMR (200 MHz, CDCl ₃ ): δ 7.96 (dd, J = 9.2, 5.4 Hz, 1)
H), 7.86 (dd, J = 9.2,2.6Hz, 1H), 7.45 (ddd, J = 9.2,7.6,2.
6Hz, 1H), 4.94 (dd, J = 11.0,7.0Hz, 1H), 4.72 (dd, J = 11.0,
7.0Hz, 1H), 3.48-3.31 (m, 1H), 1.58 (d, J = 7.0Hz, 3H).

Reference Example 2 2-chloro-3-isobutyloxyquinoxaline

Embedded image

Under an argon atmosphere, sodium hydride (6
2.5% oil suspension; 768 mg) in anhydrous THF (20
ml) suspension was added to 2-methyl-1-propanol (2.03
ml) and stirred at room temperature for 1 hour. 2,3-Dichloroquinoxaline (3.96 g) was added to the stirred mixture under ice cooling.
Was added in anhydrous THF (80 ml), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride was added to the reaction solution, and after stirring, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 25: 1) to give the title compound (4.79 g) having the following physical data. NMR (200 MHz, CDCl ₃ ): δ 7.96 (dd, J = 8.0, 1.2 Hz, 1
H), 7.83 (dd, J = 7.8,1.2Hz, 1H), 7.72-7.53 (m, 2H), 4.32
(d, J = 6.6Hz, 2H), 2.22 (m, 1H), 1.10 (d, J = 7.0Hz, 6H).

Reference Example 3 2-hydrazino-3-isobutyloxyquinoxaline

Embedded image

To a solution of the compound prepared in Reference Example 2 (4.79 g) in ethanol (50 ml) was added hydrazine monohydrate (2.
2 ml) and stirred overnight. The reaction solution was concentrated, water was added thereto, and the resulting powder was collected by filtration and dried to give the title compound (3.24 g) having the following physical data. NMR (300 MHz, CDCl ₃ ): δ 7.73-7.63 (m, 2H), 7.47-
7.32 (m, 2H), 6.64 (brs, 1H), 4.29 (d, J = 6.6Hz, 2H), 4.13
(brs, 2H), 2.17 (m, 1H), 1.06 (d, J = 6.6 Hz, 6H).

Example 3 4-Isobutyloxy-1-mercapto-1,2,4-
Triazolo [4,3-a] quinoxaline

Embedded image

Compound prepared in Reference Example 3 (464 mg)
In a pyridine (6 ml) solution of carbon disulfide (120 μl)
l) was added and the mixture was stirred at 80 ° C for 1.5 hours. Further, carbon disulfide (120 μl) was added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was concentrated and azeotroped twice with toluene. The residue was purified twice by silica gel column chromatography (chloroform → chloroform: methanol = 40: 1) to obtain a solid. This was washed with chloroform / ethyl acetate to give the title compound (255 mg) having the following physical data. TLC: Rf 0.65 (chloroform: methanol = 1
0: 1); NMR (300 MHz, DMSO-d ₆ ): δ 10.26-10.21 (m, 1H),
7.71-7.66 (m, 1H), 7.58-7.46 (m, 2H), 4.31 (d, J = 6.9Hz, 2
H), 2.16 (m, 1H), 1.02 (d, J = 6.9 Hz, 6H).

Example 4 4-Isobutyloxy-1-hydroxy-1,2,4-
Triazolo [4,3-a] quinoxaline

Embedded image

Compound prepared in Reference Example 3 (464 mg)
Was added to a pyridine (6 ml) solution, and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. The reaction solution was concentrated, the residue was dissolved in methylene chloride, and the insolubles were removed by filtration. The filtrate was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution,
After drying over anhydrous sodium sulfate, the mixture was concentrated. The obtained solid was washed with diethyl ether to give the title compound (295 mg) having the following physical data. TLC: Rf 0.53 (chloroform: methanol = 1
0: 1); NMR (300 MHz, DMSO-d ₆ ): δ 8.66-8.60 (m, 1H), 7.6
2-7.56 (m, 1H), 7.48-7.37 (m, 2H), 4.27 (d, J = 6.6Hz, 2H),
2.14 (m, 1H), 1.01 (d, J = 6.9Hz, 6H).

Example 5 4-Isobutyloxy-1-methylthio-1,2,4-
Triazolo [4,3-a] quinoxaline

Embedded image

Compound prepared in Example 3 (204 mg)
To a solution of trimethyloxonium tetrafluoroborate (221) under ice-cooling.
mg) and stirred at room temperature for 6 hours. The reaction solution was diluted with water, and the organic layer was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain a solid.
This was washed with diethyl ether. The obtained powder was purified by silica gel column chromatography (methylene chloride → methylene chloride: methanol = 50: 1),
The title compound (15 mg) having the following physical data was obtained. TLC: Rf 0.69 (chloroform: methanol = 1
0: 1); NMR (300 MHz, CDCl ₃ ): δ 8.43 (m, 1H), 7.82 (m, 1
H), 7.57-7.44 (m, 2H), 4.44 (d, J = 6.6Hz, 2H), 2.99 (s, 3
H), 2.33 (m, 1H), 1.11 (d, J = 6.9 Hz, 6H).

Example 5 (1) 4-Isobutyloxy-1-methoxy-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image

The same operation as in Example 5 was performed using the compound (60 mg) produced in Example 4 to give the title compound (21 mg) having the following physical data. TLC: Rf 0.36 (chloroform: methanol = 1
0: 1); NMR (300 MHz, CDCl ₃ ): δ 9.30-9.22 (m, 1H), 7.77-
7.67 (m, 1H), 7.58-7.46 (m, 2H), 4.43 (d, J = 6.6Hz, 2H),
4.22 (s, 3H), 2.25 (m, 1H), 1.12 (d, J = 6.6Hz, 6H).

Example 6 4-Isobutyloxy-1-methylsulfinyl-1,
2,4-triazolo [4,3-a] quinoxaline

Embedded image

To a solution of the compound prepared in Example 5 (60 mg) in acetone (10 ml) was added the prepared peracid (OXON).
E (registered trademark)) and stirred overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and the obtained powder was recrystallized from ethyl acetate to give the title compound (25 mg) having the following physical data. TLC: Rf 0.55 (chloroform: methanol = 1
0: 1); NMR (300 MHz, CDCl ₃ ): δ 8.70 (m, 1H), 7.91 (m, 1
H), 7.68-7.59 (m, 2H), 4.49 (d, J = 6.6Hz, 2H), 3.51 (s, 3
H), 2.37 (m, 1H), 1.12 (d, J = 6.9 Hz, 6H).

Example 7 4-Isobutyloxy-1-methylsulfonyl-1,
2,4-triazolo [4,3-a] quinoxaline

Embedded image

The compound prepared in Example 5 (100 mg)
To a methylene chloride (10 ml) solution of was added metachloroperbenzoic acid (180 mg), and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and after stirring, the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and purified again by silica gel column chromatography (methylene chloride → methylene chloride: ethyl acetate = 4: 1) to give the title having the following physical properties. The compound (96 mg) was obtained. TLC: Rf 0.51 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.69 (dd, J = 8.4, 1.5 Hz, 1)
H), 7.90 (dd, J = 7.5,2.1Hz, 1H), 7.69-7.57 (m, 2H), 4.49
(d, J = 6.9Hz, 2H), 3.85 (s, 3H), 2.36 (m, 1H), 1.12 (d, J =
6.9Hz, 6H).

Reference Example 4 2-Ethoxalylhydrazino-3-isobutyloxyquinoxaline hydrochloride

Embedded image

Ethyl oxalyl chloride (1.05 ml) was added dropwise to a suspension of the compound (2.0 g) produced in Reference Example 3 in methylene chloride (43 ml). The mixture was stirred at room temperature for 10 minutes and concentrated. Diethyl ether and hexane were added to the residue, and the precipitate was collected by filtration. The filtrate was washed with hexane to give the title compound (2.82 g) having the following physical data. TLC: Rf 0.28 (chloroform: methanol = 10
0: 1); NMR (300 MHz, DMSO-d ₆ ): δ 11.1-10.8 (br, 1H), 7.
63 (dd, J = 7.5,2.1Hz, 1H), 7.56 (dd, J = 7.5,1.8Hz, 1H), 7.4
6-7.33 (m, 2H), 4.33 (q, J = 6.9Hz, 2H), 4.26 (d, J = 6.9Hz, 2
H), 2.15 (m, 1H), 1.32 (t, J = 6.9Hz, 3H), 1.05 (d, J = 6.6H
z, 6H).

Example 8 4-Isobutyloxy-1-ethoxycarbonyl-1,
2,4-triazolo [4,3-a] quinoxaline

Embedded image

To a suspension of the compound (2.8 g) produced in Reference Example 4 in toluene (76 ml) was added p-toluenesulfonic acid monohydrate (43 mg), and the mixture was refluxed for 2 hours. The cooled reaction solution was diluted with ether, washed with an aqueous sodium hydroxide solution, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (2.13 g) having the following physical data. TLC: Rf 0.42 (hexane: ethyl acetate = 2:
1); NMR (300 MHz, CDCl ₃ ): δ 8.76 (dd, J = 8.4, 1.5 Hz, 1)
H), 7.88 (dd, J = 8.1,1.5Hz, 1H), 7.61 (ddd, J = 8.1,7.5,1.
5Hz, 1H), 7.52 (ddd, J = 8.4,7.5,1.5Hz, 1H), 4.66 (q, J = 7.
2Hz, 2H), 4.49 (d, J = 6.9Hz, 2H), 2.36 (m, 1H), 1.56 (t, J =
7.2Hz, 3H), 1.12 (d, J = 6.9Hz, 6H).

Examples 9 (1) and 9 (2) The compound prepared in Example 8 (600
mg) in anhydrous methylene chloride (38 ml).
At C, diisobutylaluminum hydride (1 M in toluene; 3 ml) was added dropwise. The mixed solution was stirred for 30 minutes. To the reaction solution were added methanol and an aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 1 hour. The insoluble matter was removed by filtration with Celite (registered trademark). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give the following compound (Example 1)
6 (1) 267 mg, Example 16 (2) 45 mg)
I got

Example 9 (1) 4-Isobutyloxy-1-formyl-1,2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.40 (chloroform: methanol = 2
0: 1); NMR (300 MHz, CDCl ₃ ): δ 10.5 (s, 1H), 9.35 (dd, J =
8.1,1.2Hz, 1H), 7.91 (dd, J = 8.1,1.2Hz, 1H), 7.73-7.56
(m, 2H), 4.51 (d, J = 6.9Hz, 2H), 2.37 (m, 1H), 1.14 (d, J =
6.6Hz, 6H).

Example 9 (2) 4-isobutyloxy-1-hydroxymethyl-1,
2,4-triazolo [4,3-a] quinoxaline

Embedded image TLC: Rf 0.53 (chloroform: methanol = 1
0: 1); NMR (300 MHz, CDCl ₃ ): δ 8.37-8.31 (m, 1H), 7.88-
7.82 (m, 1H), 7.62-7.51 (m, 2H), 5.40 (d, J = 5.7Hz, 2H),
4.44 (d, J = 6.9Hz, 2H), 3.82-3.58 (br, 1H) 2.32 (m, 1H), 1.
11 (d, J = 6.6 Hz, 6H).

Example 10 4-Isobutyloxy-1-cyano-1,2,4-triazolo) [4,3-a] quinoxaline

Embedded image

The compound (260) produced in Example 9 (1)
mg) in pyridine (5 ml) was added with hydroxylamine hydrochloride (83 mg) and stirred at room temperature for 1 hour.
The reaction solution was diluted with chloroform (5 ml), trifluoroacetic anhydride (0.84 ml) was added, and the mixture was stirred for 15 minutes. Chloroform was distilled off from the reaction solution and diluted with ether. The organic layer was washed with water, a 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: hexane = 2: 1) to give the title compound (217 mg) having the following physical data.
I got TLC: Rf 0.43 (chloroform); NMR (300 MHz, CDCl ₃ ): δ 8.65 (d, J = 7.8, 1.5 Hz, 1)
H), 7.95 (d, J = 7.8,1.5Hz, 1H), 7.75-7.67 (m, 1H), 7.67-
7.59 (m, 1H), 4.50 (d, J = 6.6Hz, 2H), 2.34 (m, 1H), 1.13
(d, J = 6.6 Hz, 6H).

[0198]

Formulation Example Formulation Example 1 The following components were mixed in a conventional manner and tabletted to give 100 tablets each containing 50 mg of the active ingredient.・ 4- (2-fluoropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine 5.0 g ・ carboxy Methylcellulose calcium (disintegrant) ... 0.2 g-Magnesium stearate (lubricant) ... 0.1 g-Microcrystalline cellulose ... 4.7 g

Formulation Example 2 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 5 ml portions, freeze-dried by a conventional method, and contains 20 mg of the active ingredient in one ampule. 100 ampoules were obtained.・ 4- (2-fluoropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine 2.0 g mannitol …… 20g ・ Distilled water …… 500ml

Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 9/10 A61K 31/00 609G 11/06 611C 11/00 611 13/12 613G 17/00 617 17/06 617E 29 / 00629 31/04 629A 31/18 631C 35/04 631M 37/08 635B 37/06 637E 37/02 637D 37/04 637B 43/00 637C A61K 31/4985 643B C07D 487/04 145 31/495 605 495 / 14 C07D 487/04 145 495/14 D (72) Inventor Kiyoyuki Sato 3-1-1 Sakurai, Shimamotocho, Mishima-gun, Osaka Prefecture Ono Pharmaceutical Co., Ltd. Inside Minase Research Institute (72) Inventor Hiroyuki Ohno Osaka 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun Ono Pharmaceutical Co., Ltd. Minase Research Laboratory F-term (reference) 4C050 AA01 AA07 BB06 CC08 DD02 EE04 EE06 FF02 FF03 GG02 GG03 GG05 GG06 GG07 GG08 HH01 4C065 AA04 BB03 CC06 DD05 HH08 JJ01 JJ02 JJ06 KK03 KK08 LL03 L L09 PP01 PP06 PP09 4C071 AA01 BB02 CC04 CC21 EE13 FF02 GG02 GG03 HH01 HH02 HH05 HH11 HH28 LL01 4C086 AA01 AA02 AA03 CB05 CB26 MA01 MA04 NA14 ZA02 ZA45 ZA59 ZA68 ZA75 ZB13 ZAZ ZB Z

Claims (5)

[Claims] 1. A compound of the general formula (I)[Wherein, R¹And R^TwoAre independently (i) hydrogen sources
(Ii) a C1-8 alkyl group, (iii) a C2-8 alkyl
Kenyl group, (iv) C2-8 alkynyl group, (v) C1
8 alkoxy group, (vi) C1-8 alkylthio group, (vi
i) Cyc1, (viii) cyano group, (ix) formyl group,
(X) -COOR¹⁴Group (in the group, R¹⁴Is a hydrogen atom or C
Represents a 1-8 alkyl group. ), (Xi) -CONR¹⁵R
¹⁶Group (in the group, R ¹⁵And R¹⁶Are independently hydrogen sources
, A C1-8 alkyl group or a phenyl group
You. ), (Xii) a hydroxyl group, a C1-4 alkoxy group,
Nonoxy group, halogen atom, cyano group, C2-5 acyl
Group, -COOR¹⁴Group, -CONR¹⁵R¹⁶Group, -NR¹⁷R
¹⁸Group (in the group, R¹⁷And R¹⁸Are independently hydrogen sources
, A C1-8 alkyl group or an acetyl group. )
C1-8 substituted with one or two groups selected from
Alkyl group, C2-8 alkenyl group or C2-8 alkyl
Quinyl group, (xiii) C1-8 alkyl substituted with Cyc1
Group, C1-8 alkoxy group or C1-8 alkyl group
Represents an o group, or R¹And R^TwoAre connected
Together with the combined carbon atomWherein Cyc1 is a C3-15 monocyclic, bicyclic, tricyclic
Cyclic carbocycle or 1-4 nitrogen atoms, 1-2 oxygen
5-18 membered atoms containing atoms and / or one sulfur atom
Represents a monocyclic, bicyclic or tricyclic heterocyclic ring,
The prime ring or hetero ring is one or more of (i) C1
-8 alkyl group, (ii) C1-8 alkoxy group, (ii
i) nitro group, (iv) halogen atom, (v) cyano group,
(Vi) hydroxyl group, (vii) benzyloxy group, (viii)-
NR¹⁰¹R¹⁰²Group (in the group, R¹⁰¹And R¹⁰²Is German
Stands for a hydrogen atom or a C1-8 alkyl group
You. ), (Ix) -COOR^{Ten Three}Group (in the group, R¹⁰³Is hydrogen field
Or a C1-8 alkyl group. ), (X) bird
Halomethyl group, (xi) trihalomethoxy group, (xii)
Phenyl, (xiii) phenyloxy, (xiv) phenyl
Group, phenyloxy group, hydroxyl group, -NR¹⁰¹R ¹⁰²And
And -COOR¹⁰³C1-8 substituted with a group selected from
Substituted with an alkyl group or a C1-8 alkoxy group
It may beIs a C3-7 monocyclic carbocycle or 1-4 nitrogen atoms
, One or two oxygen atoms and / or one sulfur atom
A 3- to 7-membered monocyclic heterocyclic ring containing^ThreeIs 1) hydrogen atom, 2) C1-8 alkyl group, 3) C2-8 alkenyl group, 4) C2-8 alkynyl group, 5) C1-8 alkoxy group, 6) C1-8 alkylthio group, 7) halogen atom 8) nitro group, 9) cyano group, 10) hydroxyl group, 11) formyl group, 12) C2-5 acyl group, 13) -NR^FourR^FiveGroup (in the group, R^FourAnd R^FiveRespectively
Independently a hydrogen atom, a C1-8 alkyl group or acetyl
Represents a group. ), 14) -COOR⁶Group (in the group, R⁶Is a hydrogen atom or C1
Represents a -8 alkyl group. ), 15) -CONR¹⁹R²⁰Group (in the group, R¹⁹And R²⁰Haso
Each independently represents a hydrogen atom, a C1-8 alkyl group,
Or hydroxyl group, 1-2 nitrogen atoms or 1
5- to 7-membered monocyclic ring containing a nitrogen atom and one oxygen atom
C1-4 alkyl group substituted by a group selected from heterocycle
Or together form = CH-NR^{twenty one}R^{twenty two}Group (group
Medium, R^{twenty one}And R^{twenty two}Are each independently a hydrogen atom or
Represents a C1-4 alkyl group. )), 16) trihalomethyl group, 17) trihalomethoxy group, 18) phenyl group, 19) phenyloxy group, 20) phenylthio group, or 21) phenyl group-substituted C1-8 alkyl group, C1
-8 alkoxy group, C1-8 alkylthio group, or C
1-8 alkylamino group, 22) hydroxyl group, C1-4 alkoxy group, phenoxy group,
Halogen atom, cyano group, C2-5 acyl group, -COO
R⁶Group, -CONR¹⁹R²⁰Group, -NR^FourR^FiveSelected from groups
C1-8 alkyl substituted by one or two groups
Group, C2-8 alkenyl group or C2-8 alkynyl group
And n represents an integer of 1 to 5, and J represents J^aOr
J^bAnd J^aIs 1) C1-8 alkyl group, 2) Cyc2, 3) C1-8 alkyl group substituted with Cyc2, 4) C1-8 alkyl substituted with 1 to 17 halogen atoms.
5) a halogen atom or a C1-8 alkoxy group, or 5) a halogen atom;
Monocyclic, bicyclic, tricyclic carbocyclic or 1 to 4 nitrogen atoms
, One or two oxygen atoms and / or one sulfur atom
A 5- to 18-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing
Represents one or more of these carbocycles or heterocycles.
(I) a C1-8 alkyl group, (ii) a C1-8
Alkoxy group, (iii) nitro group, (iv) halogen atom,
(V) cyano group, (vi) hydroxyl group, (vii) benzyloxy
Group, (viii) -NR²⁰¹R²⁰²Group (in the group, R²⁰¹And R
²⁰²Are each independently a hydrogen atom or a C1-8 alkyl
Represents a radical. ), (Ix) -COOR^{20 Three}Group (in the group, R
²⁰³Represents a hydrogen atom or a C1-8 alkyl group.
You. ), (X) trihalomethyl group, (xi) trihalometo
Xy group, (xii) phenyl group, (xiii) phenyloxy
Group, (xiv) phenyl group, phenyloxy group, hydroxyl group,
-NR²⁰¹R ²⁰²Or -COOR²⁰³Replaced by
Substituted with C1-8 alkyl group or C1-8 alkoxy group
The J^bIs the hydroxyl group, mercapto
Group, C1-4 alkoxy group, C1-4 alkylthio group,
C1-4 alkylsulfinyl group, C1-4 alkyls
Rufonyl group, carboxyl group, C1-4 alkoxycal
Bonyl, hydroxymethyl, formyl,
Represents an ano group, E is a single bond, an oxygen atom, a sulfur atom,-
SO-, -SO_Two-, C1-4 alkylene-M- (only
And the alkylene group is bonded to the ring, and the M group is bonded to the G group.
You. And M represents an oxygen atom, a sulfur atom, -SO-,
-SO_TwoAnd G represents 1) a C1-8 alkyl group, 2) a C2-8 alkenyl group, 3) a C2-8 alkynyl group 4) -OR⁷, -SR⁸, -NR⁹R^TenOr -COR¹¹
A C1-8 alkyl group substituted with a group selected from the group consisting of: 5) Cyc3, 6) a C1-8 alkyl group substituted with Cyc3.
And C1-8 alkyl groups, C2 to C2 in the above 1) to 4).
8 alkenyl groups and C2-8 alkynyl groups are represented by the following (i)
-(Xi) may be substituted with: (i) halo
Gen atom, (ii) cyano group, (iii) sulfonyl group, (iv)-
SO- (C1-4 alkyl) group, (v) -SO_Two− (C1
4alkyl) group, (vi) -SO_TwoNR^{twenty four}R^{twenty five}Group (in the group, R
^{twenty four}And R^{twenty five}Each independently represents a hydrogen atom or C1
Represents a -4 alkyl group. ), (Vii) -NR²⁶SO_Two−
(C1-4 alkyl) group (in the group, R²⁶Is a hydrogen atom or
Represents a C1-4 alkyl group. ), (Viii) Substituted by hydroxyl group
An amidino group which may be (ix) formylamino group,
(x) C1-4 alkoxycarbonylamino group, (xi) di
(C1-4 alkyl) amine (N-oxide) group;
Cyc3 is a C3-15 monocyclic, bicyclic, tricyclic carbocyclic or
Is 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or
Or a 5-18 membered monocyclic, bicyclic or bicyclic ring containing one sulfur atom
Represents a tricyclic heterocyclic ring,
The ring is one or more (i) C1-8 alkyl
A group, (ii) a C1-8 alkoxy group, (iii) a nitro group,
(Iv) a halogen atom, (v) a cyano group, (vi) a hydroxyl group,
(Vii) benzyloxy group, (viii) -NR¹⁰¹R¹⁰²Base
(In the group, R¹⁰¹And R¹⁰²Are each independently a hydrogen atom
Or a C1-8 alkyl group. ), (Ix) -CO
OR^{Ten Three}Group (in the group, R¹⁰³Is a hydrogen atom or C1-8 al
Represents a kill group. ), (X) trihalomethyl group, (xi)
Trihalomethoxy group, (xii) phenyl group, (xiii)
Phenyloxy group, (xiv) phenyl group, phenyloxy
Group, hydroxyl group, -NR¹⁰¹R ¹⁰²And -COOR¹⁰³From
A C1-8 alkyl group or C1 substituted with a selected group
~ 8 alkoxy group and (xv) oxo group
(However, (1) J is J^aAnd G indicates 1) to
4) a C1-8 alkyl group, a C2-8 alkenyl group,
The C2-8 alkynyl group is at least one of the above
(2) J is J^aIs
At least one Cyc3 in 5) to 6) indicated by G
(3) C1-8 groups in G
The carbon atoms in the alkyl group are (i) one carbon atom in the ring structure
Even if it represents a 3- to 7-membered cycloalkyl as a constituent atom,
Or (ii) two adjacent carbon atoms form a ring
The atom may represent a 3- to 7-membered cycloalkyl.
No. ), R⁷Is a hydrogen atom, a C1-8 alkyl group, C2
8 alkenyl group, phenyl group or C1-8
A C1-8 alkyl group substituted by a alkoxy group, or C2
To 5 acyl groups;⁸Is a hydrogen atom, C1-8 al
A kill group, a C2-8 alkenyl group, or a phenyl group.
Or C1-8 alkyl substituted with a C1-8 alkoxy group
Group or -S- (C1-8 alkylene) -OR^{twenty three}Base
(In the group, R^{twenty three}Represents a hydrogen atom or a C1-8 alkyl group
The carbon atoms in C1-8 alkylene are (i) carbon atoms
A 3- to 7-membered cycloalkyl having one atom as a ring constituent atom
May represent a kill, or (ii) two adjacent charcoals
A 3- to 7-membered cycloalkyl having an element atom as a ring atom
May be represented. ) And R⁹Is a hydrogen atom, C
A 1-8 alkyl group, a C2-8 alkenyl group, or
C1-substituted by a phenyl or C1-8 alkoxy group
8 represents an alkyl group;^TenIs a hydrogen atom, C1-8 al
Killed, C2-8 alkenyl, phenyl substituted
Represents a C1-8 alkyl group or a C2-5 acyl group,
R¹¹Is (i) a C1-8 alkyl group, (ii) a C1-8 alkyl group
Oxy group, (iii) hydroxyl group, (iv) phenyl group
C1-8 alkyl group or C1-8 alkoxy group or
Is (v) -NR¹²R¹³Group (in the group, R¹²And R¹³Is it
Each independently represents a hydrogen atom or a C1-8 alkyl group or
Represents a C1-8 alkyl group substituted by a phenyl group. )
AndRepresents a single bond or a double bond. Condensation represented by
Pyrazine compounds or their non-toxic salts. 2. R¹And R^TwoBut each independently
(I) hydrogen atom, (ii) C1-8 alkyl group, (iii) C
2-8 alkenyl groups, (iv) C2-8 alkynyl groups,
(V) C1-8 alkoxy group, (vi) C1-8 alkyl
Thio group, (vii) Cyc1, (viii) cyano group, (ix)
Formyl group, (x) -COOR¹⁴Group (in the group, R¹⁴Is hydrogen
Represents an atom or a C1-8 alkyl group. ), (Xi) −
CONR¹⁵R ¹⁶Group (in the group, R¹⁵And R¹⁶Is German
Standing hydrogen atom, C1-8 alkyl group or phenyl group
Represents ), (Xii) hydroxyl group, C1-4 alkoxy
Group, phenoxy group, halogen atom, cyano group, C2-5
Acyl group, -COOR¹⁴Group, -CONR¹⁵R¹⁶Group, -N
R¹⁷R¹⁸Group (in the group, R¹⁷And R¹⁸Are independent of each other
Represents a hydrogen atom, a C1-8 alkyl group or an acetyl group
You. C) substituted with one or two groups selected from
1-8 alkyl group, C2-8 alkenyl group or C2
8 alkynyl group, (xiii) C1-8 substituted by Cyc1
Alkyl group, C1-8 alkoxy group or C1-8 alkyl
2. The compound according to claim 1, which represents a thio group. 3. R ¹ and R ² together with the carbon atom to which each is attached are The compound according to claim 1, which represents: 4. A compound according to claim 1, wherein the compound is (1) sodium 2- (1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxalin-4-yl) thioethylsulfonate,
(2) 4- (2-chloroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′:
3,4] pyrido [2,3-b] pyrazine, (3) 4-
(3-chloropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine, (4) 4- (2- (Cyanoethyl) oxy-1-trifluoromethyl-1,2,4
-Triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine, (5) 4- (2-chloro-2-propenyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3- b]
Pyrazine, (6) 4- (2-fluoroethyl) oxy-
1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine, (7) 4- [2- (Nt-butoxycarbonylamino) ) Ethylthio] -1-trifluoromethyl-1,
2,4-triazolo [4,3-a] quinoxaline, (8)
4- (2-methylsulfinylethyl) oxy-1-
Trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine, (9)
4- (2-methylsulfonylethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine, (10)
4- (2-oxo-4-methyloxazolidin-4-yl) methyloxy-1-trifluoromethyl-1,2,2
4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3
-B] pyrazine, (11) 4- [2- (2-oxopyrrolidin-1-yl) ethyl] oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4 ]
Pyrido [2,3-b] pyrazin, (12) 4- (1-oxothian-4-yl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] Pyrido [2,3-b] pyrazine, (13) 4- (1,1-dioxothian-4-yl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3, 4] pyrido [2,3-b] pyrazine, (14) N- [2- (1-
Trifluoromethyl-1,2,4-triazolo [3 ′,
4 ': 3,4] pyrido [2,3-b] pyrazin-4-yl) oxoethyl] -N, N-dimethylamine N-oxide, (15) 4- (2-sulfamoylethyl) thio-1 -Trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (16) 4- (2-cyanoethyl) thio-1-trifluoromethyl-1,2,4-
Triazolo [4,3-a] quinoxaline, (17) 4-
(2,2,2-trifluoroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine, (18)
4- (2,2,3,3,3-pentafluoropropyl)
Oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine, (19) 4- (1,3-difluoropropane-2) −
Yl) oxy-1-trifluoromethyl-1,2,4-
Triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine, (20) 4- (2,2-difluoroethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b ]
Pyrazine, (21) 4- (2,2,3,3-tetrafluoropropyl) oxy-1-trifluoromethyl-1,
2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (22) 4- (2,2-dichloroethyl) oxy-1-trifluoromethyl-1,2 ,
4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3
-B] pyrazine, (23) 4- (4,4,4-trifluorobutyl) oxy-1-trifluoromethyl-1,2,2
4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3
-B] pyrazine, (24) 4- (1,1,1-trifluoropropan-2-yl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4 ] Pyrido [2,3-b] pyrazine, (25) 4- (4-chlorobutyl) oxy-1-trifluoromethyl-1,2,4
-Triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine, (26) 4- (2,2,3,4,4,4-
Hexafluorobutyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine, (27) 4- (2 (R) −
(Chloropropyl) oxy-1-trifluoromethyl-
1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (28) 4- (2,3-dichloropropyl) oxy-1-trifluoromethyl-1 ,
2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (29) 4- (2-methylsulfonylaminoethyl) thio-1-trifluoromethyl-
1,2,4-triazolo [4,3-a] quinoxaline,
(30) 4- (cyanomethyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (31) 4- (3,3,3-trifluoro-2-hydroxy Propyl) thio-1-trifluoromethyl-
1,2,4-triazolo [4,3-a] quinoxaline,
(32) 4- (2-acetyloxy-3,3,3-trifluoropropyl) thio-1-trifluoromethyl-1,
2,4-triazolo [4,3-a] quinoxaline, (33)
4- (N-hydroxyamidinomethyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-
a] Quinoxaline, (34) 4- [2- (N-hydroxyamidino) ethyl] thio-1-trifluoromethyl-
1,2,4-triazolo [4,3-a] quinoxaline,
(35) 4- (4,4,4-trifluoro-3-hydroxybutyl) thio-1-trifluoromethyl-1,2,4
-Triazolo [4,3-a] quinoxaline, (36) 4-
[2- (N-formylamino) ethyl] thio-1-trifluoromethyl-1,2,4-triazolo [4,3-
a] Quinoxaline, (37) 4- (3-fluoropropyl) oxy-1-trifluoromethyl-1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b]
Pyrazine, (38) 4- (4-fluorobutyl) oxy-
1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (39) 4- (cyanomethylthio) -8-fluoro-
1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (40) 4- (2-cyanoethyl) thio-8-fluoro-1-trifluoromethyl-1,2,4- Triazolo [4,3-a] quinoxaline, (41) 4- (2-cyanoethyl) oxy-8-fluoro-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (42) ) 4- (3-cyanopropyl) oxy-1-trifluoromethyl-1,
2,4-triazolo [4,3-a] quinoxaline, (43)
4- (2-cyanoethyl) oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (44) 4- (2-cyanopropyl) oxy-1
-Trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (45) 4- (4-cyanobutyl) oxy-1-trifluoromethyl -1,2,4-triazolo [4,3-
a] Quinoxaline, (46) 4- (2-cyanopropyl)
Oxy-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (47) 4- (2-fluoropropyl) thio-1-trifluoromethyl-1,
2,4-triazolo [4,3-a] quinoxaline, (48)
4- (3-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (49) 4- (3-cyanopropyl) thio-1-
Trifluoromethyl-1,2,4-triazolo [3 ′,
4 ′: 3,4] pyrido [2,3-b] pyrazine, (50)
4- (3-chloropropyl) thio-1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4]
Pyrido [2,3-b] pyrazine, (51) 4- (4-cyanobutyl) thio-1-trifluoromethyl-1,2,4
-Triazolo [4,3-a] quinoxaline, (52) 4-
(4-cyanobutyl) thio-1-trifluoromethyl-
1,2,4-triazolo [3 ′, 4 ′: 3,4] pyrido [2,3-b] pyrazine, (53) 4- (2-fluoropropyl) thio-1-trifluoromethyl-1,2 , 4-
Triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine, (54) 4- (2-cyanopropyl) thio-1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (55) 4- (2-cyanopropyl) Thio-1-trifluoromethyl-1,2,4
-Triazolo [3 ', 4': 3,4] pyrido [2,3-
b] pyrazine, (56) 4- (2-chloroethyl) thio-
1-trifluoromethyl-1,2,4-triazolo [3 ', 4': 3,4] pyrido [2,3-b] pyrazine, (57) 4- (2-cyanopropyl) oxy-8-fluoro -1-trifluoromethyl-1,2,4-triazolo [4,3-a] quinoxaline, (58) 4-isobutyloxy-1-mercapto-1,2,4-triazolo [4,3-a] quinoxaline , (59) 4-isobutyloxy-1-hydroxy-1,2,4-triazolo [4,
3-a] Quinoxaline, (60) 4-isobutyloxy-
1-methylthio-1,2,4-triazolo [4,3-
a] Quinoxaline, (61) 4-isobutyloxy-1-
Methoxy-1,2,4-triazolo [4,3-a] quinoxaline, (62) 4-isobutyloxy-1-methylsulfinyl-1,2,4-triazolo [4,3-a] quinoxaline, (63) 4-isobutyloxy-1-methylsulfonyl-1,2,4-triazolo [4,3-a] quinoxaline, (64) 4-isobutyloxy-1-ethoxycarbonyl-1,2,4-triazolo [4,3 -A]
Quinoxaline, (65) 4-isobutyloxy-1-formyl-1,2,4-triazolo [4,3-a] quinoxaline, (66) 4-isobutyloxy-1-hydroxymethyl-1,2,4-triazolo [4,3-a] quinoxaline, (67) 4-isobutyloxy-1-cyano-1,
The compound according to claim 1, which is 2,4-triazolo) [4,3-a] quinoxaline or a non-toxic salt thereof. 5. An inflammatory disease, rheumatoid arthritis, allergy, bronchial asthma, comprising the condensed pyrazine compound represented by the general formula (I) according to claim 1 or a non-toxic salt thereof as an active ingredient. Atopic dermatitis, psoriasis, suppression of ischemia-reperfusion injury, nephritis, hepatitis, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, suppression of transplant organ rejection, sepsis, diabetes, autoimmune disease, cancer Metastases,
An agent for preventing and / or treating arteriosclerosis and AIDS (AIDS).