JPH1143489A - Heterocyclic compound, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new compound, having antagonistic actions on tachykinin receptors and useful as an improving agent for asthma, rheumatic arthritis, deformity ostitis, pain, cough, irritable intestinal disease or emesis, a paruria improving agent, etc. SOLUTION: This compound is represented by formula I M-ring is a heterocyclic ring having CO-N-R<1> [R<1> is H or a (substituted) hydrocarbon, etc.], CO-O, etc., as partial structual formula II; D is a divalent group; E is NR<5> [R<5> is H or a (substituted) hydrocarbon], O, etc.; R<a> and R<b> are combined each other to form A-ring or are each H or a substituent group in the M-ring; A-ring, B-ring and C-ring are each a homocyclic or a heterocyclic ring (having a substituent group); Q is a substituted linear lower alkylene} e.g. 7,8-dihydro-7- methyl-5-(4-methylphenyl)-8-oxo-N-[1(S)-phenylethyl]-1,7-naphthyridine-6- carboxamide. The compound represented by formula I is obtained by, e.g. reacting a compound represented by formula III (L is an eliminable group) with a compound represented by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel heterocyclic compound having an excellent tachykinin receptor antagonistic activity, a method for producing the same, and a medicament containing the heterocyclic compound.

[0002]

2. Description of the Related Art Tachykinin is a general term for a group of neuropeptides. In mammals, substance P (SP), neurokinin-A, and neurokinin-B are known, and these peptides are present in vivo. It is known that various biological activities are exerted by binding to the respective receptors (neurokinin-1, neurokinin-2, neurokinin-3). Among them, SP is one of the longest-established and well-studied neuropeptides. Its existence was confirmed in horse intestinal extracts in 1931, and amino acid 11 whose structure was determined in 1971 was determined. This is a peptide consisting of

[0003] SP is widely distributed in the central and peripheral nervous systems. In addition to its function as a transmitter of primary sensory neurons, vasodilatory action, vascular hyperpermeability, smooth muscle contraction, nerve cell excitability, It has physiological activities such as salivation, diuretic enhancement, and immunity. In particular, it is known that SP released from the terminal of the dorsal horn of the spinal cord by pain impulses transmits pain information to secondary neurons, and that SP released from peripheral terminals causes an inflammatory response to its receptor. For these reasons, SP is considered to be involved in various pathological conditions (eg, pain, inflammation, allergy, frequent urination, incontinence, airway disease, mental illness, vomiting, etc.), and SP is considered to be Alzheimer's disease. It is also thought to be involved in type dementia [Review: Physiological Reviews, 73, 229-
308 pages (published in 1993), Journal of Autonomic Pharmacology
Pharmacology), 13, 23-93 (issued in 1993)]. At present, as a compound having an SP receptor antagonistic action, (1) JP-A-1-287095 discloses a compound represented by the formula: R ¹ -A-D-Trp (R ² ) -Phe-R ³ [wherein R ¹ Is a hydrogen atom or an amino protecting group, R ² is a hydrogen atom, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R ³ is an ar (lower) alkyl Group, formula:

Embedded image (Wherein R ⁴ and R ⁵ each represent a hydrogen atom, an aryl group or a lower alkyl group optionally having a substituent, or R ⁴ and R ⁵ are bonded to each other to form a benzene-condensed lower alkylene; Or a group represented by the formula: -OR ⁶ (wherein R ⁶ represents a hydrogen atom, an aryl group or a lower alkyl group optionally having a suitable substituent). And the group A represents a single bond or one or two amino acid residues, and when A represents one amino acid residue of -D-Trp-, R ⁴ is not a hydrogen atom. And salts thereof are disclosed.

(2) EP-A-436 and 334 have the formula

Embedded image Are represented by (3) EP-A-429,
366 contains the formula

Embedded image Compounds represented by (4) Journal of
Medicinal chemistry (Journal of MedicinalCh)
emistry), 34, 1751 (issued in 1991)

Embedded image And the like are disclosed.

[0005] Further, (5) WO91 / 09844 includes a formula

Embedded image The compound represented by the following formula (6) is EP-A-522,
In 808, the formula

Embedded image And the like are disclosed. (7) WO
In 93/01169, the formula

Embedded image Compounds represented by the following formula (8): EP-A-532,
In 456, the expression

Embedded image And the like are disclosed.

Further, (9) Bioorganic and Medicinal Chemistry Letters (Bioorganic
& Medicinal Chemistry Letters), vol. 4, p. 1903 (issued in 1994) include the formula:

Embedded image Is represented by (10) European Journal of Pharmacology
acology), vol. 250, p. 403 (issued in 1993), the formula:

Embedded image The compound represented by

(11) EP-A-585,913 describes:
formula:

Embedded image [Wherein, ring A may have a substituent; ring B is a benzene ring which may have a substituent; X and Y are each one of -NR ^1- (R ¹ is A hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent), -O- or -S- , The other being -CO-, -C
S- or ^{-C (R 2) R 2a -} (R 2 and R ^2a represent, respectively, a hydrogen atom or a substituent optionally may hydrocarbon group having a), or one is -N =, the other = C
R ^3- (R ³ has a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an amino group optionally having a substituent, a hydroxyl group having a substituent or a substituent; Represents a mercapto group which may be substituted with an optionally substituted hydrocarbon group)

Embedded image D is a C _1-3 alkylene group optionally substituted with an oxo group or a thioxo group, or D and Y together form a 5- to 7-membered ring optionally substituted with an oxo group or a thioxo group. E is -NR ^5- (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent, or R ⁵ and Y together are substituted by an oxo group or a thioxo group; May form a 5- to 7-membered ring), -O- or -S (O) _n- (n represents 0, 1 or 2); G represents a bond or a C _1-3 alkylene group; Ar represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent. However,
(I) -XY- is -O-CO- or -CO-O-,
D is is -CO- and E -NR ⁵ - when it is, (a)
G is a C _1-3 alkylene group, Ar is a substituted aryl group or a substituted heterocyclic group, or (b) G is a bond and R ⁵ is a hydrocarbon group which may have a substituent, and (Ii) when -XY- is -NH-CO-, D is-
CO- is shown. The compound represented by the formula (11): EP-A
-733,632 is of the formula:

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or a ring M;
A homocyclic or heterocyclic ring which may have a substituent, at least one of which is a heterocyclic ring which may have a substituent; and ring C is an homo or heterocyclic ring which may have a substituent. Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer of 1 to 6. Or a salt thereof, and the like.

At present, as compounds having a neurokinin A receptor antagonistic activity, (1) Life Sciences, vol. 50, p. 101 (published in 1992),

Embedded image Compounds represented by (2) Bio-Organic and Medicinal Chemistry Letters (Bi
oorganic & Medicinal Chemistry Letters), Volume 4,
On page 1951 (issued in 1994), the formula

Embedded image Compounds represented by the formula (3), AFMC International Medicinal Chemistry Symposium
osium) (Tokyo), P6M page 139 (issued in September 1995)

Embedded image Compounds represented by

(4) Tachykinins (Florence) (Ta
chykinins (Florence)), page 21 (October 1995) has the formula

Embedded image (5) Journal of Medicinal Chemistry
istry), vol. 38, p. 3772 (issued in 1995),

Embedded image (6) Bio-organic
And Medicinal Chemistry Letters (Bioo
rganic & Medicinal Chemistry Letters), Volume 5, 2
On page 879 (issued in 1995), the formula

Embedded image And the like are described.

[0010]

At present, it has excellent tachykinin receptor antagonism (particularly SP receptor antagonism) as a therapeutic agent for the above-mentioned various conditions (particularly pollakiuria, urinary incontinence, etc.) and is safe. No compound has yet been found which is sufficiently satisfactory in terms of its longevity and sustainability. Therefore, there is a demand for the development of a compound having a different chemical structure from the known compounds, having excellent tachykinin receptor antagonism, and sufficiently satisfying clinical effects as the therapeutic agent. In addition, some of the conventional compounds have a mixture of isomers due to axial asymmetry, and there is a problem that the separation is difficult. Therefore, development of a new drug having no problem with isomers is also an issue.

[0011]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, have found that the straight-chain lower alkylene group bonded to the C ring at the side chain terminal has a substituent. Formulas with specific chemical structure

Embedded image [Wherein the M ring has a partial structure

Embedded image -CO-NR ^1- (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent), -CS-NR ¹
— (R ¹ is as defined above), —CO—O— or —N ま た は CR ² — (R ² is a hydrogen atom, a hydrocarbon group which may have a substituent, Represents an optionally substituted hydroxy group or an optionally substituted amino group), D represents a divalent group, and E represents -NR
^5- (R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and may be bonded to R ¹ or R ² to form a heterocyclic ring which may have a substituent. good), - O-or indicates -S (O) n- (n is 0, 1 or 2), or R ^a and R ^b form a ring a bonded, or the same or different and each is hydrogen Ring A, ring B and ring C are the same or different and each may be a homo- or heterocyclic ring which may have a substituent, and Q represents a substituted linear group; Shows a lower alkylene group. A heterocyclic compound represented by the formula (I) or a salt thereof is synthesized for the first time, and in a compound having an asymmetric carbon in the lower alkylene group, one of the isomers is preferentially produced in the production process, The active substance obtained efficiently has unexpectedly excellent tachykinin receptor antagonism (particularly SP receptor antagonism) based on its unique chemical structure, and is sufficiently satisfactory as a drug. And completed the present invention based on these.

That is, the present invention relates to (1) a compound represented by the above formula (I) or a salt thereof,

Embedded image (1) the compound according to the above (1), which has -CO-NR ^1- (R ¹ has the same meaning as the above (1)), and (3) the above wherein R ^a and R ^b combine to form an A ring (1) The compound according to (1), (4) the compound according to (1) above, wherein the C ring is an optionally substituted benzene ring, and (5) the compound according to (1), wherein D is substituted with an oxo group or a thioxo group. A compound according to the above (1), which is a good C _1-3 alkylene group;

Embedded image [Wherein, R ³ and R ⁴ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent. Wherein the compound represented by the above (1), wherein E is -N
R ^5- (R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent), wherein R ⁵ is bonded to R ¹ or R ² to form a heterocyclic ring. The compound described,

(8) E is -NR ^5- (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent), and R ⁵ is not bonded to R ¹ or R ^2. The compound according to (1), the formula (9)

Embedded image [Wherein, L represents a leaving group, and other symbols have the same meanings as described in the above (1). And a salt thereof or a reactive derivative thereof, and a compound represented by the formula

Embedded image [Wherein, ring C and E have the same meanings as described in the above (1), and R ³ and R ⁴ have the same meanings as described in the above (6). ]
Characterized by reacting a compound represented by or a salt thereof

Embedded image [Wherein the symbols have the same meanings as described above. And (10) a pharmaceutical composition containing the compound described in (1) above, and (11) a tachykinin receptor containing the compound described in (1) above. Antagonist, (1
2) a substance P receptor antagonist comprising the compound of the above (1), (13) a dysuria improving agent comprising the compound of the above (1), and (14) a dysuria And an agent for improving asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease or vomiting, and the like. Further, the compound or a salt thereof according to the above (1) may be either a hydrate or an anhydrate.

Hereinafter, the present invention will be described in detail. “M ring, X and Y” In the above formula (I), the M ring has a partial structure

Embedded image —CO—NR ¹ — (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent);
-NR ^1- (R ¹ has the same meaning as described above), -CO-
O— or —N ＝ CR ² — (R ² is a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxy group which may have a substituent or may have a substituent. Which represents an amino group). Preferred M ring has a partial structure

Embedded image -CO-NR ^1- (R ¹ has the same meaning as described above).

As the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R ¹ and R ² , for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and Aryl group and the like, preferably an alkyl group, a cycloalkyl group and an aryl group,
Particularly, an alkyl group is widely used. As the “alkyl group”, a linear or branched one having 1 to 6 carbon atoms is used, and preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
A linear or branched alkyl group having 1 to 4 carbon atoms such as butyl is used. As the "alkenyl group", an alkenyl group having 2 to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl and sec-butenyl is used, and preferably, an alkenyl group having 2 carbon atoms such as ethenyl, propenyl and isopropenyl is used. Up to 4 alkenyl groups are used. As the "alkynyl group", an alkenyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl and the like are preferably used. Up to 4 alkynyl groups are used. As the “cycloalkyl group”, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is used,
Preferably, a C _3-6 cycloalkyl group such as cyclopropyl and cyclobutyl is used. "Aryl group"
As the phenyl, naphthyl, anthryl, an aryl group having 6 to 14 carbon atoms such as phenanthryl is used,
Preferably, for example, C 6 carbon atoms such as phenyl and naphthyl
10 to 10 aryl groups are used.

The "substituent" of the "optionally substituted hydrocarbon group" represented by R ¹ and R ² includes, for example, (i) a halogen atom (for example, fluorine, chlorine, bromine, (Ii) an alkyl group which may have a substituent, (iii) a cycloalkyl group (for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (iv A) an optionally substituted aryl group, (v) an optionally halogenated alkoxy group (for example, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoro Ethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy Fluorine, such as hexyl group, etc. a C _1-6 alkoxy group optionally substituted with a halogen atom such as chlorine), (vi) a nitro group, (vi
i) cyano group, (viii) hydroxyl group, (ix) aryloxy group (for example, C _6-14 aryloxy group such as phenoxy and naphthyloxy group), (x) alkylthio group which may be halogenated ( For example, methylthio, difluoromethylthio, trifluoromethylthio,
A C _1-6 alkylthio group (especially a C _1-4 alkylthio group) which may be substituted with a halogen atom such as fluorine or chlorine such as ethylthio, propylthio, isopropylthio, and butylthio groups, (xi) an amino group, xii) mono - or di - alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, mono- such diethylamino group - or di -C _1-6 alkylamino group (particularly, mono- - or di -C _1-4 alkylamino group)), (xiii) cyclic amino group (for example, 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom) (E.g., pyrrolidino, piperidino, morpholino group, etc.), (xiv) alkyl-carbonylamino group (e.g., acetylamino, propioni) (Xv) aryl-carbonylamino group (for example, C _1-6 alkyl-carbonylamino group such as
A C _6-14 aryl-carbonylamino group such as a benzoylamino group, (xvi) an acyloxy group (eg, a C _1-3 acyloxy group such as a formyloxy, acetoxy, propionyloxy group, etc.), and (xvii) an aminocarbonyloxy group A (xviii) mono- or di-alkylamino-carbonyloxy group (for example, a mono- or di-C _1-6 such as methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylamino-carbonyloxy group, etc.) alkylaminocarbonyl - carbonyl group), (xix) an alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino, etc. C _1-6 alkylsulfonylamino group such as propylsulfonyl amino group), (xx)
An alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.
₆ alkoxy - carbonyl group), (xxi) aralkyloxy - carbonyl group (e.g., C _7-15 aralkyloxycarbonyl such as benzyloxycarbonyl group - carbonyl group), (xxii) aryloxy - carbonyl group (e.g., A C _6-14 aryloxy-carbonyl group such as a phenoxycarbonyl group), (xxiii) a carboxyl group,
(Xxiv) alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.
_1-6 alkyl - carbonyl group), (xxv) cycloalkyl - carbonyl group (e.g., cyclopentyl carbonyl, C _3-6 cycloalkyl such as cyclohexyl group - carbonyl group), (xxvi) aryl - carbonyl group (e.g. , A _C6-14 aryl-carbonyl group such as a benzoyl group), (xxvii) a carbamoyl group, (x
xviii) thiocarbamoyl, (xxix) mono- or di-alkyl-carbamoyl groups (for example, mono- or di-C _1-6 such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.) Alkyl-
A carbamoyl group), (xxx) an alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl group, propylsulfonyl group, etc.), and (xxxi) a cycloalkylsulfonyl group (eg, cyclopentylsulfonyl, And a C _3-6 cycloalkylsulfonyl group such as a cyclohexylsulfonyl group). The number of these substituents is about 1 to 5 (preferably 1 to 2), and when there are two or more substituents, the substituents may be the same or different.

The "alkyl group optionally having substituent (s)" includes the "hydrocarbon group optionally having substituent (s)" of the above-mentioned "hydrocarbon group optionally having substituent (s)" represented by R ¹ and R ^2. In addition to the “alkyl group” exemplified as examples, for example, a halogenated C _1-6 alkyl group (eg, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trialkyl Fluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl, etc.), a C _1-4 alkyl group substituted with an amino group (eg, aminomethyl, 2-aminoethyl, etc.), mono - or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group (e.g., methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylcarbamoyl Such as aminoethyl groups), C _1-4 alkyl group substituted with a carboxyl group (e.g., carboxymethyl, etc. carboxyethyl group), C _1-4 alkoxy - C _1-4 substituted with a carbonyl group
An alkyl group (eg, methoxycarbonylethyl, ethoxycarbonylethyl group, etc.), a C _1-4 alkyl group substituted with a hydroxy group (eg, hydroxymethyl, hydroxyethyl group, etc., or a C _1-4 alkoxy-carbonyl group) C _1-4
And an alkyl group (for example, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl group, etc.). Preferred examples of the “optionally substituted alkyl group” are exemplified by the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ^2. Other than the “alkyl group” described above, for example, halogenated C
_1-6 alkyl groups and the like, and among them, for example, a linear or branched C 1 -C 4 radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. A substituted alkyl group or the like is preferably used.

The "aryl group" of the "aryl group optionally having substituent (s)" includes, for example, phenyl,
6 carbon atoms such as naphthyl, anthryl, phenanthryl
And aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl. "Aryl group optionally having substituent (s)"
Examples of the “substituent” include (i) a halogen atom such as fluorine and chlorine, (ii) an optionally halogenated C _1-4 alkyl group such as methyl, ethyl and trifluoromethyl, or ( iii) C _1-4 alkoxy groups such as methoxy and ethoxy groups. Examples of the “optionally substituted hydroxy group” represented by R ² include:
For example, (i) hydroxy group, (ii) C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy group, etc.), (iii) C
_6-10 aryloxy group (for example, phenyloxy, naphthyloxy group and the like), (iv) C _1-4 alkyl-carbonyloxy group (for example, formyloxy, acetoxy, propionyloxy group and the like) and (v) C _{6- 10} aryl-carbonyloxy groups (for example, benzyloxy, naphthyl-carbonyloxy group and the like) and the like, preferably, a hydroxy group and a C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy group and the like) Is raised. The “C _1-4 alkoxy group”, “C _6-10 aryloxy group”, “C _1-4 alkyl-carbonyloxy group” and “C _1-4 alkoxy group” exemplified as these “hydroxy group optionally having substituent (s)” The “C _6-10 aryl-carbonyloxy group” is further substituted by the same as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² above. These substituents may be particularly a halogen atom (for example, fluorine,
Chlorine, bromine and the like). As the “optionally substituted amino group” represented by R ² ,
(I) C _1-4 alkyl group (for example, methyl, ethyl, propyl, isopropyl group, etc.), (ii) C _1-4 alkyl-
A carbonyl group (eg, acetyl, propionyl, butyryl group, etc.), (iii) a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl,
(Iv) phenyl group,
(V) a C _1-4 alkyl-phenyl group (for example, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl group, etc.), (vi) a halogenated phenyl group (for example, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl group) and (vii) one or two substituents selected from C _1-4 alkoxy-phenyl groups (eg, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl group and the like). Examples include an amino group which may be substituted, and in particular, an amino group, a mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino,
Propylamino, dimethylamino, diethylamino, etc.) are widely used. R ¹ is preferably a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), and particularly preferably a methyl group. R ² is preferably a hydrogen atom.

Regarding “R ^a and R ^b ”, in the above formula (I), R ^a and R ^b are bonded together to form a ring A, or are the same or different and represent a hydrogen atom or a substituent on an M ring. . As R ^a and R ^b , a case where they are bonded together to form a ring A is preferable. R ^a and R ^b as substituents on the M ring include, for example,
(I) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) an alkyl group which may have a substituent, (iii) an alkoxy group which may be halogenated (for example, methoxy , Difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,
2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy and the like, even when substituted with a halogen atom such as fluorine. such as a C _1-6 alkoxy group), (iv) optionally halogenated alkylthio group (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, fluorine, such as butylthio group, such as chlorine A C _1-6 alkylthio group (particularly, a C _1-4 alkylthio group) which may be substituted with a halogen atom, and (v) a cycloalkyl group (for example, C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) Cycloalkyl group), (vi) Aryl group (e.g., phenyl, naphthyl, anthryl, C such phenanthryl
_6-14 an aryl group), (vii) an acylamino group (e.g., formylamino, C, such as propionylamino group
_1-3 etc. acylamino group), (viii) acyloxy group (e.g., formyloxy, acetoxy, etc. C _1-3 acyloxy group such as a propionyloxy group), (ix) hydroxy group, (x) nitro, (xi) Cyano group, (xii)
Amino group, (xiii) mono - or di - alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, mono- such diethylamino group - or di -C _1-6 alkylamino group (particularly, mono - or di -C _1-4 alkylamino group), etc.), (xiv) a cyclic amino group (e.g., an oxygen atom in addition to the nitrogen atom, 5 to may contain three from 1 hetero atom such as sulfur atom 9- (E.g., pyrrolidino, piperidino, morpholino, thiomorpholino groups, etc.), (x
v) alkyl-carbonylamino group (for example, C _1-6 alkyl-carbonylamino group such as acetylamino, propionylamino, butyrylamino group), (xvi) alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino, a C _1-6 alkylsulfonylamino group such as propylsulfonyl amino group), (xvii) alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, C _1-6 alkoxy, such as isobutoxycarbonyl group -Carbonyl group), (x
viii) carboxyl group, (xix) alkyl-carbonyl group (for example, C _1-6 alkyl-carbonyl group such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), (xx) carbamoyl group, (xxi) thiocarbamoyl group, ( xxii) mono - or di - alkyl - carbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, mono- such dibutylcarbamoyl groups - such as carbamoyl group), - or di -C _1-6 alkyl
(Xxiii) alkylsulfonyl groups (for example, C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl group, and propylsulfonyl group). Examples of the “optionally substituted alkyl group” include, for example, the “substituent group” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² described above. The same as the “alkyl group optionally having substituent (s)” exemplified above.

Regarding “Ring A and Ring B” In the formula (I), the rings A and B represent the same or different homo- or heterocyclic rings which may have a substituent. The "homologous or heterocyclic ring" includes, for example, (i) an aromatic group containing preferably 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Group heterocyclic rings or non-aromatic heterocycles, or (ii) cyclic hydrocarbons consisting of carbon atoms (homocycles). As the "aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, pyridine , Pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole,
Isothiazole, oxazole, and isoxazole rings). Preferred aromatic heterocycles include, for example, pyridine, pyrazine, thiophene rings and the like, as well as, for example, pyrrole, thiazole rings and the like. In particular, (i) one or two nitrogen atoms other than carbon atoms
6-membered nitrogen-containing heterocycle (eg, pyridine, pyrazine ring, etc.) or (ii) 5-membered aromatic heterocycle containing 1 sulfur atom other than carbon atom (eg, thiophene ring, etc.)
Are preferred.

The "non-aromatic heterocycle" includes, for example, a 5- to 9-membered non-aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. For example, for ring A, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydro Examples include isoxazole ring, and for ring B, in addition to those described above, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, Tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, And La tetrahydroisoquinoline isoxazole ring. As the ring A, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (eg, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring, etc.) is preferable, and a tetrahydropyridine ring is particularly preferable. Are commonly used. As the ring B, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (for example, a piperidine or piperazine ring) is preferable, and a piperazine ring and the like are particularly used.

The "cyclic hydrocarbon (homocycle)" includes, for example, a 3- to 10-membered (for example, 5- to 9-membered) cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. . For example, for ring A, benzene, C
_3-10 cycloalkenes (for example, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and the like.
Preferred are _5-6 cycloalkenes (eg, cyclopentene, cyclohexene, etc.). For the B ring and C ring, in addition to those described above, C _3-10 cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) is also included, such as, C ₅ is a cycloalkane _-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) is preferred. As the ring A and the ring B, for example, a 6-membered homocyclic ring such as a benzene ring or a cyclohexene ring is preferable, and a benzene ring or the like is particularly preferable.

Examples of the substituent which the "homologous or heterocyclic ring" represented by ring A and ring B may have include, for example,
(I) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) an alkyl group which may have a substituent, (iii) an alkoxy group which may be halogenated (for example, methoxy , Difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,
2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy and the like, even when substituted with a halogen atom such as fluorine. such as a C _1-6 alkoxy group), (iv) optionally halogenated alkylthio group (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, fluorine, such as butylthio group, such as chlorine A C _1-6 alkylthio group (especially a C _1-4 alkylthio group) which may be substituted with a halogen atom, (v) an aryl group (for example, a C _6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, etc.) ), (Vi) acylamino group (for example, Rumiruamino, etc. C _1-3 acylamino group such as propionylamino group), (vii) an acyloxy group (e.g., formyloxy, acetoxy,
(C _1-3 acyloxy group such as propionyloxy group), (viii) hydroxy group, (ix) nitro group, (x)
Cyano group, (xi) amino group, (xii) mono- or di-
An alkylamino group (for example, a mono- or di-C _1-6 alkylamino group such as a methylamino, ethylamino, propylamino, dimethylamino, diethylamino group (particularly, a mono- or di-C _1-4 alkylamino group) And (xiii) a cyclic amino group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom (for example,
Pyrrolidino, piperidino, morpholino groups, etc.)
(Xiv) alkyl-carbonylamino group (for example, C _1-6 alkyl-carbonylamino group such as acetylamino, propionylamino, butyrylamino group, etc.), (x
v) an alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino, etc. C _1-6 alkylsulfonylamino group such as propylsulfonyl amino group), (xvi) alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, (C _1-6 alkoxy-carbonyl group such as propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl group), (xvii) carboxyl group, (xiii) alkyl-carbonyl group (for example, C _1-6 such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.) _1-6 alkyl-carbonyl group), (xix) carbamoyl group, (xx) mono-
Or a di-alkyl-carbamoyl group (for example, a mono- or di-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), (xxi) Examples thereof include an alkylsulfonyl group (for example, a C _1-6 alkylsulfonyl group such as a methylsulfonyl, an ethylsulfonyl group, and a propylsulfonyl group), and (xxii) an oxo group. Examples of the “optionally substituted alkyl group” include, for example, the “substituent group” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² described above. The same as the “alkyl group optionally having substituent (s)” exemplified above.

Preferred substituents that the rings A and B may have include a halogen atom, a C _1-6 alkyl group,
Halogenated C _1-6 alkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, C _1-3 acyloxy group, hydroxyl group, amino Groups, mono- or di-C _1-6 alkylamino groups, carboxyl groups, C _1-6 alkoxy-carbonyl groups and oxo groups. More preferred substituents that the ring A and the ring B may have include a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6
Examples include an alkyl group, an optionally halogenated C _1-6 alkoxy, a C _1-3 acyloxy group, a hydroxyl group, an amino group, a mono- or di-C _1-6 alkylamino group and an oxo group. In particular, a halogen atom, C _1-6 alkyl group, such as a C _1-6 alkoxy group which may be C _1-6 alkyl group and a halogenated was halogenated is preferable.

The substituents on ring A and ring B may be substituted at any substitutable position on the ring. When there are two or more substituents, the substituents may be the same or different. And the number thereof may be about 1 to 4. The number of substituents is preferably about 1 to 3.
When the A ring and the B ring have a nitrogen atom, they may form a quaternary ammonium salt. For example, a negative ion such as a halogen ion (eg, Cl ⁻ , Br ⁻ , I ⁻ ), a sulfate ion, a hydroxy ion, etc. It may form a salt with an ion.

As the preferred homocyclic ring in the ring A for the “ring A”, an homocyclic ring composed of an optionally substituted carbon atom, for example, a compound represented by the formula (A-
1)

Embedded image [Wherein A ¹ represents a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, , 2,2-trifluoroethyl, pentafluoroethyl and the like) or an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- Trifluoroethoxy,
Pentafluoroethoxy group, etc.), or the formula (A-2)

[0027]

Embedded image [Wherein A ² and A ³ are the same or different and are each a halogen atom (eg, fluorine, chlorine atom, etc.), a C _1-4 alkyl group which may be halogenated (eg, methyl, isopropyl, trifluoro A methyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group or the like, or an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, Ethoxy,
2,2,2-trifluoroethoxy, pentafluoroethoxy, etc.). More preferred homocycles include, for example, compounds of the formula (A-3)

Embedded image Wherein A ⁴ and A ⁵ are the same or different and are each a halogen atom (eg, fluorine, chlorine atom, etc.) or a C _1-4 alkyl group which may be halogenated (eg, methyl, trifluoro Methyl, trichloromethyl,
Ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl group, etc.], and the like (e.g., a benzene ring).

As the homocyclic ring, for example, the following formula (A-4)

Embedded image [Each symbol in the formula is as defined above. A benzene ring which may have a substituent represented by formula (1) is also preferable. In the homocyclic ring represented by the above formula, particularly preferably, an homocyclic ring having the following substituent is included. (1) A ^{1 wherein} A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.) or an optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, ethyl, isopropyl group, etc.) A ring, (2) A ² and A ³ are the same or different and each may be a halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, ethyl, isopropyl group, etc.), or halogen (3) A ⁴ and A ^{5, which} are the same or different and are the same or different, are C ₁ -C ₄ alkoxy groups (for example, methoxy, trifluoromethoxy, ethoxy groups and the like). A homocycle that is a _4- alkyl group (eg, a methyl, ethyl, isopropyl group, etc.), (4) A ¹
Is a halogen atom (for example, fluorine, chlorine atom, etc.),
(5) A ² and A ³ are identical or different, C _1-4
Alkoxy group (for example, methoxy, ethoxy group, etc.)
An allocyclic ring

The preferred aromatic or non-aromatic heterocyclic ring in the ring A is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring such as pyridine, pyrazine,
Thiophene, tetrahydropyridine, pyrrole, thiazole ring and the like. Specifically, for example, the formula (A-
The heterocyclic ring represented by 5) is preferred.

Embedded image Preferred examples of the aromatic or non-aromatic heterocyclic ring which may have a substituent include, for example, an oxo group and an alkyl group which may have a substituent (the above-mentioned "R ¹ and R ² _C6-10 aryl group (e.g., "alkyl group _optionally having substituent (s)" exemplified as "substituent" of "hydrocarbon group optionally having substituent (s)") Pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole, thiazole ring and the like which may have one or two substituents selected from a phenyl group and a halogen atom (for example, fluorine, chlorine, bromine and the like). Specifically, for example, an aromatic or non-aromatic heterocyclic ring represented by the following formula (A-6) is preferable.

Embedded image [Wherein, D ¹ represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), E ¹ represents a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), compounds having a partial structure represented by (ii) a halogen ion ^{(e.g., Cl -, Br -, I} -
Quaternary ammonium salts with sulfate ions or hydroxy ions. G is a hydrogen atom or C
_1-4 alkyl groups (eg, methyl, ethyl, propyl,
J represents a hydrogen atom, a C _1-4 alkyl group (eg, a methyl, ethyl, propyl, isopropyl group, etc.) or a C _6-10 aryl group (eg, a phenyl group). Ring A is a 5- or 6-membered nitrogen-containing heterocycle, for example,
(I) a 6-membered aromatic nitrogen-containing heterocyclic ring containing one or two nitrogen atoms other than carbon atoms (for example, pyridine and pyrazine rings); and (ii) one or two nitrogen atoms other than carbon atoms.
It is preferably a six-membered non-aromatic heterocyclic ring (for example, a tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring or the like). Particularly preferred A
The ring includes an aromatic nitrogen-containing heterocycle, especially a pyridine ring.

As the preferred homocyclic ring in the ring B for the “ring B”, an homocyclic ring consisting of an optionally substituted carbon atom, for example, a compound represented by the formula (B-
1)

Embedded image [Wherein B ¹ represents a halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated], and a compound represented by the formula (B-2)

Embedded image [In the formula, B ² and B ³ are the same or different and each represent a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group.] Or formula (B-3)

Embedded image [In the formula, B ⁴ , B ⁵ and B ⁶ are the same or different and each is a halogen atom, an optionally halogenated C _1-4
Alkyl group and C _1-4 alkoxy group which may be halogenated].

Further preferred homocyclic rings include those represented by the formula (B-4)

Embedded image [Wherein, B ⁷ , B ⁸ and B ⁹ are the same or different and are each a halogen atom, an optionally halogenated C _1-4
An alkyl group or a C _1-4 alkoxy group which may be halogenated]. Particularly preferred homocyclic rings include the following formula (B-5)

Embedded image [Wherein B ¹⁰ represents a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group].

In the above formula, the halogen atoms in B ^{1 to} B ¹⁰ include, for example, fluorine, chlorine, bromine atoms and the like;
Examples of the optionally halogenated C _1-4 alkyl group include, for example, methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,
2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl, 2,
2,3,3-Tetrafluoropropyl, isopropyl group and the like, and optionally halogenated C _1-4 alkoxy group include, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2 2-trifluoroethoxy, 2,2,2-trichloroethoxy,
1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, propoxy, 2,2,3,3-tetrafluoropropoxy, isopropoxy group and the like are included.

It is also preferred that ring B is a benzene ring which may have a substituent. Such a benzene ring has, for example, the formula (B-6)

Embedded image Is more preferable, and more preferably, formula (B-7)

Embedded image In particular, the formula (B-8)

Embedded image [The symbols in the formula are as defined above.] And the like.

Among the substituents in the above formula, particularly preferred substituents are (1) B ¹ , B ² , B ³ , B ⁴ , B ⁵ and B ⁶ are the same or different and each have a halogen atom (Eg, fluorine, chlorine atom, etc.) or optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, ethyl, isopropyl group, etc.), (2)
B ¹ , B ² , B ³ , B ⁴ , B ⁵ and B ⁶ are the same or different and each may be a halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy,
An ethoxy group, etc.), (3) B ⁷ , B ⁸ and B ⁹ are a halogen atom (for example, fluorine, chlorine atom, etc.), (4)
B ¹⁰ is a fluorine atom, and (5) B ¹⁰ is a C _1-4 alkyl group (for example, a methyl group). As a benzene ring which may have a more preferable substituent, the following formula (B-9)

Embedded image And a phenyl group represented by

Preferred examples of the aromatic or non-aromatic hetero ring in the ring B include 5- or 6-membered aromatic or non-aromatic hetero rings such as pyridine, thiophene and piperidine rings. The ring of the above A
It may have the same preferred substituents as those exemplified in the section of the ring. When the ring B is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, particularly preferred aromatic heterocyclic rings or non-aromatic heterocyclic rings include, for example, those represented by the formula (B-10)

Embedded image And the like. When both or one of the ring A and the ring B is a heterocyclic ring, the heterocyclic ring is also preferably an unsubstituted heterocyclic ring.

“C ring” In the above formula, the C ring represents an optionally substituted homocyclic or heterocyclic ring. The homocyclic or heterocyclic ring may have about 1 to 5, preferably about 1 to 3, identical or different substituents. Further, these substituents may be substituted at any position of the homocyclic ring or the heterocyclic ring. The homocyclic ring includes the same “cyclic hydrocarbon (homocyclic ring)” as described in the section “A ring and B ring”, for example, benzene, C
3- to 10-members such as _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) , Preferably a 5- or 6-membered cyclic hydrocarbon. Preferred homocyclic rings include a 6-membered homocyclic ring such as a benzene, cyclohexene, and cyclohexane ring, and a benzene ring is particularly preferred.

Examples of the substituent on the homocyclic ring such as the benzene ring include (i) a halogen atom (for example, fluorine,
Chlorine, bromine, iodine atom), (ii) optionally halogenated C _1-10 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2,2
-Trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl, decyl group, etc.), (iii) amino A C _1-4 alkyl group substituted with a group (eg, aminomethyl, 2-aminoethyl group, etc.),
(Iv) mono- or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group (e.g., methylaminomethyl,
Dimethylaminomethyl, 2-methylaminoethyl, 2-
Dimethylaminoethyl group, etc.), (v) C _1-4 alkyl group substituted with carboxyl group (for example, carboxymethyl, carboxyethyl group, etc.), (vi) C _1-4 substituted with C _1-4 alkoxy-carbonyl group. _1-4 alkyl groups (eg, methoxycarbonylethyl, ethoxycarbonylethyl groups, etc.), (vii) C _1-4 alkyl groups substituted with hydroxyl groups (eg, hydroxymethyl, hydroxyethyl groups, etc.), (viii) C A C _1-4 alkyl group substituted with a _1-4 alkoxy-carbonyl group (eg, methoxymethyl, methoxyethyl, ethoxyethyl group, etc.), (ix) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.),
(X) nitro group, (xi) cyano group, (xii) hydroxy group, (xiii) optionally halogenated C _1-10 alkoxy group (for example, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy ,
2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, octyloxy, decyloxy group, etc.), (xiv) halogenation C that may be
_1-4 alkylthio groups (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio groups, etc.),
(Xv) amino group, (xvi) mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like), (xvii) cyclic amino group (for example, Other than a nitrogen atom, an oxygen atom, a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms such as a sulfur atom, specifically,
For example, pyrrolidino, piperidino, morpholino group, thiomorpholino group, etc.), (xviii) C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), (xix) aminocarbonyloxy group, (xx A) mono- or di-C _1-4 alkylaminocarbonyloxy group (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), (xxi) C _1-4 alkylsulfonylamino group (E.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.),
(Xxii) a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl group, etc.), (xxiii) a C _7-15 aralkyloxy-carbonyl group (eg, benzyloxy (Xxiv) carboxyl group, (xxv) C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), (xxvi) C
_3-6 cycloalkyl-carbonyl group (eg, cyclohexylcarbonyl group), (xxvii) carbamoyl group, (xxviii) thiocarbamoyl group, (xxix) mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl) , Ethyl carbamoyl, propyl carbamoyl, butyl carbamoyl, diethyl carbamoyl,
Dixxxcarbamoyl group), (xxx) C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.) and (xxxi)
C _1-3 acyloxy group (for example, acetoxy group and the like) and the like.

Further, the homocyclic ring as the ring C is, for example,
One 5- or 6-membered aromatic monocyclic heterocyclic group (for example,
Furyl, thienyl, oxazolyl, isoxazolyl,
Thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.), and these aromatic monocyclic heterocyclic groups are It may be substituted by about C _1-4 alkyl groups which may be halogenated (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, isopropyl groups, etc.).

Preferred substituents to be substituted on the homocyclic ring (benzene ring or the like) as ring C include, for example, (i) a halogen atom (eg, fluorine, chlorine, bromine atom, etc.),
(Ii) an optionally halogenated C _1-6 alkyl group (for example, methyl, chloromethyl, difluoromethyl,
Trichloromethyl, trifluoromethyl, ethyl, 2-
Bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3
-Trifluoropropyl, butyl, s-butyl, t-butyl, perfluorobutyl, etc.), (iii) nitro, (iv) hydroxyl, (v) optionally halogenated C _1-6 alkoxy. (Eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, 3,3,3-trifluoropropoxy, butoxy group, etc.), (vi) amino group, (vii) mono- or di-C _{1 -4} alkylamino C _1-4 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl group), (viii) mono- - or di -C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino group, etc.), (ix) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl group, etc.), (x) carboxyl And (xi) a C _1-3 acyloxy group (eg, an acetoxy group) and (xii) a carbamoyl group.

In particular, (i) a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), (ii) a C _1-4 alkyl group which may be halogenated (eg, methyl, chloromethyl, difluoromethyl, trichloro) Methyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-
Trichloroethyl, 2,2,2-trifluoroethyl,
Perfluoroethyl, propyl, isopropyl, t-butyl, etc.), (iii) optionally halogenated C
_1-4 alkoxy groups (e.g., methoxy, trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy,
2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy group, etc.), (iv) di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.), (v) C _1-3 acyloxy Groups such as acetoxy groups and (vi) hydroxyl groups are preferred. The number of these substituents is preferably, for example, about 1 to 3.

The “heterocycle” of the “heterocycle optionally having substituent (s)” includes, for example, a nitrogen atom,
It includes a 5- to 10-membered heterocyclic ring containing 1 to 4 kinds of one or two kinds of hetero atoms such as an oxygen atom and a sulfur atom.
Specific examples of the heterocycle include (1) furyl,
Thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
5- or 6-membered aromatic monocyclic heterocycle such as pyrazinyl, triazinyl and the like;

(2) Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2- Benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , Thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
9- or 10-membered fused aromatic heterocycle such as 1,2,4-triazolo [4,3-b] pyridazinyl; or

(3) 5- to 10-membered non-aromatic heterocycles such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and pyrazinyl. The heterocycle (1) to
Among (3), for example, a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom is preferably used. Such heterocycles include, for example, furyl, thienyl, pyrrolyl,
Oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl and the like. Examples of the substituent which the heterocyclic ring may have include the same substituents as those described in the above section “Homocyclic ring which may have a substituent”.

A more preferred ring C is a benzene ring which may have a substituent (particularly, a benzene ring substituted by a substituent), for example, a halogen atom or a halogenated C _1-4. Substituted with 1 to 3 substituents selected from an alkyl group, an optionally halogenated C _1-4 alkoxy group, a di-C _1-4 alkylamino group, a C _1-3 acyloxy group and a hydroxy group. Benzene ring (particularly, a benzene ring substituted with the substituent). Specifically, preferred C ring includes, for example, the following formula (C-1)

Embedded image [In the formula, C ¹ , C ² and C ³ are the same or different and are each independently a hydrogen atom, a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C
_1-4 alkoxy group, mono- or di-C _1-4 alkylamino group, C _1-3 acyloxy group or hydroxyl group], or the following formula (C-2)

Embedded image [Wherein C ⁴ and C ⁵ are the same or different and are each a hydrogen atom, a halogen atom, an optionally halogenated C
_1-4 alkyl group or optionally halogenated C
_1-4 represents an alkoxy group] which may be substituted.

Here, a halogen atom represented by C ¹ , C ² , C ³ , C ⁴ or C ⁵ , an optionally halogenated C
_1-4 alkyl group, optionally halogenated C _1-4 alkoxy group and mono- or di-C _1-4 alkylamino group may be the aforementioned halogen atom, optionally halogenated C _1-4 The same alkyl groups, optionally halogenated C _1-4 alkoxy groups and mono- or di-C _1-4 alkylamino groups are used. More preferred C ring includes, for example, a benzene ring in which C ^{1 to} C ⁵ in the formulas (C-1) and (C-2) are the following substituents. (1) C ¹ , C ² and C ³ are the same or different and are each a halogen atom or an optionally halogenated C _1-4
Alkyl group or halogenated which may be C _1-4 alkoxy ^{group, (2) C 1, C} 2 and C ³ are the same or different and optionally C _1-4 be halogen atoms or halogenated Alkyl groups, (3) C ¹ , C ² and C
³ is the same or different and is a halogen atom, (4) C
¹ , C ² and C ³ are the same or different and each may be a halogenated C _1-4 alkyl group,

(5) C ¹ , C ² and C ³ are the same or different and C _1-4 alkoxyl group which may be halogenated; (6) C ⁴ and C ⁵ are the same or different The halogen atom, (7) C ⁴ and C ⁵ may be the same or different and each may be a halogenated C _1-4
An alkyl group or (8) a C _1-4 alkoxy group in which C ⁴ and C ⁵ are the same or different and may be halogenated. In the embodiments (1) to (8), the “optionally halogenated C _1-4 alkyl group”, the “optionally halogenated C _1-4 alkoxy group” and the “halogen atom” The same groups or atoms as described above can be exemplified.

Further preferred ring C is, for example, a benzene ring in which C ⁴ and C ⁵ in the formula (C-2) are the following substituents. (A) one of C ⁴ and C ⁵ is a hydrogen atom, the other is a methoxy group, (b) C ⁴ and C ⁵ are chlorine atoms, (c) C 4
One is a methoxy group of ⁴ and C ^5, the other is an isopropyl group, (d) one of C ⁴ and C ⁵ is a methoxy group and the other is 1-methoxy-1-methylethyl group, (e)
C ⁴ and C ⁵ are trifluoromethyl groups, or (f)
C ⁴ and C ⁵ are methoxy groups.

Regarding “D”, in the formula (I), D represents a divalent group. Examples of the “divalent group” represented by D include a divalent aliphatic hydrocarbon group which may have a substituent. “2” of “a divalent aliphatic hydrocarbon group which may have a substituent”
A "valent aliphatic hydrocarbon group" refers to a group formed by removing one hydrogen atom (two in total) bonded to the same or different carbon atoms of a saturated or unsaturated aliphatic hydrocarbon,
Preferably it has 6 or less carbon atoms. Specifically, (i) C
_1-6 alkylene group _{(e.g., -CH 2 -, - CH 2} CH
_{2 -, - CH 2 CH 2} CH 2 -, - CH (CH 3) -CH 2 -,
—CH ₂ CH ₂ CH ₂ CH ₂ —, etc.), (ii) C _2-6 alkenylene group (for example, —CH ＝ CH—, —CH ＝ CH—C
H ₂ —, —CH ₂ —CH ＝ CH—CH ₂ —, — (CH ₂ ) _{2
-CH = CH-CH 2 -,} - (CH 2) 2 -CH = CH-
_{(CH 2) 2 -, -} (CH 2) 3 -CH = CH-CH 2 - , etc.) (iii) C _2-6 alkynylene group (e.g.,

Embedded image Are used.

Among them, a C _1-3 alkylene group (for example,
_{-CH 2 -, - CH 2 CH} 2 -, - CH 2 CH 2 CH 2 - and -CH (CH ₃₎ -CH ₂ -, etc.) are widely used. Preferably -CH ₂ - and -CH ₂ CH ₂ - it is universal.
"A divalent aliphatic hydrocarbon group which may have a substituent"
Examples of the “substituent” include the same as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² , and an oxo group (-CO
-) And a thioxo group (-CS-). D is preferably a C _1-3 alkylene group optionally substituted with an oxo group or a thioxo group. More preferred specific examples of D include -CO-, -CS-, -CH
_{2 -, - CH 2 CH 2} -, - CH 2 CO -, - CH 2 CS
—, —CH ₂ CH ₂ CO— and —CH ₂ CH ₂ CS—, and the like, and —CO— and the like are widely used.

In the above formula for “E” , E is —NR ⁵ — (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent, and is bonded together with R ¹ or R ² to form a substituent. And may form a heterocyclic ring which may be present), -O- or -S (O) _n- (n is 0, 1 or 2). Examples of the “optionally substituted hydrocarbon group” represented by R ⁵ include, for example, the “optionally substituted hydrocarbon group” represented by R ¹ and R ^2. And the like are used. Preferred examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ⁵ include, for example, C _1-4 alkyl such as methyl, ethyl, propyl, isopropyl and butyl. Group. Preferred examples of the “substituent” of the “optionally substituted hydrocarbon group” represented by R ⁵ include a hydroxyl group and a C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy). Such),
Amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl ), Carboxyl groups,
Examples thereof include a carbamoyl group and a phenyl group, and particularly, a carboxyl group and a carbamoyl group are widely used.

The compounds when R ⁵ form a heterocyclic ring which may have a substituent taken together with R ¹ or R ² (I) are, for example, when attached to R ¹ has the formula

Embedded image [Wherein, the ring Z represents a heterocyclic ring which may have a substituent, and the other symbols have the same meanings as described above].
^When combining with ² , the expression

Embedded image [Wherein, the Z ′ ring represents a heterocyclic ring which may have a substituent, and other symbols have the same meanings as described above]. Preferable examples of E include -NR ^5- (R ⁵ has the same meaning as described above) and -O-, particularly -NR ^5- (R ⁵ has the same meaning as described above).

Regarding “Z ring” and “Z ′ ring” In the above formulas (V) to (VII), the Z ring and the Z ′ ring may be an optionally substituted heterocyclic ring (preferably a 5- to 12-membered heterocyclic ring). , More preferably a 5- to 9-membered heterocyclic ring). Z
Examples of the ring substituent include various substituents, for example, (i) alkyl groups (for example, having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups). A linear or branched alkyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms), (ii) an alkenyl group (for example, ethenyl,
An alkenyl group having 2 to 6 carbon atoms, preferably an alkenyl group having 2 to 4 carbon atoms, such as propenyl, isopropenyl, butenyl, isobutenyl and sec-butenyl groups), (ii)
i) alkynyl group (for example, alkynyl group having 2 to 6 carbon atoms, preferably alkynyl group having 2 to 4 carbon atoms, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl group), (iv) cycloalkyl Groups (eg, C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, preferably C _3-6 cycloalkyl groups), (v) cycloalkyl-alkyl groups (eg, cyclopropylmethyl, cyclopropyl C _3-6 cycloalkyl-C _1-4 alkyl groups such as propylethyl and cyclohexylmethyl groups), (v
i) aryl groups (eg, phenyl, 1-naphthyl, 2
An aryl group having 6 to 14 carbon atoms, such as a naphthyl, anthryl or phenanthryl group, preferably an aryl group having 6 to 10 carbon atoms, particularly a phenyl group), (vii) a nitro group,
iii) cyano group, (ix) hydroxy group, (x) C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy,
(Xi) a C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio group, etc.), (xii) amino group, (xiii) mono- or di-C _1-4 alkylamino group (Eg, methylamino, ethylamino, propylamino, dimethylamino,
(Xiv) a cyclic amino group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom) Is, for example, pyrrolidino, piperidino,
Morpholino, thiomorpholino group, etc.), (xv) C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.),
(Xvi) a C _1-4 alkylsulfonylamino group (for example,
(Xvii) a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), (xviii) a carboxyl group,
(Xix) C _1-6 alkyl-carbonyl group (for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc.), (xx) carbamoyl group, (xxi) mono- or di-C _1-4 alkylcarbamoyl group (for example, Methylcarbamoyl, ethylcarbamoyl, etc.), (xxii)
C _1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.),
(Xxiii) oxo group, (xxiv) thioxo group and the like. These substituents preferably include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group, etc.), a hydroxy group, an oxo group, a thioxo group and the like. And especially C _1-4 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, etc.) or oxo. The number of these substituents is, for example, about 1 to 5, preferably 1 depending on the size of the Z ring or Z ′ ring.
Or about two.

The Z ring and the Z ′ ring are heterocyclic rings which may contain at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom, and It may be. Preferred Z ring and Z ′ ring include the following formulas (Z-1) and (Z-1) ′

Embedded image (Wherein, D ′ and G each represent a group that forms the Z ring or the Z ′ ring together with the nitrogen atom adjacent to D ′). Examples of D 'and G forming the Z ring or Z' ring include an alkylene group, an oxyalkylene group, and an iminoalkylene group, at least one of which may be oxo-modified. Desirable D 'and G are, for example, an alkylene group or an oxyalkylene group which may be oxoated. The optionally oxidized alkylene group, oxyalkylene group and iminoalkylene group represented by D ′ and G are a 5- to 12-membered heterocyclic ring having a Z-ring and a Z′-ring, preferably a 5- to 9-membered heterocyclic ring. It preferably has a carbon number that forms a ring. In addition,
The carbon numbers of the alkylene groups represented by D 'and G may be the same or different.

Preferred G includes, for example, a C _1-7 alkylene group which may be oxo-modified (particularly a C _1-5 alkylene group which may be oxo- _modified ) and a C _1-7 oxyalkylene group (particularly C _{1-7 1-5} oxyalkylene group) and C _1-7 iminoalkylene group (especially C _1-5 imialkylene group). More preferred G, the formula - (CH _{2) m} - (wherein, m is 1-7) alkylene group represented by the formula -O-
An oxyalkylene group represented by (CH ₂ ) _p — (where p is an integer of 1 to 7), a formula —NH— (CH ₂ ) _q — (wherein
q is an integer of 1 to 7). In the above formula, m is preferably 1 to 6, particularly 2 to 5, and p and q are each preferably 1 to 5, particularly preferably 1 to 4. Preferred D ′ is, for example, a C _1-3 alkylene group which may be oxo-modified, particularly an alkylene group having 1 or 2 carbon atoms which may be oxo-modified, and especially a methylene group which may be oxo-modified. Is included. The number of oxo groups that can be substituted on the Z ring or the Z ′ ring is not particularly limited, and may be 1 depending on the size of the Z ring or the Z ′ ring.
The number of oxo groups is about 1 or 2 when the Z ring or the Z ′ ring has 5 to 10 members. The oxo group is preferably substituted on at least one of D ′ and / or G. In a preferred Z ring or Z ′ ring, the oxo group is substituted on D ′.

In a preferred Z ring or Z ′ ring, G is an alkylene group or oxyalkylene group having 1 to 5 carbon atoms, particularly 2 to 5 carbon atoms, and D ′ is an oxo-modified alkylene group having 1 or 2 carbon atoms. Groups, especially> C = O. More preferred Z ring or Z ′ ring includes, for example, the following formula (Z-
2), (Z-3), (Z-2) ', (Z-3)'

Embedded image (Wherein, m 'and p' are each an integer of 2-5, a hydrogen atom or a C _1-4 alkyl group (methyl, ethyl, propyl, etc.) each Z ^a and Z ^b identical or different. ) Is included.

“Regarding Q” In the above formula (I), Q represents a substituted linear lower alkylene group. Examples of the “linear lower alkylene group” of the “substituted linear lower alkylene group” represented by Q include, for example, a linear C _1-6 alkylene group (for example,
Methylene, ethylene, propylene, butylene, etc.), preferably a linear C _1-4 alkylene group (eg, methylene, ethylene, propylene, butylene, etc.), and particularly preferably a methylene group And so on. As the “substituent” to be substituted for the “linear lower alkylene group” of the “substituted linear lower alkylene group” represented by Q, for example, a hydrocarbon group which may have a substituent And so on. The “substituent” of the “linear lower alkylene group” is 1 to 5 at a substitutable position on a carbon atom of the “linear lower alkylene group”,
Preferably, one to four substituents may be substituted. When the “linear lower alkylene group” has two or more substituents, the respective substituents may be the same or different, but are different from each other. Is preferred. Examples of the "hydrocarbon group" of the "hydrocarbon group optionally having substituent (s)" include, for example, "hydrocarbon group optionally having substituent (s)" represented by R ¹ and R ² above. And the like, and among them, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl group, etc.), particularly a methyl group, etc. can be mentioned.

The "substituent" of the "hydrocarbon group which may have a substituent" includes, for example, (i) a halogen atom (for example, fluorine and chlorine), (ii) a hydroxy group, and (iii) ) C _1-3 alkoxy group (for example, methoxy, ethoxy, propoxy group, etc.), (iv) C _1-3 alkyl-
Carbonyloxy group (for example, formyloxy, acetoxy, propionyloxy group, etc.), (v) amino group,
(Vi) mono- or di-C _1-5 alkylamino group (for example, methylamino, ethylamino, diethylamino group and the like), (vii) _C1-5 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxy) Carbonyl group), (viii) carboxyl group,
(Ix) carbamoyl group and the like. The “substituent” of the “hydrocarbon group optionally having substituent (s)” may be substituted at 1 to 5, preferably 1 to 3 at substitutable positions on the hydrocarbon. When the group has two or more substituents, each substituent may be the same or different. Q is preferably, for example,

Embedded image [Wherein R ³ and R ⁴ are different from each other and represent a hydrogen atom or a hydrocarbon group which may have a substituent]. Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ³ and R ⁴ include, for example, “substituent” as a “substituent” to be substituted with the above “linear lower alkylene group”. And the same as the "hydrocarbon group which may have a substituent". As R ³ and R ⁴ , one is preferably a hydrogen atom and the other is a hydrocarbon group which may have a substituent, and the other is a hydrogen atom and the other is a C _1-4 alkyl group. Is more preferable, and the case where one is a hydrogen atom and the other is a methyl group is still more preferable.

Compound (I) In the compound represented by the formula (I),
ring",

Embedded image , “R ^a ”, “R ^b ”, “A ring”, “B ring”, “C ring”,
The combination of "D", "E" and "Q" is not particularly limited, and the compound (I) can be constructed by appropriately combining. Preferred compound (I) is the “M ring” of the preferred embodiment.

Embedded image , “R ^a ”, “R ^b ”, “A ring”, “B ring”, “C ring”,
It is constructed by combining "D", "E" and "Q".

Among the compounds represented by the general formula (I), preferred compounds include the following compounds or salts thereof. (1 set

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof represented by the formula (2):

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof, (3) wherein the M ring has a partial structure

Embedded image As -CONR ¹ - (R ¹ is as defined above) have to form a ring A bonded R ^a and R ^b are both either one of rings A and B are carbon atoms And a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom and a sulfur atom, the other being a benzene ring, the A ring and the B ring being a halogen atom and a halogenated _May have one or two substituents selected from an optionally substituted C _1-4 alkyl group, wherein the C ring is a halogen atom, an optionally halogenated C _1-6 alkyl group ( Preferably a C _1-4 alkyl group and an optionally halogenated C _1-6 alkoxy group (preferably C
_A benzene ring optionally having 1 to 3 substituents selected from _1-4 alkoxy groups), D represents -CO-, and E represents NR ⁵ (R ⁵ has the same meaning as described above). ) And Q
Is the expression

Embedded image Wherein R ³ and R ⁴ are as defined above, or a salt thereof. The above “5 or 6
As the membered heterocycle, for example, pyridine, pyrazine,
Examples include pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine, and the like. Specifically, the ring A includes the heterocycle represented by the formula (A-5), and the ring B includes the formula (A) B-7) and (B-8), particularly the benzene ring represented by the formula (B-10). The “halogen atom” includes, for example, fluorine, chlorine, bromine atom and the like, and “optionally halogenated C _1-4
Examples of the “alkyl group” include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 2
-Trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-
A butyl group and the like are mentioned, and the “optionally halogenated C _1-6 alkyl group” includes a pentyl, hexyl group and the like in addition to the above-mentioned alkyl group or halogenated alkyl group.

As the “optionally halogenated C _1-4 alkoxy group”, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, te
Examples of the rt-butoxy group include “optionally halogenated C _1-6 alkoxy group” which includes pentyloxy, hexyloxy group and the like in addition to the above-mentioned alkoxy group or halogenated alkoxy group. Formula (I),
When the compounds represented by (Ia) and (Ib) form a salt, which is used as a medicament, the salt is preferably a pharmaceutically acceptable salt. As pharmaceutically acceptable salts,
For example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid, or acetic acid, malic acid,
Maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid,
Examples thereof include salts with organic acids such as lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid, and stearic acid.

The compound (I) of the present invention or a salt thereof includes:
Stereoisomers such as cis and trans isomers based on the amide structure, optical isomers based on asymmetric carbon, optical isomers based on axial asymmetry, and conformational isomers based on the cyclic structure of the Z ring in addition to the racemic form Body etc. are included. The compound of the present invention includes a mixture of these isomers or a single compound.

Method for Producing Compound or a Salt Thereof Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. Compound (I) of the present invention or a salt thereof,
For example, it can be manufactured by the following methods.
That is, the expression

Embedded image [In the formula, L represents a leaving group, and other symbols have the same meanings as described above. And a salt thereof having a leaving group L represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof, or a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof represented by the formula:

Embedded image [In the formula, L ′ represents a leaving group, and other symbols have the same meanings as described above. The compound (I) or a salt thereof is produced by reacting the compound (I) or a salt thereof. Examples of the leaving group L include hydroxy, a halogen atom (eg, chlorine, bromine, iodine, etc.), substituted sulfonyloxy (eg, methanesulfonyloxy, p
-Toluenesulfonyloxy, etc., acyloxy (acetoxy, benzoyloxy, etc.), oxy group substituted with a heterocyclic ring or an aryl group (succinimide, benzotriazole, quinoline, 4-nitrophenyl, etc.) are used. As the leaving group L ', among the leaving groups exemplified for L above, a halogen atom, substituted sulfonyloxy and the like are used. Hereinafter, the method will be described in detail. Method: This method is a compound (VIII) in which the moiety that binds to L in D is i) an acylation reaction when the oxo group (—CO—) or thioxo group (—CS—), and ii) an alkylene group. It is roughly divided into the alkylation reaction in the case. i) Acylation reaction: When the leaving group L of the compound (VIII) or a salt thereof (for example, a salt with an alkali metal such as sodium, potassium or magnesium, or an alkaline earth metal) is a hydroxyl group, a suitable condensing agent is usually used. Or by converting the hydroxyl group, which is a leaving group, to another leaving group (for example, an oxy group substituted with an acyloxy group, a heterocycle, or an aryl group as described above) as appropriate.
X) or a salt thereof (eg, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid or a salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, or maleic acid). Is preferred.
Examples of such a condensing agent include dicyclohexylcarbodiimide (DCC) and diethyl cyanophosphate (DEP).
C), diphenylphosphoryl azide (DPPA) and the like are used. When these condensing agents are used, usually a solvent (eg, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, N, N-
Ethers such as dimethylformamide and dimethylsulfoxide, esters, hydrocarbons, amides and sulfoxides). This reaction may be promoted in the presence of a base.
The reaction is carried out at a temperature of from about 0.degree.
The reaction time is generally 1 to 96 hours, preferably 0.5 to 72 hours. The amount of the compound (IX) or a salt thereof and the condensing agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 moles, per 1 mol of the compound (VIII) or a salt thereof.
It is a molar equivalent. As the base, for example, alkylamines such as triethylamine, and cyclic amines such as N-methylmorpholine and pyridine are used. The amount of the base to be used is 1 to 5 molar equivalents, preferably 1 mol of compound (VIII) or a salt thereof. One to three molar equivalents. Compound (VIII) as a reactive derivative (D is -CO-, L is-
OH) is, for example, an acid halide (eg, chloride, bromide, etc.), an acid anhydride, a mixed acid anhydride (eg, an anhydride with methyl carbonate, an anhydride with ethyl carbonate, an anhydride with isobutyl carbonate, etc.), an activity Esters (for example, esters with hydroxysuccinimide, esters with 1-hydroxybenzotriazole, esters with N-hydroxy-5-norbornene-2,3-dicarboximide, p
Esters with nitrophenol, esters with 8-oxyquinoline, etc.), and acid halides are particularly preferred. Compound (IX) or a salt thereof and compound (VI
When reacting with (II), a halogenated hydrocarbon such as a solvent (eg, chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine, N, N-dimethylformamide) is usually used. , Ethers, esters, hydrocarbons, aromatic amines, amides, etc.). This reaction may promote the reaction in the presence of a base. The reaction temperature is usually about -10 ° C to 12 ° C.
0 ° C., preferably about 0 ° C. to 100 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 0.5 to 2 hours.
4 hours. The amount of compound (IX) to be used is compound (VIII)
Or 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of a salt thereof. Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, and sodium carbonate and potassium carbonate. Alkali metal carbonate, sodium hydrogen carbonate, alkali metal bicarbonate such as potassium hydrogen carbonate and the like are used,
The amount of use is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IX) or a salt thereof. When a solvent that is immiscible with water is used in this reaction, water may be added to the reaction system and the reaction may be performed in a two-phase system.

Ii) Alkylation reaction: As the leaving group L of the compound (VIII), the aforementioned halogen atom and substituted sulfonyloxy group are preferably used in the reaction with the compound (IX).
Compound (IX) may be used as it is, or may be subjected to the reaction as a salt, for example, an alkali metal salt such as lithium, sodium or potassium. Compound (VI
II) 1 to 10 mol, preferably 1 to 5 mol of compound (IX) or a salt thereof is reacted with 1 mol of the compound (IX). Usually, the reaction is performed in a solvent. As the solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide are preferably used. Addition of a base favors the reaction.
As such a base, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine and the like are preferable.
In this reaction, instead of using a base, compound (IX) may be converted to, for example, an alkali metal salt or an alkaline earth metal salt as described above, and this may be reacted with compound (VIII). When E of compound (IX) is —NR ⁵ — (R ⁵ has the same meaning as described above), compound (IX) itself may be used as a base instead of using the above base. . The amount of base used depends on the compound used (VII
Although it depends on the types of I) and (IX) and the solvent and other reaction conditions, it is usually 1 to 10 mol, preferably 1 to 5 mol per 1 mol of compound (IX). The reaction temperature is in the range of about -50C to 200C, preferably -20C to 150C. The reaction time depends on the type of compound (VIII) and compound (IX)
Or depending on the type of salt, reaction temperature, etc.,
It is 1 to 72 hours, preferably 1 to 24 hours.

Method: This method is carried out by a method similar to the alkylation reaction described in Method ii). That is, the compound (X) is used in place of the compound (VIII) in ii), and the compound (XI) or a salt thereof is used instead of the compound (IX) or a salt thereof by a method similar to the method described in ii). Will be implemented.

As a preferred example of the compound (I), the compound (Ia) described above is a compound of the formula (IX) or a salt thereof instead of the compound (IX) or a salt thereof.

Embedded image [Wherein the symbols have the same meanings as described above. The compound (IX ') or a salt thereof represented by the formula (Ib) is replaced with the compound (VIII) or a salt or a reactive derivative thereof,

Embedded image [Wherein the symbols have the same meanings as described above. A compound (VIII ') or a salt thereof or a reactive derivative thereof,
Instead of compound (IX) or a salt thereof, a compound of the formula

Embedded image [Wherein the symbols have the same meanings as described above. And the salts thereof can be produced by the same method as in the above acylation reaction or alkylation reaction.

The compound (Ia) described as a preferred example of the compound (I) is a compound of the formula (XI) or a salt thereof instead of the compound (XI) or a salt thereof.

Embedded image [Wherein the symbols have the same meanings as described above. The compound (XI ′) or a salt thereof is represented by the formula (Ib):

Embedded image [Wherein the symbols have the same meanings as described above. The compound (X ') or a salt thereof represented by the formula (I) can be produced in the same manner as in the above-mentioned alkylation reaction by using the compound (XI') in place of the compound (XI) or a salt thereof. it can. Among the compounds (I) of the present invention, a compound in which Ring A is a tetrahydropyridine ring can be produced by subjecting a compound in which Ring A is a pyridine ring to a reduction reaction. This reaction is carried out by various methods. For example, a method of reducing in the presence of a metal catalyst for catalytic reduction is preferably used. Examples of the catalyst used in this catalytic reduction method include platinum black, platinum oxide, platinum catalysts such as platinum carbon, palladium black, palladium oxide, palladium barium sulfate, palladium catalysts such as palladium carbon, reduced nickel, nickel oxide, Nickel catalysts such as Raney nickel and Urushibara nickel are exemplified. This reaction is usually performed in a solvent. As the solvent, for example, alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, and esters such as ethyl acetate are preferably used. The reaction temperature is 0 ° C to 200 ° C, preferably 2 ° C.
Performed at 0 ° C to 110 ° C. The reaction time is usually 0.1.
It is 5 to 48 hours, preferably 1 to 16 hours. The reaction is usually carried out under normal pressure, but if necessary under pressure (3 to 10 atm). The amount of the catalyst used depends on the type of the catalyst, but is usually 0.1 to 10% (w / w) based on the compound (I). Other aromatic heterocycles can also be converted to non-aromatic heterocycles using similar methods.

Further, a compound in which Ring A is a tetrahydropyridine ring is a compound in which Ring A is a pyridine ring of the formula W-
L '' (XII) (wherein, W represents an alkyl group which may have a substituent, and L '' represents a leaving group (L '' is the same as L).) To produce a quaternary salt, and then subjecting the quaternary salt to a reduction reaction. Examples of the alkylating agent (XII) used in the conversion to a quaternary salt include alkane halides (eg, chloride, bromide, iodide, etc.), sulfates, and sulfonates (eg, methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc.). ) And the like, and alkyl halides are particularly preferably used. The amount of the alkylating agent to be used is 1 to 100 equivalents, preferably 1 to 30 equivalents, per 1 mol of the substrate. This reaction is usually performed in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, dichloromethane,
Although halogenated hydrocarbons such as 1,2-dichloroethane are used, the alkylating agent itself may be used as a solvent. The reaction temperature is from 10 ° C to 200 ° C, preferably from 20 ° C to 110 ° C. The reaction time is generally 0.5 to 24 hours, preferably 1 to 16 hours.

The reduction reaction to the quaternary salt tetrahydropyridine ring thus obtained is carried out using a metal hydride in an inert solvent. For example, the reaction can be performed using sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium aluminum hydride, or the like. Preferably, sodium borohydride is used. As the reaction solvent, lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and hydrocarbons such as benzene and toluene can be used alone or as a mixture. The reaction temperature is usually about -100 ° C to 40 ° C.
C., preferably at about -80.degree. C. to 25.degree.
The reaction time is generally 5 minutes to 10 hours, preferably 10 minutes.
Minutes to 5 hours. The amount of the reducing agent to be used is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the quaternary salt.

In the reduction reaction of the quaternary salt, a dihydropyridine ring, which is one of the target compounds of the present invention, may be obtained depending on the kind of the compound. Can further convert to a reduced tetrahydropyridine ring. When the ring A is a tetrahydropyridine ring and the nitrogen atom has a hydrogen atom, a compound in which a W group has been introduced into the nitrogen atom can be obtained using the above-mentioned alkylating agent (XII). This alkylation reaction can be carried out in the same manner as in the production of compound (I) by the reaction of compounds (X) and (XI) described above. Further, the compound in which the ring A is a quaternary salt of a pyridine ring is subjected to an oxidation reaction,
Compounds in which the ring is a pyridone ring can also be prepared.
The oxidation reaction can be carried out, for example, by a known method [EA Prill et al., Organic Synthetic Sheath (O.
rganic Syntheses), Vol. 2, p. 419 (1957)
Year)) or a method based on it.

When ring B is a heterocyclic ring, it can be converted to a non-aromatic heterocyclic ring by subjecting it to the same reduction reaction as described above.

The partial structure of the M ring in the compound (I) of the present invention

Embedded image There -CS-NR ¹ - Compounds that are part thereof is -CO
The compound can be produced by reacting a compound represented by -NR ¹ -with an appropriate sulfide. As the sulfide used in this reaction, for example, phosphorus pentasulfide, Lowesson reagent and the like are used. This reaction is usually performed in a solvent such as dichloromethane, chloroform, dioxane, tetrahydrofuran, benzene, and toluene under anhydrous conditions. The amount of sulfide used is at least equimolar, preferably 2 to 5
And the reaction temperature is in the range of 20 ° C to 120 ° C. The reaction time varies depending on the type of the starting compound or sulfide, the reaction temperature and the like, but is usually 1 to 8 hours.

When the compound (I) or a salt thereof produced by the above method contains a lower (C _1-6 ) alkoxy group in the ring represented by ring A, ring B and ring C, if necessary, this may be added to, for example, By reacting with boron bromide or the like, it can be converted to a hydroxyl group. This reaction is usually carried out in a solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, benzene and toluene, hydrocarbons, etc.) at about -20 ° C to 80 ° C, preferably about 0 ° C.
C. to 30.degree. C., and the amount of boron tribromide used is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per lower alkoxy group. Reaction time is usually 1
5 minutes to 24 hours, preferably 30 minutes to 12 hours
Time. When the compound (I) or a salt thereof produced by the above method contains a hydroxyl group in the ring represented by A ring, B ring and C ring, if necessary, the compound is subjected to an alkylation or acylation reaction. , Respectively, can be converted to an alkoxy or acyloxy group. The alkylation reaction is carried out in a solvent (for example, alcohols such as methanol, ethanol and propanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran, ketones such as acetone, and amides such as N, N-dimethylformamide). In the presence of a base (eg, an organic base such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide). And optionally substituted alkane halides (eg, chloride, bromide, iodide, etc.), sulfates or sulfonic acid esters (eg, methanesulfonate, p-toluenesulfonate, benzenesulfonate, etc.). It is performed by reacting the alkylating agent. The reaction temperature is usually -10 ° C to 100
° C, preferably about 0 ° C to 80 ° C. The amount of the alkylating agent to be used is about 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

The acylation reaction is carried out by reacting a desired carboxylic acid or a reactive derivative thereof. This reaction differs depending on the type of the acylating agent and the type of the starting phenolic derivative, but is usually a solvent (for example, benzene, toluene, ethyl ether, ethyl acetate, chloroform,
Dichloromethane, dioxane, tetrahydrofuran,
The reaction is carried out in hydrocarbons such as N, N-dimethylformamide and pyridine, ethers, esters, halogenated hydrocarbons, amides, aromatic amines and the like, and an appropriate base (for example, sodium hydrogen carbonate,
Bicarbonate such as potassium bicarbonate, sodium carbonate,
Carbonates such as potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and aromatic amines such as pyridine). As the reactive derivative of the carboxylic acid, an acid anhydride, a mixed acid anhydride, an acid halide (eg, chloride, bromide) and the like are used. The amount of the acylating agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction temperature is usually 0 ° C to 150 ° C, preferably about 10 ° C to 100 ° C. The reaction time is generally 15 minutes to 12 hours, preferably 30 minutes to 6 hours.

In the compound (I) of the present invention or a salt thereof, when E is combined with R ¹ or R ² to form a Z ring or a Z ′ ring, for example,

Embedded image [Wherein L ′ ″ represents a leaving group, R ^1a and R ^2a each represent a divalent group formed by removing one hydrogen atom from R ¹ and R ² , and other symbols represent Is equivalent to Or a salt thereof, by subjecting the compound to a cyclization reaction to close the ring. The compound (Ia) described above as a preferable example of the compound (I) is a compound represented by the formula (XIII) to (XV) or a salt thereof instead of

Embedded image [Wherein the symbols have the same meanings as described above. ] (XIII ') to (XV') or a salt thereof. The compound (Ib) described as a preferred example of the compound (I) is the compound (XI)
II) or (XV) or their salts in place of the formula

Embedded image [Wherein the symbols have the same meanings as described above. ] (XIII ") to (XV") or a salt thereof. Compound (XIII)
Or (XV), (XIII ') or (XV') and (XII
Examples of the leaving group L "" of I ") to (XV") include, for example, a halogen atom (for example, chlorine, bromine, iodine atom and the like) or a substituted sulfonyloxy group (for example, methanesulfonyloxy, ethanesulfonyl) Oxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.). Compounds (XIII) to (XV),
(XIII ') to (XV') and (XIII '') to (X
V ″) may be used as a free compound or may be subjected to the reaction in the form of a salt thereof (eg, an alkali metal salt such as lithium, sodium, potassium, etc.). The reaction is usually performed in a solvent inert to the reaction. As the solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide Is preferably used.

The addition of a base favors the reaction. Examples of such a base include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and alkali metals such as sodium carbonate and potassium carbonate). Metal carbonates, alkali metal hydrides such as sodium hydride, potassium hydride, alkoxides such as sodium amide, sodium methoxide, and sodium ethoxide; organic bases (amines such as trimethylamine, triethylamine, and diisopropylethylamine);
Preferred are cyclic amines such as pyridine. In addition,
In the cyclization reaction, instead of using a base, a compound (XI
II) to (XV), (XIII ') to (XV') and (XI
II ″) to (XV ″) may be converted to a salt with a base (eg, the above-mentioned alkali metal salt, alkaline earth metal salt, etc.) and reacted. The amount of the base depends on the compound (XIII) used.
Or (XV), (XIII ') or (XV') and (XII
I ″) to (XV ″), the type of the solvent, and other reaction conditions, and usually, the compounds (XIII) to (X
V), (XIII ′) to (XV ′) and (XIII ″) to (XV ″) are each 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol. The reaction temperature is, for example, about-
The reaction temperature is in the range of 50 ° C. to 200 ° C., preferably about −20 ° C. to 150 ° C., and the reaction time is from compound (XIII) to (X
V), (XIII ′) to (XV ′) and (XIII ″) to (XV ″), or the salt thereof, the reaction temperature, etc., for example, for 1 to 72 hours, preferably 1 to 2 hours.
It is about 4 hours.

The partial structure of the ring Z or the ring Z ′ formed by bonding R ¹ or R ² and E is represented by —R ^1a —E— or —R ^2a
-E- (each symbol is as defined above) is an oxyalkylene group -O- (CH ₂ ) q ^a- (q ^a is an integer of 0 to 5) or an iminoalkylene group -NH- (CH ₂ )
A compound which is q ^a- (q ^a is as defined above) is represented by R
^Leaving group L substituted on ring M without via ^1a or R ^2a
and a (such as the leaving group L, a nitrogen atom in a substituent may amide group which may have a such as a halogen atom), the R ⁵ (R ⁵ where E is NR ⁵ as defined above ) With a reactive group (for example, an active hydrogen atom such as a hydroxyl group, an amino group, or a mono-C _1-6 alkylamino group) according to the above-mentioned method.

When the compound (I) is obtained in a free state by the above-mentioned method, an inorganic acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (eg, methanesulfonic acid, benzene, etc.) can be used in a conventional manner. Sulfonic acid, toluene sulfonic acid,
Oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium, etc.) or organic bases (eg, trimethylamine, triethylamine, pyridine) , Picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, etc.), and when compound (I) is obtained in the form of a salt, It can also be converted into the free form or other salts according to the method. The target compound (I) or a salt thereof obtained by the above method can be purified and collected by using a separation and purification means known per se (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).

Compounds (VIII) to (XV), (VIII '), (IX'), which are starting compounds of the compound (I) of the present application,
(IX ''), (X '), (XI'), (XIII '), (XIII''),
(XIV ′), (XIV ″), (XV ′) and (XV ″) are, for example, EP-A-566069, EP-A-585913, EP-A-634402,
It is produced by the method described in EP-A-652218 and EP-A-733632. Compounds (VIII) to (XI),
(XIII) to (XV), (VIII '), (IX'), (I
X ''), (X '), (XI'), (XIII '), (XIII''), (X
IV ′), (XIV ″), (XV ′) and (XV ″) may form a salt, for example, an inorganic acid (eg, hydrochloric acid, phosphoric acid, hydrogen bromide) Acid, sulfuric acid, etc.) or organic acid (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfone) Acid and the like). Further, when these compounds have an acidic group such as —COOH, an inorganic base (for example, an alkali metal or alkaline earth metal such as sodium, potassium, calcium, or magnesium, ammonia, or the like) or an organic base (for example, triethylamine or the like) And a tri-C _1-3 alkylamine of the formula (I). In each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the desired compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the amino-protecting group include, for example, an optionally substituted C _1-6 alkylcarbonyl (eg, formyl,
Methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.),
For example, phenyloxycarbonyl (eg, benzooxycarbonyl), C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl), trityl, phthaloyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used. And the number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) , Phenyl, trityl, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the protecting group for the hydroxyl group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, n-propyl, i-propyl, n
- butyl, tert- butyl, etc.), phenyl, C _7-10 aralkyl (e.g., benzyl etc.), C _1-6 alkylcarbonyl (e.g., formyl, methylcarbonyl, ethyl-carbonyl), phenyloxycarbonyl (e.g., benzoxy Carbonyl), C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl), pyranyl, furanyl, silyl and the like.
As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used. Or about four.

As a method for removing the protecting group, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium A method of treating with fluoride, palladium acetate or the like is used. The compound (I) obtained by the above method can be isolated and purified by a usual separation means such as recrystallization, distillation, chromatography and the like. When the compound (I) thus obtained is obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto (eg, neutralization, etc.) Can be converted into a free form or another salt by a method known per se or a method analogous thereto.

The compound (I) of the present invention or a salt thereof has an excellent tachykinin receptor antagonistic action, particularly an SP receptor antagonistic action. Capsaicin is the main stimulant of pepper, and SP, neurokinin A (NKA) and calcitonin gene-related peptide (C) among primary sensory nerves
C-fiber containing GRP)
Is known as a substance that selectively stimulates and releases their endogenous neuropeptides. From such a thing,
Capsaicin-induced suppression of vascular permeability enhancement has been used as an evaluation system for SP receptor antagonism in vivo. The compound (I) of the present invention or a salt thereof suppressed the enhancement of vascular permeability in the trachea of guinea pigs induced by capsaicin. The compound (I) or a salt thereof of the present invention has low toxicity and is safe. Therefore, the compound (I) of the present invention or a salt thereof having an excellent SP receptor antagonistic activity can be used for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) , Inflammatory or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, rheumatoid arthritis,
Osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, and diseases of the central nervous system [eg, schizophrenia, Parkinson's disease, psychosomatic disease, dementia ( For example, Alzheimer's disease, etc.), digestive disorders [eg, irritable bowel disease, ulcerative colitis, Crohn's disease, urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori etc.) (eg, Helicobacter pylori etc.) , Gastritis, gastric ulcer, etc.), vomiting, urinary abnormalities (eg, pollakiuria, urinary incontinence, etc.), cardiovascular diseases (eg, angina, hypertension, heart failure, thrombosis, etc.) and safe prevention of immune abnormalities, etc. It is useful as a therapeutic agent. In particular, the compound (I) of the present invention or a salt thereof is useful as a tachykinin receptor antagonist, an agent for improving dysuria such as pollakiuria and urinary incontinence, and a therapeutic agent for these dysuria.

The preparation containing the compound (I) of the present invention or a salt thereof may be any of solid preparations such as powders, granules, tablets and capsules, and liquid preparations such as syrups, emulsions and injections. The prophylactic / therapeutic preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulating, tableting, coating, sterilizing treatment, emulsification, etc., depending on the form of the preparation.
In addition, regarding the production of the preparation, for example, each section of the Japanese Pharmacopoeia Act general provisions of the preparation can be referred to. In the preparation of the present invention, the content of compound (I) or a salt thereof varies depending on the form of the preparation.
%, Preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.

When the compound (I) of the present invention or a salt thereof is used as the above-mentioned drug, it may be used as it is or as an appropriate pharmacologically acceptable carrier such as an excipient (eg,
Starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin,
Polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, calcium carboxymethylcellulose, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), Additives (stabilizer, preservative, colorant, fragrance, dissolution aid, emulsifier,
Buffers, isotonic agents, etc.) and orally or parenterally in the form of solids such as powders, fine granules, granules, tablets, capsules or liquids such as injections. Can be administered. The dose varies depending on the type of compound (I) or a pharmaceutically acceptable salt thereof, the route of administration, symptoms, age of the patient, and the like. For example, when administered orally to an adult patient with dysuria, the daily dose Weight 1kg
Per compound (I) or a salt thereof,
50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg can be divided and administered in 1 to 3 times.

The compound (I) of the present invention or a salt thereof can be used by being appropriately mixed with other pharmaceutically active ingredients in an appropriate amount. Examples of such active ingredients include central nervous system drugs (eg, imipramine, benzodiazepines, etc.), anticholinergic drugs (eg, oxybutynin, etc.), α ₁ -receptor blockers (eg, tamsulosin, etc.) , Muscle relaxants (eg, baclofen, etc.), potassium channel openers (eg, nicorandil, etc.), calcium channel blockers (eg, nifedipine, etc.).

[0085]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to examples and reference examples. However, the present invention is not limited by the examples, and May be changed.

Elution in column chromatography in Reference Examples and Examples was performed by TLC (Thin
It was performed under observation by Layer Chromatography (thin layer chromatography). In TLC observation, TLC
Using 60F ₂₅₄ Merck (Merck) manufactured as a plate, it was used as a developing solvent, the solvent used as an elution solvent in column chromatography. In addition, U
A V detector was employed. As silica gel for column chromatography, silica gel 60 (70 manufactured by Merck) is used.
-230 mesh). Room temperature is usually about 1
Meaning a temperature between 0 ° C and 35 ° C. Further, sodium sulfate or magnesium sulfate was used for drying the extract.

The meanings of the abbreviations in the examples and reference examples are as follows. NMR: nuclear magnetic resonance spectrum EI-MS: electron impact mass spectrometry spectrum SI-MS: secondary electron ion mass spectrometry spectrum DMF: dimethylformamide, THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, Hz: hertz, J: coupling constant, m: multiplet, q:
Quartet, t: triplet, d: doublet,
s: singlet, b: broad, like: approximation.

[0088]

【Example】

Reference Example 1 (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine hydrochloride and (R) -1- [3,
5-bis (trifluoromethyl) phenyl] ethylamine hydrochloride (±) -N-benzyloxycarbonyl-1- [3,5
-Bis (trifluoromethyl) phenyl] ethylamine using an optically active column (CHIRALCEL OD20mmfφ2
Using 50 mm), optical isomers ((R) -form and (S) -form) were separated (mobile phase: hexane / isopropanol = 95).
/ 5, flow rate: 8.0 ml / min). Each of the obtained compounds was subjected to catalytic reduction in the presence of Pd-C, and then treated with 4N hydrochloric acid-ethyl acetate to give the title compound as colorless crystals. (S) field [absolute configuration is based on literature values (Simeon T, et al., J. A.
m. Chem. Soc., 112,5741 (1990); (S) form: [a] _D :
−9.8 ° (neat, 0.5 dm), 71% ee) was determined by comparing the sign of the optical rotation. Melting point: about 220 ° C. (sublimation) (recrystallized from ethyl alcohol-hexane) NMR (200 MHz, DMSO-d ₆ ) ppm: 1.58 (3H, d, J = 6.6 H)
z), 4.68 (1H, m), 8.14 (1H, s), 8.34 (2H, s), 8.81
(3H, m) Elemental analysis: C ₁₀ H ₁₀ NClF ₆ Calculated (%): C 40.90, H 3.43, N 4.77 Actual (%): C 40.78, H 3.50, N 4.72 [α] _D :- 3.3 ° (c = 0.250, MeOH). (R) form Melting point: about 220 ° C. (sublimation) (recrystallized from ethyl alcohol-hexane) NMR (200 MHz, DMSO-d ₆ ) ppm: 1.58 (3H, d, J = 6.6 H)
z), 4.68 (1H, m), 8.14 (1H, s), 8.34 (2H, s), 8.81
(3H, m) Elemental analysis: C ₁₀ H ₁₀ NClF ₆ -1 / 2H ₂ O Calculated (%): C 39.69, H 3.66, N 4.63 Observed (%): C 39.36, H 3.52, N 4.63 [Α] _D : + 3.2 ° (c = 0.252, MeOH). Example 1 7,8-Dihydro-7-methyl-5- (4-methylphenyl) -8-oxo-N- [1 (S) -phenylethyl] -1,7-naphthyridine-6-carboxamide

Embedded image 7,8-dihydro-7-methyl-5- (4-methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxylic acid (590 mg), DMF (catalytic amount), thionyl chloride (0.74 ml) And 1,2-dichloroethane (2
(0 ml) was heated under reflux for 3 hours, and then the solvent was distilled off. After the residue was dissolved in 1,2-dichloroethane (30 ml), (S) -1-phenylethylamine (0.
31 ml) and triethylamine (0.84 ml) were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent, the precipitated crystals were collected by filtration and washed sequentially with water, ethyl ether and isopropyl ether to give the title compound as colorless crystals (530 mg). Melting point: 287-288 ° C. (recrystallized from methanol-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.25 (3H, d, J = 7.0 H)
z), 2.44 (3H, s), 3.47 (3H, s), 5.01 (1H, m), 7.0-
7.6 (12H, m), 8.61 (1H, m) Elemental analysis: C ₂₅ H ₂₃ N ₃ O ₂ -1 / 2H ₂ O Calculated (%): C 73.87, H 5.95, N 10.34 Actual measured (% ): C 73.67, H 5.71, N 10.19.

Example 2 7,8-Dihydro-N, 7-dimethyl-5- (4-methylphenyl) -8-oxo-N- [1 (S) -phenylethyl] -1,7-naphthyridine-6 -Carboxamides (axial asymmetric isomers I and II)

Embedded image Compound (450 mg) obtained in Example 1 was added to DMF (20 m
l) and sodium hydride (60% oil) (99m
g) was added and the mixture was stirred at 40-50 ° C for 30 minutes. After cooling to 0 ° C., methyl iodide (0.5 ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography on silica gel (ethyl acetate: methanol = 9: 1), separated and purified to give Isomer I (18.6 mg) and Isomer II of the title compound
(142 mg) was obtained as colorless crystals.

Isomer I [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf large] Melting point: 229-231 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 6.8 H
z), 2.39 (3H, s), 2.45 (3H, s), 3.66 (3H, s), 5.86
(1H, q, J = 6.8 Hz), 7.12-7.52 (10H, m), 7.69 (1H,
dd, J = 8.4, 2.0 Hz), 8.90 (1H, dd, J = 4.0, 2.0
Hz) EI-MS m / z : 411 (M +) [(C 26 H 25 N 3
O ₂ ) +] [α] _D : + 36.0 ° (c = 0.1785, MeO
H)

Isomer II [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf small] Melting point: 233-234 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.52 (3H, d, J = 6.8 H
z), 2.40 (3H, s), 2.54 (3H, s), 3.69 (3H, s), 5.82
(1H, q, J = 6.8 Hz), 6.47 (2H, d, J = 7.4 Hz), 7.0
-7.3 (5H, m), 7.35-7.55 (3H, m), 7.62 (1H, dd, J =
8.2, 1.8 Hz), 8.90 (1H, dd, J = 4.4, 1.8 Hz) Elemental analysis: C ₂₆ H ₂₅ N ₃ O ₂ Calculated (%): C 75.89, H 6.12, N 10.21 Actual measurement (%) ): C 75.47, H 6.06, N 10.21 [α] _D : -54.2 ° (c = 0.184, MeO
H).

Example 3 5- (4-methylphenyl) -8-oxo-N- [1
(S) -phenylethyl] -8H-pyrano [3,4-
b] pyridine-6-carboxamide

Embedded image 5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxylic acid (0.8
5 g), DMF (catalytic amount), thionyl chloride (1.0 m
After a mixture of 1) and 1,2-dichloroethane (30 ml) was heated under reflux for 2 hours, the solvent was distilled off. After the residue was dissolved in THF (30 ml), (S) -1-phenylethylamine (0.47 ml) and triethylamine (1.27 ml) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed successively with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried, and then the solvent was distilled off to give the title compound as colorless crystals (0.95%).
g). Melting point: 168-169 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.51 (3H, d, J = 6.8 H)
z), 2.44 (3H, s), 5.16 (1H, m), 7.1-7.4 (10H, m),
7.56 (2H, m), 8.93 (1H, dd, J = 4.0, 2.0 Hz) Elemental analysis: Calculated (%) as C ₂₄ H ₂₀ N ₂ O ₃ : C 74.98, H 5.24, N 7.29 Actual measurement ( %): C 74.67, H 5.10, N 7.30.

Example 4 7,8-Dihydro-7- (4-hydroxybutyl) -5
-(4-methylphenyl) -8-oxo-N- [1
(S) -phenylethyl] -1,7-naphthyridine-6
-Carboxamide

Embedded image Compound (0.90 g) obtained in Example 3 in THF (15 m
l) 4-Amino-1-butanol (0.3 ml) was added to a solution of -methanol (5 ml), and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off from the reaction mixture, and toluene (40 ml) and 1,8-diazabicyclo [5.4.
0] -7-undecene (DBU) (0.3 ml) was added and the mixture was refluxed for 2 hours. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and saturated saline. After drying the organic layer, the solvent was distilled off to obtain the title compound as a white powder (1.03 g). NMR (200MHz, CDCl ₃ ) ppm: 1.19 (3H, d, J = 6.4 H
z), 1.43 (2H, m), 1.7-2.0 (2H, m), 2.44 (3H, s),
3.52 (2H, m), 3.7-4.1 (2H, m), 4.95 (1H, m), 7.0-7.
4 (10H, m), 7.50 (2H, dd, J = 8.4, 2.0 Hz), 8.62
(1H, dd, J = 4.0, 2.0 Hz).

Example 5 8,9,10,11-Tetrahydro-5- (4-methylphenyl) -7- [1 (S) -phenylethyl] -7H
-[1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-dione (axially asymmetric isomers I and I
I)

Embedded image Compound (1.03 g) obtained in Example 4, triethylamine (1.89 ml), methanesulfonyl chloride (1.05 g)
ml) and THF (30 ml) at room temperature for 15 minutes.
After stirring for 20 minutes, saturated aqueous sodium hydrogen carbonate (20 m
l) was added and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with diluted hydrochloric acid and saturated saline, dried, and the solvent was distilled off. After the residue was dissolved in THF (50 ml), sodium hydride (60% oil) (530 mg) was added, and the mixture was heated under reflux for 2 hours. . The reaction mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate and saturated saline, dried, and the solvent is distilled off to give the isomer II of the title compound.
Was obtained as colorless crystals (120 mg). The solvent of the mother liquor was distilled off, and the residue was subjected to column chromatography using silica gel (ethyl acetate: methanol = 9: 1), separated and purified to obtain the isomer I of the title compound as colorless crystals (75 mg). Was done.

Isomer I [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf large] Melting point: 155-157 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.75 (1H, m), 1.15-1.40
(1H, m), 1.29 (3H, d, J = 7.0Hz), 1.6-2.0 (2H, m),
2.44 (3H, s), 3.35-3.60 (3H, m), 5.04 (1H, dd, J
= 14, 6.0 Hz), 5.73 (1H, q, J = 7.0 Hz), 6.97 (1H,
d, J = 7.6 Hz), 7.15-7.50 (9H, m), 7.61 (1H, dd,
J = 8.2, 1.6 Hz), 8.88 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₈ H ₂₇ N ₃ O ₂ Calculated (%): C 76.86, H 6.22, N9.60 Value (%): C 76.53, H 6.11, N 9.58 [α] _D : −174.2 ° (c = 0.935, MeO)
H)

Isomer II [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf small] Melting point: 253-254 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.5-2.0 (3H, m), 1.67 (3
H, d, J = 7.4 Hz), 2.18 (1H, m), 2.50 (3H, s), 2.9
-3.3 (2H, m), 3.61 (1H, m), 5.17 (1H, dd, J = 13,
6.2 Hz), 5.75 (1H, q, J = 7.4 Hz), 6.70 (2H, d, J
= 5.8 Hz), 6.90 (1H, d, J = 5.8 Hz), 7.1-7.6 (8H,
m), 8.88 (1H, dd, J = 4.2, 1.6 Hz) [α] _D : + 53.7 ° (c = 0.945, MeO
H).

Example 6 N- [1 (S)-[3,5-bis (trifluoromethyl) phenyl] ethyl] -7,8-dihydro-7-methyl-5- (4-methylphenyl) -8 -Oxo-1,7
-Naphthyridine-6-carboxamide

Embedded image (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine hydrochloride obtained in Reference Example 1 and 7,8-
Dihydro-7-methyl-5- (4-methylphenyl)-
When 8-oxo-1,7-naphthyridine-6-carboxylic acid was used and reacted and treated in the same manner as in Example 1, the title compound was obtained as colorless crystals. Melting point: 197-19
9 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.40 (3H, d, J = 7.0 H)
z), 2.38 (3H, s), 3.07 (1H, m), 3.50 (3H, s), 5.10
(1H, m), 7.05-7.30 (3H, m), 7.36 (1H, d, J = 6.6 H
z), 7.49 (1H, d, J = 8.0 Hz), 7.79 (1H, s), 7.89
(2H, s), 8.13 (1H, d, J = 8.6 Hz), 8.62 (1H, d, J
= 3.2 Hz) Elemental analysis: C ₂₇ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 60.79, H 3.97, N 7.88 Actual (%): C 61.00, H 4.10, N 7.66 [α] _D : -19.0 ° (c = 0.25, CHCl ₃ ).

Example 7 N- [1 (S)-[3,5-bis (trifluoromethyl) phenyl] phenylethyl] -7,8-dihydro-N, 7-dimethyl-5- (4-methylphenyl ) -8
-Oxo-1,7-naphthyridine-6-carboxamide (axial asymmetric isomers I and II)

Embedded image When the compound obtained in Example 6 was reacted and treated in the same manner as in Example 2, isomer I and isomer II of the title compound were obtained as colorless crystals. Isomer I [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf large] Melting point: 194-196 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.94 (3H , d, J = 7.1 H
z), 2.43 (3H, s), 2.46 (3H, s), 3.66 (3H, s), 5.92
(1H, q, J = 7.1 Hz), 7.19 (1H, dd, J = 7.8,1.9 H
z), 7.30 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.
8 Hz), 7.42 (1H, dd, J = 7.8, 1.9 Hz), 7.49 (1H, d
d, J = J = 8.4, 4.3 Hz), 7.71 (1H, dd, J = 8.4, 1.7
Hz), 7.71 (2H, s), 7.83 (1H, s), 8.92 (1H, dd, J
= 4.3, 1.7 Hz) Elemental analysis: C ₂₈ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 61.43, H 4.23, N 7.67 Actual (%): C 61.27, H 4.20, N 7.48 [ α] _D : + 43.7 ° (c = 0.207, CHC
l ₃ ). Isomer II [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf small] Melting point: 164-165 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60 (3H , d, J = 7.1 H
z), 2.35 (3H, s), 2.59 (3H, s), 3.68 (3H, s), 5.88
(1H, q, J = 7.1 Hz), 6.96 (1H, dd, J = 7.8,1.9 H
z), 7.11 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 7.8
Hz), 7.31 (1H, dd, J = 7.8, 1.9 Hz), 7.37 (2H, s),
7.45 (1H, dd, J = 8.4, 4.3 Hz), 7.55 (1H, dd, J =
8.4, 1.7 Hz), 7.78 (1H, s), 8.90 (1H, dd, J = 4.3,
1.7 Hz) Elemental analysis: C ₂₈ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 61.43, H 4.23, N 7.67 Actual (%): C 61.31, H 4.29, N 7.53 [α] _D : -50.9 ° (c = 0.242, CHC
l ₃ ).

Example 8 N- [1 (R)-[3,5-bis (trifluoromethyl) phenyl] ethyl] -7,8-dihydro-7-methyl-5- (4-methylphenyl) -8 -Oxo-1,7
-Naphthyridine-6-carboxamide

Embedded image (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethylamine hydrochloride obtained in Reference Example 1 and 7,8-
Dihydro-7-methyl-5- (4-methylphenyl)-
When 8-oxo-1,7-naphthyridine-6-carboxylic acid was used and reacted and treated in the same manner as in Example 1, the title compound was obtained as colorless crystals. Melting point: 197-19
9 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.40 (3H, d, J = 7.0 H)
z), 2.38 (3H, s), 3.07 (1H, m), 3.50 (3H, s), 5.10
(1H, m), 7.05-7.30 (3H, m), 7.36 (1H, d, J = 6.6 H
z), 7.49 (1H, d, J = 8.0 Hz), 7.79 (1H, s), 7.89
(2H, s), 8.13 (1H, d, J = 8.6 Hz), 8.62 (1H, d, J
= 3.2 Hz) Elemental analysis: C ₂₇ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 60.79, H 3.97, N 7.88 Actual (%): C 60.33, H 4.18, N 8.00 [α] _D : + 18.2 ° (c = 0.248, CHC
l ₃ ).

Example 9 N- [1 (R)-[3,5-bis (trifluoromethyl) phenyl] phenylethyl] -7,8-dihydro-N, 7-dimethyl-5- (4-methylphenyl ) -8
-Oxo-1,7-naphthyridine-6-carboxamide (axial asymmetric isomers I and II)

Embedded image When the compound obtained in Example 8 was reacted and treated in the same manner as in Example 2, isomer I and isomer II of the title compound were obtained as colorless crystals. Isomer I [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf large] Melting point: 194-196 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.94 (3H , d, J = 7.1 H
z), 2.43 (3H, s), 2.46 (3H, s), 3.66 (3H, s), 5.92
(1H, q, J = 7.1 Hz), 7.19 (1H, dd, J = 7.8,1.9 H
z), 7.30 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.
8 Hz), 7.42 (1H, dd, J = 7.8, 1.9 Hz), 7.49 (1H, d
d, J = J = 8.4, 4.3 Hz), 7.71 (1H, dd, J = 8.4, 1.7
Hz), 7.71 (2H, s), 7.83 (1H, s), 8.92 (1H, dd, J
= 4.3, 1.7 Hz) Elemental analysis: C ₂₈ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 61.43, H 4.23, N 7.67 Actual (%): C 61.43, H 4.24, N 7.48 [ α] _D : −43.7 ° (c = 0.212, CHC
l ₃ ). Isomer II [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf small] Melting point: 164-165 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60 (3H , d, J = 7.1 H
z), 2.35 (3H, s), 2.59 (3H, s), 3.68 (3H, s), 5.88
(1H, q, J = 7.1 Hz), 6.96 (1H, dd, J = 7.8,1.9 H
z), 7.11 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 7.8
Hz), 7.31 (1H, dd, J = 7.8, 1.9 Hz), 7.37 (2H, s),
7.45 (1H, dd, J = 8.4, 4.3 Hz), 7.55 (1H, dd, J =
8.4, 1.7 Hz), 7.78 (1H, s), 8.90 (1H, dd, J = 4.3,
1.7 Hz) [α] _D : + 51.1 ° (c = 0.242, CHC
l ₃ ).

Example 10 (±) -7,8-Dihydro-N- [1- (3,5-dimethoxyphenyl) ethyl] -7-methyl-5- (4-
Methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxamide

Embedded image (±) -1- (3,5-dimethoxyphenyl) ethylamine and 7,8-dihydro-7-methyl-5- (4-methylphenyl) -8-oxo-1,7-naphthyridine-6
When the reaction and treatment were carried out in the same manner as in Example 1 using carboxylic acid, the title compound was obtained as colorless crystals. Melting point: 200-201 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.14 (3H, d, J = 6.8 H)
z), 2.41 (3H, s), 3.51 (3H, s), 3.77 (6H, s), 4.91
(1H, m), 6.35 (1H, t, J = 2.2 Hz), 6.41 (2H, d, J
= 2.2 Hz), 7.03 (1H, d, J = 8.8 Hz), 7.18-7.32 (4
H, m), 7.47 (2H, m), 8.68 (1H, dd, J = 4.4, 1.8 Hz) Elemental analysis: C ₂₇ H ₂₇ N ₃ O ₄ Calculated (%): C 70.88, H 5.95, N 9.18 Found (%): C 70.68, H 5.99, N 9.24.

Example 11 (±) -7,8-Dihydro-N- [1- (3,5-dimethoxyphenyl) ethyl] -N, 7-dimethyl-5
(4-methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxamide (axially asymmetric isomers I and I
I)

Embedded image When the compound obtained in Example 10 was reacted and treated in the same manner as in Example 2, isomer I and isomer II of the title compound were obtained as colorless crystals. Isomer I [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf large] Melting point: 208-209 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 7.4 H
z), 2.41 (3H, s), 2.44 (3H, s), 3.68 (3H, s), 3.76
(6H, s), 5.78 (1H, m), 6.39 (3H, s like), 7.15 (1
H, dd, J = 8.2, 1.2 Hz), 7.27-7.44 (3H, m), 7.47
(1H, dd, J = 8.2, 4.4 Hz), 7.70 (1H, dd, J = 8.2,
1.4 Hz), 8.90 (1H, dd, J = 4.4, 1.4 Hz) Elemental analysis: C ₂₈ H ₂₉ N ₃ O ₄ Calculated (%): C 71.32, H 6.20, N 8.91 Actual (%): C 71.28, H 6.23, N 8.76. Isomer II [TLC, SiO ₂ (ethyl acetate: methanol = 9: 1); Rf small] Melting point: 161-163 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.48 (3H , d, J = 6.8 H
z), 2.43 (3H, s), 2.49 (3H, s), 3.67 (3H, s), 3.75
(6H, s), 5.68 (1H, m), 5.91 (2H, d, J = 2.2Hz), 6.
32 (1H, t, J = 2.2 Hz), 6.97 (1H, dd, J = 7.8, 1.8
Hz), 7.14 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J =
7.8 Hz), 7.40 (1H, dd, J = 7.8, 1.8 Hz), 7.44 (1H,
dd, J = 8.4, 4.4 Hz), 7.61 (1H, dd, J = 8.4, 1.8
Hz), 8.89 (1H, dd, J = 4.4, 1.8 Hz) Elemental analysis: C ₂₈ H ₂₉ N ₃ O ₄ Calculated (%): C 71.32, H 6.20, N 8.91 Actual (%): C 70.36, H 6.22, N 8.99.

Example 12 (±) -7,8-Dihydro-N- [1- (2-methoxyphenyl) ethyl] -7-methyl-5- (4-methylphenyl) -8-oxo-1,7 -Naphthyridine-6
-Carboxamide

Embedded image Using (±) -1- (2-methoxyphenyl) ethylamine and 7,8-dihydro-7-methyl-5- (4-methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxylic acid, When the reaction and treatment were carried out in the same manner as in Example 1, the title compound was obtained as colorless crystals. Melting point: 250-251 ° C. (recrystallized from ethyl acetate-methanol-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.08 (3H, d, J = 7.0 H)
z), 2.32 (3H, s), 3.65 (3H, s), 3.80 (3H, s), 5.12
(1H, m), 6.74-6.90 (3H, m), 6.99 (1H, dd, J = 7.4,
1.8 Hz), 7.10-7.28 (5H, m), 7.41 (1H, dd, J = 8.2,
4.4 Hz), 7.62 (1H, dd, J = 8.2, 1.8 Hz), 8.84 (1H,
dd, J = 4.4, 1.8 Hz) Elemental analysis: C ₂₆ H ₂₅ N ₃ O ₃ Calculated (%): C 73.05, H 5.89, N 9.83 Actual (%): C 72.73, H 5.94, N 9.83 .

Example 13 (±) -7,8-Dihydro-N- [1- (2-methoxyphenyl) ethyl] -N, 7-dimethyl-5- (4
-Methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxamide (mixture of axially asymmetric isomers I and I)

Embedded image When the compound obtained in Example 12 was reacted and treated in the same manner as in Example 2, a mixture of the isomers I and II of the title compound (isomer I: isomer II = 1: 1) was obtained as colorless crystals. Was. Melting point: 214-217 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H × 1/2, d, J = 7)
0 Hz), 1.46 (3H × 1/2, d, J = 7.4 Hz), 2.29 (3H × 1 /
2, s), 2.42 (3H × 1/2, s), 2.44 (3H × 1/2, s), 2.72
(3H × 1/2, s), 3.61 (3H × 1/2, s), 3.64 (3H × 1/2,
s), 3.70 (3H × 1/2, s), 3.80 (3H × 1/2, s), 5.64 (1H
× 1/2, m), 5.94 (1H × 1/2, m), 6.7-7.5 (9H, m), 7.57
(1H × 1/2, dd, J = 8.2, 1.6 Hz), 7.68 (1H × 1/2, d
d, J = 8.2, 1.6 Hz), 8.88 (1H, m) Elemental analysis: C ₂₇ H ₂₇ N ₃ O ₃ Calculated (%): C 73.45, H 6.16, N 9.52 Actual (%): C 73.13, H 6.29, N 9.44.

Formulation Example 1 (1) Compound of Example 2 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl methylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg 10.0 mg of the compound obtained in Example 2 and 60.0 lactose
mg and 35.0 mg of corn starch,
After granulation using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), the mixture was dried at 40 ° C. and sieved. The obtained granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting uncoated tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain coated tablets.

Formulation Example 2 (1) 10.0 mg of the compound of Example 1 (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg 10.0 mg of the compound obtained in 2 and 3.0 mg of magnesium stearate were added to an aqueous solution of soluble starch in 0.
After granulation with 07 ml (7.0 mg as soluble starch), it was dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give tablets.

[0107]

The compound of the present invention or a salt thereof has excellent tachykinin receptor antagonism and can be widely used as a drug such as a therapeutic drug for dysuria.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/435 ACJ A61K 31/435 ACJ ACP ACP ACV ACV AED AED C07D 471/14 102 C07D 471/14 102 491/052 491/052

Claims (14)

[Claims] (1) Formula (1) Wherein the M ring has a partial structure -CO-NR ^1- (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent), -CS-NR ¹
— (R ¹ is as defined above), —CO—O— or —N ま た は CR ² — (R ² is a hydrogen atom, a hydrocarbon group which may have a substituent, Represents an optionally substituted hydroxy group or an optionally substituted amino group), D represents a divalent group, and E represents -NR
^5- (R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and may be bonded to R ¹ or R ² to form a heterocyclic ring which may have a substituent. good), - O-or indicates -S (O) n- (n is 0, 1 or 2), or R ^a and R ^b form a ring a bonded, or the same or different and each is hydrogen Ring A, ring B and ring C are the same or different and each may be a homo- or heterocyclic ring which may have a substituent, and Q represents a substituted linear group; Shows a lower alkylene group. Or a salt thereof. 2. The M ring has a partial structure. The compound according to claim 1, which has -CO-NR ^1- (R ¹ has the same meaning as described in claim 1). 3. The compound according to claim 1, wherein R ^a and R ^b combine to form a ring A. 4. The compound according to claim 1, wherein the ring C is a benzene ring which may have a substituent. 5. The compound according to claim 1, wherein D is a C _1-3 alkylene group optionally substituted with an oxo group or a thioxo group. 6. Q is a compound of the formula [Wherein, R ³ and R ⁴ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent. The compound according to claim 1, which is a group represented by the formula: 7. E represents -NR ^5- (R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent), and R
^{5. A} compound according to claim 1, wherein ⁵ is combined with R ¹ or R ² to form a heterocyclic ring.
A compound as described. 8. A compound according to claim 1, wherein E is -NR ^5- (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent),
The compound according to claim ^{1, wherein 5} does not bind to R ¹ or R ² . 9. A compound of the formula [Wherein, L represents a leaving group, and other symbols are as defined in claim 1
The meaning is as described. And a salt thereof or a reactive derivative thereof, and a compound represented by the formula: [Wherein, ring C and E are as defined in claim 1,
R ³ and R ⁴ are as defined in claim 6. Wherein the compound or a salt thereof is reacted. [Wherein the symbols have the same meanings as described above. ] Or a salt thereof. 10. A pharmaceutical composition comprising the compound according to claim 1. 11. A tachykinin receptor antagonist comprising the compound according to claim 1. 12. A substance P receptor antagonist comprising the compound according to claim 1. [13] An agent for improving abnormal urination, comprising the compound according to [1]. 14. An agent for improving asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease or vomiting comprising the compound according to claim 1.