JPH09216823A - Prolactin production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor useful for suppressing puerperal lactation and useful as a preventive/therapeutic agent for galactorrhea, hyperprolactinemic ovulatory disorders, etc., comprising, as active ingredient, a specific condensed cyclic compound (salt) containing at least bicyclic structure. SOLUTION: This prolactin production inhibitor comprises, as active ingredient, a condensed cyclic compound of formula I [W-ring and Y-ring are each (substituted) homycyclic or heterocyclic 5- to 7-membered ring; W-ring is e.g. a group of formula II (R<1a> and R<2a> are each H or a C-, N-, O- or S-mediated group) or formula III (R<3a> -R<6a> are each the same as R<1a> or R<2a> , respectively); Y-ring is a group of formula IV (R<7a> is the same as R<1a> ), etc.] [pref. a compound of formula V (R<13b> is H, an alkoxyl, etc.; R<14b> is H or an alkyl; R<15b> is H or a halogen; R<16b> is an alkoxyl, etc.; R<17b> is carboxyl; (v'), (t') and (u') are each 1-3)]. This inhibitor is useful as a preventive/therapeutic agent for amenorrhea- galactorrhea syndrome, prolactinoma or diencephalic tumor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a prolactin production inhibitor containing a fused ring compound or a salt thereof, which contains at least a fused bicyclic structure. More preferably, the present invention relates to a prolactin production inhibitor containing a thieno [2,3-b] pyridine derivative, a thieno [2,3-d] pyrimidine derivative or salts thereof.

[0002]

BACKGROUND OF THE INVENTION Prolactin is produced and secreted from the anterior pituitary gland, acts on mammary gland tissue, and plays an important role in the initiation and maintenance of lactation, as well as water, electrolyte metabolism, gonadal action, and immunity. It shows various functions such as effects on the system and brain functions. It is recognized that such pituitary prolactin-producing cells have distinctly characteristic properties. For example, the peptide hormones known so far as various pituitary hormone secretion / production stimulating hormones secreted from the hypothalamus include
It has been clearly observed that it acts preferentially and specifically on a specific pituitary hormone-secreting / producing cell in the anterior pituitary. Typically, gonadotropin-releasing hormone {GnRH (Go
nadotropin releasing hormone): Luteinizing hormone-releasi
ng hormone)]} is an anterior pituitary follicle-stimulating hormone [FSH (follicle stimulating hormon
e)], luteinizing hormone [LH (Luteinizing hormon
e)] and the like are preferentially and specifically acting on cells that secrete / produce, but it has not been observed that the cells that produce / secrete prolactin, which is also the anterior pituitary gland, act to secrete prolactin. Among the hormone-secreting / producing cells of the anterior pituitary, it is considered that the cells have completely different characteristics. From these facts as well, in order to control the production / secretion of prolactin, the drug used therefor is at least in the prolactin-producing cells of the pituitary gland, which is said to be clearly distinguishable from other peptide hormone-secreting / producing cells of the pituitary gland. It has to work. By the way, hyperprolactinemia is known as a disease involving excessive production and secretion of prolactin,
It presents with clinical symptoms such as sexual function suppression and milk leakage (Clinical Neuroscience, Vol. 8, No. 4, 1990, Chugai Medical Co., Japan Clinical, Vol. 51 No. 10, 1993, Nippon Clinical Co., Ltd.). As a cause of this hyperprolactinemia, prolactin-secreting pituitary adenoma (prolactinoma) is frequently found,
In addition, functional hyperprolactinemia due to impaired secretion of prolactin inhibiting factor and drug-induced hyperprolactinemia associated with drug administration are also known (Clinical Neuroscience, Vol. 8, No. 4, 1990). ,
Chugai Medical Co., Japan Clinic, Vol. 51, No. 10, 1993, Nippon Clinic). Prolactin is also involved in puerperal milk secretion and milk leakage.

[0003]

[Problems to be Solved by the Invention] Hyperprolactinemia is mainly treated by surgery and drug therapy.
Dopaminergic drugs such as bromocriptine are used as therapeutic drugs, but some problems have been pointed out. First, it is not completely cured by bromocriptine therapy, and after the drug is withdrawn, prolactin levels are re-elevated and adenomas are increased. In addition, gastrointestinal symptoms such as nausea, vomiting, and constipation, and side effects such as orthostatic hypotension and headache are observed. Furthermore, some prolactin adenomas are resistant to bromocriptine. In order to solve such a problem, development of a new prolactin production inhibitor has been desired. Fused bicyclic compounds such as thieno [2,3-
The b] pyridine derivative and the thieno [2,3-d] pyrimidine derivative are known to have excellent gonadotropin-releasing hormone antagonistic activity (PCT International Publication W).
O95 / 28405). By the way, pituitary prolactin-producing cells secrete and produce other peptide hormones of the pituitary, especially FSH and LH.
It is said that it can be clearly distinguished from cells that produce it, and among the peptide pituitary hormone secretory / stimulatory hormones that are actually secreted from the hypothalamus, it shows activity for the GnRH receptor and acts on prolactin-producing cells to produce prolactin. It was not known that it showed secretion. Therefore, it was necessary to develop a new prolactin production inhibitor from a unique viewpoint. Furthermore, in order to treat diseases / diseases and the like caused by prolactin excess as described above, a prolactin production inhibitor that acts specifically on prolactin-producing cells can cure hyperprolactinemia and the like. Since it is possible to reduce side effects, it is a drug that directly suppresses or inhibits prolactin production in pituitary gland and prolactin production in secretory cells, and is highly stable and can be administered orally There is a strong demand for agents, especially non-peptide prolactin production inhibitors.

[0004]

The object of the present invention is to provide an excellent prolactin production inhibitor. In view of the above circumstances, the present inventors have made diligent efforts to find a compound that can be used as a prolactin production inhibitor, and have found that a compound having at least a fused bicyclic structure has an excellent prolactin production inhibitory action. ..
The present inventors have further studied based on this finding and completed the present invention.

That is, the present invention comprises (1) at least containing an optionally substituted fused bicyclic structure of a homo or hetero 5 to 7 membered ring and a homo or hetero 5 to 7 membered ring. A prolactin production inhibitor comprising a characteristic condensed ring compound or a salt thereof, and (2) a condensed ring compound represented by the general formula

Embedded image [In the formula, W ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group, and Y ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group] The prolactin production inhibitor according to the above (1), which is represented by:
(3) W ring is a general formula

Embedded image [Wherein R ^1a and R ^2a may be the same or different and each represents a hydrogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom] (2) Item 4, the prolactin production inhibitor, (4) W ring has the general formula

Embedded image [In the formula, R ^3a , R ^4a , R ^5a and R ^6a may be the same or different and each represents a hydrogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom] The prolactin production inhibitor according to the above (2), wherein (5) the Y ring has the general formula

Embedded image [In the formula, R ^7a may be the same or different, and each of R ^11a and R ^12a may be the same or different; Well, each represents a hydrogen atom or an optionally substituted hydrocarbon residue, and o represents an integer of 1 to 2], and the prolactin according to the above item (2). Production inhibitor,

(6) The Y ring has the general formula

Embedded image [In the formula, R ^4b may be the same or different and each represents a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ^11b represents a hydrocarbon residue which may be substituted. And o represents an integer of 1 to 2] or a group represented by the general formula

Embedded image [Wherein R ^11c and R ^12b may be the same or different and each represent a hydrogen atom or a group through a carbon atom], and the prolactin production inhibitor according to the above (2), (7) The fused ring compound has the general formula (X)

Embedded image [Wherein R ^1e and R ^2e are each a hydrogen atom or a group through which a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom is present, R ^3e is an optionally substituted homologous or heterocyclic group, R ^4e Is hydrogen, a group through a carbon atom, a group through a nitrogen atom, an oxygen atom or a sulfur atom or an optionally substituted heterocyclic group, R ^5e is a group through a hydrogen atom or a carbon atom, and n is 0 to 3 Indicates the integers of. ] The compound (X) represented by the general formula (XX)

Embedded image Wherein R ^1f is (1) a hydrogen atom, (2) a group via a carbon atom, or (3) a formula — (CH ₂ ) n-R ^1f ′ (wherein, R ^1f ′ is a group via a carbon atom or An optionally substituted homo- or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, R ^3f
And R ^4f each represent a group via a carbon atom. ] The compound (XX) represented by the general formula (X)
XX)

Embedded image ^{Wherein, R 1g, R 2g, R} 3g, R 4g, R 6g and R ^{7 g} are the same or different, a hydrogen atom or a carbon atom, a nitrogen atom, a group via an oxygen atom or a sulfur atom, R ^{5 g} is A group via a carbon atom or an optionally substituted homo- or heterocyclic group, and n represents an integer of 0 to 3. However,
R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all simultaneously hydrogen. ] The prolactin production inhibitor according to the above (1), which is a compound (XXX) represented by the following:
(8) The condensed ring compound has the general formula

[Chemical 21] [Wherein, R ^13a may have 1 to 5 substituents and may be the same or different, and each represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom or an alkanoylamino group, and R ^14a represents a hydrogen atom or an alkyl A group represented by R ^15a
May have 1 to 5 substituents and may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, and R ^16a represents 1
Up to 5 substituents, which may be the same or different, may each be a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group, and R ^17a may have 1 or 2 substituents, which may be the same or different. Well, each represents a carboxyl group which may be esterified or amidated, an alkylcarbonyl group, an arylcarbonyl group or an alkyl group which may be substituted, and v, t and u may be the same or different, and 1-4
And the compound represented by the formula [1] above, wherein the prolactin production inhibitor is a compound represented by the above (1),

(9) The fused ring compound has the general formula

Embedded image [In the formula, 1 to 3 R ^13b may be substituted and may be the same or different, and each represents a hydrogen atom, a C _1-6 alkoxy group or an alkanoylamino group, and R ^14b represents a hydrogen atom or a C _{1- 6} alkyl groups, R ^15b may have 1 to 3 substituents and may be the same or different, and hydrogen atom or halogen, R ^16b may have 1 to 3 substituents, and they may be the same or different. R ^17b may be substituted with 1 or 2 hydrogen atoms, halogen or C _1-6 alkoxy, and may be the same or different.
It represents a carboxyl group or an alkylcarbonyl group which may be esterified or amidated, and v ′, t ′ and u ′ may be the same or different and each is 1 to
Which represents an integer of 3] above (1)
The prolactin production inhibitor described in (10), wherein the condensed ring compound is 4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl)-
2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof, the prolactin production inhibitor according to the above (1), (11) condensation The ring compound is 2- (4-acetylaminophenyl) -4,7-dihydro-3- (N-
Methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof, as described in the above item (1). Prolactin production inhibitor, (1
2) The fused ring compound is 5-n-butyryl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl)
-7- (2-Fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof, the prolactin production inhibitor according to the above (1), ( 13) The fused ring compound is 5-benzoyl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2-
(4-methoxyphenyl) -4-oxo-thieno [2,
3-b] pyridine or a salt thereof, the prolactin production inhibitor according to the above (1), and the condensed ring compound (14),
7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2
-(4-isobutyrylaminophenyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine or a salt thereof, the prolactin production inhibitor according to the above (1), (15) condensed ring The compound is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5-isobutyryl-2.
-(4-propionylaminophenyl) -4-oxo-
The prolactin production inhibitor according to the above item (1), which is thieno [2,3-b] pyridine or a salt thereof, and the condensed ring compound (16) is 5-benzoyl-7- (2,6-difluorobenzyl) -4. , 7-Dihydro-3- (N-methyl-
N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b]
The prolactin production inhibitor according to the above (1), which is pyridine or a salt thereof,

(17) A combination of a fused ring compound or a salt thereof with a drug selected from the group consisting of steroidal or nonsteroidal androgen agents or anti-estrogen agents, somatostatin receptor agonists, and antitumor agents. (1) The prolactin production inhibitor according to (1) above, (18) the above-mentioned (1) which is a prophylactic / therapeutic agent for milk leakage, hyperprolactin-induced ovulatory disorder, milk leak amenorrhea syndrome, prolactinoma or diencephalic tumor The prolactin production inhibitor according to (1), and the prolactin production inhibitor according to (1) above, which is (19) a puerperal lactation inhibitor.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the above fused bicyclic structure, the W ring group represents an optionally substituted homo- or hetero 5- to 7-membered ring group. For example, 5 to 7 having at least one (preferably 1 to 2) nitrogen atom, sulfur atom or oxygen atom.
Membered heterocyclic groups. The W ring group is preferably a homo- or hetero 5- or 6-membered ring group. Preferred specific examples of the W ring group include, for example,

Embedded image And a ring group represented by Expressions in these

Embedded image The ring group represented by is preferred. Further equations

Embedded image The ring group represented by is particularly preferable.

The most preferred specific examples of the optionally substituted W ring group include, for example, the general formula

Embedded image Wherein R ^1a and R ^2a may be the same or different;
Each represents a hydrogen atom, or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom], or a ring group represented by the general formula

Embedded image [In the formula, R ^3a , R ^4a , R ^5a and R ^6a may be the same or different and each represents a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom.] And a ring group.

Examples of the homo- or hetero 5- to 7-membered ring group represented by the Y ring group in the above fused bicyclic structure include, for example,
A 5- to 7-membered heterocyclic group having one or more (preferably 1 to 2) nitrogen atoms, sulfur atoms or oxygen atoms is exemplified.
As the Y ring group, a homo or hetero 5- or 6-membered ring group is preferable, and a homo or hetero 6-membered ring group is particularly preferable. Preferred specific examples of the Y ring group include, for example,

Embedded image And a ring group represented by Expressions in these

Embedded image The ring group represented by is preferred. Further equations

Embedded image The ring group represented by is particularly preferable.

The most preferred specific examples of the optionally substituted Y ring group include those represented by the general formula:

Embedded image [Wherein, R ^4b may be the same or different and each represents a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ^11b represents a hydrocarbon group which may be substituted. And o represents an integer of 1 to 2].

Embedded image [Wherein, R ^11c and R ^12b may be the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group]. Examples of the substituent which the condensed ring compound may have include a group having a halogen atom, a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, or a heterocyclic group which may have a substituent. To be

The fused ring compound has the general formula (X)

Embedded image [Wherein, R ^1e and R ^2e each represent a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, R ^3e represents an optionally substituted homo- or heterocyclic group, R ^4e Is a group via a hydrogen, carbon, nitrogen, oxygen or sulfur atom or a heterocyclic group which may be substituted, R ^5e is a group via a hydrogen atom or a carbon atom,
n shows the integer of 0-3, respectively. 4-
Oxothieno [2,3-b] pyridine derivative (X), general formula (XX)

Embedded image Wherein R ^1f is (1) a hydrogen atom, (2) a group via a carbon atom, or (3) a formula — (CH ₂ ) n-R ^1f ′ (wherein, R ^1f ′ is a group via a carbon atom or An optionally substituted homo- or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, R ^3f
And R ^4f each represent a group via a carbon atom. 2,4 (1H, 3H) -dioxothieno [2,3-d] pyrimidine derivative (XX) or the general formula (XXX)

Embedded image ^{Wherein, R 1g, R 2g, R} 3g, R 4g, R 6g and R ^{7 g} are the same or different, a hydrogen atom or a carbon atom, a nitrogen atom, a group via an oxygen atom or a sulfur atom, R ^{5 g} is A group via a carbon atom or an optionally substituted homo- or heterocyclic group, and n represents an integer of 0 to 3. However,
R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all simultaneously hydrogen. And a quinoline derivative (X
XX) is preferred.

In the above formula, the group containing a carbon atom is
For example, each may be substituted, (1) a hydrocarbon group, (2) an acyl group, (3) a carbamoyl group, (4) a heterocyclic group having a bond at a carbon atom, and the like. Five)
Examples also include an optionally esterified or amidated carboxyl group, (6) cyano group, and (7) amidino group. The carboxyl group which may be esterified,
And a group represented by the formula —COO—R ²¹ (in the formula, R ²¹ represents a hydrogen atom, a hydrocarbon group or a heterocyclic group),
Each of these hydrocarbon group and heterocyclic group may be substituted. The carboxyl group which may be amidated is represented by the formula —CO—NR ²² R ²³ (wherein R ²² is
A hydrogen atom, a hydrocarbon group, a heterocyclic group or a group through a sulfur atom is shown. R ²³ represents a hydrogen atom or a hydrocarbon group.
R ²² and R ²³ may form a 5- to 8-membered cyclic amino group together with the adjacent nitrogen atom, and R ²² and R ²³ are
It may be a nitrogen-containing heterocyclic group formed with an adjacent nitrogen atom. ). These hydrocarbon groups, heterocyclic groups, cyclic amino groups and nitrogen-containing heterocyclic groups may be substituted. The optionally amidated carboxyl group may be substituted with 1 to 3 groups similar to the groups which may be substituted with a hydrocarbon group described later.

In the above formula, the group via the nitrogen atom is
For example, (1) nitro group, (2) formula -NR ²⁴ R ²⁵ [wherein R ²⁴
Represents hydrogen, a hydrocarbon group, a hydrocarbon-oxy group, an acyl group,
Hydroxyl group, a heterocyclic group, bicyclic isocyclic group or (wherein, p is an integer of 0 to 2, R ²⁶ represents a hydrocarbon group) wherein -SOp-R ²⁶ fused to a group represented by, R ²⁵ represents hydrogen or a hydrocarbon group, and the group represented by the formula —NR ²⁴ R ²⁵ may form a cyclic amino group or a nitrogen-containing heterocyclic group] and the like. Hydrogen group, hydrocarbon-oxy group, acyl group, hydroxyl group,
The heterocyclic group and the cyclic amino group may each have a substituent. The group via the nitrogen atom may be substituted with the same 1 to 3 groups as the group which may be substituted with the hydrocarbon group described later. In the above formula, examples of the group via an oxygen atom include a group represented by —O—R ²⁷ (wherein R ²⁷ represents a hydrogen atom, a hydrocarbon group, an acyl group or a heterocyclic group), Each of these hydrocarbon group, acyl group and heterocyclic group may have a substituent. In the above formula, examples of the group via a sulfur atom include -S (O) te-R
²⁸ (in the formula, R ²⁸ represents a hydrogen atom, a hydrocarbon group or a heterocyclic group, and te represents an integer of 0 to 2). These hydrocarbon group and the heterocyclic group are each represented by It may have a substituent.

As the above-mentioned hydrocarbon group in the optionally substituted hydrocarbon group and the optionally substituted hydrocarbon-oxy group, the C _1-20 hydrocarbon group is preferable. Examples of the C _1-20 hydrocarbon group include (1) C _1-15 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- Examples thereof include butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc. Among them, C _1-10 is preferable, and C _1-6 alkyl group is particularly preferable.), (2) C _3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like, among which C _3-6 cycloalkyl group is preferable) or C _7-20 bicycloalkyl group (for example, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3,2,1] octyl Bicyclo [3,2,1] nonyl, bicyclo [4,2,2]
1] nonyl, bicyclo [4,3,1] decyl and the like. ), (3) C _2-10 alkenyl group (for example, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-octenyl and the like can be mentioned. The
Of these, a C _2-6 alkenyl group is preferable. ), (4) C _2-10
Alkynyl groups (eg, ethynyl, 2-propynyl,
Examples thereof include isopropynyl, butynyl, t-butynyl and 3-hexynyl, and among them, C _2-6 alkynyl is preferable. ), (5) C _3-10 cycloalkenyl (for example,
Examples thereof include cyclopropenyl, cyclopentenyl, cyclohexenyl and the like, and among them, a C _3-6 cycloalkenyl group is preferable. ), (6) C _6-14 aryl group (as examples, phenyl, 1- or 2-naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.,
Of these, phenyl and naphthyl are preferable. ), (7) C
_7-20 aralkyl (for example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like can be mentioned, of which benzyl and phenethyl are preferable) and the like.

Examples of the substituent of the above-mentioned hydrocarbon group and hydrocarbon-oxy group include (1) halogen, (2) nitro,
(3) nitroso, (4) cyano, (5) substituent {eg, (i) C _1-6 alkyl (wherein C _1-6 alkyl is a hydroxyl group, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkoxy, C _1-3 alkylthio, hydroxy-C _1-3 alkoxy, C _1-6 alkyl-carbonyl, carboxy, carbamoyl, C _1-6 alkyl-carbamoyl, nitrogen-containing 5- to 8-membered heterocyclic group, C _6-10
It may have aryl, C _7-13 aralkyl, halogen or nitro as a substituent. ), (Ii) C _1-4 acyl, (iii) C _7-20 aralkyl (the C _7-20 aralkyl group is halogen, C _1-3 alkoxy, C _1-6 alkyl, C
_6-14 aryl, C _7-13 aralkyl, nitro may have as a substituent), (iv) C _6-14 aryl (the C _6-14
Aryl is C _1-6 alkyl, C _6-14 aryl, C _7-13
Aralkyl, C _1-3 alkoxy-C _1-6 alkoxy, optionally having halogen or nitro as a substituent),
(v) C _2-6 alkenyl, (vi) C _3-7 cycloalkyl, (vii)
C _1-3 alkoxy-carbonyl, (viii) mono- or di-C _1-6 alkylamino, (ix) C _2-6 alkenylamino,
(x) C _1-3 alkoxy-carbonyl, (xi) C _1-6 alkyl-carbonyl, (xii) C _3-6 cycloalkyl-oxycarbonyl, (xiii) C _6-14 aryl-carbonyl, (xiv)
C _7-20 aralkyl-carbonyl, (xv) C _6-14 aryl-
Oxycarbonyl, (xvi) trifluorosulfonyl, (xv
ii) pyranyl, (xviii) furanyl or (xix) tri (C _1-4
Alkyl) silyl (eg, trimethylsilyl, triethylsilyl, etc.)} optionally having hydroxyl, (6) Formula —S (O) f—R ³¹ {wherein, f is an integer of 0 to 2, R ³¹ Is a hydrogen atom or a hydrocarbon group which may have a substituent (eg, halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano-C _6-14 aryl, halogeno C _6-14 aryl, etc.), or Mono- or di-C
_1-4 , amino which may be substituted with alkyl may be mentioned, and as the hydrocarbon group, a C _1-20 alkyl group, particularly C _1-6
Alkyl, C _6-14 aryl, C _7-20 aralkyl are preferred. )}, (7) optionally substituted amino group [eg, formula —NR ³² R ³³ {in the formula, R ³² and R
³³ is the same or different and is (i) a hydrogen atom, (ii) C _1-6 alkyl, (iii) C _1-6 acyl, (iv) mono- or di-C.
Carbamoyl optionally substituted by _1-4 alkyl, C _1-4 alkylthio or C _6-14 aryl, (v) C _1-8 alkanoyl, (vi) C _6-14 aryl, (vii) C _1-4 Alkylthio, (viii) C _1-4 alkyl-sulfonyl, (ix) C _1-4 alkyl-sulfinyl, or (x) represents a cyclic amino group or a nitrogen-containing heterocyclic group described below. } Or an amino group represented by the above, or a group via the above nitrogen atom], (8)
Formula —CO—R ³⁴ (wherein R ³⁴ is (i) hydrogen atom, (ii) hydroxy, (iii) C _1-10 alkyl, (iv) C _1-6 alkoxy (wherein this alkoxy is halogen, nitro) , C _6-14 aryl and the like, which may be substituted with C _6-14 aryl which may have a substituent), (v) C _3-6 cycloalkyl, (v
i) C _6-14 aryl, (vii) C _6-14 aryl-oxy, (vi
ii) C _7-20 aralkyl, (ix) C _7-20 aralkyloxy,
(x) an optionally substituted amino group defined in the above item (7), (xi) formula —O—NR ³² R ³³ (wherein R ³² and R ³³
Has the same meaning as above. ) Optionally substituted aminooxy group, (xii) 5-8 membered heterocyclic group or (xiii)
A 5- to 8-membered heterocycle-oxy group is shown. } The group represented by
Among them, C _1-10 acyl is preferable, (9) a 3- to 9-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is (i) halogen atom, (ii) C _1-4 alkyl, (iii) C _1-3
Alkoxy, (iv) C _1-4 alkylthio, (v) optionally substituted with halogen, optionally substituted with phenoxy. }, (10) Sulfo, (11) C _6-14 aryl (eg, phenyl, naphthyl, anthryl, acenaphthyl, anthracenyl, etc.) The C _6-14 aryl group is (a) hydroxyl, (b)
Amino, (c) mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
It may be substituted with 1 to 4 substituents selected from dimethylamino, diethylamino, etc.), (d) C _1-6 alkoxy, (e) halogen, (f) cyano and the like. ), (12) C _3-7
Cycloalkyl, (13) C _1-6 alkylenedioxy (eg,
Methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy, etc.), (14) oxo,
(15) Thioxo, (16) C _1-15 alkyl, (17) C _2-10 alkynyl, (18) C _3-10 cycloalkyl group, (19) C _2-10 alkenyl group (eg vinyl, allyl, Isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl, etc. Among them, a C _2-6 alkenyl group is preferable),
(20) C _5-7 cycloalkenyl, (21) C _7-20 aralkyl,
(22) amidino, (23) azide, (24) -B (OH) ₂ , (25) epoxy (-O-), (26) phosphono, (27) dihydroxyboryl, (28) formula -A-R ³⁵ (wherein A represents an intervening group, R ³⁵
_{Represents a} C _1-10 alkyl group), (29) phthaloyl, (30) a group through the above sulfur atom, (31) hexamethylenetetraamino, (32) indanyl, (33) phthalimide, etc. Can be mentioned.

The substituent on the hydrocarbon group having a substituent described above may further have a substituent. Examples of the substituent which may be further possessed include (1) hydroxyl, (2) amino, (3) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino , Dimethylamino, diethylamino, etc.), (4) C _1-4 alkoxy, (5) C _1-6 alkyl optionally substituted with halogen, (6) C _6-14 aryl (wherein the aryl is halogen or cyano). , (7) C _7-13
Aralkyl, (8) C _1-6 alkoxy-carbonyl, (9) 5
~ 8-membered heterocyclic group, (10) C _1-10 acyl, (11) carboxy,
(12) C _1-6 alkoxy-carbonyl, (13) C _6-14 aryl-carbonyl, (14) C _1-6 alkylenedioxy, (15)
Sulfamoyl, (16) carbamoyl, (17) C _1-4 alkylthio, (18) C _1-4 alkylsulfinyl, (19) C _1-4 alkylsulfonyl, (20) halogen, (21) nitro, (22) mercapto And 1 to 4 groups selected from (23) cyano and the like, and more preferably 1 to 2 groups. When the hydrocarbon group is a cycloalkyl, cycloalkenyl, alkynyl, aryl or aralkyl group, it may have 1 to 3 C _1-6 alkyl as a substituent, and the C _1-6 alkyl is Furthermore, 1 to 3 hydroxy, oxo, C _1-3 alkoxy, C _1-3 acyl,
It may be substituted with C _1-3 alkylthio, halogen, carbamoyl or the like. The substituted C _1-6 alkyl includes formyl (methyl substituted by oxo), carboxyl (methyl substituted by oxo and hydroxy), C _1-6 alkoxy-carbonyl (methyl substituted by oxo and Those substituted by alkoxy) (eg, C _1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl), hydroxy C _1-6 alkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxy) Propyl, etc.), C _1-3 alkoxy-C _1-6 alkyl (eg, methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, propoxyhexyl, etc.) and the like. The number of the substituents in the above is 1 to 6, preferably 1 to 5, more preferably 1 to 3,
Most preferred is 1-2. The number of substituents that the substituent may further have is preferably 1 to 3, and particularly preferably 1 to 2.

Examples of the acyl group in the above-mentioned optionally substituted acyl group include hydrocarbon-carbonyl, and above all, an acyl group derived from a C _1-24 aliphatic carboxylic acid. Examples of the acyl group include formyl, C _1-10 alkyl-carbonyl (eg, acetyl,
Propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, etc.), C _1-13 alkoxy-carbonyl, C _6-14 aryl-carbonyl (eg, benzoyl, naphthylcarbonyl, anthracenylcarbonyl, etc.), C
_6-14 aryloxy-carbonyl (eg, phenoxycarbonyl etc.), C _7-20 aralkyl-carbonyl (eg, benzylcarbonyl etc.), C _7-19 aralkyloxy-carbonyl (eg, benzyloxycarbonyl etc.), C _{3- 10} cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C _2-6 alkenyl-carbonyl (eg, vinylcarbonyl, butenylcarbonyl, butadienylcarbonyl, hexatrienylcarbonyl) Etc.) and the like. Of these, C _1-10 acyl is preferable. Examples of the substituent of the acyl group include the same as the above-mentioned substituents of the hydrocarbon. _Examples of the substituent of the C _1-10 acyl group include the same ones. C _1-13 alkoxy in C _1-13 alkoxy-carbonyl includes
It may be linear or branched. As the straight-chain alkoxy, a C _1-9 alkoxy group is preferable and, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, neopentyloxy, hexyloxy, octyloxy and the like can be mentioned. As the branched alkoxy group, , C
_3-13 branched alkoxy groups (eg, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy, sec-pentyloxy, tert-pentyloxy, 3-pentyloxy, isohexyloxy, sec-
Hexyloxy, tert-hexyloxy, isooctyloxy, sec-octyloxy, tert-octyloxy,
Cyclopentyloxy, cyclopropyloxy, cyclobutyloxy, cycloheptyloxy, 2-indanyloxy, 4-piperidinyloxy, tetrahydro-4H
-Pyrazol-4-nyloxy). As the branched alkoxy group, a C _3-7 branched alkoxy group is particularly preferable. Examples of the group which may be substituted on the acyl group include the same groups as those which may be substituted on the hydrocarbon group described above. Examples of the above-mentioned optionally substituted carbamoyl group include the above-mentioned _optionally substituted C _1-20 hydrocarbon group or the _optionally substituted cyclic amino optionally substituted carbamoyl group. To be Examples of the C _1-20 hydrocarbon group are the same as those mentioned above. Preferred examples of optionally substituted carbamoyl include, for example, a mono- or di-C _1-15 alkylcarbamoyl group, and examples thereof include methylcarbamoyl, ethylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl and methylethylcarbamoyl. Etc. Examples of the group which may be substituted on the carbamoyl group include the same groups as those described above which may be substituted on the hydrocarbon group.

In the present invention, examples of the above-mentioned heterocyclic group include a heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms, and a bicyclic group condensed therewith. Alternatively, a tricyclic fused heterocyclic group and the like can be mentioned. Among them, a 3- to 9-membered heterocyclic group is preferable, and a 5- to 8-membered heterocyclic group is particularly preferable. Specific examples of the heterocyclic group include, for example, (1) thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl,
Imidazolinyl, imidazolidinyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, flazanyl, 1,2,4-
Thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5
-Thiadiazolyl, 1,2,3-triazolyl, 1,2,4
-Triazolyl, triazinyl, triazolidinyl, 1
5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom such as H- or 2H-tetrazolyl; (2) pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl , Pyrrolidinyl, piperidinyl, piperidyl, piperazino, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl and other oxygen atoms. Examples thereof include a 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from atoms, sulfur atoms, nitrogen atoms and the like. (2) Bicyclic or tricyclic fused heterocyclic groups include benzofuranyl, isobenzofuranyl, benzothiazolyl, 1,2-benzisothiazolyl, benzo [b] thienyl, benzoxazolyl, 1H-benzotriaryl. Zolyl, 1,2-benzisoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl. , Indolyl, isoindolyl, 1
H-indazolyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenanthridinyl, chromanyl, benzoxazinyl, Phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,
2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-
a] Pyrimidinyl, 1,2,4-triazolo [4,3-a]
Bicyclic or tricyclic containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom such as pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl Examples thereof include condensed heterocyclic groups, and further, three-membered rings such as (3) oxiranyl and aziridinyl, and four-membered rings such as (4) azetidinyl. The heterocycle may be a hydrogenated product.

Examples of the heterocyclic group and the groups which may be substituted on the above-mentioned heterocyclic group include (1) C _1-6 alkyl, (2)
C _2-6 alkenyl, (3) C _2-6 alkynyl, (4) C _3-6 cycloalkyl, (5) C _5-7 cycloalkenyl, (6) C _7-11 aralkyl, (7) C _{6- 14} aryl, (8) C _1-6 alkoxy,
(9) C _6-14 aryloxy (eg, phenoxy etc.), (10)
C _1-6 alkanoyl (eg formyl, acetyl, propionyl, n-butyryl, iso-butyryl etc.), (11) C _6-14 aryl-carbonyl (eg benzoyl etc.), (12) C _1-6
Alkanoyloxy (eg, formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, etc.), (13) C _6-14 aryl-carbonyloxy (eg, benzoyloxy, etc.), (14) carboxyl,
(15) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), (16) carbamoyl group , (17) N-mono-C _1-4 alkyl-carbamoyl (eg, N-methylcarbamoyl, N-
Ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), (1
8) N, N-di-C _1-4 alkyl-carbamoyl (eg, N,
N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), (19) cyclic aminocarbonyl (eg,
1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.), (20) halogen, (21) mono -, Di- or tri-halogeno-C _1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), (22) oxo group, (23) amidino, (24)
Imino group, (25) amino, (26) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino , Dibutylamino, etc.), (27) carbon atoms and 1
3 to 6-membered cyclic amino group (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc., in addition to the nitrogen atoms. Pyrrolyl, imidazolyl, birazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), (28)
C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide,
Butyrylamide, isobutyrylamide, etc.), (29) benzamide, (30) carbamoylamino, (31) N—C _1-4 alkyl-carbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N -Propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), (32) N,
N-di-C _1-4 alkyl-carbamoylamino (eg, N,
N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), (33)
C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (34) -B (OH) ₂ , (35) hydroxyl, (36) epoxy (—O—), (37) nitro, (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino, (4
2) Phosphono, (43) dihydroxyboryl, (44) sulfamoyl, (45) C _1-6 alkylsulfamoyl (eg, N-
Methylsulfamoyl, N-ethylsulfamoyl, N
-Propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (46) diC _1-6
Alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (47) C _{1 -6} alkylthio (eg, methylthio,
(Ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), (48)
Phenylthio, (49) C _1-6 alkylsulfinyl (eg,
(Methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), (50) phenylsulfinyl, (51) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), (52) C _6-14 arylsulfonyl (eg, phenylsulfonyl) and the like can be mentioned. The number of substitutions is 1 to 6, preferably 1 to 3 and more preferably 1 to 2.

The heterocyclic group in the heterocyclic group having a bond at an optionally substituted carbon atom includes 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom. Examples thereof include a 5- to 8-membered heterocyclic group, and a bicyclic or tricyclic condensed heterocyclic group condensed therewith, which includes a heterocyclic group having a bond at a carbon atom constituting a ring. Specific examples of the heterocyclic group in the heterocyclic group having a bond at the optionally substituted carbon atom include (1) 2- or 3-thienyl, 2- or 3-furyl, 2- or 3- Pyrrolyl, 3- or 4-pyrrolinyl 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2- or 3-pyrrolidinyl, 2-, 4- Or 5
-Imidazolyl, 2-imidazolinyl, 2-imidazolidinyl, 3-, 4- or 5-isoxazolyl, 3
-, 4- or 5-isothiazolyl, 3- or 5-
(1,2,4-oxadiazolyl), 2-, 5- or 6-
(1,3,4-oxadiazolyl), 3- or 4-flazanyl, 3- or 5- (1,2,4-thiadiazolyl), 2
-Or 5- (1,3,4-thiadiazolyl), 4-or 5- (1,2,3-thiadiazolyl), 3-or 4- (1,
2,5-thiadiazolyl), 2- or 5- (1,2,3-
Triazolyl), 3- or 5- (1,2,4-triazolyl), 5- (1H- or 2H-tetrazolyl) and the like, as well as a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. A 5-membered heterocyclic group containing 4 to 4; (2) 2
-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, 2- or 4-triazinyl,
2-, 3- or 4-piperidinyl, 2- or 3-pyranyl, 2- or 3-thiopyranyl, 2- or 3-
(1,4-oxazinyl), 2- or 3- (1,4-thiazinyl), 1- or 4- (1,3-thiazinyl), 2- or 3-piperazinyl, 3- or 6-triazinyl,
6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms such as 3- or 4-pyridazinyl, 2- or 3-pyrazinyl, 3- or 4-pyridazinyl Group; (3) benzofuranyl, isobenzofuranyl, benzothiazolyl, 1,2-benzoisothiazolyl, benzo [b] thienyl, benzoxazolyl, 1H-benzotriazolyl, 1,2-benzoisoxazolyl , Tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolyl, isoindolyl, 1H-indazolyl, quinolidinyl, 1,8 -Naphthyridinyl,
Purinyl, pteridinyl, dibenzofuranyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, Thianthrenyl, phenanthridinyl, phenanthrolinyl, inodoridinyl, pyrrolo [1,2-
b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2- a] pyrimidinyl, 1,2,4-triazolo [4,
3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to 2
And a group having a bond at a carbon atom of the cyclic or tricyclic fused heterocyclic group. The heterocyclic group may be a hydrogenated product. Examples of the group which may be substituted on the heterocyclic group having a bond at a carbon atom include the same groups as the above groups which may be substituted on the heterocyclic group.

The cyclic amino group is preferably a 3- to 8-membered ring, for example, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl,
Imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,2,3-triazolidinyl, 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, azepinyl, hexamethyleneamino, oxazolidino, Examples include morpholino, thiazolidino, phthalimide or thiomorpholino. Of these, 5- to 6-membered ones are preferable, and for example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferable. The nitrogen-containing heterocyclic group in the above definition is preferably a 5- to 7-membered one or one which forms a bicyclic condensed ring with it, for example, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, Triazolyl, tetrazolyl, flazanil,
Pyridyl, pyrimidinyl, pyridazinyl, oxadiazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,
3-triazinyl, 1,2,3-triazolidinyl, 1,2,
Examples thereof include 3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethylene aminyl, oxazolidinyl, thiazolidinyl, indolyl, indazolyl, purinyl and quinolyl. These may be hydrogenated. Among them, 5
A 6-membered heterocyclic group is preferred. Among the 5- or 6-membered heterocyclic groups, especially pyrrolidinyl, pyrazolinyl, pyrazolyl,
Piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl are preferred. The cyclic amino group and the nitrogen-containing heterocyclic group may have a substituent, and as the substituent,
Examples of the above include C _1-6 alkyl, C _6-14
Aryl, C _7-13 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _1-6 alkoxy-carbonyl are preferred. More preferable substituents include C _1-6 alkyl, and among them, C _1-3 alkyl is particularly preferable.

The homocyclic group in the above-mentioned optionally substituted homocyclic group includes a 3- to 10-membered cyclic hydrocarbon group consisting only of carbon atoms. Examples thereof include C _6-10 aryl (eg, phenyl, naphthyl), C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), C _3-7 cycloalkenyl (eg, , Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.) and the like. Examples of the bicyclic homocyclic group include indanyl, indenyl and the like. The homocyclic group has 3 carbon atoms.
To 7 are preferred.

The substituent which the homocycle may have is, for example, (1) C _1-15 alkyl (among them, C _1-6 alkyl is preferable, and it may be substituted with halogen). ,
(2) C _3-10 cycloalkyl, (3) C _2-10 alkenyl, (4)
C _2-10 alkynyl, (5) C _3-10 cycloalkyl, (6) C
_6-10 aryl, (7) C _7-19 aralkyl, (8) nitro, (9)
Hydroxyl, (10) mercapto, (11) oxo, (12) thioxo, (13) cyano, (14) carbamoyl, (15) carboxyl, (16) C _1-5 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl Etc.), (17) sulfo, (1
8) halogen, (19) C _1-6 alkoxy, (20) C _6-10 aryloxy (eg, phenoxy etc.), (21) C _1-6 acyloxy (eg, acetoxy, propionyloxy etc.), (22) C
_1-6 alkylthio (eg, methylthio, ethylthio, n-
Propylthio, isopropylthio, n-butylthio, t
-Butylthio etc.), (23) C _6-10 arylthio (eg, phenylthio etc.), (24) C _1-6 alkylsulfinyl (eg,
(Methylsulfinyl, ethylsulfinyl, etc.), (25) C
_6-10 arylsulfinyl (eg, phenylsulfinyl, etc.), (26) C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), (27) C _6-10 arylsulfonyl (eg, phenylsulfonyl, etc.), (28) Amino,
(29) C _1-6 acylamino (eg, acetylamino, propionylamino etc.), (30) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,
(Dimethylamino, diethylamino, etc.), (31) C _3-8 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), (32) C _6-10 arylamino (eg, anilino etc.) ), (33) C _1-6 alkanoyl (eg, formyl, acetyl, hexanoyl, etc.), (34) C _1-6 alkanoyloxy (eg, acetyloxy, propionyloxy, etc.), (35)
C _6-10 aryl-carbonyl (eg, benzoyl etc.), (3
6) 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms (eg,
2- or 3-thienyl, 2- or 3-furyl, 3
-, 4- or 5-pyrazolyl, 2-, 4- or 5-
Thiazolyl, 3-, 4- or 5-isothiazolyl, 2
-, 4- or 5-oxazolyl, 3-, 4- or 5
-Isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 3- or 4-
Pyridanidyl, quinolyl, isoquinolyl, indolyl, etc.) and the like. The number of substitutions is one to six, preferably one to three, more preferably one or two.

As n in the above formula, 1 is preferable. Halogen in the definition of the above groups includes fluorine, chlorine, bromine and iodine. Examples of C _1-6 alkyl in the definition of the above group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. To be C _1-4
Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl. C _1-3 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl. Examples of C _2-10 alkenyl in the definition of the above groups are, for example, vinyl, allyl
l), propenyl, 2-methylallyl, isopropenyl, 2-butenyl, 3-butenyl, butadienyl, hexatrienyl, 3-octenyl and the like. C
Examples of _2-6 alkenyl include, for example, vinyl, allyl, propenyl, isopropenyl, butenyl,
Hexatrienyl may be mentioned. Examples of C _2-4 alkenyl include vinyl, allyl, isopropenyl and butenyl. Examples of C _2-10 alkynyl in the definition of the above groups include, for example, ethynyl, 1-propynyl, 2-propynyl, propargyl, 3-hexynyl and the like. Examples of C _2-6 alkynyl and C _2-4 alkynyl in the above definition of the group include, for example, ethynyl, 1-propynyl, 2-propynyl and the like. Examples of C _3-10 cycloalkyl in the definition of the above group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Examples of C _3-8 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As C _3-7 cycloalkyl, for example, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl and cycloheptyl are mentioned. Examples of C _3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C _3-7 in the definition of the above group
Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl, and examples of C _5-7 cycloalkenyl include cyclopentenyl and cyclohexenyl.

Examples of C _6-14 aryl in the definition of the above groups include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl and anthracenyl. Examples of C _6-10 aryl include phenyl, naphthyl. Of these, phenyl is preferred. Examples of C _7-20 aralkyl or C _7-19 aralkyl in the above group definitions include, for example, benzyl, phenethyl, benzhydryl, trityl. Examples of C _7-15 aralkyl and C _7-13 include, for example, benzyl, phenethyl, benzhydryl. Examples of C _7-11 aralkyl and C _7-10 aralkyl include, for example, benzyl, α-methylbenzyl and phenethyl.
Examples of C _1-6 alkoxy in the definition of the above group include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyl. Oxy, hexyloxy and the like can be mentioned. Examples of C _1-4 alkoxy include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy. Examples of C _1-3 alkoxy include, for example, methoxy, ethoxy, propoxy, isopropoxy. Examples of C _1-6 acyl in the definition of the above group include, for example, —CO—R ³⁶ (wherein R ³⁶ is a hydrogen atom or C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec- butyl, t- butyl, and a C _1-6 alkanoyl represented by showing a pentyl)). Examples of C _1-4 acyl in the definition of the above group include, for example, the formula —CO—R
^And a group represented by ³⁷ (in the formula, R ³⁷ represents a hydrogen atom, methyl, ethyl, propyl or isopropyl). Examples of C _1-8 alkanoyl in the definition of the above group include formyl, acetyl, propionyl, butyryl, isobryl, valeryl, isovaleryl, octanoyl and the like.

Examples of the intervening group represented by A above include chemical bonds, C _1-4 alkylene (eg, methylene, ethylene, etc.), C _2-6 alkenylene (eg, vinylene, butadienylene, etc.), — (CH _{2) m'NR} ³⁸ - wherein, m 'is 0
To an integer of 3 to 3, R ³⁸ represents hydrogen or C _1-6 alkyl (specific examples are the same as those mentioned above), a group represented by —CO—, —CONR ³⁸ ′ — [formula R ³⁸ 'is hydrogen,
C _1-6 alkyl (specific examples are the same as the above), C _3-7 cycloalkyl (specific examples are the same as the above), C _6-14 aryl (the specific examples are the same). , The same as those described above), a heterocyclic group (specific examples thereof are the same as those described above)], —S (O) m ″-
(M ″ represents an integer of 0 to 2), —O
A group represented by —, —NR ³⁸ ′ S (O) m ′ ″ — (wherein m ′ ″ represents an integer of 0 to 2 and R ³⁸ ′ has the same meaning as defined above) and the like. Can be mentioned.

In the compound represented by the general formula (X), the compound represented by the general formula (XI)

Embedded image [Wherein, R ¹ and R ² each represent a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ³ represents an optionally substituted homo- or heterocyclic group;
R ⁴ is substituted with (1) hydrogen, (2) formyl group, (3) cyano group, (4) group through sulfur atom, optionally substituted hydroxyl group or optionally substituted hydrocarbon group A lower alkyl group, (5) a carbonyl group which may be substituted with an optionally substituted hydrocarbon residue, or (6) a carboxyl group which may be esterified or amidated is represented by R ⁵
Is a group having a hydrogen atom or a carbon atom, and n is an integer of 0 to 3]. R ¹ ,
R ² , R ³ and R ⁵ have the same meanings as those of R ^1e , R ^2e , R ^3e and R ^5e described above.

Examples of the group having a sulfur atom represented by R ⁴ include mercapto and optionally substituted alkylthio, alkylsulfinyl, cycloalkylthio, arylthio, aralkylthio, and heterocyclic thio groups. . The alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in the optionally substituted alkylthio, alkylsulfinyl, cycloalkylthio, arylthio, aralkylthio and heterocyclic thio groups have the same meanings as described above. The group which may be substituted on these has the same meaning as the substituent in the group via the nitrogen atom.

Examples of the ester group in the etherified carboxyl group represented by R ⁴ include alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups, which have the same meanings as described above. R above
^{As the} amidated carboxyl group represented by ⁴ ,
For example, a carbonyl group substituted with a group via a nitrogen atom can be mentioned. Examples of the group via the nitrogen atom have the same meaning as described above. Examples of the lower alkyl group in the substituted lower alkyl group represented by R ⁴ above include methyl,
Examples thereof include C _1-6 alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, pentyl and hexyl. Examples of the optionally substituted hydrocarbon group in the lower alkyl group substituted with the optionally substituted hydrocarbon group include the same as those described above.

Examples of the substituent in the optionally substituted hydroxyl group include (1) halogen (eg, chlorine, bromine, fluorine, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), C _{7 -12} aralkyl (eg benzyl, phenylethyl etc.) and C _1-6 alkyl _optionally having 1 to 4 substituents selected from nitro etc. (eg methyl,
Ethyl, n-propyl, i-propyl, n-butyl, te
(2) Halogen (eg chlorine, bromine, fluorine etc.), C _1-6 alkyl (eg methyl, ethyl, n-propyl etc.), C _6-10 aryl (eg phenyl, naphthyl) Etc.), C _7-12 aralkyl (eg benzyl, phenylethyl etc.) and C _6-10 aryl _optionally having 1 to 4 substituents selected from nitro etc. (eg phenyl, naphthyl etc.) (3) Halogen (eg, chlorine, bromine, fluorine etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl etc.), C _6-10 aryl (eg, phenyl, naphthyl etc.), C _{7 -12} aralkyl (eg, benzyl, phenylethyl, etc.) and C _7-12 aralkyl (eg, benzyl, _optionally having 1 to 4 substituents selected from nitro, etc.)
Phenylethyl, naphthylmethyl, etc.); (4) formyl,
Halogen (eg chlorine, bromine, fluorine etc.), C _1-6 alkyl (eg methyl, ethyl, n-propyl etc.), C _6-10 aryl (eg phenyl, naphthyl etc.), C _7-12 aralkyl ( (Eg, benzyl, phenylethyl etc.) and C optionally having 1 to 3 substituents selected from nitro etc.
_1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.); (5) halogen (eg, chlorine, bromine, fluorine, etc.),
C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.),
C _7-12 aralkyl (eg, benzyl, phenylethyl, etc.)
And C _6-10 aryloxy-carbonyl _optionally having 1 to 4 substituents selected from nitro and the like (eg,
Phenyloxycarbonyl, naphthyloxycarbonyl etc.); (6) Halogen (eg chlorine, bromine, fluorine etc.), C
_1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.),
C _7-12 aralkyl (eg, benzyl, phenylethyl, etc.)
And C _6-10 aryl-carbonyl _optionally having 1 to 4 substituents selected from nitro and the like (eg, benzoyl, naphthylcarbonyl and the like); (7) halogen (eg, chlorine, bromine, fluorine and the like) ), C _1-6 alkyl (eg, methyl,
1 to 4 substituents selected from ethyl, n-propyl etc.), C _6-10 aryl (eg phenyl, naphthyl etc.), C _7-12 aralkyl (eg benzyl, phenylethyl etc.) and nitro etc. C _7-12 aralkyl-carbonyl (eg, benzylcarbonyl, phenethylcarbonyl etc.) which may have; (8) halogen (eg chlorine, bromine, fluorine etc.), C _1-6 alkyl (eg methyl, ethyl) , N-propyl etc.), C _6-10 aryl (eg phenyl, naphthyl etc.), C _7-12 aralkyl (eg benzyl, phenylethyl etc.) and nitro etc. Optionally pyranyl or furanyl, tri (C
_1-4 alkyl) silyl (eg, trimethylsilyl, triethylsilyl, etc.) and the like are used. The group via the sulfur atom has the same meaning as described above.

The hydrocarbon residue in the carbonyl group substituted by the optionally substituted hydrocarbon residue represented by R ⁴ is, for example, saturated or unsaturated carbon number 2
Up to 5 hydrocarbon residues are included. Preferred specific examples include, for example, alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
C _1-8 alkyl such as t-butyl, pentyl, isopentyl, hexyl, heptyl, etc., cycloalkyl (eg, C _3-6 cycloalkyl such as cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl), alkoxyalkyl (eg, methoxymethyl) C _1-3 alkoxy C _1-6 alkyl such as, ethoxymethyl, ethoxybutyl, propoxyhexyl), alkenyl (eg, C _2-6 alkenyl such as vinyl, butenyl, butadienyl, hexatrienyl), aryl (eg, phenyl) , Naphthyl, anthracenyl, etc.
_6-14 aryl), aralkyl (eg, C _7-20 aralkyl such as benzyl, benzhydryl, trityl, etc.) and the like. The substituent has the same meaning as the substituent in the group via the carbon atom.

[0034] R ¹ and R ^2, on the other hand (preferably R ¹⁾ is the general formula R ⁹ - (CH ₂₎ m- wherein, R ⁹ is a group bonded through a optionally substituted nitrogen atom, m Represents an integer of 0 to 3], and the other (preferably R ² ) is a group represented by the general formula R ¹⁰ -A- [wherein R ¹⁰ represents a phenyl group which may be substituted;
Represents an intervening group].
The group represented by R ⁹ via the optionally substituted nitrogen atom has the same meaning as described above. The group having a nitrogen atom which may be substituted is represented by the formula —NR ³⁹ R ⁴⁰ (in the formula, R ³⁹ represents an alkyl group and R ⁴⁰ represents an aralkyl group), and is particularly preferable. The substituent in the optionally substituted phenyl group represented by R ¹⁰ is, for example, 1 to 3 halogen (fluorine, chlorine, bromine, iodine), halogen (fluorine, chlorine, bromine, iodine). Optionally substituted C _1-8 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), halogen (fluorine, chlorine, bromine, C _1-8 alkoxy optionally substituted by 1 to 3 with iodine) (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.),
1 to 3 with halogen (fluorine, chlorine, bromine, iodine)
Optionally substituted C _1-8 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t
ert-butylthio, pentylthio, isopentylthio,
Neopentylthio, etc.), C _1-6 alkanoylamino (eg, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, etc.), C _1-6 alkanoyloxy (eg, formyl Oxy, acetoxy, propionyloxy, etc.), hydroxyl, carboxyl, C _1-6
Alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), cyano, nitro, amino, mono- or di-C _1-6 alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.), etc. Is mentioned. The number of substitutions is 1 to 5, preferably 1 to 3. Examples of the intervening group represented by A include those described above, and particularly preferable are a chemical bond and a methylene group.

R ³ is a general formula

Embedded image [In the formula, R ⁷ is substituted with a group via hydrogen, halogen, or carbon, nitrogen, oxygen or sulfur atom, and R ⁸ is substituted with a group via hydrogen, halogen, nitro, cyano or carbon, oxygen, nitrogen or sulfur atom. Represents an aliphatic hydrocarbon residue which may be substituted]. The group represented by R ⁷ via an optionally substituted carbon, nitrogen, oxygen or sulfur atom has the same meaning as described above. The aliphatic hydrocarbon residue which may be substituted in the aliphatic hydrocarbon residue which may be substituted via an oxygen, nitrogen or sulfur atom represented by R ⁸ is, for example, C _1-15 alkyl. (Eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc.), C _{3- 8} cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _2-10 alkenyl (eg, vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl, etc.), C _{2- 10} alkynyl (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.), C _1-6 alkoxy (e.g., methoxy Ethoxy, propoxy, butoxy, etc.). Examples of the substituent which the hydrocarbon group may have include, for example, nitro, hydroxyl, oxo, thioxo, cyano, carbamoyl, carboxyl, C _1-4 alkoxy-carbonyl (eg,
Methoxycarbonyl, ethoxycarbonyl, etc.), sulfo, halogen (fluorine, chlorine, bromine, iodine), C _1-4
Alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.), C _1-4 alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, etc.), amino, C
_1-6 alkanoylamino (eg, acetylamino, propionylamino, etc.), mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethyl) Amino, diethylamino etc.), C _1-4 alkanoyl (eg formyl, acetyl, propionyl etc.), (a)
Halogen (eg, fluorine, chlorine, bromine, iodine); (b) C
_1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.) which may have 1 to 4 substituents such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2
-, 4- or 5-thiazolyl, 3-, 4- or 5-
Isothiazolyl, 2-, 4- or 5-oxazolyl,
3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-3
-Or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridanidyl, quinolyl, isoquinolyl, indolyl and the like, in addition to 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like. And a 5- or 6-membered heterocyclic group, C _1-6 haloalkyl (eg, difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl, etc.). The number of substitutions is 1-4, preferably 1-3. R ₄ is preferably a carbonyl group substituted with an optionally substituted hydrocarbon group. R ⁵ is preferably a hydrogen atom.

Among the compounds represented by the general formula (XI), particularly the general formula

Embedded image [Wherein, R ^13a may have 1 to 5 substituents and may be the same or different, and each represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom or an alkanoylamino group, and R ^14a represents a hydrogen atom or an alkyl A group represented by R ^15a
May have 1 to 5 substituents and may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, and R ^16a represents 1
Up to 5 substituents, which may be the same or different, may each be a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group, and R ^17a may have 1 or 2 substituents, which may be the same or different. Well, each represents a carboxyl group which may be esterified or amidated, an alkylcarbonyl group, an arylcarbonyl group or an alkyl group which may be substituted, and v, t and u may be the same or different, and 1-4
Which represents an integer of] is preferable.

Further, in the compound represented by the general formula (XI),

Embedded image [In the formula, 1 to 3 R ^13b may be substituted and may be the same or different, and each represents a hydrogen atom, a C _1-6 alkoxy group or an alkanoylamino group, and R ^14b represents a hydrogen atom or a C _{1- 6} alkyl groups, R ^15b may have 1 to 3 substituents and may be the same or different, and hydrogen atom or halogen, R ^16b may have 1 to 3 substituents, and they may be the same or different. R ^17b may be substituted with 1 or 2 hydrogen atoms, halogen or C _1-6 alkoxy, and may be the same or different.
It represents a carboxyl group or an alkylcarbonyl group which may be esterified or amidated, and v ′, t ′ and u ′ may be the same or different and each is 1 to
A compound represented by an integer of 3] is preferable.

Among the compounds represented by the general formula (XI), (1) 4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2 -(4-Methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or salt thereof, (2) 2- (4-acetylaminophenyl) -4,7-dihydro -3- (N-methyl-N-benzylaminomethyl)
-7- (2-methoxybenzyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof, (3) 5-n-butyryl-4,7-dihydro-3 -(N-methyl-N-benzylaminomethyl)-
7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof, (4) 5-benzoyl-4,7-dihydro-
3- (N-methyl-N-benzylaminomethyl) -7-
(2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof, (5) 7- (2,6-difluorobenzyl)-
4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -5-isobutyryl-4-oxo-thieno [2,3
-B] pyridine or a salt thereof, (6) 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5-isobutyryl-2
-(4-propionylaminophenyl) -4-oxo-
Thieno [2,3-b] pyridine or a salt thereof, (7) 5-benzoyl-7- (2,6-difluorobenzyl) -4,7
-Dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -4
-Oxo-thieno [2,3-b] pyridine or a salt thereof is preferred.

As the compound used in the composition of the present invention, the compound of the general formula (XII) in the compound (X) is used.

Embedded image [Wherein, R ^1h and R ^2h are each hydrogen or a group via a carbon, nitrogen, oxygen or sulfur atom, R ^3h is an optionally substituted homo- or heterocyclic group, and R ^4h is substituted. An ^{optionally substituted} heterocyclic group or a group via a hetero atom,
Represents a hydrogen or a group via a carbon atom, and n ^h represents an integer of 0 to 3, respectively. Or a salt thereof. The radicals R ^1h , R ^2h , R ^3h and R ^5h are
It has the same meaning as R ^1e , R ^2e , R ^3e and R ^5e described above.
The group having a heteroatom represented by R ^4h above includes
Examples thereof include a group via a nitrogen atom, a group via an oxygen atom, and a group via a sulfur atom, which are the same as those defined for R ^4e .

The compound represented by the general formula (XII) (XI
In I), preferable examples of R ^1h include groups having a carbon atom or a nitrogen atom therebetween. As the group via a carbon atom, a C _1-20 hydrocarbon group which may have a substituent, particularly a C _1-10 alkyl group which may have a substituent is preferable, and among them, a substituent is preferable. May have C
_1-6 alkyl groups are preferred. The substituent in the C _1-20 hydrocarbon group which may have a substituent represented by R ^1h is
(1) halogen, (2) nitro, (3) cyano, (4) an optionally substituted amino group, (5) substituted or also from a hydroxyl group (6) -S (O) t ^h -R ^6h (In the formula, t ^h is 0
A group represented by an integer of 2 to R ^6h is a hydrogen atom or an optionally substituted hydrocarbon group). R
^1h preferably includes substituted aminoalkyl such as N, N-disubstituted aminoalkyl group. Preferably, N-
Aralkyl-N-alkylaminoalkyl, among others,
N-C _7-11 Aralkyl-N-C _1-6 Alkylamino-C
_1-6 alkyl is mentioned.

Preferred examples of R ^2h include groups via a carbon atom. As a group via a carbon atom,
A C _1-20 hydrocarbon group which may have a substituent, particularly a C _6-14 aryl group which may have a substituent is preferable.
The substituent in the C _1-20 hydrocarbon group which may have a substituent represented by R ^2h is (1) an optionally substituted amino group, (2) an optionally substituted hydroxyl group, ( Preferred are (3) optionally substituted carbamoyl group, (4) optionally substituted caboxyl group, (5) optionally substituted alkenyl group, (6) acyl group or (7) nitro group. R
Specific examples of the substituent of the optionally substituted aryl group represented by ^2h include (1) alkoxy, (2) alkylcarbonyl, (3) alkylaminocarbonyl, and (4) optionally substituted Alkenyl (preferable examples of the substituents include alkylcarbonyl, alkylaminocarbonyl), or (5) optionally substituted amino (preferable examples of the substituents are alkyl, alkanoyl and hydroxy-substituted) Alkyl and hydroxy are mentioned). Particularly, alkanoylamino or alkoxy is preferable. The most preferable examples of R ^2h include (i) nitro, (ii) C _1-6 alkoxy, (iii)
C _6-14 aryl which may be substituted with a group selected from an amino group which may be substituted with C _1-6 alkanoyl may be mentioned.

Preferable examples of R ^3h include an ^optionally substituted homocyclic group. The homocyclic group in the optionally substituted homocyclic group is preferably a C _6-14 aryl group. The substituent in the optionally substituted homocyclic group represented by R ^3h is (1) halogen, (2) nitro, (3) optionally substituted hydroxyl group or (4)
Wherein ^{-S (O) t h -R 6h} ( wherein, t ^h is an integer of 0 to 2, R
^6h is preferably a hydrogen atom or an optionally substituted hydrocarbon group). Preferred examples of the group represented by R ^3h include an aryl group substituted with halogen, and the aryl is preferably phenyl. It is preferable that 1 to 2 halogens are substituted. R
^As the more preferable group represented by ³ , fluorine-substituted phenyl is particularly preferable.

In the ^optionally substituted heterocyclic group represented by R ^4h , the heterocyclic group is preferably 3 to 8
And a 5- to 8-membered heterocyclic group having at least one nitrogen atom. More preferably, 5-6 having at least one nitrogen atom
Membered heterocyclic groups. Preferred examples of the heterocyclic group include, for example, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolyl, and thiazinyl. In particular, isoxazolyl is preferred. The substituent in the ^optionally substituted heterocyclic group represented by R ^4h is (1) halogen, (2) nitro, (3) optionally substituted hydroxyl group, (4) formula —S (O) m ^h
A group represented by —R ^6h (in the formula, m ^h represents an integer of 0 to 2, R ^6h represents a hydrogen atom or an optionally substituted hydrocarbon group), (5) optionally substituted amino Group or (6) C
_1-10 hydrocarbon groups are preferred. The substituent in the optionally substituted amino group, the optionally substituted hydroxyl group or the optionally substituted mercapto group represented by R ^4h is (1) substituted with C _1-6 alkoxycarbonyl or carbamoyl. which may be a C _1-10 hydrocarbon group, (2) C _1-10 acyl groups or (3) -S (O) t ^h -R ^6h
(Wherein, t ^h is an integer of 0 to 2, R ^6h is a hydrogen atom or an optionally substituted hydrocarbon group) group represented by are preferred. The most preferred group represented by R ^4h is (1) a 5- or 6-membered heterocyclic group containing one nitrogen atom and one oxygen atom and having a bond at a carbon atom,
(2) (i) C _1-6 alkoxycarbonyl or C _1-6 alkyl optionally having carbamoyl, with a group selected from (ii) C _1-6 alkanoyl and (iii) C _1-6 alkylsulfonyl Optionally substituted hydroxyl group, formula (3)-
^{S (O) t h -R 6h} '( wherein, the integer t ^h is 0 to 2, R ^6h'
_{Represents a} C _1-6 alkyl group), (4) C _1-6
An amino group which may be substituted with alkanoyl may be mentioned.

Preferred examples of R ^5h include a hydrogen atom or a hydrocarbon group which may have a substituent,
Among them, a hydrogen atom or an optionally substituted C
Preferred are _1-20 hydrocarbon groups. Furthermore, a hydrogen atom or C
_1-10 alkyl groups are preferred. Particularly, hydrogen is preferable. In the above compound (XII), R ^1h is halogen or N—C _7-13.
R ^2h is (i) nitro, (ii) C, a C _1-6 alkyl group which may be substituted with aralkyl-N—C _1-6 alkylamino.
_1-6 alkoxy and (iii) a C _6-14 aryl group optionally substituted with a group selected from amino optionally substituted by C _1-6 alkanoyl, wherein R ^3h is mono- or di-
A halogeno C _6-14 aryl group, wherein R ^4h contains (1) a nitrogen atom and an oxygen atom and has a bond at a carbon atom
Membered heterocyclic group, (2) (i) C 1-6 alkoxycarbonyl or C _1-6 alkyl optionally having carbamoyl, (i
i) C _1-6 alkanoyl and (iii) C _1-6 alkylsulfonyl which may be substituted by a group selected from alkylsulfonyl hydroxyl group, (3) ^{-S (O) t h -R 6h} '( wherein, t ^h is an integer of 0 to 2, R ^6h 'represents a group represented by C _1-6 alkyl group) or (4) an amino group which may be substituted with C _1-6 alkanoyl, and R ^5h is Compounds each of which represents a hydrogen atom and n ^h is 1 are particularly preferred. n ^h preferably represents 1. Specific examples of each group in the above-mentioned preferable groups include the same ones as described above.

As the compound used in the composition of the present invention, the compound of the general formula (XIII) in the compound (X) is used.

Embedded image [Wherein R ¹ⁱ is a formula

Embedded image (In the formula, R ⁶ⁱ is (1) fluorine, bromine, sulfamoyl, a phenyl group optionally substituted with methylthio or nitro, (2) 2- or 3-pyridyl group, (3) even if substituted with methyl) A 3-indolyl group, a (4) propyl group or a (5) butylcarbamoyl group, R ⁷ⁱ represents a methyl group) or a hexamethylenetetraaminomethyl group, and R ²ⁱ represents methoxycarbonylvinyl, Ethoxycarbonyl vinyl, carboxy vinyl, benzoyl vinyl, acetyl vinyl, propionyl vinyl, isobutyryl amino, propionyl amino, 3-oxobutylamino, 3-oxopentylamino, 2-hydroxycyclohexylamino, trifluoroacetylamino, 2
-Hydroxypropylamino, 2-hydroxybutylamino, 2-hydroxyisobutylamino, N-ethyl-
R ³ⁱ is a phenyl group substituted with N-trifluoroacetylamino, methylamino, ethylamino, propylamino, butylamino, isobutylamino, diethylamino, 1-pyrrolidinylamino, ethanesulfonamide or acetonyloxy, and R ³ⁱ is 2 A -fluorobenzyl group or a 2,6-difluorobenzyl group, and R ⁴ⁱ represents a (1) acyl group or (2) a C _1-6 alkyl group which may be substituted with hydroxy or alkylcarbonyloxy. ]
Compound (XIII) represented by or a salt thereof is preferable.

Preferred examples of the group represented by R ¹ⁱ in the compound (XIII) of the present invention include N-methyl-N-benzylaminomethyl. Compound (X) of the present invention
The number of substituents for R ²ⁱ and R ⁴ⁱ in III) is 1 to 6, among which 1 to 3 is preferable, and 1 or 2 is more preferable. Compound (XII) of the present invention
Preferred as the group represented by R ²ⁱ in I) is the formula R ¹⁰ⁱ —R ⁹ⁱ — (wherein R ⁹ⁱ is a vinyl group,
¹⁰ⁱ represents methoxycarbonyl, ethoxycarbonyl, carboxy, benzoyl, acetyl and propionyl, respectively. ) Or a group represented by the formula R ¹¹ⁱ —NH—
(In the formula, R ¹¹ⁱ represents 3-oxobutyl, 3-oxopentyl or 2-hydroxycyclohexyl) or a group represented by the formula R ¹²ⁱ —O— (in the formula, R ¹²ⁱ represents acetonyl). The phenyl group that has been described is included. The acyl represented by R ⁴ⁱ in the compound (XIII) of the present invention is an acyl group derived from a carboxylic acid, for example, formula —CO—R ⁸ⁱ (wherein —R ⁸ⁱ has a substituent). Is a hydrocarbon residue or a heterocyclic group which may have a substituent).

Specific examples of the hydrocarbon residue include the same ones as described above. Examples of the substituent of the hydrocarbon residue include, for example, nitro, hydroxy, oxo,
Thioxo, cyano, sulfo, carbamoyl, carboxy, halogen (eg, fluorine, chlorine, bromine, iodine), C
_1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), C _1-3 alkoxy-C _1-6 alkoxy, amino, mono- or di-C _1-6 alkylamino (eg, methylamino , Ethylamino, propylamino, dimethylamino, diethylamino, etc.), C
_1-6 alkyl-carbonyl, C _1-6 alkyl-carbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc.),
C _1-6 alkyl-thio, C _1-6 alkyl-sulfonyl, C
_1-6 alkyl-sulfinyl, benzoyl, phenoxy, alkylenedioxy, the heterocyclic group mentioned below, etc. are mentioned. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

Examples of the heterocyclic group include those mentioned above. As the substituent of the heterocyclic group,
For example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl etc.), C _2-6 alkenyl (eg vinyl, 1-methylvinyl, 1-propenyl, allyl etc.), C _2-6 alkynyl (eg ethynyl, 1-propynyl, propargyl etc.), C _{3- 6} cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C
_5-7 cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, etc.), C _7-11 aralkyl (eg, benzyl, α
-Methylbenzyl, phenethyl etc.), C _6-14 aryl (eg phenyl, naphthyl etc.), C _1-6 alkoxy (eg methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- Butoxy, tert-
Butoxy etc.), C _6-14 aryloxy (eg phenoxy etc.), C _1-6 alkanoyl (eg formyl, acetyl,
Propionyl, n-butyryl, iso-butyryl, etc.), C _6-14
Aryl-carbonyl (eg, benzoyl etc.), C _1-6 alkanoyloxy (eg, formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy etc.), carboxyl, C _1-6 alkoxy-carbonyl (eg, Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl etc.), carbamoyl group, halogen (fluorine, chlorine, bromine, iodine), oxo, amino, mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino) , Butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide, etc.) , Carbamoylamino, N-C _1-4 alkylcarbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), nitro, Shea , Mercapto, sulfo, Surufuino, phosphono, sulfamoyl, C _1-6
Alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), di-C _1-6 alkyl Sulfamoyl (eg, N, N
-Dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropyl) Thio, n-
Butylthio, sec-butylthio, tert-butylthio, etc.),
C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), C _1-6 alkylsulfonyl (eg,
Methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

[0049] Preferable examples of the hydrocarbon residue represented by R ⁸ⁱ in the above -CO-R ⁸ⁱ is optionally substituted C _6-14 aryl group, optionally substituted And C _1-6 alkyl group. As the substituent in the C _6-14 aryl group which may have a substituent, alkyl, alkoxy, alkoxy-alkoxy, alkylenedioxy, phenoxy, hydroxy, alkylcarbonyloxy, mono- or dialkylamino, alkylthio and the like are preferable. . C which may have a substituent
Examples of the substituent in the _1-6 alkyl group include hydroxy, halogen, nitro, cyano, alkoxycarbonyl, alkoxy or the formula —S (O) p ⁱ —R ⁷ⁱ (wherein p ⁱ is an integer of 0 to 2). , R ⁷ⁱ represents alkyl) and alkylenedioxy. Preferred examples of the heterocyclic group represented by R ⁸ⁱ include thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, morpholinyl, oxoimidazonyl, pyrrolidinyl, piperidinyl, and thiazinyl. Particularly, thienyl is preferable. Preferred examples of the substituent of the heterocyclic group include C _1-6 alkyl, C _1-6 alkoxy, carboxyl and C _1-6 alkoxy.
-Carbonyl, carbamoyl group, halogen, oxo, amino, mono- or diC _1-4 alkylamino, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, C _1-6 alkylthio and the like.

Further preferred examples of the group -CO-R ⁸ⁱ include (1) benzoyl group substituted with alkoxy, alkoxy-alkoxy, alkylenedioxy, phenoxy, hydroxy, alkylcarbonyloxy, mono- or dialkylamino or alkylthio, (2) Alkylcarbonyl group substituted with alkylenedioxy or (3)
A thienyl carbonyl group is mentioned. Preferred examples of the C _1-6 alkyl group which may be substituted with hydroxy or alkylcarbonyloxy represented by R ⁴ⁱ include an alkyl group substituted with hydroxy or acetyloxy, and further include 2-hydroxyisobutyl, 2-acetoxyisobutyl is preferred.

In the above definition, examples of the alkylenedioxy group include C _1-3 alkylenedioxy group,
Specific examples thereof include methylenedioxy, ethylenedioxy, propylenedioxy and the like.
As the alkyl group in the above definition, a C _1-6 alkyl group is preferable, and specific examples thereof include methyl,
Examples thereof include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl, and among them, a C _1-3 alkyl group is preferable. In the above definition, examples of the alkoxy group include C _1-6 alkoxy groups, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-
Examples thereof include butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like, and among them, a C _1-3 alkoxy group is preferable.

As the compound used in the composition of the present invention, the compound of the general formula (XIV)

Embedded image [In the formula, R ^1j represents a branched alkoxy group which may have a substituent or a hydroxyl group, and R ^2j represents a C _1-8 alkanoylamino group. ] The compound or its salt represented by these is preferable.

In the above formula, the branched alkoxy group of the branched alkoxy group which may have a substituent represented by R ^1j is a C _3-13 branched alkoxy group (for example, , Isopropoxy, sec-butoxy, tert-
Butoxy, isopentoxy, sec-pentyloxy, tert
-Pentyloxy, 3-pentyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy,
Isooctyloxy, sec-octyloxy, tert-octyloxy, cyclopentyloxy, cyclopropyloxy, cyclobutyloxy, cycloheptyloxy, 2
-Indanyloxy, 4-piperidinyloxy, tetrahydro-4H-pyra-4-nyloxy) is preferred.
As the branched alkoxy group, among them, a C _3-7 branched alkoxy group is preferable, and isopropoxy, sec-
Butoxy, 3-pentyloxy or 2,4-dimethyl-3-pentyloxy are particularly preferred. The branched alkoxy group may have a substituent, and examples of the substituent include C _1-4 alkyl, halogen, amino, mono- or di-C _1-4 alkylamino, C _{1-4 Examples} thereof include alkoxy and C _3-7 cycloalkyl. Among them, C _1-4 alkyl and halogen are preferred. C _1-4 alkyl and mono-
Or, as C _1-4 alkyl in di-C _1-4 alkylamino, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and the like can be mentioned. Among them, C _1-2 alkyl is preferred. Examples of the halogen include fluorine, chlorine, bromine and iodine, and among them, fluorine and chlorine are preferable. C _1-4
Examples of the alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and the like, of which methoxy and ethoxy are preferable. Examples of C _3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and among them, cyclohexyl is preferable.
The number of the substituents is 1 to 3, preferably 1 to 2.

[0054] Specific examples of the alkoxy group may branched optionally having the substituent, the R ^3j of the group represented by the formula -O-R ^3j, for example, isopropyl, sec- butyl, tert
-Butyl, isopentyl, sec-pentyl, tert-pentyl, 3-pentyl, isohexyl, sec-hexyl, tert
-Hexyl, isooctyl, sec-octyl, tert-octyl, 1,3-difluoro-2-propyl, 2,6-dimethyl-1-cyclohexyl, 3,5-dimethyl-1-cyclohexyl, cyclopentyl, cyclopropyl, 4- Methyl-1-cyclohexyl, cyclobutyl, cycloheptyl, 4-ethylcyclohexyl, 2-indanyl, 4
-Piperidinyl, N-methyl-4-piperidinyl, N-
Ethyl-4-piperidinyl, tetrahydro-4H-pyra-4-nyl, 1,3-bis (dimethylamino) -2-propyl, 1,3-dimethoxy-2-propyl, 4-amino-1-cyclohexyl, dicyclohexylmethyl And the like. As R ^1j , a C _1-4 alkyl or a C _3-7 branched alkoxy group optionally substituted by halogen is preferable, and further, isopropoxy optionally substituted by halogen is particularly preferable. In the above formula, examples of the C _1-8 alkanoylamino group represented by R ^2j include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, octanoylamino and the like. As the alkanoylamino group represented by R ^2j , a C _3-5 alkanoylamino group is preferable, and isobutyrylamino is particularly preferable. R ^2j has a phenyl group of 1 to
It is preferable that two substitutions be made, and one at the 4-position of the phenyl group.
Those having individual substitutions are particularly preferable.

As the compound used in the composition of the present invention, the compound of the general formula (XV) in the compound (X) is used.

Embedded image [Wherein R ^1k is an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl optionally substituted with alkyl, and R ^2k is an alkyl group or an aryl group. Alternatively, it represents an alkoxy group which may have a substituent. ] The compound (XV) represented by or its salt is preferable.

In the above formula, the alkoxy group in the alkoxy group represented by R ^1k , which is substituted with a group selected from (i) halogen, (ii) cycloalkyl, and (iii) alkyl-alkenyl optionally substituted, is , C _1-6 alkoxy groups are preferred, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentoxy, hexyloxy and the like. Of these, a C _1-3 alkoxy group is preferable, and methoxy is particularly preferable. In the above formula, R ^1k
In the above, halogen as a substituent on the alkoxy group includes fluorine, chlorine, bromine and iodine. Of these, fluorine is preferred. As the cycloalkyl as a substituent on the alkoxy group, C _3-10 cycloalkyl is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl. Among them, C _3-6
Cycloalkyl is preferred and cyclopropyl is especially preferred. The alkenyl group in the alkenyl group which may be substituted with alkyl as a substituent on the alkoxy group is preferably C _2-10 alkenyl, and examples thereof include vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl and isopropenyl. , Hexatrienyl, 3-octenyl and the like. Among them, a C _2-6 alkenyl group is preferable, and a C _2-4 alkenyl group is particularly preferable. As the alkyl in the alkenyl group which may be substituted with alkyl, C _1-3 alkyl is preferable, and examples thereof include methyl, ethyl, propyl and isoproyl, and particularly preferable is methyl, and the preferable alkenyl group substituted with alkyl is preferable. An example is 2-methylallyl.

R ^1k includes (i) halogen, (ii) C _3-10
A C _1-3 alkoxy group substituted with a group selected from cycloalkyl and (iii) C _2-10 alkenyl is preferred, vinyl-C _1-3 alkoxy is preferred, and allyloxy is particularly preferred. As the number of substituents in R ^1k ,
1 to 3 are preferable, and 1 to 2 are particularly preferable. As the alkyl group represented by R ^2k , a C _1-6 alkyl group is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. . Among them, a C _1-3 alkyl group is preferable, and a C ₃ alkyl group (n-propyl, isopropyl) is particularly preferable. As the aryl group represented by R ^2k , a C _6-14 aryl group is preferable, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, and anthracenyl. The alkoxy group in the alkoxy group which may have a substituent represented by R ^2k is preferably a linear or branched C _1-9 alkoxy group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentyloxy, sec-pentyloxy,
tert-pentyloxy, 3-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, se
c-hexyloxy, tert-hexyloxy, octyloxy, isooctyloxy, sec-octyloxy, tert
-Examples include octyloxy. Among them, a C _3-7 alkoxy group is preferable, and a C ₃ alkoxy group (n-propoxy, isopropoxy) is particularly preferable. Examples of the substituent of the optionally substituted alkoxy group represented by R ^2k include halogen, alkoxy, alkyl and cycloalkyl. As the halogen, fluorine,
Chlorine, bromine and iodine. Among them, fluorine,
Chlorine is preferred. As the alkoxy, C _1-4 alkoxy is preferable, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Among them, methoxy is particularly preferred. As the alkyl, C _1-4 alkyl is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these, methyl is particularly preferred. As the cycloalkyl, C _3-8 cycloalkyl is preferable, and for example,
Cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. Substituted alkoxy also includes cyclopentyloxy, cyclopropyloxy, cyclobutyloxy, cycloheptyloxy, 2-indanyloxy, 4-piperidinyloxy, tetrahydro-4H-pyra-4-nyloxy.

R ^2k is (1) C _1-3 alkyl, (2) C
_6-14 aryl group or (3) halogen, C _1-3 alkyl or C _3-7 alkoxy group optionally substituted by C _1-3 alkoxy is preferable, and isopropyl, phenyl or isopropoxy is particularly preferable. . The number of substituents in the R ^2k group is preferably 1 to 3, and 1 to 2
Individuals are particularly preferred. R ^2k is preferably substituted with one or two phenyl groups, and particularly preferably substituted with one phenyl group at the 4-position.

As the compound used in the composition of the present invention, the compound of the general formula (XXI) in compound (XX)

Embedded image {In the formula, R ^1y is hydrogen, an alkyl group or a formula — (CH ₂ ) p
Q [In the formula, p is an integer of 0 to 3, and Q is (1) 1 or 2
More than one (i) halogen, (ii) nitro, (iii) cyano, (iv)
Amino, (v) optionally substituted carboxyl group, (vi)
(Wherein, the A ^y is a chemical bond or a spacer group, R ^5y is an alkyl group) alkylenedioxy group or (vii) formula -A ^y -R ^5y may be substituted with a group represented by aryl Group, (2) represents a cycloalkyl group which may be substituted or (3) represents a heterocyclic group which may be substituted), R ^2y may be substituted with hydrogen or alkoxy. An alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group, R ^3y is an optionally substituted amino group, and R ^4y is substituted. An optionally substituted aryl group, r represents an integer of 0 to 3} (XX
I) or salts thereof are preferred.

Examples of the alkyl group in the alkyl group represented by R ^1y and R ^5y and the alkyl group represented by R ^2y which may be substituted with alkoxy include C _1-6 alkyl groups, examples of which are given below. As, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl,
Hexyl and the like are mentioned, and among them, an alkyl group having 1 to 3 carbon atoms is preferable. Examples of the aryl group in Q and the aryl group in the optionally substituted aryl group represented by R ^2y and R ^4y include a monocyclic or condensed polycyclic aromatic hydrocarbon group. Preferable specific examples thereof include C _6-14 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

The number of substituents on the aryl group is 1 or 2 or more, preferably 1 to 3. Examples of the substituent include (1) C _1-6 alkyl group (eg, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl and the like. The alkyl group may be substituted with alkyl-carbonyl or alkoxy-carbonyl. ), (2) optionally substituted C _2-6 alkenyl group (eg, vinyl, allyl, 1-butenyl,
2-butenyl and the like. The alkenyl group may be substituted with one or more C _1-10 acyl or C _1-6 alkoxy-carbonyl. ), (3) C _2-6 alkynyl group (eg, ethynyl, propargyl, 2-butynyl, 5-hexynyl, etc.), (4) C _3-7 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) ), (5) C _6-14 aryl group (eg, phenyl,
Naphthyl etc. The aryl group has, as a substituent, one or more (i) halogen, (ii) alkyl, (iii) alkoxy which may be further substituted with alkoxy, (iv)
Nitro, (v) cyano, (vi) formula ^{-S (O) n y -R 6y} ( wherein,
n represents an integer of 0 to 2 and R ^6y represents an alkyl group or amino. ) Group, (vii) amino, (viii) acyl, (i
It may have x) carbamoyl, (x) carboxy and (xi) hydroxy. ), (6) heterocyclic group [eg, 3 to 9-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg, furyl, thienyl, pyrrolyl) , Thiazolyl, imidazolyl, pyrazolyl, pyridyl, etc.), a 5- to 9-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg,
Oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl,
Piperidinyl, tetrahydropyranyl, morpholinyl,
Thiomorpholinyl, piperazinyl, etc.). The heterocyclic group is one or more of (i) halogen, (ii) alkyl, (iii) amino, (iv) acyl, (v) carbamoyl, (vi)
Carboxy, (vii) nitro, (viii) hydroxy, (ix) alkoxy and (x) equation ^{-S (O) n y -R 6y} ( wherein, n 0
~ 2, ^R6y represents an alkyl group. ) May have a group represented by) as a substituent. ], (7) C _7-13 aralkyl group (eg, benzyl, phenethyl, benzhydryl and the like. The aralkyl group may have one or two or more halogens), formula (8)

[0062]

Embedded image [In the formula, R ^11y is (i) hydrogen, (ii) C _1-6 alkyl ^optionally substituted with hydroxy, (iii) acyl (eg, C _1-6 alkyl-carbonyl, formyl, arylcarbonyl.
The acyl may be substituted with one or more halogen or alkoxy. ), (Iv) optionally substituted alkoxy, (v) hydroxy optionally substituted C _3-7 cycloalkyl, (vi) formula —S (O) ^ny —R
^6y (in the formula, n ^y is an integer of 0 to 2 and R ⁶ is an alkyl group). R ^12y represents hydrogen or C _1-6 alkyl. ] A group represented by the formula (9)

[0063]

Embedded image (In the formula, R ^24y represents hydrogen, an alkyl group or an aryl group, R ²⁵ represents hydrogen or an alkyl group, and R ^24y and R ^25y
And may form a 5- to 7-membered nitrogen-containing cyclic group which may have a substituent together with the adjacent nitrogen atom. xy is 0
Represents an integer of 3), (10) amidino group, (1
1) an acyl group (eg, C _1-8 alkanoyl group such as formyl, acetyl, propionyl, butyryl, octanoyl, etc., eg, methoxycarbonyl, ethoxycarbonyl,
C such as propoxycarbonyl and butoxycarbonyl
_1-8 Alkoxycarbonyl group, C _6-14 such as benzoyl
Aryl-carbonyl group, C such as benzylcarbonyl
_8-11 aralkylcarbonyl group, C _7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl and the like. These may be substituted, and as the substituent, for example,
1 to 3 halogens, alkylthio, alkoxy, oxo, hydroxy are mentioned. ), (12) optionally substituted carbamoyl group (eg, carbamoyl, N-monosubstituted carbamoyl group (eg, N- (C _1-7 alkyl) carbamoyl such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl) Groups), N, N-disubstituted carbamoyl groups (eg, N, N-di (C _1-6 , such as dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-propyl-N-methylcarbamoyl). (Alkyl) carbamoyl group, etc.), (13) sulfamoyl group, (14) N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl group, etc., N- (C _1-6 alkyl) ) Sulfamoyl group etc.),
(15) N, N-disubstituted sulfamoyl group (for example, N, N- such as dimethylsulfamoyl and diethylsulfamoyl)
Di (C _1-6 alkyl) sulfamoyl group), (16) carboxyl group, (17) C _1-3 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (18) hydroxyl group, (19) optionally substituted alkoxy group (eg, methoxy,
Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, hexyloxy and the like. Examples of the substituent include C
_1-6 alkanoyl (same as above),
C _1-3 alkyl group, halogen, C _1-3 alkylthio, C
_1-3 alkoxy, C _3-7 cycloalkyl (the same as those mentioned above), oxo and hydroxyl group can be mentioned. ),
(20) C _2-4 alkenyloxy group (eg, vinyloxy, allyloxy, etc.), (21) C _3-7 cycloalkyl-oxy group (eg, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, etc.), (22) C _{7 -13} aralkyl-oxy group (eg benzyloxy, benzhydryloxy etc.), (23) C _6-14 aryloxy group (eg phenyloxy, naphthyloxy etc.), (24) mercapto group, (25) C _{7 -13} aralkylthio groups (eg benzylthio, benzhydrylthio etc.), (26) C _6-14 arylthio groups (eg phenylthio, naphthylthio etc.), (27)
Wherein ^{-S (O) n y -R 6y} ( wherein, n represents an integer of 0 to 2, R
^6y represents an alkyl group. A group represented by (for example, methylthio, ethylthio, propylthio, methylsulfinyl,
Ethylsulfinyl, propylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), (28) C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, etc.), (29) sulfo group, (30) cyano group, (31) azido group, (3
2) nitro group, (33) nitroso group, (34) halogen (eg, fluorine, chlorine, bromine, iodine) and the like.

Examples of the cycloalkyl group in the ^optionally substituted cycloalkyl group represented by Q and R ^2y of R ^1y include a C _3-10 cycloalkyl group and a C _3-10 bicycloalkyl group. To be Specific examples thereof include, for example, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3,2,1] octyl, bicyclo [3,2,1] nonyl, Bicyclo [4,2,
1] nonyl, bicyclo [4,3,1] decyl and the like. Among them, cyclopentyl and cyclohexyl are preferred. The substituent of the cycloalkyl group is the aforementioned R ^2y
And the same substituents as those in the aryl group represented by R ^4y . Of these, alkyl, alkoxy and halogen are preferable.

The heterocyclic group in the ^optionally substituted heterocyclic group represented by Q of R ^1y is, for example, oxygen (O), sulfur (S), as a ring-constituting atom (ring atom), And a 5- to 13-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen (N),
Alternatively, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like can be mentioned. Suitable examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
Aromatic monocyclic heterocyclic groups such as tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl , Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-
Carborinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [ 1,
5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
And aromatic condensed heterocyclic groups such as 2,4-triazolo [4,3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl. Suitable as a non-aromatic heterocyclic group, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Preferred as the heterocyclic group are furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, benzofuryl, indolyl and quinolyl. Further, the heterocyclic group may have one or more, preferably 1 to 3 suitable substituents, and the substituent is substituted by the above-mentioned R ^2y and R ^4y. And the same substituents as those in the aryl group which may be used. Of these, halogen, alkyl, alkylthio and alkoxy are preferable.

In the above formula, the halogen as the substituent of the aryl represented by Q includes fluorine, chlorine, bromine and iodine. Examples of the substituent of the carboxyl group which may have a substituent in Q include alkyl, cycloalkyl, aryl, aralkyl, and heterocyclic group, which have the same meanings as described above. Examples of the alkylenedioxy in Q above include C _1-6
Examples include alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylmethylenedioxy, etc.). Examples of the intervening group represented by A ^y include C _1-4 alkylene (eg, methylene, ethylene, etc.), C _2-6 alkenylene (eg, vinylene, butadienylene, etc.), — (CH ₂ ) cNR ^26y — [ In the formula, c represents an integer of 0 to 3 and R ^26y represents hydrogen or C _1-6 alkyl (specific examples are the same as those described above).
A group represented by -CO-, -CONR ^27y- [wherein R
^27y is hydrogen, C _1-6 alkyl (specific examples are the same as those described above), C _3-7 cycloalkyl (specific examples are the same as those described above), C _6-14 aryl (Specific examples are
The same as above is shown. ), A heterocyclic group (specific examples thereof are the same as those mentioned above)], —S (O) m
^y - (. m ^y is represents an integer of 0 to 2) groups represented by, -O
^{-, - NR 27y S (O} ) z y - ( wherein, z ^y is an integer of 0 to 2, R ^27y is of the same meaning as defined above), and the like groups represented by.

Alkoxy in alkyl optionally substituted with alkoxy represented by the group R ^2y is C
_1-6 alkoxy is mentioned. Examples of the aralkyl group in the optionally substituted aralkyl group represented by R ^2y include an aryl-alkyl group. The aryl has the same meaning as the aryl group in the optionally substituted aryl group represented by R ² above. Examples of the alkyl include a C _1-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl, and hexyl. Examples of the substituent are the same as those of the optionally substituted aryl group represented by R ^2y and R ⁴ .

Examples of the ^optionally substituted amino group represented by R ^3y include compounds represented by the formula (1)

Embedded image (In the formula, R ^22y represents an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group, each of which may be substituted, w ^y is an integer of 0 to 3, and R ^23y is hydrogen or may be substituted. And (2) hexamethylenetetraamino. The alkyl group, cycloalkyl group, aryl group and heterocyclic group in this group have the same meanings as described above. Examples of the group which may be substituted on these include the same substituents as the above-mentioned ^optionally substituted aryl group represented by R ^2y and R ^4y .

As a preferred example of the intervening group represented by A ^y , a group represented by —O— or —S (O) m ^y — (in the formula, m ^y represents an integer of 0 to 2) is shown. Can be mentioned. Preferable examples of the group R ^1y, formula ^{_{Q- (CH 2) p y -}} ( wherein, Q and p ^y are as defined above.) Include groups represented by. In the above formula, preferred examples of the group R ^1y are for example hydrogen or the formula ^{_{- (CH 2) p y Q}} ' wherein, Q' is halogen, nitro, cyano, amino or formula -A'-R ^5y ' (In the formula, A ^y ′ represents —O— or —S—, and R ^5y ′ represents alkyl) represents an aryl group which may be substituted. p ^y has the same meaning as defined above]. As a further preferred example of R ^1y, the ^formula-
(CH ₂₎ p ^y Q wherein the integer p ^y is 0 to 3, Q is one or two or more (i) halogen and wherein -A ^y -R ^5y
(Wherein, A ^y is -O- or -S (O) m ^y - (wherein, m ^y
Represents an integer of 0 to 2), and R ^5y represents an alkyl group).
Represents an aryl group which may be substituted with a group represented by]. More preferred examples of R ^1y include halogen or the formula —A ^y ″ —R ^5y ″ (wherein A ^y ″ represents —O— or —S—, and R ^5y ″ represents an alkyl group). And a C _6-14 aryl-methyl group which may be substituted with a group represented by. More preferable examples of R ^1y the formula _{Q '''- (CH 2} ) p y - ( wherein, Q''' is an aryl which may be substituted by halogen, p ^y is 0
Indicates an integer of 3. ) The group represented by is mentioned.

Preferable examples of R ^2y include (1) an alkyl group optionally substituted with alkoxy, (2) one or more (i) amino, (ii) acyl, (iii) carbamoyl, (iv) carboxy, (v) nitro, (vi) hydroxy, (vi
i) an alkoxy which may be substituted with an alkoxy, (vii
i) halogen and (ix) formula ^{-S (O) n y -R 6y} ( wherein, n ^y
Is an integer of 0 to 2, R ^6y represents an alkyl group), an aryl group which may be substituted with a group represented by (3) an aralkyl group which may be substituted with a halogen, or (4) cycloalkyl Groups. In the above formula, preferred examples of the group represented by R ^2y include, for example, (1) a C _1-6 alkyl group optionally substituted by C _1-3 alkoxy, (2) one or more. amino, acyl, carbamoyl, carboxy, nitro, hydroxy, C _1-3 alkoxy, sulfo, in a halogen or the formula ^{-S (O) n y -R 6y} ( wherein, n ^y
Represents an integer of 0 to 2, and R ^6y represents C _1-3 alkyl. ) A C _6-14 aryl group which may be substituted with a group represented by
(3) C _3-10 cycloalkyl group can be mentioned. More preferable examples of R ^2y include (1) an alkyl group optionally substituted with alkoxy, (2) one or more (i) hydroxy, and alkoxy optionally substituted with (ii) alkoxy. , (Iii) halogen and (iv) formula —S (O) n—R ⁶ (in the formula, n ^y represents an integer of 0 to 2 and R ^6y represents an alkyl group)
An aryl group which may be substituted with a group represented by (3)
Examples thereof include an aralkyl group and a (4) cycloalkyl group. In the above formula, preferred examples of the group represented by R ^2y include, for example, (1) a C _1-6 alkyl group optionally substituted by C _1-3 alkoxy, (2) C _1-3 alkoxy or wherein ^{-S (O) n y -R 6y} ( wherein, n ^y is an integer of 0 to 2, R ^6y
_Represents C _1-3 alkyl. And an aryl group which may be substituted with a group represented by), and (3) C _3-10 cycloalkyl group. Further preferred examples of R ^2y include alkoxy optionally substituted with one or more (1) alkoxy, (2) halogen and (3) formula —S (O) ^ny —R.
^An aryl group which may be substituted with a group represented by ^6y (in the formula, n ^y is an integer of 0 to 2 and R ^6y is an alkyl group) is ^exemplified .

In the above formula, preferred examples of the ^optionally substituted amino group represented by R ^3y are:

Embedded image [Wherein R ^22y 'is (1) one or more (i) amino,
(ii) acyl, (iii) carbamoyl, (iv) carboxy, (v)
Nitro, (vi) hydroxy, (vii) alkoxy optionally substituted alkoxy, (viii) halogen, (ix) alkyl and (x) equation ^{-S (O) n y -R 6y} ( wherein, n 0-2
R ^6y represents an alkyl group), an aryl group which may be substituted with a group represented by (6), (2) one or more (i) amino, (ii) acyl, (iii) Carbamoyl, (iv)
Carboxy, (v) nitro, (vi) hydroxy, (vii) alkoxy, (viii) halogen, (ix) alkyl and (x) formula-S
(O) n ^y -R ^6y (wherein, n ^y is an integer of 0 to 2, R ^6y is an alkyl group shows a) represented by heterocyclic group which may be substituted with a group, (3) halogen An aralkyl group which may be substituted with, formula (4)

Embedded image (In the formula, R ^24y represents hydrogen, an alkyl group or an aryl group, R ^25y represents hydrogen or an alkyl group, and R ^24y and R
^25y may form a 5- to 7-membered nitrogen-containing cyclic group (which may be substituted) together with the adjacent nitrogen atom.
^xy represents an integer of 0 to 3) or an alkyl group which may be substituted with (5) alkylthio, w ^y represents an integer of 0 to 3, and R ^23y ′ represents hydrogen or alkyl. Indicates a group. Or a hexamethylenetetraamino group.

In the above formula, preferred examples of the ^optionally substituted amino group represented by R ^3y are, for example,

Embedded image [Wherein R ^22y ″ is (1) alkyl, (2) one or more halogen, nitro, alkyl or formula —S (O) n
(wherein the integer n ^y is 0 to 2, R ^6y is alkyl or amino.) ^y -R ^6y may be substituted with a group represented by phenyl, substituted with (3) halogen or alkyl Represents an optionally substituted heterocyclic group or (4) N-monosubstituted alkylcarbamoyl. w ^y represents an integer of 0 to 3.
R ^23y ″ represents hydrogen or an alkyl group. Or a hexamethylenetetraamino group. Further preferred examples of the group R ^3y include those of the formula

Embedded image [Wherein R ^22y '''is (1) an aryl group optionally substituted by alkylthio, (2) a heterocyclic group, (3)

Embedded image (In the formula, R ^24y 'represents hydrogen or an alkyl group, R ^25y ' represents hydrogen or an alkyl group, and R ^24y 'and R ^25y ' together with the adjacent nitrogen atom form a 5- to 7-membered nitrogen-containing cyclic group. Or (4) or an alkyl group which may be substituted with (4) alkylthio, w ^y represents an integer of 0 to 3, and R ^23y ′ ″ represents hydrogen or an alkyl group. . And an optionally substituted amino group represented by the formula: In the above formula, more preferable examples of the group represented by R ^3y include, for example, the formula:

Embedded image Wherein, R ^22y 'is (wherein the integer n ^y is 0 to 2, R ^6y is alkyl.) Formula -S (O) n ^y -R ^6y optionally substituted by a group represented by Optionally represents phenyl or pyridyl. w ^y is an integer of 0 to 3, R ^23y 'is hydrogen or an alkyl group. ] The group represented by this is mentioned.

In the above formula, preferable examples of the optionally substituted aryl group represented by R ^4y include one or more (1) optionally substituted amino groups and (2) acyl. , (3) optionally substituted albamoyl group, (4) carboxy, (5) nitro, (6) hydroxy, (7) optionally substituted alkoxy and (8) optionally substituted alkenyl group And an aryl group which may be substituted with. More preferred R ^4y is one or more formula (1).

Embedded image [Wherein R ^11y 'is (i) hydrogen, (ii) alkyl, (iii) optionally substituted alkoxy, (iv) optionally substituted acyl or (v) formula —S (O) n ^y −R ^6y (where n ^y is 0
To R 2, R ^6y represents an alkyl group), and R ^12y ′ represents hydrogen or an alkyl group. ] A group represented by: (2) acyl, (3) carbamoyl, (4) N-mono or di-alkylamino, (5) nitro, (6) one or more alkoxy, alkanoyl, oxo, An alkoxy group which may be substituted with hydroxy, cycloalkyl and halogen, (7) an alkenyl group which may be further substituted with alkoxycarbonyl or alkylcarbonyl, and (8) an aryl group which may be substituted with alkenyloxy, Can be mentioned. More preferred R ^4y is one or more formula (1).

Embedded image [Wherein R ^11y ″ is (i) hydrogen, (ii) alkyl, (iii) alkoxy optionally substituted with halogen or alkoxy, (iv) formyl, (v) substituted with halogen or alkoxy, which may alkanoyl, (vi) a group (wherein, n ^y is an integer of 0 to 2, R ^6y is an alkyl group) benzoyl or (vii) expression -S (O) n ^y -R ^6y represented by To R
^12y '' represents hydrogen or an alkyl group. ] A group represented by: (2) alkoxy, alkanoyl or cycloalkyl-substituted alkoxy group, (3) N-mono or di-alkylcarbamoyl, (4) nitro, (5) alkoxycarbonyl or alkyl Examples thereof include an alkenyl group which may be further substituted with carbonyl or an aryl group which may be further substituted with (6) alkenyloxy.

In the above formula, a preferred example of aryl in the ^optionally substituted aryl group represented by R ^4y is phenyl. Preferred examples of the substituents include amino, acyl, carbamoyl, N-monosubstituted alkylcarbamoyl, carboxy, nitro, hydroxy,
C _1-3 alkoxy optionally substituted with C _1-3 alkoxy, formula

Embedded image (In the formula, R ^31y represents C _1-6 alkyl, C _1-3 alkoxy optionally substituted with C _1-3 alkoxy, formyl, and R ³² represents hydrogen, C _1-6 alkyl). Mention may be made of the groups represented, C _2-4 alkenyl groups optionally substituted by alkoxycarbonyl or alkylcarbonyl. In the above formula, a preferred example of aryl in the ^optionally substituted aryl group represented by R ^4y is phenyl. Preferable examples of the substituents include amino, acyl, N-monosubstituted alkylcarbamoyl, nitro, C _1-3 alkoxy optionally substituted by C _1-3 alkoxy, formula

Embedded image (Wherein, R ^33y is C _1-6 alkyl, C _1-3 alkoxy optionally substituted C _1-3 acyl, C _1-4 acyl with optionally substituted C _1-3 alkoxy, benzoyl , Formyl, and R ^34y represents hydrogen, C _1-6 alkyl), C _1-3 alkoxy-carbonyl or C _1-3.
C2-4 alkenyl groups substituted with alkyl-carbonyl are mentioned.

In any of the above cases, the number of substituents is preferably 1 to 3. r is preferably 1. p
Is preferably 1. wy is preferably 1. Examples of the 5- to 7-membered nitrogen-containing cyclic group include, for example, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,
2,3-triazolidinyl, 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethyleneamino, oxazolidino,
Examples include morpholino, thiazolidino or thiomorpholino. Of these, 5- to 6-membered ones are preferable, and for example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferable. The nitrogen-containing cyclic amino group may have a substituent, and examples of the substituent include C _1-6 alkyl, C _6-14 aryl, C _7-10 aralkyl, benzhydryl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C
_1-6 alkoxy-carbonyl is mentioned. Preferred substituents include C _1-6 alkyl, among which C
_1-3 alkyl is more preferred.

As the alkyl in the above definition of the group, alkyl having 1 to 10 carbon atoms is preferable, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, Pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned, among which alkyl having 1 to 6 carbon atoms is preferable,
Particularly, alkyl having 1 to 3 carbon atoms is preferable. As the acyl in the definition of the above group, C _1-10 acyl is preferable,
Examples of the acyl include alkanoyl, aryl-carbonyl, aralkyl-carbonyl, aralkyloxy-
Carbonyl can be mentioned, and as these alkanoyl, aryl and aralkyl, the same ones as mentioned above can be mentioned. Preferable examples of acyl or alkanoyl include alkyl-carbonyl, and the alkyl includes the same ones as described above. As alkoxy in the definition of the above group, C _1-6 alkoxy is preferable, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
t-butoxy, pentyloxy, isopentyloxy,
Neopentyloxy, hexyloxy and the like can be mentioned, and among them, alkoxy having 1 to 3 carbon atoms is preferable. Preferred alkenyl in the above group definition is C
_2-4 alkenyl, and examples thereof include, for example,
Examples include vinyl, allyl, 1-butenyl and 2-butenyl. Preferred aryl in the above definition of the group is C _6-14 aryl, examples of which include phenyl and naphthyl. Preferred as aralkyl in the definition of the above group are:
Examples include C _7-10 aralkyl, examples of which include benzyl and phenethyl. Halogen in the definition of the above groups includes fluorine, chlorine, bromine and iodine.

As the compound used in the composition of the present invention, among the compounds (XXX), the compound of the general formula (XXX
I)

Embedded image [ ^Wherein , R ^1z is a formula

Embedded image (Wherein, R ^5z represents an aralkyl group, R ^6z represents an alkyl group,
X ^z represents an alkylene group) or an optionally halogenated alkyl group; R ^2z represents an acylaminoaryl group; R ^3z represents a halogenoaralkyl group;
^4z represents a carboxyl group which may be esterified or amidated].
I) or a salt thereof is preferred.

The aralkyl group represented by R ^5z in the above-mentioned group R ^1z is preferably a C _7-19 aralkyl group, and examples thereof include benzyl, phenethyl, biphenylmethyl, benzhydryl and the like. Among them, benzyl is preferred. The alkyl group ^represented by the above-mentioned group R ^6z is preferably a C _1-6 alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, Examples include n-pentyl, isopentyl, neopentyl, hexyl and the like. Among them, a C _1-3 alkyl group is preferable. The alkylene group represented by X ^z in the above group R ^1z is preferably C _1-6 alkylene, and examples thereof include methylene, ethylene, propylene,
Butylene such as pentylene and hexylene.
Among them, a C _1-3 alkylene group is preferable. Examples of the alkyl group in the ^optionally halogenated alkyl group in the group R ^1z include the same ones as described above. Examples of the halogen include fluorine, chlorine, bromine, and iodine. Preferred examples of the optionally halogenated alkyl group include bromomethyl. Examples of the acylaminoaryl group represented by R ^2z include C
_1-6 acyl-amino-C _6-14 aryl group is preferred, and C
Examples of _1-6 acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and the like, and examples of C _6-14 aryl include phenyl, naphthyl, anthryl, and the like.

As the halogenoaralkyl group represented by R ^3z , a halogeno C _7-19 aralkyl group is preferable.
Examples of the halogen in the halogenoaralkyl group include fluorine, chlorine, bromine, and iodine. Examples of the aralkyl group in the halogenoaralkyl group include, for example,
Examples include benzyl, phenethyl, benzhydryl, and the like. Among them, benzyl is preferred. The esterified carboxyl group ester represented by R ^4z is preferably a C _1-6 alkyl ester, and examples thereof include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl. Ester, s-butyl ester, t-butyl ester, n-pentyl ester, isopentyl ester, neopentyl ester, n-hexyl ester and the like can be mentioned. Of these, ethyl ester is most preferable. ^Examples of the amidated carboxyl group represented by R ^4z include carbamoyl, methylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl and isopropylcarbamoyl. The above compound (XX
The most preferable one of XI) is N as the group R ^1z.
-Benzyl-N-methylaminomethyl, R ^2z is propionylaminophenyl or isobutyrylaminophenyl, R ^3z is difluorobenzyl, and R ^4z is ethoxycarbonyl.

Compounds (X) to (X used in the present invention
V), (XX), (XXX), (XXI) and (XX)
XI) and salts thereof can be easily produced by a known method or by itself. Specific examples of the method include, for example, the following production methods or methods analogous thereto. [Production Method 1] An appropriate ketone or aldehyde (i) having an active methylene group was prepared by the method of Karl Gewald et al. [K. Gewald, E. Schinke and H. Bφttcher, Chem. Ber.,
99 , 94-100 (1966)], and reacting a cyanoacetate derivative with sulfur to produce a 2-aminothiophene derivative (ii)
Convert to That is, in the case of a ketone (R ¹ ≠ H), (i) and a cyanoacetate derivative are heated and refluxed in an appropriate solvent, for example, toluene, in the presence of acetic acid and ammonium acetate, and the alkylidene cyanoacetate derivative is once heated. After heating in a suitable solvent, for example, ethanol in the presence of sulfur and a base, the 2-aminothiophene derivative (ii)
Get. In the case of the aldehyde (R ¹ ′ = H), the aldehyde is heated in an appropriate solvent, for example, N, N-dimethylformamide in the presence of a cyanoacetate derivative, sulfur and a base.
-An aminothiophene derivative (ii). The resulting compound (ii) is reacted with diethyl ethoxymethylenemalonate under heating according to the method of Kuwata et al. [German Patent No. 2,435,025] to obtain an adduct (iii), which is then added to a solvent which does not adversely influence the reaction (eg, In the presence of an alcohol such as ethanol or methanol), a base (eg, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide).
After stirring at 70 ° C. to obtain carboxylic acid (iv), the obtained carboxylic acid (iv) is converted to polyphosphate (PPE)
In the middle, heat ring closure is performed to obtain a thieno [2,3-b] pyridine derivative (v). In the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as pyridine, triethylamine, etc.), the compound (v) is subjected to a solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide) which does not adversely affect the reaction. Amides) at about 10 to 100 ° C. to give 4,7-dihydro-4-compound represented by formula (XIa)
An oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative is obtained. Then, the compound (XIa) is dissolved in a solvent that does not adversely affect the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile (AIBN). Stir at about 30-100 ° C. with N-bromosuccinimide (NBS) to obtain compound (XIb). If necessary, a halogen atom is converted to an alkylsulfonyloxy or alkylarylsulfonyloxy group. Further, the compound (XIb) the presence of a base, does not adversely affect the reaction with various amines (H-R ⁹⁾ solvent (e.g., N, N- dimethylformamide,
Amides such as N, N-dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol)
The mixture is stirred at about 10 to 100 ° C. to give a free form of compound (XI ′), and then compound (XI ′) is produced with hydrochloric acid-ethanol. The above manufacturing method 1 is shown in [Equation 1]. Where R ¹ ′
Is hydrogen or an alkyl group which may be substituted, R ′ is an alkyl group, X is a leaving group, Xa is halogen, R ⁴ ′
Is ethoxycarbonyl, R ⁵ ′ is hydrogen, R ² , R ³ , R
⁹ and n have the same meaning as described above. The alkyl group represented by R ¹ 'and R'has the same meaning as described above. m is 0-6
Indicates an integer.

[0081]

[Equation 1]

The leaving group represented by X is, for example, a nucleophile [eg, a hydrocarbon residue having a negatively charged hetero atom (eg, oxygen atom, sulfur atom, nitrogen atom, etc.)] , A group which can easily undergo a substitution reaction. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), alkanoyloxy (eg, acetoxy, etc.), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-arylsulfonyloxy (eg, p-toluene) Sulfonyloxy etc.) and the like. The halogen represented by Xa is fluorine, bromine, chlorine, iodine, preferably bromine.

[Production Method 2] The method of Karl Gewald, et al. [K. Gewald, Chem. Ber., 98 , 3571-3577 (1965); K. Gew
aldand E. Schinke, Chem. Ber., 99 , 2712-2715 (196
6)] and reacting the 5-position-unsubstituted 2-aminothiophene derivative (vi) with diethyl ethoxymethylenemalonate under heating according to the method of Kuwata et al. [German Patent No. 2,435,025] in the same manner as in Production Method 1 described above. The adduct (vi
After i), use a solvent that does not adversely affect the reaction (eg, alcohols such as ethanol and methanol)
In the presence of a suitable base (eg, alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, etc.), about 10-6
Stir at 0 ° C. to obtain carboxylic acid (viii). The obtained (viii) is subjected to various electrophilic substitution reactions, where appropriate, a suitable functional group conversion is carried out, a substituent represented by R ² ″ is introduced, and then ring closure by heating in polyphosphate (PPE) is performed. Thus, a thieno [2,3-b] pyridine derivative (ix) is obtained. The electrophilic substitution reaction includes, for example, nitration (fuming nitric acid-concentrated sulfuric acid, sodium nitrate-concentrated sulfuric acid), acylation (acid chloride-aluminum chloride), formylation (phosphorus oxychloride-N, N-dimethylformamide or N
-Methylformanilide), halogenated (N-bromosuccinimide, bromine-pyridine) and the like. Hereinafter, compounds (XIa ′), (XIb) and (XI ′) can be produced from compound (ix) in the same manner as in Production Method 1 described above.
The above manufacturing method 2 is shown in [Equation 2]. In the formula, each symbol has the same meaning as described above.

[0084]

[Equation 2]

[Production Method 3] The allantonyl acid derivative (x) is used in an amount equivalent to or excess of the compound (x) in a solvent that does not adversely influence the reaction (eg, tetrahydrofuran, ethers such as 1,4-dioxane). Equation (CCl
₃ O) compound represented by the added ₂ CO, about 30-110
Stir at ° C to obtain isatoic anhydride derivative (xi). Then, the aralkyl halide derivative represented by the formula (xii) is converted into a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, N, Hydrogenation of bases (eg, alkali metal carbonates such as potassium carbonate, sodium hydride, potassium hydride, etc.) in amides such as N-dimethylformamide and N, N-dimethylacetamide, and alkylsulfoxides such as dimethylsulfoxide. Agitation at about 40 to 130 ° C. in the presence of an alkali metal, an alkali metal alkoxide such as potassium-butoxide, etc.
This is referred to as an aralkyl-substituted derivative (xiii). The derivative (xii
i) is not adversely affected in the presence of a base (eg, an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride or potassium hydride, or an alkali metal alkoxide such as potassium-butoxide). Solvents (eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene,
In amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and alkylsulfoxides such as dimethylsulfoxide at 40 to 110 ° C., an equivalent or a small excess of the compound (xiii) (eg, about 1. 1 to 1.5 equivalents)
Compound (Va) can be produced by reacting with the β-keto acid ester derivative (xiv). The above manufacturing method 3 is shown in [Equation 3]. In the formula, each symbol has the same meaning as described above.

[0086]

(Equation 3)

[Production Method 4] The pyridine derivative (xv) is used in a solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran, 1,4-dioxane, etc.) in an amount equivalent to or excess of the compound (xv). A compound represented by (CCl ₃ O) ₂ CO is added, and the mixture is stirred at about 30 to 110 ° C. to give an acid anhydride derivative (xvi). Next, the aralkyl halide derivative (xii) represented by the formula (xii) is converted into a solvent that does not adversely affect the reaction (eg, tetrahydrofuran, 1,4-
Ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, N, N-dimethylformamide, N, N
Bases (eg, alkali metal carbonates such as potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, potassium butoxide and the like) in amides such as dimethylacetamide, alkylsulfoxides such as dimethylsulfoxide, etc. In the presence of an alkali metal alkoxide, etc., the mixture is stirred at about 40 to 130 ° C. to obtain an aralkyl-substituted derivative (xvii). The derivative (xvii) is converted to a base (eg,
Alkali metal carbonates such as potassium carbonate, sodium hydride,
In the presence of alkali metal hydrides such as potassium hydride, alkali metal alkoxides such as potassium-butoxide, etc., solvents that do not adversely affect the reaction (eg, ethers such as tetrahydrofuran, 1,4-dioxane, benzene, toluene, etc.) In the form of aromatic hydrocarbons, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and alkylsulfoxides such as dimethylsulfoxide at 40 to 110 ° C. in equivalent or small amounts to the compound (xvii). The compound (Vb) can be produced by reacting with an excess (eg, about 1.1 to 1.5 equivalents) of the β-keto acid ester derivative (xiv). The above manufacturing method 4 is shown in [Equation 4]. In the formula, each symbol has the same meaning as described above.

[0088]

(Equation 4)

[Production Method 5] The 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (Va) was treated with a suitable solvent (eg, tetrahydrofuran) which does not adversely influence the reaction. , Ether such as ethyl ether and dioxane), a suitable reducing agent (eg, lithium aluminum hydride) is added, and the mixture is stirred at about 0 to 80 ° C. to obtain a reduced derivative (Vb). The compound (Vb) is stirred at about 10 to 100 ° C. in a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide and dimethylacetamide) in the presence of a halogenated aralkyl derivative and a base,
A 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative represented by the formula (XIc) is obtained. The derivative is combined with a suitable oxidizing agent (eg, manganese dioxide) in a suitable solvent (eg, dichloromethane, chloroform) with about 10-8.
Stir at 0 ° C. to give the 5-position formyl derivative. The obtained derivative (XId) is mixed with a Grignard reagent (R ^25d MgXa) in a suitable solvent (eg, ethers such as tetrahydrofuran and ethyl ether) which does not adversely affect the reaction.
By stirring at ~ 80 ° C, the corresponding secondary alcohol derivative (XIe) is obtained, and a suitable oxidizing agent (eg, a metal such as manganese dioxide) in a suitable solvent (eg, halogenated hydrocarbons such as dichloromethane and chloroform) Oxide) and about 10-80
Stir at <RTIgt; C </ RTI> to obtain the 5-position carbonyl derivative (XIf).
The above Production Method 5 is shown in [Equation 5]. In the formula, R ^25d represents a hydrocarbon residue, and other symbols have the same meanings as described above. The hydrocarbon residue represented by R ^25d has the same meaning as the hydrocarbon residue in the carbonyl group substituted by the hydrocarbon residue represented by R ⁴ .

[0090]

(Equation 5)

[Production Method 6] 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (XIa ') was prepared in advance in a suitable solvent (example Produced from a suitable aluminum reagent (eg, trimethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines in a halogenated hydrocarbon such as dichloromethane, ether such as tetrahydrofuran, ethyl ether, dioxane) Stir with the amide derivative at about 10 to 100 ° C. to obtain 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid amide derivative
(XIa ''). The derivative (XIa ″) is mixed with a Grignard reagent in a suitable solvent that does not adversely influence the reaction (eg, tetrahydrofuran, ethyl ether, etc.) with about −78 to 8-8.
Stir at 0 ° C. to obtain the corresponding ketone derivative (XIf). The above Production Method 6 is shown in [Equation 6].

[0092]

(Equation 6)

[0093] wherein, R ^{26 d} is an alkyl or aryl group, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols are of the same meaning as defined above] is represented by the above R ^{26 d} Alkyl and aryl have the same meanings as above. The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted by the hydrocarbon residue represented by R ⁴ . Other symbols are as defined above.

[Production method 7] The 4,7-dihydro-5-hydroxymethyl-4-oxothieno [2,3-b] pyridine derivative (XIc) was prepared in advance in a suitable solvent (eg, dichloromethane) which does not adversely influence the reaction. Halogenated hydrocarbons such as etc., tetrahydrofuran, ethyl ether, ethers such as dioxane, pyridine), suitable halogenating reagents (eg, thionyl chloride, methanesulfonyl chloride etc.)
And stirred at about 0 to 100 ° C. to give 4,7-dihydro-5-
Let be a halomethyl-4-oxothieno [2,3-b] pyridine derivative (XIg). The derivative is stirred with a suitable nucleophile at about 0 to 100 ° C. in a suitable solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran and ethyl ether, amides such as dimethylformamide).
The corresponding 5-substituted derivative (XIh) is prepared. The above Production Method 7 is shown in [Equation 7].

[0095]

(Equation 7)

[Wherein X ′ is a leaving group, Z is an oxygen atom,
A sulfur atom, a group represented by the formula —NH or a nitrogen atom substituted with a hydrocarbon residue, and other symbols have the same meanings as above] Examples of the leaving group represented by X ′ include A nucleophile [eg, a hydrocarbon residue having a negatively charged hetero atom (eg, oxygen atom, sulfur atom, nitrogen atom, etc.) represented by the above ^- ZR ²⁷ etc.] can easily perform a substitution reaction. Acceptable groups are mentioned. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), aralkyloxy (eg, acetoxy, etc.), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-arylsulfonyloxy (eg, p-toluenesulfonyl). Oxy etc.) and the like. The hydrocarbon residue in the nitrogen atom which may be substituted by the hydrocarbon residue is the same as the hydrocarbon residue in the carbonyl group which may be substituted by the hydrocarbon residue represented by R ^4. Having.

[Production Method 8] 4,7-Dihydro-5-formyl-4-oxothieno [2,3-b] pyridine derivative
(XId) is converted to a suitable solvent which does not adversely affect the reaction in advance (eg, ethers such as tetrahydrofuran, ethyl ether, dioxane, pyridine)
(Wittig) Reagent (XI)
j). The derivative is added to a suitable reducing agent [approx. For example, under a hydrogen stream, catalyst (eg,
Hydrogenation using palladium carbon catalyst) and about 10
After stirring at １００100 ° C., the corresponding 5-substituted derivative (XI
j). The above Production Method 8 is shown in [Equation 8].

[0098]

(Equation 8)

[In the formula, R ^29d and R ^30d each represent hydrogen or a hydrocarbon residue, and each other symbol has the same meaning as described above] As the hydrocarbon residue represented by R ^29d and R ^30d above, Is
It has the same meaning as the hydrocarbon residue in the carbonyl group substituted by the hydrocarbon residue represented by R ⁴ .

[Production method 9] 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (XIf ') was prepared in advance in a suitable solvent (eg, , Ethers such as tetrahydrofuran, dioxane, alcohols such as ethyl alcohol, etc.) in an acid (eg, an inorganic acid such as hydrochloric acid) or an aqueous alkali solution (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) Alkali metal (1 to 4 N aqueous solution) is added and stirred at about 10 to 100 ° C. for hydrolysis. A suitable solvent that does not adversely affect the reaction of the obtained 5-position carboxylic acid derivative (XIk) (eg, ethers such as diphenyl ether, aromatic hydrocarbons such as toluene)
Heating at about 50-200 ° C. in the middle gives the corresponding decarboxylated derivative (XIn). The above Production Method 9 is shown in [Equation 9].
In the formula, each symbol has the same meaning as described above.

[0101]

[Equation 9]

[Production Method 10] The urea derivative (II) is produced from the 2-aminothiophene derivative (ii) by, for example, the following Method A or B. 1. Method A: produced by the method described in Production Method 1
The aminothiophene derivative (ii) or a salt thereof is reacted with an isocyanate derivative. Examples of the isocyanate derivative include a derivative represented by the formula R ^2f -NCO (wherein R ^2f has the same meaning as described above). The reaction of compound (ii) or a salt thereof with an isocyanate derivative does not adversely affect the reaction (eg, tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene)
Medium, at about 15-130 ° C. The isocyanate derivative is used in an amount of about 1-5 equivalents, preferably about 1.1-2.5 equivalents, relative to compound (ii). The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days. 2. Method B: produced by reacting a 2-aminothiophene derivative (ii) or a salt thereof with phosgene or an equivalent thereof (eg, diphosgene such as bis (trichloromethyl) carbonate, triphosgene such as trichloromethylchloroformate). An amine (eg, a compound represented by the formula R ^2f —NH ₂ (where R ^2f has the same meaning as described above) or the like is added to the isocyanate derivative. The reaction of compound (ii) or a salt thereof with phosgene or an equivalent thereof is carried out in a solvent that does not adversely affect the reaction (eg, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform).
Performed at 0-120 ° C. Phosgene or an equivalent thereof is used in an amount of about 0.5 to 2 equivalents, preferably about 0.9 to 1.1 equivalents, relative to compound (ii). The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days. The amine addition reaction is carried out in a solvent that does not adversely influence the reaction (eg, pyridine, tetrahydrofuran, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene) at about 15 to 130 ° C. The amine is used in an amount of about 1-5 equivalents, preferably about 1.1 equivalents, relative to compound (ii).
Use ~ 3 equivalents. The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days. The obtained compound (xv) or a salt thereof is treated with a base to carry out a ring-closure reaction to obtain a thieno [2,3-d] pyrimidine derivative (xvi). The ring closure reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol; dioxane;
Ethers such as tetrahydrofuran; As the base, for example, alkali metal alkoxides such as sodium methylate, sodium ethylate, and sodium isopropoxide, and alkali metal hydrides such as sodium hydride are used. The amount of the base used is the compound (xv)
About 1.1 to 5 equivalents, preferably about 1.5 to 3 equivalents are used. The reaction temperature is about 10 ° C to the boiling point of the working solvent, preferably about 25 ° C to the boiling point of the working solvent. The reaction time is several minutes to several days, preferably about 10 minutes to
Two days. Compound (xvi) is reacted with a aralkyl halide derivative and a base (eg, an organic base such as pyridine, triethylamine, etc.) in a solvent (eg, amides such as dimethylformamide, dimethylacetamide) that does not adversely affect the reaction in the presence of about 10%. Stir at ~ 100 ° C,
2,4-Dioxothieno [2,3-d] pyrimidine derivative (IIa) is obtained. Then, the compound (IIa) is treated with N-bromo compound in a solvent that does not adversely affect the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile. Succinimide (NB
S) and stirred at about 30-100 ° C to give compound (II)
get b). Further, a solvent which does not adversely affect the reaction of the compound with various amines in the presence of a base (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol)
Then, the mixture is stirred at about 10 to 100 ° C to produce the compound (II). If necessary, the compound is salted with a suitable acid (eg, hydrochloric acid, oxalic acid). The above-mentioned production method 10
0]. In the formula, each symbol has the same meaning as described above.

[0103]

(Equation 10)

[Production Method 11] The amino group of the 2-aminothiophene derivative (xvii) is protected (eg, Boc), and Ge is used.
r. Pat. , 2155403 (1972) or J
ap. Pat. , 73, 01664 (1973) in the presence of an acyl halide derivative and a base in a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide and dimethylacetamide) at about 0 to 100 ° C.
Stirring to obtain the derivative (xviii), stirring with a suitable salt (eg, lithium iodide) in a suitable solvent (eg, acetone, methyl ethyl ketone) to give a derivative (xix), and then a suitable amine (eg, A solvent that does not adversely affect the reaction (eg, toluene, dimethylformamide, dimethylacetamide,
If necessary, use a suitable catalyst (eg, methanol, ethanol, etc.) (eg sodium ethoxide, toluene sulfonic acid,
Etc.) and the mixture is stirred at about 30 to 120 ° C. to obtain the derivative (VIIa) by a dehydration ring closure reaction. In the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as potassium carbonate, pyridine, triethylamine, etc.) in a solvent (eg, amides such as dimethylformamide, dimethylacetamide) that does not adversely influence the reaction, 10 to
Stir at 100 ° C. to remove 2-oxothieno [2,3
-E] An azepine derivative (VIIb) is obtained. Then, the compound (VIIb) in a solvent that does not adversely influence the reaction (eg, carbon tetrachloride, halogenated hydrocarbons such as chloroform),
The mixture is stirred with N-bromosuccinimide (NBS) in the presence of α, α′-azobisisobutyronitrile at about 30 to 100 ° C. to obtain the compound (VIIc). Further, about 10 to 10 of the compound in the presence of a base in a solvent that does not adversely affect the reaction with various amines (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol). Stir at 100 ° C. to produce compound (VIId). If necessary, the compound is salified with a suitable acid (eg, hydrochloric acid, oxalic acid). The above manufacturing method 2 is shown in [Equation 11].

[0105]

[Equation 11] [Wherein each symbol has the same meaning as described above]

[Production Method 12] The amino group of the 2-aminothiophene derivative (ii) produced by the method described in Production Method 1 is protected (eg, Boc), and a halogenated aralkyl derivative and a base (eg, potassium carbonate are included). , An organic base such as pyridine or triethylamine) in the presence of a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide and dimethylacetamide) at about 10 to 100 ° C. to obtain the derivative (xxi). After alkaline hydrolysis with a suitable alkali (eg, sodium hydroxide etc.) in a suitable solvent (eg, methanol, tetrahydrofuran), the resulting derivative does not adversely affect the reaction (eg, toluene,
In tetrahydrofuran, dimethylformamide, dimethylacetamide, ethanol), stir with diphenylphosphazide (DPPA) at about 0-100 ° C,
The carbamic acid ester derivative (xxii) is prepared with an appropriate alcohol (eg, ethanol). The derivative is stirred in a solvent (eg, dimethylformamide, dimethylacetamide, etc.) which does not adversely affect the reaction in the presence of a base (eg, sodium ethoxide) at about 0 to 100 ° C. to give 2-oxothieno [2,3 -D] An imidazoleone derivative (VIIe) is obtained. In the presence of an alkyl halide derivative and a base, the compound is dissolved in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide and dimethylacetamide).
Stir at about 0-100 ° C to obtain compound (VIIf). Then, the compound (VIIf) is dissolved in a solvent that does not adversely influence the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile (AIBN). N-bromosuccinimide (N
BS) at about 30 to 100 ° C. and the compound (VI
Ig). Further, a solvent which does not adversely affect the reaction of the compound with various amines in the presence of a base (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol)
Then, the mixture is stirred at about 10 to 100 ° C to produce the compound (VIIh). If necessary, the compound may be a suitable acid (eg, hydrochloric acid,
Salt with oxalic acid). The above manufacturing method 12 is referred to as [Formula 1
2]. In the formula, each symbol has the same meaning as described above.

[0107]

(Equation 12)

[Production Method 13] From the 2-aminothiophene derivative (ii) or a salt thereof produced by the method described in Production Method 1, J. M. Baker's method [JMBarker,
J. Chem. Res. (M), 1980, 113; JMBarker, J. Chem. Re
s. (s), 6 (1980)], to give 4,5-dihydro-7-hydroxy-5-oxothieno [3,2-b] pyridine-6-
An ethyl carboxylate derivative (VIIj) is produced. That is, the 2-aminothiophene derivative (ii) or a salt thereof is reacted with a malonic ester to obtain a compound (xxiii),
In the presence of a suitable base (eg, sodium hydride), a solvent that does not adversely affect the reaction (eg, dimethylformamide (D
MF), amides such as dimethylacetamide)
It is manufactured by stirring at 0 to 100 ° C. The derivative (VII
j) in the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as potassium carbonate, pyridine, triethylamine, etc.) in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide, dimethylacetamide) The derivative (VIIk) is obtained by stirring at about 10 to 100 ° C., and the derivative is not dissolved in a solvent (eg,
Halogenated hydrocarbons such as carbon tetrachloride and chloroform)
Medium, α, α'-azobisisobutyronitrile (AIBN)
In the presence, N-bromosuccinimide (NBS) and about 30
Stir at １００100 ° C. to give compound (VIIm). Furthermore, the compound is used in the presence of a base in a solvent that does not adversely affect the reaction with various amines (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol) in about 10 100
Stir at 0 ° C. to produce compound (VIIn). If necessary, the compound is salted with a suitable acid (eg, hydrochloric acid, oxalic acid). The above manufacturing method 13 is shown in [Equation 13]. In the formula, each symbol has the same meaning as described above.

[0109]

(Equation 13)

[Production Method 14] 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid ester derivative (Va ')
In a suitable solvent that does not adversely affect the reaction in advance (eg, halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, ethyl ether, dioxane) in a suitable aluminum reagent (eg, trimethylaluminum, triethylaluminum). Aluminum amide derivative produced from diisobutylaluminum hydride (DIBAL)) and amines and about 10 to 10
The mixture was stirred at 0 ° C. to obtain a 1,4-dihydro-4-oxoquinoline-3-carboxylic acid amide derivative (Va ″). The derivative is converted to a suitable solvent that does not adversely affect the reaction (for example,
Stirring with Grignard reagent (R ^14d MgXa) in tetrahydrofuran, ethyl ether, etc.) at about 0-80 ° C. gives the corresponding ketone derivative (Vc). The above manufacturing method 14 is shown in [Equation 14].

[0111]

[Equation 14]

[0112] wherein the R ^{26 d} is alkyl or aryl, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols are of the same meaning as defined above] represented by R ^{26 d} Alkyl and aryl have the same meanings as above. The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted with the hydrocarbon residue represented by R ′.

[Production Method 15] The 1,4-dihydro-4-oxopyrido [2,3-b] pyridine-3-carboxylic acid ester derivative (Vd) is added to a suitable solvent which does not adversely influence the reaction in advance (eg, Manufactured from a suitable aluminum reagent (eg, trimethylaluminum, triethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines in halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, ethyl ether, dioxane) With an aluminum amide derivative of 1,4-dihydro-
4-oxopyrido [2,3-b] pyridine-3-carboxylic acid amide derivative (Vd ′). The derivative is stirred with a Grignard reagent in a suitable solvent that does not adversely influence the reaction (eg, tetrahydrofuran, ethyl ether, etc.) at about 0 to 80 ° C., and the corresponding ketone derivative (Ve) is obtained.
Get. The above Production Method 15 is shown in [Equation 15].

[0114]

(Equation 15)

[0115] wherein the R ^{26 d} is alkyl or aryl, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols are of the same meaning as defined above] represented by R ^{26 d} Alkyl and aryl have the same meanings as above. The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted with the hydrocarbon residue represented by R ′.

[Production Method 16] 4,7-Dihydro-2-halogeno 4-oxothieno [2,3-b] pyridine derivative
(XIp) is previously dissolved in a suitable solvent that does not adversely affect the reaction (eg, ethers such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane, alcohols such as ethyl alcohol, etc.), and the equivalent to excess (2 ~
10 equivalents) of a suitable base (eg, sodium carbonate) in the presence of a suitable aryl boric acid derivative (eg, phenylboric acid, 3-methoxyphenylboric acid, 4-ethoxycarbonylphenylboronic acid, etc.), and adding an inert gas (eg, An appropriate catalyst (for example, palladium metal such as tetrakis (triphenylphosphine) palladium) is added under a stream of (argon gas), and the mixture is stirred at about 10 to 100 ° C. for several minutes to several hours. Excluding the insolubles, the desired derivative (XIq) is obtained. The above manufacturing method 16 is shown in [Equation 16]. In the formula, R ^30d represents an aryl group which may be substituted, X ¹ represents a halogen, and other symbols have the same meanings as described above.

[0117]

(Equation 16)

[Production Method 17] A method for producing a derivative in which the 5-position is a 2,5-dioxo-4-imidazolidinyl group from a compound in which the 5-position is a formyl group:
The formyl derivative (ih) obtained by the above Production Method 5 or a method analogous thereto is added with sodium bisulfite in a suitable solvent (eg, water, ethanol) which does not adversely influence the reaction, and the mixture is stirred at about 0 to 80 ° C. To give a sulfuric acid adduct (iih).
The adduct (iih) is reacted with a cyanide compound in an appropriate solvent that does not adversely affect the reaction (eg, aqueous ethanol, aqueous tetrahydrofuran, dioxane) in the presence of an equivalent to excess amount of an appropriate base (eg, ammonium carbonate). (Eg, potassium cyanide, sodium cyanide), and the mixture is stirred at about 0 to 80 ° C. and, if necessary, heated to reflux to obtain a 5-position imidazolidinyl derivative (XIIa). The above manufacturing method 17 is shown in [Equation 17]. The symbols in the formula have the same meanings as described above.

[0119]

[Equation 17]

[Production Method 18] Production method of a derivative having an oxazolyl group at the 5-position: The derivative (iiih) having a formyl group at the 5-position is treated in a suitable solvent (eg, methanol, ethanol) that does not adversely influence the reaction. In the presence of an equivalent to an excess amount of a base (eg, potassium carbonate), an equivalent to excess amount of tosylmethyl isocyanide is added, and the addition amount is about 0.
The mixture is stirred at 80 ° C. and, if necessary, heated to reflux to obtain the 5-position oxazolyl derivative (XIIb). The above manufacturing method 18
8]. In Formula 18, each group has the same meaning as described above.

[0121]

(Equation 18)

[Production Method 19] Production method of derivative having 5-imidazolyl group or 4-thiazolyl group at 5-position: 4,7-dihydro-5 produced by the same method as Production Method 5 or Production Method 6 above. -Acyl-4
-Oxothieno [2,3-b] pyridine derivative (ivh)
In a suitable solvent that does not adversely affect the reaction (eg, acetic acid, methanol, tetrahydrofuran, ethyl ether, dioxane), add an equivalent or a small excess of a suitable halogenating reagent (eg, bromine, iodine) dropwise at room temperature or under ice-cooling. And about 0
Stir at ８０80 ° C. to obtain α-haloketone derivative (vh).
The α-haloketone derivative (vh) is dissolved in an appropriate solvent that does not adversely affect the reaction (eg, methanol, tetrahydrofuran, ethyl ether, dioxane, dimethylformamide) in an equivalent amount to a small excess of the appropriate amidine derivative at room temperature or ice-cooled. Add to the mixture, stir at about 0 to 80 ° C, and if necessary, heat to reflux to produce the 4-imidazolyl derivative (XIIc). Alternatively, the α-haloketone derivative (vh) is stirred with a thiocarbamoyl derivative in a solvent that does not adversely affect the reaction (eg, methanol, ethanol, dimethylformamide, dimethylacetamide) at about 10 to 100 ° C.
-To produce thiazolyl derivatives (XIId). Similarly, α
Reacting the haloketone derivative with thioglycolic acid amide followed by dehydration ring closure to produce the 1,4-thiazinyl derivative. Among the above production methods, the production methods of the 4-imidazolyl derivative (XIIc) and the 4-thiazolyl derivative (XIId) are shown in [Equation 19]. In the formula, R ^43h represents a hydrogen atom, C _1-6 alkyl or C _6-14 aryl.
R ^44h represents a hydrogen atom, C _1-6 alkyl, C _6-14 aryl. R ¹ , R ² , R ³ , R ⁵ and n are as defined above. Xa represents a halogen.

[0123]

[Equation 9]

Production Method 20: Production method of derivative having 2-oxazolyl group at 5-position: 4,7-dihydro-5-carbamoyl-4-oxothieno [2,3] produced by the first reaction of Production Method 6 above. -B]
The pyridine derivative (vih) is added dropwise in an appropriate solvent that does not adversely influence the reaction (eg, methanol, ethanol, tetrahydrofuran, dioxane) to an equivalent to a small excess of an appropriate α-haloketone compound at room temperature or under ice-cooling, 0-80
Stir at で ° C and heat to reflux if necessary to obtain the 2-oxazolyl derivative (XIIe). The above manufacturing method 20 is expressed as
0]. In the formula, R ^45h is a hydrogen atom, C
_{Represents 1-6} alkyl or C _6-14 aryl. Xa represents a halogen. R ¹ , R ² , R ³ , R ⁵ and n are as defined above.

[0125]

(Equation 20)

[Production Method 21] Production method of derivative having 2-thiazolyl group at 5-position: 4,7
Thioamidation of -dihydro-5-carbamoyl-4-oxothieno [2,3-b] pyridine derivative (vih) in a suitable solvent that does not adversely affect the reaction (eg, toluene, tetrahydrofuran, dioxane) in an equivalent amount or a small excess Add a reagent (eg, Lawson's reagent) at room temperature or under ice-cooling,
The mixture was stirred at 80 ° C., and heated to reflux as necessary, so that 4,7-dihydro-5-thiocarbamoyl-4-oxothieno [2,
3-b] A pyridine derivative (viih) is obtained. In a suitable solvent (eg, methanol, ethanol, tetrahydrofuran, dioxane) which does not adversely affect the reaction, the thiocarbamoyl derivative (viih) is added dropwise with an equivalent to a small excess of a suitable α-haloketone compound at room temperature or under ice-cooling, About 0 ° C to 80 ° C
And heat to reflux if necessary to obtain the 2-thiazolyl derivative (XIIf). The above manufacturing method 21 is shown in [Equation 21]. In the formula, R ^46h represents a hydrogen atom, C _1-6 alkyl or C _6-14 aryl. Xa represents a halogen. R ¹ , R ² , R ³ , R ⁵ and n are as defined above.

[0127]

(Equation 21)

[Production Method 22] An example of the method for producing a derivative in which the 5-position is a 3-pyrazolyl group is shown. 4,7-dihydro-
4,7-Dihydro-5-acetyl-4-oxothieno [2,3-b produced from 4-oxothieno [2,3-b] pyridine-5-carboxylate derivative (prepared by Production Method 6) In a suitable solvent that does not adversely affect the reaction (eg, methanol, ethanol, tetrahydrofuran, dioxane), pyridine derivative (viii) is mixed with excess ethyl formate and a suitable base (eg, sodium ethoxide) at room temperature or ice. The mixture is added dropwise under cooling and stirred at about 0 to 80 ° C. to obtain an α-formyl ketone derivative (ixh). The α-
The formyl ketone derivative (ixh) is dissolved in a suitable solvent that does not adversely influence the reaction (eg, water, methanol, tetrahydrofuran, dioxane, dimethylformamide) in an equivalent amount to
In the presence of a small excess of a suitable base (eg, sodium carbonate)
An equivalent to a small excess of the hydrazine derivative or a salt of the hydrazine derivative is added at room temperature or under ice-cooling, and the mixture is stirred at about 0 to 80 ° C. and, if necessary, heated to reflux to give the 3-pyrazolyl derivative (X
IIg). The above manufacturing method 22 is shown in [Equation 22]. In the formula [12], R ¹ , R ² , R ³ , R ⁵ and n have the same meaning as described above.

[0129]

(Equation 22)

[Production Method 23] Production method of derivative having 2-triazolyl group at 5-position: 4,
7-dihydro-5-thiocarbamoyl-4-oxothieno [2,3-b] pyridine derivative (xh) (first of production method 21)
In a suitable solvent that does not adversely affect the reaction (e.g., ethyl ether, dimethylformamide, tetrahydrofuran, dioxane, dichloromethane), an equivalent to a small excess of methyl iodide is added dropwise at room temperature or under ice-cooling, The mixture is stirred at about 0 ° C. to 80 ° C. and, if necessary, heated to reflux to obtain a quaternary salt derivative. The derivative is converted to a suitable solvent that does not adversely affect the reaction (eg, dimethylformamide)
In or in the absence of a solvent, excess formic acid hydrazide is added at room temperature or under ice-cooling and stirred at room temperature to 200 ° C. to prepare a 2-triazolyl derivative (XIIh). The above manufacturing method 23 is shown in [Equation 23]. In the equation of [Equation 23], R ¹ ,
R ² , R ³ , R ⁵ and n are as defined above.

[0131]

(Equation 23)

[Production Method 24] Production method of 2-oxazolinyl derivative: 4,7-dihydro-4-produced by the same method as the above Production Method 1 or 2.
The oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (xiih) was added dropwise to a separately prepared excess ethanolamine aluminum amide dichloromethane solution under ice-cooling, and the mixture was stirred at room temperature for 1 to 4 hours. An amide derivative is produced. Using the amide derivative in a suitable solvent (eg, dichloromethane, ethyl ether, tetrahydrofuran)
Mediumly, thionyl chloride is added dropwise under ice-cooling, and the mixture is stirred at 0 ° C. to room temperature to obtain a 2-oxazolinyl derivative (XIIi). The above manufacturing method 24 is shown in [Equation 24]. In the equation of [Equation 24],
R ¹ , R ² , R ³ , R ⁵ and n are as defined above.

[0133]

(Equation 24)

[Production Method 25]: Production method of derivative wherein R ⁴ is a group via N: 5-acetyl derivative (xivh) obtained by the same method as in Production Method 5 or 6 is used as a suitable solvent. An oxime derivative (xvh) is prepared by dissolving in (eg, pyridine), adding an equivalent amount or a slight excess of a hydroxylamine derivative or a salt thereof, and heating at room temperature or heating. The oxime derivative (xvh) is dissolved in a suitable solvent (eg, pyridine), an equivalent amount of a small excess of an acylating agent (eg, acid halide, acid anhydride, sulfonic acid halide, etc.) is added, and the mixture is allowed to stand at room temperature or under heating. After reacting for 1 to 12 hours, a rearranged product (XIIj) is obtained. The rearranged product (XIIjk) is dissolved in a suitable solvent (eg, ethyl alcohol), and subjected to an alkaline hydrolysis reaction (reaction conditions: for example, aqueous sodium hydroxide solution is added, and at room temperature,
Stir for about 2 hours. ), The corresponding primary amino derivative (XIIk) can be produced. The above manufacturing method 25 is shown in [Equation 25]. In [Equation 25], R
¹ , R ² , R ³ , R ⁵ and n are as defined above. Ac
Represents an acetyl group.

[0135]

(Equation 25)

Primary amino derivative thus obtained
(XIIk) as a raw material, a commonly used alkylation reaction,
Various derivatives can be produced by subjecting them to an acylation reaction, a sulfonylation reaction, an imidation reaction, or the like.

[Production method 26] Production method of derivative wherein R ⁴ is a group mediated by O: Acyl derivative (xvih) obtained by a method similar to the method described in the above Production method 5 or 6 is used in a suitable solvent (eg, , Dichloromethane), and under ice-cooling or room temperature, a small excess (eg, 1.2 to 1.5 times equivalent) of peroxide (eg, chlorobenzoic acid) is added, and the mixture is stirred at room temperature for 1 to 6 hours. Then, a rearrangement product (XIIm) is obtained. The product (XIIm) is added to a suitable solvent (eg, tetrahydrofuran) under basic conditions (eg, by adding a 2N sodium hydroxide solution) at room temperature or by heating (eg, 40 to 60 ° C.). After stirring for ~ 12 hours, the alcohol derivative (XIIn) is obtained. The alcohol derivative (XIIn) is prepared by adding an alkyl halide (eg, isopropyl bromide) in a suitable solvent (eg, dimethylformamide) in the presence of a base (eg, potassium carbonate), and heating at room temperature or heating (eg, , 40-80 ° C.) and stirring for about 1-24 hours to give the alkoxy derivative (XIIo). Further, for example, when the alkoxy group is an isopropoxy group, the alkoxy derivative is dissolved in a suitable solvent (eg, dichloromethane), and cooled with ice or in the presence of an excess of a suitable Lewis acid (eg, boron trichloride). Stirring at room temperature for 1-6 hours gives the dealkylated alcohol derivative (XIIn). The above manufacturing method 26 is shown in [Equation 26]. In [Equation 16], R ¹ , R ² , R ³ , R ⁵ and n have the same meaning as described above. R ^30h and R ⁴ 'represents an alkyl group, respectively. X
a represents a halogen atom.

[0138]

(Equation 26)

Alcohol derivative thus obtained
(XIIn) as a raw material, a commonly used alkylation reaction,
Various derivatives can be produced by subjecting them to an acylation reaction, an alkenylation reaction, a sulfonylation reaction, or the like.

Production Method 27; (Production Method of Derivative in which R ⁴ is a S-Mediated Group) First, a thioglycolic acid ester is reacted with an alkyl iodide, and then a dimethylaminomethylene compound is reacted to give a compound (xviih) To manufacture. A 2-aminothiophene derivative (xviiih) produced by a method similar to the method described in the above-mentioned production method 1 is converted into a suitable solvent (eg, ethyl alcohol).
In a medium, a compound (xixh) obtained by adding a base (eg, an aqueous solution of sodium hydroxide) to carry out an alkali hydrolysis reaction and the compound (xviih) are heated in a suitable solvent or without a solvent (eg, 80 to 80). (150 ° C.) for 1-6 hours to give the amino-substituted derivative (xxh). The derivative (xxh) is heated (for example, 150 to 2) in a suitable solvent (for example, diphenyl ether).
50 ° C.) and react for 30 minutes to 3 hours.
xih). The ring-closure compound (xxih) was prepared by the same method as the method of reacting the compound (v) shown in the above-mentioned production method 1 with the formula Xa- (CH ₂ ) n-R ³ , the formula Xa- (CH ₂ ) n- React R ³ ,
The compound (XIIp) is obtained. Further, the compound (XIIp) is reacted with an equivalent or a slight excess of a peroxide (eg, metachlorobenzoic acid) in a suitable solvent (eg, dichloromethane) by stirring under ice cooling for 5 minutes to 2 hours to give a sulfoxide. Derivative (XII
get q). The above manufacturing method 27 is shown in [Equation 27]. In [Equation 27], R ¹ , R ² , R ³ and n have the same meanings as described above. R ⁴ ″ represents an alkyl group.

[0141]

[Equation 27]

[Production Method 28]: Production method of a derivative which is phenyl substituted at the 2-position with an optionally substituted alkenyl group: 4,7-dihydro-2
-(4-aminophenyl) -4-oxothieno [2,3
-B] a pyridine derivative (XIIr) in a suitable solvent that does not adversely influence the reaction (eg, acetic acid, dimethylformamide,
Dichloronium, tetrahydrofuran, dioxane, acetonitrile, water, etc.) and a suitable diazotizing agent (eg, sodium nitrite, isoamyl nitrite) are added to form a diazonium salt in the system. To this, a palladium catalyst [for example, bis (dibenzylideneacetone) palladium] and 1 equivalent to an excess amount of various alkenyl derivatives (eg, olefin compounds) are added, and the mixture is stirred at about 0 to 80 ° C. to give the desired derivative (XII
s) get. The above manufacturing method 28 is shown in [Equation 28].
In the formula [Formula 28], R ^32h and R ^33h are the same or different and each represents an acyl group, and R ^34h represents hydrogen or C _1-6 alkyl. Other groups are as defined above.

[0143]

[Equation 28]

[Production Method 29] Production method of a derivative which is an aminophenyl group substituted with an alkyl group which may be substituted at the 2-position or an allocyclic group which may be substituted: 4,7-dihydro -2-
(4-aminophenyl) -4-oxothieno [2,3-
b] The pyridine derivative (XIIt) is dissolved in a suitable solvent that does not adversely influence the reaction (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane). To this, 1 equivalent to excess amount of various Michael acceptor derivatives (for example, acrylates) or oxirane derivatives (for example, epoxy compounds) are added, and the mixture is stirred at about 0 to 80 ° C. to obtain the desired derivative (XIIu).
The above manufacturing method 29 is shown in [Equation 29]. In the formula of [Formula 29], R ^{35h to} R ^39h represent an alkyl group. -R ^{40h is-}
C (R ^36h ) -CO-R ^35h or -C (OH) R ^36h R
^{Shows 39h} . Other groups are as defined above.

[0145]

(Equation 29)

[Production Method 30] Production method of a derivative which is an aminophenyl group substituted with an alkyl group which may be substituted at the 2-position or an allocyclic group which may be substituted: 4,7-dihydro -2-
(4-aminophenyl) -4-oxothieno [2,3-
b] A pyridine derivative (XIIv) is converted into a suitable solvent that does not adversely influence the reaction (eg, pyridine, dimethylformamide,
Dissolved in dichloromethane, tetrahydrofuran, ethyl ether, dioxane), and reacted with 1 equivalent to an excess of acid chloride or acid anhydride (for example, trifluoroacetic anhydride). If necessary, one equivalent to an excess of a base (eg, potassium carbonate, triethylamine) is added, and the mixture is stirred at about 0 to 80 ° C. to obtain a derivative (XIIw). The obtained derivative is dissolved in a suitable solvent that does not adversely influence the reaction (eg, pyridine, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane, acetone), and 1 equivalent to a small excess of a base (eg, carbonate) Potassium, triethylamine, sodium hydride) and 1 equivalent to an excess of an alkyl halide derivative (eg, methyl iodide, propyl iodide, benzyl iodide) are added, and the mixture is stirred at about 0 to 80 ° C. The resulting derivative is subjected to alkaline hydrolysis (for example, by adding a small excess of 1N sodium hydroxide) in a suitable solvent that does not adversely influence the reaction (eg, tetrahydrofuran, dioxane, ethanol, methanol, acetone),
Produce the desired derivative (XIIx). The above manufacturing method 30 is shown in [Equation 30]. The group R ^41h in [ ^Formula 30] is a group represented by C
_{Represents 1-6} alkyl or trifluoromethyl. Group R ^42h
Represents an optionally substituted alkyl group or an optionally substituted homocyclic group. Other groups are as defined above.

[0147]

[Equation 30]

[Production Method 31]: Conversion of Substituent at 3-Position: Compound (XI in which 3-position is hydrogen atom or C _1-6 alkyl group produced by the above-mentioned production method)
Iy) in a solvent that does not adversely affect the reaction (eg, carbon tetrachloride, halogenated hydrocarbons such as chloroform, etc.), α,
In the presence of α′-azobisisobutyronitrile (AIBN), N-bromosuccinimide (NBS) and about 30 to 1
The mixture was stirred at 00 ° C. to obtain a compound (II ′).
A fatty acid, an alkylsulfonic acid, an alkylarylsulfonic acid, or the like is reacted to perform a conversion reaction with the 3-position substituent. The compound (II ′) thus obtained is equimolar to a small excess (about 3 mol) of various primary or secondary amines (eg, R ¹ ′ ″ -H).
And compound (III ′) can be produced by reacting The reaction is performed in a suitable solvent that does not adversely influence the reaction. Suitable solvents include, for example, amides such as dimethylformamide and dimethylacetamide,
Nitriles such as acetonitrile, alcohols such as ethanol, dimethoxyethane, tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, ethyl ether, acetone, ethyl acetate and the like are used.
This reaction may be performed in the presence of a base, if necessary. Examples of the base include tertiary organic amines (eg, triethylamine, trimethylamine, diisopropylethylamine), pyridine, 1,8-diazabicyclo [5,
4,0] -7-undecene (DBU) or an inorganic salt (eg, anhydrous potassium carbonate) is used. The reaction temperature is about 10-100 ° C. The reaction time is about 0.5 to
8 hours. This reaction is efficient when performed with stirring. Thus, compound (III ′) is produced. The above manufacturing method 31 is shown in [Equation 31]. In the formula described in [Formula 31], R ¹ ″ represents hydrogen or C _1-6 alkyl. , R
¹ '''represents a group via a nitrogen atom. R ² , R ³ , R ⁴ , R ⁵
And n have the same meaning as described above. m shows the integer of 0-6. X represents a leaving group. Examples of the leaving group represented by X include a nucleophile [eg, a hydrocarbon residue having a negatively charged hetero atom (eg, oxygen atom, sulfur atom, nitrogen atom, etc.)] Examples include groups that can undergo a substitution reaction. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), alkanoyloxy (eg, acetoxy, etc.), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-arylsulfonyloxy (eg, p-toluene) Sulfonyloxy etc.) and the like.

[0149]

(Equation 31)

Production Method 32: Thienopyridine-5-carboxylic acid derivative which is a branched alkoxycarbonyl group which may be substituted at the 5-position is described in PCT International Publication WO95 /
No. 28405, a compound or a salt thereof in which the 5-position is an alkoxycarbonyl group produced by a method similar to the production method described in JP-A No. 28405, and a general formula R ^4j —OH wherein R ^4j has a substituent Represents a branched alkoxy group. Specific examples are as defined above. Or a salt thereof. In this reaction, the raw material compound is dissolved in a suitable solvent (eg, isopropyl alcohol, 3-pentyl alcohol, etc.), and a general formula Ti (OR ^4j ) ₄ [wherein, R ⁴ represents a branched alkoxy group . (E.g., isopropyl titanate (titanium tetraisopropoxide), titanate (3-pentyl)) or a salt thereof, and a reaction temperature of about 0 to 0.
120 ° C, more preferably about 10-20 ° C, about 1
The stirring is performed for 24 hours, preferably for about 1 to 12 hours. Alternatively, a compound having a carboxyl group at the 5-position is prepared by adding an acid chloride reagent (eg, phosphorus oxychloride), a base (eg, N, N-dimethylaminopyridine) and an alcohol in a suitable solvent (eg, dimethylformamide). (Eg, in the presence of 2,4-dimethyl-3-pentanol) at room temperature or by heating (about 100 ° C.) to about 1-1.
It can also be produced by stirring for 2 hours.

Production Method 33: A thienopyridine-5-carboxylic acid derivative in which the 5-position is a carboxyl group is produced by a method similar to the production method described in PCT International Publication WO95 / 28405. It can be carried out by subjecting a compound or a salt thereof to a hydrolysis reaction. In the hydrolysis reaction, the raw material compound is previously dissolved in a suitable solvent (for example,
Dissolved in ethers such as tetrahydrofuran and dioxane, alcohols such as ethyl alcohol, etc.) and acid (eg, inorganic acid such as hydrochloric acid) or alkaline aqueous solution (eg,
Sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, a 1 to 4N aqueous solution) and stirring at about 10 to 100 ° C. for about 1 to 4 hours.

Production Method 34: Compound (X
V) is a method known per se, for example, PCT International Publication WO
It can be produced by the method described in JP-A-95 / 28405 or a method similar thereto. Among them, the compound (XV) of the present invention is disclosed in PCT International Publication WO95 / 28405.
Manufactured by the same method as the manufacturing method described in
Carboxy-4,7-dihydro-4-oxothieno [2,
3-b] a pyridine derivative or a salt thereof, and a compound represented by the general formula R ^2k '-
Y ^{k wherein} R ^2k ′ is (i) halogen, (ii)
An alkyl group having 1 to 3 alkenyl optionally substituted with cycloalkyl or (iii) alkyl,
^k represents a halogen atom. Or a salt thereof. Here, this reaction is usually performed in a reaction solvent. Examples of such a solvent include amides such as dimethylformamide, nitriles such as acetonitrile, and ethers such as tetrahydrofuran. In this reaction, the starting compound is dissolved in these solvents, and the compound represented by the general formula R ^2k ′ -Y ^k
(Eg, allyl bromide, cyclopropylmethyl chloride, 1-bromo-2-butene, crotyl bromide (that is, 1-bromo-2-methyl-2-propene), 1
-Bromo-3-butene, 2,2,2-trifluoroethyl iodide) or a salt thereof and a basic compound (eg, potassium carbonate, sodium hydride, triethylamine, etc.). The reaction temperature is about 0-100 ° C,
More preferably, it is about 0 to 40 ° C. Reaction time is about 1
~ 200 hours, preferably about 1-48 hours. This reaction is efficiently performed by stirring. Production Method 35: A thienopyridine derivative in which R ^2k is an optionally substituted alkoxy group in Formula (XV) was produced by a method similar to the production method described in PCT International Publication WO95 / 28405. 5-ethoxycarbonyl-4,7-dihydro-4-oxothieno [2,3-
b] A pyridine derivative or a salt thereof and a general formula R ^2k —H wherein R ^2k is as defined above. Or a salt thereof, thereby subjecting the compound to a transesterification. This reaction is usually performed
It is performed in a reaction solvent. As such a solvent, for example, alcohols such as isopropyl alcohol are used. In this reaction, the raw material compounds are dissolved in these solvents, and a compound represented by the general formula Ti (R ^2k ) ₄ (eg, isopropyl titanate [titanium (N) tetraisopropoxide] or the like) is added thereto. It is performed by The reaction temperature is about 0-100 ° C, more preferably about 0-40 ° C. The reaction time is about 1 to 24 hours, preferably about 1 to 6 hours. This reaction is efficiently performed by stirring. Alternatively, a compound in which R ^2k is a carboxyl group is dissolved in a solvent (eg, amides of dimethylformamide) and reacted with an alcohol (eg, 2,4-dimethyl-3-pentanol). Will be This reaction is carried out by adding an acid chloride-forming reagent such as phosphorus oxychloride and a base such as N, N-dimethylaminopyridine. The reaction is carried out at room temperature to heating (about 10
(Around 0 ° C.). The reaction time is about 1 to 12 hours. This reaction is efficiently performed by stirring.

Production Method 36: --CO-- in Formula (XV)
The thieno [2,3-b] pyridine-5-carboxylic acid derivative in which R ^2k is a carboxy group is produced by, for example, the method described in PCT International Publication WO95 / 28405 or a method similar thereto. It can be produced by subjecting a compound in which ² is an alkoxy group or a salt thereof to a hydrolysis reaction. In the hydrolysis reaction, a raw material compound is dissolved in a solvent and an acid (eg, an inorganic acid such as hydrochloric acid) or an aqueous alkali solution (eg, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) is dissolved. ~ 4N
Aqueous solution). Here, as the solvent, for example, ethers such as tetrahydrofuran and dioxane, alcohols such as ethyl alcohol, and the like are used. The reaction temperature is about 10-100 ° C.
The reaction time is about 1 to 4 hours. The reaction is efficiently performed by stirring.

The compound (XXI) used in the present invention is
It can be produced by a method known per se. For example,
It can be easily manufactured by the above-mentioned manufacturing method 10, the following manufacturing method or a method analogous thereto.

Manufacturing method 37: [Equation 1 of manufacturing method 13 above]
Instead of the method of producing compound (IIa) from compound (ii) shown in 3), compound (IIa) can be produced from compound (ii) by a method known per se, for example, the following method. That is, 2N sodium hydroxide solution is added to compound (ii) in a suitable solvent (a solvent that does not adversely affect the reaction; the same applies hereinafter) (for example, methanol and ethanol), and the solution is heated at room temperature to 100 ° C under heating (up to 100 ° C). Incubate for 12 hours. The obtained compound (-COOEt is converted to -COOH) is dissolved in a suitable solvent (eg, dioxane), an equivalent amount of triphosgene is added, and the mixture is stirred and reacted at 80 to 150 ° C for 1 to 10 hours. The obtained 1-hydroxyoxazine derivative is subjected to the same operation as in the above-mentioned reaction step for producing compound (IIa) from compound (XVI). The oxazine compound (R ^1y is introduced at the 1-position) thus obtained is dissolved in a suitable solvent (eg, dichloromethane), and an equivalent to a small excess of an amine (eg, ammonia, alkylamine, arylamine) is dissolved. And 1 to 12 under room temperature to heating (up to 100 ° C.).
Stir for hours to react. Next, triphosgene and triethylamine as a base are added again, and the mixture is reacted at about 100 ° C. under reflux for 1 to 6 hours to obtain a compound (IIa).

The compound (XXX) and salts thereof of the present invention can be produced by a method known per se.
As an example, the above-mentioned production methods 3 and 14 and the following production methods can be mentioned. In the following, ^Yz represents a halogen. Examples of the halogen include the same as those described above. Z ^z represents a leaving group. As the leaving group represented by Z ^z , for example, a nucleophile (eg, a hydrocarbon residue having a negatively charged hetero atom (eg, an oxygen atom, a sulfur atom, a nitrogen atom, etc.)) can be easily used. Examples include groups that can undergo a substitution reaction. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), alkanoyloxy (eg, acetoxy), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-arylsulfonyloxy (eg, p-toluenesulfonyloxy). Etc.) and the like.

Production Method 38 To the 3-halogenated aniline derivative (iz), an equal amount to a small excess of ethoxymethylene malonic acid diethyl ester was added, and 1
Stir at 00 ° C to 150 ° C for 1 to 4 hours.
(iiz). The derivative (iiz) is added little by little to a suitable solvent (eg, polyphosphoric acid, polyphosphate ester (PPE), Dowtherm, etc.) and stirred at room temperature or while heating,
The quinoline derivative (iiiz) is produced. The derivative (iiiz) is dissolved in a suitable solvent that does not adversely affect the reaction (eg, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane, acetone, etc.), and 1 equivalent to a small excess of a base (eg, carbonate) Potassium, triethylamine, sodium hydride, etc.) and 1 equivalent to an excess of an alkyl halide derivative (eg, methyl iodide, propyl iodide, benzyl iodide, etc.),
Stir at ~ 80 ° C. Equimolar to a small excess (3 moles) of the compound of the formula R ^III -B (OH) ₂ with the obtained derivative (ivz) or a salt thereof.
By reacting with the aryl boric acid derivative represented by the formula, the target compound (XXXa) is produced. The reaction is performed in a suitable solvent that does not adversely influence the reaction. Suitable solvents include, for example, ethyl ether, dioxane, dimethoxyethane, ethers such as tetrahydrofuran, benzene, aromatic hydrocarbons such as toluene,
Amides such as dimethylformamide and dimethylacetamide, and alcohols such as ethanol are used. This reaction is performed in the presence of a base. Examples of the base include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine. In order to accelerate the reaction, a catalytic amount of a palladium derivative (eg, tetrakistriphenylphosphine palladium or the like) may be added. This reaction is preferably performed under a stream of an inert gas (eg, argon gas, nitrogen gas, or the like). The reaction temperature is from about room temperature to 150 ° C., and the reaction is usually performed under reflux. The reaction time is about 1 to 12 hours. Thus, the target compound (XXXa) can be produced. Manufacturing process 3 above
7 is shown in [Equation 32]. Note that in [Equation 32], E
t is ethyl, Y ^z is halogen, and the other groups are as defined above.

[0158]

(Equation 32)

Production Method 39: Conversion of 6th Group: [Numerical Formula 33]
In a solvent (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform) which does not adversely affect the reaction, the compound (vz) in the reaction formula of α, α′-azobisisobutyronitrile (A
IBN) in the presence of N-bromosuccinimide (NBS)
And stirred at 30 to 100 ° C for 0.5 to 6 hours.
z). The compound (XXXb) or a salt thereof of the present invention is produced by reacting the compound (viz) or a salt thereof with an amine (R ¹ ′ ″ -H) in a substantially equimolar amount. The reaction is performed in a suitable solvent that does not adversely influence the reaction. Examples of the suitable solvent include amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol, ethers such as dimethoxyethane, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and the like. Halogenated hydrocarbons, nitriles such as acetonitrile, ketones such as acetone, esters such as ethyl acetate, etc. are used.
This reaction is performed in the presence of a base. As the base,
For example, a tertiary organic amine (eg, triethylamine,
Trimethylamine, diisopropylethylamine, N-
Methylmorpholine). The reaction temperature is usually about 10 to 100 ° C. The reaction time is about 1 to 10 hours. The reaction is preferably carried out with stirring. Thus, compound (XXXb) can be produced. The above manufacturing process 38 is shown in [Equation 33]. In Formula 33, R ¹ ′ ″ represents an optionally substituted amino group;
^z represents a leaving group, and the other groups are as defined above.

[0160]

[Equation 33]

Production Method 40: Anthranilic acid derivative (viiz)
In a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, etc.)
Add an equivalent or excess of triphosgene and add about 30-110
The mixture was stirred at ℃ C to give isatoic anhydride derivative (vii). Then, the halogenated derivative is converted into a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene,
In an amide such as N, N-dimethylformamide and N, N-dimethylacetamide, an alkyl sulfoxide such as dimethyl sulfoxide, and the like, a base (eg, an alkali metal carbonate such as potassium carbonate, sodium hydride, potassium hydride and the like) Alkali metal hydride, alkali metal alkoxides such as potassium butoxide, etc.) in the presence of about 40 to 13
Stir at 0 ° C. to give the substituted derivative (ixz). The derivative (ixz)
In the presence of a base (eg, an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium-butoxide) in a solvent that does not adversely affect the reaction ( For example, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene,
In amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and alkylsulfoxides such as dimethylsulfoxide at 40 to 110 ° C. in equivalent or small excess (eg, about 1.1 to 1.5). Compound (XXXc) can be produced by reacting the compound (XXXc) with an equivalent amount of a β-keto acid ester derivative. The above manufacturing process 39 is represented by [Expression 34].
Shown in In the formula, Xa represents a leaving group (particularly, halogen)
Is shown. R ^g ′ represents an alkyl group. Other groups are as defined above.

[0162]

(Equation 34)

Other Production Method: The substituent in the group of the compound used in the present invention can be converted into another substituent by a commonly used method known per se.
An example of the method is shown below. (i). A nitro group as a substituent can be converted to an amino group. For example, a raw material compound is dissolved in an appropriate solvent (eg, ethanol, methanol), and (a) palladium-carbon is added and reacted at room temperature for 1 to 12 hours under a hydrogen stream, or (b) iron is added to the above solution. Add flour and hydrochloric acid,
Incubate at room temperature for 1 to 12 hours. (ii). The amino group as a substituent can be converted to an acylated amino group. For example, the raw material compound is dissolved in a suitable solvent (eg, tetrahydrofuran, dimethylsulfoxide), potassium carbonate, and pyridine and triethylamine as a base are added, and further an acid anhydride or an acid halide is added. The mixture is stirred and reacted at room temperature for 1 to 10 hours. (iii). The compound having an amino group can be an alkenylamino compound. For example, the starting compound is converted to a suitable solvent (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile).
, A diazotizing agent (eg, sodium nitrate, isoamyl nitrate) is added, and a palladium catalyst {eg, bis (dibenzylideneacetone) palladium} and one equivalent to a small excess of an alkenyl derivative are added. 1)
Let react for ~ 12 hours.

(Iv). A carbon atom can be introduced into the amino group. For example, a raw material compound is dissolved in an appropriate solvent (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane), an acrylic acid derivative or an oxirane derivative (eg, an epoxide compound) is added, and the mixture is stirred at 0 to 80 ° C. for 6 to 6 hours. Incubate for 24 hours. (V). A sulfur atom can be introduced into an amino group. For example, the starting compound is dissolved in an appropriate solvent (eg, pyridine, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane), a halide of a sulfur compound is added, and the mixture is reacted at 0 to 80 ° C. with stirring for 6 to 24 hours. (vi). A formyl group as a substituent can be converted to a methyl group. For example, the raw material compound may be a suitable solvent (eg,
Tetrahydrofuran), an organic borane derivative (eg, dimethylsulfide borane) is added, and the mixture is reacted at room temperature to heating under reflux for several hours (eg, 1 to 3 hours).

(Vii). An acetonyl compound can be produced from a methoxy compound. For example, a starting compound is dissolved in a suitable solvent (eg, dichloromethane), and 1 equivalent to an excess of Lewis acid {eg, aluminum chloride and a thiol compound or a sulfide compound (eg, dimethyl sulfide)} are added thereto. For 1 to 10 hours, and then
The obtained hydroxy compound is dissolved in a suitable solvent (eg, dimethylformamide), and a base (eg, sodium hydroxide, potassium carbonate) and an alkyl halide are added.
Let react for ~ 12 hours. (viii). A methoxy group can be converted to an isopropoxy group. For example, a starting compound is dissolved in a suitable solvent (eg, dichloromethane), and 1 equivalent to an excess of a Lewis acid (eg, aluminum chloride) and a thiol compound or a sulfide compound (eg, dimethyl sulfide) are added.
The reaction is performed under ice cooling to room temperature for 1 to 10 hours. (ix). An aminocarbonyl group can be introduced. For example, a raw material compound having a halogen is added to a suitable solvent (eg,
Dimethoxyethane), and an arylboric acid derivative, a base (eg, sodium carbonate) and a palladium compound {eg, tetrakis (triphenylphosphine) palladium (0)} as a catalyst were added, and the mixture was reacted under reflux for 1 to 6 hours.

(X). The alkylthio compound may be an alkylsulfinyl compound or an alkylsulfonyl compound. For example, the starting compound is reacted with an oxidizing agent (eg, metachloroperbenzoic acid) in a suitable solvent (eg, dichloromethane) under ice cooling or overheating. Excessive heating or excessive use of an oxidizing agent results in an alkylsulfonyl compound. (xi). The hydroxyl group in the molecule can be substituted with various groups. The reaction is carried out in a suitable solvent such as dimethylformamide (DMF), acetonitrile, acetone, etc., in a halide (eg, alkyl halide (eg, propyl iodide, isobutyl iodide, ethyl acetate), aralkyl halide (eg, benzyl chloride). } Is added.
The reaction is carried out by stirring the mixture at 0-40 ° C. for 2-18 hours. For example, in the case of using ethyl acetate, the obtained acetate ester is mixed with a suitable solvent and a base (eg,
The reaction is carried out at room temperature for 2 to 12 hours using 1N NaOH in ethyl alcohol). The acetic acid compound is dissolved in a suitable solvent {eg, tetrahydrofuran (THF)}, isobutyl chloroformate is added in the presence of a suitable base (eg, triethylamine) and the reaction is carried out at 0 ° C. for 1-4 hours. An appropriate amine compound (eg, methylamine, propylamine, piperidine, etc.) is added to the reaction solution, and the reaction is performed at 0 ° C. to room temperature for 1 to 12 hours. In addition, the compound which has a hydroxyl group in a molecule | numerator which is said raw material compound can be performed by subjecting the compound which has an alkoxy group in a molecule to acid hydrolysis, for example. The acid hydrolysis is carried out by adding 1N hydrochloric acid in a commonly used method, for example, a suitable solvent {eg, alcohols (eg, methanol, ethanol)}, and reacting at 0 ° C. to room temperature for 1 to 10 hours.

(Xii). The compound having an alkanoyl-phenyl group can be produced by introducing an alkanoyl-phenyl group into a compound having a halogenated group. In order to introduce an alkanoyl-phenyl group, first, a halogenated compound is dissolved in a suitable solvent (eg,
In carbon tetrachloride, chloroform), N-bromosuccinimide and a catalytic amount of 2,2'-azobis (isobutyronitrile) are added and reacted. The reaction is carried out at 100 to 120 ° C. for 1 to 4 hours. Introduction of the alkanoyl-phenyl group is performed in a suitable solvent (eg, dimethoxyethane (DME)). Alkanoyl-phenylborate, palladium compound {eg, P
Add d (PPh ₃ ) ₄ , Ph = phenyl} and sodium carbonate (2M, Na ₂ CO ₃ ). The reaction is carried out under an inert gas stream at room temperature to about 120 ° C. for about 1 to 12 hours. The production of alkanoyl-phenylborate can be carried out by using an alkanoyl-phenylbromide and a boric acid compound {eg, (i
-PrO) ₃ B, Pr = propyl} is converted to a suitable base (eg,
(BuLi, Bu = butyl). (xiii) The compound which is an alkyl-phenyl group in the compound of the present invention can be obtained by performing the same reaction using the alkyl-phenyl borate in place of the alkanoyl-phenyl borate in the above method (xii). Further, the introduction of other groups in the compound of the present invention can be carried out using a method known per se.

(Xiv). The compound having an alkoxycarbonyl group in the compound of the present invention can be produced by introducing a cyano group into a starting compound and then esterifying the obtained compound. The reaction for introducing a cyano group is carried out by dissolving the starting compound in an appropriate solvent (eg, dimethyl sulfoxide (DMSO)), adding sodium cyanate to the solution, and reacting at 40 to 60 ° C. for 2 to 12 hours. The subsequent esterification reaction is carried out using a starting compound and an alcohol solution (eg, ethyl alcohol) in a suitable solvent (eg, ethyl alcohol). Those saturated with hydrochloric acid. ｝ At 80 to 120 ° C. for 12 to 48 hours. (xv) To introduce a sulfonamide group in the compound of the present invention, the alkyl group in the starting compound is halogenated,
Subsequently, the reaction can be carried out by subjecting to a nucleophilic substitution reaction with sulfonamides. The halogenation is carried out in a suitable solvent (eg, carbon tetrachloride) with N-bromosuccinimide or a catalytic amount of 2,2′-azobis (isobutyronitrile).
Is added and the reaction is carried out at 100 to 120 ° C. for 1 to 4 hours. The nucleophilic substitution reaction is carried out, for example, by washing sodium hydride and a sulfonamide derivative (eg, methanesulfonamide, ethanesulfonamide) with n-hexane in a suitable solvent {eg, N, N-dimethylformamide (DMF)}. , Benzenesulfonamide)
The reaction is performed at 0 to 40 ° C for 1 to 24 hours.

(Xvi). A method for eliminating the protective group added to the hydroxyl group in the compound used in the present invention will be shown. For example, a compound having a protecting group such as methoxymethyl is dissolved in a suitable solvent (eg, ethanol), and an acid (eg, saturated ethanol containing hydrochloric acid and hydrogen chloride) is added thereto under ice-cooling to give 0.1%. By stirring for 5 to 5 hours, a compound from which the protecting group has been eliminated is produced. (xvii) A method for introducing an acyl group or an acetonyl group into a hydroxyl group in the compound used in the present invention will be described. For example, a compound having a hydroxyl group is dissolved in a suitable solvent (eg, dichloromethane, dimethylformamide), a suitable base (eg, triethylamine, pyridine) is added thereto, and excess acid anhydride, acid chloride or alkyl halide is added thereto. And stirring at room temperature for 6 to 24 hours to produce a compound having an acyl group introduced into a hydroxyl group. (xviii). In the compound used in the present invention, the carbonyl group of the compound having a carbonyl group is -C (O
H) A method for converting to an H-group will be described. For example, a compound having a carbonyl group is dissolved in an appropriate solvent (eg, methanol or ethanol), a small excess of a reducing agent (eg, sodium borohydride) is added thereto, and the mixture is stirred at room temperature for 1 to 3 hours. A compound having a C (OH) H- group is produced.

The salt of the compound used in the present invention thus obtained is preferably a physiologically acceptable acid addition salt. Examples of such a salt include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, etc.). For example, salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used. Further, the compound (I) of the present invention is -CO
In the case of having an acidic group such as OH, an inorganic base (eg,
Alkali metal salts or alkaline earth metals such as sodium, potassium, calcium, magnesium, ammonia, etc. or organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N) '-Dibenzylethylenediamine and the like) may form a salt. The compound or salt thereof used in the present invention thus obtained is, for example, recrystallized, distilled,
Isolation by usual separation means such as chromatography,
It can be purified. Thus, when the compound used in the present invention is obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se. Alternatively, it can be converted into a free form or other salt by a method similar thereto. When the compound or salt thereof used in the present invention is an optically active substance, it can be separated into d-form and l-form by a usual optical resolution means.

The compound or a salt thereof used in the present invention has a prolactin production inhibitory action and low toxicity, so that it can be used in mammals (eg, human, monkey, cow, horse, pig, sheep, dog, cat, rabbit, (Rat, mouse, etc.), it can be safely used for the prevention or treatment of diseases caused by excessive production / secretion of prolactin or increased reactivity to prolactin. That is, the composition of the present invention, for puerperal lactation suppression, also, milk leakage, hyperprolactinemia ovulation disorder, milk leakage amenorrhea syndrome (for example, Chiari-Frommel.
Syndrome, Argonz-del Castillo Syndrome, Forbes-Albrigh
t syndrome), prolactinoma, diencephalic tumor, acromegaly, pituitary giant, especially Lactosomatotroph-
It is useful as a prophylactic or therapeutic drug for type acromegaly, pituitary giant, or Parkinson's syndrome.
Particularly in experimental observation, the composition of the present invention has an inhibitory effect on pituitary hormone production that is not mediated by LHRH receptors,
That is, it shows a prolactin production inhibitory action. The composition of the present invention acts on prolactin-producing cells of the pituitary gland, and is considered to be effective in suppressing or inhibiting prolactin production / secretion. Further, other compositions including tumor cells that produce / secrete prolactin due to canceration, etc. It is considered to be effective in acting on cells and the like to suppress or inhibit prolactin production / secretion. The composition of the present invention acts on the pituitary lactorope,
It has the effect of suppressing or inhibiting the production and secretion of prolactin. It is also useful for diseases involving prolactin, such as tumors that express the prolactin receptor.However, when these diseases are sex hormone-dependent, this drug may induce gonadotropin. It is also particularly useful as a therapeutic drug because it also has a release hormone antagonism. These diseases include, for example, breast cancer and prostate cancer, but may be any diseases as long as prolactin is involved, and their usefulness is not particularly limited to these cancers. Furthermore, the composition of the present invention can be used for treating animal diseases and the like in the field of animal husbandry. It can also be used for fish. The compounds of the invention may be used alone or in combination with steroidal or non-steroidal antiandrogens or antiestrogens, somatostatin receptor agonists, or cancer chemotherapeutic agents (eg adriamycin). .

The prolactin production inhibitor of the present invention is used as a preparation for oral administration or parenteral administration according to a method known per se for the prevention / treatment of the above-mentioned mammalian diseases. The fused ring compound or a salt thereof is mixed with a pharmaceutically acceptable carrier and is usually orally administered as a solid preparation such as tablets, capsules, granules and powders, or injected by intravenous, subcutaneous or intramuscular injection. It is parenterally administered as a drug, drip, external preparation, suppository or sublingual tablet. Further, it may be administered sublingually, subcutaneously, intramuscularly, etc. as a sustained release preparation such as sublingual tablets and microcapsules. The daily dose is
Degree of symptom; Age, sex, body weight, sensitivity difference of the administration subject;
The timing and interval of administration, the nature of the pharmaceutical preparation, the preparation and the type; vary depending on the type of the active ingredient, and are not particularly limited,
Usually, the condensed ring compound or a salt thereof is about 0.020 to 20 mg, preferably about 0.1 to 10 per kg body weight of a mammal.
mg, which is usually administered in 1 to 4 divided doses per day. The dose for use in the livestock or fishery field is also the same as described above, but is about 0.0 / kg body weight of the target organism.
1 to 50 mg, preferably 0.1 to 10 mg of the drug is usually administered in 1 to 3 times per day. In the case of the above combination,
The compound used in combination is used in an amount of about 0.1 to 1 part by weight based on 1 part by weight of the condensed ring compound or a salt thereof.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances which are commonly used as pharmaceutical materials can be used. These carrier substances include excipients in solid formulations, lubricants, binders, disintegrants; solvents in liquid formulations,
It is mixed as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent, and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; Alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,
Hydrophilic polymers such as hydroxyethyl cellulose and hydroxypropyl cellulose are included. Preferable examples of the isotonicity agent include glucose, sodium chloride, glycerin, D-sorbitol, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the above preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the above antioxidant include sulfite, ascorbic acid and the like. Examples of the colorant include red iron oxide, titanium oxide and the like.

The condensed ring compound or its salt may be added to the above-mentioned suspending agent, solubilizing agent, stabilizing agent, isotonic agent, preservative and the like, if necessary, and then the vein, subcutaneous or muscle can be prepared by a method known per se. It is an internal injection. At that time, if necessary, a freeze-dried product can be prepared by a method known per se. When the fused ring compound or a salt thereof is administered to, for example, a human, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and orally or parenterally as a pharmaceutical composition. It can be safely administered. Specific examples of the above-mentioned pharmaceutical composition include oral administration agents (eg, powders, granules, capsules, tablets), injections, drip infusions, and external preparations (eg, nasal preparations, transdermal preparations, etc.) , Suppositories (eg, rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process. Specifically, the fused ring compound or a salt thereof is a dispersant (eg, Tween 80).
(Atlas Powder Co., USA), HOC 60 (Nikko Chemicals) polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (eg,
Methylparaben, propylparaben, benzyl alcohol, etc.), an isotonic agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) with an aqueous injection, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc. It can be dissolved, suspended or emulsified in to form an oil-based injection, which can be used as an injection or drip.

To prepare a preparation for oral administration, a fused ring compound or a salt thereof can be prepared according to a method known per se, for example, an excipient (eg lactose, sucrose, starch etc.), a disintegrant (eg starch, calcium carbonate etc.). , Binders (eg starch,
Gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.)
Alternatively, a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded to produce tablets or granules. Then, if necessary, it may be coated by a method known per se for the purpose of taste masking, enteric coating or sustainability, to give an oral administration preparation. As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,
Hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Bourronic F 68,
Cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm Co., Germany, methacrylic acid / acrylic acid copolymerization) and dyes (eg red iron oxide, titanium dioxide, etc.) are used. In the case of an enteric-coated preparation, it is preferable to provide an intermediate phase between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

As the external preparation, the fused ring compound or a salt thereof can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the above-mentioned solid, the condensed ring compound or its salt is used as it is, or an excipient (eg, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative, acrylic Acid polymer, etc.) is added and mixed to obtain a powdery composition. As the above liquid,
Almost the same as in the case of injection, it is an oily or aqueous suspension. If semi-solid, an aqueous or oily gel,
Alternatively, an ointment is preferable. In addition, all of these are pH adjusting agents (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid,
Sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.) and the like may be added. For example, in the case of a suppository, the condensed ring compound or a salt thereof can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the above composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) ], Or vegetable oil (eg,
Sesame oil, soybean oil, cottonseed oil, etc.) and the like. Further, as the aqueous base, for example, polyethylene glycols, propylene glycol, and as the aqueous gel base, for example, natural gums, cellulose derivatives, vinyl polymers,
Examples thereof include acrylic acid polymers.

[0177]

EXAMPLES The present invention will be described more specifically with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. Of the four compounds used in Example 1 shown below, compound E-1 was 4,
7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4-
Methoxyphenyl) -4-oxothieno [2,3-b]
Pyridine-5-carboxylic acid ethyl ester hydrochloride, and compound E-2 is 2- (4-acetylaminophenyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7 -(2-methoxybenzyl)-
4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester, and compound E-3 is 5-n
-Butyryl-4,7-dihydro-3- (N-methyl-N
-Benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine hydrochloride, compound E-4
Is 5-benzoyl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2, 3-b] pyridine hydrochloride, and compound E-5 is 7- (2,6-difluorobenzyl) -4,
7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl)-
5-isobutyryl-4-oxothieno [2,3-b] pyridine, and compound E-6 is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N- Benzylaminomethyl) -5-isobutyryl-2
-(4-propionylaminophenyl) -4-oxothieno [2,3-b] pyridine hydrochloride, the compound E-
7 is 5-benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl)- 4-oxothieno [2,3-b] pyridine hydrochloride. These are PCT International Publication No. WO95 /
No. 28405.

Test Example 1 Prolactin (PRL) secretion inhibitory activity of rat pituitary primary culture cells: The anterior pituitary gland isolated from 40 Wistar rats (8 weeks old, male) was treated with buffer A (0.7 mM hydrogen phosphate). 2 sodium, 137 mM sodium chloride, 5 mM potassium chloride, 25 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid (HEPE
S), 50 μg / ml gentamicin sulfate, pH 7.3), transfer to a petri dish, wash once with buffer A, then 4
Divided into pieces. Enzyme solution I (0.4%
Collagenase, 0.4% BSA (bovine serum albumin), 10 μg / ml deoxyribonuclease, 0.2%
The mixture was placed in an Erlenmeyer flask with a stopper containing 30 ml of buffer solution A) containing glucose and incubated at 37 ° C. for 1 hour while shaking. After inhaling and discharging with Komagome pipette to disperse the tissue pieces, transfer them to a centrifuge tube and transfer to 6 at 480 × g.
The mixture was centrifuged for minutes and the supernatant was removed. 30 ml of enzyme solution II (buffer A containing 0.25% pancreatin) was added, incubated at 37 ° C. for 8 minutes while shaking, and 2 ml of FCS (fetal calf serum) was added and mixed. After centrifugation again at 480 xg for 6 minutes to remove the supernatant, 10 ml of culture medium I (10% F
CS, 20 mM HEPES, 50 U / ml penicillin G, 5
0 μg / ml streptomycin, 3.7 g / L DMEM (Dulbecco modified Egourmetium) containing sodium hydrogen carbonate) was added and suspended, and the suspension was filtered using a nylon mesh. After further washing twice with 10 ml of the culture medium I, the cells were suspended in the culture medium I at 5 × 10 ⁵ cells / ml. 1 ml of the cell suspension was dispensed into each hole of a 24-well plate, and 5% CO ₂ -95% air, 3% in a carbon dioxide incubator.
After culturing at 7 ° C for 3 days, 2 ml of culture medium II
(0.2% BSA, 20 mM HEPES, 50 U / ml penicillin G, 50 μg / ml streptomycin, 3.7 g / L
Wash the cells with DMEM containing sodium bicarbonate,
After adding 2 ml of culture solution II and culturing for 1 hour, remove the culture solution,
90 μl of culture medium II was newly added to each well of the 24-well plate. Then, 20 of Compounds 1 to 4 dissolved in 0.2% (v / v) DMSO (dimethyl sulfoxide) aqueous solution
100 μl of μM or 100 μM solution was added (final compound concentration 2 μM or 10 μM). Cultures without compound were used as a control. After culturing at 37 ° C. for 3 hours, 500 μl of the culture supernatant was collected, centrifuged at 1000 × g for 8 minutes,
The supernatant was collected. The concentration of PRL in the supernatant was measured using a RIA (radioimmunoassay) kit (Amersham).

The PRL secretion inhibitory rate (%) of each compound was calculated by calculating the following formula. [(Control PRL concentration)-(PRL concentration at the time of compound addition)] / (Control PRL concentration) x 100

The inhibition rate of compound E-1 was 34% (final compound concentration: 2 μM) and 62% (final compound concentration: 1).
0%), the inhibition rate of Compound E-2 was 12% (final compound concentration: 2 μM) and 37% (final compound concentration: 10
μM), the inhibition rate of Compound E-3 is 52% (final compound concentration: 2 μM), and the inhibition rate of Compound E-4 is 50%.
(Final compound concentration: 2 μM). The cells after collecting the supernatant were cultured at 37 ° C for 1 day, and then MTT [3- (4,5-Dimet
hyl-2-thiazolyl) 2,5-diphenyl-2H-tetrazolium
.Br] was used to examine the cytotoxicity of each compound. After removing the culture supernatant, 500 μl of the culture solution II containing 1 mg / ml MTT was added.
Each 1 μl was dispensed into each well of a 24-well plate and incubated at 37 ° C for 1 hour. The supernatant was removed, and a dye extract (1% sodium dodecyl sulfate, 0.04N hydrochloric acid, 86% (v / v) isopropanol aqueous solution) was added to each well (200 μl) to extract MTT formazan produced in living cells. 5 colors
It was quantified by absorption at 88 nm. When any of the compounds was added, the absorbance at 588 nm was not significantly different from that of the control group, and no cytotoxicity was observed for these compounds.

Example 1 Compounds E-1, E-2, E-3, E-4 or E-5
(100 mg), lactose 165 mg, corn starch 25 mg, hydroxypropylcellulose 9 mg and magnesium stearate 1 mg are used to produce tablets in a conventional manner.

Example 2 Compound E-6 or E-7 (100 mg), crystalline cellulose 50 mg, low-substituted hydroxypropyl cellulose-31 (30 mg), hydroxypropyl cellulose-
L (6 mg) and 1 mg of magnesium stearate are used to produce tablets in a conventional manner.

Example 3 The compound (100 m
g), lactose 150 mg, croscarmellose sodium 30 mg, hydroxypropylcellulose 6 mg and magnesium stearate 1 mg are used to produce tablets in a conventional manner.

Example 4 The compound (100 m
g), lactose 165 mg, corn starch 25 m
g, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate are used to produce tablets in a conventional manner.

Example 5 The compound (100 m
g), lactose 150 mg, low-substituted hydroxypropylcellulose-31 (30 mg), polyvinylpyrrolidone 1
Tablets are produced in a conventional manner using 0 mg and 1 mg of magnesium stearate.

Example 6 Compound (100 m) prepared in Reference Example 5-5 (1) described later
g), lactose 150 mg, carboxymethylcellulose calcium 30 mg, hydroxypropylcellulose 6 m
g and 1 mg of magnesium stearate are used to produce tablets in a conventional manner.

Example 7 Compound (100 m) produced in Reference Example 6-21 described later
g), lactose 165 mg, corn starch 25 m
g, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate are used to produce tablets in a conventional manner.

Example 8 Compound (100 m) produced in Reference Example 7-6 described later
g), lactose 165 mg, corn starch 25 m
g, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate are used to produce tablets in a conventional manner.

Example 9 Compounds E-1, E-2, E-3, E-4 or E-5
(0.5 g) and 1 g of mannitol in distilled water for injection to make a total volume of 100 ml. 0.22 μm
Aseptically filtered using a membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 10 ml portions into washed and sterilized vials, lyophilized by a conventional method, and freeze-dried 50 mg / vial in a vial. To manufacture.

Example 10 (1) Compound E-1, E-2, E-3, E-4 or E-5 100 g (2) Lactose 234 g (3) Corn starch 150 g (4) Hydroxypropyl cellulose 15 g (5 ) Light anhydrous silicic acid 1 g (500 g in total) (1), (2) and (3) are mixed in a fluidized bed granulator and (4) dissolved in purified water is sprayed to obtain fine particles. After mixing with (5), pack 500 mg each.

In the following Reference Examples, ¹ H-NMR spectra were measured using a Varian GEMINI 200 (200 MHz) type spectrum meter, JEOL LAMBDA300 (300 MHz) using tetramethylsilane as an internal standard.
Type spectrometer or Brooker AM 500 (50
0MHz) type spectrometer and measure all δ values in pp
Indicated by m. The symbols used in this specification have the following meanings. s: singlet, d: doublet, t: triplet, d
t: double triplet, m: multiplet, br: wide

Reference Example 1 According to the method described in PCT International Publication WO95 / 28405, the compounds shown in the following [Table 1] to [Table 21] are produced.

[0193]

[Table 1]

[0194]

[Table 2]

[0195]

[Table 3]

[0196]

[Table 4]

[0197]

[Table 5]

[0198]

[Table 6]

[0199]

[Table 7]

[0200]

[Table 8]

[0201]

[Table 9]

[0202]

[Table 10]

[0203]

[Table 11]

[0204]

[Table 12]

[0205]

[Table 13]

[0206]

[Table 14]

[0207]

[Table 15]

[0208]

[Table 16]

[0209]

[Table 17]

[0210]

[Table 18]

[0211]

[Table 19]

[0212]

[Table 20]

[0213]

[Table 21]

Reference Example 2-1 (1) 4,7-Dihydro-5-hydroxy-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-
Production of methyl-4-oxothieno [2,3-b] pyridine: 4-hydroxy-5-hydroxymethyl-2- (4-methoxyphenyl) -3- obtained in Reference Example 11 of PCT International Publication WO95 / 28405. The title compound is prepared from methyl thieno [2,3-b] pyridine, 2-fluorobenzyl chloride and potassium iodide. mp 159-160C. (2) 4,7-dihydro-2-phenyl-3-methyl-7-
Preparation of (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The title compound was prepared in the same manner as in Reference Example 2-1 (1). You. mp 184-186 <0> C. Reference Example 2-2 Preparation of methyl 2-isopropylthioacetate: The title compound is prepared from methyl thioglycolate and isopropyl iodide. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 6.6 Hz), 3.01-3.09 (1H,
m), 3.25 (2H, s), 3.72 (3H, s). Reference Example 2-3 Production of 2- (N, N-dimethylaminomethylene) -2-isopropylthioacetic acid methyl ester: The title compound was prepared from the compound obtained in Reference Example 2-2 and N, N-dimethylformamide dimethyl acetal. Is manufactured. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 2.89-2.98 (1H,
m), 3.26 (6H, s), 3.72 (3H, s), 7.88 (1H, s).

Reference Example 2-4 2-Amino-5-phenyl-4-methylthiophene-3
-Production of carboxylic acids: PCT International Publication WO 95/284
The title compound is produced from 2-amino-5-phenyl-4-methylthiophene-3-carboxylic acid ethyl ester obtained in Reference Example 3 of JP-A-05 and 2N sodium hydroxide. The obtained compound is used for the next reaction without purification. Reference Example 2-5 Production of (3-carboxy-5-phenyl-4-methylthiophen-2-yl) -aminomethylene- (2-isopropylthio) acetic acid methyl ester: Compound obtained in Reference Example 2-4 and reference The title compound is prepared from the compound obtained in Example 2-3. mp 119-121 ° C. Reference Example 2-6 Production of 4-hydroxy-2-phenyl-3-methyl-5-isopropylthiothieno [2,3-b] pyridine: The title compound was prepared from the compound obtained in Reference Example 2-5 and diphenyl ether. Manufactured. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.6 Hz), 2.64 (3H, s),
3.07-3.16 (1H, m), 7.37-7.54 (5H, m), 8.45 (1H, s). Reference Example 2-7 4,7-dihydro-2- (4-methoxyphenyl) -3
-Methyl-5- (oxazol-5-yl) -7- (2
-Fluorobenzyl) -4-oxothieno [2,3-
b] Production of pyridine: PCT International Publication WO95 / 284
4,7-dihydro- obtained in Example 28 of JP-A-05
Production of the title compound from 2- (4-methoxyphenyl) -3-methyl-5-formyl-7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine, tosylmethyl isocyanide and potassium carbonate Is done. mp 235-236 ° C.

Reference Example 2-8 4,7-Dihydro-2- (4-methoxyphenyl) -3
-Bromomethyl-5- (oxazol-5-yl) -7
-(2-Fluorobenzyl) -4-oxothieno [2,
3-b] Production of pyridine: The title compound is produced from the compound obtained in Reference Example 2-7, N-bromosuccinimide and α, α′-azobisisobutyronitrile. mp 234-236 <0> C. Reference Example 2-9 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-2- (4-methoxyphenyl) -5
Production of (oxazol-5-yl) -7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine: the compound obtained in Reference Example 2-8, ethyldiisopropylamine and N-benzylmethylamine Produces the title compound. mp 144-150 ° C. Reference Example 2-10 4,7-dihydro-2-phenyl-3-methyl-5-acetylamino-7- (2,6-difluorobenzyl)-
Production of 4-oxothieno [2,3-b] pyridine: PC
Example 3 (13) of T International Publication WO95 / 28405
From O-methyl-N-methylhydroxylamine hydrochloride and diisopropylethylamine to obtain a compound in which the 5-position is N-methyl-O-hydroxamic acid. Then, the obtained compound is reacted with methylmagnesium chloride, and 4,7-dihydro-2-phenyl-3-methyl-5-acetyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3 -B] pyridine is obtained. The resulting compound is reacted with hydroxylamine hydrochloride and then with p-toluenesulfonic acid chloride to produce the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.70 (3H, s), 5.23 (2H,
s), 6.99 (2H, t), 7.3-7.5 (6H, m), 8.53 (1H, s), 9.11 (1
H, s).

Reference Example 2-11 Preparation of 4,7-dihydro-2-phenyl-3-methyl-5-amino-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine Method: Reference Example 2-
The title compound is prepared from the compound prepared in 10 and 2N sodium hydroxide. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 3.3-4.3 (2H, brs), 5.14
(2H, s), 6.98 (2H, t), 7.17 (1H, s), 7.3-7.5 (6H, m). Reference Example 2-12 4,7-dihydro-2- (4-nitrophenyl) -3-
Production method of methyl-5-acetoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: 4,7 produced by the method of Reference Example 2-10 above
-Dihydro-2-phenyl-3-methyl-5-acetyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine and m-chloroperbenzoic acid gave the title compound Manufactured. mp 216-217 ° C. Reference Example 2-13 4,7-dihydro-2- (4-nitrophenyl) -3-
Production method of methyl-5-isopropoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: hydrolyzing the compound obtained in Reference Example 2-12 with 1N sodium hydroxide Then, isopropyl bromide is reacted to produce the title compound. mp. 188-189 ° C.

Reference Example 2-14 (1) Using the compound produced in Reference Example 2-13, the following compound is produced in the same manner as in Reference Example 2-8. 4,7-Dihydro-2- (4-nitrophenyl) -3-
Bromomethyl-5-isopropoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b]
Pyridine. Yellow amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d), 4.68 (1H, m), 5.04 (2H,
s), 5.27 (2H, s), 7.03 (2H, t), 7.4-7.5 (2H, m) .7.85 (2H,
d), 8.33 (2H, d). (2) Using the compound produced in Reference Example 2-14 (1), the following compound is produced in the same manner as in Reference Example 2-9. 4,7-Dihydro-2- (4-nitrophenyl) -3-
(N-benzyl-N-methylaminomethyl) -5-isopropoxy-7- (2,6-difluorobenzyl) -4
-Oxothieno [2,3-b] pyridine. Yellow amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (6H, d), 2.23 (3H, s), 3.70 (2H,
s), 4.23 (2H, s), 4.64 (1H, m), 5.22 (2H, s), 7.01 (2H,
t), 7.1-7.5 (7H, m), 8.11 (2H, d), 8.23 (2H, d). (3) Using the compound produced in Reference Example 2-14 (2), the following compound is produced in the same manner as in Reference Example 2-26 described below. 4,7-Dihydro-2- (4-aminophenyl) -3-
(N-benzyl-N-methylaminomethyl) -5-isopropoxy-7- (2,6-difluorobenzyl) -4
-Oxothieno [2,3-b] pyridine. Colorless amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d), 2.18 (3H, s), 3.70 (2H,
s), 3.92 (2H, brs), 4.18 (2H, s), 5.16 (2H, s), 6.70 (2H,
d), 6.95 (2H, t), 7.1-7.5 (7H, m), 7.60 (2H, d).

(4) Reference Example 2-14 Using the compound produced in (3), the following compound is produced in the same manner as in Reference Example 2-27 described later. 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropoxy-7- (2,6-difluorobenzyl) -4- Oxothieno [2,3-b] pyridine. Yellow amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d), 1.35 (6H, d), 2.42 (3H,
s), 2.95 (1H, m), 3.73 (2H, s), 4.25 (2H, s), 4.63 (1H,
m), 5.35 (2H, s), 6.99 (2H, t), 7.2-7.5 (8H, m), 7.69 (1
H, s), 7.95 (2H, d), 9.82 (1H, brs). Reference Example 2-15 4,7-dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-hydroxy-7- (2,6-difluorobenzyl ) Method for producing 4-oxothieno [2,3-b] pyridine: The title compound is produced from the compound obtained in Reference Example 2-14 (4) and boron trichloride. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d), 2.12 (3H, s), 2.60 (1H,
m), 3.63 (2H, s), 4.14 (2H, s), 5.17 (2H, s), 6.98 (2H, s
t), 7.1-7.3 (5H, m), 7.3-7.5 (2H, m), 7.5-7.9 (5H, m).

Reference Example 2-16 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropylsulfonyloxy-7- (2 ,
6-difluorobenzyl) -4-oxothieno [2,3
-B] Method for producing pyridine hydrochloride: The compound obtained in Reference Example 2-15 is reacted with isopropylsulfonyl chloride, and colorless crystals are obtained as the hydrochloride with hydrogen chloride-ether. Hydrochloride: mp 172-177 ° C. Reference Example 2-17 4,7-dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isobutyryloxy-7- (2,6 Production of -difluorobenzyl) -4-oxothieno [2,3-b] pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 2-15 and isobutyryl chloride. mp 169-172 ° C.

Reference Example 2-18 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-ethoxycarbonylmethoxy-7- (2 , 6
-Difluorobenzyl) -4-oxothieno [2,3-
b] Production of pyridine and hydrochloride thereof: The title compound is produced from the compound obtained in Reference Example 2-15 and ethyl bromoacetate. Free form: ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.3 (9H, m), 2.20 (3H, s), 2.83 (1
H, brs), 3.74 (2H, s), 4.1-4.2 (4H, m), 4.82 (2H, s), 5.2
2 (2H, s), 6.97 (2H, t), 7.0-7.3 (7H, m), 7.39 (1H, m), 7.
58 (1H, brs), 7.83 (2H, brs). Hydrochloride: mp 190-194 ° C. Reference Example 2-19 4,7-dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-carbamoylmethoxy-7- (2,6-difluoro Production of benzyl) -4-oxothieno [2,3-b] pyridine: The title compound is produced from the educt obtained in Reference Example 2-18 and ammonia-ethanol. 237-238 ° C. Reference Example 2-20 4,7-dihydro-2-phenyl-3-methyl-5-isopropylthio-7- (2,6-difluorobenzyl)
Preparation of -4-oxothieno [2,3-b] pyridine: The title compound is prepared from the compound obtained in Reference Example 2-6 and 2,6-difluorobenzyl chloride. mp 129-131 ° C.

Reference Example 2-21 4,7-dihydro-2-phenyl-3-methyl-5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine Production: The title compound is produced from the compound obtained in Reference Example 2-20 and metachloroperbenzoic acid. mp 217-219 ° C. Reference Example 2-22 Production of 4,7-dihydro-2-phenyl-3-methyl-5-isopropylsulfonyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: Reference The compound is prepared as a by-product in Example 2-21. mp 231-233 ° C. Reference Example 2-23 4,7-dihydro-2- (4-nitrophenyl) -3-
Methyl-5-isopropylsulfinyl-7- (2.6
-Difluorobenzyl) -4-oxothieno [2,3-
b) Production of pyridine: The title compound is produced from the compound obtained in Reference Example 2-21 and a concentrated sulfuric acid solution of sodium nitrate. 212-214 ° C. Reference Example 2-24 4,7-dihydro-2- (4-nitrophenyl) -3-
Bromomethyl-5-isopropylsulfinyl-7-
Production of (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: Compound obtained in Reference Example 2-23, N-bromosuccinimide (NBS) and α,
The title compound is prepared from α'-azobisisobutyronitrile (AIBN). mp 176-181 ° C.

Reference Example 2-25 4,7-dihydro-2- (4-nitrophenyl) -3-
Production of (N-benzyl-N-methylaminomethyl) -5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: obtained in Reference Example 2-24 The title compound is prepared from the compound, ethyldiisopropylamine and N-methylbenzylamine. mp 98-103 ° C. Reference Example 2-26 4,7-dihydro-2- (4-aminophenyl) -3-
Production of (N-benzyl-N-methylaminomethyl) -5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: obtained in Reference Example 2-25 The title compound is prepared from the compound, iron powder and concentrated hydrochloric acid. mp 105-115 ° C. Reference Example 2-27 4,7-dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropylsulfinyl-7- (2,6-
Difluorobenzyl) -4-oxothieno [2,3-
b] Production of pyridine: The title compound is produced from the compound obtained in Reference Example 2-26 and isobutyryl chloride. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.8 Hz), 1.27 (3H, d, J =
6.8Hz), 1.51 (3H, d, J = 7.1Hz), 2.16 (3H, s), 2.07-2.67
(1H, m), 3.48-3.60 (1H, m), 3.68 (2H, s), 4.02-4.22 (2H,
Abq, J = 12Hz), 5.31-5.42 (2H, Abq, J = 15.0Hz), 6.99 (2H,
t, J = 8.1Hz), 7.14-7.45 (6H, m), 7.68-7.75 (4H, m), 7.86
(1H, s), 7.93 (1H, s). Reference Example 2-28 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropylsulfinyl-7- (2,6-
Difluorobenzyl) -4-oxothieno [2,3-
b] Production of pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 2-27 and a 1 M hydrogen chloride ether solution. mp 185-187 ° C. Reference Example 2-29 The following compound is produced in the same manner as described above. 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl)
-5-isopropylsulfonyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyrimidine and its hydrochloride.

The compounds described in Reference Examples 2-7 to 2-29 are shown in the following [Table 22] to [Table 24].

[0225]

[Table 22]

[0226]

[Table 23]

[0227]

[Table 24]

Reference Example 3-1 4,7-Dihydro-7- (2.6-difluorobenzyl)
-2-phenyl-3-methyl-4-oxothieno [2,
3-b] Production of ethyl pyridine-5-carboxylate: 4-hydroxy-2-phenyl-3-methylthieno [2, obtained by the method of Reference Example 9 (1) of PCT International Publication WO95 / 28405. 3-b] pyridine-5-
The title compound is prepared from carboxylic acid ethyl ester and 2,6-difluorobenzyl chloride. mp 171-173 ° C. Reference Example 3-2 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-nitrophenyl) -3-methyl-4-
Production of Oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The title compound is produced from the compound obtained in Reference Example 3-1 and a concentrated sulfuric acid solution of sodium nitrate. mp 260-261 ° C. Reference Example 3-3 3-bromomethyl-4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-nitrophenyl) -4
Preparation of -oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: title compound from the compound obtained in Reference Example 3-2, N-bromosuccinimide and α, α'-azobisisobutyronitrile A compound is produced. mp 200-201 <0> C.

Reference Example 3-4 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-nitrophenyl) -4-oxothieno [2,
3-b] Production of pyridine-5-carboxylic acid ethyl ester hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-3, ethyldiisopropylamine and N-benzylmethylamine. mp 118-119 ° C [hydrochloride]. Reference Example 3-5 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-aminophenyl) -4-oxothieno [2,
3-b] Production of pyridine-5-carboxylic acid ethyl ester hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-4, iron powder and concentrated hydrochloric acid. mp 195-196 ° C. Reference Example 3-6 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-trifluoroacetylaminophenyl) -4
Preparation of -oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The title compound is prepared from the compound obtained in Reference Example 3-5 and trifluoroacetic anhydride. mp 147-149 ° C.

Reference Example 3-7 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-trifluoroacetylaminophenyl) -4
Preparation of -oxothieno [2,3-b] pyridine-5- (N-methyl-O-methyl) hydroxamic acid: Reference is made to a mixture of N, O-dimethoxyhydroxylamine hydrochloride, diisopropylamine and trimethylaluminum in hexane. The title compound is prepared by reacting the compound obtained in Examples 3-6. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 3.35 (3H,
s), 3.63 (2H, s), 3.73 (2H, s), 4.15 (2H, s), 5.20
(2H, s), 7.00 (1H, t), 7.12-7.30 (5H, m), 7.42 (1H,
m), 7.64 (2H, d, J = 8.7Hz), 7.72 (1H, s), 7.90 (2H, d,
J = 8.4 Hz). Mass m / z 685 (MH) ⁺ .

Reference Example 3-8 Example 2 of PCT International Publication WO95 / 28405
[Table 25] shows compounds produced by the same method as described in Reference Examples 3-6 and 3-7 using 7 (2) or the compound obtained in Reference Example 3-14 described later as a raw material.

[0232]

[Table 25]

[0233] "N- methyl -O- methyl hydroxamic acid" in Table 25], the formula _{-CO-N (OCH 3) CH} 3
Represents a group represented by

Reference Example 3-9 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
Production of 5-isobutyryl-2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine hydrochloride: Using the compound of Reference Example 3-8 (Compound No. 1) and isopropylmagnesium chloride The addition of tetrabutylammonium bromide to suppress side reactions produces the title compound. mp 192-197 ° C [hydrochloride]. Reference Example 3-10 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
5-benzoyl-2- (4-methoxyphenyl) -4-
Production of oxothieno [2,3-b] pyridine hydrochloride: Using the compound obtained in Reference Example 3-8 (Compound No. 3) as a starting material, in the same manner as in the method described in Reference Example 3-9,
The title compound is prepared. Reference Example 3-11 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
5-isobutyryl-2- (4-methoxyphenyl) -4
Preparation of -oxothieno [2,3-b] pyridine hydrochloride:
Using the compound obtained in Reference Example 3-8 (Compound No. 3) as a raw material, the title compound is produced by a method similar to the method described in Example 54 of PCT International Publication WO95 / 28405.

Reference Example 3-12 4-hydroxy-2- (4-methoxyphenyl) -3-
Preparation of bromomethylthieno [2,3-b] pyridine-5-acetic acid ethyl ester: PCT International Publication WO95 / 28
The title compound is produced using the compound obtained in Reference Example 8 of JP-A-405-405 as a raw material in the same manner as in the method described in Reference Example 3-3. Reference Example 3-13 4-hydroxy-2- (4-methoxyphenyl) -3-
Production of (N-benzyl-N-methylaminomethyl) thieno [2,3-b] pyridine-5-acetic acid ethyl ester: The compound obtained in Reference Example 3-12 was used as a raw material and described in Reference Example 3-4. The title compound is prepared in an analogous manner. Reference Example 3-14 4,7-dihydro-7- (2,6-difluorobenzyl)
Preparation of 2- (4-methoxyphenyl) -3- (N-benzyl-N-methylaminomethyl) thieno [2,3-b] pyridine-5-acetic acid ethyl ester: Reference Example 3-13
The title compound is produced in the same manner as described in Reference Example 3-1 using the compound obtained in the above as a raw material.

Reference Example 3-15 4,7-Dihydro-7- (2,6-difluorobenzyl)
-2- (4-hydroxyphenyl) -5-benzoyl-
3- (N-benzyl-N-methylaminomethyl) -4-
Production of oxothieno [2,3-b] pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-10, aluminum chloride and methyl disulfide. Reference Example 3-16 4,7-dihydro-7- (2,6-difluorobenzyl)
-2- (4-hydroxyphenyl) -5-isobutyryl-3- (N-benzyl-N-methylaminomethyl) -4
Preparation of -oxothieno [2,3-b] pyridine hydrochloride:
Using the compound obtained in Reference Example 3-11 as a raw material, the title compound is produced in the same manner as in the method described in Reference Example 3-15.

Reference Example 3-17 3- [N-methyl-N- (N-methylindol-3-ylmethyl) aminomethyl-4,7-dihydro-7- (2,
6-difluorobenzyl) -5-isobutyryl-2-
Production of (4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine hydrochloride: Reference Example 3-2
From the compound obtained in 5- (N-methyl-O-methyl)
Hydroxamic acid, which is a 5-isobutyryl form,
Next, 4-nitrophenyl at the 2-position is converted to 4-aminophenyl, and acylated (introducing an isobutyryl group).
3-methyl bromide-4,7 produced by bromination of methyl
-Dihydro-7- (2,6-difluorobenzyl) -5
-Isobutyryl-2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine and 3-
The title compound is prepared from N-methylaminomethyl-N'-methylindole. mp 170-172 ° C [hydrochloride].

Reference Example 3-18 By the same method as described in Reference Example 3-17, [Table 2
6] and the compounds shown in [Table 27] are produced.

[0239]

[Table 26]

[0240]

[Table 27]

Reference Example 3-19 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
Preparation of -benzoyl-2- (4-trifluoroacetylaminophenyl) -4-oxothieno [2,3-b] pyridine: From the compound obtained in Reference Example 3-7 and a solution of phenylmagnesium chloride in tetrahydrofuran,
The title compound is prepared. mp 133-135 ° C.

Reference Example 3-20 Example 5 of PCT International Publication WO95 / 28405
Using the compound obtained in 4, the compounds shown in [Table 28] and [Table 29] are produced in the same manner as in the method described in Reference Example 3-19.

[0243]

[Table 28]

[0244]

[Table 29]

Reference Example 3-21 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
Preparation of -benzoyl-2- [4- (3-oxobutyl) aminophenyl] -4-oxothieno [2,3-b] pyridine hydrochloride: a compound obtained in Example 54 of PCT International Publication WO95 / 28405. The title compound is prepared from methyl vinyl ketone. mp 165-168 ° C [hydrochloride].

Reference Example 3-22 Example 5 of PCT International Publication WO95 / 28405
Using the compound obtained in 4 above, various vinyl compounds or oxirane compounds are reacted to produce the compounds shown in [Table 30].

[0247]

[Table 30]

Reference Example 3-23 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
Production of -benzoyl-2- [4- (2-acetylvinylenephenyl)]-4-oxothieno [2,3-b] pyridine hydrochloride: a solution of isoamyl nitrite in acetic acid containing the compound obtained in Reference Example 3-10, Bisdibenzylideneacetone palladium and methyl vinyl ketone are reacted, and the obtained compound is produced by a conventional method to give the title compound. mp 149-151 ° C [hydrochloride].

Reference Example 3-24 From the compound obtained in Reference Example 3-10 and various vinyl compounds, the compounds shown in [Table 31] are produced.

[0250]

[Table 31]

Reference Example 3-25 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
Production of -benzoyl-2- [4- (N-ethyl-N-trifluoroacetylaminophenyl)]-4-oxothieno [2,3-b] pyridine: the compound obtained in Reference Example 3-19, ethyl iodide And potassium carbonate produces the title compound. ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.23 (3H, t, J = 7.2Hz),
2.12 (3H, s), 3.62 (2H, s), 3.83 (2H, q, J = 7.2Hz), 4.
16 (2H, s), 5.31 (2H, s), 7.03 (2H, t, J = 7.8Hz), 7.1
2-7.32 (7H, m), 7.37-7.47 (3H, m), 7.55 (1H, m), 7.89
(2H, d, J = 7.8Hz), 7.96 (3H, m). Reference Example 3-26 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
-Benzoyl-2- (4-ethylaminophenyl) -4
Preparation of -oxothieno [2,3-b] pyridine hydrochloride:
The title compound is produced from the compound obtained in Reference Example 3-25 and 5N potassium hydroxide. mp 166-168 ° C [hydrochloride].

Reference Example 3-27 A method similar to the method described in Reference Example 3-25 or Reference Example 3-26 from the compound obtained in Reference Example 3-19 or Reference Example 3-21 and various halogen compounds. Thus, the compounds shown in [Table 32] are produced.

[0253]

[Table 32]

Reference Example 3-28 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
-(4-hydroxybenzoyl) -2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-
b] Production of pyridine hydrochloride: The title compound is produced from Compound No. 1 of Reference Example 3-20 and a 10 M solution of hydrogen chloride in ethanol. mp 192-194 ° C [hydrochloride]. Reference Example 3-29 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
-(4-acetoxybenzoyl) -2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-
b] Production of pyridine hydrochloride: A free form of the title compound is produced from the compound obtained in Reference Example 3-28, triethylamine and acetic anhydride, and then a hydrochloride is produced by a conventional method. mp 167-169 ° C [hydrochloride]. Reference Example 3-30 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
-(1-hydroxyisobutyl) -2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-
b] Production of pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-9 and sodium borohydride. mp 232-234 ° C [hydrochloride].

Reference Example 3-31 3- (N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -5
-(1-acetoxyisobutyl) -2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-
b] Production of pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-30, pyridine and acetic anhydride. mp 166-168 ° C [hydrochloride]. Reference Example 3-32 4,7-dihydro-7- (2,6-difluorobenzyl)
-2- (4-acetonyloxyphenyl) -5-benzoyl-3- (N-benzyl-N-methylaminomethyl)
Production of 4-oxothieno [2,3-b] pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-15 and chloroacetone. Reference Example 3-33 4,7-dihydro-7- (2,6-difluorobenzyl)
Production of -2- (4-acetonyloxyphenyl) -5-isobutyryl-3- (N-benzyl-N-methylaminomethyl) -4-oxothieno [2,3-b] pyridine hydrochloride: Reference Example 3- The title compound is produced using the compound obtained in Step 16 as a raw material.

Reference Examples 3-17, 3-19, 3-2
1,3-23,3-25,3-26,3-28 to 3-3
The compounds shown in Table 3 are listed in the following [Table 33].

[0257]

[Table 33]

Reference Example 4-1 4,7-Dihydro-7- (2,6-difluorobenzyl)
-2- (4-isobutyrylaminophenyl) -3- (N
-Methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester (hereinafter referred to as compound 4-B): PCT
The title compound is produced from the compound of Example 27 (hereinafter referred to as compound 4-A) of International Publication WO95 / 28405 and isobutyryl chloride. mp 233-235 ° C. Compounds 4-A and 4-B of the above Reference Example were prepared as follows [Table 3
4].

[0259]

[Table 34]

Reference Example 4-2 4,7-Dihydro-7- (2,6-difluorobenzyl)
-2- (4-isobutyrylaminophenyl) -3- (N
-Methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester hydrochloride: The title compound was prepared from an isopropyl alcohol solution of compound 4-B and isopropyl titanate. Is manufactured. mp 168-170 ° C.

Reference Example 4-3 By the same method as described in Reference Example 4-2, [Table 35].
To produce the compound shown in. ([Table 35] describes including the compound of Reference Example 4-2.)

[0262]

[Table 35]

Reference Example 5-1 (1) 4,7-Dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl)
Preparation of ethyl-3-methyl-thieno [2,3-b] pyridine-5-carboxylate: PCT International Publication WO9
Compound of Example 3 (10) of JP-A-5 / 28405: 4-oxo-7- (2,6-difluorobenzyl) -2- (4
-Methoxyphenyl) -3-methyl-thieno [2,3-
b] The title compound is prepared from pyridine-5-carboxylic acid ethyl ester, aluminum chloride and dimethyl disulfide. mp 244-246 ° C. (2) 4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl) -3-methyl-thieno [2,3-b] pyridine-
Production of 5-carboxylic acid ethyl ester: Reference Example 5-1
The title compound is produced from the compound of (1), sodium hydride and chloromethyl methyl ether. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2Hz),
2.65 (3H, s), 3.50 (3H, s), 4.40 (2H, q, J = 7.2Hz), 5.2
2 (2H, s), 5.25 (2H, s), 7.00 (2H, t, J = 8.3Hz), 7.10
(2H, d, J = 6.8Hz), 7.33-7.41 (3H, m), 8.37 (1H, s). (3) 4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl) -3- (N-benzyl-N-methylaminomethyl) -thieno [ Production of 2,3-b] pyridine-5-carboxylic acid ethyl ester: Reaction of the compound obtained in Reference Example 5-1 (2), N-bromosuccinimide and α, α′-azobisisobutyronitrile The resulting compound is reacted with ethyldiisopropylamine and N-methylbenzylamine to produce the title compound. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2Hz),
2.20 (3H, s), 3.51 (3H, s), 3.93 (2H, s), 4.20 (2H, s),
4.40 (2H, q, J = 7.2Hz), 5.23 (2H, s), 5.27 (2H, s),
7.00 (2H, t, J = 8.3Hz), 7.10 (2H, d, J = 6.8Hz), 7.18-
7.26 (5H, m), 7.36-7.44 (1H, m), 7.72-7.75 (2H, m), 8.
37 (1H, s). (4) 4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl) -3- (N-benzyl-N-methylaminomethyl) -thieno [ Production of 2,3-b] pyridine-5-N-methyl-O-methylhydroxamic acid: Reference Example 5-1 (3)
The title compound is produced from the compound obtained in the above, N-methyl-O-methylhydroxylamine hydrochloride, N-ethyldiisopropylamine and trimethylaluminum. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.21 (3H, s), 3.34 (3H,
s), 3.54 (3H, s), 3.72 (2H, s), 3.76 (3H, s), 4.19 (2H,
s), 5.23 (2H, s), 5.30 (2H, s), 6.95 (2H, t, J = 8.3H
z), 7.12 (2H, d, J = 6.8Hz), 7.15-7.22 (5H, m), 7.33-
7.41 (1H, m), 7.70-7.74 (2H, m), 8.33 (1H, s).

(5) 4,7-dihydro-4-oxo-7
Production of-(2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3- (N-benzyl-N-methylaminomethyl) -5-benzoylthieno [2,3-b] pyridine: Reference Example The title compound is produced from the compound obtained in 5-1 (4), phenylmagnesium bromide and 6N hydrochloric acid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 3.91 (2H,
s), 4.30 (2H, s), 5.38 (2H, s), 6.98-7.05 (4H, m),
7.21-7.38 (5H, m), 7.43-7.48 (5H, m), 7.55-7.59 (1H,
m), 7.90 (2H, d, J = 7.1Hz), 8.06 (1H, s). (6) 4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl)
-3- (N-benzyl-N-methylaminomethyl) -5
Preparation of -isobutyrylthieno [2,3-b] pyridine:
The title compound is produced from the compound obtained in Reference Example 5-1 (4), isopropylmagnesium chloride and 6N hydrochloric acid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18 (6H, d), 2.10 (3H,
s), 3.61 (2H, s), 4.1-4.2 (3H, m), 5.26 (2H, s), 6.90
(2H, d), 6.99 (2H, t), 7.1-7.2 (6H, m), 7.40 (1H, m),
7.65 (2H, d), 8.28 (1H, s).

Reference Example 5-2 The compound obtained in Reference Example 5-1 (3) and 1N sodium hydroxide were converted into a compound in which the substituent at the 5-position was a carboxyl group, and this was mixed with N, N-dimethyl. Aminopyridine and alcohol (isopropanol, cyclohexanol, sec-butanol, 3-pentanol or 2,4-
Dimethyl-3-pentanol) and phosphorus oxychloride are reacted to produce a compound in which the substituent at the 5-position is an ester. Compounds obtained by subjecting the ester derivative to demethylation in the same manner as described in Reference Example 5-1 (1) are shown in [Table 36].

[0266]

[Table 36]

Reference Example 5-3 3- (N-methyl-N-benzylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-allyloxyphenyl) -5-benzoyl-
Production of 4-oxothieno [2,3-b] pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 5-1 (5), potassium carbonate and allyl iodide. mp 120-122 ° C.

Reference Example 5-4 Using the compound obtained in Reference Example 5-1 (5) as a starting material, a compound prepared by a method similar to the method described in Reference Example 5-3 was prepared as in Reference Example 5-3. The compounds are shown in [Table 37].

[0269]

[Table 37]

Reference Example 5-5 [Table 38] shows compounds produced by the same method as described in Reference Example 5-3 using the compound obtained in Reference Example 5-1 (6) as a starting material.

[0271]

[Table 38]

Reference Example 5-6 Reference Example 5 was prepared using the compound obtained in Reference Example 5-2 as a starting material.
Compounds produced by a method similar to that described in -3 are shown in [Table 39].

[0273]

[Table 39]

Reference Example 6-1 Reference Example 2 of PCT International Publication WO95 / 28405
Table 40 shows compounds produced using the acetone derivative in the same manner as described in Table 40.

[0275]

[Table 40]

Reference Example 6-2 PCT using the compound obtained in Reference Example 2, 3 or 19 of PCT International Publication WO95 / 28405 as a raw material
The compounds produced according to the method described in Reference Example 20 of International Publication WO95 / 28405 are shown in [Table 41].

[0277]

[Table 41]

Reference Example 6-3 [Table 42] shows compounds produced according to the method described in Reference Example 23 of PCT International Publication WO95 / 28405 using the compound obtained in Reference Example 6-2 as a raw material.

[0279]

[Table 42]

Reference Example 6-4 Compounds produced by the same method as in Reference Example 6-35 described later using the compound of Reference Example 6-3 as a starting compound are shown in [Table 43].

[0281]

[Table 43]

Reference Example 6-5 3-isobutyl-2,4 (1H, 3H) -dioxo-5-
Methyl-6- (4-methoxyphenyl) thieno [2,3
-D] Production of pyrimidine: PCT International Publication WO95 / 2
From the compound of Reference Example 2 of JP 8405, isovaleric acid, diphenylphosphoryl azide and triethylamine,
The title compound is prepared. mp 215-216 ° C.

Reference Example 6-6 Reference Example 2 of PCT International Publication WO95 / 28405
Alternatively, Table 44 shows compounds produced by using the compound of Reference Example 19 of PCT International Publication WO95 / 28405 as a raw material in the same manner as in the method of Reference Example 6-5.

[0284]

[Table 44]

Reference Example 6-7 2-Amino-4-methyl-5- (4-methoxyphenyl)
Preparation of thiophene-3-carboxylic acid: PCT International Publication W
The title compound is produced from the compound of Reference Example 2 of O95 / 28405 and 2N sodium hydroxide. mp 142-145 ° C.

Reference Example 6-8 Preparation of 2,4 (1H) -dioxo-6- (4-methoxyphenyl) -5-methylthieno [2,3-d] oxazine: Compound of Reference Example 6-7 and triphosgene The title compound is prepared from. mp 209-210 ° C. Reference Example 6-9 Production of 2,4 (1H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -5-methylthieno [2,3-d] oxazine: Reference Example 6 The title compound is prepared from compound 8, potassium carbonate, potassium iodide and 2-fluorobenzyl chloride. mp 162-163 ° C. Reference Example 6-10 Production of 2,4 (1H) -dioxo-1- (2,6-difluorobenzyl) -6- (4-methoxyphenyl) -5-methylthieno [2,3-d] oxazine: Reference Example 6-9
From 2,6-difluorobenzyl chloride, potassium carbonate and potassium iodide to produce the title compound. mp 189-190 ° C (recrystallized from ethyl acetate-hexane).

Reference Example 6-11 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -3- (3-
Methoxypropyl) -5-methylthieno [2,3-d]
Preparation of pyrimidine: The title compound is prepared from the compound of Reference Example 6-9 and 3-methoxypropylamine. mp 113-115 ° C.

Reference Example 6-12 [Table 45] shows compounds produced by the same method as in Reference Example 6-7 using the compound obtained in Reference Example 6-10 as a starting material.

[0289]

[Table 45]

Reference Example 6-13 2,4 (1H, 3H) -Dioxo-3-phenyl-5-methyl-6- (4-methoxyphenyl) thieno [2,3-
d] Production of pyrimidine: PCT International Publication WO 95/28
The title compound is produced from the compound obtained in Reference Example 19 of JP-A-405-405 and phenyl isocyanate. mp> 300 ° C. Reference Example 6-14 2,4 (1H, 3H) -dioxo-5-methyl-3- (3
-Methoxyphenyl) -6- (4-methoxyphenyl)
Production of thieno [2,3-d] pyrimidine: Using the compound obtained in Reference Example 19 of PCT International Publication WO95 / 28405, 3-methoxyphenyl was prepared in the same manner as in the method described in Reference Example 6-13. Isocyanate and 2
The title compound is prepared using 8% sodium methoxide. mp> 300 ° C. Reference Example 6-15 2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5-methyl-3- (3-methylsulfinylphenyl) -6- (4-methoxyphenyl) thieno Production of [2,3-d] pyrimidine: The title compound is produced from compound 6-12 (2) of Table 45 synthesized in Reference Example 6-12 and m-chloroperbenzoic acid. mp 267-268 ° C.

Reference Example 6-16 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -5-methyl-3- (3-methylsulfonylphenyl) -6- (4-methoxy Production of (phenyl) thieno [2,3-d] pyrimidine: In the same manner as in the method described in Reference Example 6-15, using m-chloroperbenzoic acid again, the title compound was obtained from the compound obtained in Reference Example 6-15. The compound is produced. mp 256-257 ° C.

Reference Example 6-17 A method described in Reference Example 6-9 using a compound obtained by a method similar to the method described in Reference Example 6-5, 6-6, 6-13 or 6-14 as a starting material. Compounds produced by the same method as in [Table 46] are shown in [Table 46].

[0293]

[Table 46]

Reference Example 6-18 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -5-bromomethyl-6- (4-methoxyphenyl) -3- (3-methoxypropyl) thieno [2,3
-D] Production of pyrimidine: The title compound is produced from the compound obtained in Reference Example 6-11, N-bromosuccinimide, α, α′-azobisisobutyronitrile and carbon tetrachloride. mp 105-107 ° C.

Reference Example 6-19 Reference Example 6-1 using the compound obtained in Reference Example 6-11, 6-12, 6-15, 6-16 or 6-17 as a starting material.
Compounds produced by a method similar to that described in 8 are shown in [Table 47].

[0296]

[Table 47]

Reference Example 6-20 2,4 (1H, 3H) -Dioxo-6- (4-methoxyphenyl) -3-phenyl 1- (2-fluorobenzyl)
Production of -5- (N-benzyl-N-methylaminomethyl) -thieno [2,3-d] pyrimidine (referred to as compound 6-A): Reference Example 26 (5) of PCT International Publication WO95 / 28405 The title compound is produced from the compound obtained in the above, ethyldiisopropylamine and methylbenzylamine. mp 140-143 ° C. Using the compound obtained in Reference Example 26 of PCT International Publication No. WO95 / 28405 or the compound obtained in Reference Example 6-4 as a raw material, compounds obtained by the above method are shown in [Table 48] and [Table 49].

[0298]

[Table 48]

[0299]

[Table 49]

Reference Example 6-21 6- (4-aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5-
Production of (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine: Reference Example 6
-20 using compound 17 obtained in PCT International Publication W
The title compound is produced in the same manner as in Example 60 of O95 / 28405. Table 5 shows the structure of the compound obtained.
0]. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05 (3H, s), 3.56 (2H,
s), 3.81 (2H, br s), 3.88 (2H, s), 5.36 (2H, s), 6.71
(2H, d, J = 8.7 Hz), 6.91 (2H, t, J = 8.7 Hz), 7.21-7.5
3 (13H, m). Reference Example 6-22 6- (4-acetylaminophenyl) -2,4 (1H, 3
H) -Dioxo-1- (2-fluorobenzyl) -5
Preparation of (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine: From the compound obtained in Example 60 of PCT International Publication WO95 / 28405 and acetic anhydride, the title compound Is manufactured. The structure of the obtained compound is shown in [Table 50]. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.06 (3H, s), 2.19 (3H,
s), 3.57 (2H, s), 3.90 (2H, s), 5.30 (2H, s), 7.04-
7.57 (16H, s), 7.70 (2H, d, J = 8.4Hz).

Reference Example 6-23 Example 6 of PCT International Publication WO95 / 28405
The following compound was produced in the same manner as in Reference Example 6-22, using the compound obtained in Step 0. The structure of the obtained compound is shown in [Table 50]. Reference Example 6-23, Compound No. 1: 2,4 (2H, 3H)-
Dioxo-1- (2-fluorobenzyl) -5- (N-
Methyl-N-benzylaminomethyl) -3-phenyl-
6- (4-propionylaminophenyl) thieno [2,
3-d] Pyrimidine hydrochloride (mp 172-175 ° C). Reference Example 6-23, Compound No. 2: 2,4 (2H, 3H)-
Dioxo-1- (2-fluorobenzyl) -6- (4-
Isobutyrylaminophenyl) -5- (N-methyl-N
-Benzylaminomethyl) -3-phenylthieno [2,
3-d] Pyrimidine hydrochloride (mp 185-188 ° C). Reference Example 6-23, compound number 3: 2,4 (2H, 3H)-
Dioxo-1- (2-fluorobenzyl) -6- (4-
Methoxyacetylaminophenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine hydrochloride (mp 157-162 ° C).

[0302]

[Table 50]

Reference Example 6-24 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methoxyphenyl) Preparation of 3- (3-methoxypropyl) thieno [2,3-d] pyrimidine Hydrochloride: The title compound is prepared from the compound obtained in Reference Example 6-18, ethyldiisopropylamine and methylbenzylamine. Table 5 shows the structure of the compound obtained.
0]. mp 95-100 <0> C.

Reference Example 6-25 [Table 51] shows compounds produced by the same method as described in Reference Example 6-24 using the compound obtained in Reference Example 6-19 as a starting material. Compound 19 and compound 20 are produced by hydrolyzing compound 21 to give compound 22, and then reacting compound 22 with an alkyl halide in the presence of a base.

[0305]

[Table 51]

Reference Example 6-26 6- (4-aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5-
(N-benzyl-N-methylaminomethyl) -3- (3
Production of -methoxyphenyl) thieno [2,3-d] pyrimidine hydrochloride: Compound No. 1 obtained in Reference Example 6-25
3 and 50% palladium-carbon powder are reacted under a hydrogen atmosphere to produce the title compound. The structure of the obtained compound is shown in [Table 52]. mp 162-165 ° C.

Reference Example 6-27 Using the compound obtained in Reference Example 6-25, Reference Example 6-2
Compounds produced by a method similar to the method described in No. 6 are shown in [Table 52].

[0308]

[Table 52]

Reference Example 6-28 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-formamide Phenyl) -3-
Production of Phenylthieno [2,3-d] pyrimidine: The title compound is produced from compound No. 2 obtained in Reference Example 6-27, acetic anhydride and formic acid. The structure of the obtained compound is shown in [Table 53]. mp 194-196 ° C.

Reference Example 6-29 [Table 53] shows compounds produced by the same method as described in Reference Example 6-28 using the compound obtained in Reference Example 6-26 or 6-27.

[0311]

[Table 53]

Reference Example 6-30 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methyl Aminophenyl) -3-
Production of (3-methoxyphenyl) thieno [2,3-d] pyrimidine hydrochloride: Compound N obtained in Reference Example 6-29
o.2 and dimethyl sulfide borane to give a free form of the title compound, followed by 1N ethereal hydrochloric acid (pH <
The hydrochloride is obtained according to 2). The structure of the obtained compound is shown in [Table 54]. mp 155-160 ° C.

Reference Example 6-31 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -6- (4-propionylaminophenyl) -5- (N-benzyl-N-methyl) Aminomethyl)
-3- (3-Methoxyphenyl) thieno [2,3-d]
Preparation of pyrimidine hydrochloride: The compound obtained in Reference Example 6-26 is reacted with triethylamine and propionyl chloride, and the obtained compound is treated with 1N ethereal hydrochloric acid to prepare the title compound. The structure of the obtained compound is shown in [Table 54]. mp 218-224 ° C.

[0314]

[Table 54]

Reference Example 6-32 [Table 55] shows compounds produced by the same method as described in Reference Example 6-31 using the compound obtained in Reference Example 6-26 or 6-27 as a starting material. .

[0316]

[Table 55]

Reference Example 6-33 Using the compound obtained in Reference Example 6-26 or 6-27 as a starting material and using trifluoroacetic anhydride in the same manner as in Reference Example 6-31, trifluoroacetylamino A derivative was obtained, and in the presence of a base (eg, potassium carbonate), a halogen compound (eg, propyl bromide, isopropyl bromide) was used, and then 2N sodium hydroxide was used [Table 5
6] is produced.

[0318]

[Table 56]

Reference Example 6-34 Using the compound obtained in Reference Example 6-26 or 6-27 as a starting material, isoamyl nitrite, a vinyl compound and a palladium compound (eg, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium) were used. ,
The compounds shown in [Table 57] are produced.

[0320]

[Table 57]

Reference Example 6-35 Compound 6-3 (1) or 6-3 obtained in Reference Example 6-3
(2) Compounds obtained using a mixture of arylboric acid derivative, 2M sodium carbonate and 1,2-dimethoxyethane, and tetrakis (triphenylphosphine) palladium (0) were prepared in Reference Examples 6-18 and 6-2.
The compound shown in [Table 58] is produced by introducing an N-methylbenzylamino group in the same manner as in Example 0.

[0322]

[Table 58]

Reference Example 6-36 Using the compound obtained in Reference Example 6-20 as a raw material, dimethyl sulfide and aluminum chloride were reacted to produce a derivative in which R ⁴ was phenol. Acetone) and a base (eg potassium carbonate) are used to produce the compounds shown in [Table 59].

[0324]

[Table 59]

Reference Example 7-1 Preparation of (3-bromo-4-methylphenyl) aminomethylenemalonic acid diethyl ester: The title compound was prepared from 3-bromo-4-methylaniline and ethoxymethylenemalonic acid diethyl ester. It mp 66-67 ° C. Reference Example 7-2 4-hydroxy-6-methyl-7-bromoquinoline-3
-Production of carboxylic acid ethyl ester: The title compound is produced from the compound obtained in Reference Example 7-1 and Dowtherm. mp> 250 ° C. Reference Example 7-3 1,4-dihydro-1- (2,6-difluorobenzyl)
-6-methyl-7-bromo-4-oxoquinoline-3-
Production of carboxylic acid ethyl ester: Compound obtained in Reference Example 7-2, potassium carbonate, potassium iodide and 2,2
The title compound is prepared from 6-difluorobenzyl chloride. mp 199-200 ° C.

Reference Example 7-4 1,4-dihydro-1- (2,6-difluorobenzyl)
Preparation of -6-methyl-7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester: The compound obtained in Reference Example 7-3 was treated with 4-propionylaminophenyl boric acid and The title compound is prepared using tetrakistriphenylphosphine palladium (0). mp 263-264 ° C. Reference Example 7-5 Production of ethyl 6-bromomethyl-1,4-dihydro-1- (2,6-difluorobenzyl) -7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylate: Compound obtained in Reference Example 7-4, N-
The title compound is prepared from bromosuccinimide and α, α′-azobisisobutyronitrile. mp 251-253 ° C. Reference Example 7-6 6- (N-benzyl-N-methylaminomethyl) -1,
4-dihydro-1- (2,6-difluorobenzyl)-
Preparation of 7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester hydrochloride: Titled from the compound obtained in Reference Example 7-5, ethyldiisopropylamine and N-benzyl-N-methylamine A free form of the compound is prepared, which is then prepared from this and 1N ethereal hydrochloric acid to produce the title compound. mp 165-168 ° C [hydrochloride].

The structures of the compounds described in Reference Examples 7-4 to 7-6 are shown in [Table 60] below.

[0328]

[Table 60]

[0329]

INDUSTRIAL APPLICABILITY The prolactin production inhibitor of the present invention can be used as a prophylactic or therapeutic agent for a disease associated with excessive prolactin production or a disease with increased reactivity with prolactin. Specifically, it is used for suppressing puerperal lactation, and also for milk leakage, hyperprolactinemia of ovulation, and milk leakage amenorrhea syndrome (for example, Chiari-Frommel).
Syndrome, Argonz-del Castillo Syndrome, Forbes-Albrigh
t syndrome), prolactinoma, diencephalic tumor, acromegaly, pituitary giant, especially Lactosomatotroph-
It is useful as a prophylactic or therapeutic drug for type acromegaly, pituitary giant, and Parkinson's syndrome.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/55 A61K 31/55 // C07D 215/56 C07D 215/56 495/04 105 495/04 105A 105Z

Claims (19)

[Claims] 1. A condensed ring compound containing at least a fused bicyclic ring structure of an homologous or hetero 5- to 7-membered ring and an homologous or hetero 5- to 7-membered ring, which may be substituted, or A prolactin production inhibitor comprising the salt. 2. A fused ring compound is represented by the general formula: [Wherein, W ring represents an optionally substituted homologous or hetero 5 to 7 membered ring group, and Y ring represents an optionally substituted homologous or hetero 5 to 7 membered ring group] The prolactin production inhibitor according to claim 1, which is a substance. 3. The W ring has the general formula: The group represented by the formula [wherein R ^1a and R ^2a may be the same or different and each represents a hydrogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom]. Prolactin production inhibitor. 4. The W ring has the general formula: [In the formula, R ^3a , R ^4a , R ^5a and R ^6a may be the same or different and each represents a hydrogen atom or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom] The prolactin production inhibitor according to claim 2. 5. The Y ring is represented by the general formula: [In the formula, R ^7a may be the same or different, and a hydrogen atom or a group having a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom interposed therebetween, and R ^11a and R ^12a may be the same or different. A hydrogen atom or an optionally substituted hydrocarbon residue, o is an integer of 1 to 2], and the prolactin production inhibitor according to claim 2. . 6. The Y ring has the general formula: [Wherein, R ^4b may be the same or different and each represents a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ^11b represents a hydrocarbon residue which may be substituted. And o represents an integer of 1 to 2] or a group represented by the general formula: The prolactin production inhibitor according to claim 2, which is a group represented by [wherein R ^11c and R ^12b may be the same or different and each represents a group through a hydrogen atom or a carbon atom]. 7. The fused ring compound has the general formula: [Wherein R ^1e and R ^2e are each a hydrogen atom or a group through which a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom is present, R ^3e is an optionally substituted homologous or heterocyclic group, R ^4e Is hydrogen, a group through a carbon atom, a group through a nitrogen atom, an oxygen atom or a sulfur atom or an optionally substituted heterocyclic group, R ^5e is a group through a hydrogen atom or a carbon atom, and n is 0 to 3 Indicates the integers of. ] Or a compound represented by the general formula: [Wherein, R ^1f represents (1) a hydrogen atom, (2) a group via a carbon atom or (3) a formula — (CH ₂ ) n-R ^1f ′ (wherein, R ^1f ′ is a group via a carbon atom or An optionally substituted homo- or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, R ^3f
And R ^4f each represent a group via a carbon atom. ] Or a compound represented by: ^{Wherein, R 1g, R 2g, R} 3g, R 4g, R 6g and R ^{7 g} are the same or different, a hydrogen atom or a carbon atom, a nitrogen atom, a group via an oxygen atom or a sulfur atom, R ^{5 g} is A group via a carbon atom or an optionally substituted homo- or heterocyclic group, and n represents an integer of 0 to 3. However,
R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all simultaneously hydrogen. ] The prolactin production inhibitor of Claim 1 which is a compound represented by these. 8. A fused ring compound is represented by the general formula: [Wherein, R ^13a may have 1 to 5 substituents and may be the same or different, and each represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom or an alkanoylamino group, and R ^14a represents a hydrogen atom or an alkyl A group represented by R ^15a
May have 1 to 5 substituents and may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, and R ^16a represents 1
Up to 5 substituents, which may be the same or different, may each be a hydrogen atom, an alkyl group, a halogen atom or an alkoxy group, and R ^17a may have 1 or 2 substituents, which may be the same or different. Well, each represents a carboxyl group which may be esterified or amidated, an alkylcarbonyl group, an arylcarbonyl group or an alkyl group which may be substituted, and v, t and u may be the same or different, and 1-4
The compound according to claim 1, wherein the prolactin production inhibitor is a compound represented by the formula. 9. The fused ring compound has the general formula: [In the formula, 1 to 3 R ^13b may be substituted and may be the same or different, and each represents a hydrogen atom, a C _1-6 alkoxy group or an alkanoylamino group, and R ^14b represents a hydrogen atom or a C _{1- 6} alkyl groups, R ^15b may have 1 to 3 substituents and may be the same or different, and hydrogen atom or halogen, R ^16b may have 1 to 3 substituents, and they may be the same or different. R ^17b may be substituted with 1 or 2 hydrogen atoms, halogen or C _1-6 alkoxy, and may be the same or different.
It represents a carboxyl group or an alkylcarbonyl group which may be esterified or amidated, and v ′, t ′ and u ′ may be the same or different and each is 1 to
The compound represented by the formula [3]], The prolactin production inhibitor according to claim 1. 10. The fused ring compound is 4,7-dihydro-3.
-(N-methyl-N-benzylaminomethyl) -7-
(2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5
-The prolactin production inhibitor according to claim 1, which is carboxylic acid ethyl ester or a salt thereof. 11. A fused ring compound is 2- (4-acetylaminophenyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -4. The prolactin production inhibitor according to claim 1, which is -oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof. 12. The fused ring compound is 5-n-butyryl-
4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2-
(4-methoxyphenyl) -4-oxo-thieno [2,
3-b] pyridine or a salt thereof, The prolactin production inhibitor according to claim 1. 13. The fused ring compound is 5-benzoyl-4,
7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-
Methoxyphenyl) -4-oxo-thieno [2,3-
b) The prolactin production inhibitor according to claim 1, which is pyridine or a salt thereof. 14. The condensed ring compound is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylamino). Phenyl) -5-isobutyryl-4-oxo-
The prolactin production inhibitor according to claim 1, which is thieno [2,3-b] pyridine or a salt thereof. 15. The condensed ring compound is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5-isobutyryl-2.
-(4-propionylaminophenyl) -4-oxo-
The prolactin production inhibitor according to claim 1, which is thieno [2,3-b] pyridine or a salt thereof. 16. The fused ring compound is 5-benzoyl-7-
(2,6-difluorobenzyl) -4,7-dihydro-3
-(N-methyl-N-benzylaminomethyl) -2-
The prolactin production inhibitor according to claim 1, which is (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof. 17. A combination of a fused ring compound or a salt thereof and a drug selected from the group consisting of steroidal or nonsteroidal androgen agents or antiestrogens, somatostatin receptor agonists and antitumor agents. The prolactin production inhibitor according to claim 1. 18. The prolactin production inhibitor according to claim 1, which is a prophylactic / therapeutic agent for milk leakage, hyperprolactinic ovulatory disorder, milk leakage amenorrhea syndrome, prolactinoma or diencephalic tumor. 19. The prolactin production inhibitor according to claim 1, which is a puerperal milk secretion inhibitor.