JPH1045625A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition effective for preventing transient aggravation (flare phenomenon) developing immediately after administration and useful for the treatment and prevention of sex hormone dependent diseases by combining respectively specific peptidergic compound and non-peptidergic compound with each other. SOLUTION: This composition is produced by combining (A) a compound having the action of gonadotropic hormone-releasing hormone, preferably a peptidergic compound with (B) a non-peptidergic compound having an antagonistic action on gonadotropic hormone-releasing hormone. Preferably, the component A is a polypeptide expressed by formula I [R1 is His, Trp, etc.; R2 is Tyr or Phe; R3 is Gly, etc.; R4 is Leu, Ile, etc.; R5 is Gly-NH-R6 (R6 is H, etc.)], concretely leuprorelin, gonadrelin, etc., and the component B is a condensed-ring compound of formula II [W is a (substituted) homocyclic or heterocyclic 5 to 7-membered ring; Y is a (substituted) homocyclic or heterocyclic 5 to 7-membered ring].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a compound having a gonadotropin-releasing hormone action and a non-peptidic compound having a gonadotropin-releasing hormone antagonistic action.

[0002]

2. Description of the Related Art Luteinizing hormone releasing hormone (luteinizing hormone releas), one of the hypothalamic hormones
ing hormone (hereinafter sometimes abbreviated as LH-RH) [Schally AV et al., Journal of Biological Chemistry (J. B.)
Natl. Acad. Sci., 246, pp. 7230-7236, 1971 and Burgus, R. et al., Proceeding of National Academic Science USA. .USA),
69, 278-282, 1972] is a super-agonist (super-agonist) or agonist (agonist) for LH-RH receptor, and when administered repeatedly, gonadotropin in the pituitary gland Reduces testoster and ovarian responsiveness to gonadotropins and suppresses testosterone and estrogen secretion. As a result, it is known to exhibit antitumor activity against such hormone-dependent cancers, for example, prostate cancer, and has been clinically applied. It is also widely used clinically as a remedy for endometriosis, uterine fibroids, and precocious puberty. Peptic LH
There are reports on the use of -RH (super) agonists in combination with peptidic antagonists, but no reports on the use of LH-RH superagonists or agonists in combination with non-peptidic antagonists.

[0003]

Since these peptidic compounds are super-agonists or agonists, they are accompanied by an increase in serum testosterone and estrogen levels due to pituitary-gonad stimulating action (acute action) immediately after the first administration. Transient hatred (flare phenomenon) has been observed. It takes 2-3 weeks for the peptidic super-agonist or agonist to exhibit its efficacy stably, and the prevention and treatment of disease progression / hate during this period is an issue. Furthermore, development of a non-peptidic antagonist having LH-RH antagonism that can be orally administered is desired for enhancing the action of a peptidic or non-peptidic superagonist or agonist.

[0004]

Means for Solving the Problems The present inventors have developed an excellent L
Focusing on the fact that thieno [2,3-b] pyridine derivatives and thieno [2,3-d] pyrimidine derivatives having H-RH antagonism are orally administrable, the efficacy of the drug is controlled by adjusting the dosage and the administration interval. The inventors considered that the super-agonist or the agonist could be administered while adjusting, and as a result of various studies, completed the present invention.

The present invention relates to (1) a medicine comprising a combination of a compound having a gonadotropin-releasing hormone action and a non-peptidic compound having a gonadotropin-releasing hormone antagonistic action; (3) the medicament according to (1), wherein the compound having the peptide compound is a peptidic compound; (3) the medicament according to (2), wherein the peptidic compound is a natural hormone or an analog thereof;
The peptidic compound has the formula (Pyr) Glu-R ₁ -Trp-Ser-R ₂ -R ₃ -R ₄ -Arg-Pro-R ₅ (I) wherein R ₁ is His, Tyr, Trp or p- NH ₂ -Phe, R ₂ is Ty
r or Phe, R ₃ is Gly or a D-type amino acid residue which may have a substituent, R ₄ is Leu, Ile or Nle, R
₅ is a group represented by the formula Gly-NH-R ₆ (R ₆ represents a hydrogen atom or an optionally substituted alkyl group) or a formula NH-
The pharmaceutical according to (2), which is a polypeptide represented by R ₆ ′ (R ₆ ′ represents a group represented by hydrogen atom, alkyl or ureide optionally substituted by an amino group or a hydroxyl group). (5) the medicament according to (2), wherein the peptidic compound is a compound selected from leuprorelin, gonadorelin, buserelin, triptrelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin; The medicine according to (1), wherein the compound having a releasing hormone action is used as a sustained-release preparation, (7) the medicine according to (6), wherein the sustained-release preparation is a microcapsule preparation,
(8) the medicament according to (6), wherein the sustained-release preparation is a nasal preparation or an implant; (9) the non-peptidic compound may be substituted, allo- or hetero- or 5- to 7-membered, (10) The medicament according to (1), which is a condensed ring compound or a salt thereof, which comprises at least a condensed bicyclic structure of a ring and a homo- or heterocyclic 5- to 7-membered ring.
The fused ring compound has the general formula

Embedded image [Wherein, ring W represents an optionally substituted homo- or hetero 5- to 7-membered ring group, and ring Y represents an optionally substituted homo- or hetero 5- to 7-membered ring group]. (9) The medicament according to (9), wherein the ring (11) is a compound represented by the 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 via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom]. The pharmaceutical according to the above item (12), wherein the W ring is
General formula

Embedded image Wherein R ^3a , R ^4a , R ^5a and R ^6a may be the same or different and each represent a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. (13) the medicament according to (10), which is
A ring represented by the general formula

Embedded image [Wherein, R ^7a 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 ^11a and R ^12a may be the same or different. And each represents a hydrogen atom or a hydrocarbon residue which may be substituted, and o represents an integer of 1 to 2].
The drug according to the above item 0), wherein (14) the Y ring has a 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 hydrocarbon group which may be substituted. , (15) a fused ring compound represented by the general formula:

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 or carbon atom, a group via a nitrogen atom, an oxygen atom or a sulfur atom or an optionally substituted heterocyclic group, R ^5e is a group via a hydrogen atom or a carbon atom, and n is 0 to 3 Each represents an integer], or a compound represented by the general formula

Embedded image [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.]

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 pharmaceutical according to item (9), which is a compound represented by the general formula (16),

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
R ^17a may be substituted with 1 to 2 hydrogen atoms, alkyl groups, halogen atoms or alkoxy groups, and may be further identical or different. A carboxyl group, an alkylcarbonyl group, an arylcarbonyl group or an optionally substituted alkyl group which may be esterified or amidified, and v, t and u may be the same or different; 0-3
Wherein the compound represented by the formula (9), wherein the condensed ring compound is a compound represented by the general formula:

Embedded image [In the formula, R ^13b may be substituted by 1 to 3 substituents and may be the same or different, and represents a hydrogen atom, a C _1-6 alkoxy group or a C _1-8 alkanoylamino group, and R ^14b represents a hydrogen atom Or a C _1-6 alkyl group, R ^15b may be substituted with 1 to 3 substituents, and may be the same or different; a hydrogen atom or halogen; and R ^16b may be substituted with 1 to 3 substituent (s). Furthermore, they may be the same or different, and include a hydrogen atom,
Halogen or C _1-6 alkoxy, R ^17b is 1 or 2
May be further substituted or may be the same or different, and represent a carboxyl group or a C _1-6 alkylcarbonyl group which may be esterified or amidated,
v ', t' and u 'may be the same or different and each represents an integer of 0 to 3], the pharmaceutical of (9), (18) a gonadotropin-releasing hormone antagonist Non-peptidic compounds having an effect are 4,
7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4-
Methoxyphenyl) -4-oxo-thieno [2,3-
b] The medicine according to (1), which is pyridine-5-carboxylic acid ethyl ester or a salt thereof, (19) the non-peptidic compound having gonadotropin-releasing hormone antagonistic activity 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. The medicament according to item (1), (2)
0) Non-peptidic compound having gonadotropin-releasing hormone antagonistic activity is 5-n-butyryl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl)
(21) The drug according to (1), which is -7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof,
Non-peptidic compounds having gonadotropin-releasing hormone antagonism are 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 according to (1), (22) gonadotropin release Non-peptidic compounds having hormone antagonism include 7- (2,6-difluorobenzyl) -4,7
-Dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -5
The pharmaceutical according to (1), which is -isobutyryl-4-oxo-thieno [2,3-b] pyridine or a salt thereof, (2)
3) The non-peptidic compound having gonadotropin-releasing hormone antagonistic activity is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5- (24) isobutyryl-2- (4-propionylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof according to the above (1), which has a gonadotropin-releasing hormone antagonistic effect; Having a non-peptidic compound of 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 the salt thereof according to the above (1), (25) having a gonadotropin-releasing hormone antagonistic effect; Having a non-peptidic compound of 3-
(N-benzyl-methylaminomethyl) -4,7-dihydro-2- (4-allyloxyphenyl) -5-isobutyryl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b The pharmaceutical of (1), which is pyridine or a salt thereof, wherein (26) the non-peptidic compound having gonadotropin-releasing hormone antagonistic activity is isopropyl [3- (N-benzyl-N-methylaminomethyl)- 2- (4-isobutyrylaminophenyl) -4-
The pharmaceutical according to (1), which is oxo-7- (2,6-difluorobenzyl) thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof, (27) gonadotropin-releasing hormone antagonist Non-peptidic compound having an action is isopropyl [3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-7- (2,6-difluorobenzyl) ) -6-Methylthieno [2,3-b] pyridine-5
-Carboxylate] or a salt thereof, (28) the non-peptidic compound having a gonadotropin-releasing hormone antagonistic action is isopropyl [3
-(N-benzyl-N-methylaminomethyl) -2-
(4-allyloxyphenyl) -4-oxo-6-methyl-7- (2,6-difluorobenzyl) thieno [2,
3-b] pyridine-5-carboxylate] or a salt thereof, (29) a compound having a gonadotropin-releasing hormone action and a non-peptidic compound having a gonadotropin-releasing hormone antagonistic action (30) a parenteral administration preparation of a compound having a gonadotropin-releasing hormone action, and a non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, which is a combination of the compound and the compound. (29) The kit according to (29), which is combined with an oral administration preparation, and (31) has a gonadotropin-releasing hormone antagonistic action for reducing a flare phenomenon after administration of a compound having a gonadotropin-releasing hormone action. Uses of non-peptidic compounds, and (32) gonadotropin releasing hormone action Uses for non-peptidic compounds having a gonadotropin releasing hormone antagonistic action for the effect enhancer of a compound having.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having an LH-RH action may be a peptidic compound or a non-peptidic compound, and any compound having the action may be used. Peptidic compounds having LH-RH action include, for example, natural hormones (R _{1 in the following} (I)).
= His, R ₂ = Tyr, R ₃ = Gly, R ₄ = Leu, R ₅ = Gly-NH ₂
Or an analog thereof, of the formula (Pyr) Glu-R ₁ -Trp-Ser-R ₂ -R ₃ -R ₄ -Arg-Pro-R ₅ (I) wherein R ₁ is His, Tyr, Trp or p-NH ₂ -Phe, R ₂ is T
The yr or Phe, R ₃ is an amino acid residue of good D-type have a Gly or a substituent, R ₄ is Leu, and Ile or Nle, R ₅
Is a group represented by the formula Gly-NH-R ₆ (R ₆ represents a hydrogen atom or an optionally substituted alkyl group) or a group represented by the formula NH-
R ₆ ′ (R ₆ ′ is (1) a hydrogen atom, (2) an alkyl group optionally substituted with an amino group or a hydroxyl group, or (3) ureido (−
NH-CO-NH ₂ )] or its analogs. In the above formula (I), examples of the D-type amino acid residue represented by R ₃ include α-D-amino acids having up to 11 carbon atoms (eg, D-Leu, Ile, Nle, Va)
l, Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala, Trp), etc., which are appropriately substituted (eg, methyl, t-
C _1-4 alkyl groups such as butyl, C-alkyl such as t-butoxy
C _1-4 such as _1-4 alkoxy group and t-butoxycarbonyl
C _6-10 such as an alkoxy-carbonyl group and 2-naphthyl
Aryl group, indol-3-yl, 2-methyl-indolyl, each C _1-4 alkyl such as benzyl imidazol-2-yl, substituted by C _6-10 aryl or C _6-10 aryl-C _1-4 alkyl An indolyl group or an imidazolyl group which may be present). Examples of the substituent in the optionally substituted alkyl group represented by R ₆ include a hydroxyl group and amino. Examples of the alkyl group in the alkyl group which may be substituted with an amino group or a hydroxyl group include a C _1-4 alkyl group, and among them, a C _1-3 alkyl group is preferable. Examples of C _1-4 alkyl groups include, for example, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. The number of substituents may be 1 to 3, preferably 1 or 2, and particularly preferably 1. Peptide (I) salts with acids (inorganic acids, organic acids) and metal complex compounds are also peptides (I)
Can be used as well.

The peptide compound having an LH-RH action is preferably, for example, a compound represented by the formula (Pyr) Glu-R ₁ -Trp-Ser-R ₂ -R ₃ '-R ₄ -Arg-Pro-R ₅ ' ( Wherein R ₁ is His, Tyr, Trp or p-NH ₂ -Phe, R ₂ is Tyr
Or Phe, R ₃ 'is a Gly or D type amino acid residue, R ₄ is L
eu, Ile or Nle, R ₅ ′ is Gly-NH—R ₆ ″ (R ₆ ″ is a hydrogen atom or a C _1-3 alkyl group which may have a hydroxyl group) or NH—R ₆ ″ ( R ₆ '' has the same meaning as defined above)) or a salt thereof [US Pat. No. 38
53837, 408209, 398285
9, UK Patent 1423083, Proceedings
Of the national academy of science
(Proceedings of the National Academy of Sciences o
f the United States of America) Volume 78, 6509-6512
(1981)]. In the above formula (I ′), examples of the D-type amino acid residue represented by R ₃ ′ include α-D-amino acids having up to 11 carbon atoms (eg, D-Leu, Ile, Nle, Val,
Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala, Trp) , and the like, they are suitably protected group (e.g., C _1-4 alkyl group such as t- butyl, C ₁ such as t- butoxy _-4 alkoxy group, C _1-4 alkoxy-carbonyl group such as t-butoxycarbonyl). R
Examples of the C _1-3 alkyl group in the C _1-3 alkyl group _optionally having a hydroxyl group represented by ₆ ″ include methyl, ethyl, propyl, and isopropyl. The number of substituents (hydroxyl groups) may be 1 to 2;
Are particularly preferred. Salts of the peptide (I ′) with acids (inorganic acids and organic acids) and metal complex compounds can also be used in the same manner as the peptide (I). When amino acids, peptides, protecting groups, and the like in the polypeptides represented by the formulas (I) and (I ′) are indicated by abbreviations, IUPAC-IUB Comm
Abbreviations based on ission on Biochemical Nomenclature or conventional abbreviations in the field,
When an amino acid may have an optical isomer, the L-form is indicated unless otherwise specified. Examples of abbreviations are shown below. Abu: aminobutyric acid Ala: alanine Arg: arginine Gly: glycine His: histidine Ile: isoleucine Leu: leucine Met: methionine Nle: norleucine Nval: norvaline Phe: phenylalanine Phg: progylglycinePh: glycine Serine Thr: Threonine Trp: Tryptophan Tyr: Tyrosine Val: Valine In the present specification, the above (I) and (I ′)
In the formula, R ₁ = His, R ₂ = Tyr, R ₃ = D-Leu, R ₄ = L
eu, common name polypeptide is R ₅ = NHCH ₂ -CH ₃ is leuprorelin (Leuprorelin).

The peptidic compound having an LH-RH action used in the present invention includes leuprorelin, R ₁ = His, R ₂ = Tyr, R ₃ = D-Al in the above formula (I).
a, a polypeptide wherein R ₄ = Leu and R ₅ = NHCH ₂ —CH ₃ , Gonadrelin

Embedded image (German Patent No. 2213737),

[0009] Buserelin

Embedded image (US Patent No. 4,024,248, German Patent No. 2
438352, JP-A-51-41359),

[0010] Triptorelin

Embedded image (U.S. Pat. No. 4,010,125;
No. 3),

Goserelin

Embedded image (U.S. Pat. No. 4,100,274;
No. 72),

[0012] Nafarelin

Embedded image (U.S. Pat. No. 4,234,571;
No. 63, No. 63-264498, No. 64-257
No. 94),

[0013] Histrelin

Embedded image ,

[0014] Deslorelin

Embedded image (U.S. Pat. Nos. 4,569,967 and 4,218,439)
issue),

[0015] Meterelin

Embedded image (PCT WO9118016),

[0016] Lecirelin

Embedded image (Belgium JP 899455, JP 59-596A)
No. 54). Leuprorelin is preferred as a peptide compound having an LH-RH action.

In the formulas shown in [Formula 24] to [Formula 31], the amino acid corresponding to R ₃ in the general formula (I) is a D-form. Non-peptidic compounds include, for example,
And morphinan derivatives (JP-A-61-271275).

The compound having LH-RH antagonism used in the present invention may be a substituted or unsubstituted 5- or 7-membered homo- or heterocyclic ring and a homo- or hetero- or 5- to 7-membered ring.
A condensed ring compound characterized by containing at least a condensed bicyclic structure with a member ring or a salt thereof is used. Specifically, for example, in the above fused bicyclic structure, the W ring group is
It represents an optionally substituted homo- or hetero 5- to 7-membered ring group.

The homocyclic group in the optionally substituted 5- to 7-membered ring group in the W ring group includes a 5- to 7-membered cyclic hydrocarbon group consisting only of carbon atoms. Examples thereof include phenylene, C _5-7 cycloalkylene (eg, cyclopentylene, cyclohexylene, cycloheptylene, etc.), and C _5-7 cycloalkenylene (eg, cyclopentenylene, cyclohexenylene, cycloheptenylene) Etc.).

Examples of the substituent which the homocyclic ring may have include R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b which will be described later.
Is preferably a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, for example, (1) C _1-15 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
Undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like. Among them, C _1-6 alkyl is preferable,
About 1 to 3 halogens may be substituted. ),
(2) C _3-10 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), (3) C
_2-10 alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-
Octenyl, etc.), (4) C _2-10 alkynyl (eg, ethynyl, 2-propynyl, propargyl, 3-hexynyl, etc.), (5) C _6-10 aryl (eg, phenyl, naphthyl), (6) C _{7 -19} aralkyl (eg, phenyl-C _1-6 alkyl such as benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, etc.), (7) nitro, (8) hydroxyl, (9) mercapto, (10) oxo, (11) ) Thioxo, (12) cyano, (13) carbamoyl, (14) carboxyl, (15) _C1-5 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (16) sulfo, (1)
7) halogen, (18) C _1-6 alkoxy (eg, methoxy, ethoxy, butoxy, etc.), (19) C _6-10 aryloxy (eg, phenoxy, etc.), (20) C _1-6 acyloxy (eg,
Acetoxy, propionyloxy C _1-6 alkanoyloxy oxy etc., etc.), (21) C _1-6 alkylthio (e.g., methylthio, ethylthio, n- propylthio, isopropylthio, n- butylthio, t-butylthio, etc.), (22) C _6-10
Arylthio (eg, phenylthio, etc.), (23) C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), (24) C _6-10 arylsulfinyl (eg, phenylsulfinyl, etc.), (25) C _{1 -6} alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), (26) C _6-10 arylsulfonyl (e.g., phenylsulfonyl, etc.), (27) amino, (28) C _1-6 acylamino (e.g., acetylamino _1-6 such as, propionylamino
Alkanoylamino, etc.), (29) mono- or di-C _1-4
Alkylamino (eg, methylamino, ethylamino, n
-Propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, etc.), (30) C
_3-8 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), (31) C _6-10 arylamino (eg, anilino, etc.), (32) C _1-6 alkanoyl ( (Eg, formyl, acetyl, hexanoyl, etc.), (33) C _1-6 alkanoyloxy (eg, acetyloxy, propionyloxy, etc.), (34) C _6-10 aryl-carbonyl (eg, benzoyl, etc.), (35) 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like 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,
Indrill etc.). The number of substitutions is one to six, preferably one to three, more preferably one or two. Examples of the optionally substituted heterocyclic group in the W ring group include a 5- to 7-membered heterocyclic group having one or more (preferably 1 to 2) nitrogen, sulfur, or oxygen atoms. As the W ring group, allo or hetero 5
And a 6-membered ring group is preferred. 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,

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.
Examples of the homo or hetero 5- to 7-membered ring group in the Y ring group include the same as the above-mentioned W ring group. Particularly, an oxo-substituted homo- or hetero 5- to 7-membered ring group is preferred. 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, for example, 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].

The above R ^1a , R ^2a , R ^3a , R ^4a , R ^5a ,
Examples of the group via a carbon atom in R ^6a and R ^4b include, for example, (1) a hydrocarbon group, (2) an acyl group, (3) a carbamoyl group, and (4) a carbon atom which may be substituted. Heterocyclic group having a bond, and further (5) carboxyl group which may be esterified or amidated,
(6) a cyano group and (7) an amidino group.

The above R ^1a , R ^2a , R ^3a , R ^4a , R ^5a ,
As the hydrocarbon group in the group via a carbon atom of R ^6a and R ^{4b and} the hydrocarbon group in R ^11b , R ^12b and R ^11c , a C _1-20 hydrocarbon group is preferable. Examples of the C _1-20 hydrocarbon group include, for example, (1) C _1-15 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl) Butyl, pentyl,
Hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like are preferred, among which C _1-10 is preferred, and a C _1-6 alkyl group is particularly preferred. ), (2) C _3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like.
_{A 3-6} cycloalkyl group is preferred. ) Or a 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 [4,2,1] nonyl, bicyclo [4,3,1] decyl and the like. ), (3) _C2-10 alkenyl groups (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-
Examples include methylallyl, hexatrienyl, 3-octenyl and the like, and among them, a C _2-6 alkenyl group is preferable. ), (4) C _2-10 alkynyl group (for example, ethynyl, 2-propynyl, isopropynyl, butynyl, t-
Butynyl, 3-hexynyl and the like.
_2-6 alkynyl is preferred. ), (5) _C3-10 cycloalkenyl (for example, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc., among which a _C3-6 cycloalkenyl group is preferable), (6) _C6-14 aryl Groups (for example, phenyl, 1- or 2-naphthyl, anthryl, phenanthryl, acenaphthyl and the like, among which phenyl and naphthyl are preferred);
(7) C _7-20 aralkyl (for example, phenyl-C _1-6 alkyl such as benzyl, phenethyl and phenylpropyl, benzhydryl, trityl and the like, among which phenyl-C _1-6 alkyl such as benzyl and phenethyl Groups are preferred.) And the like.

Examples of the substituent of the hydrocarbon group include (1) halogen, (2) nitro, (3) nitroso, (4) cyano, and (5) a substituent, for example, (i) C _1-6 Alkyl (the C _1-6 alkyl is a hydroxyl group, a C _1-6 alkoxy, a 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 aryl, C _7-13 aralkyl, halogen or nitro May be present as about 1 to 3 substituents. ), (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 about 1 to 3 substituents), (iv) C _6-14 aryl (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, halogen or nitro may have about 1 to 3 substituents), (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, (xvii) 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 0 to 2 R ³¹ represents 1 to 3 hydrogen atoms or substituents (eg, halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano-C _6-14 aryl, halogeno C _6-14 aryl, etc.) And a mono- or di-C _1-4 alkyl optionally substituted amino group.Examples of the hydrocarbon group include a C _1-20 alkyl group, particularly a C _1- alkyl group. ₆ alkyl, C _6-14 aryl, C
_7-20 aralkyl is preferred. Group represented by｝, (7)
An amino group which may be substituted [eg, a compound of the formula -NR ³² R
^{33 In the} formula, R ³² and R ³³ may be the same or different and include (i) a hydrogen atom, (ii) C _1-6 alkyl, (iii) C _1-6
Acyl, (iv) mono- or di-C _1-4 alkyl, C _1-4
Carbamoyl optionally substituted with alkylthio or C _6-14 aryl, (v) C _6-14 aryl, (vi) C _1-4 alkylthio, (vii) C _1-4 alkyl-sulfonyl, (viii) C
_1-4 alkyl-sulfinyl, or (ix) an amino group represented by｝ representing a cyclic amino group or a nitrogen-containing heterocyclic group described below), (8) Formula -CO-R ^{34 wherein} R ³⁴
Represents (i) a hydrogen atom, (ii) hydroxy, (iii) C _1-10 alkyl, (iv) C _1-6 alkoxy (this alkoxy is substituted with one substituent such as halogen, nitro, C _6-14 aryl, etc.) May be substituted with C _6-14 aryl _optionally having about 3 to about 3), (v) C _3-6 cycloalkyl, (vi) C _6-14 aryl, (vii) C _{6- 14} aryl-oxy, (viii) C _7-20 aralkyl, (ix) C _7-20 aralkyloxy, (x) an _optionally substituted amino group defined in the above section (7), −
O-NR ³² R ³³ (wherein, R ³² and R ³³ are as defined above.) An optionally substituted amino group represented by, (xii) 5 to 8 membered heterocyclic group or (xiii) 5 Represents an 8-membered heterocyclic-oxy group. A group represented by the formula: (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; (i) a halogen atom, (ii) C _1-4 alkyl, (iii) C _1-3 alkoxy, (iv) C _1-4 alkylthio,
(v) It may be substituted with phenoxy which may be substituted with 1 to 3 halogens. ｝, (10) Sulfo, (11) C
_6-14 aryl (eg, phenyl, naphthyl, anthryl,
Acenaphthyl and the like. The C _6-14 aryl group includes (a) hydroxyl, (b) amino, (c) mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc. ), (D) C _1-6
1 selected from alkoxy, (e) halogen, (f) cyano, etc.
And may be substituted with 4 to 4 substituents. ), (12)
C _3-7 cycloalkyl, (13) C _1-6 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylol dioxy, 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 groups (eg, vinyl, allyl, isopropenyl,
1-butenyl, 2-butenyl, butadienyl, hexatrienyl and the like. Especially, a _C2-6 alkenyl group is preferable. ), (20) _C5-7 cycloalkenyl, (21) _C7-20 aralkyl, (22) amidino, (23) azide, (24) -B (O
H) _2, (25) epoxy (-O -), (26) phosphono, (27) -A-R ³⁵ (wherein, A is an intervening group, R ³⁵ represents a C _1-10 alkyl group) And (28) phthaloyl, (29) hexamethylenetetraamino, (30) indanyl, (31) phthalimide and the like.

Examples of the intervening group represented by A include a chemical bond, 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
R ³⁸ is hydrogen or C _1-6 alkyl (eg,
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), -CO-, -CONR ³⁸ '. -[Wherein, R ³⁸ ′ is hydrogen, C _1-6 alkyl (specific examples are the aforementioned R ³⁸
Shows the same as ), C _3-7 cycloalkanediyl (eg, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene), C
_6-14 arylene (eg, phenylene, naphthylene), a heterocyclic group (specific examples are shown in a))], a group represented by -S
(O) m '' - ( m '' is an integer of 0 to 2.) The group represented ^{by, -O -, - NR 38 '} S (O) m''' - ( wherein, m ''' Represents an integer of 0 to 2, and R ³⁸ ′ has the same meaning as described above.)
And the like.

The substituent on the above-mentioned hydrocarbon group having a substituent may further have 1 to 3 substituents. Examples of the substituent that may further have, for example, (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 1 to 3 halogens, (6) C _6-14 aryl (the aryl is 1 to 3 halogens Or (7) C _7-13 aralkyl, (8) C _1-6
Alkoxy-carbonyl, (9) 5- to 8-membered heterocyclic group, (10)
C _1-10 acyl, (11) carboxy, (12) C _1-6 alkoxy-carbonyl, (13) C _6-14 aryl-carbonyl, (14)
_C1-6 alkylenedioxy, (15) sulfamoyl, (16)
Carbamoyl, (17) _C1-4 alkylthio, (18) _C1-4 alkylsulfinyl, (19) _C1-4 alkylsulfonyl, (2
0) halogen, (21) nitro, (22) mercapto and (23) cyano. The hydrocarbon group is cycloalkyl,
When it is a cycloalkenyl, alkynyl, aryl or aralkyl group, C _1-6 alkyl is substituted as 1
The C _1-6 alkyl may further have 1 to 3 hydroxy, oxo, C _1-3 alkoxy, C _1-3 acyl, C _1-3 alkylthio, halogen, carbamoyl And so on. When the hydrocarbon group is a cycloalkyl, cycloalkenyl, alkynyl, aryl or aralkyl group, the substituted C _1-6 alkyl which may be present includes formyl (in which methyl is substituted by oxo), carboxyl ( Methyl substituted by oxo and hydroxy), C _1-6
Alkoxy-carbonyl (in which methyl is substituted by oxo and alkoxy) (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
_1-6 alkoxy-carbonyl), hydroxy-C _1-6 alkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl, etc.), C _1-3 alkoxy-C _1-6 alkyl (eg, methoxymethyl, ethoxy) Methyl, ethoxybutyl, propoxymethyl, propoxyhexyl, etc.). The number of substituents in the hydrocarbon group is 1 to 6, preferably 1 to 5, more preferably 1 to 3, and most preferably 1 to 2. The number of substituents which the substituent of the hydrocarbon group may further have is preferably 1 to 3, and among them,
Two are preferred.

R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R
Among the groups via the carbon atom of ^4b, the acyl group in the acyl group which may be substituted includes a hydrocarbon-carbonyl or a hydrocarbon oxy-carbonyl, among which, for example, a group derived from a C _1-24 aliphatic carboxylic acid Acyl group to be used. 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), C _2-6 alkenyl-carbonyl (eg, vinylcarbonyl, butenylcarbonyl, butadienylcarbonyl, hexatrienylcarbonyl, etc.). Among them, C _1-10 alkyl-carbonyl or C _1-13 alkoxy-carbonyl is preferred. Examples of the substituent for the acyl group include the same substituents as those for the hydrocarbon group. The number of substituents is 1-3
About one. Among the above acyl groups, C _1-13 alkoxy in C _1-13 alkoxy-carbonyl may be linear or branched. As the straight-chain alkoxy, a C _1-9 alkoxy group is preferable, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy,
Neopentyloxy, hexyloxy, octyloxy and the like. Examples of the branched alkoxy group include 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-pyran-4-yloxy). As the branched alkoxy group, a C _3-7 branched alkoxy group is particularly preferable. R ^1a , R ^2a , R ^3a , R ^4a , R ^5a ,
Of the groups via a carbon atom of R ^6a and R ^4b, the optionally substituted carbamoyl group includes, for example, the above-mentioned _optionally substituted C _1-20 hydrocarbon group or _optionally substituted cyclic group And a carbamoyl group optionally substituted with amino. As the C _1-20 hydrocarbon group, the same groups as those defined for the hydrocarbon group among the groups via carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b are used. Things. Examples of the group that may be substituted on the carbamoyl group include the same groups as those described above that may be substituted on the hydrocarbon group. Preferred examples of the optionally substituted carbamoyl include, for example, mono-
Or a di-C _1-15 alkylcarbamoyl group is preferred,
Examples include methylcarbamoyl, ethylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl,
Methylethylcarbamoyl and the like.

R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R
Among the groups via the carbon atom of ^4b, the heterocyclic group in the heterocyclic group having a bond at the carbon atom which may be substituted includes, in addition to the carbon atom, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc. A 5- to 8-membered heterocyclic group containing 1 to 4 and a bicyclic or tricyclic condensed heterocyclic group condensed therewith, such as a heterocyclic group having a bond at a carbon atom constituting the ring. Can be Specific examples of the heterocyclic group in the heterocyclic group having a bond at the carbon atom which may be substituted include, for example, (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-furazanyl, 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,
Containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as 2,4-triazolyl) and 5- (1H- or 2H-tetrazolyl) 5
Membered heterocyclic group; (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, 3- or 4-pyridazinyl,
In addition to a carbon atom such as 2- or 3-pyrazinyl, one heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc.
Or a 6-membered heterocyclic group containing 4 to 4 units; , 2-Benzisoxazolyl, tetrazolo [1,5-b] pyridazinyl,
Triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolyl, isoindolyl, 1H-indazolyl, quinolizinyl, 1,8-naphthyridinyl, prynyl, diphenylidinyl Carbazolyl,
α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenanthrinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, thianthrenyl, phenanthrinyl, phenanthrolyl Nil, indolizinyl, pyrrolo [1,2-b]
Pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] Pyrimidinyl, 1,2,4-triazolo [4,
3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and 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 with a heterocyclic group having a bond at a carbon atom 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 and the like),
(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.), (18) N, N-di-C _1-4 alkyl-carbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-di) Propylcarbamoyl, 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)
In addition to carbon and one nitrogen, oxygen, sulfur,
A 3- to 6-membered cyclic amino group optionally containing 1 to 3 heteroatoms selected from a nitrogen atom and the like (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, Dihydropyridyl, N-
Methylpiperazinyl, N-ethylpiperazinyl, etc.), (2
8) C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide, etc.), (29) benzamide, (30) carbamoylamino, (31) NC _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.), (3
3) 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) sulfamoyl, (44) C _1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-
Ethylsulfamoyl, N-propylsulfamoyl,
N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (45) diC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N , N- dipropyl sulfamoyl, N, N- dibutylsulfamoyl etc.), (46) C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, n- butylthio, sec- butylthio, tert- butylthio Etc.), (47) phenylthio, (48) C
_1-6 alkylsulfinyl (eg, methylsulfinyl,
Ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), (49) phenylsulfinyl, (50) C
Examples thereof include _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and (51) C _6-14 arylsulfonyl (eg, phenylsulfonyl). The number of substitutions is 1 to 6,
Preferably it is 1-3, more preferably 1-2. Of the groups via a carbon atom of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b, a carboxyl group which may be esterified includes a group represented by the formula -COO-R ²¹ (wherein , R
²¹ represents a hydrogen atom, a hydrocarbon group or a heterocyclic group. ), And the hydrocarbon group and the heterocyclic group may each be substituted. Examples of the hydrocarbon group and its substituent include the above-mentioned C _1-20 hydrocarbon group and its substituent. As the heterocyclic group and its substituent, those described in a) below are used. The carboxyl group which may be amidated includes a compound of the formula -CO-NR ²² R
²³ (wherein, R ²² represents a hydrogen atom, a hydrocarbon group, a heterocyclic group or a group via a sulfur atom. R ²³ represents a hydrogen atom or a hydrocarbon group. R ²² and R ²³ are adjacent to each other. nitrogen atom may form a 5- to 8-membered cyclic amino group together with the further group and R ²² and R ^23, represented by may be a nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom.) These hydrocarbon group, heterocyclic group, cyclic amino group and nitrogen-containing heterocyclic group may be substituted.
As the hydrocarbon group for R ²² and R ^23, the above-mentioned C
_1-20 hydrocarbon groups. As the heterocyclic group, those described in a) below are used. As the group via the sulfur atom, those described below are used. The carboxyl group which may be amidated may be substituted with 1 to 3 groups similar to the above-mentioned groups which may be substituted with the hydrocarbon group.

In the above formula, the group via a nitrogen atom includes
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,
A hydroxyl group, a heterocyclic group, a fused bicyclic homocyclic group or a group represented by the formula —SO _p —R ²⁶ (wherein p represents an integer of 0 to 2 and R ²⁶ represents a hydrocarbon group) , R ²⁵ represents a 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). Hydrocarbon group, hydrocarbon-oxy group, acyl group, hydroxyl group,
The heterocyclic group and the cyclic amino group may each have a substituent. A hydrocarbon group in R ²⁴ , R ²⁵ , R ²⁶ or a hydrocarbon group in a hydrocarbon-oxy group, R ²⁴ , R ²⁵
As the acyl group in the above, R ^1a , R ^2a , R ^3a ,
The same as those defined for R ^4a , R ^5a , R ^6a and R ^4b can be mentioned. Examples of the heterocyclic group, condensed bicyclic homocyclic group, cyclic amino group, and nitrogen-containing heterocyclic group include those described below under a), d), b) and c). The group via the nitrogen atom may be substituted with 1 to 3 groups similar to the above-mentioned groups which may be substituted on the hydrocarbon group. In the above formula, as the group via an oxygen atom, for example, -OR
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. Examples of the hydrocarbon group and the acyl group for R ²⁷ or a substituent thereof include the aforementioned R ^1a , R
^Examples similar to those defined in ^2a , ^R3a , ^R4a , ^R5a , ^R6a , and ^R4b can be given. The heterocyclic group and its substituent include those described in a) below. In the above formula, the group via the sulfur atom includes, for example, -S (O) _te-
R ²⁸ (wherein, R ²⁸ represents a hydrogen atom, a hydrocarbon group, or a heterocyclic group, and te represents an integer of 0 to 2), and these hydrocarbon groups and heterocyclic groups are Each may have a substituent. Examples of the hydrocarbon group and the substituent for R ²⁸ include the aforementioned R ^1a , R ^2a , R ^3a , R ^4a ,
^{The same} ones as defined in ^5a , ^R6a and ^R4b can be mentioned. The heterocyclic group and its substituent include those described in a) below.

In the present specification, a) as a heterocyclic group, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like besides a carbon atom.
Heterocyclic group, and bicyclic or 3 fused thereto
And a cyclic fused heterocyclic group. 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 (1) thienyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, isoxazolyl, isothiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,4-thiadiazolyl, 1,2,
3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,
5-members containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms such as 2,3-triazolyl, 1,2,4-triazolyl, triazolidinyl, 1H- or 2H-tetrazolyl Heterocyclic group; (2)
Oxygen atoms other than carbon atoms such as pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, piperidinyl, piperidyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, pyridazinyl, pyrazinyl and the like; 1 to 4 heteroatoms selected from a sulfur atom, a nitrogen atom, etc.
And a 6-membered heterocyclic group. (3) Examples of the bicyclic or tricyclic fused heterocyclic group include benzofuranyl, isobenzofuranyl, benzothiazolyl, 1,2-benzoisothiazolyl, benzo [b] thienyl, benzoxazolyl, and 1H-benzotrial Zolyl, 1,2-benzisoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolyl , Isoindolyl, 1H-indazolyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,
α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenanthrinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, thianthrenyl, phenanthrinyl, phenanthrolinyl Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] Oxygen other than carbon atoms such as pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl Bicyclic or 3 containing 1 to 4 heteroatoms selected from atoms, sulfur atoms, nitrogen atoms, etc.
Examples include a cyclic fused heterocyclic group and the like, and further include (4) a three-membered ring such as oxiranyl and aziridinyl, and (5) a four-membered ring such as azetidinyl. The heterocycle may be a hydrogenated product. Examples of the group which may be substituted on the heterocyclic group include
For example, (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.), (18) 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-aziridini) Carbonyl, 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, (2
5) amino, (26) mono- or di-C _1-4 alkylamino (eg methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, dimethylamino,
(27) containing, in addition to carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc., such as diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc. A 3- to 6-membered cyclic amino group (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, N-methylpiperazinyl,
N-ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (eg, formamide, acetamide, propionylamide, butyrylamide, isobutyrylamide, etc.), (2
9) Benzamide, (30) carbamoylamino, (31) NC
_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-dibutyi) Rucarbamoylamino, 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, (42) phosphono, (43) sulfamoyl, (44) C _1-6
Alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (45) di C _{1 -6} alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (46) C _1-6
Alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), (47) phenylthio, (48) C
_1-6 alkylsulfinyl (eg, methylsulfinyl,
Ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), (49) phenylsulfinyl, (50) C
Examples thereof include _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and (51) C _6-14 arylsulfonyl (eg, phenylsulfonyl). The number of substitutions is 1 to 6,
Preferably it is 1-3, more preferably 1-2.

B) The cyclic amino group is 3 to 8
Preferred are those having a membered ring. , 3
-Triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, azepinyl, hexamethyleneamino, oxazolidino, morpholino, thiazolidino,
Examples include phthalimide or thiomorpholino. Of these, those having 5 to 6 members are preferred, and for example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferred. c) As the nitrogen-containing heterocyclic group in the above definition, 5 to
7-membered or those forming a bicyclic fused ring therewith are preferred. Morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,2,3-triazolidinyl, piperidinyl, piperazinyl, hexamethylene aminyl, oxazolidinyl, inazolidinyl, thiazolinyl, thiazolinidyl , Purinyl, quinolyl and the like. These may be hydrogenated. Among them, a 5- to 6-membered heterocyclic group is preferable. Among the 5- to 6-membered heterocyclic groups, in particular, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl,
Thiomorpholinyl is preferred. The cyclic amino group and the nitrogen-containing heterocyclic group may have 1 to 3 substituents,
Examples of the substituent 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 preferred substituents include C
_Examples thereof include _1-6 alkyl, and among them, C _1-3 alkyl is particularly preferable. d) Examples of the bicyclic homocyclic group include indanyl, indenyl and the like.

E) Halogen in the definition of the above groups includes fluorine, chlorine, bromine and iodine. f) As the C _1-6 alkyl in the definition of the above group,
Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. C _1-4 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. C _1-3 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl. g) Examples of C _2-10 alkenyl in the above group definition include, for example, vinyl, allyl, propenyl, 2-methylallyl, isopropenyl, 2-butenyl, 3-butenyl, butadienyl, hexatrienyl,
3-octenyl and the like. Examples of C _2-6 alkenyl include, for example, vinyl, allyl, propenyl, isopropenyl, butenyl, hexatrienyl. Examples of C _2-4 alkenyl include vinyl, allyl, isopropenyl and butenyl. h) 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. C _2-6 alkynyl and C
Examples of _2-4 alkynyl include, for example, ethynyl, 1-
And propynyl and 2-propynyl. i) As the C _3-10 cycloalkyl in the definition of the above groups, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like can be mentioned. 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. j) C _3-7 cycloalkenyl in the above group definition includes, for example, cyclopropenyl, cyclobutenyl,
Cyclopentenyl, cyclohexenyl and the like, as C _5-7 cycloalkenyl, for example, cyclopentenyl,
Cyclohexenyl and the like.

K) Examples of C _6-14 aryl in the definition of the above groups include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl. Examples of C _6-10 aryl include phenyl, naphthyl. Of these, phenyl is preferred. l) C _7-20 aralkyl or C in the above group definition
Examples of _7-19 aralkyl include, for example, phenyl-C _1-6 alkyl such as benzyl, phenethyl, benzhydryl, and trityl. C _7-15 aralkyl and C
Examples of _7-13 include, for example, phenyl-C _1-6 alkyl such as benzyl and phenethyl, and benzhydryl. Examples of C _7-11 aralkyl and C _7-10 aralkyl include, for example, phenyl-C _1-5 alkyl and phenyl-C _1-4 alkyl such as benzyl, α-methylbenzyl, phenethyl and the like. m) Examples of C _1-6 alkoxy in the above group definition include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, Neopentyloxy, 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. n) As the C _1-6 acyl in the definition of the above group, for example, a group represented by the formula —CO—R ³⁶ (where R ³⁶ is a hydrogen atom or C _1-5 alkyl (eg, methyl, ethyl, propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, t
- butyl, C _1-6 alkanoyl represented by showing a pentyl)). C _1-4 in the definition of the above group
The acyl, for example, the formula -CO-R ³⁷ (wherein, R ³⁷
Represents a hydrogen atom, C _1-3 alkyl such as methyl, ethyl, propyl, isopropyl, etc.). 0) C _1-8 alkanoyl in the definition of the above groups includes, for example, formyl, acetyl, propionyl, butyryl, isobril, valeryl, isovaleryl, octanoyl and the like.

The fused ring compound is represented by 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. The above formulas (X), (XX), (XX
Examples of the group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, an optionally substituted heterocyclic group or an allocyclic group in X) include those described above.

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 by (1) hydrogen, (2) formyl group, (3) cyano group, (4) a group via a sulfur atom, an optionally substituted hydroxyl group or an optionally substituted hydrocarbon group. A lower alkyl group, (5) a carbonyl group substituted with an optionally substituted hydrocarbon residue or (6) a carboxyl group which may be esterified or amidated, wherein R ⁵ is hydrogen or a carbon atom Wherein n represents 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 via the sulfur atom represented by R ⁴ include mercapto, each of which may be substituted, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _3-7 cycloalkylthio, C _{3-7 6-14} arylthio,
C _7-11 aralkylthio, a heterocyclic thio group and the like. Said optionally substituted C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _3-7 cycloalkylthio, C _6-14 arylthio, C _7-11 aralkylthio,
In the heterocyclic thio group, C _1-6 alkyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-11 aralkyl, and the heterocyclic group have the same meanings as f), i), k) and a) above. Have. 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 esterified carboxyl group represented by R ⁴ include C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyloxycarbonyl, C _3-7
6-14 aryloxycarbonyl, C _7-11 aralkyloxycarbonyl, oxycarbonyl substituted with a heterocyclic group and the like, and these C _1-6 alkyl, C _3-7 cycloalkyl, C _6-14 aryl, The C _7-11 aralkyl and the heterocyclic group have the same meanings as in the above f), i), k) and a). Examples of the amidated carboxyl group represented by R ⁴ include a carbonyl group substituted with a group via a nitrogen atom. 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 include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, pentyl and hexyl. Can be 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 C _1-6 alkyl _optionally having 1 to 4 substituents selected from _-12 aralkyl (eg, benzyl, phenylethyl, etc.) and 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, phenyl-C _1-6 alkyl such as benzyl, phenylethyl and the like) and nitro and the like, which may have 1 to 4 substituents.
_6-10 aryl (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, phenyl-C such as benzyl, phenylethyl, etc.)
1 to 4 selected from _1-6 alkyl, etc.) and nitro, etc.
C _7-12 aralkyl _optionally having two substituents (eg,
Phenyl-C _1-6 alkyl such as benzyl and phenylethyl, naphthyl-C _1-2 alkyl such as 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, phenyl-C _1-6 alkyl such as benzyl, phenylethyl, etc.) And optionally substituted 1 to 3 substituents selected from nitro and the like.
_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 _6-10 aralkyl which may have 1 to 4 substituents selected from C _7-12 aralkyl (eg, phenyl-C _1-6 alkyl such as benzyl and phenylethyl) and nitro and the like. Carbonyl (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, phenyl-C such as benzyl, phenylethyl, etc.)
1 to 4 selected from _1-6 alkyl, etc.) and nitro, etc.
C _6-10 aryl-carbonyl _optionally having two substituents (eg, benzoyl, naphthylcarbonyl, etc.); (7)
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 ( For example, phenyl-C such as benzyl and phenylethyl
1 to 4 selected from _1-6 alkyl, etc.) and nitro, etc.
_C7-12 aralkyl-carbonyl _optionally having two substituents (eg, benzylcarbonyl, phenethylcarbonyl, etc.); (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, phenyl-C _1-6 alkyl such as benzyl, phenylethyl and the like) and pyranyl or furanyl optionally having 1 to 4 substituents selected from nitro and the like; _1-4 alkyl) silyl (eg,
Trimethylsilyl, triethylsilyl, etc.). The group via the sulfur atom is represented by R ^1a , R ^2a , R ^3a ,
It has the same meaning as defined for R ^4a , R ^5a or R ^6a .

The hydrocarbon residue in the carbonyl group substituted by the optionally substituted hydrocarbon residue represented by R ⁴ includes, for example, a saturated or unsaturated
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, phenyl-C _1-6 alkyl such as benzyl, C _7-20 aralkyl such as _benzhydryl and trityl) and the like. The substituent has the same meaning as the substituent in the group via the carbon atom.

R ¹ and R ² are one (preferably R ¹ )
(1) General formula _{^{R 9 - (CH 2) m}} - wherein, R ⁹ is halogen, hydroxy, cyano, optionally substituted heterocyclic group, or a group bonded through a optionally substituted nitrogen atom , M represents an integer of 0 to 3], or (2) a C _6-14 aryl group which may be substituted, and the other (preferably R ² ) has the general formula R ¹⁰ -A- [Wherein, R ¹⁰ represents an _optionally substituted C _6-14 aryl group, an _optionally substituted C _1-6 alkyl group, a C _6-14 aryl-carbonyl group, a C _7-11 aralkyl- A represents a carbonyl group or a halogen, and A represents an intervening group]. The halogen represented by R ⁹ has the same meaning as in the above e). The optionally substituted heterocyclic group has the same meaning as in the above a). The group via the optionally substituted nitrogen atom has the same meaning as described above. As the group via the optionally substituted nitrogen atom, a mono- or di-substituted amino group is preferable.
(1) (i) sulfamoyl, (i)
i) C _1-6 alkoxy, (iii) C _1-6 alkylthio, (iv) halogen, (v) nitro, (vi) C _6-14 aryl optionally substituted with 1 to 3 cyano, (vii ) 1-3 optionally substituted by C _1-6 alkyl halogen, (viii) hydroxy, or (ix) C _1-6 alkoxy - 1-3 carbonyl
Optionally substituted C _7-11 aralkyl, (2) C _6-14
Aryl, (3) (i) heterocyclic group optionally substituted with C _1-6 alkyl, (ii) amino, (iii) hydroxy, (iv) oxo, (v) C _1-6 alkoxy, (vi ) C _1-6 1 to 3 alkyl or C _6-14 aryl with one to two optionally substituted carbamoyl or (vii) 1 to 3 amino optionally substituted C _6-14 aryl nitro, Optionally substituted C _1-6 alkyl, (4) C _1-6 alkyl-carbonyl, (5) C
C _2-10 alkenyl optionally substituted with _6-14 aryl, or (6) heterocyclic group is preferable. In particular, the formula -NR ³⁹
R ⁴⁰ (wherein, R ³⁹ represents a C _1-6 alkyl group, and R ⁴⁰ represents a C _7-11
Aralkyl groups) are particularly preferred. Which may C _6-14 aryl group or C _6-14 ants substitution at R ¹⁰ - Le - said k is as C _6-14 aryl groups in carbonyl group), an optionally substituted C _1-6 alkyl Examples of the C _1-6 alkyl group in the group include the above f), and the C _1-11 alkyl group in the C _7-11 aralkyl-carbonyl group.
_{The 7-11} aralkyl group has the same meaning as in 1) above, and the halogen has the same meaning as in e) above. Examples of the substituent in the optionally substituted C _6-14 aryl group represented by R ¹⁰ include (1) halogen, (2) halogen, C _1-6 alkyl-carbonyl, C _2-10 alkenyl or C _2-10 alkenyl. C _1-6 alkoxy optionally substituted with 1 to 3 _3-7 cycloalkyl, (3) C _1-6 alkoxy-carbonyl, (4) nitro, (5)
C _1-6 alkoxy-C _1-6 alkoxy (6) mono- or di-C _1-6 alkyl-carbonyl, (7) (i) C 1-3 optionally substituted with C _1-6 alkyl-carbonyl _2-10 alkenyl, (ii) C _3-7 cycloalkyl optionally substituted with 1 to 3 hydroxy, (iii) 1 to 3 substituted with oxo, hydroxy or C _1-6 alkyl-carbonyl. also a C _1-6 alkyl, (iv) halogen or C _1-6 alkoxy with 1-3 optionally substituted by C _1-6 alkyl -
Carbonyl, (v) formyl, (vi) (a) C _1-6 alkyl, (b)
C _1-6 alkylthio, (c) C _6-14 aryl or (d) 1-
Carbamoyl optionally substituted with one or two C _1-6 alkoxy optionally substituted with three halogens, (vi
i) C _6-14 aryl-carbonyl, (viii) C _1-6 alkyl-sulfinyl, (ix) C _1-6 alkoxy-carbonyl,
(x) heterocyclic-carbonyl, or (xi) amino optionally substituted by 1 to 2 C _1-6 alkoxy, (8) hydroxy, 1 to 3 substituted by (9) nitro C _1-6 alkyloxy-carbonyl, (10) C _7-11 aralkyl, (1
1) 1 to 3 C _6-14 aryl, hydroxy, C _1-6 alkoxy or C _1-6 alkyl optionally substituted
_2-10 alkenyl, (12) cyclic amino, (13) C _2-10 alkenyloxy optionally substituted by 1-3 alkyl with C _1-6 alkyl, or (14) C _2-10 alkenyl with 1-3 An optionally substituted C _1-6 alkyl is preferred. The number of substituents is
The number is 1 to 5, preferably 1 to 3. Examples of the substituent in the optionally substituted C _1-6 alkyl represented by R ¹⁰ include (1) halogen, and (2) amino optionally substituted by 1 to 3 C _7-11 aralkyl. preferable. 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. Examples of the aliphatic hydrocarbon residue which may be substituted in the aliphatic hydrocarbon residue which may be substituted with a group via an oxygen, nitrogen or sulfur atom represented by R ⁸ include, 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 (e.g., ethynyl, 2-propynyl, 3-hexynyl, etc.), C _1-6 alkoxy (e.g., methemoglobin Shi, 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. The R ⁷ or R ⁸ (1) C _1-6 alkoxy, (2) 1-3 optionally substituted C _1-6 alkyl halogen, (3) C _1-6 alkyl - carbonyloxy, ( 4) C _1-6 alkylthio, (5) cyano or C _1-6 alkoxy - 1-3 optionally substituted C _6-14 aryl carbonyl, (6) halogen, 1-3 (7) halogen An optionally substituted _C7-11 aralkyl is preferred. R ⁴ is halogen, cyano, a hydrocarbon group which may be substituted, a hydrocarbon-oxy group which may be substituted, a carbonyl group which is substituted by a hydrocarbon group which may be substituted, A sulfonyl group substituted with an optionally substituted hydrocarbon group, a sulfonyl-oxy group substituted with an optionally substituted hydrocarbon group, a mono- or di-substituted amino group, a mono- or di-substituted amino-carbonyl group, or a heterocyclic group Is preferred. Examples of the hydrocarbon group or the hydrocarbon group in the hydrocarbon-oxy group and the substituent thereof include R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R
^4b . The heterocyclic group has the same meaning as in the above a). Examples of the substituent of the amino group include the same substituents as those described above for the group via a nitrogen atom of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a or R ^6a . R ⁴ is preferably (1) (i) hydroxy, (ii) C _1-6 alkyl-carbonyloxy, (iii) C _1-6 alkylthio,
(iv) C _6-14 aryl _optionally substituted by 1 to 3 halogens, (v) C _3-7 cycloalkyl, (vi) C _1-6 alkyl-carbonyl, (vii) C _1-6 alkyl Sulfinyl, or (viii) C _1-6 alkyl optionally substituted with 1 to 3 C _6-14 aryl-carbonyloxy, (2) C _1-6 alkoxy-carbonyl, (3) halogen, C _{1- 6} alkyl to 1
1 to 2 amino, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkyl or C _6-14 aryloxy
Optionally substituted C _6-14 aryl-carbonyl, (4) C _1-6 alkyl-carbonyl, (5) formyl, (6)
Heterocyclic - carbonyl, (7) (i) C 7-11 aralkyl - heterocyclic group, with (ii) a heterocyclic group, (iii) C _1-6 alkyl with one to two optionally substituted amino 1 (C) _1-6 alkyl optionally substituted with 1 to 3 or (iv) amino-carbonyl optionally substituted with 1 to 2 heterocyclic -C _1-6 alkyl,
(8) C _1-6 alkoxycarbonyl or amino - 1-3 optionally substituted by C _1-6 alkoxy carbonyl,
(9) cyano, (10) C _3-7 cycloalkyl - carbonyl, (1
1) a heterocyclic group, (12) C _1-6 alkyl-carbonyl,
Optionally substituted amino, (13) C _1-6 alkyl-
Carbonyloxy, (14) hydroxy, (15) C _1-6 alkylsulfonyloxy, (16) C _1-6 alkylthio, (17) C
_1-6 alkylsulphinyl or (18) C _1-6 alkylsulfonyl. R ⁵ is preferably a hydrogen atom or C _1-6
Alkyl. Particularly, a hydrogen atom is preferable.

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

Embedded image [In the formula, R ^13a may be substituted with 1 to 5 and may be the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a C
_1-8 alkanoylamino group, R ^14a is hydrogen atom or C
_{In the 1-6} alkyl group, 1 to 5 R ^15a may be substituted and may be the same or different, and each represents a hydrogen atom,
A halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-6 alkylthio group, R ^16a may have 1 to 5 substituents and may be the same or different, and each may be a hydrogen atom, In the C _1-6 alkyl group, halogen atom or C _1-6 alkoxy group, one or two R ^17a may be substituted and may be the same or different, and may be esterified or amidified, respectively. A carboxyl group, a C _1-6 alkylcarbonyl group, a C _6-14 arylcarbonyl group or an optionally substituted C _1-6 alkyl group, wherein v, t and u may be the same or different and each represents 0 And an integer of from 3 to 3] are preferred. Examples of the substituent of the C _1-6 alkyl group in R ^17a (i) hydroxy, (ii) C _{1 -6} alkyl - carbonyloxy, (iii) C _1-6 alkylthio, 1-3 in (iv) halogen Optionally substituted C _6-14 aryl, (v)
C _3-7 cycloalkyl, (vi) C _1-6 alkyl-carbonyl, (vii) C _1-6 alkylsulfinyl, or (viii) C
_6-14 aryl-carbonyloxy is preferred. The number of substitution is preferably 1 to 3. The above C _1-6 alkyl group, C _{1-6
Alkylthio} group, C _1-6 alkylcarbonyl group or C
_In C _1-6 alkyl-carbonyloxy, the above-mentioned f) is used as C _1-6 alkyl, the above-mentioned m) is used as C _1-6 alkoxy group, the above-mentioned e) is used as halogen, and C _1-6 in C _1-6 alkanoylamino group _{Examples of 1-8} alkanoyl include o) described above, and examples of C _6-14 aryl include k) described above. Examples of the carboxyl group which may be esterified or amidated include R ^1a , R ^2a , R ^3a ,
Those defined for R ^4a , R ^5a , R ^6a and R ^4b can be used.

Further, among the compounds represented by the general formula (XI),

Embedded image [In the formula, R ^13b may be substituted by 1 to 3 substituents and may be the same or different, and represents a hydrogen atom, a C _1-6 alkoxy group or a C _1-8 alkanoylamino group, and R ^14b represents a hydrogen atom Or a C _1-6 alkyl group, R ^15b may be substituted with 1 to 3 substituents, and may be the same or different; a hydrogen atom or halogen; and R ^16b may be substituted with 1 to 3 substituent (s). Furthermore, they may be the same or different, and include a hydrogen atom,
Halogen or C _1-6 alkoxy, R ^17b is 1 or 2
May be further substituted or may be the same or different, and represent a carboxyl group or a C _1-6 alkylcarbonyl group which may be esterified or amidated,
v ', t' and u 'may be the same or different and each represents an integer of 0 to 3]. As the above C _1-6 alkoxy group, m) described above,
As the C _1-8 alkanoyl in the C _1-8 alkanoylamino group, the above-mentioned o), as the C _1-6 alkyl group or the C _1-6 alkyl in the C _1-6 alkylcarbonyl group, the above-mentioned f), and as the halogen, The above e) can be mentioned. Examples of the carboxyl group which may be esterified or amidated include the aforementioned R ^1a , R ^2a , R ^3a , R ^4a ,
Those defined for R ^5a , R ^6a and R ^4b can be used. R ^17a and R ^17b are preferably attached at the 5-position.

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 a 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, a compound represented by the general formula (XII)

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 ^optionally substituted heterocyclic group represented by R ^4h is R
^It has the same meaning as ^4e . Examples of the group via a hetero atom represented by R ^4h include a group via a nitrogen atom, a group via an oxygen atom, and a group via a sulfur atom.
^They are the same as those defined for R ^4e .

In the compound represented by the general formula (XII), R
Preferred examples of ^1h include groups via a carbon atom or a nitrogen atom. 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 a C _1-6 alkyl group which may have As C _1-6 alkyl, the above f) can be mentioned. Substituents in the ^optionally substituted C _1-20 hydrocarbon group represented by R ^1h include (1) halogen, (2)
Nitro, (3) cyano, (4) optionally substituted amino group, (5) optionally substituted hydroxyl group or (6)
Wherein ^{-S (O) t h -R 6h} ( wherein, t ^h is an integer of 0 to 2,
R ^6h represents a hydrogen atom or an optionally substituted hydrocarbon group). R ^1h is preferably a substituted aminoalkyl such as an N, N-disubstituted amino-C _1-6 alkyl group. Preferably, N-aralkyl-N-alkylaminoalkyl, especially N-C
_7-11 aralkyl -N-C _1-6 alkylamino -C _1-6 alkyl.

Preferred examples of R ^2h include a group 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 above k) is used as the C _6-14 aryl group. R
Examples of the substituent in the _optionally substituted C _1-20 hydrocarbon group represented by ^2h include (1) an optionally substituted amino group, (2) an optionally substituted hydroxyl group, 3)
An optionally substituted carbamoyl group, (4) an optionally substituted carboxyl group, (5) an optionally substituted C
_{A 2-10} alkenyl group, (6) C _1-6 acyl group or (7) nitro group is preferred. The C _2-10 alkenyl group includes the above g), and the C _1-6 acyl group includes the above n).
Specific examples of the substituent of the optionally substituted C _6-14 aryl group represented by R ^2h include, for example, (1) C _1-6 alkoxy, (2) C _1-6 alkylcarbonyl, (3) C _1-6 alkylaminocarbonyl, (4) C _2-10 alkenyl which may be substituted (preferable examples of the substituent include C _1-6 alkylcarbonyl and C _1-6 alkylaminocarbonyl), Or (5) optionally substituted amino (preferable examples of the substituent include C _1-6 alkyl, C _1-8 alkanoyl, C _1-6 alkyl substituted with hydroxy, and hydroxy). Can be Particularly, C _1-8 alkanoylamino or C _1-6 alkoxy is preferred.
Most preferred R ^2h include (i) nitro, (ii) C
_1-6 alkoxy and (iii) C _6-14 aryl optionally substituted with a group selected from amino groups optionally substituted with C _1-8 alkanoyl. The above C _1-6 alkoxy is m), the C _1-6 alkyl or C _1-6 alkylcarbonyl, and the C _1-6 alkyl in C _1-6 alkylaminocarbonyl is f) or C _2-10 alkenyl is the g), C _1-8 alkanoyl or C _{1 -8}
The C _1-8 alkanoyl in alkanoylamino includes the above-mentioned o).

Preferred examples of R ^3h include an ^optionally substituted homocyclic group. The homocyclic group has the same meaning as that described for the W ring group. The homocyclic group in the optionally substituted homocyclic group is preferably a C _6-14 aryl group. The above k) is used as the C _6-14 aryl group. Substituents in the optionally substituted homocyclic group represented by R ^3h are (1) halogen, (2) nitro, (3)
An optionally substituted hydroxyl group or (4)
(O) a group represented by t ^h -R ^6h (wherein t ^h is an integer of 0 to 2, and R ^6h represents a hydrogen atom or a C _1-20 hydrocarbon group which may be substituted) . Preferred examples of the group represented by R ^3h include a C _6-14 aryl group substituted with one or two halogens, and phenyl is preferred as the aryl. As a more preferred group represented by R ^3h , phenyl substituted with fluorine is particularly preferred. Preferred examples of R ^4h include an ^optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted hydroxyl group, and an optionally substituted mercapto group.

Preferred examples of the heterocyclic group in the ^optionally substituted heterocyclic group represented by R ^4h include 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. Examples of the heterocyclic group include the aforementioned a)
Is mentioned. 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) an optionally substituted hydroxyl group, (4) a formula —S (O) m ^h -R
^6h (wherein the integer m ^h is 0 to 2, R ^6h is a hydrogen atom or an optionally substituted C _1-20 hydrocarbon group) a group represented by the optionally substituted (5) Good amino group or (6)
C _1-10 hydrocarbon groups are preferred. ^Examples of the substituent in the optionally substituted amino group, the optionally substituted hydroxyl group or the optionally substituted mercapto group represented by R ^4h include (1) C _1-6 alkoxycarbonyl or carbamoyl. Up to 3 optionally substituted C
_1-10 hydrocarbon group, (2) C _1-6 acyl group or (3) formula -S
A group represented by (O) t ^h -R ^6h (where, t ^h is an integer of 0 to 2, and R ^6h is a hydrogen atom or a C _1-20 hydrocarbon group which may be substituted) is preferable. . In the above C _1-6 alkoxycarbonyl, the C _1-6 alkoxy includes the above m), and the C _1-6 acyl group includes the above n).
The most preferred group represented by R ^4h is (1) 1
A 5- to 6-membered heterocyclic group containing one nitrogen atom and one oxygen atom and having a bond at a carbon atom, (2) (i) may have a C _1-6 alkoxycarbonyl or carbamoyl. C _1-6 alkyl, (ii) C _1-8 alkanoyl and (ii)
i) C _1-6 alkylsulfonyl group optionally substituted hydroxyl group selected from, (3) -S (O) t ^h -
A group represented by R ^6h ′ (wherein, t ^h is an integer of 0 to 2, and R ^6h ′ represents a C _1-6 alkyl group), and (4) a group represented by C _1-8 alkanoyl. An amino group is mentioned. The 5-6 membered heterocyclic group having a bond to the carbon atom may be mentioned the ^{R 1a, R 2a, R 3a} , R 4a, R 5a, R 6a, those defined in R ^4b. The C _1-6 alkoxy in the C _1-6 alkoxycarbonyl includes the above m),
As C _1-6 alkyl or C _1-6 alkylsulfonyl, C _1-6 alkyl includes the above-mentioned f), and C _1-8 alkanoyl includes the above-mentioned o).

R^5hAre preferably hydrogen atoms or
Or a hydrocarbon group which may have a substituent,
Among them, a hydrogen atom or an optionally substituted C
_1-20Hydrocarbon groups are preferred. Furthermore, a hydrogen atom or C
_1-6Alkyl groups are preferred. Particularly, hydrogen is preferable. The
C_1-6As the alkyl group, the above f) is used. the above
In the compound (XII), R^1hIs halogen or N-C_7-13A
RALKYL-NC _1-6Substituted with alkylamino
Good C_1-6An alkyl group represented by R^2hIs (i) nitro, (ii) C
_1-6Alkoxy and (iii) C_1-8Substituted with alkanoyl
Substituted with a group selected from amino which may be
Good C_6-14An aryl group is represented by R^3hIs mono- or di-
Halogeno C_6-14An aryl group is represented by R^4hIs (1) a nitrogen atom and
5-6 containing an oxygen atom and having a bond at a carbon atom
Membered heterocyclic group, (2) (i) C_1-6Alkoxycarbonyl or
Is C which may have carbamoyl_1-6Alkyl, (i
i) C_1-8Alkanoyl and (iii) C_1-6Alkylsulfo
Hydroxy optionally substituted with a group selected from nyl
Group, formula (3) -S (O) t^h-R^6h'(Where t^hIs 0-2
Integer, R^6h'Is C_1-6Represents an alkyl group)
Group or (4) C_1-8Optionally substituted with alkanoyl
An amino group is represented by R^5hRepresents a hydrogen atom, n^hIndicates 1
Compounds are particularly preferred. As the halogen,
e), N-C_7-13Aralkyl-NC_1-6Alkylam
C in ノ_7-13As aralkyl, the above l), C_1-6
Alkyl group or N-C_7-13Aralkyl-NC_1-6A
Lucylamino or C_1-6In alkylsulfonyl
C_1-6As the alkyl, the above f), C_1-6Alkoxy
Or C_1-6C in alkoxycarbonyl_1-6Arco
As the xy, the above m), C_1-8Before as alkanoyl
Note o), C_6-14Aryl group or mono- or di-
Halogeno C_6-14C in the aryl group_6-14As an aryl
And the above-mentioned k). In addition, carbon atoms
The 5- or 6-membered heterocyclic group having a bond at
^1a, R^2a, R^3a, R^4a, R^5a, R^6a, R^4bAlso defined in
Can be mentioned. n^hPreferably represents 1.

As the compound used in the composition of the present invention, a compound represented by the general formula (XIII)

Embedded image [Wherein R ¹ⁱ is a formula

Embedded image (Wherein R ⁶ⁱ represents (1) a phenyl group optionally substituted with 1 to 3 fluorine, bromine, sulfamoyl, methylthio or nitro, (2) a 2- or 3-pyridyl group, (3)
3-indolyl group optionally substituted with methyl, (4)
R ⁷ⁱ represents a propyl group or (5) butylcarbamoyl group, and R ⁷ⁱ represents a methyl group. ) Or a hexamethylenetetraaminomethyl group, R ²ⁱ represents methoxycarbonylvinyl, ethoxycarbonylvinyl, carboxyvinyl,
Benzoylvinyl, acetylvinyl, propionylvinyl, isobutyrylamino, propionylamino, 3-oxobutylamino, 3-oxopentylamino, 2-hydroxycyclohexylamino, trifluoroacetylamino, 2-hydroxypropylamino, 2-hydroxybutyl Amino, 2-hydroxyisobutylamino, N
-Ethyl-N-trifluoroacetylamino, methylamino, ethylamino, propylamino, butylamino,
R ³ⁱ represents a 2-fluorobenzyl group or 2,6-difluorobenzyl group, and R ⁴ⁱ represents a phenyl group substituted with isobutylamino, diethylamino, 1-pyrrolidinylamino, ethanesulfonamide or acetonyloxy.
(1) an acyl group or (2) a C _1-6 alkyl group which may be substituted with 1 to 3 hydroxy or alkylcarbonyloxy groups. Or a salt thereof.

Preferred examples of the group represented by R ¹ⁱ in 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 examples of the group represented by R ²ⁱ in I) include a compound represented by the formula R ¹⁰ⁱ -R ^9i-wherein R ⁹ⁱ represents a vinylene group,
R ¹⁰ⁱ represents C _1-6 alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, and C _1-8 alkanoyl such as carboxy, benzoyl, acetyl and propionyl. Or a group represented by the formula R ¹¹ⁱ −
NH- (wherein, R ¹¹ⁱ represents 3-oxobutyl, 3-oxopentyl or 2-hydroxycyclohexyl) or a group represented by the formula R ¹²ⁱ —O— (where R ¹²ⁱ represents acetonyl). And a phenyl group substituted with. R ⁴ⁱ in the compound (XIII) of the present invention
As the acyl represented by, an acyl group derived from a carboxylic acid, for example, -CO-R ⁸ⁱ (wherein -R ⁸ⁱ represents a hydrocarbon residue or a substituent which may have a substituent, A heterocyclic group which may be present).

Specific examples of the hydrocarbon residue include the aforementioned R
^Examples are the same as those defined for ^1a , ^R2a , ^R3a , ^R4a , ^R5a and ^R6a . Examples of the substituent of the hydrocarbon residue include 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
Examples include _1-6 alkyl-sulfinyl, bayzoyl, phenoxy, C _1-6 alkylenedioxy, heterocyclic groups and the like. The number of substitutions is 1 to 6, preferably 1 to 3,
More preferably, it is 1-2.

Examples of the heterocyclic group include the same as those described in the above a). Examples of the substituent of the heterocyclic group include 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) Phenyl-C _1-5 alkyl, such as 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 ( For example, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide, etc.), carbamoylamino, NC _1-4
Alkylcarbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), nitro, cyano, mercapto, sulfo, sulfino, phosphono, Sulfamoyl, C _1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl,
N-butylsulfamoyl, etc.), di-C _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl,
N, N-dibutylsulfamoyl, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), C _1-6 alkylsulfinyl (eg, , methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl, etc.), C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and the like. The number of substitutions is 1 to 6, preferably 1 to 3,
More preferably, it is 1-2.

[0058] 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 a C _1-6 alkyl group. _Examples of the substituent in the _optionally substituted C _6-14 aryl group include C
_1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C
Preferred are _1-6 alkoxy, C _1-6 alkylenedioxy, phenoxy, hydroxy, C _1-6 alkylcarbonyloxy, mono- or di-C _1-6 alkylamino, C _1-6 alkylthio and the like. Examples of the substituent in the C _1-6 alkyl group which may have a substituent include, for example, hydroxy, halogen, nitro, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkoxy or the formula —S (O) _p ⁱ -R ⁷ⁱ
(Wherein the integer p ⁱ is 0 to 2, R ⁷ⁱ represents a C _1-6 alkyl) group represented by include C _1-6 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 substituents on the heterocyclic group include, for example, C
_1-6 alkyl, C _1-6 alkoxy, carboxyl, C _1-6
Alkoxy-carbonyl, carbamoyl group, halogen,
Oxo, amino, mono- or di-C _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) C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, C _1-6 alkylenedioxy, phenoxy, hydroxy, C _1-6 alkylcarbonyloxy, mono- or di -C _1-6 alkylamino or C _1-6 alkylthio substituted benzoyl group, (2) C _1-3 C _1-6 alkylcarbonyl substituted with alkylenedioxy Or (3) a thienylcarbonyl group. Preferred examples of the C _1-6 alkyl group _optionally substituted with hydroxy or C _1-6 alkylcarbonyloxy represented by R ⁴ⁱ include C _1-6 substituted with hydroxy or acetyloxy.
_{A 1-6} alkyl group is mentioned, and 2-hydroxyisobutyl and 2-acetoxyisobutyl are more preferable.

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

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

Embedded image [Wherein, R ^1j is a formula -XR ^4j (wherein, when X is O, R ^4j
Is a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent (preferably 1 to 2
And when X is S, R ^4j may be an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a group which has a substituent. A hydroxyl group or a group represented by a good oxygen-containing 6-membered heterocyclic group (preferably containing 1 to 2 oxygen atoms)
^2j represents a C _1-8 alkanoylamino group, and R ^3j represents a hydrogen atom or an alkyl group.] Or a salt thereof.

In the above formula, as the branched alkyl group in the ^optionally substituted branched alkyl group represented by R ^4j , a C _3-13 branched alkyl group (for example, , Isopropyl, sec-butyl, tert-butyl,
Isopentyl, sec-pentyl, tert-pentyl, 3-pentyl, isohexyl, sec-hexyl, tert-hexyl, isooctyl, sec-octyl, tert-octyl). Examples of the branched alkyl group include C
_3-7 branched alkyl groups are preferred, isopropyl, s
ec-butyl, 3-pentyl or 2,4-dimethyl-3-
Pentyl is particularly preferred. The branched alkyl group may have a substituent, and the substituent may be a C _1-4 alkyl, halogen, amino, mono- or di-C _1-4 alkylamino, C _1-4 Alkoxy and C _3-7 cycloalkyl. Among them, C _1-4 alkyl and halogen are preferred. C _1-4 alkyl and mono- - or as a C _1-4 alkyl in di -C _1-4 alkylamino, for example, methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, s- butyl, t- butyl, etc. Is 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 alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and the like, among which methoxy and ethoxy are preferred. C _3-7 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Of these, cyclohexyl is preferred. The number of the substituents is 1 to 3, preferably 1 to 2.

Specific examples of the branched alkyl group which may have a substituent include isopropyl, sec-butyl,
tert-butyl, isopentyl, sec-pentyl, tert-pentyl, 3-pentyl, isohexyl, sec-hexyl, te
rt-hexyl, isooctyl, sec-octyl, tert-octyl, 1,3-difluoro-2-propyl and the like.

As the cycloalkyl group in the optionally substituted cycloalkyl group, a C _3-10 cycloalkyl group is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. No. Among them, C _3-7 cycloalkyl group is preferred. The cycloalkyl group may form a bicyclic fused ring. Examples of the fused ring group include indanyl and the like. Examples of the substituent for the cycloalkyl group include (1) halogen, (2) C _1-6 alkoxy, (3) C _1-6 alkyl, and (4) C
_3-7 cycloalkyl, (5) C _1-6 alkylthio, (6) amino, (7) mono - or di -C _1-6 alkylamino, (8) nitro, (9) hydroxyl, (10) oxo, (11) carbamoyl, (12) cyano, (13) mercapto, (14) sulfo and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2. Preferred examples of the group which may be substituted on the cycloalkyl group include halogen, nitro and amino.

Specific examples of the optionally substituted cycloalkyl group include 2,6-dimethyl-1-cyclohexyl, 3,5-dimethyl-1-cyclohexyl, 4-methyl-1-cyclohexyl and 4-ethylcyclohexyl ,
4-Amino-1-cyclohexyl can be mentioned.

Examples of the halogen include those described in the above e). As the alkoxy, C _1-6 alkoxy is preferred.
Preferred is _1-6 alkyl, for example, those described in f) above.

[0067] The mono - Examples of alkylamino, preferably mono- -C _1-4 alkylamino, for example, N- methylamino, N- ethylamino, N- propylamino,
N-n-butylamino, N-isobutylamino and the like. The di-alkylamino includes di-C _1-4
Alkylamino is preferable, and examples thereof include N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino and the like. The alkylthio includes C
_1-4 alkylthio is preferable, and examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio and the like.

Examples of the oxygen-containing 6-membered heterocyclic group in the oxygen-containing 6-membered heterocyclic group which may be substituted include pyranyl, tetrahydropyranyl, dioxanyl, oxazinyl, isoxazinyl and the like. These hydrogenated products may be used. As the substituent of the oxygen-containing 6-membered heterocyclic group, for example,
(1) C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te
rt-butyl, etc.), (2) C _1-6 alkoxy (eg, methoxy,
Ethoxy, propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy, etc.), (3)
Carbamoyl group, (4) halogen (eg, fluorine, chlorine, bromine, iodine), (5) oxo group, (6) hydroxyl group, (7)
Amino, (8) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), (9) nitro, (10) cyano, (11) mercapto, (12) sulfo, (13) Surufuino, (14) C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, n- butylthio, sec -Butylthio, tert-butylthio, etc.). The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2. Preferred substituents on the heterocyclic group include halogen, nitro, amino, mono-
Or di-C _1-4 alkylamino, oxo, hydroxy, C _1-6 alkyl (among others, C _1-4 alkyl), C
_1-6 alkoxy (among others, C _1-4 alkoxy), C _1-6
And alkylthio (among them, C _1-4 alkylthio).

When X in the formula -XR ^4j is S, R
^The alkyl group in the alkyl group in which ^4j may have a substituent is preferably a C _1-13 alkyl group, which may be linear or branched. Examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl,
n-pentyl, n-hexyl, n-octyl and the like. Examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, 3-pentyl,
Neopentyl, isohexyl, sec-hexyl, tert-hexyl, isooctyl, sec-octyl, tert-octyl and the like can be mentioned. As the alkyl group, among others,
A C _1-6 alkyl group is preferred, and when branched, a C _3-8 branched alkyl group is preferred. Examples of the substituent in the alkyl group which may have a substituent include the same as the above-described substituent of cycloalkyl.

R ^1j is a group represented by the formula ^{-XR 5j} (wherein X is O, and R ^5j is (1) C _3-13 branched _optionally substituted by C _1-4 alkyl or halogen). An alkyl group (more preferably a C _3-7 branched alkyl group) or (2) halogen,
Represents an oxygen-containing 6-membered heterocyclic group which may be substituted by C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio). Furthermore, isopropoxy, sec-butoxy, 3-
Pentyloxy or 2,4-dimethyl-3-pentyloxy is particularly preferred.

In the above formula, C _1-8 represented by R ^2j
Examples of the alkanoylamino group include, for example, 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 is preferably substituted with one or two phenyl groups, and particularly preferably substituted with one phenyl group at the 4-position.

In the above formula, examples of the alkyl represented by R ^3j include the C _1-6 alkyl defined in the above f). R ^3j is preferably a hydrogen atom.

As the compound used in the composition of the present invention, a compound of the formula (XV)

Embedded image [Wherein, R ^1k represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl optionally substituted with alkyl, and R ^2k represents an alkyl group or an aryl group. or a group formula -X-R ^4k (wherein, the R ^4k is optionally substituted alkyl or optionally substituted cycloalkyl group, X represents O or S) represented by, R ^3k Represents a hydrogen atom or an alkyl group.]
The compound (XV) represented by or a salt thereof is preferred.

In the above formula, an alkoxy group substituted by 1 to 3 groups selected from (i) halogen, (ii) cycloalkyl, and (iii) alkenyl optionally substituted with alkyl represented by R ^1k Examples of the alkoxy group include C
_{A 1-6} alkoxy group is preferred, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy and the like. Above all, C _1-3
Alkoxy groups are preferred, and methoxy is particularly preferred. In the above formula, in R ^1k , examples of the halogen of the substituent on the alkoxy group include 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 particularly preferred. As the alkenyl group in the alkenyl group which may be substituted with alkyl as a substituent on the alkoxy group, C _2-10 alkenyl is preferable, for example, vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl , Hexatrienyl, 3-
Octenyl and the like can be mentioned, and 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 optionally substituted with alkyl, C _1-3 alkyl is preferable,
For example, methyl, ethyl, propyl, and isopropyl are preferable, methyl is particularly preferable, and a preferable example of the alkenyl group substituted with alkyl is 2-methylallyl.

As R ^1k , (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. As the alkyl group of the ^optionally substituted alkyl group represented by R ^4k , a linear or branched C _1-9 alkyl group is preferable, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, 3-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, octyl, isooctyl, sec-octyl, tert-octyl and the like. Among them, a C _3-7 alkyl group is preferable, and a C ₃ alkoxy group (n-propoxy, isopropoxy) is particularly preferable. Examples of the substituent of the alkyl group include halogen, nitro, amino, alkoxy, alkyl and cycloalkyl. Examples of the halogen include fluorine, chlorine, bromine, and iodine. Of these, fluorine and chlorine are preferred. Alkoxy includes C
_1-4 alkoxy is preferred, for example, for example,
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,
For example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned. Of these, methyl is particularly preferred.
As the cycloalkyl, C _3-8 cycloalkyl is preferable, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The cycloalkyl group in the optionally substituted cycloalkyl group represented by R ^4k is
_{A 3-10} cycloalkyl group is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among them, C _3-7 cycloalkyl group is preferred. The cycloalkyl group may form a bicyclic fused ring. Examples of the fused ring group include indanyl and the like. As a substituent of the cycloalkyl group,
For example, (1) halogen, (2) alkoxy, (3) alkyl,
(4) cycloalkyl, (5) alkylthio, (6) amino, (7)
Mono- or di-alkylamino, (8) nitro, (9) hydroxyl, (10) oxo, (11) carbamoyl, (12) cyano, (13) mercapto, (14) sulfo and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2. Preferred examples of the group which may be substituted on the cycloalkyl group include halogen, nitro and amino.

The halogen, alkoxy, alkyl and cycloalkyl have the same meanings as those described above for R ^4k .

The mono- or di-alkylamino and alkylthio have the same meanings as R ^4j .

As R ^1k , a C _1-4 alkoxy group substituted with C _2-6 alkenyl, particularly vinyl-C _1-3 alkoxy or allyloxy is preferable.

As R ^2k , (1) C _1-3 alkyl, (2) C
_{A 6-14} aryl group or (3) a C _3-7 alkoxy group optionally substituted with halogen, C _1-3 alkyl or C _1-3 alkoxy is preferable, and among them, isopropyl, phenyl, isopropoxy, sec- Butoxy, 3-pentyloxy or 2,4-dimethyl-3-pentyloxy are particularly preferred. The number of substituents in the R ^2k group is 1 to
Three are preferred, and one or two 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 alkyl for R ^3k, the same as the C _1-6 alkyl defined in the above f) can be mentioned. R ^3k is preferably a hydrogen atom.

As the compound used in the composition of the present invention, a compound represented by the general formula (XXI)

Embedded image 中 wherein, R ^1y is hydrogen, an alkyl group or a formula — (CH ₂ ) ^py
Q wherein the integer p ^y is 0 to 3, Q is (1) 1-3
(i) halogen, (ii) nitro, (iii) cyano, (iv) amino,
(v) an optionally substituted carboxyl group, (vi) an alkylenedioxy group or (vii) a formula -A ^y -R ^5y (where A ^y represents a chemical bond or an intervening group, and R ^5y represents an alkyl group) )
An aryl group which may be substituted with a group represented by (2)
A cycloalkyl group which may be substituted or (3) a heterocyclic group which may be substituted];
^2y is hydrogen, an alkyl group which may be substituted by alkoxy, optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group, R ^3y is substituted An ^optionally substituted amino group, R ^4y represents an ^optionally substituted aryl group, and r represents 0
The compound (XXI) represented by｝ showing an integer of ~ 3 or a salt thereof is preferable.

Examples of the alkyl group in the alkyl group represented by R ^1y and R ^5y and the alkyl group optionally substituted by alkoxy represented by R ^2y include a C _1-6 alkyl group. Are, 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. Preferred examples include phenyl, naphthyl, anthryl, phenanthryl, be like a C _6-14 aryl group such as acenaphthylenyl, inter alia phenyl, 1-naphthyl, C _6-10 aryl groups such as 2-naphthyl preferable.

The number of substituents on the aryl group represented by R ^2y and R ^4y is 1 to 3. Examples of the substituent include (1) C _1-6 alkyl group (e.g., methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, pentyl, hexyl and the like. The alkyl group, C _1-6 alkyl −
It may be substituted by carbonyl, C _1-6 alkoxy-carbonyl. ), (2) an optionally substituted _C2-6 alkenyl group (e.g., vinyl, allyl, 1-butenyl, 2-butenyl and the like. The alkenyl group may have 1 to 3 _C1-6 acyl or C _1-6 alkoxy -. which may be substituted by carbonyl), (3) C _2-6 alkynyl group (e.g., 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 1 to 3 substituents (i)
Halogen, (ii) C _1-6 alkyl, (iii) C _1-6 alkoxy optionally further substituted with C _1-6 alkoxy, (iv)
Nitro, (v) cyano, (vi) formula _{^{-S (O) n y -R 6y}} ( wherein,
n ^y represents an integer of 0 to 2, and R ^6y represents a C _1-6 alkyl group or amino. ), (Vii) amino, (viii) C _1-6
Acyl, (ix) carbamoyl, (x) carboxy and (xi)
It may have hydroxy. ), (6) a heterocyclic group [eg, one selected from a nitrogen atom, an oxygen atom and a sulfur atom
A 5- or 6-membered aromatic heterocyclic group containing from 4 to 4 heteroatoms (eg, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, etc.), a nitrogen atom, an oxygen atom and a sulfur atom Or 4
3- to 9-membered non-aromatic heterocyclic group containing two heteroatoms (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.).
Heterocyclic groups, 1 to 3 (i) halogen, (ii) C _1-6 alkyl, (iii) amino, (iv) C _1-6 acyl, (v) carbamoyl, (vi) carboxy, ( vii) nitro, (viii) hydroxy, (ix) C _1-6 alkoxy and (x) equation -S (O) _n ^y -R ^6y
(Wherein the integer n ^y is 0 to 2, R ^6y is. Showing a C _1-6 alkyl group) which may have as a substituent a group represented by. And (7) C _7-13 aralkyl groups (eg, benzyl, phenethyl, benzhydryl and the like.
It may have three halogens. ), Equation (8)

[0084]

Embedded image [Wherein, R ^11y represents (i) hydrogen, (ii) C _1-6 alkyl optionally substituted with 1 to 3 hydroxy, (iii) acyl (eg,
C _1-6 alkyl -, formyl, C _6-14 arylcarbonyl. The acyl has 1 to 3 halogens or C
_It may be substituted with _1-6 alkoxy. ), (Iv) optionally substituted C _1-6 alkoxy, (v) hydroxy
Up to 3 optionally substituted C _3-7 cycloalkyl, (v
i) formula -S (O) in _n ^y -R ^6y (wherein, n ^y is an integer of 0 to 2,
R ⁶ represents a C _1-6 alkyl group. ).
R ^12y represents hydrogen or C _1-6 alkyl. An amino group represented by formula (9)

[0085]

Embedded image ( ^Wherein , R ^24y represents hydrogen, a C _1-6 alkyl group or a C _6-14 aryl group, R ^25y represents a hydrogen or a C _1-6 alkyl group, and R ^24y and R ^25y together with an adjacent nitrogen atom A 5- to 7-membered nitrogen-containing cyclic group which may have a substituent; xy represents an integer of 0 to 3);
0) amidino group, (11) acyl group (e.g., formyl, acetyl, propionyl, butyryl, octanoyl, etc.
_1-8 alkanoyl group, for example, C _1-8 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, C _6-14 aryl-carbonyl group such as benzoyl, C _8-11 aralkylcarbonyl such as benzylcarbonyl Groups, C _7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl (phenyl-C _1-6 alkyloxy-carbonyl and the like) and the like. These may be substituted, and examples of the substituent include 1 to 3 halogens, C _1-6 alkylthio, C _1-6 alkoxy, oxo, and hydroxy. ), (12) optionally substituted carbamoyl groups (eg, carbamoyl, N-monosubstituted carbamoyl groups (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, etc.)
-(C _1-6 alkyl) carbamoyl group), N, N-disubstituted carbamoyl group (for example, dimethylcarbamoyl,
N, N-di (C _1-6 alkyl) carbamoyl groups such as diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-propyl-N-methylcarbamoyl, etc.), (1
3) sulfamoyl group, (14) N-monosubstituted sulfamoyl group (for example, N- (C _1-6 alkyl) sulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl and the like), (15) ) N, N-disubstituted sulfamoyl groups (eg, N, N-di (C _1-6 alkyl) such as dimethylsulfamoyl and diethylsulfamoyl)
(16) carboxyl group, (17) C
_1-3 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl), (18) hydroxyl group, (19) 1-3 optionally substituted C _1-6 alkoxy group (Examples include C _1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, hexyloxy, etc. Examples of the substituent include C _1-8 alkanoyl (described above. o)), C _1-3 alkyl group, halogen, C _1-3 alkylthio, C _1-3 alkoxy, C _3-7 cycloalkyl (as in f), m) and i) above. Oxo, and a hydroxyl group. ), (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- An oxy group (eg, phenyl-C _1-3 such as benzyloxy);
Alkyloxy, benzhydryloxy, etc.), (23) C
_6-14 aryloxy group (eg, phenyloxy, naphthyloxy, etc.), (24) mercapto group, (25) C _7-13 aralkylthio group (for example, phenyl-C _1-3 such as benzylthio, etc.)
Alkylthio, benzhydrylthio, etc.), (26) _C6-14
An arylthio group (e.g., phenylthio, etc. naphthylthio), (27) -S (O) in _n ^y -R ^6y (wherein, ^{n y} is 0-2
And R ^6y represents a C _1-6 alkyl group. Group (e.g. represented by), methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulfinyl, propyl-sulfinyl, methylsulfonyl, ethylsulfonyl, etc. propylsulfonyl), (28) C _1-3 alkylenedioxy (e.g., methylenedi Oxy, ethylenedioxy, propylenedioxy, etc.), (29) sulfo group, (30) cyano group, (31)
Azide group, (32) 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 of R ^1y and R ^2y include a C _3-10 cycloalkyl group and a C _4-10 bicycloalkyl group. Can 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 . Among them, C _1-6 alkyl, C _1-6 alkoxy and halogen are preferred. The number of substituents is 1-3
Are preferred.

The heterocyclic group in the ^optionally substituted heterocyclic group represented by Q in R ^1y includes, for example, oxygen (O), sulfur (S), And a 5- to 13-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen and nitrogen (N), or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group). Can be Suitable aromatic heterocyclic groups include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
Aromatic monocyclic heterocyclic groups such as 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
For example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , Purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiadinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1 , 2-b] pyridazinyl, pyrazolo [1,
5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
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, C _1-6 alkyl, C _1-6 alkylthio and C _1-6 alkoxy are preferred.

In the above formula, examples of the halogen which is a substituent of the aryl represented by Q include fluorine, chlorine, bromine and iodine. Examples of the optionally substituted carboxyl group in Q include, for example, carboxyl, C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyloxycarbonyl, C _6-14 aryloxycarbonyl, C _7-20
Aralkyloxycarbonyl, oxycarbonyl substituted with a heterocyclic group and the like.
_1-6 alkyl, C _3-7 cycloalkyl, C _6-14 aryl,
_C7-20 aralkyl is the above f), i), k), l), a)
Has the same meaning as Examples of the alkylenedioxy in Q include C _1-6 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.),-(C
H ₂ ) cNR ^26y — wherein 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 for f). )], A group represented by -CO-,-
CONR ^27y — wherein R ^27y is the same as ^{defined above} for hydrogen and C _1-6 alkyl (specific examples are f). ), C _3-7
The cycloalkyl (the specific example is the same as the above-mentioned i) is shown. ), C _6-14 aryl (specific examples are the same as those described above for k). ), A heterocyclic group (specific examples are the same as those described in the above a). Groups represented ^{_{by)], -S (O) m y -}} (m y
Represents an integer of 0 to 2. ), -O-, -N
^{_{R 27y S (O) z y}} - ( wherein, z ^y is an integer of 0 to 2, R
^27y has the same meaning as described above).

The alkoxy in the alkyl optionally substituted by alkoxy represented by the group R ^2y includes
_1-6 alkoxy (the same meaning as in the above m)). The aralkyl group in the optionally substituted aralkyl group represented by R ^2y includes, for example, C _6-14 aryl-
And C _1-6 alkyl groups. As the aryl,
It has the same meaning as the aryl group in the optionally substituted aryl group represented by R ² . Examples of the alkyl include a C _1-6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl, and hexyl. Examples of the substituent include the same substituents as those described above for the ^optionally substituted C _6-14 aryl group represented by R ^2y and R ⁴ .

Examples of the ^optionally substituted amino group represented by R ^3y include, for example, those represented by formula (1)

Embedded image (Wherein, R ^22y is each ^optionally substituted, C _1-6
An alkyl group, a C _3-7 cycloalkyl group, a C _6-14 aryl group or a heterocyclic group, wy represents an integer of 0 to 3, R ^23y represents hydrogen or a C _1-6 alkyl group which may be substituted ^; Show. )
And (2) hexamethylenetetraamino. The C _1-6 alkyl group, C _3-7 cycloalkyl group, C _6-14 aryl group and heterocyclic group in the group are the above-mentioned f),
It has the same meaning as i), k) and a). 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 .

[0091] Preferred examples of the intervening group represented by A ^y are, -O- or -S (O) _m ^y - (wherein, m ^y is an integer of 0 to 2.) A group represented by No. 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 include, for example, hydrogen or a formula — (CH ₂ ) ^py Q ′, wherein Q ′ is a halogen, nitro, cyano, amino or a formula —A ^y ′ —R ^5y Wherein A ^y ′ represents —O— or —S— and R ^5y ′ represents C _1-6 alkyl.
_{6-14 represents an} aryl group. p ^y is as defined above.
And the group represented by More preferable examples of R ^1y is the formula - (CH _{2) p} ^y Q wherein the integer p ^y is 0 to 3, Q is 1 to 3 (i) halogen and wherein -A ^y -R
^5y (wherein, A ^y is -O- or -S (O) _m ^y - (wherein, m ^y
Is shown) an integer of 0 to 2, R ^5y is a group represented by showing a C _1-6 alkyl group shows a) represented by good C _6-14 aryl group optionally substituted with a group] No. Further preferred examples of R ^1y include halogen or a group represented by the formula -A ^y ″-
R ^5y ″ (where A ^y ″ represents —O— or —S— and R ^5y ″ represents a C _1-6 alkyl group); And a C _6-14 aryl-methyl group. More preferred examples of R ^1y include the formula Q ′ ″-(CH
_{2) p} ^y - (wherein, Q '''is 1-3 optionally substituted C _6-14 aryl halogen, a group represented by p ^y is an integer of 0 to 3). Is mentioned.

Preferred examples of R ^2y include (1) a C _1-6 alkyl group which may be substituted with 1 to 3 C _1-6 alkoxy, (2) 1 to 3 (i) amino, (ii) C _1-6 acyl, (iii)
Carbamoyl, (iv) carboxy, (v) nitro, (vi) hydroxy, (vii) C _1-6 alkoxy with 1-3 optionally substituted C _1-6 alkoxy, (viii) halogen and (ix)
Wherein _{^{-S (O) n y -R 6y}} ( wherein, n ^y is an integer of 0 to 2, R
^6y represents a C _1-6 alkyl group), a C _6-14 aryl group which may be substituted by 1 to 3 groups represented by a group represented by the ^formula : _7-20 aralkyl groups or (4) C _3-10 cycloalkyl groups. In the above formula, preferred examples of the group represented by the group R ^2y include, for example, (1) a C _1-6 alkyl group optionally substituted with 1 to 3 C _1-3 alkoxy groups, (2) 1 to Three amino, C _1-6 acyl, carbamoyl, carboxy, nitro, hydroxy,
C _1-3 alkoxy, sulfo, halogen or formula —S
In (O) _n ^y -R ^6y (wherein, n ^y is an integer of 0 to 2, R ^6y is C
_{Represents 1-3} alkyl. _C6-14 aryl group and (3) _C3-10 cycloalkyl group which may be substituted by the group represented by the _formula (1). More preferred examples of R ^2y include (1)
C _1-6 optionally substituted by 1 to 3 C _1-3 alkoxy
An alkyl group, (2) 1 to 3 (i) hydroxy, (ii) C _1-3
C _1-3 alkoxy optionally substituted with alkoxy,
(iii) halogen or (iv) formula _{^{-S (O) n y -R 6y}} ( wherein,
n ^y represents an integer of 0 to 2, and R ^6y represents a C _1-3 alkyl group.
And a C _6-14 aryl group, (3) C _7-20 aralkyl group or (4) C _3-7 cycloalkyl group which may be substituted with a group represented by In the above formula, preferred examples of the group represented by the group R ^2y include, for example, (1) a C _1-6 alkyl group optionally substituted with 1 to 3 C _1-3 alkoxy groups,
_1-3 alkoxy 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 by 1 to 3 groups, and (3) a C _3-7 cycloalkyl group. R ^2y
More preferred examples of C _1-3 alkoxy optionally substituted with one to three C _1-3 alkoxy with one to three (1) C _1-3 alkoxy, (2) halogen or (3) Formula -S (O ) _n ^y −R ^6y (where
n ^y represents an integer of 0 to 2, and R ^6y represents a C _1-3 alkyl group.
And a C _6-14 aryl group which may be substituted with a group represented by

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

Embedded image [Wherein, R ^22y ′ represents (1) 1 to 3 (i) amino, (ii) C _1-6
Acyl, (iii) carbamoyl, (iv) carboxy, (v) nitro, (vi) hydroxy, (vii) C _1-6 alkoxy optionally substituted with 1 to 3 C _1-6 alkoxy, (viii) Halogen, (ix) C _1-6 alkyl or (x) formula —S (O) _n ^y —R ^6y
( ^Wherein n is an integer of 0 to 2, and R ^6y represents a C _1-6 alkyl group). A C _6-14 aryl group which may be substituted by 1 to 3 groups represented by ) 1 to 3 (i) amino, (ii) C
_1-6 acyl, (iii) carbamoyl, (iv) carboxy, (v)
Nitro, (vi) hydroxy, (vii) _C1-6 alkoxy, (vii
i) halogen, (ix) C _1-6 alkyl or (x) formula -S (O) _n
^y -R ^6y (wherein, n ^y is an integer of 0 to 2, R ^6y represents a C _1-6 alkyl group) 1-3 optionally substituted heterocyclic group with a group represented by, (3) a C _7-20 aralkyl group _optionally substituted with 1 to 3 halogen atoms, formula (4)

Embedded image ( ^Wherein , R ^24y represents hydrogen, a C _1-6 alkyl group or a C _6-14 aryl group, R ^25y represents a hydrogen or a C _1-6 alkyl group, and R ^24y and R ^25y together with an adjacent nitrogen atom 5- to 7-membered nitrogen-containing cyclic group (said group may be substituted) groups represented by the good .xy be formed is an integer of 0 to 3) or (5) C _1-6 A C _1-6 alkyl group optionally substituted with 1 to 3 alkylthio, wy represents an integer of 0 to 3, and R ^23y ′ represents hydrogen or a C _1-6 alkyl group. ] Or a hexamethylenetetraamino group.

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

Embedded image Wherein R ^22y ″ is (1) C _1-6 alkyl, (2) 1 to 3 halogens, nitro, C _1-6 alkyl or a formula —S (O) _n ^y
-R ^6y (wherein the integer n ^y is 0 to 2, R ^6y is. Showing a C _1-6 alkyl or amino) optionally 1-3 substituted with a group represented by phenyl, ( 3) Halogen or C
_A heterocyclic group which may be substituted by 1 to 3 alkyl groups with _1-6 alkyl or (4) N-monosubstituted C _1-6 alkylcarbamoyl is shown. wy represents an integer of 0 to 3. R ^23y ″ is hydrogen or C
_{1-6 represents} 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 ′ ″ represents (1) a C _6-14 aryl group optionally substituted with 1 to 3 C _1-6 alkylthio, (2) a heterocyclic group,
Equation (3)

Embedded image ( ^Wherein R ^24y ′ represents hydrogen or a C _1-6 alkyl group,
R ^25y ′ represents hydrogen or a C _1-6 alkyl group, and R ^24y ′ and R ^25y ′ may form a 5- to 7-membered nitrogen-containing cyclic group together with an adjacent nitrogen atom. ) Or a group represented by (4) C
_1-6 may be 1-3 alkylthio C _1-6
In the alkyl group, wy represents an integer of 0 to 3, and R ^23y ′ ″ represents hydrogen or a C _1-6 alkyl group. And an optionally substituted amino group represented by the formula: In the above formula, R
More preferred groups represented by ^3y include, for example,

Embedded image Wherein, R ^22y 'is a group (wherein, n ^y is the integer of 0 to 2, R ^6y represents a C _1-6 alkyl.) Formula -S (O) n ^y -R ^6y represented by Represents phenyl or pyridyl which may be substituted with wy represents an integer of 0 to 3, and R ^23y ′ represents hydrogen or a C _1-6 alkyl group. ] The group represented by this is mentioned.

In the above formula, preferred examples of the ^optionally substituted aryl group represented by R ^4y include 1 to 3
(1) an optionally substituted amino group, (2) C _1-6 acyl,
(3) optionally substituted carbamoyl group, (4) carboxy, (5) nitro, (6) hydroxy, (7) optionally substituted _C1-6 alkoxy or (8) optionally substituted Good C
_{And a} C _6-14 aryl group which may be substituted with a _2-10 alkenyl group. As more preferred R ^4y , one to three formulas (1)

Embedded image Wherein R ^11y ′ is (i) hydrogen, (ii) C _1-6 alkyl, (iii)
Optionally substituted C _1-6 alkoxy, (iv) an optionally substituted C _1-6 acyl or (v) expression -S (O) _n ^y -R ^6y
( ^Wherein , ^y represents an integer of 0 to 2, R ^6y represents a C _1-6 alkyl group), and R ^12y ′ represents hydrogen or a C _1-6 alkyl group. A group represented by the formula (2) C _1-6 acyl,
(3) carbamoyl, (4) N-mono or di-C _1-6 alkylamino, (5) nitro, (6) 1-3 C _1-6 alkoxy, C _1-8 alkanoyl, oxo, hydroxy, C _1-6 alkoxy group optionally substituted with 1 to 3 C _3-7 cycloalkyl and halogen, (7) further substituted with 1 to 3 C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl _{Optionally a} C _2-10 alkenyl group or (8) C
_A C _6-14 aryl group _optionally substituted with _2-10 alkenyloxy is _exemplified . As more preferred R ^4y , one to three formulas (1)

Embedded image [Wherein R ^11y ″ is (i) hydrogen, (ii) C _1-6 alkyl, (iii)
_C1-6 alkoxy optionally substituted with 1 to 3 halogens or _C1-6 alkoxy, (iv) formyl, (v) 1 to 3 optionally substituted with halogen or _C1-6 alkoxy C _1-8 alkanoyl, (vi) benzoyl or (vii) expression -S (O) in _n ^y -R ^6y (wherein, n ^y is an integer of 0 to 2, R ^6y
_{Represents a} C _1-6 alkyl group), and R ^12y ″ represents hydrogen or a C _1-6 alkyl group. A group represented by
(2) C _1-6 alkoxy, C _1-8 alkanoyl or C _3-7 cycloalkyl with 1-3 optionally substituted by C _1-6 alkoxy group, (3) N-mono- or di -C _{1 -6} alkylcarbamoyl, (4) nitro, (5) C _1-6 alkoxycarbonyl or C _1-6 further have one to three substituents alkylcarbonyl optionally C _2-10 alkenyl group or also (6) C _{2 -Ten}
And a C _6-14 aryl group _optionally substituted with 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 substituent include amino, C _1-6 acyl, carbamoyl, N-monosubstituted C _1-6 alkylcarbamoyl, carboxy, nitro,
Hydroxy, C _1-3 alkoxy optionally substituted with 1 to 3 C _1-3 alkoxy, formula

Embedded image (Wherein, R ^31y is C _1-6 alkyl, C _1-3 alkoxy and 1
Represents _1-3 optionally substituted C _1-3 alkoxy or formyl, and R ³² represents hydrogen or C _1-6 alkyl. ), C 1-3 optionally substituted by C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl
_2-4 alkenyl groups. Preferred examples of the substituent include amino, C _1-6 acyl, N-monosubstituted C _1-6 alkylcarbamoyl, nitro, C _1-3 alkoxy and 1-3.
Optionally substituted C _1-3 alkoxy, formula

Embedded image ( ^Wherein R ^33y is C _1-6 alkyl, C _1-3 alkoxy and 1
To three optionally substituted C _1-3 acyl, C _1-4 acyl with 1-3 optionally substituted by C _1-3 alkoxy, benzoyl, shows a formyl, R ^34y is hydrogen, C _{1 Represents -6} alkyl. And _C2-4 alkenyl groups substituted by 1 to 3 _C1-3 alkoxy-carbonyl or _C1-3 alkyl-carbonyl.

In any of the above cases, the number of substituents is preferably 1 to 3. r is preferably 1. p
^y 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-triazolidinyl,
1,2,3-Triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethyleneamino, oxazolidino, morpholino, thiazolidino or thiomorpholino. Of these, those having 5 to 6 members are preferable, and for example, pyrrolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferable. The nitrogen-containing cyclic amino group may have a substituent, and the substituent includes 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. Preferred substituents include C _1-6 alkyl, among which C _1-3 alkyl is more preferred.

The alkyl in the definition of the above group is preferably an alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, Examples thereof include pentyl, isopentyl, and neopentyl, and alkyl having 1 to 3 carbon atoms is particularly preferable. As the acyl in the definition of the above group, C _1-6 acyl is preferable, and examples of the acyl include C _1-6 alkanoyl, C _6-14 aryl-carbonyl, C _7-20 aralkyl-carbonyl,
_7-20 aralkyloxy-carbonyl, and these alkanoyl, aryl, aralkyl are the same as those described in o),
The same ones as k) and l) can be mentioned. Preferred examples of the acyl or alkanoyl include C _1-6 alkyl-carbonyl, and the alkyl includes the same as those described in the above f). 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
_2-10 alkenyl is preferable, and C _2-4 alkenyl is preferable. Examples thereof include vinyl, allyl (ally
l), 1-butenyl, 2-butenyl. Preferred aryl in the definition of the above group include:
C _6-14 aryl includes, for example, phenyl, naphthyl. Preferred aralkyl in the definition of the above groups include C _7-20 aralkyl,
Preferably, C _7-10 aralkyl is mentioned, and examples thereof include phenyl-C _1-4 alkyl such as 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 represented by 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 group R ^1z is preferably a C _7-19 aralkyl group. Examples thereof include phenyl-C _1-4 alkyl such as benzyl and phenethyl, biphenylmethyl, Benzhydryl and the like. Among them, benzyl is preferred. Examples of the alkyl group ^represented by the group R ^6z include C _1-6
Alkyl groups are preferred, for example, methyl, ethyl, n-propyl, isopropyl, butyl,
Isobutyl, s-butyl, t-butyl, n-pentyl,
Examples include isopentyl, neopentyl, and hexyl. Among them, a C _1-3 alkyl group is preferable. The above group R ^1z
As the alkylene group represented by X ^z , C _1-6
Alkylene is preferred and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. 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 as those described in the above f). Examples of the halogen include fluorine, chlorine, bromine, and iodine. The number of substituents is 1-3. Preferred examples of the optionally halogenated alkyl group include bromomethyl. Examples of the acylaminoaryl group represented by R ^2z include, for example, C _1-6 acyl-amino-C
_{A 6-14} aryl group is preferable, and examples of C _1-6 acyl include C.sub.1 such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and the like.
Examples include _1-6 alkanoyl and the like, and examples of C _6-14 aryl include phenyl, naphthyl, anthryl and the like.

The halogenoaralkyl group represented by R ^3z is preferably a halogeno C _7-19 aralkyl group. Examples of the halogen in the halogenoaralkyl group include fluorine, chlorine, bromine, and iodine. The number of the halogen is 1 to 3. Examples of the aralkyl group in the halogenoaralkyl group include, for example, benzyl, phenethyl, benzhydryl and the like. Among them, benzyl is preferred. As the esterified carboxyl group represented by R ^4z, C _1-6 alkyloxy - carbonyl are preferred, the C _1-6 alkyloxy - methyl as C _1-6 alkyl group in group, ethyl, n -Propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like. Among them, ethoxycarbonyl is most preferred.
^Examples of the amidated carboxyl group represented by R ^4z include N—C _1-4 alkyl-carbamoyl such as carbamoyl, methylcarbamoyl, and isopropylcarbamoyl, and N—C _7-11 aralkylcarbamoyl such as 2-pyridylcarbamoyl and benzylcarbamoyl. And the like. Most preferred of the above compound (XXXI) is a group R ^{1z which} is N-benzyl-N-methylaminomethyl, R ^2z is propionylaminophenyl or isobutyrylaminophenyl, and R ^3z is difluorobenzyl. R ^4z includes 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 groups represented by R ¹ ′ and R ′ have the same meaning as in the above f). m is 0
Represents an integer of from 6 to 6.

[0103]

(Equation 1)

As the leaving group represented by X, 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.)) And groups which can easily undergo a substitution reaction. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), C _1-8 alkanoyloxy (eg, acetoxy, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), C _{1- 6} alkyl-C _6-14 arylsulfonyloxy (eg, p-toluenesulfonyloxy, etc.), C _6-14 arylsulfonyloxy (eg, benzenesulfonyloxy, etc.) and the like can be mentioned. 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.

[0106]

(Equation 2)

[Production Method 3] The allantonilic acid derivative (x) is added to a solvent (eg, ethers such as tetrahydrofuran, 1,4-dioxane, etc.) having no adverse effect on the reaction in an equivalent amount or an excess amount with the compound (x). Formula (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.

[0108]

(Equation 3)

[Production Method 4] In a solvent (eg, ethers such as tetrahydrofuran, 1,4-dioxane, etc.) which does not adversely affect the reaction of pyridine derivative (xv), an equivalent amount or an excess amount of compound (xv) to compound (xv) A compound represented by (CCl ₃ O) ₂ CO is added and stirred at about 30 to 110 ° C. to obtain 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.

[0110]

(Equation 4)

[Production Method 5] 4,7-Dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (Va) is converted into a suitable solvent (eg, tetrahydrofuran) which does not adversely affect the reaction. , Ethyl ether, dioxane, etc.), add an appropriate reducing agent (eg, lithium aluminum hydride) and stir 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 .

[0112]

(Equation 5)

[Production Method 6] 4,7-Dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (XIa ') is converted into an appropriate solvent which does not adversely affect the reaction in advance (eg, , And halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, ethyl ether and dioxane) and aluminum produced from an appropriate aluminum reagent (eg, trimethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines Stir at about 10 to 100 ° C with the amide derivative to obtain a 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].

[0114]

(Equation 6)

Wherein R ^26d is C _1-6 alkyl or C _6-14
An aryl group, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols alkyl and aryl represented by] the R ^{26 d} having the same meaning as defined above is the f), k) and It has the same meaning. 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] A 4,7-dihydro-5-hydroxymethyl-4-oxothieno [2,3-b] pyridine derivative (XIc) is converted into a suitable solvent which does not adversely affect the reaction (for example, dichloromethane) And other halogenated hydrocarbons, ethers such as tetrahydrofuran, ethyl ether and dioxane, and pyridine) in a suitable halogenating reagent (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].

[0117]

(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 described above.] Examples of the leaving group represented by X 'include, for example, nucleophile ^- by [example, the heteroatom bearing a negative charge represented by ZR ^27d, etc. (e.g., an oxygen atom, a sulfur atom, a nitrogen atom, etc.) such as a hydrocarbon residue having] a readily substitution reaction Groups that can be used. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), C _7-20 aralkyloxy (eg, acetoxy, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), C _1-6 Alkyl-
C _6-14 arylsulfonyloxy (eg, p-toluenesulfonyloxy and the like) 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].

[0120]

(Equation 8)

[0121] wherein, R ^29d and R ^30d each represent a hydrogen or a hydrocarbon residue, and other symbols are of the same meaning as defined above as the hydrocarbon residue represented by R ^29d and R ^30d 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 ') is converted into a suitable solvent which does not adversely affect the reaction in advance (eg, Acid (eg, inorganic acid such as hydrochloric acid) or alkaline aqueous solution (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in water, ethers such as tetrahydrofuran and dioxane, alcohols such as ethyl alcohol, etc. (1-4N aqueous solution of an alkali metal) is added, and the mixture is stirred and hydrolyzed at about 10-100 ° C. 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.

[0123]

(Equation 9)

[Production Method 10] Urea derivative (II) is produced from 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.

[0125]

(Equation 10)

[Production Method 11] The amino group of 2-aminothiophene derivative (xvii) is protected (eg, Boc) and
r. Pat. , 2155403 (1972) or J
According to the method of P-B 73-01664 (1973), in the presence of an acyl halide derivative and a base, stirring is carried out at about 0 to 100 ° C. in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide and dimethylacetamide). To give a derivative (xviii), which is then stirred with a suitable salt (eg, lithium iodide) in a suitable solvent (eg, acetone, methyl ethyl ketone) to form a derivative (xix), and a suitable amine (eg, ammonia) In a solvent (eg, toluene, dimethylformamide, dimethylacetamide, methanol, ethanol, etc.) which does not adversely affect the reaction, if necessary, in a suitable catalyst (eg, sodium ethoxide, toluenesulfone) Acid, etc.) in the presence of about 30
The mixture is stirred at -120 ° C to obtain a 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) which does not adversely affect the reaction, The mixture is stirred at 10 to 100 ° C. to give 2-oxothieno [2,3-e] azepine derivative (VIIb). Then, the compound (VIIb) is treated with N-bromo 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. Stir with succinimide (NBS) at about 30-100 ° C to obtain compound (VIIc). Further, the compound is reacted with various amines in the presence of a base in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol). Stir at 100 ° C, and add compound (VI
Id) to manufacture. 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].

[0127]

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

[Production Method 12] The amino group of 2-aminothiophene derivative (ii) produced by the method described in Production Method 1 is protected (eg, Boc), and an aralkyl halide derivative and a base (eg, potassium carbonate) , Pyridine, triethylamine, etc.) in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide, dimethylacetamide) at about 10 to 100 ° C. to obtain the derivative (xxi). After alkali hydrolysis with a suitable alkali (eg, sodium hydroxide, etc.) in a suitable solvent (eg, methanol, tetrahydrofuran), the resulting derivative is converted into a solvent (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.

[0129]

(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.I. 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). Further, the compound is dissolved in a solvent (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol) in a solvent that does not adversely affect the reaction with various amines in the presence of a base. -10
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.

[0131]

(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,
Stir with a Grignard reagent (R ^14d MgXa) at about 0-80 ° C. in tetrahydrofuran, ethyl ether, etc. to give the corresponding ketone derivative (Vc). The above manufacturing method 14 is shown in [Equation 14].

[0133]

[Equation 14]

Wherein R ^26d is C _1-6 alkyl or C _6-14
Aryl, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols C _1-6 alkyl and C _6-14 aryl represented by] the R ^{26 d} having the same meaning as defined above is It has the same meaning as f) and k). R ^27d and R
^The hydrocarbon residue represented by ^28d has the same meaning as the hydrocarbon residue in the carbonyl group optionally substituted by the hydrocarbon residue represented by R '.

[Production Method 15] A 1,4-dihydro-4-oxopyrido [2,3-b] pyridine-3-carboxylate derivative (Vd) is converted into a suitable solvent which does not adversely affect the reaction in advance (eg, Manufactured from a suitable aluminum reagent (eg, trimethylaluminum, triethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and an amine in halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran, ethyl ether and dioxane. Stirring at about 10-100 ° C. with 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].

[0136]

(Equation 15)

Wherein R ^26d is C _1-6 alkyl or C _6-14
Aryl, R ^27d and R ^28d each represent a hydrogen or a hydrocarbon residue, and other symbols C _1-6 alkyl and C _6-14 aryl represented by] the R ^{26 d} having the same meaning as defined above is It has the same meaning as f) and k). R ^27d and R
^The hydrocarbon residue represented by ^28d has the same meaning as the hydrocarbon residue in the carbonyl group optionally substituted by 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.

[0139]

(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.

[0141]

[Equation 17]

[Production method 18] Production method of derivative having 5-position oxazolyl group: Derivative (iiih) having 5-formyl group in a suitable solvent (eg, methanol, ethanol) which does not adversely influence the reaction. In the presence of an equivalent to an excess of a base (eg, potassium carbonate), add an equivalent to an excess of tosylmethyl isocyanide, and add about 0 to about
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.

[0143]

(Equation 18)

[Production method 19] Production method of derivative in which the 5-position is 4-imidazolyl group or 4-thiazolyl group: 4,7-dihydro-5 produced by the same method as in the above-mentioned production method 5 or production method 6 -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.

[0145]

[Equation 19]

Production method 20: Production method of derivative in which 5-position is 2-oxazolyl group: 4,7-dihydro-5-carbamoyl-4-oxothieno [2,3] produced by the first reaction of Production method 6 -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.

[0147]

(Equation 20)

[Production Method 21] Production method of derivative in which 5-position is 2-thiazolyl group: 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.

[0149]

(Equation 21)

[Production Method 22] An example of a method for producing a derivative in which the 5-position is a 3-pyrazolyl group will be described. 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.

[0151]

(Equation 22)

[Production Method 23] Production method of derivative in which 5-position is 2-triazolyl group:
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)
An excess of formic hydrazide is added at room temperature or under ice-cooling without or using a solvent, and the mixture is stirred at room temperature to 200 ° C. to produce 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.

[0153]

(Equation 23)

[Production method 24] Production method of 2-oxazolinyl derivative: 4,7-dihydro-4- produced by the same method as in 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.

[0155]

(Equation 24)

[Production method 25]: Production method of derivative in which R ⁴ is a group mediated by N: A 5-acetyl derivative (xivh) obtained by the same method as described in Production method 5 or 6 is dissolved in a suitable solvent. (E.g., pyridine), an equivalent or a small excess of a hydroxylamine derivative or a salt thereof is added, and the mixture is heated to room temperature or heated to produce an oxime derivative (xvh). The oxime derivative (xvh) is dissolved in a suitable solvent (eg, pyridine), and an equivalent to a small excess of an acylating agent (eg, acid halide, acid anhydride, sulfonic acid halide, etc.) is added, and the mixture is added at room temperature or under heating. For 1 to 12 hours to obtain a rearranged product (XIIj). The rearrangement product (X
IIjk) is dissolved in an appropriate solvent (eg, ethyl alcohol) and subjected to an alkali hydrolysis reaction (reaction conditions: for example, adding an aqueous solution of sodium hydroxide and stirring at room temperature for about 2 hours) to obtain the corresponding compound. Primary amino derivative (X
IIk). 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.

[0157]

(Equation 25)

The thus obtained primary amino derivative
(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 in which R ⁴ is a group mediated by O: Acyl derivative (xvih) obtained by the same method as described in the above production method 5 or 6, is converted to a suitable solvent (eg, , Dichloromethane), add a small excess (eg, 1.2-1.5 equivalents) of peroxide (eg, chlorobenzoic acid) under ice cooling or at room temperature, and stir at room temperature for 1-6 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 ′ each represent a C _1-6 alkyl group. Xa represents a halogen atom.

[0160]

(Equation 26)

The 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 group via S) First, an alkyl iodide is reacted with a thioglycolic acid ester, and then a dimethylaminomethylene compound is reacted to give 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). In the closed ring member (xxih), the compound shown in the Production Method 1 (v) by the formula Xa- (CH ₂₎ a method similar to the method of reacting _n -R ^3, wherein Xa- (CH _{2) n} - The compound (XIIp) is obtained by reacting R ³ . Further, the compound (XIIp) is reacted with an equivalent or a small 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 (XIIq)
Get. The above manufacturing method 27 is shown in [Equation 27]. [Equation 2
In 7], R ¹ , R ² , R ³ and n are as defined above. R ⁴ ″ represents a C _1-6 alkyl group.

[0163]

[Equation 27]

[Production method 28]: Production method of derivative which is phenyl substituted at the 2-position with an alkenyl group which may be substituted: 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, R ^32h and R ^33h are the same or different and each represents a C _1-6 acyl group, and R ^34h represents hydrogen or C _1-6 alkyl. C _1-6 acyl and C _1-6 alkyl have the same meanings as in n) and f). Other groups are as defined above.

[0165]

[Equation 28]

[Production method 29] Production method of derivative in which 2-position is an alkyl group which may be substituted or an aminophenyl group which is substituted by an optionally substituted homocyclic group: 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 [29], R ^{35h to} R ^39h represent a C _1-6 alkyl group. -R ^40h
Is -C ( ^R36h ) -CO- ^R35h or -C (OH) R
Indicates ^36h R ^39h . Other groups are as defined above.

[0167]

(Equation 29)

[Production Method 30] Production method of derivative which is an alkyl group which may be substituted at the 2-position or an aminophenyl group which is substituted by an optionally substituted homocyclic group: 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 C _1-6 alkyl group or an optionally substituted homocyclic group. Other groups are as defined above.

[0169]

[Equation 30]

[Production Method 31]: Conversion of Substituent at 3-Position: Compound (XI) produced by the above-mentioned production method, wherein the 3-position is a hydrogen atom or a C _1-6 alkyl group.
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. The group through the nitrogen atom is as defined above. 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. As the leaving group represented by X,
For example, a group which can be easily subjected to a substitution reaction by a nucleophilic agent [eg, a hydrocarbon residue having a negatively charged hetero atom (eg, an oxygen atom, a sulfur atom, a nitrogen atom, etc.)] can be mentioned. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), C _1-8 alkanoyloxy (eg, acetoxy, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), C _{1- 6-} alkyl-C _6-14 arylsulfonyloxy (eg, p-toluenesulfonyloxy and the like) and the like.

[0171]

(Equation 31)

Production method 32: A thienopyridine-5-carboxylic acid derivative which is a branched alkoxycarbonyl group which may be substituted at the 5-position is prepared according to 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 prepared by a method similar to the production method described in PCT International Publication WO95 / 28405, and the 5-position is an alkoxycarbonyl group. 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) used in the present invention
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
２００200 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 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: In the formula (XV), -CO-
The thieno [2,3-b] pyridine-5-carboxylic acid derivative in which R ^2k is a carboxy group can be prepared, for example, by a 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.

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.

Production method 37: [Formula 1]
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) of the present invention and a salt thereof 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.), C _1-8 alkanoyloxy (eg,
Acetoxy), C _1-6 alkylsulfonyloxy (eg,
Methanesulfonyloxy, etc.), C _1-6 alkyl-C _6-14
Arylsulfonyloxy (eg, p-toluenesulfonyloxy and the like) and the like.

Production Method 38 To a 3-halogenated aniline derivative (iz), an equimolar amount to a small excess of ethoxymethylenemalonic acid diethyl ester was added.
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. As the base, for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and thallium hydroxide, or an organic base such as triethylamine is used. 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
8 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.

[0180]

(Equation 32)

Production method 39: Conversion of 6-position group:
The compound (vz) in the reaction formula of α, α′-azobisisobutyronitrile (A) in a solvent that does not adversely affect the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform)
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, dimethoxyethane, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, and dichloromethane. Halogenated hydrocarbons, nitriles such as acetonitrile, ketones such as acetone, esters such as ethyl acetate and the like 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 10-100 ° 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.

[0182]

[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.

[0184]

(Equation 34)

Other Production Method: The substituent in the group of the compound used in the present invention can be converted to another substituent by a commonly used method known per se.
The following is an example of the method. (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 starting compound is dissolved in a suitable solvent (eg, tetrahydrofuran, dimethyl sulfoxide), potassium carbonate, pyridine and triethylamine as bases are added, and an acid anhydride or an acid halide is further 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 an 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 starting compound is converted to 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) The acetonyl form can be produced from the methoxy form. 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 allowed to proceed for 1 to 10 hours under ice cooling to room temperature. (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, for example, dimethylformamide (DMF), acetonitrile, acetone or the like. Add｝.
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) A compound which is 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 performed at 100-120 ° C for 1-4 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). The introduction of other groups in the compound of the present invention can be carried out by a method known per se.

(Xiv) A 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).
And reacting 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 removing a protecting group added to a hydroxyl group in a compound used in the present invention will be described. 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 medicament of the present invention includes (1) a pharmaceutical composition containing a compound having LH-RH action and a compound having LH-RH antagonistic action, (2) a compound having LH-RH action, and LH-RH. Any of those separately formulated with a compound having an antagonistic action is included. The medicament of the present invention has an effect of suppressing a transient increase in blood steroid hormone (eg, testosterone, estrogen) concentration (flare phenomenon). In addition, the pituitary LH and FS
H-secreting cells are brought into a state of desensitization, and the action is sustained. Furthermore, the effect of lowering testosterone or estrogen is enhanced. Also, its toxicity is low. Accordingly, the medicament of the present invention can be used for mammals (eg, humans, monkeys, cows, horses,
Dogs, cats, rabbits, rats, mice, etc.)
It can be used effectively and safely in the treatment and prevention of diseases dependent on sex hormones (male or female hormones) and in the treatment and prevention of diseases caused by excess of these hormones. That is, the medicament of the present invention includes sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, amenorrhea , Premenstrual syndrome, polycystic ovary syndrome,
It is useful for treating and preventing dysmenorrhea and acne. The medicament of the present invention is also useful for regulating reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The medicament of the present invention can be further used as a contraceptive for males or females, or for the treatment of infertility by inducing ovulation using the rebound effect after withdrawal. Furthermore, the medicament of the present invention is useful in the field of animal husbandry for regulating estrus in animals, improving meat quality for meat, and promoting animal growth.

The medicament of the present invention is also effective when used in combination with a steroidal or nonsteroidal antiandrogen or antiestrogen. It may be used in combination with a chemotherapeutic agent for cancer. Preferred specific examples of the combination include the following hormonal drugs, alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, immunotherapeutics, and the like. As hormonal drugs, for example, phosphestrol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, meparttricin, raloxifene, Olmeloxifene, revolmeloxifen, antiestrogen (eg, tamoxifen citrate, toremifene citrate, etc.), mepithiostane, testolactone, aminoglutethimide, droloxifene, epithiostanol, ethinylestradiol sulfonate,
Aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5
α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone,
Triamcinolone and the like; androgen synthesis inhibitors (for example, abiraterone, ketoconazole, 17α-hydroxylase / C _17-20 lyase inhibitor and the like); agents that delay the metabolism of retinoids and retinoids (for example, rialosol); Examples of the alkylating agent include, for example, nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan,
Nimustine hydrochloride, Mitobronitol, Melphalan, Dacarbazine, Ranimustine, Estramustine sodium phosphate, Triethylene melamine, Carmustine, Lomustine, Streptozocin, Pipobroman, Etoglucid, Carboplatin, Cisplatin, Miboplatin, Nedaplatin, Oxaliplatin, Altrethamine, Amretamine Dibrospidium, fotemustine,
Prednimustine, bumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, dinostatin stimaramar, adzeresin, systemstin,
Viserecin and the like. As antimetabolites, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine,
Cytarabine, cytarabine octophosphate, ancitabine hydrochloride, 5-FU drugs (for example, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emitefur, etc.), aminopterin, leucovorin calcium, tabloid, butsin, folinate calcium, revofoline Nate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin,
Examples include pyrithrexime, idoxiuridine, mitoguazone, thiazofurin, ambamustine and the like.

As anticancer antibiotics, for example, actinomycin D, actinomycin C, mitomycin C,
Chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride,
Doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mythramycin, sarcomycin, carcinophylline, mitotane, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like. Examples of plant alkaloids include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, vinorelbine and the like. Examples of the immunotherapeutic agent (BRM) include, for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor,
Erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole and the like. In addition, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex salt, mercury hematoporphyrin / sodium, topoisomerase I
Inhibitors (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitors (eg, sobuzoxane, etc.), differentiation inducers (eg, retinoids, vitamins D, etc.), growth factor inhibitors (eg, suramin, etc.), angiogenesis inhibition Drugs, α-blockers (eg, tamsulosin hydrochloride, etc.) and the like can also be used. Other anti-cancer therapies include surgery, radiation therapy, hyperthermia, and the like. Specific examples used in combination with the medicament of the present invention in the treatment and prevention of benign prostatic hyperplasia include the above-mentioned antiandrogens,
5α-reductase inhibitors, androgen synthesis inhibitors,
In addition to aromatase inhibitors, therapeutic agents for dysuria (such as Harnal) and the like can be mentioned. For the treatment and prevention of prostate cancer, ifosfamide, UTF, adriamycin, peplomycin
A chemotherapeutic agent such as cin) and cisplatin can be used in combination with the medicament of the present invention. For the treatment and prevention of breast cancer, cyclophosphamide (Cyclophos
pamide), 5-FU, UFT, methotrexate
xate), Adriamycin, Mitomycin C, Mitoxantrone
And the like.

The compound used in the medicament of the present invention may form a salt, and the salt 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, boric acid, etc.) and organic acids (eg, formic acid,
Examples thereof include salts with acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Further, when the compound used in the present invention has an acidic group such as —COOH, an inorganic base (eg, an alkali metal salt or an alkaline earth metal such as sodium, potassium, calcium, and magnesium, ammonia, etc.) or an organic base (Eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) and may form a salt.

The compound or a salt thereof used in the medicament of the present invention can be isolated and purified by a conventional separation means such as recrystallization, distillation, chromatography and the like. Thus, when the compound used in the present invention is obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto.
It can be converted to a free form or another salt by a method known per se or a method analogous thereto. When the compound or a salt thereof used in the medicament of the present invention is an optically active form, it can be separated into d-form and l-form by ordinary optical resolution means.

As the dosage form for administering the medicament of the present invention, a compound having an LH-RH action and a compound having an LH-RH antagonism include, for example, oral or parenteral administration according to a method known per se. Either of them is possible, but it is particularly preferable that the compound having LH-RH action is a parenteral preparation and the compound having LH-RH antagonistic action is an oral preparation. Upon formulation, it is mixed with a pharmaceutically acceptable carrier and is usually orally administered as a solid preparation such as tablets, capsules, granules, powders, or injections, suppositories intravenously, subcutaneously, intramuscularly, etc. Or parenterally as a sublingual tablet or as a nasal drug. Further, it may be administered sublingually, subcutaneously or intramuscularly as a sustained release preparation such as sublingual tablets and microcapsules. Particularly, as the dosage form of the compound having a gonadotropin releasing hormone action, for example, injection administration, subcutaneous administration (including an implant), nasal administration and the like are preferable. For example, a suspending agent, a solubilizing agent, a stabilizing agent, an isotonic agent, a preservative, and the like are added to a compound used in the medicament of the present invention, and intravenous, subcutaneous, or intramuscular injection is prepared by a method known per se. I do.
At that time, if necessary, a freeze-dried product can be obtained by a method known per se. When administering the compound used in the present invention or a salt thereof to, for example, a human, the compound itself or an appropriate pharmacologically acceptable carrier, excipient, or diluent is mixed, and the compound is orally or parenterally administered as a pharmaceutical composition. Can be safely administered. Examples of the above preparations include oral preparations (eg, powders, granules, capsules, tablets), injections, drops, external preparations (eg, nasal administration preparations, transdermal preparations, etc.), suppositories (eg, rectal suppositories) Agents, vaginal suppositories) and the like. As the above-mentioned pharmaceutically acceptable carrier, various organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids Agents, suspending agents, tonicity agents, buffers,
It is formulated as a soothing agent. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.

Suitable 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, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
And sodium carboxymethyl starch. Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Suitable examples of the solubilizer include, for example, polyethylene glycol,
Examples include propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include, for example, stearyltriethanolamine,
Surfactants such as sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxy And hydrophilic polymers such as propylcellulose. Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, 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. Suitable examples of the preservative include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

These preparations can be manufactured by a method known per se, which is generally used in the preparation process.

The compound used in the present invention or a salt thereof may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HOC 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.) Agents (eg, methyl paraben, propyl paraben, benzyl alcohol, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol,
Such as glucose or the like), or by dissolving, suspending or emulsifying in vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like, and shaping into an oily injection to give an injection. In order to prepare a preparation for oral administration, the compound used in the present invention or a salt thereof can be added to an excipient (eg, lactose,
Sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, stearin Magnesium oxide, polyethylene glycol 6000, etc.), and compression-molded, and if necessary, coated with a method known per se for the purpose of taste masking, enteric coating or long-lasting to obtain a preparation for oral administration. it can. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bruronic F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (ROHM) Co., Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, red iron oxide, titanium dioxide, etc.). In the case of an enteric preparation, an intermediate layer is preferably provided between the enteric layer and the drug-containing layer by a method known per se for the purpose of separating the two layers. In order to prepare an external preparation, the compound or a salt thereof used in the present invention can be converted into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid, the compound used in the present invention or a salt thereof as it is,
Alternatively, excipients (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) are added and mixed to form a powdery composition. And The liquid is almost the same as the injection, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred. These are all pH regulators (eg, carbonic acid, phosphoric acid, citric acid,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.) may be added.

For example, in order to prepare a suppository, the compound used in the present invention or a salt thereof can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.) and intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) And vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers. Examples of the sustained-release preparation include sustained-release microcapsules. In order to prepare sustained-release microcapsules, a method known per se can be used. Among them, for example, a water-soluble drug and a drug-retaining substance (eg, natural or synthetic rubber (eg, gelatin) or a polymer compound (eg, For example, a solution containing a high molecular weight polymer (eg, polylactic acid, lactic acid-glycolic acid copolymer) is used as an oil layer.
O-float is created, in which case the inner water layer has a viscosity of about 5000
The sustained release microcapsules (JP-A-1-57087), which are produced by subjecting the floated product to a water-in-water drying method and thickening or solidifying it to at least cp or more, and then adding about 20 to The composition ratio of lactic acid / glycolic acid to the internal aqueous phase liquid containing 70% by weight is 80 / 20-100.
/ 0 and an oil phase solution containing a copolymer or homopolymer having a weight average molecular weight of 7,000 to 30,000 as a release controlling substance by microencapsulation. It is preferable to administer it by molding it into a sustained-release microcapsule (JP-A-4-321622). The sustained-release microcapsules may be used as sustained-release solid injections (such as implants).

In order to prepare the above-mentioned nasal administration agent, in accordance with a method known per se, the compound or a salt thereof used in the present invention is, for example, an isotonic agent (eg, sodium chloride, sodium citrate, glycerin, sorbitol mannitol, glucose) , Boric acid, sucrose, polyethylene glycol, Tween 80, sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.), buffers, (eg, sodium chloride, sodium citrate, boric acid, borax, sodium monohydrogen phosphate,
Sodium dihydrogen phosphate, etc.), preservatives (eg, parabens such as methylparaben, inverted soaps such as benzalkonium chloride, alcohol derivatives such as benzyl alcohol,
Organic acids such as sorbic acid and salts thereof, preservatives such as phenol, etc.), stabilizers (eg, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, etc.), thickeners (Eg, glycerin, polyethylene glycol, sorbitol, mannitol, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc.), suspending agents (eg, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl) Methylcellulose, hydroxypropylcellulose, polyethylene glycol, Tween 80), bile acid surfactants (eg, glycocholinic acid, choline acid) Taukokorin acid cholanic acid, Etokorin acid, Desokishikorin acid, Quai Node Sokishi choline acid,
Cyclodextrins (eg, α-cyclodextrin, β-cyclodextrin, β-cyclodextrin, etc.)
Cyclodextrin, γ-cyclodextrin, and derivatives thereof (eg, methylated form, hydroxyethyl form,
Glycosylated form, carboxymethylethyl form, etc.) and JP-B-2-19092) are added to prepare an aqueous solution or suspension. Further, the compound used in the present invention may be formed into an aerosol (JP-A-63-21).
No. 1237).

The daily dose of the medicament of the present invention includes the degree of symptoms, age, sex, weight, sensitivity difference of administration subject, timing of administration, interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. It is not particularly limited. LH-RH
As a compound having an effect, the dosage is pituitary LH
And an amount capable of inducing a desensitization state of FSH-secreting cells, as long as it does not cause a problem of side effects, and is not particularly limited, and is usually about 0.00003 to 3 mg, preferably about 0.0003-
0.3 mg, more preferably about 0.002 to 0.0.
1 mg, 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.
003 to 3 mg, preferably about 0.001 to 0.03 mg
Is usually administered once to three times a day. Also, in the case of sustained release preparations, the same doses as described above are used per day.

The period and amount of administration of the compound having LH-RH antagonism can suppress the flare caused by the compound having LH-RH activity and induce the desensitization of pituitary LH and FSH secreting cells. For example, any period and amount can be set as long as side effects are not a problem. The daily dose as a compound having LH-RH antagonism depends on the degree of symptoms, age, sex, weight, sensitivity difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, type, and active ingredient. Although it differs depending on the kind and the like, it is not particularly limited, but is usually about 0.1 to 160 mg, preferably about 0.1 to 40 m per kg of mammal by oral administration.
g, more preferably about 0.1 to 30 mg or about 0.1 to 20 mg, most preferably 0.1 to 1 mg.
0 mg, which is usually administered once to four times a 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 10 mg, preferably about 0.02 to 5 mg, is usually administered in 1 to 3 times a day. Also, in the case of sustained release preparations, the same doses as described above are used per day.

In the composition of the present invention, the ratio of the dose of the compound having the LH-RH action to the compound having the LH-RH antagonistic action is, for example, 1 weight of the compound having the LH-RH action to 1 weight of the compound having the LH-RH action. compounds of about 10 to 10 ⁶ times the weight with RH antagonist, preferably about 10 to 10 ⁵ times by weight, more preferably about 10 to 10 ⁴ times by weight, and most preferably from about 10 ² to 10 ⁴ times the weight is there.

When the medicament of the present invention is administered, it may be administered at the same time, but the compound having LH-RH antagonistic action is administered first, and then the compound having LH-RH action is administered. Is preferred. When administration is performed at such a time lag, a compound having LH-RH antagonistic activity is administered, and after the blood compound concentration is sufficiently increased, L
It is desirable to administer a compound having an H-RH action, and the preferable time difference varies depending on administration and dosage form.
For example, a compound having LH-RH action is administered 1 hour or more after administration of the compound having LH-RH antagonism, and 1 hour or more to 1 day to 1 hour after administration of the compound having LH-RH antagonism. A method of administering a compound having an LH-RH effect after a week is mentioned.

As a preferable administration method, for example, about 0.1 to 10 mg / kg of a compound having LH-RH antagonism formed into an oral administration preparation is orally administered, and after about 2 to 6 hours, the sustained release preparation (E.g., microcapsules) or a compound having an LH-RH action, formed into a preparation for nasal administration, in an amount of about 0.001 to 0.03 mg / kg per day (for example, 3 mg / kg).
In the case of a 0-day sustained-release preparation, the dose is 30 times the daily dose). Thereafter, a method in which the oral preparation is administered 1 to 4 times a day (a daily dose of 0.1 to 10 mg / kg) for 3 to 14 consecutive days can be mentioned. Compounds having LH-RH antagonistic activity formed into subcutaneous (injection) administration preparations about 0.1 to 1
0 mg / kg is administered subcutaneously, and after about 1 to 6 hours, a compound having an LH-RH action of about 0.001 to 0.000, which is formed into a sustained-release preparation (eg, microcapsule) or an intranasal preparation.
03 mg / kg is administered as a daily dose (for example, in the case of a 30-day sustained-release preparation, the dose is 30 times the daily dose). Thereafter, the preparation for subcutaneous administration is administered 1 to 4 times a day (a daily dose of 0.1 to
mg / kg) for 3 to 14 consecutive days. Compounds having LH-RH antagonism formed into sustained-release preparations (eg, microcapsules) about 0.1 to 0.1
10 mg / kg is administered subcutaneously as a daily dose (for example, in the case of a 30-day sustained release formulation, 30 times the daily dose), and after about 1 to 6 hours, a sustained release formulation (eg, microcapsules) )
Compound having an LH-RH action of about 0.00
A method in which 1 to 0.03 mg / kg is subcutaneously administered as a daily dose (for example, in the case of a 30-day sustained-release preparation, 30 times the daily dose) is exemplified. Alternatively, a compound having an LH-RH antagonistic action may be administered before a certain period of time, and then a compound having an LH-RH action may be administered. For example, LH-RH
After subcutaneously or orally administering 0.1 to 10 mg / kg per day of a compound having an antagonistic action for 1 to 3 weeks, or a similar amount of a sustained-release preparation,
A compound having an LH-RH action is administered.

The compound having LH-RH action and the compound having LH-RH antagonistic action used in the present invention are used in combination, for example, by the above-mentioned method. When used in combination, those separately formulated may be used in combination or as a kit. More specifically, the L
Each of the preparation of the compound having the H-RH action and the preparation of the compound having the LH-RH antagonism may be described in the direct container or encapsulation or the package insert to be used together. For example, a tablet or injection of the compound having LH-RH antagonism is administered to each direct container or encapsulation or package insert of the preparation, and then 1 to 6 times.
After a lapse of time, a sustained-release preparation or a nasal preparation of the compound having the LH-RH action is administered; tablets or injections of the compound having the LH-RH antagonism are repeated 1 to 3 times.
After administration for 3 weeks, administration of a sustained-release preparation or a nasal preparation of the compound having the LH-RH action is described. A compound having an LH-RH action and a compound having an LH-RH antagonistic action are usually contained in a drug in an amount of 1 to 99% by weight.

[0209]

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.

Reference Example (a) Example 5 of PCT International Publication WO95 / 28405
4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -3- (N-
Methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -5-isobutyrylthieno [2,3-b] pyridine (Compound No. 1, the structural formula is ) (100 mg), lactose 1
Tablets are prepared by a conventional method using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg.

Reference Example (b) Compound No. 1 (0.5 g) was dissolved in distilled water for injection to make a total volume of 100 ml. This solution was aseptically filtered using a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml portions into vials that had been washed and sterilized, and lyophilized by a conventional method to give 100 mg / ml. Produce lyophilized injections in vials.

Reference Example (c) (1) Compound No. E-5 5 g (2) Lactose / crystalline cellulose (grain) 330 g (3) D-mannitol 29 g (4) Low-substituted hydroxypropylcellulose 20 g (5) Talc 25 g (6) hydroxypropyl cellulose 50 g (7) aspartame 3 g (8) dipotassium glycyrrhizinate 3 g (9) hydroxypropyl methylcellulose 2910 30 g (10) titanium oxide 3.5 g (11) yellow iron sesquioxide 0.5 g (12) Light silicic anhydride 1g (1), (3), (4), (5), (6), (7) and (8) are suspended or dissolved in purified water and coated on the core particles of (2) Prepare fine granules. The fine particles are coated with (9)-(11) to prepare coated fine particles, and mixed with (12) to prepare 1%, 500 g of fine particles of Compound No. E-5. This is packaged in 500 mg portions.

Reference Example (d) Compound 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.

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

Reference Example (f) The compound (100m) produced in Reference Example 2-16 described later
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.

Reference Example (g) The compound (100m) produced in Reference Example 3-30 described below.
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.

Reference Example (h) The compound (100m) produced in Reference Example 4-2 described later.
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.

Reference Example (i) The compound (100m) produced 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.

Reference Example (j) The compound (100m) produced in Reference Example 6-21 described below.
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.

Reference Example (k) The compound (100m) produced in Reference Example 7-6 described below.
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.

Reference Example (l) Compound 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.

Reference Example (m) (1) 100 g of Compounds E-1, E-2, E-3, E-4 or E-5 (2) Lactose 234 g (3) Corn starch 150 g (4) Hydroxypropyl cellulose 15 g (5) 1 g of light anhydrous silicic acid (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 granules. After mixing with (5), pack 500 mg each.

In the following Reference Examples, the ¹ H-NMR spectrum was measured by using a Varian GEMINI 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and JEOL LAMBDA300 (300 MHz).
Type spectrometer or Brooker AM 500 (50
0MHz) type spectrometer and measure all δ values in pp
Indicated by m. The symbols used in the present 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 following compounds shown in Tables 1 to 21 are produced.

[0225]

[Table 1]

[0226]

[Table 2]

[0227]

[Table 3]

[0228]

[Table 4]

[0229]

[Table 5]

[0230]

[Table 6]

[0231]

[Table 7]

[0232]

[Table 8]

[0233]

[Table 9]

[0234]

[Table 10]

[0235]

[Table 11]

[0236]

[Table 12]

[0237]

[Table 13]

[0238]

[Table 14]

[0239]

[Table 15]

[0240]

[Table 16]

[0241]

[Table 17]

[0242]

[Table 18]

[0243]

[Table 19]

[0244]

[Table 20]

[0245]

[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 Production 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. m.p. 188-189 ° C.

Reference Example 2-14 (1) Using the compound prepared in Reference Example 2-13, the following compound is prepared 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 below. 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 Preparation of 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].

[0257]

[Table 22]

[0258]

[Table 23]

[0259]

[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-
Preparation of oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The title compound is prepared from the compound obtained in Reference Example 3-1 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 prepared by using the compound obtained in 7 (2) or Reference Example 3-14 to be described later as a raw material and in the same manner as that described in Reference Examples 3-6 and 3-7.

[0264]

[Table 25]

The “N-methyl-O-methylhydroxamic acid” in Table 25 is a compound of 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 In the same manner as described in Reference Example 3-17, [Table 2
6] and the compounds shown in [Table 27] are produced.

[0271]

[Table 26]

[0272]

[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.

[0275]

[Table 28]

[0276]

[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 165-1
68 ° 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].

[0279]

[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.

[0282]

[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. As a result, the compounds shown in [Table 32] are produced.

[0285]

[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].

[0289]

[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].

[0291]

[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 In the same manner as described in Reference Example 4-2, [Table 35]
Compounds shown in (4-3 (1), 4-3 (2), 4-3 (3), 4-3 (4), 4-4,
4-5) is manufactured. ([Table 35] shows Reference Example 4-2.
Are described. )

Reference Example 4-4 4,7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -5- (4-tetrahydropyranyl) thiocarbonyl-4-oxothieno [2,
Preparation of 3-b] pyridine: 4-mercaptotetrahydrofuran (470 mg, 4.00 mmole) was added to dichloromethane (2 ml).
l), and trimethylaluminum (15
%, 0.48 ml, 1.00 mmol) in hexane (15 ml)
Was added dropwise under ice cooling. After stirring at the same temperature for 1 hour, a dichloromethane solution (1 ml) of the compound (129 mg, 0.20 mmole) obtained in Reference Example 3 was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 1 hour, poured into 200 ml of distilled water, extracted with chloroform, washed with saturated saline, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow amorphous (30 mg, 11%). Dissolve the obtained amorphous in chloroform,
A salt was added by adding 10N hydrochloric acid-ethanol solution, and recrystallized from chloroform-ether to obtain the title compound as yellow powdery crystals. Compound 4 having the structure shown in the following [Table 35]
-6 is shown. mp 174-176 ° C. Elemental analysis: C ₃₉ H ₃₉ N ₃ O ₄ S ₂ F ₂ .HCl.2.5 H ₂ O, CH N Calculated: 58.75; 5.69; 5.27 (%) Found: 58.77; 5.59; 5.54 (%) . ^{1 H-NMR (300MHz, CDCl3} ) δ: 1.28 (6H, d, J = 6.8H
z), 1.75-1.87 (2H, m), 1.97-2.04 (2H, m), 2.11 (3H,
s), 2.56 (1H, m), 3.54-3.61 (2H, m), 3.66 (2H, s), 3.
87 (1H, m), 3.96-4.01 (2H, m), 4.19 (2H, s), 5.30 (2H,
m), 7.01 (2H, dd, J = 8.1Hz), 7.12-7.32 (5H, m), 7.42
(1H, m), 7.62 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6H
z), 8.37 (1H, s).

Reference Example 4-5 Using Compound 4-4 shown in Table 35 as a starting material and treating in the same manner as in Reference Example 4-4, Compounds 4-7 and 4-8 shown in Table 35 below were obtained. Was manufactured.

[0296]

[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 5-position substituent was a carboxyl group. 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].

[0300]

[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 raw material, a compound produced by the same method as that described in Reference Example 5-3 was used. The compounds are shown in [Table 37].

[0303]

[Table 37]

Reference Example 5-5 Table 38 shows compounds prepared by using the compound obtained in Reference Example 5-1 (6) as a raw material in the same manner as in the method described in Reference Example 5-3.

[0305]

[Table 38]

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

[0307]

[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.

[0309]

[Table 40]

Reference Example 6-2 PCT using the compound obtained in Reference Examples 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].

[0311]

[Table 41]

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

[0313]

[Table 42]

Reference Example 6-4 Table 43 shows compounds prepared by using the compound of Reference Example 6-3 as a starting compound in the same manner as in Reference Example 6-35 described below.

[0315]

[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.

[0318]

[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 Produces the title compound. 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 The compounds prepared in the same manner as in Reference Example 6-7 using the compound obtained in Reference Example 6-10 as a raw material are shown in [Table 45].

[0323]

[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, m-chloroperbenzoic acid was used again, and the title compound was obtained from the compound obtained in Reference Example 6-15. A compound is produced. mp 256-257 ° C.

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

[0327]

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

[0330]

[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].

[0332]

[Table 48]

[0333]

[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).

[0336]

[Table 50]

Reference Example 6-24 2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methoxyphenyl) Production of -3- (3-methoxypropyl) thieno [2,3-d] pyrimidine hydrochloride: The title compound is produced 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 The compounds prepared in the same manner as described in Reference Example 6-24 using the compound obtained in Reference Example 6-19 as a starting material are shown in [Table 51]. 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.

[0339]

[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].

[0342]

[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, acetic anhydride and formic acid obtained in Reference Example 6-27. The structure of the obtained compound is shown in [Table 53]. mp 194-196 ° C.

Reference Example 6-29 The compounds prepared in Reference Example 6-28 using the compounds obtained in Reference Example 6-26 or 6-27 are shown in [Table 53].

[0345]

[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.

[0348]

[Table 54]

Reference Example 6-32 The compounds prepared by using the compound obtained in Reference Example 6-26 or 6-27 as a starting material and in the same manner as described in Reference Example 6-31 are shown in [Table 55]. .

[0350]

[Table 55]

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

[0352]

[Table 56]

Reference Example 6-34 Using the compound obtained in Reference Example 6-26 or 6-27 as a raw 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.

[0354]

[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.

[0356]

[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, and this was converted to an alkyl halide (eg, chloro). The compounds shown in [Table 59] are produced using acetone) and a base (eg, potassium carbonate).

[0358]

[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. You. 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 the following [Table 60].

[0362]

[Table 60]

Example 8-1 4,7-Dihydro-7- (2,6-difluorobenzyl)-
2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -6-methyl-4-
Preparation of oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester hydrochloride: The compound (1.98 g, 2.78 mmole) obtained in Reference Example 4-2 was dissolved in anhydrous tetrahydrofuran (50 ml). Methylmagnesium bromide in diethyl ether (3.0 M, 4.63 ml,
13.9 mmole) and copper iodide (529 mg, 2.78 mmol)
The mixture of e) was added dropwise under ice cooling. After stirring at the same temperature for 0.5 hour, 1N hydrochloric acid was added under ice cooling to adjust the pH to 2 or less, and the mixture was further stirred at room temperature for 0.5 hour. The reaction solution was poured into 500 ml of a 0.1 N potassium hydroxide solution, extracted with chloroform, washed with a saturated saline solution, and dried (Na ₂ SO ₄ ).
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give a colorless amorphous (1.80).
g, 96%). Sodium hydride was suspended in tetrahydrofuran (15 ml), and the above-obtained amorphous (1.80 g, 2.67 mmole) solution of tetrahydrofuran (15 ml) was added dropwise at room temperature. The reaction solution was added at 50 ° C for 0.1 hour.
After stirring for 5 hours, phenylselenyl chloride (1.02 g,
(5.34 mmole) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was further stirred at 50 ° C overnight. The reaction solution is distilled water 50
The mixture was poured into 0 ml, extracted with chloroform, washed with brine, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless amorphous (1.00 g, 86%). The obtained amorphous was dissolved in chloroform, 10N hydrochloric acid-ethanol solution was added to make a salt, and the salt was recrystallized from chloroform-ether to obtain the title compound as white powdery crystals. The structure of the obtained compound is shown in [Table 61] below. mp 163-165 ° C. Elemental _{analysis: C 38 H 39 N 3 O} 4 SF 2 · HCl · 1.5H 2 O as a C H N Calculated: 62.07; 5.89; 5.71 (%) Found: 62.31; 5.81; 6.04 (%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23 (6H, d, J = 6.8H)
z), 1.38 (6H, d, J = 6.8Hz), 2.10 (3H, s), 2.45 (3H,
s), 2.54 (1H, m), 3.63 (2H, s), 4.13 (2H, s), 5.30 (1
H, m), 5.34 (3H, s), 6.93 (2H, dd, J = 8.1Hz), 7.14-7.
39 (6H, m), 7.59 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6H
z).

Reference Example 8-2 Reference Example 4-1 or Reference Example 4-3 (compound 4-3 (2), 4-
Using the compound obtained in 3 (3), 4-3 (4)) as a raw material,
The same processing as in the above-mentioned Reference Example 8-1 was performed, and the following [Table 61]
The following compounds 8-2 (1), 8-2 (2), 8-2 (3) and 8-2 (4) were produced.

Example 8-3 Using the compound obtained in Reference Example 4-1 as a raw material, and using ethylmagnesium bromide in place of methylmagnesyl muchloride in Reference Example 8-1 described above,
Compound 8-3 shown in [Table 61] described below was produced by treating in the same manner as -1.

Reference Example 8-4 The compound 5-6 (1) or 5-6 (22) obtained in Reference Example 5-6 was used as a starting material, and treated in the same manner as in Reference Example 8-1 described above. Compound 8-4 (1) or 8-4 (2) shown in Table 61
Was manufactured respectively. Further, using the compound 5-6 (2), 5-6 (3), 5-6 (6), 5-6 (7) or 5-6 (8) obtained in Reference Example 5-6 as a raw material , Processed in the same manner as in Reference Example 8-1 above.
Compounds 8-4 (3) to 8-4 (7) shown in [Table 61] described below are produced respectively.

[0367]

[Table 61]

Reference Example A 550 mg of leuprorelin acetate was dissolved in 1 ml of distilled water, and this was dissolved in poly-DL-lactic acid (Lot. 890717; molecular weight;
14100: Dispersion degree 2.00) was added to a solution prepared by dissolving 4 g of each in 7.5 ml of dichloromethane.
Mix for 2 seconds to obtain a W / O emulsion. This emulsion was poured into 1000 ml of a 0.25% aqueous solution of polyvinyl alcohol (PVA) which had been previously heated to 15 ° C.
Use a small homogenizer to make a W / O / W emulsion. Thereafter, the W / O / W emulsion is solidified by volatilization of dichloromethane while stirring the W / O / W emulsion, and then collected by a centrifuge.
This is dispersed again in distilled water, and further centrifuged to wash away the released drug and dispersant. The collected microcapsules are subjected to more complete desolvation and dehydration by freeze-drying, and then powdered to obtain microcapsules.

Reference Example B 550 mg of leuprorelin acetate was dissolved in 1 ml of a 20% aqueous gelatin solution, and this was dissolved in a lactic acid-glycolic acid copolymer (composition ratio of lactic acid: glycolic acid; 75:25, average molecular weight: 14,000). 4) was added to a solution prepared by dissolving 4 g in 7.5 ml of dichloromethane, and mixed with a small homogenizer (Polytron, manufactured by Kinematica, Switzerland) for about 60 seconds.
Obtain a type emulsion. This emulsion was previously brought to 15 ° C. with 0.25% polyvinyl alcohol (PV
A) Inject into 1000 ml of an aqueous solution and use a small homogenizer to make a W / O / W emulsion. After this,
The W / O / emulsion liquid is solidified by volatilization of dichloromethane while stirring the W / O / emulsion liquid, and then collected by a centrifuge. This is dispersed again in distilled water, and further centrifuged to wash away the released drug and dispersant. The collected microcapsules are subjected to more complete desolvation and dehydration by freeze-drying, and then powdered to obtain microcapsules.

Reference Example C Methyl paraben 0.12%, propyl paraben 0.01%
Was dissolved in 16 ml of a pH 7.4 isotonic buffer in which α-cyclodextrin and 2 g of leuprorelin acetate were dissolved.
(4000, Shin-Etsu Chemical Co., Ltd.), add 200 mg, and stir well to make a uniform viscous solution, and make up the total weight to 20 g with buffer. 100 mg of this is filled in a nasal administration applicator and administered intranasally.

Example 1 The injection obtained in Reference Example (b) and the microcapsule obtained in Reference Example A or B are separately prepared into a pharmaceutical composition kit.

Example 2 The injection obtained in Reference Example (b) and the preparation for nasal administration obtained in Reference Example C were prepared as separate preparations and used as a kit for a pharmaceutical composition.

Example 3 The tablet obtained in Reference Example (a) and the microcapsule obtained in Reference Example A or B are separately prepared into a pharmaceutical composition kit.

Example 4 The tablet obtained in Reference Example (a) and the nasally administered preparation obtained in Reference Example C were prepared as separate preparations, and used as a kit for a pharmaceutical composition.

Test Example 1 Compound No. E-5 (hereinafter sometimes referred to as antagonistic compound 1) was added to a solution I (0.5 mg / ml) at a concentration of 7.5 mg / ml.
5% methylcellulose-saline)
A single dose was subcutaneously administered to D rats (10 weeks old, n = 6).
The dose was 30 mg / kg body weight. Animals that received Vehicle alone were used as a control group. 24 hours after administration, blood was collected from the carotid artery under ether anesthesia, and the final concentration was 3 mg / ml.
EDTA (ethylenediaminetetraacetic acid) and final concentration 300
U / ml of aprotinin was added immediately. 3000x
After centrifugation at 15 g for 15 minutes, the testosterone concentration in the obtained plasma was measured by radioimmunoassay. 100
-(Testosterone concentration in blood of compound administration group) / (Testosterone concentration in blood of control group) x 100 was calculated to determine the testosterone inhibition rate (%) of the compound. Antagonistic compound 1 showed an inhibition rate of 90% ± 5.

Test Example 2 Solution I was prepared so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
A single subcutaneous dose was administered to male cynomolgus monkeys (age 4-6, n = 3). The dose was 30 mg / kg body weight. Ve
Animals to which only hicle was administered were used as a control group. Twenty-four hours after administration, blood was collected under anesthesia, and the final concentration of EDT was 3 mg / ml.
A (ethylenediaminetetraacetic acid) and aprotinin at a final concentration of 300 U / ml were immediately added. 15 at 3000 × g
After centrifugation for minutes, the testosterone concentration in the obtained plasma was measured by radioimmunoassay. 100- (blood testosterone concentration in the compound administration group) / (blood testosterone concentration in the control group) × 100 was calculated to determine the testosterone suppression rate (%) of the compound. Antagonist compound 1
The inhibition rate was 80% ± 5.

Test Example 3 Solution I was prepared so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
A single subcutaneous administration to male cynomolgus monkeys (4-6 ages, n = 3). The dose is 30 mg / kg body weight. Ve
Animals administered hicle only are used as a control group. Three hours after administration, a physiological saline solution of an LH-RH agonist (leuprorelin acetate) was subcutaneously administered under anesthesia (5 μg / k).
g) Yes. Blood was collected 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration, and the final concentration was 3 mg.
/ ml EDTA (ethylenediaminetetraacetic acid) and final concentration 3
Immediately add 00 U / ml aprotinin. 300
After centrifugation at 0 × g for 15 minutes, the concentration of LH and testosterone in the obtained plasma is measured by a bioassay method and a radioimmunoassay method. Calculate 100− (blood LH or testosterone concentration in compound administration group) / (blood LH or testosterone concentration in control group) × 100 to determine the LH or testosterone suppression rate (%) of the compound
Ask for. This indicates that a transient increase (flare phenomenon) in serum LH or testosterone concentration due to pituitary-gonad stimulating action (acute action) that occurs immediately after the first administration of leuprorelin acetate is avoided.

Test Example 4 Solution I was prepared so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
Male cynomolgus monkey (4-6 years old, n = 3) twice daily
Oral administration is performed every 2 hours for 7 days (15 times in total). The dose is 60 mg / kg body weight. Animals receiving Vehicle alone are used as a control group. One hour after the first oral administration on the second day (the third oral administration), LH-R
An H agonist sustained-release preparation (leuprorelin depot, a microcapsule manufactured in Reference Example A) is subcutaneously administered (0.15 mg / kg as leuprorelin amount). Blood is collected at 1 hour, 4 hours, 8 hours, 18 hours, 30 hours, 48 hours, and 72 hours after administration, and then once a day for 2 weeks. The collected blood has a final concentration of 3 mg / ml EDTA (ethylenediaminetetraacetic acid)
And aprotinin at a final concentration of 300 U / ml are added immediately. After centrifugation at 3000 × g for 15 minutes, the LH and testosterone concentrations in the obtained plasma are measured by a bioassay method and a radioimmunoassay method. 100-
(Blood LH or testosterone concentration in compound administration group)
/ (Blood LH or testosterone concentration in control group) × 1
Calculate 00 to determine the LH or testosterone inhibition (%) of the compound. This avoids the transient hatred (flare phenomenon) associated with an increase in serum LH or testosterone concentration due to the pituitary-gonad stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot. I understand.

Test Example 5 Solution I was adjusted so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
Male cynomolgus monkey (4-6 years old, n = 3) twice daily
Oral administration is performed every 2 hours for 7 days (15 times in total). The dose is 60 mg / kg body weight. Animals receiving Vehicle alone are used as a control group. One hour after the first oral administration on the second day (the third oral administration), LH-R
An H-agonist sustained-release preparation (leuprorelin depot, a microcapsule manufactured in Reference Example A) is subcutaneously administered (0.45 mg / kg as leuprorelin amount). Blood is collected at 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after administration, and then once a day for 2 weeks. The collected blood has a final concentration of 3 mg / ml EDTA (ethylenediaminetetraacetic acid)
And aprotinin at a final concentration of 300 U / ml are added immediately. After centrifugation at 3000 × g for 15 minutes, the LH and testosterone concentrations in the obtained plasma are measured by a bioassay method and a radioimmunoassay method. 100-
(Blood LH or testosterone concentration in compound administration group)
/ (Blood LH or testosterone concentration in control group) × 1
Calculate 00 to determine the LH or testosterone inhibition (%) of the compound. This shows that transient hatred (flare phenomenon) accompanied by an increase in serum LH testosterone concentration due to pituitary-gonad stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided. .

Test Example 6 Solution I was prepared so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
Male cynomolgus monkey (4-6 years old, n = 3) twice daily
Oral administration is performed every 2 hours for 7 days (15 times in total). The dose is 60 mg / kg body weight. Animals receiving Vehicle alone are used as a control group. One hour after the first oral administration on the second day (the third oral administration), LH-R
An H agonist sustained release preparation (leuprorelin depot, a microcapsule manufactured in Reference Example B) is subcutaneously administered (0.15 mg / kg as leuprorelin amount). Blood is collected at 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after administration, and then once a day for 2 weeks. The collected blood has a final concentration of 3 mg / ml EDTA (ethylenediaminetetraacetic acid)
And aprotinin at a final concentration of 300 U / ml are added immediately. After centrifugation at 3000 × g for 15 minutes, the LH and testosterone concentrations in the obtained plasma are measured by a bioassay method and a radioimmunoassay method. 100-
(Blood LH or testosterone concentration in compound administration group)
/ (Blood LH or testosterone concentration in control group) × 1
Calculate 00 to determine the LH or testosterone inhibition (%) of the compound. This indicates that transient hatred (flare phenomenon) associated with an increase in serum testosterone concentration due to the pituitary-gonad stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided.

Test Example 7 Solution I was prepared so that antagonistic compound 1 was at a concentration of 7.5 mg / ml.
(0.5% methylcellulose-saline)
Male cynomolgus monkey (4-6 years old, n = 3) twice daily
Oral administration is performed every 2 hours for 28 days (57 times in total). The dose is 60 mg / kg body weight. Animals receiving Vehicle alone are used as a control group. One hour after the first oral administration on the 15th day (the third oral administration), LH
-RH agonist sustained release preparation (leuprorelin depot,
The microcapsules prepared in Reference Example B) are administered subcutaneously (0.15 mg / kg as leuprorelin amount). 1 hour, 4 hours, 8 hours, 12 hours, 24 hours after administration
Blood is collected at time, 48 hours and 72 hours, and thereafter blood collection is performed once every three days for four weeks. EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml are immediately added to the collected blood. After centrifugation at 3000 × g for 15 minutes, the LH and testosterone concentrations in the obtained plasma are measured by a bioassay method and a radioimmunoassay method. 1
00- (blood LH or testosterone concentration in compound administration group) / (blood LH or testosterone concentration in control group) × 100 is calculated to determine the LH or testosterone suppression rate (%) of the compound. This shows that transient hatred (flare phenomenon) accompanied by an increase in serum LH testosterone concentration due to pituitary-gonad stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided. .

[0382]

The pharmaceutical composition of the present invention provides a transient exacerbation (flare phenomenon) accompanied by an increase in serum testosterone concentration due to a pituitary-gonad stimulating action (acute action) which occurs immediately after administration of a compound having an action. Can be avoided. Moreover, the action is enhanced. Therefore, the pharmaceutical composition of the present invention can be advantageously used as a medicament for treating or preventing a sex hormone-dependent disease.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/495 ADU A61K 31/495 ADU 38/00 AED 37/02 AED

Claims (32)

[Claims] 1. A medicament comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptidic compound having a gonadotropin releasing hormone antagonistic action. 2. The medicament according to claim 1, wherein the compound having a gonadotropin releasing hormone action is a peptide compound. 3. The medicament according to claim 2, wherein the peptide compound is a natural hormone or an analog thereof. 4. The compound of the formula (Pyr) Glu-R ₁ -Trp-Ser-R ₂ -R ₃ -R ₄ -Arg-Pro-R ₅ (I) wherein R ₁ is His, Tyr , Trp or p-NH ₂ -Phe, R ₂ is Ty
r or Phe, R ₃ is Gly or a D-type amino acid residue which may have a substituent, R ₄ is Leu, Ile or Nle, R
₅ is a group represented by the formula Gly-NH-R ₆ (R ₆ represents a hydrogen atom or an optionally substituted alkyl group) or a formula NH-
R ₆ '(R _6' is hydrogen atom, an amino substituted with a group or a hydroxyl group represents an alkyl or ureido even if) the pharmaceutical according to claim 2, wherein the polypeptide represented by a group represented by]. 5. The medicament according to claim 2, wherein the peptide compound is a compound selected from leuprorelin, gonadorelin, buserelin, triptrelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin. 6. The medicament according to claim 1, wherein the compound having a gonadotropin releasing hormone action is used as a sustained release preparation. 7. The medicament according to claim 6, wherein the sustained-release preparation is a microcapsule preparation. 8. The medicament according to claim 6, wherein the sustained-release preparation is a nasal preparation or an implant. 9. The non-peptidic compound contains at least a condensed bicyclic structure of an optionally substituted homo- or hetero 5- to 7-membered ring and an homo- or hetero 5- to 7-membered ring. The medicament according to claim 1, which is a fused ring compound or a salt thereof. 10. A fused ring compound represented by the general formula: [Wherein, W 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 medicament according to claim 9, which is a medicament. [11] a ring represented by the general formula: Wherein R ^1a and R ^2a 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. Medicine. [12] a ring represented by the general formula: [Wherein, 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] The medicament according to claim 10, which is: (13) the ring represented by the general formula: [Wherein, R ^7a 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 ^11a and R ^12a may be the same or different. Each of which is a hydrogen atom or a hydrocarbon residue which may be substituted, and o is an integer of 1 to 2]. 14. The ring represented by 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: 11. The medicament according to claim 10, wherein R ^11c and R ^12b may be the same or different and each represents a hydrogen atom or a hydrocarbon group which may be substituted. 15. A fused ring compound represented by the following general formula: [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 or carbon atom, a group via a nitrogen atom, an oxygen atom or a sulfur atom or a heterocyclic group which may be substituted, R ^5e is a group via a hydrogen atom or a carbon atom, and n is 0 to 3 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 the formula: ^{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 medicament according to claim 9, which is a compound represented by the formula: 16. A fused ring compound 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
R ^17a may be substituted with 1 to 2 hydrogen atoms, alkyl groups, halogen atoms or alkoxy groups, and may be further identical or different. A carboxyl group, an alkylcarbonyl group, an arylcarbonyl group or an optionally substituted alkyl group which may be esterified or amidified, and v, t and u may be the same or different; 0-3
The compound according to claim 9, which is a compound represented by the formula: 17. A fused ring compound represented by the following general formula: [In the formula, R ^13b may be substituted by 1 to 3 substituents and may be the same or different, and represents a hydrogen atom, a C _1-6 alkoxy group or a C _1-8 alkanoylamino group, and R ^14b represents a hydrogen atom Or a C _1-6 alkyl group, R ^15b may be substituted with 1 to 3 substituents, and may be the same or different; a hydrogen atom or halogen; and R ^16b may be substituted with 1 to 3 substituent (s). Furthermore, they may be the same or different, and include a hydrogen atom,
Halogen or C _1-6 alkoxy, R ^17b is 1 or 2
May be further substituted or may be the same or different, and represent a carboxyl group or a C _1-6 alkylcarbonyl group which may be esterified or amidated,
v ', t' and u 'may be the same or different and each represents an integer of 0 to 3]. 18. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action is 4,7-dihydro-3
-(N-methyl-N-benzylaminomethyl) -7-
(2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5
The medicament according to claim 1, which is -carboxylic acid ethyl ester or a salt thereof. 19. The non-peptidic compound having gonadotropin-releasing hormone antagonistic activity is 2- (4-acetylaminophenyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl)- The medicament according to claim 1, which is 7- (2-methoxybenzyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof. 20. A non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein 5-n-butyryl-
4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2-
(4-methoxyphenyl) -4-oxo-thieno [2,
3. The medicament according to claim 1, which is 3-b] pyridine or a salt thereof. 21. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein 5-benzoyl-4,
7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-
Methoxyphenyl) -4-oxo-thieno [2,3-
b) The medicament according to claim 1, which is pyridine or a salt thereof. 22. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -5-isobutyryl-4-oxo-
The medicament according to claim 1, which is thieno [2,3-b] pyridine or a salt thereof. 23. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5-isobutyryl-2
-(4-propionylaminophenyl) -4-oxo-
The medicament according to claim 1, which is thieno [2,3-b] pyridine or a salt thereof. 24. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein 5-benzoyl-7-
(2,6-difluorobenzyl) -4,7-dihydro-3
-(N-methyl-N-benzylaminomethyl) -2-
The medicament according to claim 1, which is (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof. 25. A non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein 3- (N-benzyl-)
Methylaminomethyl) -4,7-dihydro-2- (4-
(Allyloxyphenyl) -5-isobutyryl-7-
The medicament according to claim 1, which is (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine or a salt thereof. 26. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein isopropyl [3-
(N-benzyl-N-methylaminomethyl) -2- (4
-Isobutyrylaminophenyl) -4-oxo-7-
(2,6-difluorobenzyl) thieno [2,3-b]
Pyridine-5-carboxylate] or a salt thereof. 27. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein isopropyl [3-
(N-benzyl-N-methylaminomethyl) -2- (4
-Isobutyrylaminophenyl) -4-oxo-7-
The medicament according to claim 1, which is (2,6-difluorobenzyl) -6-methylthieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. 28. The non-peptidic compound having a gonadotropin-releasing hormone antagonistic action, wherein isopropyl [3-
(N-benzyl-N-methylaminomethyl) -2- (4
-Allyloxyphenyl) -4-oxo-6-methyl-
7- (2,6-difluorobenzyl) thieno [2,3-
b) pyridine-5-carboxylate] or a salt thereof. 29. A pharmaceutical kit for preventing / treating a sex hormone-dependent disease, comprising a compound having a gonadotropin releasing hormone action and a non-peptidic compound having a gonadotropin releasing hormone antagonistic action. 30. The kit according to claim 29, wherein a parenteral administration preparation of a compound having a gonadotropin releasing hormone action and an oral administration preparation of a non-peptidic compound having a gonadotropin releasing hormone antagonistic action are combined. 31. Use of a non-peptidic compound having a gonadotropin releasing hormone antagonistic action for reducing a flare phenomenon after administration of a compound having a gonadotropin releasing hormone action. 32. Use of a non-peptidic compound having a gonadotropin releasing hormone antagonistic action for enhancing the action of a compound having a gonadotropin releasing hormone action.