JP2007302703A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition that comprises a compound having a gonadotropic hormone-releasing action and a compound having a gonadotropic hormone-releasing hormone antagonistic action. <P>SOLUTION: By using a combination of the compound having the gonadotropic hormone-releasing action and a compound having a gonadotropic hormone-releasing hormone antagonistic action, can avoid the transient exasperation (flare phenomena) accompanied by the rise of the serum testosterone and estrogen concentration caused by the action of pituitary gland and sexual gland stimulating (acute action) immediately after administration of the compound having the gonadotropic hormone-releasing action and a compound having a gonadotropic hormone-releasing hormone antagonistic action. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptide compound having a gonadotropin releasing hormone antagonistic action.

  One of the hypothalamic hormones, luteinizing hormone releasing hormone (hereinafter sometimes abbreviated as LH-RH) [Schally AV et al., Journal of Biological Chemistry. (J. Biological Chemistry), 246, 7230-7236, 1971 and Burgus, R. et al., Proc. Of Natl. Acad. Sci. USA), 69, 278-282, 1972] is a super-agonist (super agonist) or agonist (agonist) for the LH-RH receptor. Decrease the release and production of gonadotropins in the pituitary gland and cause decreased responsiveness to gonadotropins in the testis and ovaries, Suteron and suppresses the secretion of estrogen. As a result, it is known to exhibit antitumor activity against such hormone-dependent cancers such as prostate cancer, and has been clinically applied. It is also widely used clinically as a therapeutic agent for endometriosis, uterine fibroids, and precocious puberty. Although there is a report on the combination of a peptide LH-RH (super) agonist and a peptide antagonist, there has been no report on the use of a combination of an LH-RH super agonist or agonist and a non-peptide antagonist. .

  Since these peptidic compounds are super-agonists or agonists, transient aversion (flare phenomenon) with an increase in serum testosterone and estrogen levels due to pituitary-gonadal stimulating action (acute action) immediately after the first administration Is allowed. It takes 2-3 weeks for the peptide superagonist or the agonist to stably show the drug effect, and therefore, prevention and treatment of disease progression and aversion during this period have been problems. Furthermore, in order to enhance the action of peptidic or non-peptidic superagonists or agonists, development of non-peptidic antagonists having LH-RH antagonistic action that can be administered orally is desired.

  The present inventors focused on the fact that thieno [2,3-b] pyridine derivatives and thieno [2,3-d] pyrimidine derivatives having an excellent LH-RH antagonistic action can be administered orally. As a result of various studies, it was considered that the super-agonist or the agonist can be administered while adjusting the drug efficacy by adjusting the administration interval. As a result, the present invention was completed.

The present invention comprises (1) a pharmaceutical comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptide compound having a gonadotropin releasing hormone antagonistic action, and (2) a compound having a gonadotropin releasing hormone action. The pharmaceutical according to (1), which is a peptidic compound, (3) the pharmaceutical according to (2), wherein the peptidic compound is a natural hormone or an analog thereof, and (4) the peptidic compound is represented by 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 Tyr or Phe, R ₃ is Gly or an optionally substituted D-type amino acid residue. , R ₄ represents Leu, Ile or Nle, R ₅ represents 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 ′ represents a group represented by a hydrogen atom, an amino group or an alkyl or ureido optionally substituted with a hydroxyl group)], the pharmaceutical according to item (2), (5) ) The pharmaceutical compound according to item (2), wherein the peptidic compound is a compound selected from leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resilerin; (6) gonadotropin releasing hormone action The compound having (1) The pharmaceutical according to item (1) used as a releasable preparation, (7) the pharmaceutical according to item (6) wherein the sustained-release preparation is a microcapsule preparation, (8) the sustained-release preparation is a nasal preparation or The medicament according to item (6), which is an embedding agent, and (9) a non-peptide compound, which may be substituted, of an allo- or hetero 5- to 7-member ring and an allo- or hetero 5- to 7-member ring The medicament according to item (1), which is a condensed ring compound or a salt thereof containing at least a condensed bicyclic structure, and (10) the condensed ring compound is represented by the general formula:

[Wherein the W ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group, and the Y ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group] (11) The ring according to (9), wherein the W ring is a compound of 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] (12) The W ring is 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, nitrogen atom, oxygen atom or sulfur atom. The medicament according to item (10), wherein (13) Y ring is 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. The pharmaceutical according to item (10), wherein each is a hydrogen atom or an optionally substituted hydrocarbon residue, o represents an integer of 1 to 2], (14) Ring Y is 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, nitrogen atom, oxygen atom or sulfur atom, and R ^11b represents an optionally substituted hydrocarbon residue. Group, o represents an integer of 1 to 2] or a general formula

[Wherein R ^11c and R ^12b may be the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group], (15) the condensed ring compound has the general formula

Wherein each of R ^1e and R ^2e hydrogen atom or a carbon atom, a nitrogen atom, a group via an oxygen atom or a sulfur atom, an R ^3e are homo- optionally substituted or a heterocyclic group, R ^4e Is a group via hydrogen, a 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 A compound represented by the general formula:

[Wherein R ^1f is (1) a hydrogen atom, (2) a group via a carbon atom, or (3) a formula — (CH ₂ ) n—R ^1f ′ (where R ^1f ′ is a group via a carbon atom or An optionally substituted homologous or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, and R ^3f and R ^4f represent Each of which represents a group through a carbon atom], or

^{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 N represents an integer of 0 to 3, which is a group through a carbon atom or an optionally substituted homologous or heterocyclic group. However, R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all hydrogen at the same time. The pharmaceutical according to item (9), which is a compound represented by the formula (16):

[Wherein R ^13a may be substituted by 1 to 5 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 group. R ^15a may be substituted with 1 to 5 groups which may be the same or different, and each of R ^16a is substituted with 1 to 5 hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups or alkylthio groups. R ^17a may be substituted with one or two hydrogen atoms, alkyl groups, halogen atoms or alkoxy groups, and may be the same or different, and each may be esterified. Alternatively, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group or a substituted group that may be amidated Wherein v, t and u may be the same or different and each represents an integer of 0 to 3], (17) a condensed ring compound Is the general formula

[In the formula, R ^13b may be substituted by 1 to 3 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 by 1 to 3 groups, and may be the same or different, and a hydrogen atom or halogen, and R ^16b may be substituted by 1 to 3 groups. Further, they may be the same or different, and hydrogen atom, halogen or C _1-6 alkoxy, R ^17b may be substituted by 1 or 2 and may be the same or different and are esterified or amidated. A carboxy group or a C _1-6 alkylcarbonyl group, v ′, t ′ and u ′ may be the same or different and each represents an integer of 0 to 3]. 9) the medicine according to the item 8) A non-peptidic compound having gonadotropin releasing hormone antagonistic activity is 4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4 -Methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof according to (1), (19) gonadotropin releasing hormone antagonistic activity The non-peptidic compound having 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 according to (1), (20) a non-gonadotropic hormone-releasing hormone antagonistic activity The peptide compound is 5-n-butyryl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4 -The drug according to (1), which is -oxo-thieno [2,3-b] pyridine or a salt thereof, and (21) a non-peptidic compound having a gonadotropin releasing hormone antagonistic activity, 7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or The pharmaceutical according to item (1), which is a salt thereof, and (22) a non-peptidic compound having a gonadotropin releasing hormone antagonistic action is 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N- (Til-N-benzylaminomethyl) -2- (4-isobutyrylaminophenyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine or a salt thereof according to item (1) (23) Non-peptidic compound having gonadotropin releasing hormone antagonistic activity is 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 according to (1), (24) gonadotropin releasing hormone A non-peptidic compound having an antagonistic action is 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 according to (1), (25) gonadotropin releasing hormone antagonistic activity The non-peptidic compound having 3- (N-benzyl-methylaminomethyl) -4,7-dihydro-2- (4-allyloxyphenyl) -5-isobutyryl-7- (2,6-difluorobenzyl)- The drug according to item (1), which is 4-oxothieno [2,3-b] pyridine or a salt thereof, and (26) a non-peptidic compound having gonadotropin releasing hormone antagonistic activity is isopropyl [3- (N Benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-7- (2,6-difluorobenzyl) thieno [2,3-b] pyridy -5-carboxylate] or a salt thereof, the pharmaceutical according to item (1), (27) a non-peptidic compound having gonadotropin releasing hormone antagonistic activity is isopropyl [3- (N-benzyl-N-methyl] Aminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-7- (2,6-difluorobenzyl) -6-methylthieno [2,3-b] pyridine-5-carboxylate] or its The medicament according to item (1), which is a salt, and (28) a non-peptidic compound having an antagonistic action on gonadotropin releasing hormone 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 drug according to item (1), which is a salt thereof, (29) a sex hormone-dependent disease comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptide compound having a gonadotropin releasing hormone antagonistic action (30) A combination of a parenteral preparation of a compound having a gonadotropin releasing hormone action and an oral administration preparation of a non-peptide compound having a gonadotropin releasing hormone antagonistic action (29) (31) Use of a non-peptide compound having a gonadotropin-releasing hormone antagonistic action for reducing flare phenomenon after administration of a compound having a gonadotropin-releasing hormone action, and (32) Gonadostimulation for enhancing the action of compounds with gonadotropin-releasing hormone action It uses for non-peptidic compounds with Rumon releasing hormone antagonizing activity.

  The pharmaceutical composition of the present invention can avoid a transient aversion (flare phenomenon) accompanied by an increase in serum testosterone concentration due to a pituitary-gonad stimulating action (acute action) that occurs immediately after administration of a compound having an action. it can. Moreover, the action is enhanced. Therefore, the pharmaceutical composition of the present invention can be advantageously used as a medicament for the treatment / prevention of sex hormone-dependent diseases.

The compound having an LH-RH action may be a peptidic compound or a non-peptidic compound, and any compound having such an action may be used. Peptide compounds having an LH-RH action are, for example, natural hormones (R ₁ = His, R ₂ = Tyr, R ₃ = Gly, R ₄ = Leu, R ₅ = Gly-NH ₂ in the following (I)) Polypeptide) or analogs thereof, 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 Tyr or Phe, R ₃ is Gly or an optionally substituted D-type amino acid residue. , R ₄ represents Leu, Ile or Nle, R ₅ represents 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 ′ represents (1) a hydrogen atom, (2) an alkyl group optionally substituted with an amino group or a hydroxyl group, or (3) a ureido (—NH—CO—NH ₂ )) or a polypeptide represented by 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, which are optionally substituted (eg, C _1-4 alkyl groups such as methyl and t-butyl, t- C _1-4 alkoxy group such as butoxy, t C _1-4 alkoxy such as butoxycarbonyl - carbonyl group, C _6-10 aryl group such as 2-naphthyl, indol-3-yl, 2-methyl-indolyl, each C _1-4, such as benzyl-imidazol-2-yl alkyl, represented by C _6-10 aryl or C _6-10 aryl-C _1-4 such as an optionally substituted indolyl group or an imidazolyl group in alkyl) which may have 1 to 3 .R ₆ substituents Examples of the substituent in the optionally substituted alkyl group include a hydroxyl group and amino, and examples of the alkyl group in the alkyl group optionally substituted with the amino group or hydroxyl group include a C _1-4 alkyl group. , examples of inter alia C _1-3 alkyl group is preferred .C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutylene The number of substituents is 1 to 3, preferably 1 to 2, and particularly preferably 1. The acid of the peptide (I) (inorganic acid) , A salt with an organic acid), and a metal complex compound can also be used in the same manner as peptide (I).

As the peptidic compound having LH-RH action, preferably, for example, 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 Tyr or Phe, R ₃ ′ is a Gly or D type amino acid residue, R ₄ is Leu, Ile or Nle, R ₅ ′ is Gly-NH—R ₆ ″ (R ₆ ″ is a hydrogen atom or a C _1-3 alkyl group optionally having a hydroxyl group) or NH—R ₆ ″ (R ₆ ″ is as defined above) (U.S. Pat. Nos. 3,835,837, 4,088,209, 3,972,859, British Patent 1,143,833, Proceedings of the National Academy of Science). (See Proceedings of the National Academy of Sciences of the United States of America) 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, such as t- butoxy C _1-4 1 to 2 alkoxy groups, C _1-4 alkoxy-carbonyl groups such as t-butoxycarbonyl, etc.). Examples of the C _1-3 alkyl group in the C _1-3 alkyl group _optionally having a hydroxyl group represented by R ₆ ″ include methyl, ethyl, propyl and isopropyl. The number of substituents (hydroxyl groups) may be 1 to 2, but 1 is particularly preferable. A salt of a peptide (I ′) with an acid (inorganic acid, organic acid) or a metal complex compound may be used in the same manner as the peptide (I). Regarding amino acids, peptides, protecting groups and the like in the polypeptides represented by the formulas (I) and (I ′), when expressed by abbreviations, they shall be based on abbreviations by IUPAC-IUB Commission on Biochemical Nomenclature or conventional abbreviations in the field, In addition, when there are optical isomers with respect to amino acids, L form is shown 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: phenylglycine Pro: proline (PyrG) Serine Thr: Threonine Trp: Tryptophan Tyr: Tyrosine Val: Valine In the present specification, in the above formulas (I) and (I ′), R ₁ = His, R ₂ = Tyr, R ₃ = D-Leu, R The generic name for a polypeptide where ₄ = Leu, R ₅ = NHCH ₂ —CH ₃ is Leuprorelin.

Peptide compounds having LH-RH activity used in the present invention include leuprorelin, R ₁ = His, R ₂ = Tyr, R ₃ = D-Ala, R ₄ = Leu, R in the above formula (I). ₅ = polypeptide, NHCH ₂ —CH ₃ , Gonadrelin

(German Patent No. 2213737),

  Buserelin

(U.S. Patent No. 4,024,248, German Patent No. 2,438,352, JP-A-51-41359),

  Triptorelin

(U.S. Pat. No. 4,010,125, JP-A 52-31073),

  Goserelin

(U.S. Pat. No. 4,100,204, JP-A-52-136172),

  Nafarelin

(U.S. Pat. No. 4,234,571, JP-A 55-164663, JP-A 63-264498, and JP-A 64-25794),

  Histrelin,

  Deslorelin

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

  Meterelin

(PCT WO9118016),

  Recirelin

(Belgium JP-A No. 877455, JP-A No. 59-59654) and the like. Leuprorelin is preferred as a peptidic compound having an LH-RH action.

In the formulas shown in the above [Chemical Formula 13] to [Chemical Formula 20], the amino acid corresponding to R ₃ in the general formula (I) is a D-form. Examples of non-peptidic compounds include morphinan derivatives (Japanese Patent Laid-Open No. 61-271275).

  The compound having an LH-RH antagonistic activity used in the present invention contains at least a condensed bicyclic structure of an allo- or hetero 5- to 7-membered ring and an allo- or hetero 5- to 7-membered ring which may be substituted. A condensed ring compound or a salt thereof is used. Specifically, for example, in the above condensed bicyclic structure, the W ring group represents an optionally substituted homo- or hetero 5- to 7-membered ring group.

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

Examples of the substituent that the homocycle may have include a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom in R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b described later. Groups such as (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, etc. Among them, C _1-6 alkyl is preferable, and about 1 to 3 may be substituted with halogen.), (2) C _3-10 cyclo alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), (3) C _2-10 alkenyl (e.g., vinyl, allyl, isopropenyl Cycloalkenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc.), (4) C _2-10 alkynyl (e.g., 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) C _{1- 5} alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (16) sulfo, (17) halogen, (18) C _1-6 alkoxy (eg, methoxy, ethoxy, butoxy, etc.), (19) C _{6- 10} aryloxy (eg, Fe Noxy, etc.), (20) C _1-6 acyloxy (eg, C _1-6 alkanoyloxy such as acetoxy, propionyloxy, etc.), (21) C _1-6 alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropyl) Thio, 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 (eg, methylsulfonyl, ethylsulfonyl, etc.), (26) C _6-10 arylsulfonyl (eg, phenylsulfonyl, etc.) , (27) amino, (28) C _1-6 acylamino (e.g., acetylamino, C _1-6 alkanoylamino, such as propionylamino, etc.), (29) mono- - or di -C _1-4 alkylamine Roh (e.g., methylamino, ethylamino, n- propylamino, isopropylamino, n- butylamino, dimethylamino, diethylamino, etc.), (30) C _3-8 cycloalkylamino (e.g., 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 (e.g., acetyloxy, propionyloxy, etc.), (34) C _6-10 aryl - carbonyl (e.g., benzoyl, etc.), (35) an oxygen in addition to carbon atoms, sulfur, heteroatoms selected from nitrogen, etc. 5- to 6-membered heterocyclic group containing 1 to 4 groups (eg, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, -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-pyrididyl, quinolyl, isoquinolyl, indolyl, etc. ) And the like. The number of substitutions is 1 to 6, preferably 1 to 3, more preferably 1 or 2. 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 atoms, sulfur atoms, or oxygen atoms. The W ring group is preferably a homologous or hetero 5- or 6-membered ring group. Preferable specific examples of the W ring group include, for example, the formula

The cyclic group represented by these is mentioned. Among these the formula

The cyclic group represented by these is preferable. Further formula

Is particularly preferable.

  The most preferred specific examples of the optionally substituted W ring group include, for example, 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], or a 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] A cyclic group is mentioned.

  Examples of the allotrope or hetero 5- to 7-membered ring group represented by the Y ring group in the condensed bicyclic structure include 5 to 7 having one or more (preferably 1 to 2) nitrogen, sulfur, or oxygen atoms. A membered heterocyclic group. Examples of the same or hetero 5- or 7-membered ring group in the Y ring group include those similar to the W ring group. Particularly preferred is an allo- or hetero 5- to 7-membered cyclic group substituted with oxo. The Y ring group is preferably an allocyclic or hetero 5- to 6-membered ring group, and more preferably an allo- or hetero 6-membered ring group. Preferable specific examples of the Y ring group include, for example, the formula

The cyclic group represented by these is mentioned. Among these the formula

The cyclic group represented by these is preferable. Further formula

Is particularly preferable.

  The most preferred specific examples of the optionally substituted Y ring group include, for example, 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 an optionally substituted hydrocarbon group. Wherein o represents an integer of 1 to 2] or a general formula

[Wherein R ^11c and R ^12b may be the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group].

Examples of the group having a carbon atom in R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b include, for example, (1) a hydrocarbon group, (2 ) An acyl group, (3) a carbamoyl group, (4) a heterocyclic group having a bond on a carbon atom, (5) a carboxyl group that may be esterified or amidated, (6) a cyano group, (7) amidino group.

The hydrocarbon group represented by ^{R 1a, R 2a, R 3a} , R 4a, R 5a, R 6a, a hydrocarbon group and R ^11b in the group via a carbon atom of ^{R 4b, R 12b, R 11c} , C 1- _Twenty hydrocarbon groups are preferred. Examples of the C _1-20 hydrocarbon group include, for example, (1) C _1-15 alkyl group (for example, 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 which C _1-10 is preferable, and a C _1-6 alkyl group is particularly preferable. (2) C _3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., among which C _3-6 cycloalkyl group is preferable) or C _7-20 bicycloalkyl groups (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, etc.), (3) C _2-10 alkenyl groups (for example Vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc., among which C _2-6 alkenyl groups are preferred. (4) C _2-10 alkynyl group (examples include ethynyl, 2-propynyl, isopropynyl, butynyl, t-butynyl, 3-hexynyl, etc., among which C _2-6 alkynyl is preferred). as 5) C _3-10 cycloalkenyl (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, and the like, among which C _3-6 cycloalkenyl group is preferable.), (6) C _6-14 aryl group (e.g. And, phenyl, 1- or 2-naphthyl, anthryl, phenanthryl, acenaphthyl, and the like. Among them, phenyl, naphthyl are preferred.) As (7) C _7-20 aralkyl (e.g., benzyl, phenethyl, phenylpropyl And phenyl-C _1-6 alkyl such as benzyl, benzhydryl, trityl and the like, and phenyl-C _1-6 alkyl groups such as benzyl and phenethyl are particularly preferred.

Examples of the substituent of the hydrocarbon group include (1) halogen, (2) nitro, (3) nitroso, (4) cyano, (5) substituent {eg, (i) C _1-6 alkyl C _1-6 alkyl is a hydroxyl group, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkoxy, C _1-3 alkylthio, hydroxy-C _1-3 alkoxy, C _1-6 alkyl-carbonyl, carboxy , Carbamoyl, C _1-6 alkyl-carbamoyl, nitrogen-containing 5- to 8-membered heterocyclic group, C _6-10 aryl, C _7-13 aralkyl, halogen or nitro as a substituent. (Ii) C _1-4 acyl, (iii) C _7-20 aralkyl (the C _7-20 aralkyl group is halogen, C _1-3 alkoxy, C _1-6 alkyl, C _6-14 aryl) , C _7-13 aralkyl, nitro may have a 1 to 3 or so substituents), (iv) C _6-14 aryl (said C _6-14 aryl C _1-6 alkyl, C _6-14 aryl, C _7-13 aralkyl, C _1-3 alkoxy -C _1-6 alkoxy, may have a halogen or nitro as a 1-3 degree 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.)} (O) _f -R ³¹ {wherein, f is an integer of 0 to 2, R ³¹ is a hydrogen atom or a substituent (e.g., halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano -C _{6- 14} aryl, halogeno C _6-14 aryl, etc.) which may have about 1 to 3 hydrocarbon groups or amino optionally substituted with mono- or di-C _1-4 alkyl, The hydrogen group is preferably a C _1-20 alkyl group, particularly a C _1-6 alkyl, C _6-14 aryl, or C _7-20 aralkyl. )}, (7) an optionally substituted amino group [eg, —NR ³² R ³³ , wherein R ³² and R ³³ may be the same or different, and (i) hydrogen Substituted with an atom, (ii) C _1-6 alkyl, (iii) C _1-6 acyl, (iv) mono- or di-C _1-4 alkyl, C _1-4 alkylthio or C _6-14 aryl Carbamoyl, (v) C _6-14 aryl, (vi) C _1-4 alkylthio, (vii) C _1-4 alkyl-sulfonyl, (viii) C _1-4 alkyl-sulfinyl, or (ix) below An amino group represented by a cyclic amino group or a nitrogen-containing heterocyclic group to be described]], (8) Formula —CO—R ³⁴ {wherein R ³⁴ is (i) a hydrogen atom, (ii) hydroxy, (iii) C _1-10 alkyl, (iv) C _1-6 alkoxy (this alkoxy, halogen, nitro, optionally having 1 to 3 or so substituents, such as C _6-14 aryl C _{6- 14} May be substituted by a reel), (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 as defined in item (7) above, (xi) Formula —O—NR ³² R ³³ (wherein R ³² and R ³³ is the same as defined above)), an optionally substituted aminooxy group, (xii) a 5- to 8-membered heterocyclic group or (xiii) a 5- to 8-membered heterocyclic-oxy group. }, (9) a 3- to 9-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom {the heterocyclic group is 1 to 3 (i) halogen atom, (ii) C _1-4 alkyl, (iii) C _1-3 alkoxy, (iv) C _1-4 alkylthio, (v) phenoxy optionally substituted with 1 to 3 halogens May be substituted. }, (10) sulfo, (11) C _6-14 aryl (eg, phenyl, naphthyl, anthryl, acenaphthyl, etc.) 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 alkoxy, (e) halogen, (f) cyano, etc. 1 to 4 substituents), (12) C _3-7 cycloalkyl, (13) C _1-6 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, Propylenedioxy, 2,2-dimethylenedioxy, etc.), (14) oxo, (15) thioxo, (16) C _1-15 alkyl, (17) C _2-10 alkynyl, (18) C _3-10 cyclo alkyl group, (19) C _2-10 alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-Buteni , Butadienyl, hexatrienyl, or the like. Among them, C _2-6 alkenyl group are preferable.), (20) C _5-7 cycloalkenyl, (21) C _7-20 aralkyl, (22) amidino, (23) azide , (24) -B (OH) ₂ , (25) Epoxy (—O—), (26) Phosphono, (27) Formula —A—R ³⁵ (wherein A is an intervening group and R ³⁵ is C _{1 -10} alkyl group), (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 an integer of 0 to 3, R ³⁸ is hydrogen or C _1-6 alkyl (e.g., 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) Represents the same as R ^38. ), C _3-7 cycloalkanediyl (eg, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene), C _6-14 allylene (eg, phenylene, Naphthylene), multiple A group represented by a cyclic group (specific examples will be described later in a))], a group represented by —S (O) m ″ — (m ″ represents an integer of 0 to 2), — A 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), etc. Is mentioned.

The substituent on the hydrocarbon group having the above-described substituent may further have 1 to 3 substituents. Examples of the substituent which may be further included include (1) hydroxyl, (2) amino, (3) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino). , Dimethylamino, diethylamino, etc.), (4) C _1-4 alkoxy, (5) C _1-6 alkyl optionally substituted with 1 to 3 halogens, (6) C _6-14 aryl (the aryl May be substituted with 1 to 3 halogens or cyano.), (7) C _7-13 aralkyl, (8) C _1-6 alkoxy-carbonyl, (9) 5-8 membered heterocyclic group (10) C _1-10 acyl, (11) carboxy, (12) C _1-6 alkoxy-carbonyl, (13) C _6-14 aryl-carbonyl, (14) C _1-6 alkylenedioxy, (15 ) Sulfamoyl, (16) carbamoyl, (17) C _1-4 alkylthio, (18) C _1-4 alkylsulfinyl, (19) C _1-4 alkylsulfonyl, (20) Halogen, (21) nitro, (22) mercapto and (23) cyano. The hydrocarbon group is cycloalkyl, cycloalkenyl, alkynyl, if aryl or aralkyl group may have one to three C _1-6 alkyl as a substituent, the C _1-6 alkyl, Further, it may be substituted with 1 to 3 hydroxy, oxo, C _1-3 alkoxy, C _1-3 acyl, C _1-3 alkylthio, halogen, carbamoyl and the like. As the substituted C _1-6 alkyl that may be present when the hydrocarbon group is a cycloalkyl, cycloalkenyl, alkynyl, aryl or aralkyl group, formyl (methyl substituted by oxo), carboxyl ( Methyl substituted with oxo and hydroxy), C _1-6 alkoxy-carbonyl (methyl substituted with oxo and alkoxy) (eg, C _1-6 such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.) Alkoxy-carbonyl), hydroxy-C _1-6 alkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl, etc.), C _1-3 alkoxy-C _1-6 alkyl (eg, methoxymethyl, ethoxymethyl, ethoxy) Butyl, propoxymethyl, propoxyhexyl Etc.), and the like. 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 that the hydrocarbon group substituents may further have is preferably 1 to 3, more preferably 1 to 2.

Among the groups through the carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b , the acyl group in the optionally substituted acyl group includes hydrocarbon-carbonyl or hydrocarbon Oxy-carbonyl, among them, for example, an acyl group derived from a C _1-24 aliphatic carboxylic acid. Examples of the acyl group include formyl, C _1-10 alkyl-carbonyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, etc.), C _1-13 alkoxy-carbonyl, C _6-14 aryl-carbonyl (eg, benzoyl, naphthylcarbonyl, anthracenylcarbonyl, etc.), C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _7-20 aralkyl-carbonyl (eg, benzylcarbonyl) Etc.), C _7-19 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.), C _3-10 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C _{2− 6} alkenyl Le - carbonyl (e.g., vinyl carbonyl, butenylcarbonyl, butadienyl carbonyl, hexatrienyl carbonyl, etc.) and the like. Of these, C _1-10 alkyl-carbonyl or C _1-13 alkoxy-carbonyl is preferred. Examples of the substituent of the acyl group include the same substituents as the above-described hydrocarbon group. The number of substituents is about 1 to 3. Among the acyl groups, the C _1-13 alkoxy in C _1-13 alkoxy-carbonyl may be linear or branched. As the linear alkoxy, a C _1-9 alkoxy group is preferable, and examples thereof include methoxy, ethoxy, propoxy, butoxy, pentoxy, neopentyloxy, hexyloxy, octyloxy and the like, and 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-ylo Shi), and the like. As the branched alkoxy group, a C _3-7 branched alkoxy group is particularly preferable. Of the groups through the carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b , examples of the optionally substituted carbamoyl group include the above-described substituted groups. Examples thereof include a C _1-20 hydrocarbon group or a carbamoyl group which may be substituted with an optionally substituted cyclic amino. The C _1-20 hydrocarbon group is the same as that defined for the hydrocarbon group among the groups having the carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b . Things. Examples of the group which may be substituted on the carbamoyl group include the same groups as those described above which may be substituted on the hydrocarbon group. Preferable examples of the optionally substituted carbamoyl include, for example, a mono- or di-C _1-15 alkylcarbamoyl group, and examples thereof include methylcarbamoyl, ethylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, and methylethylcarbamoyl. Etc.

Among the groups through the carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b , the heterocyclic group in the heterocyclic group having a bond to an optionally substituted carbon atom A 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a carbon atom, and a bicyclic or tricyclic condensed heterocyclic group fused thereto And a heterocyclic group having a bond at a carbon atom constituting the ring. Specific examples of the heterocyclic group in the heterocyclic group having a bond to the optionally substituted carbon atom include (1) 2- or 3-thienyl, 2- or 3-furyl, 2- or 3- Pyrrolyl, 3- or 4-pyrrolinyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2- or 3-pyrrolidinyl, 2-, 4 -Or 5-imidazolyl, 2-imidazolinyl, 2-imidazolidinyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 2 -, 5- or 6- (1,3,4-oxadiazolyl), 3- or 4-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- 5-membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as (1,2,4-triazolyl) and 5- (1H- or 2H-tetrazolyl) 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 6-membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as 3- or 6-triazinyl, 3- or 4-pyridazinyl, 2- or 3-pyrazinyl Group: (3) benzofuranyl, isobenzofuranyl, benzothiazolyl, 1,2-benzoisothiazolyl, benzo [b] thienyl, benzoxazolyl, 1H-benzotriazolyl, 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, quinolidinyl, 1,8 -Naphthyridinyl, purinyl, pteridinyl, gibe Zofuranyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenanthridinyl, chromanyl, benzooxazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, thianthenyl, 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, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc. Other than the above carbon atoms, bicyclic or cyclic containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen 3 and a group having a bond to a carbon atom of the ring of condensed heterocyclic group. The heterocyclic group may be a hydrogen adduct.

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, 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, et Toxicarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), (16) carbamoyl group, (17) N-mono-C _1-4 alkyl-carbamoyl ( Examples, 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-aziridinylcarbonyl, 1-azetidinyl) Carbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, Morpholinocarbonyl, etc.), (20) halogen, (21) mono -, di- - or tri - halogeno -C _1-4 alkyl (e.g., 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) 1 to 3 hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom and one nitrogen atom 3 to 6-membered cyclic amino groups (eg aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazole) Lysinyl, piperidino, morpholino, dihydropyridyl, N- methylpiperazinyl, N- ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (e.g., formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide , Isobutyrylamide, etc.), (29) benzamide, (30) carbamoylamino, (31) N—C _1-4 alkyl-carbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N—) Propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), (32) N, N-di-C _1-4 alkyl-carbamoylamino (eg, N, N-dimethylcarbamoylamino, N, N-) Diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutyl Rubamoiruamino etc.), (33) C _1-3 alkylenedioxy (e.g., 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 (example) 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 ( Example: 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 _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), (51) C _6-14 arylsulfonyl (eg, phenylsulfonyl) and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2. Of the groups through the carbon atoms of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b , the optionally esterified carboxyl group is 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-described C _1-20 hydrocarbon group and its substituent. As the heterocyclic group and its substituent, those described later in a) are used. The carboxyl group which may be amidated is represented by 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 the .R ²² and R ²³ represents a hydrogen atom or a hydrocarbon group may form a 5- to 8-membered cyclic amino group together with the adjacent nitrogen atom, further, the R ²² and R ^23, the adjacent nitrogen Or a nitrogen-containing heterocyclic group formed with an atom.), And the hydrocarbon group, heterocyclic group, cyclic amino group and nitrogen-containing heterocyclic group may each be substituted. . Examples of the hydrocarbon group for R ²² and R ²³ include the C _1-20 hydrocarbon groups described above. As the heterocyclic group, those described in a) below are used. As the group via a sulfur atom, those described later are used. The carboxyl group which may be amidated may be substituted with 1 to 3 groups similar to the groups which may be substituted with the above-described hydrocarbon group.

In the above formula, examples of the group via a nitrogen atom include (1) nitro group, (2) formula —NR ²⁴ R ²⁵ [wherein R ²⁴ is hydrogen, hydrocarbon group, hydrocarbon-oxy group, acyl group, A hydroxyl group, a heterocyclic group, a condensed 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 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. The hydrocarbon group, hydrocarbon-oxy group, acyl group, hydroxyl group, heterocyclic group and cyclic amino group may each have a substituent. Examples of the hydrocarbon group in R ²⁴ , R ²⁵ , R ²⁶ or the hydrocarbon group in the hydrocarbon-oxy group, and the acyl group in R ²⁴ , R ²⁵ include the aforementioned R ^1a , R ^2a , R ^3a , R ^4a , R ^5a. , R ^6a and R ^4b can be exemplified. Examples of the heterocyclic group, the condensed bicyclic homocyclic group, the cyclic amino group, and the nitrogen-containing heterocyclic group include those described below for a), d), b), and c). The group through the nitrogen atom may be substituted with 1 to 3 groups similar to the group which may be substituted with the above-described hydrocarbon group. In the above formula, examples of the group via an oxygen atom include a group represented by —O—R ²⁷ (wherein R ²⁷ represents a hydrogen atom, a hydrocarbon group, an acyl group, or a heterocyclic group). These hydrocarbon group, acyl group and heterocyclic group may each have a substituent. Examples of the hydrocarbon group and acyl group for R ²⁷ or their substituents are the same as those defined above for R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , and R ^4b . be able to. Examples of the heterocyclic group and the substituent thereof include those described later in a). In the above formula, as the group via a sulfur atom, 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). The hydrocarbon group and the heterocyclic group each may have a substituent. Examples of the hydrocarbon group and its substituent in R ²⁸ are the same as those defined for R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^{4b described} above. Examples of the heterocyclic group and the substituent thereof include those described later in a).

In this specification,
a) As the heterocyclic group, a heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom, and a bicyclic or tricyclic condensed heterocyclic ring condensed thereto Groups and the like. Of these, 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, furazanyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4 A 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as triazolyl, triazolidinyl, 1H- or 2H-tetrazolyl; (2) pyridyl, pyrimidinyl, Thiomorpholinyl, morpholinyl, triazinyl, piperidinyl In addition to carbon atoms such as piperidyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, pyridazinyl, pyrazinyl and the like, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc. Examples thereof include a 6-membered heterocyclic group containing 1 to 4 groups. (3) Examples of the bicyclic or tricyclic fused heterocyclic group include benzofuranyl, isobenzofuranyl, benzothiazolyl, 1,2-benzisothiazolyl, benzo [b] thienyl, benzooxazolyl, 1H-benzotria 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, phenanthridinyl, chromanyl, ben Oxazinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, thiantenyl, phenanthridinyl, phenanthrolinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] Bicyclic or tricyclic containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl Examples thereof include fused heterocyclic groups, and (4) 3-membered rings such as oxiranyl and aziridinyl and (5) 4-membered rings such as azetidinyl. The heterocycle may be a hydrogen adduct. Examples of the group which may be substituted on the heterocyclic group include (1) C _1-6 alkyl, (2) C _2-6 alkenyl, (3) C _2-6 alkynyl, and (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 (e.g., methoxycarbonyl, ethoxycarbonyl, n- flop Po butoxycarbonyl, iso- propoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, etc.), (16) carbamoyl group, (17) N-mono--C _1-4 alkyl - carbamoyl (e.g., N- methyl Carbamoyl, 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-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrole) Dinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.) (20) halogen, (21) mono -, di- - or tri - halogeno -C _1-4 alkyl (e.g., chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), (22) oxo group, (23 ) Amidino, (24) imino group, (25) amino, (26) mono- or diC _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, Dipropylamino, diisopropylamino, dibutylamino, etc.) (27) may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom and one nitrogen atom 3- to 6-membered cyclic amino groups (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino Morpholino, dihydropyridyl, N- methylpiperazinyl, N- ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (e.g., formamide, acetamide, propionylamide, butyrylamide, isobutyryl amides), ( 29) benzamide, (30) carbamoylamino, (31) N—C _1-4 alkyl-carbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino) , N-butylcarbamoylamino, etc.), (32) N, N-di-C _1-4 alkyl-carbamoylamino (eg, N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-di) propylcarbamoyl amino, N, N-dibutyl carbamoyl amino etc.), (33) C _1-3 Arukirenjio Shi (e.g., 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-ethylsulfa) Moyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (45) diC _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 (e.g., methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (49) phenylsulfinyl, (50) C _1-6 alkylsulfonyl (e.g., methyl Sulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), (51) C _6-14 arylsulfonyl (eg, phenylsulfonyl) and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

b) The above cyclic amino group is preferably a 3- to 8-membered ring, for example, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3- Triazinyl, 1,2,3-triazolidinyl, 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, azepinyl, hexamethyleneamino, oxazolidino, morpholino, thiazolidino, phthalimide or thiomorpholino It is done. Among them, those having 5 to 6 members are preferable, and for example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferable.
c) The nitrogen-containing heterocyclic group in the above definition is preferably a 5- to 7-membered group or a bicyclic condensed ring formed with it, such as pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, Imidazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyrimidinyl, pyridazinyl, oxadiazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,2,3-triazinyl, 1,2,3-triazinyl Examples include piperidinyl, piperazinyl, hexamethyleneaminyl, oxazolidinyl, thiazolidinyl, indolyl, indazolyl, purinyl, quinolyl and the like. These may be hydrogenated. Especially, a 5-6 membered heterocyclic group is preferable. Of the 5- to 6-membered heterocyclic groups, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl are particularly preferable. The cyclic amino group and the nitrogen-containing heterocyclic group may have 1 to 3 substituents, such as 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 _1-6 alkyl, with C _1-3 alkyl being particularly preferred.
d) Examples of the bicyclic homocyclic group include indanyl, indenyl and the like.

e) The halogen in the definition of the above group includes fluorine, chlorine, bromine and iodine.
f) Examples of C _1-6 alkyl in the above group definition include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. Is mentioned. Examples of C _1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. Examples of C _1-3 alkyl include methyl, ethyl, n-propyl, and 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 can be mentioned. Examples of C _2-6 alkenyl include 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 group include ethynyl, 1-propynyl, 2-propynyl, propargyl, 3-hexynyl and the like. Examples of C _2-6 alkynyl and C _2-4 alkynyl in the definition of the above group include ethynyl, 1-propynyl, 2-propynyl and the like.
i) Examples of C _3-10 cycloalkyl in the definition of the above group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Examples of C _3-8 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of C _3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of C _3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
j) Examples of the C _3-7 cycloalkenyl in the above group definition include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like, and examples of the C _5-7 cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. Can be mentioned.

k) Examples of C _6-14 aryl in the above group definition include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl. Examples of C _6-10 aryl include phenyl and naphthyl. Of these, phenyl is preferable.
l) Examples of C _7-20 aralkyl or C _7-19 aralkyl in the definition of the above group include phenyl-C _1-6 alkyl such as benzyl and phenethyl, benzhydryl and trityl. Examples of C _7-15 aralkyl and C _7-13 include phenyl-C _1-6 alkyl such as benzyl and phenethyl, and benzhydryl. Examples of C _7-11 aralkyl and C _7-10 aralkyl include phenyl-C _1-5 alkyl such as benzyl, α-methylbenzyl, phenethyl and phenyl-C _1-4 alkyl.
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) Examples of C _1-6 acyl in the above group definition include, for example, the formula —CO—R ³⁶ (wherein R ³⁶ is a hydrogen atom, or C _1-5 alkyl (eg, methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec- butyl, t- butyl, and a C _1-6 alkanoyl represented by showing a pentyl)). Examples of the C _1-4 acyl in the above group definition include, 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.) The group represented by these is mentioned.
o) Examples of C _1-8 alkanoyl in the definition of the above group include formyl, acetyl, propionyl, butyryl, isobryl, valeryl, isovaleryl, octanoyl and the like.

  Examples of the fused ring compound include those represented by the general formula (X)

Wherein each of R ^1e and R ^2e hydrogen atom or a carbon atom, a nitrogen atom, a group via an oxygen atom or a sulfur atom, an R ^3e are homo- optionally substituted or a heterocyclic group, R ^4e Is a group through hydrogen, carbon atom, nitrogen atom, oxygen atom or sulfur atom or an optionally substituted heterocyclic group, R ^5e is a group through hydrogen atom or carbon atom, and n is an integer of 0-3. Each is shown. A 4-oxothieno [2,3-b] pyridine derivative (X) represented by the general formula (XX)

[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 homologous or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, and R ^3f and R ^4f represent Each represents a group via a carbon atom. 2,4 (1H, 3H) -dioxothieno [2,3-d] pyrimidine derivative (XX) represented by the general formula (XXX)

^{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 N represents an integer of 0 to 3, which is a group through a carbon atom or an optionally substituted homologous or heterocyclic group. However, R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all hydrogen at the same time. ] The quinoline derivative (XXX) represented by these is preferable. Examples of the group through the carbon atom, nitrogen atom, oxygen atom or sulfur atom in the above formulas (X), (XX) and (XXX), the optionally substituted heterocyclic group or homocyclic group are those described above. Is mentioned.

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

[Wherein, R ¹ and R ² are each a hydrogen atom or a group via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, R ³ is an optionally substituted allotrope or heterocyclic group, R ⁴ Is lower alkyl substituted with (1) hydrogen, (2) formyl group, (3) cyano group, (4) group via sulfur atom, optionally substituted hydroxyl group or optionally substituted hydrocarbon group A group, (5) a carbonyl group substituted with an optionally substituted hydrocarbon residue, or (6) a carboxyl group optionally esterified or amidated, and R ⁵ represents a group via hydrogen or a carbon atom. , N represents an integer of 0 to 3] is preferred. R ¹ , R ² , R ³ and R ⁵ have the same meaning 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, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _3-7 cycloalkylthio, C _6-14 , which may be substituted, respectively. Arylthio, C _7-11 aralkylthio, heterocyclic thio group and the like can be mentioned. The may be respectively substituted, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _3-7 cycloalkylthio, C _6-14 arylthio, C _7-11 aralkylthio, C in the heterocyclic thio group _{1 6} alkyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-11 aralkyl and heterocyclic groups have the same meanings as f), i), k) and a) above. The group which may be substituted with these has the same meaning as the substituent in the group through the nitrogen atom.

Examples of the esterified carboxyl group represented by R ⁴ include C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyloxycarbonyl, C _6-14 aryloxycarbonyl, C _7-11 aralkyloxycarbonyl. Oxycarbonyl substituted with a heterocyclic group, and the like. These C _1-6 alkyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-11 aralkyl, and the heterocyclic group are the above-mentioned f), It has the same meaning as i), k), 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, hexyl and the like. It is done. Examples of the hydrocarbon group which may be substituted in the lower alkyl group substituted with an optionally substituted hydrocarbon group include the same as those described above.

Examples of the substituent in the optionally substituted hydroxyl group include (1) halogen (eg, chlorine, bromine, fluorine, etc.), C _6-10 aryl (eg, phenyl, naphthyl etc.), C _7-12 aralkyl. C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n) optionally having 1 to 4 substituents selected from (eg, benzyl, phenylethyl, etc.) and nitro etc. -Butyl, tert-butyl, etc.); (2) halogen (eg, chlorine, bromine, fluorine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), C _6-10 aryl (eg, _Optionally having 1 to 4 substituents selected from phenyl, naphthyl, etc., C _7-12 aralkyl (eg, phenyl-C _1-6 alkyl such as benzyl, phenylethyl, etc.) and nitro. _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 _1-6 alkyl such as benzyl and phenylethyl) and C _7-12 aralkyl _optionally having 1 to 4 substituents selected from nitro and the like (eg, benzyl, phenylethyl) Phenyl-C _1-6 alkyl such as naphthyl-C _1-2 alkyl such as naphthylmethyl); (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.), nitro, etc. 1 to 3 substitutions chosen Which may have a C _1-6 alkyl - carbonyl (e.g., acetyl, propionyl, etc.); (5) halogen (e.g., chlorine, bromine, fluorine, etc.), C _1-6 alkyl (e.g., 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 nitro etc. C _6-10 aryloxy-carbonyl (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.) _optionally having 4 substituents; (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 _1-, such as benzyl, phenylethyl, etc.) ₆ alkyl etc.) and D C _6-10 aryl-carbonyl (eg, benzoyl, naphthylcarbonyl, etc.) _optionally having 1 to 4 substituents selected from Toro, 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 (eg, phenyl-C such as benzyl, phenylethyl, etc.) _1-6 alkyl, etc.) and C _7-12 aralkyl-carbonyl (eg, benzylcarbonyl, phenethylcarbonyl, etc.) optionally having 1 to 4 substituents selected from nitro, 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, benzyl) , Phenylethyl, etc. Eniru -C _1-6 alkyl, etc.), and one to four may have a substituent pyranyl or furanyl nitro or the like, tri (C _1-4 alkyl) silyl (eg, trimethylsilyl, triethylsilyl, etc. ) Etc. are used. The group via the sulfur atom has the same meaning as defined for R ^1a , R ^2a , R ^3a , R ^4a , R ^5a or R ^6a .

Examples of the hydrocarbon residue in the carbonyl group substituted with the optionally substituted hydrocarbon residue represented by R ⁴ include saturated or unsaturated hydrocarbon residues having up to 25 carbon atoms. Preferred specific examples include alkyl (eg, C _1-8 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, etc.), cycloalkyl ( Examples, C _3-6 cycloalkyl such as cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, etc.), alkoxyalkyl (eg, C _1-3 alkoxy C _1-6 alkyl such as methoxymethyl, ethoxymethyl, ethoxybutyl, propoxyhexyl), Alkenyl (eg, C _2-6 alkenyl such as vinyl, butenyl, butadienyl, hexatrienyl, etc.), aryl (eg, C _6-14 aryl such as phenyl, naphthyl, anthracenyl, etc.), aralkyl (eg, phenyl-C such as benzyl) _1-6 alkyl, benzhydryl, trityl, etc. C _7-20 Aralkyl) and the like. The substituent has the same meaning as the substituent in the group via the carbon atom.

R ¹ and R ^2, on the other hand (preferably R ¹⁾ is (1) the general formula _{^{R 9 - (CH 2) m}} -
[Wherein R ⁹ represents halogen, hydroxy, cyano, an optionally substituted heterocyclic group, or an optionally substituted group via a nitrogen atom, and m represents an integer of 0 to 3.] Or (2) an optionally substituted C _6-14 aryl group, the other (preferably R ² ) is represented by 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 carbonyl group or a halogen, and A is an intervening group]. The halogen represented by R ⁹ has the same meaning as in the above e). The heterocyclic group which may be substituted has the same meaning as in the above a). The group through the optionally substituted nitrogen atom has the same meaning as described above. The group through the optionally substituted nitrogen atom is preferably a mono- or di-substituted amino group. (1) (i) sulfamoyl, (ii) C _1-6 alkoxy, (iii) C _1-6 alkylthio, (iv) halogen, (v) nitro, (vi) 1 ~ 3 optionally substituted C _6-14 aryl, (vii) 1 to 3 optionally substituted C _1-6 alkyl, (viii) hydroxy, or (ix) C _1-6 alkoxy -C _7-11 aralkyl _optionally substituted with 1 to 3 carbonyl, (2) C _6-14 aryl, (3) (i) a heterocyclic group optionally substituted with C _1-6 alkyl, (ii) amino, (iii) hydroxy, (iv) oxo, (v) C _1-6 alkoxy, (vi) carbamoyl optionally substituted by 1-2 with C _1-6 alkyl or C _6-14 aryl Or (vii) C _1-6 alkyl optionally substituted with 1 to 3 C _6-14 aryl optionally substituted with nitro, (4) C _1-6 alkyl-carbonyl, (5) C _6-14 Ally In an optionally substituted C _2-10 alkenyl, or (6) a heterocyclic group are preferred. Particularly preferred is a group represented by 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 group). 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 The C _1-6 alkyl group in the group has the same meaning as the above f), the C _7-11 aralkyl group in the C _7-11 aralkyl-carbonyl group has the above 1), and the halogen has the same meaning as the above e). 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 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 _2-10 alkenyl optionally substituted by 1 to 3 C _1-6 alkyl-carbonyl, (ii) hydroxy in 1-3 optionally substituted C _3-7 cycloalkyl, (iii) oxo, hydroxy or C _1-6 alkyl - 1-3 optionally substituted by C _1-6 alkyl carbonyl, ( iv) halogen or C _1-6 alkoxy with 1-3 optionally substituted by C _1-6 alkyl - carbonyl, (v) Hol Le, (vi) (a) C 1-6 alkyl, (b) C _1-6 alkylthio, (c) C _6-14 aryl or (d) optionally C ₁ optionally substituted with 1-3 halogens 1-2 optionally substituted carbamoyl _-6 alkoxy, (vii) 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 with 1-2 by C _1-6 alkoxy, (8) hydroxy, (9) optionally 1-3 substituted with nitro 1-3 substituted with _1-6 alkyloxy-carbonyl, (10) C _7-11 aralkyl, (11) C _6-14 aryl, hydroxy, C _1-6 alkoxy, or C _1-6 alkyl good C _2-10 alkenyl, (12) cyclic amino, (13) C _1-6 alkyl with 1-3 substituents which may be C _2-10 alkenyloxy or (14), C _2-10 alkenyl 1-3 C _1-6 alkyl optionally substituted preferably with Le. The number of substituents 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 or (2) amino optionally substituted by 1 to 3 by C _7-11 aralkyl. preferable. Examples of the intervening group represented by A include those described above, and a chemical bond and a methylene group are particularly preferable.

R ³ is a general formula

[Wherein R ⁷ is a hydrogen, halogen, or a group via a carbon, nitrogen, oxygen or sulfur atom, and R ⁸ is a hydrogen, halogen, nitro, cyano, or a group via a carbon, oxygen, nitrogen or sulfur atom. Is a group represented by the following formula: The group via an optionally substituted carbon, nitrogen, oxygen or sulfur atom represented by R ⁷ 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 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 that 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 ( Examples, 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 (e.g., methyl amino, ethylamino, n- propylamino, isopropyl Amino, n- butylamino, dimethylamino, diethylamino, etc.), C _1-4 alkanoyl (eg, formyl, acetyl, propionyl, etc.),; (a) halogen (e.g., fluorine, chlorine, bromine, iodine), (b ) _Optionally having 1 to 4 substituents selected from C _1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.), 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 -Pi Rimijiru, 3- or 4-Piridanijiru, quinolyl, isoquinolyl, oxygen in addition to carbon atoms of the indolyl, and the like, sulfur,, 1 to heteroatom selected from nitrogen, etc. 4 containing 5 or 6 membered heterocyclic group, C _1-6 And haloalkyl (eg, difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl, etc.). The number of substitutions is 1 to 4, preferably 1 to 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 _1-14 alkylthio, (5) C _1-34 aryl optionally substituted by 1 to 3 with cyano or C _1-6 alkoxy-carbonyl, (6) halogen, (7) 1 to 3 with halogen C _7-11 aralkyl _optionally substituted may be preferred. R ⁴ is halogen, cyano, an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon-oxy group, an optionally substituted hydrocarbon group, a carbonyl group, 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. Hydrocarbon group or a hydrocarbon - Examples of the hydrocarbon group and its substituent in group ^{R 1a, R 2a, R 3a} , R 4a, R 5a, R 6a, are those defined in R ^4b. The heterocyclic group has the same meaning as a). Examples of the substituent of the amino group include the same substituents as those in the group through the 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) optionally 1-3 substituted with halogen. 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 1-3 optionally substituted C _1-6 alkyl, (2) C _1-6 alkoxy-carbonyl, (3) halogen, amino having 1-2 C _1-6 alkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 alkyl or C _6-14 aryloxy optionally substituted by 1 to 3 C _6-14 aryl-carbonyl, (4) C _1-6 alkyl-carbonyl, ( 5) formyl, (6) heterocycle - carbonyl, (7) (i) C _7-11 aralkyl - heterocyclic group, (ii) a heterocyclic group are one to two substituents in (iii) C _1-6 alkyl There 1-3 with an amino optionally amino optionally substituted C _1-6 alkyl or (iv) heterocycle -C _1-6 alkyl with one to two optionally substituted amino, - carbonyl, (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, (11) heterocyclic A group, (12) amino optionally substituted with 1 to 2 C _1-6 alkyl-carbonyl, (13) C _1-6 alkyl-carbonyloxy, (14) hydroxy, (15) C _1-6 alkyl sulfonyloxy, a (16) C _1-6 alkylthio, (17) C _1-6 alkylsulfinyl or (18) C _1-6 alkylsulfonyl. R ⁵ is preferably a hydrogen atom or C _1-6 alkyl. A hydrogen atom is particularly preferable.

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

[In the formula, R ^13a may be substituted by 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 An alkanoylamino group, R ^14a may be a hydrogen atom or a C _1-6 alkyl group, and R ^15a may be substituted with 1 to 5 groups, and may be the same or different, and each represents a hydrogen atom, a halogen atom, C _{1- 6} alkyl group, a C _1-6 alkoxy group or a C _1-6 alkylthio group, R ^16a may be different or may further identical have 1-5 substituents, each a hydrogen atom, C _1-6 alkyl group , A halogen atom or a C _1-6 alkoxy group, R ^17a may be substituted by 1 or 2 and may be the same or different and each may be an esterified or amidated carboxyl group, C _{1- 6} Arukiruka Boniru group, C _6-14 show an arylcarbonyl group or an optionally substituted C _1-6 alkyl group, v, t and u may be the same or different, each represent an integer of 0 to 3] The compounds represented are preferred. The substituent for the C _1-6 alkyl group in R ^17a is (i) hydroxy, (ii) C _1-6 alkyl-carbonyloxy, (iii) C _1-6 alkylthio, (iv) 1 to 3 halogen atoms. 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 or C _1-6 alkyl - aforementioned f as C _1-6 alkyl in carbonyloxy), C _1-6 alkoxy As the group, the above-mentioned m), as the halogen, the above-mentioned e), as the C _1-8 alkanoyl in the C _1-6 alkanoylamino group, as described above o), as the C _6-14 aryl, as mentioned above k) Can do. As the carboxyl group which may be esterified or amidated, those defined in the aforementioned R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b can be used.

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

[In the formula, R ^13b may be substituted by 1 to 3 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 by 1 to 3 groups, and may be the same or different, and a hydrogen atom or halogen, and R ^16b may be substituted by 1 to 3 groups. Further, they may be the same or different, and hydrogen atom, halogen or C _1-6 alkoxy, R ^17b may be substituted by 1 or 2 and may be the same or different and are esterified or amidated. And may be a carboxyl group or a C _1-6 alkylcarbonyl group, and v ′, t ′ and u ′ may be the same or different and each represents an integer of 0 to 3]. The above C _1-6 alkoxy group is the aforementioned m), the C _1-8 alkanoyl in the C _1-8 alkanoylamino group is the above o), the C _1-6 alkyl group or the C _1-6 alkylcarbonyl group. Examples of C _1-6 alkyl include the aforementioned f), and examples of halogen include the aforementioned e). As the carboxyl group which may be esterified or amidated, those defined in the aforementioned R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b can be used. R ^17a and R ^17b are preferably bonded to 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 a compound used in the composition of the present invention, in the compound (X), the compound represented by the general formula (XII)

[In the formula, R ^1h and R ^2h are each hydrogen, or a group through a carbon, nitrogen, oxygen or sulfur atom, R ^3h is an optionally substituted homologous or heterocyclic group, and R ^4h is substituted. An ^{optionally substituted} heterocyclic group or a group via a hetero atom, R ^5h represents a group via hydrogen or a carbon atom, and n ^h represents an integer of 0 to 3, respectively. The compound (XII) represented by the formula (II) or a salt thereof is preferred. The groups R ^1h , R ^2h , R ^3h and R ^5h have the same meaning as R ^1e , R ^2e , R ^3e and R ^5e described above. The heterocyclic group which may be substituted represented by R ^4h have the same meaning as R ^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, and these are the same as those defined for R ^4e. is there.

In the compound represented by the general formula (XII), preferred examples of R ^1h include a group via a carbon atom or a nitrogen atom. As the group having 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. A C _1-6 alkyl group which may have a hydrogen atom is preferred. C _1-6 alkyl includes the above f). The substituent in the C _1-20 hydrocarbon group which may have a substituent represented by R ^1h is (1) halogen, (2) nitro, (3) cyano, (4) optionally substituted. amino group, (5) substituted or also from a hydroxyl group (6) ^{-S (O) t h -R 6h} ( wherein, t ^h is an integer of 0 to 2, R ^6h is hydrogen or a substituted A group represented by the following formula: 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 is used.

Preferred examples of R ^2h include a group having a carbon atom. The group having a carbon atom is preferably a C _1-20 hydrocarbon group which may have a substituent, particularly a C _6-14 aryl group which may have a substituent. As the C _6-14 aryl group, the above k) is used. Examples of the substituent in the C _1-20 hydrocarbon group which may have a substituent represented by R ^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 _2-10 alkenyl group, (6) a C _1-6 acyl group or (7) A nitro group is preferred. Examples of the C _2-10 alkenyl group include g), and examples of the C _1-6 acyl group include 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) _optionally substituted C _2-10 alkenyl (preferred examples of the substituent include C _1-6 alkylcarbonyl, C _1-6 alkylaminocarbonyl), Or (5) optionally substituted amino (preferred examples of the substituent include C _1-6 alkyl, C _1-8 alkanoyl, C _1-6 alkyl substituted with hydroxy, and hydroxy). It is done. In particular, C _1-8 alkanoylamino or C _1-6 alkoxy is preferable. Most preferred R ^2h is (i) nitro, (ii) C _1-6 alkoxy, (iii) substituted with a group selected from amino groups optionally substituted with C _1-8 alkanoyl. Good C _6-14 aryl is mentioned. The above C _1-6 alkoxy is m), C _1-6 alkyl or C _1-6 alkylcarbonyl, C _1-6 alkyl in C _1-6 alkylaminocarbonyl is the above f), C _2-10 alkenyl is the g), the o) can be cited as a C _1-8 alkanoyl in C _1-8 alkanoyl or C _1-8 alkanoylamino.

Preferable examples of R ^3h include an ^optionally substituted homocyclic group. The homocyclic group has the same meaning as that mentioned for the W ring group. The homocyclic group in the optionally substituted homocyclic group is preferably a C _6-14 aryl group. As the C _6-14 aryl group, the above k) is used. The substituent in the homocyclic group which may have a substituent represented by R ^3h is (1) a halogen, (2) nitro, (3) an optionally substituted hydroxyl group or (4) a formula —S (O) t ^h -R ^6h (wherein the integer t ^h is 0 to 2, R ^6h is hydrogen or optionally substituted C _1-20 also be a hydrocarbon group) group is preferably represented by . Preferable examples of the group represented by R ^3h include a C _6-14 aryl group substituted with 1 to 2 halogen atoms, and phenyl is preferable as the aryl. As a more preferred group represented by R ^3h , phenyl substituted with fluorine is particularly preferred. Preferable 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.

Preferable examples of the heterocyclic group in the ^optionally substituted heterocyclic group represented by R ^4h include a 3- to 8-membered heterocyclic group, and among them, a 5- to 8-membered heterocyclic group having at least one nitrogen atom. A cyclic group is preferred. More preferably, a 5- to 6-membered heterocyclic group having at least one nitrogen atom is used. Examples of the heterocyclic group include the a). Examples of preferable heterocyclic groups include oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolyl, thiazinyl and the like. In particular, isoxazolyl is preferable. Substituents in the ^optionally substituted heterocyclic group represented by R ^4h are (1) halogen, (2) nitro, (3) optionally substituted hydroxyl group, (4) formula —S (O) m ^h— R ^6h (wherein m ^h represents an integer of 0 to 2, R ^6h represents a hydrogen atom or an optionally substituted C _1-20 hydrocarbon group), (5) substituted An optionally substituted amino group or a (6) C _1-10 hydrocarbon group is 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. to three optionally substituted C _1-10 also be a hydrocarbon group, (2) C _1-6 in the acyl group, or (3) ^{-S (O) t h -R 6h} ( wherein, t ^h is 0 An integer of 2 and R ^6h is preferably a hydrogen atom or an optionally substituted C _1-20 hydrocarbon group. The C _1-6 alkoxy in the C _1-6 alkoxycarbonyl includes the above m), and the C _1-6 acyl group includes the n). As the most preferable group represented by R ^4h , (1) a 5- to 6-membered heterocyclic group containing one nitrogen atom and one oxygen atom and having a bond to a carbon atom, (2) ( i) substituted with a group selected from C _1-6 alkoxycarbonyl or carbamoyl optionally having C _1-6 alkoxycarbonyl, (ii) C _1-8 alkanoyl and (iii) C _1-6 alkylsulfonyl even from a hydroxyl group, represented by formula (3) ^{-S (O) t h -R 6h} '( wherein, t ^h is an integer of 0 to 2, R ^6h' indicates a is C _1-6 alkyl group) And (4) an amino group which may be substituted with C _1-8 alkanoyl. Examples of the 5- to 6-membered heterocyclic group having a bond on the carbon atom include those defined by R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b . Further, the m) as C _1-6 alkoxy in C _1-6 alkoxycarbonyl, wherein f) as C _1-6 alkyl in C _1-6 alkyl or C _1-6 alkylsulfonyl, a C _1-8 alkanoyl Can include those mentioned in o) above.

Preferable examples of R ^5h include a hydrogen atom or a hydrocarbon group which may have a substituent. Among them, a C _1-20 hydrocarbon group which may have a hydrogen atom or a substituent is preferable. preferable. Furthermore, a hydrogen atom or a C _1-6 alkyl group is preferable. In particular, hydrogen is preferable. As the C _1-6 alkyl group, f) is used. In the compound (XII), R ^1h represents a C _1-6 alkyl group which may be substituted with halogen or N—C _7-13 aralkyl-N—C _1-6 alkylamino, R ^2h represents (i) nitro A C _6-14 aryl group optionally substituted with a group selected from amino optionally substituted with (ii) C _1-6 alkoxy and (iii) C _1-8 alkanoyl, R ^3h is mono- Or a di-halogeno C _6-14 aryl group, wherein R ^4h is (5) a 5- or 6-membered heterocyclic group containing a nitrogen atom and an oxygen atom and having a bond to a carbon atom, (2) (i) C _{1 -6} alkoxycarbonyl or C _1-6 alkyl optionally having carbamoyl, (ii) C _1-8 alkanoyl and (iii) C _1-6 alkylsulfonyl which may be substituted by a group selected from alkylsulfonyl hydroxyl groups , (3) ^{-S (O) t h -R 6h} '( wherein, the integer t ^h is 0 to 2, R ^6h' is shown a C _1-6 alkyl group The group represented by or (4) C _1-8 amino group which may be substituted with alkanoyl in), the R ^5h is a hydrogen atom, compound n ^h represents 1 respectively are particularly preferred. Examples of the halogen e), as the C _7-13 aralkyl in N-C _7-13 aralkyl -N-C _1-6 alkylamino wherein l), C _1-6 alkyl or N-C _7-13 aralkyl - wherein f) as C _1-6 alkyl in the N-C _1-6 alkylamino or C _1-6 alkylsulfonyl, wherein as C _1-6 alkoxy in C _1-6 alkoxy or C _1-6 alkoxycarbonyl m) as the C _1-8 alkanoyl wherein o), C _6-14 aryl group or mono - or di - the C _6-14 aryl in halogeno C _6-14 aryl group include the k). Furthermore, examples of the 5- to 6-membered heterocyclic group having a bond on a carbon atom include those defined by the above R ^1a , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a and R ^4b . n ^h is preferably 1.

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

[ ^Where R ¹ⁱ is a formula

(Wherein R ⁶ⁱ is (1) 1 to 3 fluorine, bromine, sulfamoyl, phenylthio group optionally substituted with methylthio or nitro, (2) 2- or 3-pyridyl group, (3) methyl An optionally substituted 3-indolyl group, (4) propyl group or (5) butylcarbamoyl group, R ⁷ⁱ represents a methyl group) or a hexamethylenetetraaminomethyl group represented by R ²ⁱ Is methoxycarbonylvinyl, ethoxycarbonylvinyl, carboxyvinyl, benzoylvinyl, acetylvinyl, propionylvinyl, isobutyrylamino, propionylamino, 3-oxobutylamino, 3-oxopentylamino, 2-hydroxycyclohexylamino, trifluoroacetyl Amino, 2-hydroxypropylamino, 2-hydroxybutylamino, 2-hydride Substituted with xyisobutylamino, N-ethyl-N-trifluoroacetylamino, methylamino, ethylamino, propylamino, butylamino, isobutylamino, diethylamino, 1-pyrrolidinylamino, ethanesulfonamide or acetonyloxy The phenyl group, R ³ⁱ may be substituted with 2-fluorobenzyl group or 2,6-difluorobenzyl group, and R ⁴ⁱ may be substituted with 1 to 3 of (1) acyl group or (2) hydroxy or alkylcarbonyloxy A C _1-6 alkyl group is shown. The compound (XIII) represented by the above or a salt thereof is preferable.

Preferable examples of the group represented by R ¹ⁱ in compound (XIII) of the present invention include N-methyl-N-benzylaminomethyl. As the number of substituents in R ²ⁱ and R ⁴ⁱ in the compound (XIII) of the present invention, 1 to 6 may be mentioned, among which 1 to 3 is preferable, and 1 to 2 is more preferable. Preferred examples of the group represented by R ²ⁱ in the compound (XIII) of the present invention include those represented by the formula R ¹⁰ⁱ -R ^9i- (wherein R ⁹ⁱ represents a vinylene group, R ¹⁰ⁱ represents C ₁ such as methoxycarbonyl, ethoxycarbonyl, etc. Or a group represented by C _1-8 alkanoyl such as _-6 alkoxycarbonyl, carboxy, benzoyl, acetyl, propionyl, etc.) or a group represented by the formula R ¹¹ⁱ -NH- (wherein R ¹¹ⁱ represents 3-oxobutyl, 3-oxo Pentyl or 2-hydroxycyclohexyl) or a phenyl group substituted with a group represented by the formula R ¹²ⁱ —O— (wherein R ¹²ⁱ represents acetonyl). The acyl represented by R ⁴ⁱ in the compound (XIII) of the present invention includes an acyl group derived from a carboxylic acid, for example, a formula —CO—R ⁸ⁱ (wherein —R ⁸ⁱ has a substituent). A hydrocarbon residue or a heterocyclic group which may have a substituent may be preferable.

Specific examples of the hydrocarbon residue include those defined for R ^1a , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a . 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 _1-6 alkyl-sulfinyl, beizoyl, phenoxy, C _1-6 alkylenedioxy, heterocyclic groups and the like can be mentioned. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

Examples of the heterocyclic group include those similar to 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, phenyl-C _1-5 alkyl such as benzyl, α-methylbenzyl, phenethyl, etc.), C _{6 -14} aryl (eg, phenyl, naphthyl, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy C, 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, methoxy) Carbonyl, 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) Mino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyric) Rilamide, etc.), carbamoylamino, N—C _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-) Isop Pils sulfamoyl, N- butylsulfamoyl, etc.), di-C _1-6 alkylsulfamoyl (e.g., N, N- dimethylsulfamoyl, N, N- diethylsulfamoyl, N, N- dipropyl Moyl, 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, propylsulfinyl, butylsulfinyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.) and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

As a preferable thing of the hydrocarbon residue represented by R ^{< 8i>} in said -CO-R ^{<8i >} , _C6-14 aryl group which may have a substituent, C which may have a substituent _{A 1-6} alkyl group is mentioned. _Examples of the substituent in the C _6-14 aryl group that may have a substituent include C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, C _1-6 alkyl. Rangeoxy, phenoxy, hydroxy, C _1-6 alkylcarbonyloxy, mono- or di-C _1-6 alkylamino, C _1-6 alkylthio and the like are preferable. 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 formula —S (O) _and a group represented by _p ⁱ -R ⁷ⁱ (wherein p ⁱ represents an integer of 0 to 2 and R ⁷ⁱ represents C _1-6 alkyl), C _1-6 alkylenedioxy. Preferable examples of the heterocyclic group represented by R ⁸ⁱ include thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl, morpholinyl, oxoimidazolyl, pyrrolidinyl, piperidinyl, thiazinyl and the like. In particular, thienyl is preferable. Preferred examples of the substituent of the heterocyclic group include 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 can be mentioned.

More 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 A benzoyl group substituted with alkylcarbonyloxy, mono- or di-C _1-6 alkylamino or C _1-6 alkylthio, (2) a C _1-6 alkylcarbonyl group substituted with C _1-3 alkylenedioxy or ( 3) A thienylcarbonyl group can be mentioned. Preferred examples of the C _1-6 alkyl group _optionally substituted with hydroxy or C _1-6 alkylcarbonyloxy represented by R ⁴ⁱ include a C _1-6 alkyl group substituted with hydroxy or acetyloxy. Furthermore, 2-hydroxyisobutyl and 2-acetoxyisobutyl are preferable.

Specific examples of the C _1-3 alkylenedioxy group include methylenedioxy, ethylenedioxy, propylenedioxy, and the like. Specific examples of the C _1-6 alkyl group in the above definition include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and the like. , inter alia C _1-3 alkyl group is preferred. 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 preferable.

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

[Wherein, R ^1j represents a formula —X—R ^4j (wherein, when X is O, R ^4j represents a branched alkyl group which may have a substituent, or a cyclo which may have a substituent. An oxygen-containing 6-membered heterocyclic group (preferably containing 1 to 2 oxygen atoms) which may have an alkyl group or a substituent, and when X is S, R ^4j may have a substituent A good alkyl group, an optionally substituted cycloalkyl group or an optionally substituted oxygen-containing 6-membered heterocyclic group (preferably containing 1 to 2 oxygen atoms). Or a salt thereof, wherein R ^2j represents a C _1-8 alkanoylamino group, and R ^3j represents a hydrogen atom or an alkyl group, respectively.

In the above formula, the branched alkyl group in the branched alkyl group ^optionally having a substituent represented by R ^4j is 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) are preferred. As the branched alkyl group, a C _3-7 branched alkyl group is preferable, and isopropyl, sec-butyl, 3-pentyl or 2,4-dimethyl-3-pentyl is particularly preferable. The branched alkyl group may have a substituent, and examples of the substituent include C _1-4 alkyl, halogen, amino, mono- or di-C _1-4 alkylamino, C _1-4 Examples include alkoxy and C _3-7 cycloalkyl. Of these, C _1-4 alkyl and halogen are preferable. 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. Of these, C _1-2 alkyl is preferable. Examples of the halogen include fluorine, chlorine, bromine, and iodine. Among these, fluorine and chlorine are preferable. C _1-4 alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and among them, methoxy and ethoxy are preferable. Examples of C _3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, with cyclohexyl being preferred. The number of the substituents is 1 to 3, preferably 1 to 2.

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

The cycloalkyl group in the cycloalkyl group which may be substituted is preferably a C _3-10 cycloalkyl group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, a C _3-7 cycloalkyl group is preferable. The cycloalkyl group may form a bicyclic fused ring, and examples of the fused ring group include indanyl and the like. Examples of the substituent of the cycloalkyl group include (1) halogen, (2) C _1-6 alkoxy, (3) C _1-6 alkyl, (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. Preferable examples of the group that 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, 4-ethylcyclohexyl, 4- Mention may be made of amino-1-cyclohexyl.

Examples of the halogen include those described in e) above. Alkoxy is preferably C _1-6 alkoxy, and examples thereof include m) above. Alkyl is preferably C _1-6 alkyl, and examples thereof include those described in f) above.

Examples of the mono-alkylamino include mono- _C1-4 alkylamino, such as N-methylamino, N-ethylamino, N-propylamino, Nn-butylamino, N-isobutylamino and the like. Is mentioned. The di-alkylamino is preferably di-C _1-4 alkylamino, and examples thereof include N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino and the like. The alkylthio is preferably C _1-4 alkylthio, 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 optionally substituted oxygen-containing 6-membered heterocyclic group include pyranyl, tetrahydropyranyl, dioxanyl, oxazinyl, isoxazinyl and the like. Those hydrogenated products may be used. Examples of the substituent of the oxygen-containing 6-membered heterocyclic group include (1) C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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 ( Examples: 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) sulfino , (14) C _1-6 alkyl Thio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.) and the like. The number of substitution 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 (especially C _1-4 alkoxy), C _1-6 alkylthio (especially C _1-4 alkylthio).

When X in the formula -X-R ^4j is S, the alkyl group in the alkyl group that R ^4j may have a substituent is preferably a C _1-13 alkyl group, may be linear, It may be 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. As the alkyl group, a C _1-6 alkyl group is preferable, and when it is branched, a C _3-8 branched alkyl group is preferable. Examples of the substituent in the alkyl group which may have the substituent include the same substituents as those described above for the cycloalkyl.

R ^1j has the formula —X—R ^5j (wherein X is O, R ^5j is (1) a C _3-13 branched alkyl group which may be substituted with C _1-4 alkyl or halogen). (More preferably a C _3-7 branched alkyl group) or (2) an oxygen-containing 6-membered complex optionally substituted with halogen, C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio A group represented by (which represents a cyclic group) is preferred. Furthermore, isopropoxy, sec-butoxy, 3-pentyloxy or 2,4-dimethyl-3-pentyloxy which may be substituted with halogen is particularly preferred.

In the above formula, examples of the C _1-8 alkanoylamino group represented by R ^2j include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, octanoylamino and the like. As the alkanoylamino group represented by R ^2j , a C _3-5 alkanoylamino group is preferable, and isobutyrylamino is particularly preferable. R ^2j is preferably substituted by 1 to 2 on the phenyl group, particularly preferably substituted at the 4-position of the phenyl group.

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

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

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

In the above formula, as an alkoxy group in the 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 Is preferably a C _1-6 alkoxy group, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy and the like. Of these, a C _1-3 alkoxy group is preferable, and methoxy is particularly preferable. In the above formula, in R ^1k , the halogen of the substituent on the alkoxy group includes fluorine, chlorine, bromine and iodine. Of these, fluorine is preferable. The cycloalkyl as a substituent on the alkoxy group is preferably C _3-10 cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl. Of these, C _3-6 cycloalkyl is preferable, and cyclopropyl is particularly preferable. 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. Among them, a C _2-6 alkenyl group is preferable, and a C _2-4 alkenyl group is particularly preferable. The alkyl in the alkenyl group which may be substituted with alkyl is preferably C _1-3 alkyl, and examples thereof include methyl, ethyl, propyl and isopropyl. Particularly preferred is methyl, and preferred is an alkenyl group substituted with alkyl. An example is 2-methylallyl.

R ^1k is preferably a C _1-3 alkoxy group substituted with a group selected from (i) halogen, (ii) C _3-10 cycloalkyl, and (iii) C _2-10 alkenyl, and further vinyl-C _1-3 alkoxy is preferred, and allyloxy is particularly preferred. The number of substituents in R ^1k is preferably 1 to 3, and particularly preferably 1 to 2. The alkyl group represented by R ^2k is preferably a C _1-6 alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. . Of these, a C _1-3 alkyl group is preferable, and a C ₃ alkyl group (n-propyl, isopropyl) is particularly preferable. The aryl group represented by R ^2k is preferably a C _6-14 aryl group, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl and the like. The alkyl group of the ^optionally substituted alkyl group represented by R ^4k is preferably a linear or branched C _1-9 alkyl group, 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, etc. It is done. Of these, a C _3-7 alkyl group is preferable, and a C ₃ alkoxy group (n-propoxy, isopropoxy) is particularly preferable. Examples of the substituent for 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 preferable. Alkoxy is preferably C _1-4 alkoxy, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Of these, methoxy is particularly preferable. The alkyl is preferably C _1-4 alkyl, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Of these, methyl is particularly preferable. As the cycloalkyl, C _3-8 cycloalkyl is preferable, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The cycloalkyl group in the ^optionally substituted cycloalkyl group represented by R ^4k is preferably a C _3-10 cycloalkyl group. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Etc. Of these, a C _3-7 cycloalkyl group is preferable. The cycloalkyl group may form a bicyclic fused ring, and examples of the fused ring group include indanyl and the like. Examples of the substituent of the cycloalkyl group include (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. Preferable examples of the group that may be substituted on the cycloalkyl group include halogen, nitro, and amino.

The halogen, alkoxy, alkyl, and cycloalkyl have the same meaning as that represented by R ^4k above.

The mono- or di-alkylamino and alkylthio are as defined above for R ^4j .

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

The R ^2k, optionally substituted with (1) C _1-3 alkyl, (2) C _6-14 aryl group or (3) halogen, C _1-3 alkyl or C _1-3 alkoxy C _{3- 7} alkoxy groups are preferred, isopropyl, phenyl, isopropoxy, sec- butoxy, 3-pentyloxy or 2,4-dimethyl-3-pentyloxy particularly preferred. The number of substituents in the R ^2k group is preferably 1 to 3, particularly preferably 1 to 2. R ^2k is preferably substituted on the phenyl group by 1 or 2 and particularly preferably substituted at the 4-position of the phenyl group. Examples of the alkyl for R ^3k include the same alkyl as defined for C _1-6 alkyl defined in f) above. R ^3k is preferably a hydrogen atom.

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

{Wherein, R ^1y represents hydrogen, an alkyl group, or a group of the formula - (CH ₂₎ p ^y 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, R ^5y represents an alkyl group), an aryl group that may be substituted, (2) an optionally substituted cycloalkyl group, or (3) a substituted group R ^2y represents hydrogen, an alkyl group which may be substituted with alkoxy, an aryl group which may be substituted, an aralkyl group which may be substituted, or a group represented by the optionally substituted cycloalkyl group, the R ^3y is optionally substituted amino group, R ^4y is optionally substituted a The Lumpur group, r preferably compound (XXI) or a salt thereof represented by} an integer of 0 to 3.

Examples of the alkyl group in the alkyl group represented by R ^1y and R ^5y and the alkyl group optionally substituted by the alkoxy represented by R ^2y include C _1-6 alkyl groups. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like can be mentioned. Among them, an alkyl group having 1 to 3 carbon atoms is preferable. Examples of the aryl group in Q and the ^optionally substituted aryl group represented by R ^2y and R ^4y include monocyclic or condensed polycyclic aromatic hydrocarbon groups. Preferable specific examples include C _6-14 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. Among them, C _6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc. 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 -Carbonyl, optionally substituted with C _1-6 alkoxy-carbonyl), (2) an optionally substituted C _2-6 alkenyl group (eg, vinyl, allyl, 1-butenyl, 2 -Butenyl etc. The alkenyl group may be substituted by 1 to 3 C _1-6 acyl or C _1-6 alkoxy-carbonyl), (3) C _2-6 alkynyl groups (eg ethynyl) , Propargyl, 2-butynyl, 5-hexynyl, etc.), (4) C _3-7 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), (5) C _6-14 aryl group (eg, phenyl) , Naphthyl, etc. Groups, as substituents, 1 to 3 (i) halogen, (ii) C _1-6 alkyl, (iii) C _1-6 further optionally substituted by C _1-6 alkoxy alkoxy, (iv ) shows a nitro, (v) cyano, in (vi) formula _{^{-S (O) n y -R 6y}} ( wherein the integer n ^y is 0 to 2, R ^6y is a C _1-6 alkyl group, or an amino. ), (Vii) amino, (viii) C _1-6 acyl, (ix) carbamoyl, (x) carboxy and (xi) hydroxy.), (6) heterocyclic group [Examples: 5- to 6-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms (eg, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl) A 3- to 9-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom ( , Oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.). The heterocyclic group includes 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 in alkoxy and (x) equation _{^{-S (O) n y -R 6y}} ( wherein, n ^y is 0-2 integer, R ^6y is C _{A 1-6} alkyl group.) May be substituted as a substituent. (7) C _7-13 aralkyl group (eg, benzyl, phenethyl, benzhydryl, etc. The aralkyl group may have 1 to 3 halogens), formula (8)

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

( ^Wherein R ^24y represents hydrogen, a C _1-6 alkyl group or a C _6-14 aryl group, R ^25y represents hydrogen or a C _1-6 alkyl group, and R ^24y and R ^25y together with adjacent nitrogen atoms A 5- to 7-membered nitrogen-containing cyclic group which may have a substituent, xy represents an integer of 0 to 3, and a group represented by (10) an amidino group, (11) acyl groups (e.g., formyl, acetyl, propionyl, butyryl, C _1-8 alkanoyl group such as octanoyl, for example, methoxycarbonyl, C _6, such as C _1-8 alkoxycarbonyl group, benzoyl, such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl _-14 aryl - carbonyl group, C _8-11 aralkyl-carbonyl group such as benzylcarbonyl, C _7-12 aralkyloxycarbonyl such as benzyloxycarbonyl - carbonyl (phenyl -C _1-6 alkyl Oxy - carbonyl) etc. These may be substituted, and examples of the substituent include, 1 to 3 halogens, C _1-6 alkylthio, C _1-6 alkoxy, oxo, hydroxy and the like),.. (12) An optionally substituted carbamoyl group (eg, carbamoyl, N-monosubstituted carbamoyl group (eg, N- (C _1-6 alkyl) carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl) ), N, N-disubstituted carbamoyl groups (for example, N, N-di (C _1-6 alkyl) such as dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-propyl-N-methylcarbamoyl) Carbamoyl group), (13) sulfamoyl group, (14) N-monosubstituted sulfamoyl group (eg, Rusurufamoiru, ethylsulfamoyl, such as propyl sulfamoyl group N-(C _1-6 alkyl) sulfamoyl group), (15) N, N-disubstituted sulfamoyl group (e.g., dimethylsulfamoyl, diethylsulfamoyl N, N-di (C _1-6 alkyl) sulfamoyl group such as moyl), (16) carboxyl group, (17) C _1-3 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) , (18) hydroxyl group, (19) C _1-6 alkoxy group optionally having 1 to 3 substituents (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, C _1-6 alkoxy such as t-butoxy, pentyloxy, hexyloxy and the like. Examples of the substituent include C _1-8 alkanoyl (similar to the above o), C _1-3 alkyl group, halogen, C _1-3 alkylthio, C _1-3 alkoxy, C _3-7. Examples thereof include the same as cycloalkyl (described above f), m), i)), oxo and hydroxyl groups. ), (20) C _2-4 alkenyloxy groups (eg, vinyloxy, allyloxy, etc.), (21) C _3-7 cycloalkyl-oxy groups (eg, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, etc.), (22) C _7-13 aralkyl-oxy groups (eg phenyl-C _1-3 alkyloxy such as benzyloxy, benzhydryloxy etc.), (23) C _6-14 aryloxy groups (eg phenyloxy, naphthyloxy etc.) (24) mercapto group, (25) C _7-13 aralkylthio group (eg phenyl-C _1-3 alkylthio such as benzylthio, benzhydrylthio etc.), (26) C _6-14 arylthio group (eg phenylthio, naphthylthio) etc.), (27) -S (O) _n ^y -R ^6y (wherein the integer ^{n y} is 0-2, a group R ^6y is represented by.) showing a C _1-6 alkyl group ( E.g. methylthio, Chiruchio, propylthio, methylsulphinyl, ethylsulfinyl, propyl-sulfinyl, methylsulfonyl, ethylsulfonyl, etc. propylsulfonyl), (28) C _1-3 alkylenedioxy (e.g., methylenedioxy, 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), etc. .

Examples of the cycloalkyl group in the ^optionally substituted cycloalkyl group represented by Q of R ^1y and R ^2y in the above include a C _3-10 cycloalkyl group and a C _4-10 bicycloalkyl group. 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. Of these, cyclopentyl and cyclohexyl are preferred. Examples of the substituent of the cycloalkyl group include the same substituents as those in the aryl group represented by R ^2y or R ^4y described above. Of these, C _1-6 alkyl, C _1-6 alkoxy, and halogen are preferable. The number of substituents is preferably 1 to 3.

Examples of the heterocyclic group in the ^optionally substituted heterocyclic group represented by Q in R ^1y include oxygen (O), sulfur (S), and nitrogen (as atoms (ring atoms) constituting the ring). And a 5- to 13-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from N) or a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group). Preferred examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, Aromatic monocyclic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl, 1,2 -Benzisoxazolyl, benzothiazolyl, 1,2 -Benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenoxazinyl Thiazinyl, phenazinyl, phenoxathiinyl, thiantenyl, 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, 1,2,4-triazolo [4,3-a] pyridyl, 1 , 2,4-Triazolo [4,3-b] pyridazinyl and other aromatics Etc. If a heterocyclic group. Preferable examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Among these heterocyclic groups, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, benzofuryl, indolyl and quinolyl are preferable. In addition, the heterocyclic group may have one or more, preferably 1 to 3 appropriate substituents, and the substituents are substituted with the above-described substituents represented by R ^2y and R ^4y. Examples are the same as the substituents 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 preferable.

In the above formula, examples of the halogen that is the substituent of the aryl represented by Q include fluorine, chlorine, bromine, and iodine. Examples of the optionally substituted carboxyl group for Q include carboxyl, C _1-6 alkyloxycarbonyl, C _3-7 cycloalkyloxycarbonyl, C _6-14 aryloxycarbonyl, C _7-20 aralkyloxycarbonyl, Examples thereof include oxycarbonyl substituted with a heterocyclic group, and C _1-6 alkyl, C _3-7 cycloalkyl, C _6-14 aryl, and C _7-20 aralkyl in these groups are the above-mentioned f), i), It has the same meaning as k), l), a). Examples of 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.), — (CH ₂ ) cNR ^26y — [ In the formula, c represents an integer of 0 to 3, and R ^26y represents hydrogen or C _1-6 alkyl (specific examples are the same as f). )], —CO—, —CONR ^27y — [wherein R ^27y is hydrogen, and C _1-6 alkyl (specific examples are the same as those described above for f)]. ), C _3-7 cycloalkyl (specific examples are the same as those in i). ), 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 in a). Groups represented ^{_{by)], -S (O) m y -}} . (M ^{group y} is expressed by showing) an integer of ^{0~2, -O -, - NR 27y} S (O) z y - ( In the formula, z ^y represents an integer of 0 to 2, and R ^27y has the same meaning as described above.

^Examples of the alkoxy in the alkyl which may be substituted with the alkoxy represented by the group R ^2y include C _1-6 alkoxy (same meaning as m). Examples of the aralkyl group in the optionally substituted aralkyl group represented by R ^2y include a C _6-14 aryl-C _1-6 alkyl group. The aryl has the same meaning as the aryl group in the optionally substituted aryl group represented by R ² . Examples of the alkyl include C _1-6 alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the like. Examples of the substituent include the same substituents as those in 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, formula (1)

(Wherein R ^22y represents a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _6-14 aryl group or a heterocyclic group, each of which may be substituted, and wy represents an integer of 0-3. , R ^23y represents hydrogen or an ^optionally substituted C _1-6 alkyl group.), 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 have the same meanings as f), i), k) and a). Examples of the group that may be substituted with these include the same groups as the substituents in the ^optionally substituted aryl group represented by R ^2y and R ^4y .

Preferred examples of the intervening group represented by A ^y, -O- or -S (O) _m ^y - (wherein, m ^y is an integer of 0 to 2.) Include groups represented by. 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 the formula — (CH ₂ ) ^py Q ′ [where Q ′ is halogen, nitro, cyano, amino, or the formula —A ^y ′ —R ^5y. C _6-14 aryl group which may be substituted with a group represented by '(wherein A ^y ' represents -O- or -S-, R ^5y 'represents C _1-6 alkyl). ^py has the same meaning as described above]. 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, the m ^y is an integer of 0 to 2), R ^5y represents a C _1-6 alkyl group) in _{Represents a} C _6-14 aryl group which may be substituted with the group represented by the above _formula . More preferred examples of R ^1y include halogen or the formula —A ^y ″ —R ^5y ″ (wherein A ^y ″ represents —O— or —S—, R ^5y ″ represents C _1-6 alkyl). And a C _6-14 aryl-methyl group which may be substituted by 1 to 3 groups. As a more preferred example of R ^1y , the formula Q ′ ″ — (CH ₂ ) _p ^y — (wherein Q ′ ″ represents C _6-14 aryl _optionally substituted by 1 to 3 halogens, p ^y is a group represented by the show.) an integer of 0-3.

Preferable examples of R ^2y include (1) a C _1-6 alkyl group optionally substituted by 1 to 3 with 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 by C _1-6 alkoxy , represented by (viii) halogen and (ix) formula -S (O) (wherein, n ^y is an integer of 0 to 2, R ^6y represents a C _1-6 alkyl group) _n ^y -R ^6y A C _6-14 aryl group optionally substituted by 1 to 3 groups, (3) a C _7-20 aralkyl group optionally substituted by 1 to 3 halogens, or (4) C _3-10 cycloalkyl Groups. In the above formula, the preferred group represented by group R ^2y, for example, (1) C _1-3 1 to 3 or an optionally substituted C _1-6 alkyl group with an alkoxy, (2) 1 3 amino, C _1-6 acyl, carbamoyl, carboxy, nitro, hydroxy, C _1-3 alkoxy, sulfo, in a halogen or the formula _{^{-S (O) n y -R 6y}} ( wherein, n ^y is 0-2 R ^6y represents C _1-3 alkyl.) And a C _6-14 aryl group which may be substituted with a group represented by (3) C _3-10 cycloalkyl group. More preferable examples of R ^2y include (1) a C _1-6 alkyl group which may be substituted by 1 to 3 C _1-3 alkoxy, (2) 1 to 3 (i) hydroxy, (ii ) C _1-3 alkoxy optionally substituted by C _1-3 alkoxy, (iii) halogen or (iv) formula _{^{-S (O) n y -R 6y}} ( wherein, n ^y is 0-2 integer R ^6y represents a C _1-3 alkyl group) and may be substituted with a C _6-14 aryl group, (3) C _7-20 aralkyl group or (4) C _3-7 A cycloalkyl group is mentioned. In the above formula, preferable examples of the group represented by the group R ^2y include, for example, (1) a C _1-6 alkyl group which may be substituted by 1 to 3 C _1-3 alkoxy, (2) C _{1 -3} alkoxy or the formula _{^{-S (O) n y -R 6y}} ( wherein the integer n ^y is 0 to 2, R ^6y represents a C _1-3 alkyl.) a group represented by 1 to 3 _Examples thereof include a C _6-14 aryl group which may be substituted and a (3) C _3-7 cycloalkyl group. More preferred examples of R ^2y include C _1-3 alkoxy optionally substituted by 1 to 3 (1) C _1-3 alkoxy, (2) halogen, or (3) formula —S. (O) _n ^y -R ^6y (wherein, n ^y is an integer of 0 to 2, R ^6y is C _1-3 an alkyl group) may be substituted with a group represented by C _6-14 An aryl group is mentioned.

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

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

( ^Wherein R ^24y represents hydrogen, a C _1-6 alkyl group or a C _6-14 aryl group, R ^25y represents hydrogen or a C _1-6 alkyl group, and R ^24y and R ^25y together with adjacent nitrogen atoms A 5- to 7-membered nitrogen-containing cyclic group (the group may be substituted), xy represents an integer of 0 to 3) or (5) C _1-6 A C _1-6 alkyl group which may be substituted with 1 to 3 alkylthio groups, 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, the formula

Wherein, R ^22y '' is (1) C _1-6 alkyl, (2) C1-6 alkyl, nitro, C _1-6 alkyl or formula _{^{-S (O) n y -R 6y}} ( wherein , N ^y represents an integer of 0 to 2, and R ^6y represents C _1-6 alkyl or amino.) 1-3 may be substituted with phenyl, (3) halogen or C _{1 -6} alkyl with 1-3 substituents which do heterocyclic group or even shows a (4) N-mono-substituted C _1-6 alkylcarbamoyl. wy represents an integer of 0 to 3. R ^23y ″ represents hydrogen or a C _1-6 alkyl group. Or a hexamethylenetetraamino group. Further preferred examples of the group R ^3y include compounds of the formula

[Wherein R ^22y ′ ″ is (1) a C _6-14 aryl group optionally substituted by 1 to 3 C _1-6 alkylthio, (2) a heterocyclic group, (3)

( ^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 ′ represent 5-7 together with the adjacent nitrogen atom. the membered nitrogen-containing cyclic group may form a.) group or (4 represented by) C _1-6 1 to 3 or an optionally substituted C _1-6 alkyl group in an alkylthio, wy 0 Represents an integer of ˜3, and R ^23y ′ ″ represents hydrogen or a C _1-6 alkyl group. An optionally substituted amino group represented by the formula: In the above formula, more preferable examples of the group represented by R ^3y include, for example, the formula

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, preferable examples of the ^optionally substituted aryl group represented by R ^4y include 1 to 3 (1) optionally substituted amino groups, (2) C _1-6 acyl, (3) optionally substituted carbamoyl group, (4) carboxy, (5) nitro, (6) hydroxy, (7) optionally substituted C _1-6 alkoxy or (8) optionally substituted _Examples thereof include a C _6-14 aryl group which may be substituted with a good C _2-10 alkenyl group. More preferable examples of R ^4y include 1 to 3 formulas (1)

[Wherein R ^11y ′ is (i) hydrogen, (ii) C _1-6 alkyl, (iii) optionally substituted C _1-6 alkoxy, (iv) optionally substituted C _1-6 acyl or (v) expression _{^{-S (O) n y -R 6y}} ( wherein the integer n ^y is 0 to 2, R ^6y represents a C _1-6 alkyl group) a group represented by, R ^12y ′ represents hydrogen or a C _1-6 alkyl group. ] (2) C _1-6 acyl, (3) carbamoyl, (4) N-mono or di-C _1-6 alkylamino, (5) nitro, (6) 1 to 3 C _1-6 alkoxy, C _1-8 alkanoyl, oxo, hydroxy, C _3-7 cycloalkyl and a C _1-6 alkoxy group optionally substituted with 1 to 3 halogens, (7) C _1-6 alkoxy A C _2-10 alkenyl group which may be further substituted by 1 to 3 further with carbonyl or C _1-6 alkylcarbonyl or (8) a C _6-14 aryl group which may be substituted with C _2-10 alkenyloxy. Can be mentioned. More preferable examples of R ^4y include 1 to 3 formulas (1)

[Wherein R ^11y ″ is (i) hydrogen, (ii) C _1-6 alkyl, (iii) C _1-6 alkoxy optionally substituted by 1 to 3 halogens or C _1-6 alkoxy, (iv) formyl, (v) halogen or C _1-6 alkoxy with 1-3 optionally substituted C _1-8 also be alkanoyl, (vi) benzoyl or (vii) expression -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 group represented by, R ^12y '' is hydrogen or a C _1-6 alkyl group. Groups represented by], (2) C _1-6 alkoxy, C _1-8 alkanoyl or C _3-7 cycloalkyl with 1-3 optionally substituted C _1-6 have an alkoxy group, (3) N -C _2-10 alkenyl optionally further substituted by 1 to 3 mono- or di-C _1-6 alkylcarbamoyl, (4) nitro, (5) C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl A C _6-14 aryl group optionally substituted with a group or (6) C _2-10 alkenyloxy.

In the above formula, a preferred example of aryl in the ^optionally substituted aryl group represented by R ^4y is phenyl. Preferable examples of the substituent include amino, C _1-6 acyl, carbamoyl, N-monosubstituted C _1-6 alkylcarbamoyl, carboxy, nitro, hydroxy, C _1-3 alkoxy substituted with 1-3 Good C _1-3 alkoxy, formula

(Wherein R ^31y represents C _1-6 alkyl, C _1-3 alkoxy optionally substituted by _1-3 alkyl, C _1-3 alkoxy, formyl, R ³² represents hydrogen, C _1-6 alkyl And a C _2-4 alkenyl group optionally substituted by 1 to 3 groups with C _1-6 alkoxycarbonyl or C _1-6 alkylcarbonyl. Preferred examples of the substituent include C _1-3 alkoxy optionally substituted with 1 to 3 amino, C _1-6 acyl, N-monosubstituted C _1-6 alkylcarbamoyl, nitro, C _1-3 alkoxy. ,formula

(In the formula, R ^33y may be substituted with C _1-6 alkyl, C _1-3 alkoxy _1-3 , C _1-3 acyl, C _1-4 acyl _1-3 may be substituted. A good C _1-3 alkoxy, benzoyl, formyl, R ^34y represents hydrogen, C _1-6 alkyl)), a group represented by C _1-3 alkoxy-carbonyl or C _1-3 alkyl-carbonyl 1 ˜3 substituted C _2-4 alkenyl groups.

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 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. Among them, 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, such as 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 may be mentioned. Preferable substituents include C _1-6 alkyl, and C _1-3 alkyl is more preferable.

The alkyl in the definition of the above group is preferably an alkyl having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl. And neopentyl and the like, and alkyl having 1 to 3 carbon atoms is particularly preferable. As the acyl in the above group definition, C _1-6 acyl is preferable. Examples of the acyl include C _1-6 alkanoyl, C _6-14 aryl-carbonyl, C _7-20 aralkyl-carbonyl, C _{7- 20} aralkyloxycarbonyl - carbonyl. these alkanoyl, aryl, aralkyl wherein o), k), l) include the same one. Preferable examples of acyl or alkanoyl include C _1-6 alkyl-carbonyl, and examples of the alkyl include those similar to the above f). As the alkoxy in the above group definition, C _1-6 alkoxy is preferable, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, iso Examples include pentyloxy, neopentyloxy, hexyloxy, and among them, alkoxy having 1 to 3 carbon atoms is preferable. Preferable alkenyl in the above group definition includes C _2-10 alkenyl, preferably C _2-4 alkenyl, and examples thereof include vinyl, allyl, 1-butenyl, 2- Butenyl is mentioned. Preferable aryl in the definition of the above group includes C _6-14 aryl, and examples thereof include phenyl and naphthyl. Preferable examples of aralkyl in the above group definition include C _7-20 aralkyl, preferably C _7-10 aralkyl. Examples thereof include phenyl-C _1-4 alkyl such as benzyl and phenethyl. . The halogen in the definition of the above group includes fluorine, chlorine, bromine and iodine.

  As a compound used in the composition of the present invention, among the compounds (XXX), the compound represented by the general formula (XXXI)

[ ^Where R ^1z is a formula

(Wherein R ^5z represents an aralkyl group, R ^6z represents an alkyl group, and X ^z represents an alkylene group) or an optionally halogenated alkyl group, and R ^2z represents an acylaminoaryl group. R ^3z represents a halogenoaralkyl group, and R ^4z represents a carboxyl group which may be esterified or amidated, respectively] (XXXI) or a salt thereof.

The aralkyl group represented by R ^5z in the 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. Can be mentioned. Of these, benzyl is preferred. The alkyl group ^represented by the group R ^6z is preferably a C _1-6 alkyl group. Examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, Examples thereof include n-pentyl, isopentyl, neopentyl, hexyl and the like. Of these, a C _1-3 alkyl group is preferable. The alkylene group represented by X ^z in the group R ^1z is preferably C _1-6 alkylene, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Among these, a C _1-3 alkylene group is preferable. Examples of the alkyl group in the alkyl group which may be halogenated in the group R ^1z include the same groups as in the above f). Examples of halogen include fluorine, chlorine, bromine and iodine. The number of substituents is 1-3. Preferable examples of the alkyl group which may be halogenated include bromomethyl. The acylaminoaryl group represented by R ^2z is preferably, for example, a C _1-6 acyl-amino-C _6-14 aryl group. Examples of C _1-6 acyl include, for example, formyl, acetyl, propionyl, Examples thereof include C _1-6 alkanoyl such as butyryl, isobutyryl, valeryl and isovaleryl. Examples of C _6-14 aryl include phenyl, naphthyl and anthryl.

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 halogens is 1 to 3. Examples of the aralkyl group in the halogenoaralkyl group include benzyl, phenethyl, benzhydryl and the like. Of these, 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. Of these, 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, isopropylcarbamoyl, N—C _7-11 aralkylcarbamoyl such as 2-pyridylcarbamoyl, benzylcarbamoyl and the like. Etc. As the most preferable compound (XXXI), N-benzyl-N-methylaminomethyl is ^used as the group R ^1z , propionylaminophenyl or isobutyrylaminophenyl is used as R ^2z , and difluorobenzyl is used as R ^3z . R ^4z includes ethoxycarbonyl.

Compounds (X) to (XV), (XX), (XXX), (XXI) and (XXXI) and salts thereof used in the present invention can be easily produced by a method known per se or a salt thereof. Specific examples of the method include, for example, the following production methods or methods equivalent thereto.
[Production Method 1] An appropriate ketone or aldehyde (i) having an active methylene group is obtained by the method of Carl Gewald et al. [K. Gewald, E. Schinke and H. Bφttcher, Chem. Ber., 99 , 94-100 (1966)] is reacted with a cyanoacetic acid ester derivative and sulfur to convert to a 2-aminothiophene derivative (ii). That is, in the case of ketone (R ¹ '≠ H), in the presence of acetic acid and ammonium acetate, (i) and the cyanoacetic acid ester derivative are heated to reflux in a suitable solvent, for example, toluene, and once alkylidene cyanoacetic acid ester derivative. After that, the 2-aminothiophene derivative (ii) is obtained by heating in an appropriate solvent such as ethanol in the presence of sulfur and a base. In the case of an aldehyde (R ¹ ′ = H), the 2-aminothiophene derivative (ii) is heated by heating in an appropriate solvent, for example, N, N-dimethylformamide, in the presence of a cyanoacetate derivative, sulfur and a base. To do. According to the method of Kuwata et al. [German Patent 2,435,025], the resulting compound (ii) is reacted with diethyl ethoxymethylenemalonate under heating to obtain an adduct (iii), which is used in a solvent that does not adversely influence the reaction (eg, Stirring at about 10 to 70 ° C. in the presence of a base (eg, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide) to obtain a carboxylic acid (iv) Thereafter, the resulting carboxylic acid (iv) is heated and cyclized in polyphosphate ester (PPE) to obtain a thieno [2,3-b] pyridine derivative (v). The compound (v) in the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as pyridine or triethylamine) does not adversely affect the reaction (eg, N, N-dimethylformamide, N, N-dimethylacetamide) Amides) and the like, and stirring at about 10 to 100 ° C. to obtain a 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative represented by the formula (XIa) . Next, in the presence of α, α′-azobisisobutyronitrile (AIBN) in a solvent that does not adversely affect the reaction of the compound (XIa) (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform), Stir with N-bromosuccinimide (NBS) at about 30-100 ° C. to give compound (XIb). If necessary, the halogen atom is converted to an alkylsulfonyloxy or alkylarylsulfonyloxy group. Furthermore, in the presence of a base, the compound (XIb) and various amines (HR ⁹ ) are not adversely affected by the reaction (eg, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, etc.) Nitrile such as acetonitrile, alcohol such as ethanol) 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 [Formula 1]. In the formula, R ¹ ′ represents hydrogen or an optionally substituted alkyl group, R ′ represents an alkyl group, X represents a leaving group, Xa represents halogen, R ⁴ ′ represents ethoxycarbonyl, and R ⁵ ′ represents In hydrogen, R ² , R ³ , R ⁹ and n are as defined above. The alkyl group represented by R ¹ ′ and R ′ has the same meaning as in f). m shows the integer of 0-6.

As the leaving group represented by X, for example, a nucleophile (eg, a hydrocarbon residue having a negatively charged heteroatom (eg, oxygen atom, sulfur atom, 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 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. The halogen represented by Xa is fluorine, bromine, chlorine, iodine, preferably bromine.

[Production Method 2] Karl Gebald et al. [K. Gewald, Chem. Ber., 98 , 3571-3577 (1965); K. Gewaldand E. Schinke, Chem. Ber., 99 , 2712-2715 (1966) The 5-position unsubstituted 2-aminothiophene derivative (vi), which can be synthesized by the above method, is added in the same manner as in Production Method 1 above by reacting with diethyl ethoxymethylenemalonate under heating according to the method of Kuwata et al. [German Patent 2,435,025]. After forming the body (vii), in a solvent that does not adversely affect the reaction (eg, alcohols such as ethanol and methanol), an appropriate base (eg, alkali hydroxide such as potassium hydroxide and sodium hydroxide). Stirring in the presence of a metal, etc.) at about 10-60 ° C. gives the carboxylic acid (viii). The obtained (viii) is subjected to various electrophilic substitution reactions, optionally undergoing functional group conversion, introducing a substituent represented by R ² ″, and then heating ring closure in polyphosphate ester (PPE) To give a thieno [2,3-b] pyridine derivative (ix). Examples of electrophilic substitution reactions include 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. Thereafter, in the same manner as in Production Method 1, compounds (XIa ′), (XIb) and (XI ′) can be produced from compound (ix). The above production method 2 is shown in [Equation 2]. In the formula, each symbol has the same meaning as described above.

[Production Method 3] In a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran, 1,4-dioxane, etc.), allantolic acid derivative (x) is equivalent to compound (x) or an excess amount of formula ( A compound represented by CCl ₃ O) ₂ CO is added and stirred at about 30 to 110 ° C. to obtain an isatoic anhydride derivative (xi). Subsequently, the halogenated aralkyl derivative represented by the formula (xii) is converted into a solvent that does not adversely influence the reaction (for example, 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 alkyl sulfoxides such as dimethyl sulfoxide. In the presence of an alkali metal or an alkali metal alkoxide such as potassium butoxide, the mixture is stirred at about 40 to 130 ° C. to obtain an aralkyl-substituted derivative (xiii). The derivative (xiii) is adversely affected in the reaction 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, an alkali metal alkoxide such as potassium butoxide). (Eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethyl sulfoxide) The compound (xiii) is reacted with an equivalent amount or a small excess (eg, about 1.1 to 1.5 equivalents) of a β-keto acid ester derivative (xiv) at 40 to 110 ° C. Thus, compound (Va) can be produced. The above production method 3 is shown in [Equation 3]. In the formula, each symbol has the same meaning as described above.

[Production Method 4] In a solvent that does not adversely influence the reaction of the pyridine derivative (xv) (eg, ethers such as tetrahydrofuran, 1,4-dioxane, etc.), the compound (xv) and an equivalent amount or an excess amount of the formula (CCl ₃ O) A compound represented by ₂ CO is added and stirred at about 30 to 110 ° C. to obtain an acid anhydride derivative (xvi). Subsequently, the halogenated aralkyl derivative (xii) represented by the formula (xii) is converted into a solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, and aromatic hydrocarbons such as benzene and toluene). N, N-dimethylformamide, amides such as N, N-dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, etc., bases (eg, alkali metal carbonates such as potassium carbonate, sodium hydride, potassium hydride, etc.) In the presence of an alkali metal hydride, an alkali metal alkoxide such as potassium butoxide) at about 40 to 130 ° C. to obtain an aralkyl-substituted derivative (xvii). The derivative (xvii) is adversely affected in the reaction 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, an alkali metal alkoxide such as potassium butoxide). (Eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethyl sulfoxide) The compound (xvii) is reacted with an equivalent amount or a small excess (eg, about 1.1 to 1.5 equivalents) of a β-keto acid ester derivative (xiv) at 40 to 110 ° C. Thus, compound (Vb) can be produced. The above manufacturing method 4 is shown in [Equation 4]. In the formula, each symbol has the same meaning as described above.

[Production Method 5] 4,7-Dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (Va) is converted to a suitable solvent (eg, tetrahydrofuran, ethyl ether) that does not adversely influence the reaction. In addition, an appropriate reducing agent (eg, lithium aluminum hydride) is added in ethers such as dioxane, and the mixture is stirred at about 0 to 80 ° C. to obtain a reduced derivative (Vb). The compound (Vb) is stirred at about 10 to 100 ° C. in a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide and dimethylacetamide) in the presence of a halogenated aralkyl derivative and a base to give a compound of formula (XIc 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative is obtained. The derivative is stirred with a suitable oxidizing agent (eg, manganese dioxide) in a suitable solvent (eg, dichloromethane, chloroform) at about 10-80 ° C. to give a 5-position formyl derivative. The obtained derivative (XId) is stirred with a Grignard reagent (R ^25d MgXa) at about 0 to 80 ° C. in an appropriate solvent (eg, ethers such as tetrahydrofuran and ethyl ether) that does not adversely influence the reaction, and Secondary alcohol derivative (XIe) to be obtained, and a suitable oxidant (eg, metal oxide such as manganese dioxide) in an appropriate solvent (eg, halogenated hydrocarbons such as dichloromethane and chloroform) and about 10 to 80 ° C. 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 are as defined above. The hydrocarbon residue represented by R ^25d has the same meaning as the hydrocarbon residue in the carbonyl group substituted with the hydrocarbon residue represented by R ⁴ .

  [Production Method 6] 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative (XIa ′) is previously converted into an appropriate solvent that does not adversely influence the reaction (eg, dichloromethane, etc.) An aluminum amide derivative prepared from an appropriate aluminum reagent (eg, trimethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines in (halogenated hydrocarbons, ethers such as tetrahydrofuran, ethyl ether, dioxane). Stir at about 10-100 ° C. to give 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid amide derivative (XIa ″). The derivative (XIa ″) is stirred with a Grignard reagent at about −78 to 80 ° C. in a suitable solvent (for example, tetrahydrofuran, ethyl ether, etc.) that does not adversely influence the reaction to give the corresponding ketone derivative (XIf). obtain. The above production method 6 is shown in [Equation 6].

[Wherein R ^26d represents a C _1-6 alkyl or C _6-14 aryl group, R ^27d and R ^28d each represent hydrogen or a hydrocarbon residue, and other symbols have the same meanings as described above]
The alkyl and aryl represented by R ^26d have the same meanings as f) and k). The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted with the hydrocarbon residue represented by R ⁴ . Other symbols are as defined above.

  [Production Method 7] 4,7-Dihydro-5-hydroxymethyl-4-oxothieno [2,3-b] pyridine derivative (XIc) is prepared in advance by using a suitable solvent that does not adversely influence the reaction (eg, halogen such as dichloromethane). Hydrocarbons, ethers such as tetrahydrofuran, ethyl ether and dioxane, pyridine) and a suitable halogenating reagent (eg, thionyl chloride, methanesulfonyl chloride, etc.) and stirring at about 0 to 100 ° C. -Dihydro-5-halomethyl-4-oxothieno [2,3-b] pyridine derivative (XIg). The derivative is stirred in a suitable solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and ethyl ether, and amides such as dimethylformamide) with an appropriate nucleophile at about 0 to 100 ° C. To produce a 5-substituted derivative (XIh). The above production method 7 is shown in [Equation 7].

[Wherein, X ′ represents a leaving group, Z represents 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 are as defined above] Have
The leaving group represented by X ', for example, nucleophile [e.g., the ^- heteroatom bearing a negative charge represented by ZR ^27d, etc. (e.g., an oxygen atom, a sulfur atom, such as nitrogen atom) of And the like can be easily subjected to a substitution reaction. 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. The hydrocarbon residue in the nitrogen atom optionally substituted with the hydrocarbon residue is the same as the hydrocarbon residue in the carbonyl group optionally substituted with the hydrocarbon residue represented by R ^4. Have

  [Production Method 8] 4,7-Dihydro-5-formyl-4-oxothieno [2,3-b] pyridine derivative (XId) is converted into a suitable solvent (eg, tetrahydrofuran, ethyl ether, Ethers such as dioxane, pyridine) The mixture is stirred with a suitable Wittig reagent at about 0 to 100 ° C. to obtain the derivative (XIj). In a suitable solvent that does not adversely affect the reaction (eg, alcohols such as ethyl alcohol, esters such as ethyl acetate, ethers such as tetrahydrofuran, ethyl ether, dimethylformamide, etc.) Example, hydrogenation using a catalyst (eg, palladium carbon catalyst) under a hydrogen stream] and stirring at about 10 to 100 ° C. to obtain the corresponding 5-substituted derivative (XIj). The above production method 8 is shown in [Equation 8].

[Wherein R ^29d and R ^30d each represent hydrogen or a hydrocarbon residue, and other symbols have the same meaning as described above]
The hydrocarbon residue represented by R ^29d and R ^30d has the same meaning as the hydrocarbon residue in the carbonyl group substituted with 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 (eg, tetrahydrofuran, In ethers such as dioxane, alcohols such as ethyl alcohol, etc., acids (eg, inorganic acids such as hydrochloric acid) or alkaline aqueous solutions (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) 1-4N aqueous solution etc.) is added and it stirs and hydrolyzes at about 10-100 degreeC. The obtained 5-position carboxylic acid derivative (XIk) is heated at about 50 to 200 ° C. in an appropriate solvent that does not adversely influence the reaction (eg, ethers such as diphenyl ether, aromatic hydrocarbons such as toluene). To obtain 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.

[Production Method 10] A urea derivative (II) is produced from the 2-aminothiophene derivative (ii) by, for example, the following method A or B.
1. Method A: The 2-aminothiophene derivative (ii) or a salt thereof produced by the method described in Production Method 1 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 is carried out in a solvent that does not adversely influence the reaction (eg, tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene), about 15 Performed at ~ 130 ° C. The isocyanate derivative is used in an amount of about 1 to 5 equivalents, preferably about 1.1 to 2.5 equivalents, relative to compound (ii). The reaction time is a few minutes to a few days, preferably about 15 minutes to about 2 days.
2. Method B: produced by reacting 2-aminothiophene derivative (ii) or a salt thereof with phosgene or an equivalent thereof (eg, diphosgene such as bis (trichloromethyl) carbonate, triphosgene such as trichloromethyl chloroformate) An amine such as a compound represented by the formula R ^2f —NH ₂ (wherein R ^2f has the same meaning as described above) is added to the isocyanate derivative. The reaction of compound (ii) or a salt thereof with phosgene or an equivalent thereof is about 40% in a solvent that does not adversely influence the reaction (eg, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform). Performed at ~ 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 is a few minutes to a few days, preferably about 15 minutes to about 2 days. The amine addition reaction is carried out at about 15 to 130 ° C. in a solvent that does not adversely influence the reaction (eg, pyridine, tetrahydrofuran, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene). The amine is used in an amount of about 1 to 5 equivalents, preferably about 1.1 to 3 equivalents, relative to compound (ii). The reaction time is a few minutes to a few days, preferably about 15 minutes to about 2 days. The obtained compound (xv) or a salt thereof is treated with a base to perform a ring-closing 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, and ethers such as dioxane and tetrahydrofuran. Examples of the base include alkali metal alkoxides such as sodium methylate, sodium ethylate, and sodium isopropoxide, and alkali metal hydrides such as sodium hydride. The amount of the base used is about 1.1 to 5 equivalents, preferably about 1.5 to 3 equivalents, relative to compound (xv). The reaction temperature is about 10 ° C. to the boiling point temperature of the solvent used, preferably about 25 ° C. to the boiling point temperature of the solvent used. The reaction time is a few minutes to a few days, preferably about 10 minutes to 2 days. About 10% of compound (xvi) in the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as pyridine or triethylamine) in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide or dimethylacetamide). Stirring at -100 ° C gives the 2,4-dioxothieno [2,3-d] pyrimidine derivative (IIa). Next, the compound (IIa) 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 give compound (IIb). Further, in a solvent that does not adversely affect the reaction with various amines in the presence of a base (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol), Stir at 100 ° C. to produce compound (II). If necessary, the compound is salted with a suitable acid (eg, hydrochloric acid, oxalic acid). The above production method 10 is shown in [Equation 10]. In the formula, each symbol has the same meaning as described above.

  [Production Method 11] The amino group of 2-aminothiophene derivative (xvii) is protected (eg, Boc), and Ger. Pat. 2155403 (1972) or JP-B 73-01664 (1973), in the presence of an acyl halide derivative and a base, in a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide, dimethylacetamide, etc.) Stirring at 0 to 100 ° C. to obtain the derivative (xviii), stirring with an appropriate salt (eg, lithium iodide) in an appropriate solvent (eg, acetone, methyl ethyl ketone) to obtain the derivative (xix) Substitution of an amine (eg, ammonia) to form a derivative (xx), and in a solvent that does not adversely affect the reaction (eg, toluene, dimethylformamide, dimethylacetamide, methanol, ethanol, etc.), an appropriate catalyst (eg, Sodium ethoxide, toluenesulfonic acid, etc.) and stirring at about 30-120 ° C. for dehydration ring closure Obtaining a derivative (VIIa) by response. In the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as potassium carbonate, pyridine, or triethylamine) in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide or dimethylacetamide), Stir at 10-100 ° C. to give the 2-oxothieno [2,3-e] azepine derivative (VIIb). Next, the compound (VIIb) is subjected to 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 give compound (VIIc). Further, in a solvent that does not adversely affect the reaction with various amines in the presence of a base (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol), Stir at 100 ° C. to produce compound (VIId). If necessary, the compound is salified with a suitable acid (eg hydrochloric acid, oxalic acid). The above manufacturing method 2 is shown in [Equation 11].

[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 a halogenated aralkyl derivative and a base (eg, potassium carbonate, pyridine, In the presence of an organic base such as triethylamine) in a solvent that does not adversely influence the reaction (eg, amides such as dimethylformamide, dimethylacetamide) at about 10 to 100 ° C., the derivative (xxi) is obtained. A solvent (eg, toluene, tetrahydrofuran, dimethylformamide, dimethyl) that does not adversely affect the reaction after alkaline hydrolysis with a suitable alkali (eg, sodium hydroxide) in a solvent (eg, methanol, tetrahydrofuran). Acetamide, ethanol) and diphenylphosphazide (DPPA) in about 0-1 It was stirred at 0 ° C., and a suitable alcohol (e.g., ethanol) carbamic acid ester derivative (xxii). The derivative is stirred at about 0 to 100 ° C. in a solvent that does not adversely influence the reaction (eg, dimethylformamide, dimethylacetamide, etc.) in the presence of a base (eg, sodium ethoxide) to give 2-oxothieno [2,3 -D] An imidazolone derivative (VIIe) is obtained. The compound is stirred at about 0 to 100 ° C. in a solvent that does not adversely influence the reaction in the presence of an alkyl halide derivative and a base (eg, amides such as dimethylformamide and dimethylacetamide) to give compound (VIIf). obtain. Then, in the presence of α, α′-azobisisobutyronitrile (AIBN) in a solvent that does not adversely influence the reaction of the compound (VIIf) (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform), Stir with N-bromosuccinimide (NBS) at about 30-100 ° C. to give compound (VIIg). Further, in a solvent that does not adversely affect the reaction with various amines in the presence of a base (eg, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol), Stir at 100 ° C. to produce compound (VIIh). If necessary, the compound is salted with a suitable acid (eg hydrochloric acid, oxalic acid). The above production method 12 is shown in [Equation 12]. In the formula, each symbol has the same meaning as described above.

  [Production Method 13] From 2-aminothiophene derivative (ii) produced by the method described in Production Method 1 or a salt thereof, M.M. 4,5-dihydro-7-hydroxy by the method of Baker et al. [JMBarker, J. Chem. Res. (M), 1980, 113; JMBarker, J. Chem. Res. (S), 6 (1980)]. -5-Oxothieno [3,2-b] pyridine-6-carboxylic acid ethyl derivative (VIIj) is prepared. That is, a 2-aminothiophene derivative (ii) or a salt thereof is reacted with a malonic ester to give a compound (xxiii), and a solvent that does not adversely influence the reaction in the presence of a suitable base (eg, sodium hydride) (eg, In dimethylformamide (DMF), dimethylacetamide, etc.) at about 10-100 ° C. with stirring. The derivative (VIIj) is a solvent that does not adversely affect the reaction in the presence of a halogenated aralkyl derivative and a base (eg, an organic base such as potassium carbonate, pyridine, triethylamine, etc.) (eg, amides such as dimethylformamide, dimethylacetamide, etc.) ) To obtain a derivative (VIIk) by stirring at about 10 to 100 ° C., and α, α in a solvent that does not adversely influence the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform). Stirring with N-bromosuccinimide (NBS) in the presence of '-azobisisobutyronitrile (AIBN) at about 30-100 ° C. gives compound (VIIm). Further, in a solvent that does not adversely influence the reaction with various amines in the presence of a base (for example, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol), about 10 Stir at ˜100 ° C. to produce compound (VIIn). If necessary, the compound is salted with a suitable acid (eg, hydrochloric acid, oxalic acid). The above production method 13 is shown in [Equation 13]. In the formula, each symbol has the same meaning as described above.

[Production method 14] 1,4-dihydro-4-oxoquinoline-3-carboxylic acid ester derivative (Va ') is converted into an appropriate solvent that does not adversely influence the reaction in advance (eg, halogenated hydrocarbons such as dichloromethane, An aluminum amide derivative produced from an appropriate aluminum reagent (eg, trimethylaluminum, triethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines in ethers such as tetrahydrofuran, ethyl ether, dioxane, etc. Stir at 0 ° C. to give 1,4-dihydro-4-oxoquinoline-3-carboxylic acid amide derivative (Va ″). The derivative is stirred with a Grignard reagent (R ^14d MgXa) at about 0 to 80 ° C. in a suitable solvent that does not adversely influence the reaction (eg, tetrahydrofuran, ethyl ether, etc.) to obtain the corresponding ketone derivative (Vc). . The above production method 14 is shown in [Equation 14].

[Wherein R ^26d represents C _1-6 alkyl or C _6-14 aryl, R ^27d and R ^28d each represents hydrogen or a hydrocarbon residue, and other symbols have the same meanings as described above]
C _1-6 alkyl and C _6-14 aryl represented by R ^26d have the same meanings as f) and k). The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted with the hydrocarbon residue represented by R ′.

  [Production Method 15] 1,4-Dihydro-4-oxopyrido [2,3-b] pyridine-3-carboxylic acid ester derivative (Vd) is prepared in advance with a suitable solvent (eg, dichloromethane, etc.) that does not adversely influence the reaction. Aluminum amides produced from suitable aluminum reagents (eg, trimethylaluminum, triethylaluminum, diisobutylaluminum hydride (DIBAL), etc.) and amines in halogenated hydrocarbons, ethers such as tetrahydrofuran, ethyl ether, dioxane, etc. Stir with the derivative at about 10-100 ° C. to give 1,4-dihydro-4-oxopyrido [2,3-b] pyridine-3-carboxylic acid amide derivative (Vd ′). The derivative is stirred with a Grignard reagent at about 0 to 80 ° C. in a suitable solvent that does not adversely influence the reaction (for example, tetrahydrofuran, ethyl ether, etc.) to give the corresponding ketone derivative (Ve). The above production method 15 is shown in [Equation 15].

[Wherein R ^26d represents C _1-6 alkyl or C _6-14 aryl, R ^27d and R ^28d each represents hydrogen or a hydrocarbon residue, and other symbols have the same meanings as described above]
C _1-6 alkyl and C _6-14 aryl represented by R ^26d have the same meanings as f) and k). The hydrocarbon residue represented by R ^27d and R ^28d has the same meaning as the hydrocarbon residue in the carbonyl group which may be substituted with the hydrocarbon residue represented by R ′.

[Production Method 16] 4,7-Dihydro-2-halogeno-4-oxothieno [2,3-b] pyridine derivative (XIp) is converted into a suitable solvent that does not adversely influence the reaction (eg, 1,2-dimethoxyethane). , Ethers such as tetrahydrofuran and dioxane, alcohols such as ethyl alcohol, etc.) and an appropriate aryl boric acid derivative (eg, sodium carbonate) in the presence of an equivalent to excess (2 to 10 equivalents) appropriate base (eg, sodium carbonate) (for example, Palladium metal such as phenylboric acid, 3-methoxyphenylboric acid, 4-ethoxycarbonylphenylboric acid, etc.) and an appropriate catalyst (for example, tetrakis (triphenylphosphine) palladium) in an inert gas (for example, argon gas) stream Etc.) and stir at about 10-100 ° C. for several minutes to several hours. The desired derivative (XIq) is obtained by removing insolubles. The above production method 16 is shown in [Equation 16]. In the formula, R ^30d represents an ^optionally substituted aryl group, X ¹ represents a halogen, and other symbols have the same meanings as described above.

  [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: a formyl derivative obtained by the above-mentioned production method 5 or a method similar thereto ( Add sodium bisulfite in an appropriate solvent that does not adversely influence the reaction (eg, water, ethanol) and stir at about 0 to 80 ° C. to obtain a sulfuric acid adduct (iih). Cyanide compound in the presence of an equivalent to an excess of a suitable base (eg, ammonium carbonate) in a suitable solvent (eg, hydrous ethanol, hydrous tetrahydrofuran, dioxane) that does not adversely influence the reaction. (Example, potassium cyanide, sodium cyanide) is added, and the mixture is stirred at about 0 to 80 ° C. and, if necessary, heated to reflux to obtain the 5-position imidazolidinyl derivative (XIIa). The above production method 17 is shown in [Equation 17]. The symbols in the formula are as defined above.

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

[Production Method 19] Production method of derivative wherein 5-position is 4-imidazolyl group or 4-thiazolyl group: 4,7-dihydro-5-acyl- produced by the same method as Production method 5 or Production method 6 above The 4-oxothieno [2,3-b] pyridine derivative (ivh) is converted into an appropriate equivalent or small excess of an appropriate solvent in an appropriate solvent that does not adversely influence the reaction (eg, acetic acid, methanol, tetrahydrofuran, ethyl ether, dioxane). A halogenating reagent (eg, bromine, iodine) is added dropwise at room temperature or under ice cooling, followed by stirring at about 0 to 80 ° C. to obtain an α-haloketone derivative (vh). The α-haloketone derivative (vh) is converted into an appropriate amidine derivative in an appropriate solvent that does not adversely influence the reaction (eg, methanol, tetrahydrofuran, ethyl ether, dioxane, dimethylformamide) at room temperature or ice-cooling. Under addition, the mixture is stirred at about 0 to 80 ° C., and if necessary, heated to reflux to produce 4-imidazolyl derivative (XIIc). Alternatively, the α-haloketone derivative (vh) is stirred with a thiocarbamoyl derivative in a solvent that does not adversely influence the reaction (eg, methanol, ethanol, dimethylformamide, dimethylacetamide) at about 10 to 100 ° C. to give 4-thiazolyl A derivative (XIId) is produced. Similarly, a 1,4-thiazinyl derivative is produced by reacting an α-haloketone derivative with thioglycolic acid amide, followed by dehydration and ring closure. Among the above production methods, the production method of 4-imidazolyl derivative (XIIc) and 4-thiazolyl derivative (XIId) is shown in [Equation 19]. In the formula of [Equation 19], 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, or C _6-14 aryl. R ¹ , R ² , R ³ , R ⁵ and n are as defined above. Xa represents halogen.

Production method 20: Production method of a derivative in which the 5-position is a 2-oxazolyl group: 4,7-dihydro-5-carbamoyl-4-oxothieno [2,3-b] produced by the first reaction of the above production method 6 The pyridine derivative (vih) is added dropwise in an appropriate solvent that does not adversely influence the reaction (eg, methanol, ethanol, tetrahydrofuran, dioxane) in an appropriate amount to a small excess of an appropriate α-haloketone compound dropwise at room temperature or under ice cooling. Stir at 0 to 80 ° C. and, if necessary, heat to reflux to obtain the 2-oxazolyl derivative (XIIe). The above production method 20 is shown in [Equation 20]. In the formula of [Equation 20], R ^45h represents a hydrogen atom, C _1-6 alkyl or C _6-14 aryl. Xa represents halogen. R ¹ , R ² , R ³ , R ⁵ and n are as defined above.

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

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

[Production Method 23] Method for producing a derivative in which the 5-position is a 2-triazolyl group: 4,7-dihydro-5-thiocarbamoyl-4-oxothieno [2,3-b] pyridine derivative (xh) (of Production Method 21) In an appropriate solvent (eg, ethyl ether, dimethylformamide, tetrahydrofuran, dioxane, dichloromethane) that does not adversely affect the reaction (prepared in the first reaction), an equivalent to small excess of methyl iodide is added dropwise at room temperature or with ice cooling The mixture is stirred at about 0 ° C. to 80 ° C., and heated to reflux as necessary to obtain a quaternary salt derivative. The derivative is added in an appropriate solvent that does not adversely influence the reaction (eg, dimethylformamide) or without using a solvent, and an excess of formic hydrazide is added at room temperature or under ice cooling, followed by stirring at room temperature to 200 ° C. -Triazolyl derivative (XIIh) is produced. The above production method 23 is shown in [Equation 23]. In the formula of [Equation 23], R ¹ , R ² , R ³ , R ⁵ and n are as defined above.

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

[Production method 25]: Production method of derivative in which R ⁴ is a group via N: 5-acetyl derivative (xivh) obtained by the same method as described in production method 5 or 6 is used in a suitable solvent (eg, The oxime derivative (xvh) is prepared by adding an equivalent or small excess of hydroxylamine derivative or a salt thereof, and warming to room temperature or warming. Dissolve the oxime derivative (xvh) in a suitable solvent (eg, pyridine), add an equivalent to a small excess of an acylating agent (eg, acid halide, acid anhydride, sulfonic acid halide, etc.), at room temperature or under heating. , Reaction is carried out for 1 to 12 hours to obtain a rearranged product (XIIj). The rearrangement product (XIIjk) is dissolved in a suitable solvent (eg, ethyl alcohol) and subjected to an alkali hydrolysis reaction (reaction conditions: for example, an aqueous sodium hydroxide solution is added and stirred at room temperature for about 2 hours). Thus, the corresponding primary amino derivative (XIIk) can be produced. The above production 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.

  Using the primary amino derivative (XIIk) thus obtained as a raw material, various derivatives can be produced by subjecting it to a commonly used alkylation reaction, acylation reaction, sulfonylation reaction, imidation reaction, etc. it can.

[Production Method 26] Method for producing a derivative wherein R ⁴ is a group via O: Acyl derivative (xvih) obtained by the same method as described in the above production method 5 or 6 is used as an appropriate solvent (eg, dichloromethane). Dissolve in water, add a small excess (eg, 1.2 to 1.5 equivalents) of peroxide (eg, chlorobenzoic acid) under ice-cooling or room temperature, and stir at room temperature for 1 to 6 hours. The product (XIIm) is obtained. The product (XIIm) is heated in a suitable solvent (eg, tetrahydrofuran) under basic conditions (eg, 2N sodium hydroxide solution is added) at room temperature or warmed (eg, 40-60 ° C.). Stirring for ~ 12 hours gives the alcohol derivative (XIIn). The alcohol derivative (XIIn) is added to an alkyl halide (eg, isopropyl bromide) in the presence of a base (eg, potassium carbonate) in an appropriate solvent (eg, dimethylformamide) and heated at room temperature (eg, isopropyl formamide). , 40 to 80 ° C.) and stirring for about 1 to 24 hours, the alkoxy derivative (XIIo) is obtained. Further, for example, when the alkoxy group is an isopropoxy group, the alkoxy derivative is dissolved in a suitable solvent (eg, dichloromethane) and ice-cooled in the presence of an excess of a suitable Lewis acid (eg, boron trichloride) or Upon stirring at room temperature for 1-6 hours, a dealkylated alcohol derivative (XIIn) is obtained. The above production method 26 is shown in [Equation 26]. In [Equation 16], R ¹ , R ² , R ³ , R ⁵ and n are as defined above. R ^30h and R ⁴ ′ each represent a C _1-6 alkyl group. Xa represents a halogen atom.

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

Production method 27; (Production method of derivative wherein R ⁴ is a group via S)
First, a thioglycolic acid ester is reacted with an alkyl iodide, and then a dimethylaminomethylene compound is reacted to produce a compound (xviih). The 2-aminothiophene derivative (xviiih) produced by the same method as described in the above production method 1 is subjected to alkaline hydrolysis by adding a base (eg, sodium hydroxide aqueous solution) in an appropriate solvent (eg, ethyl alcohol). The compound (xixh) obtained by the reaction and the above compound (xviih) are stirred in a suitable solvent or without a solvent for 1 to 6 hours under heating (eg, 80 to 150 ° C.) to obtain an amino-substituted derivative. get (xxh). The derivative (xxh) is heated (eg, 150 to 250 ° C.) in a suitable solvent (eg, diphenyl ether) and reacted for 30 minutes to 3 hours to obtain a ring-closed product (xxih). In the same manner as in the reaction of the compound (v) shown in Preparation Method 1 with the formula Xa- (CH ₂ ) _n —R ³ , the ring-closed compound (xxih) is reacted with the formula Xa— (CH ₂ ) _n —. R ³ is reacted to obtain compound (XIIp). Further, the compound (XIIp) is reacted in an appropriate solvent (eg, dichloromethane) with an equivalent or small excess of peroxide (eg, metachlorobenzoic acid) by stirring for 5 minutes to 2 hours under ice-cooling to produce a sulfoxide. The derivative (XIIq) is obtained. The above production method 27 is shown in [Equation 27]. In [Equation 27], R ¹ , R ² , R ³ and n are as defined above. R ⁴ ″ represents a C _1-6 alkyl group.

[Production method 28]: Production method of a derivative which is phenyl substituted with an alkenyl group which may be substituted at the 2-position: 4,7-dihydro-2- (4-aminophenyl) -4-oxothieno [2, 3-b] The pyridine derivative (XIIr) is mixed with an appropriate diazotizing agent (eg, sub-acid) in an appropriate solvent that does not adversely influence the reaction (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, water, etc.). Sodium nitrate and 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 (olefin compound, etc.) are added and stirred at about 0 to 80 ° C. to obtain the target derivative (XIIs). The above production method 28 is shown in [Equation 28]. In the formula of [Formula 28], 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 are as defined above for n) and f). Other groups are as defined above.

[Production Method 29] Method for producing a derivative which is an aminophenyl group substituted with an optionally substituted alkyl group or an optionally substituted homocyclic group: 4,7-dihydro-2- (4-Aminophenyl) -4-oxothieno [2,3-b] pyridine derivative (XIIt) is dissolved in an appropriate solvent that does not adversely influence the reaction (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane). . 1 equivalent to an excessive amount of various Michael acceptor derivatives (for example, acrylic acid ester) or oxirane derivatives (for example, epoxy compound) are added and stirred at about 0 to 80 ° C. to obtain the target derivative (XIIu). The above production method 29 is shown in [Equation 29]. In the formula of [Equation 29], R ^{35h to} R ^39h represent a C _1-6 alkyl group. -R ^40h denotes a ^{-C (R 36h) -CO-R} 35h or ^{-C (OH) R 36h R 39h} . Other groups are as defined above.

[Production Method 30] Method for producing a derivative which is an aminophenyl group substituted with an optionally substituted alkyl group or an optionally substituted homocyclic group: 4,7-dihydro-2- (4-Aminophenyl) -4-oxothieno [2,3-b] pyridine derivative (XIIv) is a suitable solvent that does not adversely affect the reaction (eg, pyridine, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane) And 1 equivalent to an excess amount of acid chloride or acid anhydride (for example, trifluoroacetic acid anhydride) is reacted therewith. If necessary, 1 equivalent to an excess of base (for example, potassium carbonate, triethylamine) is added, and the mixture is stirred at about 0 to 80 ° C. to obtain the derivative (XIIw). The obtained derivative is dissolved in an appropriate 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 base (for example, carbonic acid) 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 stirred at about 0-80 ° C. The desired derivative is obtained by subjecting the obtained derivative to an alkaline hydrolysis (for example, 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). (XIIx) is manufactured. The above production method 30 is shown in [Expression 30]. The group R ^41h in [ ^Expression 30] represents C _1-6 alkyl or trifluoromethyl. The group R ^42h represents an ^optionally substituted C _1-6 alkyl group or an optionally substituted homocyclic group. Other groups are as defined above.

[Production Method 31]: Conversion of Substituent at the 3-Position: A Compound (XIIy) Produced by the Production Method above in which the 3-position is a hydrogen atom or a C _1-6 alkyl group is a solvent that does not adversely affect the reaction ( Example, halogenated hydrocarbons such as carbon tetrachloride and chloroform), in the presence of α, α′-azobisisobutyronitrile (AIBN), stirred with N-bromosuccinimide (NBS) at about 30-100 ° C. Then, compound (II ′) is obtained, and if necessary, a conversion reaction with a 3-position substituent is carried out by reacting a fatty acid, an alkylsulfonic acid, an alkylarylsulfonic acid or the like. The compound (II ′) thus obtained is reacted with an equimolar to small excess (about 3 mol) of various primary and secondary amines (eg, R ¹ ′ ″-H) to give a compound ( III ') can be produced. The reaction is carried out in a suitable solvent that does not adversely affect 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 or the like is 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 inorganic salts (eg, anhydrous). Potassium carbonate, etc.) are used. The reaction temperature is about 10-100 ° C. The reaction time is about 0.5 to 8 hours. This reaction is efficient when carried out with stirring. In this way, compound (III ′) is produced. The above production 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 has the same meaning as described 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 nucleophile (eg, a hydrocarbon residue having a negatively charged heteroatom (eg, oxygen atom, sulfur atom, 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 etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy etc.), C _{1- 6} alkyl -C _6-14 arylsulfonyloxy (e.g., p- toluenesulfonyloxy, etc.) and the like.

Production method 32: Thienopyridine-5-carboxylic acid derivative which is a branched alkoxycarbonyl group which may be substituted at the 5-position is produced in the same manner as the production method described in PCT International Publication WO95 / 28405. Or a salt thereof and a general formula R ^4j —OH wherein R ^4j represents a branched alkoxy group which may have a substituent. Specific examples are as defined above. ] Or a salt thereof can be reacted. In the reaction, the raw material compound is dissolved in an appropriate solvent (eg, isopropyl alcohol, 3-pentyl alcohol, etc.), and the general formula Ti (OR ^4j ) ₄ [wherein R ⁴ represents a branched alkoxy group. . ] (For example, isopropyl titanate (titanium tetraisopropoxide), titanate (3-pentyl)) or a salt thereof, and a reaction temperature of about 0 to 120 ° C, more preferably about 10 to 20 ° C. And stirring for about 1 to 24 hours, preferably about 1 to 12 hours. Alternatively, a compound having a carboxyl group at the 5-position in a suitable solvent (eg, dimethylformamide), a suitable acid chloride reagent (eg, phosphorus oxychloride), a base (eg, N, N-dimethylaminopyridine) and an alcohol (Eg, 2,4-dimethyl-3-pentanol) in the presence of room temperature or heating (about 100 ° C.) and stirring for about 1 to 12 hours.

  Production method 33: Thienopyridine-5-carboxylic acid derivative in which the 5-position is a carboxyl group is a compound produced by a method similar to the production method described in PCT International Publication No. WO95 / 28405, wherein the 5-position is an alkoxycarbonyl group Alternatively, the salt can be subjected to a hydrolysis reaction. In the hydrolysis reaction, the raw material compound is dissolved in advance in an appropriate solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran and dioxane, alcohols such as ethyl alcohol), and an acid (eg, inorganic such as hydrochloric acid). Acid) or aqueous alkali solution (for example, 1 to 4 N aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and stirring at about 10 to 100 ° C. for about 1 to 4 hours. Is done.

Production method 34: Compound (XV) used in the present invention can be produced by a method known per se, for example, the method described in PCT International Publication WO 95/28405 or the same method. Among them, the compound (XV) of the present invention is produced by a method similar to the production method described in PCT International Publication No. WO95 / 28405, 5-carboxy-4,7-dihydro-4-oxothieno [2,3 -B] a pyridine derivative or a salt thereof, and a general formula R ^2k '-Y ^k , wherein R ^2k ' is substituted with (i) halogen, (ii) cycloalkyl or (iii) alkyl as a substituent. An alkyl group having 1 to 3 alkenyl groups, Y ^k represents a halogen atom; ] Or a salt thereof can be reacted. Here, this reaction is usually carried out in a reaction solvent. Examples of such a solvent include amides such as dimethylformamide, nitriles such as acetonitrile, ethers such as tetrahydrofuran, and the like. In this reaction, a raw material compound is dissolved in these solvents, and a compound represented by the general formula R ^2k′- Y ^k (eg, allyl bromide, cyclopropylmethyl chloride, 1-bromo-2-butene, crotyl bromide). (Ie, 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, hydrogen) Sodium chloride, triethylamine, etc.). The reaction temperature is about 0-100 ° C, more preferably about 0-40 ° C. The reaction time is about 1 to 200 hours, preferably about 1 to 48 hours. This reaction is efficiently carried out by stirring.
Production method 35: A thienopyridine derivative in which R ^2k is an alkoxy group which may have a substituent in formula (XV) was produced by a method similar to the production method described in PCT International Publication WO 95/28405. 5-Ethoxycarbonyl-4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative or a salt thereof and a general formula R ^2k -H [wherein R ^2k is as defined above. It can manufacture by performing transesterification by making it react with the compound or its salt represented. This reaction is usually carried out in a reaction solvent. As such a solvent, for example, alcohols such as isopropyl alcohol are used. In this reaction, a raw material compound is dissolved in these solvents, and a compound represented by the general formula Ti (R ^2k ) ₄ (eg, isopropyl titanate [titanium (N) tetraisopropoxide], etc.) is added thereto. It is done 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 carried out by stirring. Alternatively, the 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). Is called. 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 or with heating (about 100 ° C.). The reaction time is about 1 to 12 hours. This reaction is efficiently carried out by stirring.

Production method 36: Thieno [2,3-b] pyridine-5-carboxylic acid derivative in which —CO—R ^2k is a carboxy group in the formula (XV) is, for example, a method described in PCT International Publication No. WO95 / 28405 or manufactured in a manner similar to this, it can be prepared by subjecting a compound R ² is an alkoxy group or a salt thereof to hydrolysis reaction. The hydrolysis reaction is performed by dissolving a raw material compound in a solvent and using an acid (eg, an inorganic acid such as hydrochloric acid) or an alkaline aqueous solution (eg, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide). To 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 can be produced by a method known per se. For example, it can be easily produced by the above production method 10, the production method shown below, or a method analogous thereto.

Production method 37: Instead of the method for producing compound (IIa) from compound (ii) shown in [Equation 13] of the above production method 13, from the compound (ii) by a method known per se, for example, the following method Compound (IIa) can be produced. 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, ethanol), and 1 to 3 at room temperature to heating (up to 100 ° C.). React for 12 hours. The obtained compound (—COOEt is converted to —COOH) is dissolved in an appropriate solvent (eg, dioxane), an equivalent amount of triphosgene is added, and the mixture is stirred at 80 to 150 ° C. for 1 to 10 hours to be reacted. The obtained 1-hydroxyoxazine compound is subjected to the same operation as in the reaction step for producing compound (IIa) from compound (XVI) described above. The oxazine compound thus obtained (R ^1y is introduced at the 1-position) is dissolved in a suitable solvent (eg, dichloromethane), and an equivalent to small excess of amine (eg, ammonia, alkylamine, arylamine). And stirred for 1 to 12 hours under room temperature to heating (up to 100 ° C.). Next, triphosamine 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 compound (IIa).

Compound (XXX) and salts thereof of the present invention can be produced using a method known per se. Examples thereof include the above-described production methods 3 and 14 and the following production methods. In the following, Y ^z represents halogen. Examples of the halogen include the same ones as 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 heteroatom (eg, oxygen atom, sulfur atom, 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
An equivalent amount of a small excess of ethoxymethylenemalonic acid diethyl ester is added to the 3-halogenated aniline derivative (iz), followed by stirring at 100 ° C. to 150 ° C. for 1 to 4 hours to obtain an addition derivative (iiz). The derivative (iiz) is added little by little to an appropriate solvent (eg, polyphosphoric acid, polyphosphoric acid ester (PPE), dowtherm, etc.), and stirred at room temperature or while warming to produce the quinoline derivative (iiiz). The derivative (iiiz) is dissolved in an appropriate solvent (eg, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane, acetone, etc.) that does not adversely influence the reaction, and 1 equivalent to a small excess of base (eg, carbonic acid) Potassium, triethylamine, sodium hydride, etc.) and 1 equivalent to an excess of an alkyl halide derivative (eg, methyl iodide, propyl iodide, benzyl iodide, etc.) are added and stirred at about 0-80 ° C. The target compound (XXXa) is produced by reacting the obtained derivative (ivz) or a salt thereof with an equimolar to small excess (3 mol) of arylboric acid derivative represented by the formula R ^III -B (OH) _2. Is done. The reaction is carried out in a suitable solvent that does not adversely influence the reaction. Suitable solvents include, for example, ethers such as ethyl ether, dioxane, dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, amides such as dimethylformamide and dimethylacetamide, and alcohols such as ethanol. Etc. 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, 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) may be added. This reaction is preferably performed under a stream of inert gas (eg, argon gas, nitrogen gas, etc.). The reaction temperature is about room temperature to 150 ° C., and it is usually carried out with heating under reflux. The reaction time is about 1 to 12 hours. In this way, the target compound (XXXa) can be produced. The above manufacturing process 38 is shown in [Equation 32]. In [Expression 32], Et is ethyl, Y ^z is halogen, and other groups are as defined above.

Production method 39: Conversion of the 6-position group: In a solvent (for example, halogenated hydrocarbons such as carbon tetrachloride and chloroform) which does not adversely influence the reaction of the compound (vz) in the reaction formula of [Equation 33] Stirring with N-bromosuccinimide (NBS) in the presence of α, α′-azobisisobutyronitrile (AIBN) at 30-100 ° C. for 0.5-6 hours gives compound (viz). Compound (XXXb) or a salt thereof of the present invention is produced by reacting compound (viz) or a salt thereof with an approximately equimolar amount of amine (R ¹ ′ ″-H). The reaction is carried out in a suitable solvent that does not adversely influence the reaction. Examples of the suitable solvent include amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol, ethers such as dimethoxyethane, tetrahydrofuran, dioxane and dimethoxyethane, 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, etc.) is used. 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. In this way, 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 ^z represents a leaving group, and the other groups have the same meaning as described above.

Production method 40: An anthranilic acid derivative (viiz) is added in an amount of about 30 to 110 in an equivalent amount or an excess amount of triphosgene in a solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran, 1,4-dioxane). Stir at 0 ° C. to obtain isatoic anhydride derivative (vii). Subsequently, the halogenated derivative is converted into a solvent that does not adversely influence the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, N, N-dimethylformamide, N, N- Amides such as dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide), bases (eg, alkali metal carbonates such as potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkalis such as potassium butoxide) In the presence of a metal alkoxide or the like, the mixture is stirred at about 40 to 130 ° C. to obtain a substituted derivative (ixz). The derivative (ixz) is adversely affected in the reaction 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, an alkali metal alkoxide such as potassium butoxide). (Eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethyl sulfoxide) Compound (XXXc) by reacting with an equivalent or small excess (eg, about 1.1 to 1.5 equivalents) of a β-keto ester derivative in an alkyl sulfoxide such as Can be manufactured. The above manufacturing process 39 is shown in [Equation 34]. In [Expression 34], Xa represents a leaving group (particularly halogen). R ^g ′ represents an alkyl group. Other groups are as defined above.

Other production methods: Substituents in the groups of the compounds used in the present invention can be converted into other substituents by a commonly known method used per se. An example of this method is shown below.
(i) A nitro group as a substituent can be converted to an amino group. For example, the 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 in a hydrogen stream, or (b) iron is added to the above solution. Powder and hydrochloric acid are added and allowed to react for 1-12 hours at room temperature.
(ii) An amino group as a substituent can be converted into an acylated amino group. For example, a raw material compound is dissolved in a suitable solvent (eg, tetrahydrofuran, dimethyl sulfoxide), potassium carbonate, pyridine and triethylamine are added as bases, and an acid anhydride or acid halide is further added. The mixture is allowed to react with stirring at room temperature for 1-10 hours.
(iii) The compound having an amino group can be an alkenylamino compound. For example, a raw material compound is dissolved in an appropriate solvent (eg, acetic acid, dimethylformamide, dichloromethane, tethydrofuran, dioxane, acetonitrile), a diazotizing agent (eg, sodium nitrate, isoamyl nitrate) is added, and a palladium catalyst {eg, bis (Dibenzylideneacetone) palladium} and 1 equivalent to a small excess of an alkenyl derivative are added and allowed to react at room temperature to warming (80 ° C.) for 1 to 12 hours.

(iv) A carbon atom can be introduced into the amino group. For example, the 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, epoxide compound) is added, and the mixture is stirred at 0-80 ° C. for 6-6 React for 24 hours.
(V) A sulfur atom can be introduced into an amino group. For example, a raw material 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, a raw material compound is dissolved in a suitable solvent (eg, tetrahydrofuran), an organic borane derivative (eg, dimethylsulfide borane) is added, and the reaction is performed for several hours (eg, 1 to 3 hours) at room temperature to heating under reflux.

(vii) An acetonyl form can be produced from a methoxy form. For example, a raw material compound is dissolved in a suitable solvent (eg, dichloromethane), 1 equivalent to an excess of Lewis acid {eg, aluminum chloride and a thiol compound or sulfide compound (eg, dimethyl sulfide)} is added, and the mixture is cooled to room temperature under ice cooling. Then, the obtained hydroxy compound is dissolved in an appropriate solvent (eg, dimethylformamide), a base (eg, sodium hydroxide, potassium carbonate) and an alkyl halide are added, and the mixture is stirred at room temperature for 1-12. Let react for hours.
(viii) A methoxy group can be converted to an isopropoxy group. For example, a raw material compound is dissolved in an appropriate solvent (eg, dichloromethane), 1 equivalent to an excess of Lewis acid (eg, aluminum chloride) and a thiol compound or sulfide compound (eg, dimethyl sulfide) are added, and the mixture is cooled to room temperature under ice cooling. For 1 to 10 hours.
(ix) An aminocarbonyl group can be introduced. For example, a halogen-containing raw material compound is dissolved in 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 And reacted under reflux for 1 to 6 hours.

(x). The alkylthio compound can be an alkylsulfinyl compound or an alkylsulfonyl compound. For example, the raw material compound is reacted with an oxidizing agent (eg, metachloroperbenzoic acid) in an appropriate solvent (eg, dichloromethane) under ice cooling or overheating. When heating is used excessively or an oxidizing agent is used excessively, an alkylsulfonyl compound is obtained.
(xi) The hydroxyl group in the molecule can be substituted with various groups. The reaction is carried out in a suitable solvent such as dimethylformamide (DMF), acetonitrile, acetone, etc., halide (eg, alkyl halide (eg, propyl iodide, isobutyl iodide, ethyl bromide)), aralkyl halide (eg, benzyl chloride). }. 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 bromide, the obtained acetic acid ester is reacted at room temperature for 2 to 12 hours using a suitable solvent and a base (eg, 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 carried out at 0 ° C. to room temperature for 1 to 12 hours. In addition, the compound which has a hydroxyl group in the molecule | numerator which is said raw material compound can be performed by attaching | subjecting the compound which has an alkoxy group in a molecule | numerator to acid hydrolysis, for example. For acid hydrolysis, 1N hydrochloric acid is added and reacted at 0 ° C. to room temperature for 1 to 10 hours in a commonly used method, for example, in an appropriate solvent {eg, alcohol (eg, methanol, ethanol)}.

(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 subjected to N-bromosuccinimide and a catalytic amount of 2,2′-azobis ( Isobutyronitrile) is added and reacted. The reaction is carried out at 100 to 120 ° C. for 1 to 4 hours. The alkanoyl-phenyl group is introduced in a suitable solvent (eg, dimethoxyethane (DME)). To the solution is added alkanoyl-phenyl borate, palladium compound {eg, Pd (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-phenyl borate is carried out by adding alkanoyl-phenyl bromide and a boric acid compound {eg, (i-PrO) ₃ B, Pr = propyl} in the presence of a suitable base (eg, BuLi, Bu = butyl). Do.
(xiii) The compound which is an alkyl-phenyl group in the compound of the present invention can be obtained by reacting in the same manner using the alkyl-phenyl borate instead of alkanoyl-phenyl borate in the above method (xii). In addition, other groups in the compound of the present invention can be introduced 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 raw material compound and then esterifying the obtained compound. The reaction for introducing the cyano group is carried out by dissolving the raw material compound in an appropriate solvent {eg, dimethyl sulfoxide (DMSO)}, adding sodium cyanide to the solution, and reacting at 40 to 60 ° C. for 2 to 12 hours. Next, the esterification reaction performed is carried out by using a raw material compound and an alcohol solution {eg, ethyl alcohol) in a suitable solvent (eg, ethyl alcohol). Saturated with hydrochloric acid. } At 80 to 120 ° C. for 12 to 48 hours.
(xv). Introduction of a sulfonamide group in the compound of the present invention can be carried out by halogenating an alkyl group in a raw material compound and then subjecting it to a nucleophilic substitution reaction with a sulfonamide. The halogenation is carried out by adding N-bromosuccinimide or a catalytic amount of 2,2′-azobis (isobutyronitrile) in a suitable solvent (eg, carbon tetrachloride), and heating at 100 to 120 ° C. for 1 to 4 hours. This is done by reacting. The nucleophilic substitution reaction may be carried out by, for example, sodium hydride and sulfonamide derivatives (eg, methanesulfonamide, ethanesulfonamide) washed with n-hexane in a suitable solvent {eg, N, N-dimethylformamide (DMF)}. , Benzenesulfonamide) is added and reacted at 0 to 40 ° C. for 1 to 24 hours.

(xvi). A method for removing a protecting group added to a hydroxyl group in the 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 under ice-cooling. By stirring for 5 to 5 hours, a compound from which a 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 an appropriate solvent (eg, dichloromethane, dimethylformamide), and an appropriate base (eg, triethylamine, pyridine) is added thereto, and an excess of acid anhydride, acid chloride or alkyl halide is added thereto. Is added and stirred at room temperature for 6 to 24 hours to produce a compound having an acyl group introduced into the hydroxyl group.
(xviii). A method for converting a carbonyl group of a compound having a carbonyl group into a -C (OH) H- group in the compound used in the present invention will be described. For example, by dissolving a compound having a carbonyl group in an appropriate solvent (eg, methanol, ethanol), adding a small excess of a reducing agent (eg, sodium borohydride), and stirring at room temperature for 1 to 3 hours, A compound having a C (OH) H-group is prepared.

  The medicament of the present invention comprises (1) a pharmaceutical composition comprising a compound having an LH-RH action and a compound having an LH-RH antagonistic action, and (2) a compound having an LH-RH action and an LH-RH antagonistic action. Any compound formulated separately from the compound it has is included. The medicament of the present invention has an action of suppressing a transient increase in blood steroid hormone (eg, testosterone, estrogen) concentration (flare phenomenon). Furthermore, LH and FSH secreting cells of the pituitary gland are brought into a desensitized state and the action continues. Furthermore, testosterone or estrogen lowering action is enhanced. It is also less toxic. Therefore, the medicament of the present invention can be used to treat a sex hormone (male hormone or female hormone) dependent disease in a mammal (eg, human, monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc.). It can be used effectively and safely for prevention and treatment / prevention of diseases caused by excess of these hormones. That is, the medicament of the present invention is a sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, uterine fibroid, endometriosis, precocious puberty, amenorrhea It is useful for the treatment and prevention of premenstrual syndrome, polycystic ovary syndrome, 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 male or female contraceptive or for the treatment of infertility by inducing ovulation by utilizing the rebound effect after the drug withdrawal. Furthermore, the medicament of the present invention is useful for regulating animal estrus, improving meat quality and promoting animal growth in the field of livestock.

The medicament of the present invention is also effective in combination with a steroidal or non-steroidal antiandrogenic agent or antiestrogenic agent. Moreover, you may use together with the chemotherapy agent of cancer. Preferable specific examples of the combined use include the following hormone drugs, alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, immunotherapeutic agents and the like. As hormonal drugs, for example, phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, Olmeloxifen, levormeloxifen, antiestrogens (eg, tamoxifen citrate, toremifene citrate), mepithiostan, testrolactone, aminoglutethimide, droloxifene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitor ( For example, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg Flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone, ketoconazole) , 17α-hydroxylase / C _17-20 lyase inhibitor, etc.), retinoids and agents that delay the metabolism of retinoids (eg, riarosol). Examples of the alkylating agent include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, toprolate tosilate, busulfan, nimustine hydrochloride, mitoblonitol, melphalan, dacarbazine , Ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospium hydrochloride, fotemustine, pretempustine , Ribomustine, Temozolomide, Treossulfan, Trophosphamide, Dinos Chinsuchimarama, adozelesin, system scan Chin, Bizereshin and the like. Antimetabolites include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur) ), Aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexim, idoxyuridine, mitoguanine, thiazofuline, etc. Is mentioned.

  Anticancer antibiotics include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocalci Examples include nostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin 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 immunotherapeutic agents (BRM) include 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, mercury hematoporphyrin / sodium, topoisomerase I inhibitor (eg irinotecan, topotecan etc.), topoisomerase II inhibitor (eg sobuzoxane etc.), differentiation inducer (For example, retinoids, vitamin Ds, etc.), growth factor inhibitors (eg, suramin, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.) 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 anti-androgen, 5α-reductase inhibitor, androgen synthesis inhibitor, aromatase inhibitor as well as therapeutic agents for dysuria (such as Harnal) ) And the like. In addition, for the treatment and prevention of prostate cancer, it is possible to use a combination of a chemotherapeutic agent such as ifosfamide, UTF, adriamycin, peplomycin, cisplatin and cisplatin in combination with the medicament of the present invention. it can. For the treatment and prevention of breast cancer, cyclophospamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C, mitoxantrone, etc. And chemotherapeutic agents.

  The compound used in the medicament of the present invention may form a salt, and a physiologically acceptable acid addition salt is preferable as the salt. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, etc.) or organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumarate). Salts with acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). Furthermore, when the compound used in the present invention has an acidic group such as —COOH, an inorganic base (eg, an alkali metal salt such as sodium, potassium, calcium, magnesium or alkaline earth metal, ammonia, etc.) or an organic base A salt may be formed with (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.).

  The compound used for the medicament of the present invention or a salt thereof can be isolated and purified by ordinary 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 into a salt by a method known per se or a method analogous thereto, and conversely, when obtained as a salt, a method known per se or It can be converted into a free form or other salt by a method equivalent thereto. When the compound used in the medicament of the present invention or a salt thereof is an optically active substance, it can be separated into d-form and l-form by ordinary optical resolution means.

  As a dosage form when administering the medicament of the present invention, the compound having LH-RH action and the compound having LH-RH antagonistic action can be administered either orally or parenterally, for example, according to a method known per se. However, among them, a compound having an LH-RH action is a parenteral preparation, and a compound having an LH-RH antagonistic action is an oral preparation. For formulation, it is usually mixed with a pharmaceutically acceptable carrier and orally administered as a solid preparation such as tablets, capsules, granules, powders, or injected, suppositories intravenously, subcutaneously, intramuscularly, etc. Alternatively, it is administered parenterally as a sublingual tablet or as a nasal agent. In addition, it may be administered sublingually, subcutaneously or intramuscularly as a sustained release preparation such as a sublingual tablet or a microcapsule. In particular, as a dosage form of a 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, suspending agents, solubilizers, stabilizers, tonicity agents, preservatives and the like are added to the compound used in the medicament of the present invention, and intravenous, subcutaneous and intramuscular injections are prepared by methods known per se. To do. At that time, if necessary, a freeze-dried product can be obtained by a method known per se. When the compound used in the present invention or a salt thereof is administered to a human, for example, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, or diluent, and orally or parenterally as a pharmaceutical composition. Safe administration. Examples of the above preparations include oral preparations (eg, powders, granules, capsules, tablets), injections, drops, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, rectal seats). And vaginal suppositories). As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.

  Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; Examples thereof include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid.

  These preparations can be produced by a method known per se generally used in the preparation process.

  The compound or salt thereof used in the present invention is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HOC 60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (eg, , Methylparaben, propylparaben, benzyl alcohol, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. for aqueous injections, or vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol It can be dissolved, suspended, or emulsified into an oily injection and made into an injection. In order to obtain a preparation for oral administration, according to a method known per se, the compound or a salt thereof used in the present invention is treated with, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), Add a binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. If necessary, it can be made into an orally-administered preparation by coating by a method known per se for the purpose of masking of taste, enteric property or sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Brulon F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) (Made in Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengara, titanium dioxide, etc.) are used. In the case of an enteric preparation, an intermediate layer is preferably provided by a method known per se between the enteric layer and the drug-containing layer for the purpose of separating both layers. In order to obtain an external preparation, the compound or 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 state, the compound used in the present invention or a salt thereof is used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, A cellulose derivative, an acrylic acid polymer, etc.) are added and mixed to obtain a powdery composition. The liquid form is almost the same as in the case of injections, and is an oily or aqueous suspension. In the case of a semi-solid form, an aqueous or oily gel or an ointment is preferred. In addition, these are all pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added.

  For example, for a suppository, the compound or salt thereof used in the present invention can be converted into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. 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 obtain a sustained-release type microcapsule, a method known per se can be adopted. Among them, for example, a water-soluble drug and a drug-retaining substance (eg, natural or synthetic rubber (eg, gelatin) or a polymer compound ( Example: Polyvinyl alcohol)) is used as an inner water layer, and a W / O type float is formed using a polymer polymer (eg, polylactic acid, lactic acid-glycolic acid copolymer) as an oil layer. In this case, the inner water layer is thickened or solidified to a viscosity of about 5000 cp or more, and then the obtained floated product is subjected to an underwater drying method (JP-A-1-57087), physiological An inner aqueous phase solution containing about 20 to 70% by weight of an active polypeptide and a copolymer having a lactic acid / glycolic acid composition ratio of 80/20 to 100/0 and a weight average molecular weight of 7,000 to 30,000 To or sustained release type microcapsules (JP-A-4-321622) produced by microencapsulating a W / O emulsion prepared from an oil phase liquid containing a homopolymer as a release controlling substance It is preferable to administer it in a molded form. The sustained-release microcapsule may be a sustained-release solid injection (such as an implant).

  In order to obtain the above-mentioned nasal preparation, according to a method known per se, 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.), buffer (eg, sodium chloride, sodium citrate, boric acid, borax, sodium monohydrogen phosphate, dihydrogen phosphate) Sodium, etc.), preservatives (eg, parabens such as methylparaben, reverse soaps such as benzalkonium chloride, alcohol derivatives such as benzyl alcohol, organic acids such as sorbic acid and salts thereof, preservatives such as phenol) , Stabilizers (eg, cysteine, thiosorbitol, tartaric acid, citric acid, carbonic acid Thorium, ascorbic acid, glycine, sodium sulfite, etc.), thickeners (eg glycerin, polyethylene glycol, sorbitol, mannitol, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc.) , Suspension agents (eg, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, Tween 80), bile acid surfactants (eg, glycocholinic acid, choline acid, chocolic acid taucolinate, etolinic acid) , Desoxycholinic acid, chenodeoxylinic acid, dehydrocholine acid, glycodesoxycholine acid, etc. Cyclodextrin (eg, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatives thereof (eg, methylated, hydroxyethyl, glycosylated) Body, carboxymethylethyl body, etc.), and Japanese Patent Publication No. 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 (Japanese Patent Laid-Open No. 63-211237).

  The daily dose of the medicament of the present invention varies depending on the degree of symptoms, age of the subject of administration, sex, body weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, preparation, type, type of active ingredient, etc. There is no particular limitation. As a compound having an LH-RH action, its dose is not particularly limited as long as it does not cause a problem of side effects as long as it can cause desensitization of pituitary LH and FSH secreting cells. The dose is about 0.00003 to 3 mg per kg body weight of the mammal, preferably about 0.0003 to 0.3 mg, more preferably about 0.002 to 0.01 mg, usually 1 to 4 times a day Divide into two doses. The dose for use in the field of livestock or fisheries is also the same as above, but about 0.0003 to 3 mg, preferably about 0.001 to 0.03 mg per kg body weight of the administration target organism, is usually 1 to 3 times a day. Divide and administer. In the case of sustained-release preparations, the same dose as described above is used per day.

  As long as the period and amount of administration of the compound having LH-RH antagonistic action can suppress flare caused by the compound having LH-RH action and cause desensitization action of pituitary LH and FSH secreting cells, side effects can be obtained. It is possible to set any period and amount within a range where no problem arises. The daily dose as a compound having LH-RH antagonistic activity is the degree of symptoms, age of subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, active ingredient Although it varies depending on the type and the like and is not particularly limited, it is generally about 0.1 to 160 mg, preferably about 0.1 to 40 mg, more preferably about 0.1 to 30 mg or about 0.1 or less per kg body weight of a mammal by oral administration. 1-20 mg is mentioned, Most preferably, it is 0.1-10 mg, and this is normally administered in 1 to 4 times a day. The dosage for use in the field of livestock or fisheries is also the same as above, but about 0.01 to 10 mg, preferably about 0.02 to 5 mg per 1 kg body weight of the subject organism is usually divided into 1 to 3 times a day. Administer. In the case of sustained-release preparations, the same dose as described above is used per day.

In the composition of the present invention, the dose ratio between the compound having LH-RH action and the compound having LH-RH antagonistic action is, for example, LH-RH antagonistic action relative to 1 weight of the compound having LH-RH action. Is about 10 to 10 ⁶ times weight, preferably about 10 to 10 ⁵ times weight, more preferably about 10 to 10 ⁴ times weight, and most preferably about 10 ² to 10 ⁴ times weight.

  When administering the medicament of the present invention, it may be administered at the same time, but it is preferable to administer a compound having an LH-RH antagonistic action first and then administering a compound having an LH-RH action. In the case of administration at such a time difference, it is desirable to administer a compound having an LH-RH antagonistic action and administering a compound having an LH-RH action after the blood compound concentration has sufficiently increased, The preferred time difference varies depending on the administration and dosage form. For example, a compound having an LH-RH antagonistic action is administered after administration of a compound having an LH-RH antagonistic action 1 hour or more after administration of a compound having an LH-RH antagonistic action. Examples include a method of administering a compound having an LH-RH action 1 hour or more to 1 day to 1 week after administration.

  As a preferable administration method, for example, about 0.1 to 10 mg / kg of a compound having an LH-RH antagonistic action formed into an oral preparation is orally administered, and a sustained-release preparation (eg, about 2 to 6 hours later) About 0.001 to 0.03 mg / kg of a compound having an LH-RH action that is formed into a microcapsule) or a nasal preparation, Administered subcutaneously as 30 times the amount). Then, the method of administering an oral preparation 1 to 4 times a day (a daily dose of 0.1 to 10 mg / kg) for 3 to 14 days continuously can be mentioned. About 0.1 to 10 mg / kg of a compound having an LH-RH antagonistic action formed into a subcutaneous (injection) preparation is subcutaneously administered, and a sustained release preparation (eg, microcapsule) or about 1 to 6 hours later About 0.001 to 0.03 mg / kg of a compound having an LH-RH action formed into a nasal preparation is administered in a daily dose (for example, 30 times the daily dose in the case of a 30-day sustained-release preparation) To be administered). Thereafter, a method of administering a subcutaneously administered preparation 1 to 4 times a day (a daily dose of 0.1 to 10 mg / kg) for 3 to 14 days in a continuous manner can be mentioned. About 0.1 to 10 mg / kg of a compound having an LH-RH antagonistic action formed into a sustained-release preparation (eg, microcapsule) is administered in a daily dose (for example, in the case of a 30-day sustained-release preparation, 1 About 0.001 to 0.03 mg of a compound having an LH-RH action, which is subcutaneously administered as 30 times the daily dose) and formed into a sustained-release preparation (eg, microcapsule) after about 1 to 6 hours / Kg may be administered subcutaneously as a daily dose (for example, in the case of a 30-day sustained-release preparation, it is 30 times the daily dose). Further, a compound having an LH-RH action may be administered after a compound having an LH-RH antagonistic action is administered for a certain period of time. For example, a compound having an LH-RH antagonistic activity is administered subcutaneously or orally at a dose of 0.1 to 10 mg / kg per day for 1 to 3 weeks, or after administration of a similar amount of sustained-release preparation. A compound having LH-RH action is administered.

  The compound having an LH-RH action and the compound having an LH-RH antagonistic action used in the present invention are used in combination, for example, by the method described above. When used in combination, those formulated separately may be used together, or may be a kit. More specifically, the fact that the preparation of the compound having the LH-RH action and the preparation of the compound having the LH-RH antagonistic action are directly used in the respective containers or envelopes or package inserts is described. May be. For example, the administration of the LH-RH antagonistic compound 1 to 6 hours after the administration of the LH-RH antagonistic compound tablet or injection to each direct container or capsule or package insert of the preparation. A releasable preparation or a nasal preparation is administered; a tablet or injection of the compound having LH-RH antagonistic action is repeatedly administered for 1 to 3 weeks, and then a sustained release preparation or transdermal preparation of the compound having LH-RH action is administered. It is described that a nasal preparation is administered. The compound having LH-RH action and the compound having LH-RH antagonistic action are usually contained in 1 to 99% by weight of a medicine.

  The present invention will be described more specifically with reference to the following reference examples, examples and test examples, but the present invention is not limited thereby. Of the four compounds used in Example 1 shown below, Compound E-1 is 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, 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, Compound E-3 is 5-n-butyryl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl) -2- (4-methoxyphenyl)- 4-oxochi [2,3-b] pyridine hydrochloride, and compound E-4 is 5-benzoyl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluoro). Benzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine hydrochloride, 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 Which is the hydrochloride salt and 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 described in PCT International Publication No. WO95 / 28405.

Reference example (a)
4,7-Dihydro-4-oxo-7- (2,6-difluorobenzyl) -3- (N-methyl-N-benzyl) prepared according to Example 57 (10) of PCT International Publication No. WO 95/28405 Aminomethyl) -2- (4-isobutyrylaminophenyl) -5-isobutyrylthieno [2,3-b] pyridine (Compound No. 1, the structural formula is shown in the above [Chemical Formula 39]) 100 mg), lactose 165 mg, corn starch 25 mg, polyvinyl alcohol 4 mg, and magnesium stearate 1 mg are prepared in a conventional manner.

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 Co., Ltd.), dispensed in 2 ml portions into washed and sterilized vials, freeze-dried by a conventional method, and 100 mg / A freeze-dried injection of a vial is produced.

Reference example (c)
(1) Compound No. E-5 5 g
(2) Lactose / crystalline cellulose (grain) 330g
(3) D-mannitol 29g
(4) Low substituted hydroxypropylcellulose 20 g
(5) Talc 25g
(6) Hydroxypropylcellulose 50g
(7) Aspartame 3g
(8) Dipotassium glycyrrhizinate 3g
(9) Hydroxypropyl methylcellulose 2910 30 g
(10) Titanium oxide 3.5g
(11) Yellow iron sesquioxide 0.5g
(12) Light anhydrous silicic acid 1g
(1), (3), (4), (5), (6), (7) and (8) are suspended or dissolved in purified water, coated on the core particles of (2), and fine particles are coated. Make it. (9)-(11) is coated on the elementary fine particles to form coated fine particles, and mixed with (12) to produce 1%, 500 g of fine particles of Compound No. E-5. Package 500 mg of this.

Reference example (d)
A tablet is produced by a conventional method using 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. .

Reference example (e)
Tablets were prepared in a conventional manner using Compound E-6 or E-7 (100 mg), crystalline cellulose 50 mg, low-substituted hydroxypropylcellulose-31 (30 mg), hydroxypropylcellulose-L (6 mg) and magnesium stearate 1 mg. To manufacture.

Reference example (f)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 2-16 described later, lactose 150 mg, croscarmellose sodium 30 mg, hydroxypropylcellulose 6 mg and magnesium stearate 1 mg.

Reference example (g)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 3-30 described later, 165 mg lactose, 25 mg corn starch, 4 mg polyvinyl alcohol and 1 mg magnesium stearate.

Reference example (h)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 4-2 described later, lactose 150 mg, low-substituted hydroxypropylcellulose-31 (30 mg), polyvinylpyrrolidone 10 mg and magnesium stearate 1 mg. .

Reference example (i)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 5-5 (1) described later, 150 mg of lactose, 30 mg of carboxymethylcellulose calcium, 6 mg of hydroxypropylcellulose and 1 mg of magnesium stearate.

Reference example (j)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 6-21 described later, 165 mg lactose, 25 mg corn starch, 4 mg polyvinyl alcohol and 1 mg magnesium stearate.

Reference example (k)
A tablet is produced by a conventional method using the compound (100 mg) produced in Reference Example 7-6 described later, 165 mg lactose, 25 mg corn starch, 4 mg polyvinyl alcohol and 1 mg magnesium stearate.

Reference example (l)
Compound E-1, E-2, E-3, E-4 or E-5 (0.5 g) and 1 g of mannitol are 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 Co., Ltd.), dispensed in 10 ml portions into washed and sterilized vials, lyophilized by a conventional method, and 50 mg / Produce lyophilized injections for vials.

Reference example (m)
(1) Compound E-1, E-2, E-3, E-4 or E-5 100 g
(2) Lactose 234g
(3) Corn starch 150g
(4) Hydroxypropylcellulose 15g
(5) Light anhydrous silicic acid 1g
(Total 500g)
(1), (2) and (3) are mixed in a fluid bed granulator, and (4) dissolved in purified water is sprayed to obtain fine granules. After mixing with (5), wrap 500 mg each.

In the following reference examples, ¹ H-NMR spectrum is obtained by using tetramethylsilane as an internal standard, Varian GEMINI 200 (200 MHz) type spectrum meter, JEOL LAMBDA300 (300 MHz) type spectrum meter, or Brucker AM 500 (500 MHz). Measured with a type spectrometer and all δ values are given in ppm. Further, symbols used in this specification have the following meanings.
s: singlet, d: doublet, t: triplet, dt: double triplet, m: multiplet, br: wide

Reference example 1
The compounds listed in the following [Table 1] to [Table 21] are produced according to the method described in PCT International Publication WO95 / 28405.

Reference Example 2-1
(1) Preparation of 4,7-dihydro-5-hydroxy-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine: PCT 4-Hydroxy-5-hydroxymethyl-2- (4-methoxyphenyl) -3-methylthieno [2,3-b] pyridine, 2-fluorobenzyl chloride and iodine obtained in Reference Example 11 of International Publication WO95 / 28405 The title compound is prepared from potassium halide.
mp 159-160 ° C.
(2) Preparation of 4,7-dihydro-2-phenyl-3-methyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The title compound is produced in the same manner as in Reference Example 2-1 (1).
mp 184-186 ° C.
Reference Example 2-2
Preparation of 2-isopropylthioacetic acid methyl ester: 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
Preparation of 2- (N, N-dimethylaminomethylene) -2-isopropylthioacetic acid methyl ester: The title compound is prepared from the compound obtained in Reference Example 2-2 and N, N-dimethylformamide dimethyl acetal.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6Hz), 2.89-2.98 (1H, m), 3.26 (6H, s), 3.72 (3H, s), 7.88 (1H, s ).

Reference Example 2-4
Production of 2-amino-5-phenyl-4-methylthiophene-3-carboxylic acid: 2-amino-5-phenyl-4-methylthiophene-3-carboxylic acid obtained in Reference Example 3 of PCT International Publication WO95 / 28405 The title compound is prepared from the acid ethyl ester and 2N sodium hydroxide. The resulting compound is used in the next reaction without purification.
Reference Example 2-5
Preparation of (3-carboxy-5-phenyl-4-methylthiophen-2-yl) -aminomethylene- (2-isopropylthio) acetic acid methyl ester: the compound obtained in Reference Example 2-4 and Reference Example 2-3 The title compound is produced from the resulting compound.
m.p. 119-121 ° C.
Reference Example 2-6
Production of 4-hydroxy-2-phenyl-3-methyl-5-isopropylthiothieno [2,3-b] pyridine: The title compound is produced from the compound obtained in Reference Example 2-5 and diphenyl ether.
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
Of 4,7-dihydro-2- (4-methoxyphenyl) -3-methyl-5- (oxazol-5-yl) -7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine Production: 4,7-dihydro-2- (4-methoxyphenyl) -3-methyl-5-formyl-7- (2-fluorobenzyl) -4 obtained in Example 28 of PCT International Publication No. WO 95/28405 The title compound is prepared from oxothieno [2,3-b] pyridine, tosylmethyl isocyanide and potassium carbonate.
mp 235-236 ° C.

Reference Example 2-8
Of 4,7-dihydro-2- (4-methoxyphenyl) -3-bromomethyl-5- (oxazol-5-yl) -7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine Production: The title compound is produced from the compound obtained in Reference Example 2-7, N-bromosuccinimide and α, α'-azobisisobutyronitrile.
mp 234-236 ° C.
Reference Example 2-9
3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-2- (4-methoxyphenyl) -5- (oxazol-5-yl) -7- (2-fluorobenzyl) -4- Production of oxothieno [2,3-b] pyridine: The title compound is produced from the compound obtained in Reference Example 2-8, ethyldiisopropylamine and N-benzylmethylamine.
mp 144-150 ° C.
Reference Example 2-10
Preparation of 4,7-dihydro-2-phenyl-3-methyl-5-acetylamino-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: PCT International Publication WO 95/28405 From the compound obtained in Example 3 (13) of the publication, O-methyl-N-methylhydroxylamine hydrochloride and diisopropylethylamine, a compound in which the 5-position is N-methyl-O-hydroxamic acid is obtained. The resulting compound is then reacted with methylmagnesium chloride to react 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 (1H, s).

Reference Example 2-11
Production method of 4,7-dihydro-2-phenyl-3-methyl-5-amino-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: In Reference Example 2-10 The title compound is prepared from the compound to be prepared 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
Method for producing 4,7-dihydro-2- (4-nitrophenyl) -3-methyl-5-acetoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: 4,7-Dihydro-2-phenyl-3-methyl-5-acetyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] produced by the method of Reference Example 2-10 The title compound is prepared from pyridine and m-chloroperbenzoic acid.
mp 216-217 ° C.
Reference Example 2-13
Method for producing 4,7-dihydro-2- (4-nitrophenyl) -3-methyl-5-isopropoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: The title compound is prepared by hydrolyzing the compound obtained in Reference Example 2-12 with 1N sodium hydroxide and reacting with isopropyl bromide.
m.p. 188-189 ° C.

Reference Example 2-14
(1) Using the compound produced in Reference Example 2-13, the following compound is produced in the same manner as in Reference Example 2-8. 4,7-Dihydro-2- (4-nitrophenyl) -3-bromomethyl-5-isopropoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine. Yellow amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d), 4.68 (1H, m), 5.04 (2H, s), 5.27 (2H, s), 7.03 (2H, t), 7.4-7.5 (2H m) .7.85 (2H, d), 8.33 (2H, d).
(2) Using the compound produced in Reference Example 2-14 (1), the following compound is produced in the same manner as in Reference Example 2-9. 4,7-Dihydro-2- (4-nitrophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropoxy-7- (2,6-difluorobenzyl) -4-oxothieno [2 , 3-b] pyridine. Yellow amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.33 (6H, d), 2.23 (3H, s), 3.70 (2H, s), 4.23 (2H, s), 4.64 (1H, m), 5.22 (2H, s ), 7.01 (2H, t), 7.1-7.5 (7H, m), 8.11 (2H, d), 8.23 (2H, d).
(3) Using the compound produced in Reference Example 2-14 (2), the following compound is produced by the same method as Reference Example 2-26 described later. 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) Using the compound produced in Reference Example 2-14 (3), the following compound is produced in the same manner as in Reference Example 2-27 described later. 4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropoxy-7- (2,6-difluorobenzyl) -4- Oxothieno [2,3-b] pyridine. Yellow amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d), 1.35 (6H, d), 2.42 (3H, s), 2.95 (1H, m), 3.73 (2H, s), 4.25 (2H, s ), 4.63 (1H, m), 5.35 (2H, s), 6.99 (2H, t), 7.2-7.5 (8H, m), 7.69 (1H, 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) -4-oxothieno [2,3-b] Pyridine Production Method: 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, 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] pyridine hydrochloride production method: The compound obtained in Reference Example 2-15 is reacted with isopropylsulfonyl chloride, and then colorless crystals are obtained as hydrochloride with hydrogen chloride-ether. Hydrochloride:
m.p. 172-177 ° C.
Reference Example 2-17
4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isobutyryloxy-7- (2,6-difluorobenzyl)- Production of 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 Preparation of oxothieno [2,3-b] pyridine and its hydrochloride: The title compound is prepared from the compound obtained in Reference Example 2-15 and ethyl bromide acetate.
Free form:
¹ H-NMR (CDCl ₃ ) δ: 1.2-1.3 (9H, m), 2.20 (3H, s), 2.83 (1H, brs), 3.74 (2H, s), 4.1-4.2 (4H, m), 4.82 (2H, s), 5.22 (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:
m.p. 190-194 ° C.
Reference Example 2-19
4,7-Dihydro-2- (4-isobutyrylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-carbamoylmethoxy-7- (2,6-difluorobenzyl) -4- Production of oxothieno [2,3-b] pyridine: The title compound is produced from the educt obtained in Reference Example 2-18 and ammonia-ethanol.
m.p. 237-238 ° C.
Reference Example 2-20
Preparation of 4,7-dihydro-2-phenyl-3-methyl-5-isopropylthio-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: In Reference Example 2-6 The title compound is prepared from the resulting compound and 2,6-difluorobenzyl chloride.
m.p. 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: In Reference Example 2-20 The title compound is produced from the resulting compound and metachloroperbenzoic acid.
m.p. 217-219 ° C.
Reference Example 2-22
Preparation of 4,7-dihydro-2-phenyl-3-methyl-5-isopropylsulfonyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: In Reference Example 2-21 The above compound is produced as a by-product.
m.p. 231-233 ° C.
Reference Example 2-23
Production of 4,7-dihydro-2- (4-nitrophenyl) -3-methyl-5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: Reference The title compound is prepared from the compound obtained in Example 2-21 and a concentrated sulfuric acid solution of sodium nitrate.
m.p. 212-214 ° C.
Reference Example 2-24
Production of 4,7-dihydro-2- (4-nitrophenyl) -3-bromomethyl-5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine: Reference The title compound is prepared from the compound obtained in Example 2-23, N-bromosuccinimide (NBS) and α, α′-azobisisobutyronitrile (AIBN).
mp 176-181 ° C.

Reference Example 2-25
4,7-Dihydro-2- (4-nitrophenyl) -3- (N-benzyl-N-methylaminomethyl) -5-isopropylsulfinyl-7- (2,6-difluorobenzyl) -4-oxothieno [2 , 3-b] Preparation of pyridine: The title compound is prepared from the compound obtained in Reference Example 2-24, ethyldiisopropylamine and N-methylbenzylamine.
m.p. 98-103 ° C.
Reference Example 2-26
4,7-Dihydro-2- (4-aminophenyl) -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 2-25, iron powder and concentrated hydrochloric acid.
m.p. 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- Production of oxothieno [2,3-b] 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 = 6.8 Hz), 1.51 (3H, d, J = 7.1 Hz), 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- Preparation of oxothieno [2,3-b] pyridine hydrochloride: The title compound is prepared from the compound obtained in Reference Example 2-27 and 1M hydrogen chloride ether solution.
m.p. 185-187 ° C.
Reference Example 2-29
The following compounds are prepared as 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].

Reference Example 3-1
Preparation of 4,7-dihydro-7- (2.6-difluorobenzyl) -2-phenyl-3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: PCT International Publication No. 4-hydroxy-2-phenyl-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester and 2,6-difluorobenzyl obtained by the method of Reference Example 9 (1) of WO 95/28405 The title compound is prepared from the chloride.
mp 171-173 ° C.
Reference Example 3-2
Preparation of 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-nitrophenyl) -3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester The title compound is produced from the compound obtained in Reference Example 3-1 and a concentrated sulfuric acid solution of sodium nitrate.
mp 260-261 ° C.
Reference Example 3-3
Preparation of 3-bromomethyl-4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester The title compound is prepared from the compound obtained in Reference Example 3-2, N-bromosuccinimide and α, α′-azobisisobutyronitrile.
mp 200-201 ° 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] Preparation of pyridine-5-carboxylic acid ethyl ester hydrochloride: The title compound is prepared from the compound obtained in Reference Example 3-3, ethyl diisopropylamine 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] Preparation of pyridine-5-carboxylic acid ethyl ester hydrochloride: The title compound is prepared 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-oxothieno [2,3 -B] Production of pyridine-5-carboxylic acid ethyl ester: The title compound is produced 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-oxothieno [2,3 -B] Preparation of pyridine-5- (N-methyl-O-methyl) hydroxamic acid: obtained in Reference Example 3-6 to a mixture of N, O-dimethoxyhydroxylamine hydrochloride, diisopropylamine and trimethylaluminum in hexane. To give the title compound.
¹ H-NMR (300MHz, 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 = 8.4Hz).
Mass m / z 685 (MH) ⁺ .

Reference Example 3-8
Produced in the same manner as described in Reference Examples 3-6 and 3-7 using the compound obtained in Example 27 (2) of PCT International Publication No. WO95 / 28405 or Reference Example 3-14 described later as a raw material The compounds obtained are shown in [Table 25].

“N-methyl-O-methylhydroxamic acid” in Table 25 represents a group represented by the formula —CO—N (OCH ₃ ) CH ₃ .

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

Reference Example 3-12
Preparation of 4-hydroxy-2- (4-methoxyphenyl) -3-bromomethylthieno [2,3-b] pyridine-5-acetic acid ethyl ester: obtained in Reference Example 8 of PCT International Publication No. WO 95/28405 The title compound is produced in the same manner as described in Reference Example 3-3 using the compound as a starting material.
Reference Example 3-13
Preparation of 4-hydroxy-2- (4-methoxyphenyl) -3- (N-benzyl-N-methylaminomethyl) thieno [2,3-b] pyridine-5-acetic acid ethyl ester: In Reference Example 3-12 The title compound is produced in the same manner as described in Reference Example 3-4 using the resulting compound as a starting material.
Reference Example 3-14
4,7-Dihydro-7- (2,6-difluorobenzyl) -2- (4-methoxyphenyl) -3- (N-benzyl-N-methylaminomethyl) thieno [2,3-b] pyridine-5 -Production of ethyl acetate: The title compound is produced in the same manner as described in Reference Example 3-1, starting from the compound obtained in Reference Example 3-13.

Reference Example 3-15
4,7-Dihydro-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -4-oxothieno [2, 3-b] Preparation of pyridine hydrochloride: The title compound is prepared 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-oxothieno [2, 3-b] Production of pyridine hydrochloride: The title compound is produced in the same manner as described in Reference Example 3-15 using the compound obtained in Reference Example 3-11 as a starting material.

Reference Example 3-17
3- [N-methyl-N- (N-methylindol-3-ylmethyl) aminomethyl-4,7-dihydro-7- (2,6-difluorobenzyl) -5-isobutyryl-2- (4-isobutyryl Preparation of Rylaminophenyl) -4-oxothieno [2,3-b] pyridine hydrochloride: The compound obtained in Reference Example 3-2 was converted to 5- (N-methyl-O-methyl) hydroxamic acid, which was converted to 5- 3-Butyl methyl-4,7 produced by converting the 4-nitrophenyl at the 2-position to 4-aminophenyl, acylating (introducing an isobutyryl group), and bromating the methyl at the 3-position -Dihydro-7- (2,6-difluorobenzyl) -5-isobutyryl-2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine and 3-N-methylaminomethyl- '- and a methylindole, the title compound is produced.
mp 170-172 [deg.] C [hydrochloride].

Reference Example 3-18
The compounds shown in Table 26 and Table 27 are produced in the same manner as described in Reference Example 3-17.

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

Reference Example 3-20
Using the compound obtained in Example 54 of PCT International Publication WO95 / 28405, the compounds shown in [Table 28] and [Table 29] are produced in the same manner as described in Reference Example 3-19. .

Reference Example 3-21
3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5-benzoyl-2- [4- (3-oxobutyl) aminophenyl] -4 -Preparation of oxothieno [2,3-b] pyridine hydrochloride: The title compound is prepared from the compound obtained in Example 54 of PCT International Publication No. WO 95/28405 and methyl vinyl ketone. mp 165-168 [deg.] C [hydrochloride].

Reference Example 3-22
Using the compound obtained in Example 54 of PCT International Publication WO95 / 28405, various vinyl compounds or oxirane compounds are reacted to produce the compounds shown in [Table 30].

Reference Example 3-23
3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5-benzoyl-2- [4- (2-acetylvinylenephenyl)]-4 -Production of oxothieno [2,3-b] pyridine hydrochloride: The compound obtained in Reference Example 3-10 is reacted with an acetic acid solution of isoamyl nitrite, bisdibenzylideneacetone palladium and methyl vinyl ketone, and the resulting compound is usually used. The title compound is prepared by the method.
mp 149-151 [deg.] C [hydrochloride].

Reference Example 3-24
The compound shown in Table 31 is produced from the compound obtained in Reference Example 3-10 and various vinyl compounds.

Reference Example 3-25
3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5-benzoyl-2- [4- (N-ethyl-N-trifluoroacetyl) Preparation of aminophenyl)]-4-oxothieno [2,3-b] pyridine: The title compound is prepared from the compound obtained in Reference Example 3-19, ethyl iodide and potassium carbonate.
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), 7.12-7.32 (7H, m), 7.37-7.47 (3H, m), 7.55 (1H, m) , 7.89 (2H, d, J = 7.8 Hz), 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-oxothieno [2 , 3-b] Preparation of pyridine hydrochloride: The title compound is prepared from the compound obtained in Reference Example 3-25 and 5N potassium hydroxide.
mp 166-168 [deg.] C [hydrochloride].

Reference Example 3-27
From the compound obtained in Reference Example 3-19 or Reference Example 3-21 and various halogen compounds, it is shown in [Table 32] by the same method as described in Reference Example 3-25 or Reference Example 3-26. A compound is produced.

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

Reference Example 3-31
3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5- (1-acetoxyisobutyl) -2- (4-isobutyrylaminophenyl) ) Preparation of 4-oxothieno [2,3-b] pyridine hydrochloride: The title compound is prepared from the compound obtained in Reference Example 3-30, pyridine and acetic anhydride.
mp 166-168 [deg.] C [hydrochloride].
Reference Example 3-32
4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-acetonyloxyphenyl) -5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -4-oxothieno [ 2,3-b] Production of 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) -2- (4-acetonyloxyphenyl) -5-isobutyryl-3- (N-benzyl-N-methylaminomethyl) -4-oxothieno [ 2,3-b] Production of pyridine hydrochloride: The title compound is produced from the compound obtained in Reference Example 3-16.

  The compounds shown in Reference Examples 3-17, 3-19, 3-21, 3-23, 3-25, 3-26, 3-28 to 3-33 are listed in the following [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] Preparation of pyridine-5-carboxylic acid ethyl ester (hereinafter referred to as compound 4-B): Compound of Example 27 (hereinafter referred to as compound 4-A) of PCT International Publication No. WO95 / 28405 and isoform The title compound is prepared from butyryl chloride.
mp 233-235 ° C.
Compounds 4-A and 4-B of the above Reference Example are shown in the following [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] Preparation of pyridine-5-carboxylic acid isopropyl ester hydrochloride: The title compound is prepared from an isopropyl alcohol solution of compound 4-B and isopropyl titanate.
mp 168-170 ° C.

Reference Example 4-3
In the same manner as in Reference Example 4-2, the compounds shown in [Table 35] (4-3 (1), 4-3 (2), 4-3 (3), 4-3 (4) , 4-4, 4-5). ([Table 35] includes the compound of Reference Example 4-2.)

Reference Example 4-4
4,7-Dihydro-7- (2,6-difluorobenzyl) -2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -5- (4-tetrahydropyrani L) Preparation of thiocarbonyl-4-oxothieno [2,3-b] pyridine: 4-mercaptotetrahydrofuran (470 mg, 4.00 mmole) was dissolved in dichloromethane (2 ml) and trimethylaluminum (15%, 0.48 ml) was dissolved therein. A hexane solution (15 ml) of 1.00 mmole was added dropwise under ice cooling. After stirring at the same temperature for 1 hour, a dichloromethane solution (1 ml) of the compound obtained in Reference Example 3 (129 mg, 0.20 mmole) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, poured into 200 ml of distilled water, extracted with chloroform, washed with saturated brine and dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain yellow amorphous (30 mg, 11%). The obtained amorphous was dissolved in chloroform, added with 10N hydrochloric acid-ethanol solution to form a salt, and recrystallized from chloroform-ether to obtain the title compound as yellow powdery crystals. The structure is shown in the following compound 4-6 in [Table 35].
mp 174-176 ° C.
Elemental analysis value: C ₃₉ H ₃₉ N ₃ O ₄ S ₂ F ₂ .HCl · 2.5 H ₂ O as C H N
Calculated value: 58.75; 5.69; 5.27 (%)
Found: 58.77; 5.59; 5.54 (%).
¹ H-NMR (300 MHz, CDCl 3) δ: 1.28 (6H, d, J = 6.8 Hz), 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 = 8.6 Hz), 8.37 (1H, s).

Reference Example 4-5
The compounds 4-4 shown in Table 35 were used as raw materials and treated in the same manner as in Reference Example 4-4 to prepare compounds 4-7 and 4-8 shown in the following [Table 35].

Reference Example 5-1
(1) 4,7-dihydro-4-oxo-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3-methyl-thieno [2,3-b] pyridine-5-carvone Preparation of acid ethyl ester: Compound of Example 3 (10) of PCT International Publication No. WO95 / 28405: 4-oxo-7- (2,6-difluorobenzyl) -2- (4-methoxyphenyl) -3- The title compound is prepared from methyl-thieno [2,3-b] 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-5 Preparation of carboxylic acid ethyl ester: The title compound is prepared from the compound of Reference Example 5-1 (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), 5.22 (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 [ 2,3-b] Pyridine-5-carboxylic acid ethyl ester: reaction of the compound obtained in Reference Example 5-1 (2) above, N-bromosuccinimide and α, α'-azobisisobutyronitrile The title compound is prepared by reacting the resulting compound with ethyldiisopropylamine and N-methylbenzylamine.
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 [ 2,3-b] Pyridine-5-N-methyl-O-methylhydroxamic acid: Compound obtained in Reference Example 5-1 (3), N-methyl-O-methylhydroxylamine hydrochloride, N-ethyl The title compound is prepared from diisopropylamine and trimethylaluminum.
¹ H-NMR (300MHz, 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 = 8.3Hz), 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- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3- (N-benzyl-N-methylaminomethyl) -5-benzoyl Production of thieno [2,3-b] pyridine: The title compound is produced from the compound obtained in Reference Example 5-1 (4), phenylmagnesium bromide and 6N hydrochloric acid.
¹ H-NMR (300MHz, 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-iso Production of butyrylthieno [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 (300MHz, 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 to a compound in which the substituent at the 5-position was a carboxyl group, and this was converted to N, N-dimethylaminopyridine and alcohol (isopropanol, cyclohexane). Hexanol, 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. The 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].

Reference Example 5-3
3- (N-methyl-N-benzylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-allyloxyphenyl) -5-benzoyl-4-oxothieno [2 , 3-b] Preparation of pyridine hydrochloride: The title compound is prepared 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, the compound produced by the same method as described in Reference Example 5-3, including the compound of Reference Example 5-3 [Table 37] Shown in

Reference Example 5-5
The compounds produced in the same manner as described in Reference Example 5-3 using the compound obtained in Reference Example 5-1 (6) as a raw material are shown in [Table 38].

Reference Example 5-6
Table 39 shows compounds produced by the same method as described in Reference Example 5-3 using the compound obtained in Reference Example 5-2 as a starting material.

Reference Example 6-1
The compounds produced using acetone derivatives in the same manner as described in Reference Example 2 of PCT International Publication WO95 / 28405 are shown in [Table 40].

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

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

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

Reference Example 6-5
Production of 3-isobutyl-2,4 (1H, 3H) -dioxo-5-methyl-6- (4-methoxyphenyl) thieno [2,3-d] pyrimidine: Reference example of PCT International Publication No. WO 95/28405 The title compound is prepared from the compound of 2, isovaleric acid, diphenylphosphoryl azide and triethylamine.
mp 215-216 ° C.

Reference Example 6-6
A compound produced by the same method as described in Reference Example 6-5 using the compound of Reference Example 2 of PCT International Publication WO95 / 28405 or Reference Example 19 of PCT International Publication WO95 / 28405 as a raw material It shows in [Table 44].

Reference Example 6-7
Preparation of 2-amino-4-methyl-5- (4-methoxyphenyl) thiophene-3-carboxylic acid: From the compound of Reference Example 2 of PCT International Publication No. WO95 / 28405 and 2N sodium hydroxide, the title compound was Manufactured.
mp 142-145 ° C.

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

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

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

Reference Example 6-13
Production of 2,4 (1H, 3H) -dioxo-3-phenyl-5-methyl-6- (4-methoxyphenyl) thieno [2,3-d] pyrimidine: Reference example of PCT International Publication No. WO 95/28405 The title compound is prepared from the compound obtained in 19 and phenyl isocyanate.
mp> 300 ° C.
Reference Example 6-14
Preparation of 2,4 (1H, 3H) -dioxo-5-methyl-3- (3-methoxyphenyl) -6- (4-methoxyphenyl) thieno [2,3-d] pyrimidine: PCT International Publication No. WO95 / The title compound is produced using 3-methoxyphenyl isocyanate and 28% sodium methoxide in the same manner as described in Reference Example 6-13 using the compound obtained in Reference Example 19 of 28405.
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 [2,3- d] Production of 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-methoxyphenyl) thieno [2,3- d] Production of pyrimidine: The title compound is produced from the compound obtained in Reference Example 6-15 using m-chloroperbenzoic acid again in the same manner as described in Reference Example 6-15.
mp 256-257 ° C.

Reference Example 6-17
Manufactured by the same method as described in Reference Example 6-9 using as a raw material a compound obtained by the same method as described in Reference Example 6-5, 6-6, 6-13 or 6-14 The compounds are shown in [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] pyrimidine The title compound is prepared 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
Compounds prepared in the same manner as described in Reference Example 6-18 using the compound obtained in Reference Examples 6-11, 6-12, 6-15, 6-16, or 6-17 as a raw material [Table 47].

Reference Example 6-20
2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -3-phenyl 1- (2-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -thieno [2, 3-d] Preparation of pyrimidine (referred to as compound 6-A): The title compound was prepared from the compound obtained in Reference Example 26 (5) of PCT International Publication WO 95/28405, ethyldiisopropylamine and methylbenzylamine. The
mp 140-143 ° C.
Tables 48 and 49 show compounds obtained by the above method using the compound obtained in Reference Example 26 of PCT International Publication No. WO95 / 28405 or Reference Example 6-4 as a raw material.

Reference Example 6-21
6- (4-aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [ 2,3-d] Pyrimidine Production: The title compound is produced in the same manner as in Example 60 of PCT International Publication No. WO95 / 28405 using Compound 17 obtained in Reference Example 6-20. The structure of the obtained compound is shown in [Table 50].
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), 7.21-7.53 (13H, m).
Reference Example 6-22
6- (4-acetylaminophenyl) -2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2 , 3-d] Pyrimidine: The title compound is prepared from the compound obtained in Example 60 of PCT International Publication No. WO 95/28405 and acetic anhydride. The structure of the obtained compound is shown in [Table 50].
¹ H-NMR (300MHz, 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 = 8.4 Hz).

Reference Example 6-23
Using the compound obtained in Example 60 of PCT International Publication WO95 / 28405, the following compound is produced in the same manner as in Reference Example 6-22. 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 No. 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.).

Reference Example 6-24
2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methoxyphenyl) -3- (3-methoxypropyl) ) Preparation of thieno [2,3-d] pyrimidine hydrochloride: The title compound is prepared from the compound obtained in Reference Example 6-18, ethyldiisopropylamine and methylbenzylamine. The structure of the obtained compound is shown in [Table 50].
mp 95-100 ° C.

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

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. 13 obtained in Reference Example 6-25 and 50% palladium-carbon powder were reacted in a hydrogen atmosphere to produce the title compound. Is done. The structure of the obtained compound is shown in [Table 52].
mp 162-165 ° C.

Reference Example 6-27
The compounds produced by the same method as described in Reference Example 6-26 using the compound obtained in Reference Example 6-25 are shown in [Table 52].

Reference Example 6-28
2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-formamidophenyl) -3-phenylthieno [ Preparation of 2,3-d] pyrimidine: The title compound is prepared 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 produced by the same method as described in Reference Example 6-28 using the compound obtained in Reference Example 6-26 or 6-27 are shown in [Table 53].

Reference Example 6-30
2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methylaminophenyl) -3- (3 -Methoxyphenyl) thieno [2,3-d] pyrimidine hydrochloride: The title compound free form was prepared from Compound No. 2 obtained in Reference Example 6-29 and dimethyl sulfide borane, and then 1N ethereal. The hydrochloride is obtained with hydrochloric acid (pH <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-methylaminomethyl) -3- (3 -Methoxyphenyl) thieno [2,3-d] pyrimidine hydrochloride: The compound obtained in Reference Example 6-26 is reacted with triethylamine and propionyl chloride, and then the resulting compound is treated with 1N ethereal hydrochloric acid. The title compound is produced. The structure of the obtained compound is shown in [Table 54].
mp 218-224 ° C.

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

Reference Example 6-33
Using the compound obtained in Reference Example 6-26 or 6-27 as a raw material and using trifluoroacetic anhydride in the same manner as described in Reference Example 6-31, a trifluoroacetylamino derivative is obtained. In the presence of (eg, potassium carbonate), a compound shown in Table 56 is produced using a halogen compound (eg, propyl bromide, isopropyl bromide) and then 2N sodium hydroxide.

Reference Example 6-34
Compounds shown in Table 57 using the compound obtained in Reference Example 6-26 or 6-27 as a raw material and using isoamyl nitrite, vinyl compound and palladium compound (eg, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium) Is manufactured.

Reference Example 6-35
Compound 6-3 (1) or 6-3 (2) obtained in Reference Example 6-3, a mixture of arylboric acid derivative, 2M sodium carbonate and 1,2-dimethoxyethane, and tetrakis (triphenylphosphine) palladium (0) N-methylbenzylamino group is introduced into the compound obtained by using the same method as in Reference Example 6-18 and Reference Example 6-20 to produce the compound shown in [Table 58].

Reference Example 6-36
Using the compound obtained in Reference Example 6-20 as a raw material, dimethyl sulfide and aluminum chloride are reacted to produce a derivative in which R ⁴ is phenol, and this is converted to an alkyl halide (eg, chloroacetone) and a base (eg, carbonic acid). Potassium) is used to produce the compounds shown in Table 59.

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

Reference Example 7-4
Production of 1,4-dihydro-1- (2,6-difluorobenzyl) -6-methyl-7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester: Reference Example 7-3 The title compound is prepared using 4-propionylaminophenylboric acid and tetrakistriphenylphosphine palladium (0) under a stream of argon.
m.p. 263-264 ° C.
Reference Example 7-5
Preparation of 6-bromomethyl-1,4-dihydro-1- (2,6-difluorobenzyl) -7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester: Reference Example 7-4 The title compound is prepared from the compound obtained in ## STR10 ## N-bromosuccinimide and α, α'-azobisisobutyronitrile.
m.p. 251-253 ° C.
Reference Example 7-6
6- (N-benzyl-N-methylaminomethyl) -1,4-dihydro-1- (2,6-difluorobenzyl) -7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid Preparation of the ethyl ester hydrochloride: The educt of the title compound is prepared from the compound obtained in Reference Example 7-5, ethyl diisopropylamine and N-benzyl-N-methylamine, and from this and 1N ethereal hydrochloric acid, the title compound is prepared. A compound is produced.
m.p. 165-168 [deg.] C [hydrochloride].

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

Example 8-1
4,7-Dihydro-7- (2,6-difluorobenzyl) -2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -6-methyl-4-oxothieno Preparation of [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) and methyl A mixture of magnesium bromide in diethyl ether (3.0 M, 4.63 ml, 13.9 mmole) and copper iodide (529 mg, 2.78 mmole) 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 0.1N potassium hydroxide solution, extracted with chloroform, washed with saturated brine and dried (Na ₂ SO ₄ ), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain colorless amorphous (1.80 g, 96%). Sodium hydride was suspended in tetrahydrofuran (15 ml), and a solution of the amorphous (1.80 g, 2.67 mmole) obtained above in tetrahydrofuran (15 ml) was added dropwise thereto at room temperature. The reaction mixture was stirred at 50 ° C. for 0.5 hour, and then a solution of phenylselenyl chloride (1.02 g, 5.34 mmol) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was further stirred at 50 ° C. overnight. The reaction solution was poured into 500 ml of distilled water, extracted with chloroform, washed with saturated brine and dried (Na ₂ SO ₄ ), and then 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, added with 10N hydrochloric acid-ethanol solution to form a salt, and 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.
m.p. 163-165 ° C.
Elemental analysis value: C ₃₈ H ₃₉ N ₃ O ₄ SF ₂ .HCl · 1.5 H ₂ O
C H N
Calculated value: 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 = 6.8 Hz), 1.38 (6H, d, J = 6.8 Hz), 2.10 (3H, s), 2.45 (3H, s), 2.54 (1H, m), 3.63 (2H, s), 4.13 (2H, s), 5.30 (1H, 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 = 8.6Hz).

Reference Example 8-2
Using the compound obtained in Reference Example 4-1 or Reference Example 4-3 (Compound 4-3 (2), 4-3 (3), 4-3 (4)) as a starting material, the above Reference Example 8- In the same manner as in Example 1, compounds 8-2 (1), 8-2 (2), 8-2 (3) and 8-2 (4) shown in Table 61 below were produced.

Example 8-3
The compound obtained in Reference Example 4-1 was used as a raw material, and treated in the same manner as in Reference Example 8-1 using ethylmagnesium bromide instead of methylmagnesyl chloride in Reference Example 8-1 above. Compound 8-3 shown in Table 61] was produced.

Reference Example 8-4
Compound 5-6 (1) or 5-6 (22) obtained in Reference Example 5-6 was treated in the same manner as in Reference Example 8-1 above, and the compound shown in [Table 61] described later was used. 8-4 (1) or 8-4 (2) was produced respectively. Also, 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 The compounds 8-4 (3) to 8-4 (7) shown in the following [Table 61] are produced in the same manner as in Reference Example 8-1.

Reference example A
550 mg of leuprorelin acetate was dissolved in 1 ml of distilled water, and this was added to a solution of 4 g of poly-DL-lactic acid (Lot. 890717; molecular weight; 14100: dispersity 2.00) in 7.5 ml of dichloromethane. Mix for about 60 seconds with a small homogenizer (Polytron, Kinematica, Switzerland) to obtain a W / O emulsion. This emulsion is poured into 1000 ml of a 0.25% polyvinyl alcohol (PVA) aqueous solution preliminarily brought to 15 ° C., and is made into a W / O / W type emulsion using a small homogenizer. Thereafter, while stirring the W / O / W emulsion liquid, the internal W / O emulsion is solidified by volatilization of dichloromethane, and then collected by a centrifuge. This is again dispersed in distilled water, and further centrifuged to wash the released drug and dispersant. The collected microcapsules are desolvated and dehydrated by lyophilization, and then made into powder to obtain microcapsules.

Reference example B
550 mg of leuprorelin acetate was dissolved in 1 ml of 20% gelatin aqueous solution, and 4 g of lactic acid-glycolic acid copolymer (composition ratio of lactic acid: glycolic acid; 75:25, average molecular weight; 14,000) was dissolved in dichloromethane. In addition to the solution dissolved in 5 ml, the mixture is mixed for about 60 seconds with a small homogenizer (Polytron, manufactured by Kinematica, Switzerland) to obtain a W / O type emulsion. This emulsion is poured into 1000 ml of a 0.25% polyvinyl alcohol (PVA) aqueous solution preliminarily brought to 15 ° C., and is made into a W / O / W type emulsion using a small homogenizer. Thereafter, while stirring the W / O / W emulsion liquid, the internal W / O emulsion is solidified by volatilization of dichloromethane, and then collected by a centrifuge. This is again dispersed in distilled water, and further centrifuged to wash the released drug and dispersant. The collected microcapsules are desolvated and dehydrated by lyophilization, and then made into powder to obtain microcapsules.

Reference example C
1 g of α-cyclodextrin and 2 g of leuprorelin acetate were dissolved in 16 ml of a pH 7.4 isotonic buffer solution in which 0.12% of methylparaben and 0.01% of propylparaben were dissolved, and methylcellulose (Metroise 90SH4000, Shin-Etsu Chemical) was dissolved therein. Add 200 mg and stir well to obtain a uniform viscous solution, with a total weight of 20 g with buffer solution. 100 mg of this is filled into a nasal applicator and administered intranasally.

Example 1
The injection obtained in Reference Example (b) and the microcapsule obtained in Reference Example A or B are made into separate preparations to form a pharmaceutical composition kit.

Example 2
The injection obtained in Reference Example (b) and the nasal administration preparation obtained in Reference Example C are made into separate preparations to form a pharmaceutical composition kit.

Example 3
The tablet obtained in Reference Example (a) and the microcapsule obtained in Reference Example A or B are used as separate preparations to form a pharmaceutical composition kit.

Example 4
The tablet obtained in Reference Example (a) and the nasal administration preparation obtained in Reference Example C are made into separate preparations to form a pharmaceutical composition kit.

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

Test example 2
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and once subcutaneously administered to male cynomolgus monkey (4-6 years, n = 3) did. The dose was 30 mg / kg body weight. Animals receiving vehicle alone were used as a control group. Blood was collected under anesthesia 24 hours after administration, and EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml were immediately added. Centrifugation was performed at 3000 × g for 15 minutes, and the testosterone concentration in the obtained plasma was measured by a radioimmunoassay method. 100− (blood testosterone concentration in the compound administration group) / (blood testosterone concentration in the control group) × 100 was calculated to determine the testosterone inhibition rate (%) of the compound. Antagonist compound 1 showed an inhibition rate of 80% ± 5.

Test example 3
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and once subcutaneously administered to male cynomolgus monkey (4-6 years, n = 3) To do. The dose is 30 mg / kg body weight. Animals receiving vehicle alone are used as a control group. 3 hours after administration, a physiological saline solution of LH-RH agonist (leuprorelin acetate) is subcutaneously administered (5 μg / kg) without anesthesia. After 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration, blood was collected, and a final concentration of 3 mg / ml EDTA (ethylenediaminetetraacetic acid) and a final concentration of 300 U / ml aprotinin were collected. Add immediately. Centrifugation is performed at 3000 × g for 15 minutes, and 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 the compound administration group) / (blood LH or testosterone concentration in the control group) × 100 is calculated to determine the LH or testosterone inhibition rate (%) of the compound. This shows that a transient increase in serum LH or testosterone concentration (flare phenomenon) due to the pituitary-gonadal stimulating action (acute action) that occurs immediately after the first administration of leuprorelin acetate is avoided.

Test example 4
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and then male cynomolgus monkey (4-6 years, n = 3) twice a day. Orally administered for 7 days (total 15 times) every hour. The dose is 60 mg / kg body weight. Animals receiving vehicle alone are used as a control group. On the second day, the first oral administration (third oral administration) 1 hour later, under anesthesia, LH-RH agonist sustained release preparation (leuprorelin depot, microcapsule produced in Reference Example A) was administered subcutaneously ( The amount of leuprorelin is 0.15 mg / kg). Blood is collected 1 hour, 4 hours, 8 hours, 18 hours, 30 hours, 48 hours, and 72 hours after administration, and thereafter, blood collection is continued once a day for 2 weeks. To the collected blood, EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml are immediately added. Centrifugation is performed at 3000 × g for 15 minutes, and 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 the compound administration group) / (blood LH or testosterone concentration in the control group) × 100 is calculated to determine the LH or testosterone inhibition rate (%) of the compound. As a result, transient aversion (flare phenomenon) accompanied by an increase in serum LH or testosterone concentration due to pituitary-gonadal stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided. I understand.

Test Example 5
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and then male cynomolgus monkey (4-6 years, n = 3) twice a day. Orally administered for 7 days (total 15 times) every hour. The dose is 60 mg / kg body weight. Animals receiving vehicle alone are used as a control group. On the second day, the first oral administration (third oral administration) 1 hour later, under anesthesia, LH-RH agonist sustained release preparation (leuprorelin depot, microcapsule produced in Reference Example A) was administered subcutaneously ( The amount of leuprorelin is 0.45 mg / kg). Blood is collected 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after administration, and thereafter, blood collection is continued once a day for 2 weeks. To the collected blood, EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml are immediately added. Centrifugation is performed at 3000 × g for 15 minutes, and 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 the compound administration group) / (blood LH or testosterone concentration in the control group) × 100 is calculated to determine the LH or testosterone inhibition rate (%) of the compound. Thereby, it is understood that a transient aversion (flare phenomenon) accompanied by an increase in serum LH testosterone concentration due to a pituitary-gonadic stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided. .

Test Example 6
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and then male cynomolgus monkey (4-6 years, n = 3) twice a day. Orally administered for 7 days (total 15 times) every hour. The dose is 60 mg / kg body weight. Animals receiving vehicle alone are used as a control group. On the second day, the first oral administration (third oral administration) 1 hour later, without anesthesia, the LH-RH agonist sustained release preparation (leuprorelin depot, microcapsule produced in Reference Example B) was administered subcutaneously ( The amount of leuprorelin is 0.15 mg / kg). Blood is collected 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after administration, and thereafter, blood collection is continued once a day for 2 weeks. To the collected blood, EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml are immediately added. Centrifugation is performed at 3000 × g for 15 minutes, and 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 the compound administration group) / (blood LH or testosterone concentration in the control group) × 100 is calculated to determine the LH or testosterone inhibition rate (%) of the compound. Thus, it can be seen that the transient aversion (flare phenomenon) accompanied by an increase in serum testosterone concentration due to the pituitary-gonadal stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided.

Test Example 7
Antagonist compound 1 was suspended in solution I (0.5% methylcellulose-saline) to a concentration of 7.5 mg / ml, and then male cynomolgus monkey (4-6 years, n = 3) twice a day. Orally for 28 days (total 57 times) every hour. The dose is 60 mg / kg body weight. Animals receiving vehicle alone are used as a control group. The first oral administration on day 15 (third oral administration) 1 hour later, under anesthesia, LH-RH agonist sustained release preparation (leuprorelin depot, microcapsule prepared in Reference Example B) was administered subcutaneously ( The amount of leuprorelin is 0.15 mg / kg). Blood is collected 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, and 72 hours after the administration, and then blood sampling is continued once every 3 days for 4 weeks. To the collected blood, EDTA (ethylenediaminetetraacetic acid) having a final concentration of 3 mg / ml and aprotinin having a final concentration of 300 U / ml are immediately added. Centrifugation is performed at 3000 × g for 15 minutes, and 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 the compound administration group) / (blood LH or testosterone concentration in the control group) × 100 is calculated to determine the LH or testosterone inhibition rate (%) of the compound. Thereby, it is understood that a transient aversion (flare phenomenon) accompanied by an increase in serum LH testosterone concentration due to a pituitary-gonadic stimulating action (acute action) that occurs immediately after the first administration of leuprorelin depot is avoided. .

  The pharmaceutical composition of the present invention can avoid a transient aversion (flare phenomenon) accompanied by an increase in serum testosterone concentration due to a pituitary-gonad stimulating action (acute action) that occurs immediately after administration of a compound having an action. it can. Moreover, the action is enhanced. Therefore, the pharmaceutical composition of the present invention can be advantageously used as a medicament for the treatment / prevention of sex hormone-dependent diseases.

Claims (32)

A medicament comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptide compound having a gonadotropin releasing hormone antagonistic action. The medicament according to claim 1, wherein the compound having a gonadotropin releasing hormone action is a peptide compound. The medicament according to claim 2, wherein the peptidic compound is a natural hormone or an analog thereof. The peptide compound is represented by 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 Tyr or Phe, R ₃ is Gly or an optionally substituted D-type amino acid residue. , R ₄ represents Leu, Ile or Nle, R ₅ represents 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 ′ The pharmaceutical agent according to claim 2, wherein R ₆ 'represents a group represented by a hydrogen atom, an amino group or an alkyl or ureido optionally substituted with a hydroxyl group. The medicament according to claim 2, wherein the peptide compound is a compound selected from leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resilerin. The medicament according to claim 1, wherein the compound having a gonadotropin-releasing hormone action is used as a sustained-release preparation. The medicament according to claim 6, wherein the sustained-release preparation is a microcapsule preparation. The pharmaceutical according to claim 6, wherein the sustained-release preparation is a nasal preparation or an implant. The non-peptidic compound contains at least a condensed bicyclic structure of an allo- or hetero 5- to 7-membered ring and an allo- or hetero 5- to 7-membered ring which may be substituted. The medicament according to claim 1, which is or a salt thereof. The fused ring compound has the general formula

[Wherein the W ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group, and the Y ring represents an optionally substituted homo- or hetero 5- to 7-membered ring group] The medicament according to claim 9, which is a pharmaceutical product. W ring is a general formula

11. In the formula, R ^1a and R ^2a may be the same or different and each represents a hydrogen atom or a group via a carbon atom, nitrogen atom, oxygen atom or sulfur atom. Medicines. W ring is a 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, nitrogen atom, oxygen atom or sulfur atom. The medicine according to claim 10. Ring Y is a 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. 11. The medicine according to claim 10, wherein each is a hydrogen atom or a hydrocarbon residue which may be substituted, and o represents an integer of 1 to 2]. Ring Y is a 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 an optionally substituted hydrocarbon residue. Group, o represents an integer of 1 to 2] or a general formula

11. The pharmaceutical according to claim 10, wherein R ^11c and R ^12b are groups represented by the formula: R ^11c and R ^12b may be the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. The fused ring compound has the general formula

[Wherein, R ^1e and R ^2e each represents 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 homologous or heterocyclic group, R ^4e Is a group through hydrogen, a carbon atom, a group through a nitrogen atom, an oxygen atom or a sulfur atom or an optionally substituted heterocyclic group, R ^5e is a group through a hydrogen atom or a carbon atom, and n is 0 to 3 A compound represented by the general formula:

[Wherein R ^1f is (1) a hydrogen atom, (2) a group via a carbon atom, or (3) a formula — (CH ₂ ) n—R ^1f ′ (where R ^1f ′ is a group via a carbon atom or An optionally substituted homologous or heterocyclic group, n represents an integer of 0 to 3), R ^2f represents a hydrogen atom or a group via a carbon atom, and R ^3f and R ^4f represent Each of which represents a group through a carbon atom], or

^{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 N represents an integer of 0 to 3, which is a group through a carbon atom or an optionally substituted homologous or heterocyclic group. However, R ^1g , R ^2g , R ^3g , R ^4g , R ^6g and R ^7g are not all hydrogen at the same time. 10. The medicament according to claim 9, which is a compound represented by the formula: The fused ring compound has the general formula

[Wherein R ^13a may be substituted by 1 to 5 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 group. R ^15a may be substituted with 1 to 5 groups, which may be the same or different, and each of R ^16a is substituted with 1 to 5 hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups or alkylthio groups. R ^17a may be substituted with one or two hydrogen atoms, alkyl groups, halogen atoms or alkoxy groups, and may be the same or different, and each may be esterified. Alternatively, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group or a substituted group that may be amidated There an alkyl group, v, t and u may be the same or different, according to claim 9, wherein a pharmaceutical is a compound represented by each an integer of 0 to 3]. The fused ring compound has the general formula

[In the formula, R ^13b may be substituted by 1 to 3 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 by 1 to 3 groups, and may be the same or different, and a hydrogen atom or halogen, and R ^16b may be substituted by 1 to 3 groups. Further, they may be the same or different, and hydrogen atom, halogen or C _1-6 alkoxy, R ^17b may be substituted by 1 or 2 and may be the same or different and are esterified or amidated. A carboxy group or a C _1-6 alkylcarbonyl group, v ′, t ′ and u ′ may be the same or different and each represents an integer of 0 to 3]. 9. The medicine according to 9. A non-peptidic compound having gonadotropin releasing hormone antagonistic activity is 4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4-methoxy) The medicament according to claim 1, which is phenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof. A non-peptidic compound having gonadotropin releasing hormone antagonistic activity is 2- (4-acetylaminophenyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2- The pharmaceutical according to claim 1, which is methoxybenzyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester or a salt thereof. Non-peptidic compounds having gonadotropin releasing hormone antagonism are 5-n-butyryl-4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -7- (2-fluorobenzyl)- The medicament according to claim 1, which is 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- The medicament according to claim 1, which is (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof. Non-peptidic compounds having gonadotropin releasing hormone antagonistic activity are 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4 The pharmaceutical according to claim 1, which is -isobutyrylaminophenyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine or a salt thereof. Non-peptidic compounds having gonadotropin releasing hormone antagonism are 7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -5-isobutyryl- The medicament according to claim 1, which is 2- (4-propionylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof. Non-peptidic compounds having gonadotropin releasing hormone antagonism are 5-benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl)- The medicament according to claim 1, which is 2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof. A non-peptidic compound having gonadotropin releasing hormone antagonism is 3- (N-benzyl-methylaminomethyl) -4,7-dihydro-2- (4-allyloxyphenyl) -5-isobutyryl-7- ( The pharmaceutical according to claim 1, which is 2,6-difluorobenzyl) -4-oxothieno [2,3-b] pyridine or a salt thereof. A non-peptidic compound having a gonadotropin releasing hormone antagonistic action is isopropyl [3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-7- ( The pharmaceutical according to claim 1, which is 2,6-difluorobenzyl) thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. A non-peptidic compound having a gonadotropin releasing hormone antagonistic action is isopropyl [3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-7- ( The pharmaceutical according to claim 1, which is 2,6-difluorobenzyl) -6-methylthieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. Non-peptidic compounds having gonadotropin releasing hormone antagonism are isopropyl [3- (N-benzyl-N-methylaminomethyl) -2- (4-allyloxyphenyl) -4-oxo-6-methyl-7. The medicament according to claim 1, which is-(2,6-difluorobenzyl) thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. A pharmaceutical kit for preventing and treating sex hormone-dependent diseases, comprising a combination of a compound having a gonadotropin releasing hormone action and a non-peptide compound having a gonadotropin releasing hormone antagonistic action. 30. The kit according to claim 29, comprising a combination of a parenteral preparation of a compound having a gonadotropin releasing hormone action and an oral administration preparation of a non-peptide compound having a gonadotropin releasing hormone antagonistic action. 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. 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.