JPH1036373A - Thienopyridine derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new thienopyridine derivative, being a specific one, having an antagonism of a releasing hormone of a gonadotropic hormone and useful as an agent for treating a cancer depending on a sex hormone, prostatic hyperplasia, myoma of the uterus, infertilitas, etc., an agent for promoting spawning of fishes, etc. SOLUTION: This thienopyridine derivative is the new one of the formula R<1> is a (substituted) alkoxy; R<2> is an alkyl, an aryl or a group of the formula X-R<41> [R<41> is a (substituted) alkyl or a (substituted) cycloalkyl; X is O or S]; R<3> is H or an alkyl) or R<1> is a 1-8C alkanoylamino; R<2> is a group of the formula X-R<43> [R<43> is a (substituted) alkyl, a (substituted) cycloalkyl or a (substituted) six-membered heterocyclic ring containing oxygen] or OH; R<3> is H or an alkyl} and useful as a preventing and treating medicine for a disease depending on a sex hormone, prostatic hyperplasia, myoma of the uterus, endometriosis, precocious puberty, amenorrhoea syndrome, multilocular ovary syndrome, acne, etc., contraceptive, a treating agent for infertilitas, a regulating agent of menorrhea, an improving agent of flesh of an animal and a controlling agent of growth and an agent for promoting spawning of fishes, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art Anterior pituitary hormones are secreted by peripheral hormones secreted from target organs of each hormone and secretagogues or secretory inhibitory hormones (hereinafter referred to as "secretory hormones") secreted from the hypothalamus, which is the upper center of the anterior pituitary gland. In the specification, these hormone groups are collectively referred to as hypothalamic hormones). Up to now, hypothalamic hormones such as thyroid stimulating hormone releasing hormone (TRH) or gonadotropin releasing hormone ｛GnRH (Gonadotropin releasing hormone): luteinizing hormone releasing hormone [LH-RH (Luleinizing)
hormone releasehormone)], and nine other types have been confirmed. These hypothalamic hormones, through receptors thought to be in the anterior pituitary gland,
It is presumed to exhibit its hormonal effects and the like, and analysis of receptor genes specific to these, including humans, is underway. Thus, specific and selective antagonists to these receptors will modulate the action of hypothalamic hormones and control anterior pituitary hormone secretion. As a result, it is possible to treat or prevent such an anterior pituitary hormone-dependent disease. Gn
Compounds having RH antagonistic activity include linear peptides which are derivatives of GnRH (U.S. Pat.
No. 5171835), cyclic hexapeptide derivatives (JP-A-61-1)
91698) and bicyclic peptide derivatives [Journal of
Medicinal Chemistry (Journal of Medicinal C)
hemistry), 36, 3265-3273, 1993]. Examples of the non-peptidic compound having GnRH antagonism include the compounds described in PCT International Publication WO95 / 28405.

[0003]

The peptidic compound has many problems such as oral absorption, administration form, drug stability, sustained action, and metabolic stability. There is a demand for a GnRH antagonist excellent in oral absorbability and a GnRH antagonist which is oral, stable in blood plasma, and excellent in sustained action.

[0004]

The present inventors have synthesized various 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivatives and studied their actions.
Specific 4,7-dihydro-4-oxothieno [2,3-
b] a pyridine derivative has a high GnRH antagonism,
It has been found that it has excellent properties of high oral absorption, stable in plasma of blood, and long lasting action. The present inventors have further studied based on this finding and completed the present invention.

That is, the present invention relates to (1) a compound represented by the general formula (I)

Embedded image [Wherein (A) R ¹ represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ² represents (1) an alkyl group and (2) an aryl group. Group,
(3) Formula -XR ⁴¹ (wherein, R ⁴¹ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and X represents O or S) Wherein R ³ represents a hydrogen atom or an alkyl group, respectively, or (B) R ¹ represents a C _1-8 alkanoylamino group, and R ² represents a group represented by the formula —X
-R ⁴³ (wherein, when X is O, R ⁴³ has a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. Represents an oxygen-containing 6-membered heterocyclic group) or a hydroxyl group, and R ³ represents a hydrogen atom or an alkyl group. A compound (I) or a salt thereof,

(2) R ¹ is a C _1-6 alkoxy group substituted by a group selected from (i) halogen, (ii) C _3-10 cycloalkyl and (iii) C _2-9 alkenyl; ² is (1) C _1-6
Alkyl, (2) C _6-14 aryl, (3) Formula —X—R ⁴² (wherein R ⁴² is C _1-13 which may have a substituent.
X represents O or S for an alkyl group or a C _3-10 cycloalkyl group. Wherein R ³ is a hydrogen atom or a C _1-6 alkyl group, (3) R ⁴² is (1) halogen, C _1-4 alkoxy or C 4
_A C _1-13 alkyl group optionally substituted with _3-8 cycloalkyl or (2) halogen, C _1-4 alkoxy or C
The compound according to the above (2), which is a C _3-10 cycloalkyl group optionally substituted with _1-4 alkyl; (4) the above-mentioned compound, wherein R ¹ is a C _1-3 alkoxy group substituted with vinyl. (5) The compound according to the above (2), wherein R ¹ is an allyloxy group.

(6) R ² is (1) C _1-3 alkyl group, (2) C
(7) The compound according to the above (2), wherein the compound is a _6-14 aryl group, (3) a C _3-7 alkoxy group optionally substituted with halogen, C _1-3 alkyl or C _1-3 alkoxy, The compound according to the above (2), wherein ² is isopropyl, phenyl or isopropoxy, (8) R ¹ is a C _1-8 alkanoylamino group, and R ² is
(1) Formula -XR ⁴⁴ (wherein, when X is O, R ⁴⁴ may have a substituent, may be a C _3-13 branched alkyl group, or may have a substituent. A C _3-10 cycloalkyl group or a 6-membered oxygen-containing heterocyclic group which may have a substituent, and when X is S, R ⁴⁴ is a C _1-13 alkyl group which may have a substituent;
Represents a C _3-10 cycloalkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent) or (2) a hydroxyl group)
The compound according to the above (1), wherein R ³ is a hydrogen atom or a C _1-6 alkyl group,

(9) (1) When X is O, R ⁴⁴ is C _1-4 alkyl, halogen, amino, mono- or di-C _1-4 alkylamino, C _1-4 alkoxy or C _3-7 A C _3-13 branched alkyl group _optionally substituted with cycloalkyl,
Halogen, nitro, C _1-4 alkyl, C _1-4 alkoxy,
A C _3-10 cycloalkyl group optionally substituted with amino or mono- or di-C _1-4 alkylamino, or halogen, nitro, oxo, hydroxy, amino,
(2) X represents an oxygen-containing 6-membered heterocyclic group which may be substituted with mono- or di-C _1-4 alkylamino, C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio. Is S
Where halogen, amino, mono- or di-C _1-4
A C _1-13 alkyl group optionally substituted with alkylamino, C _1-4 alkoxy or C _3-7 cycloalkyl, or halogen, nitro, oxo, hydroxy, amino,
The above-mentioned item (8) representing a 6-membered oxygen-containing heterocyclic group optionally substituted by mono- or di-C _1-4 alkylamino, C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio. The compound described,

(10) The compound according to the above (8), wherein R ¹ is a C _3-5 alkanoylamino group; (11) the compound according to the above (8), wherein R ¹ is isobutyrylamino; ) When X is O, R ⁴⁴ is a C _3-7 branched alkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent, The compound according to 8), (13) when X is S, R ⁴⁴ is a C _1-7 alkyl group which may have a substituent, or a 6-membered oxygen-containing group which may have a substituent The compound according to the above (8), which represents a heterocyclic group, (14) 2- (4-allyloxyphenyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-
(Benzyl-N-methylaminomethyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine, 2-
[4- (2-methyl-2-propen-1-yl-oxy) phenyl] -4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl ) -5-Isobutyryl-4-oxo-thieno [2,3-b] pyridine, isopropyl [2- (4-allyloxyphenyl) -4,7-dihydro-7- (2,6-
Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -6-methyl-4-oxo-thieno [2,
3-b] pyridine-5-carboxylate], ethyl
[2- (4-allyloxyphenyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -6-methyl-4-oxo- The compound according to the above (1), which is thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof;

(15) Isopropyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], sec-butyl [4,
7-dihydro-7- (2,6-difluorobenzyl) -3
-(N-benzyl-N-methylaminomethyl) -2- (4
-Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], cyclohexyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- ( N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4
-Oxo-thieno [2,3-b] pyridine-5-carboxylate], 3-pentyl [4,7-dihydro-7-
(2,6-difluorobenzyl) -3- (N-benzyl-N
-Methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], tetrahydropyranyl
[4,7-dihydro-7- (2,6-difluorobenzyl)
-3- (N-benzyl-N-methylaminomethyl) -2
-(4-Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl)
-2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid,

2,4-dimethyl-3-pentyl [4.7
-Dihydro-7- (2,6-difluorobenzyl) -3-
(N-benzyl-N-methylaminomethyl) -2- (4-
Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], isopropyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N -Benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6
Methyl-4-oxo-thieno [2,3-b] pyridine-
5-carboxylate], cyclohexyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-
Benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 3-pentyl [4 , 7-Dihydro-7- (2,6-
Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5- Carboxylate], 4-tetrahydropyranyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylamino Phenyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5
-Carboxylate] or a salt thereof, the compound according to the above (1),

(16) 4,7-dihydro-7- (2,6-
Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-5- (4-tetrahydropyranylthiocarbonyl) thieno [2,3- b] The compound according to the above (1), which is pyridine or a salt thereof, (17) ethyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylamino) Methyl) -2- (4-isobutyrylaminophenyl)-
6-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof, (18) ethyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3 -(N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl)-
6-ethyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof,

(19) (a) Formula (II)

Embedded image [Wherein, R ²¹ represents (1) an alkyl group, (2) an aryl group or
(3) Formula -X-R ⁴¹ (wherein, R ⁴¹ represents an alkyl group or a cycloalkyl group each of which may have a substituent, and X represents O
Or S, respectively, and R ³ represents a hydrogen atom or an alkyl group.]
I) or a salt thereof and a compound of the formula R ¹² -Y, wherein R ¹² is an alkyl group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkylalkenyl, and Y is a halogen atom Is shown. With a compound represented by the general formula (III)

Embedded image [Wherein, R ¹¹ represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ²¹ and R ³ have the same meaning as described above. Or a salt thereof, or (b) a compound of the general formula (IV)

Embedded image ^{Wherein, R 13} is a C _1-8 alkanoylamino group, R ²³
Represents a linear alkoxy group, and R ³ represents a hydrogen atom or an alkyl group. A compound represented by the formula: R ^24- OH wherein R ²⁴ is a branched alkyl group, a cycloalkyl group or a 6-membered oxygen-containing heterocyclic group which may have a substituent. Shows a ring group. Or a salt thereof or a compound represented by the formula R ²⁵ -SH, wherein R ²⁵ represents an alkyl group, a cycloalkyl group or an oxygen-containing 6-membered heterocyclic group which may have a substituent. By reacting with a compound represented by the formula
(V)

Embedded image [Wherein, R ¹³ is as defined above, and R ²² is a group represented by the formula (1) -XR
⁴³ (wherein, when X is O, R ⁴³ is a branched alkyl group, cycloalkyl group or oxygen-containing 6-membered heterocyclic group which may have a substituent, and when X is S, R ⁴³ is An alkyl group, a cycloalkyl group, or an oxygen-containing 6-membered heterocyclic group which may have a substituent) or (2) a hydroxyl group. A compound represented by the formula
(V) or a salt thereof,

(C) General formula

Embedded image Wherein, R ¹ is (1) (i) halogen, (ii) cycloalkyl and (iii) an alkoxy group or substituted by a group selected from alkenyl (2) C _1-8 alkanoylamino group, R ³
Represents a hydrogen atom or an alkyl group, respectively. Or a salt thereof represented by the formula: R ²⁷ -H wherein R ²⁷ is a group represented by the formula -XR ⁴ (wherein R ⁴ is an alkyl group which may have a substituent, , A cycloalkyl group or a 6-membered oxygen-containing heterocyclic group, and X represents O or S). With the compound represented by the general formula (VII)

Embedded image [Wherein (A) R ¹ represents an alkoxy group substituted by a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ²⁶ represents (1) an alkyl group, (2) aryl Group,
(3) Formula -X-R ⁴¹ (wherein, R ⁴¹ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and X represents O or S) Wherein R ³ represents a hydrogen atom or an alkyl group, respectively, or (B) R ¹ represents a C _1-8 alkanoylamino group, and R ²⁶ represents a group represented by the formula -X
-R ⁴⁵ (wherein, when X is O, R ⁴⁵ represents a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. Or a 6-membered oxygen-containing heterocyclic group which may be represented by the following formula: A method for producing compound (I) or a salt thereof by producing compound (VII) or a salt thereof

(20) General formula (VIII)

Embedded image [Wherein (A) R ¹ represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ² represents a formula -XR ⁴¹ (wherein R ⁴¹ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent; X represents O or S); R ³ represents a hydrogen atom or an alkyl group; (B) R ¹ is a C _1-8 alkanoylamino group, and R ² is a group represented by the formula —X
-R ⁴⁵ (wherein, when X is O, R ⁴⁵ represents a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. Or a 6-membered oxygen-containing heterocyclic group which may be substituted). And a salt thereof, and a compound represented by the formula: R ³¹ -Z wherein R ³¹ represents an alkyl group. Z represents a metal which may be halogenated. A compound of the formula (IX):

Embedded image [Wherein, R ¹ , R ² and R ³¹ have the same meaning as described above. The method for producing the compound (IX) or a salt thereof,

(21) The compound according to the above (1), which is highly orally absorbable, (22) the compound according to the above (1) or a salt thereof, which is stable in plasma, and (23) the compound according to the above (1). A medicament comprising a compound or a salt thereof; (24) the medicament according to the above (23), which is a therapeutic / prophylactic agent for a sex hormone-dependent disease; (25) a prostate cancer, a uterine cancer, (26) The medicament according to the above (24), which is a breast cancer or a pituitary tumor; (27) a pregnancy regulator comprising the compound according to the above (1) or a salt thereof; (28) a menstrual cycle regulator comprising the compound according to the above (1) or a salt thereof; (29) The above item (27) for contraception It is a birth control agent.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION
7-Dihydro-4-oxothieno [2,3-b] pyridine is represented by the following formula (X).

Embedded image

In the above formula, (i) a halogen represented by R ¹ ,
As the alkoxy group in the alkoxy group substituted with a group selected from (ii) cycloalkyl and (iii) alkenyl, a C _1-6 alkoxy group is preferable.
For example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, te
rt-butoxy, pentoxy, hexyloxy and the like. Among them, a C _1-4 alkoxy group or a C _1-3 alkoxy group is preferable, and methoxy is particularly preferable. In the above formula, in R ¹ , examples of the halogen of the substituent on the alkoxy group include fluorine, chlorine, bromine, and iodine.
Of these, fluorine is preferred. As the cycloalkyl as the substituent on the alkoxy group, C _3-10 cycloalkyl is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Among them, C _3-6 cycloalkyl is preferred, and cyclopropyl is particularly preferred.

The alkenyl as a substituent on the alkoxy group is preferably C _2-10 alkenyl. Examples thereof include vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl and hexatrienyl. , 3-octenyl and the like. Above all, C
_2-6 alkenyl is preferred, and C _2-4 alkenyl is particularly preferred. The alkenyl group may have an alkyl group as a substituent. When the alkenyl group has an alkyl substituent, it is also referred to as an alkenyl group. As the alkyl as the substituent, C _1-6 alkyl is preferable, and examples thereof include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Hexyl and the like can be mentioned, among which C _1-4 alkyl is preferable, C _1-3 alkyl is more preferable, and methyl is particularly preferable. _{Examples of the} alkenyl group having alkyl as a substituent include a C _2-13 alkenyl group, preferably a C _2-9 alkenyl group, and more preferably a C _2-7 alkenyl group. A particularly preferred example of the alkenyl group substituted with alkyl includes 2-methylallyl. The number of the substituents in R ¹ is preferably 1 to 3, and particularly preferably 1 or 2.

Preferred radicals R ¹ include (1) (i) halogen, (ii) C _3-10 cycloalkyl and (iii) C _2-10
A C _1-6 alkoxy group substituted with a group selected from alkenyl; (2) a group selected from (i) halogen, (ii) C _3-10 cycloalkyl and (iii) C _2-6 alkenyl C
_C1-6 alkoxy group; (3) (i) halogen, (ii) C _3-6 cycloalkyl and (iii) C _1-6 alkoxy group substituted by a group selected from C _2-6 alkenyl; (4) A C _1-4 alkoxy group substituted by C _2-6 alkenyl is mentioned, and particularly preferred is (5) vinyl-C _1-3 alkoxy or allyloxy. As the alkyl group represented by R ² , a C _1-6 alkyl group is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Above all, C _1-4
Alkyl groups are preferred, C _1-3 alkyl groups are more preferred, and C ₃ alkyl groups (n-propyl, isopropyl) are particularly preferred. As the aryl group represented by R ² ,
A C _6-14 aryl group is preferred, and examples include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl and the like. Above all, phenyl,
Naphthyl is particularly preferred.

In the formula -XR ⁴¹ (wherein X represents O or S), the alkyl group in the alkyl group in which R ⁴¹ may have a substituent includes a C _1-13 alkyl group. Preferably, it may be linear or branched. Examples of linear alkyl groups include, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-
Octyl and the like. Examples of branched alkyl groups include, for example, 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. The alkyl group is preferably a C _1-9 alkyl group or a C _1-9 alkyl group.
_{A 1-7} alkyl group or a C _1-6 alkyl group is preferable, and when branched, a C _3-13 branched alkyl group is preferable, and further a C _3-9 branched alkyl group or a C _3-8 branched group. An alkyl group, a C _3-7 branched alkyl group or a C _3-6 branched alkyl group is preferred. If X is O R ⁴¹ in the formula -X-R ⁴¹ is an alkyl group which may have a substituent, group represented by the formula -X-R ⁴¹ may be substituted A good alkoxy group, and the alkoxy group in the alkoxy group which may have a substituent is
_1-13 alkoxy groups are preferred, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, sec-pentyloxy, tert- Pentyloxy, 3-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, octyloxy, isooctyloxy, sec-octyloxy, tert-octyloxy and the like. The alkoxy group is preferably a C _1-10 alkoxy group or a C _1-9 alkoxy group, and more preferably a C _1-8 alkoxy group or a C _1-7 alkoxy group. Above all, C _3-9
An alkoxy group, a C _3-8 alkoxy group or a C _3-7 alkoxy group is preferred, and a C ₃ alkoxy group (n-propoxy, isopropoxy) is particularly preferred.

[0022] have a substituent represented by substituents and R ⁴ in which may have a substituent alkyl group (including a branched alkyl group) represented by R ⁴¹ in the formula -X-R ⁴¹ Examples of the substituent in the cycloalkyl group which may be, for example, (1) halogen, (2) alkoxy, (3) alkyl, (4) cycloalkyl, (5) alkulthio, (6) amino, (7) mono -Or di-alkylamino, (8) nitro,
(9) hydroxyl, (10) oxo, (11) carbamoyl, (1
2) Cyano, (13) mercapto, (14) sulfo and the like. The number of substitutions is 1 to 6, preferably 1 to 3
And more preferably 1 or 2. Preferred groups which may be substituted on the alkyl group include halogen, nitro and amino. As an expression in the -X-R ⁴¹ X is O R ⁴¹ is a substituent alkoxy group which may be substituted is an alkyl group optionally having a 2-indanyloxy, 4- Pi Also included are peridinyloxy, tetrahydro-4H-pyr-4-yloxy.

The halogen includes fluorine, chlorine, bromine and iodine. Of these, fluorine and chlorine are preferred. As the alkoxy, C _1-4 alkoxy is preferable, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Of these, methoxy and ethoxy are particularly preferred. As the alkyl, C _1-4 alkyl is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these, methyl and ethyl are particularly preferred. As the cycloalkyl, C _3-8 cycloalkyl is preferable, for example, cyclopropyl, cyclobutyl,
Examples include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among them, C _3-7 cycloalkyl is preferred.

[0024] The mono - Examples of alkylamino, preferably mono- -C _1-4 alkylamino, for example, N- methylamino, N- ethylamino, N- propylamino,
N-n-butylamino, N-isobutylamino and the like. The di-alkylamino includes di-C _1-4
Alkylamino is preferable, and examples thereof include N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino and the like. The alkylthio includes C
_1-4 alkylthio is preferable, and examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio and the like. A substituent in the optionally substituted alkyl group represented by R ⁴¹ and a substituent in the optionally substituted cycloalkyl group represented by R ⁴ of the formula —X—R ⁴¹ of R ² ; Of these, C _1-4 alkyl is particularly preferred. As preferred examples of the substituent which the alkoxy group may have, the number of the substituent is 1 to 3.
, Preferably 1-2.

As the cycloalkyl group for R ⁴¹ in the above formula -XR ⁴¹ , a C _3-10 cycloalkyl group is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Octyl and the like. Above all, C
_3-8 cycloalkyl group or a C _3-7 cycloalkyl group is preferred. The cycloalkyl group may form a bicyclic fused ring. Examples of the fused ring group include indanyl and the like. Examples of the group that may be substituted on the cycloalkyl group include the same groups as those that may be substituted on the alkyl group described above. R ⁴¹
As the substituent in the optionally substituted C _1-13 alkyl group, halogen, C _1-4 alkoxy or C _3-8 cycloalkyl is preferable. As the substituent in the optionally substituted C _3-10 cycloalkyl group represented by R ⁴¹ , halogen, C _1-4 alkoxy or C _1-4 alkyl is preferable. Preferred examples of the group R ² include (A) (1) a C _1-6 alkyl group, (2) a C _6-14 aryl group, and (3) a formula —X—R ⁴² (wherein R ⁴² is A group represented by the following formula: (B) (1) C _1-6 alkyl, which represents a C _1-9 alkyl group or a C _3-8 cycloalkyl group which may have a substituent, and X represents O or S. , (2) C _6-14 aryl, (3)
In the formula, -XR ⁴² (wherein R ⁴² represents a C _1-13 alkyl group or a C _3-10 cycloalkyl group which may have a substituent, and X represents O or S). A group represented;
(C) (1) C _1-6 alkyl group, (2) C _6-14 aryl group, (3) C
_A C _{1 -9} alkoxy group which may be substituted by _1-4 alkyl; and (D) a C 1 _-6 alkoxy group. The R ^2, (1) C _1-3 alkyl group, (2) C _6-14 aryl group, (3) halogen, C _1-3 optionally C ₃ optionally substituted by alkyl or C _1-3 alkoxy _{A -7} alkoxy group is more preferred.

As R ² , isopropyl,
Phenyl, ethoxy, isopropoxy, sec-butoxy, 3-pentyloxy, 2,4-dimethyl-3-pentyloxy, ethylthio, isopropylthio are particularly preferred. Among them, isopropyl, phenyl, isopropoxy, sec-butoxy, 3-pentyloxy or 2,4
-Dimethyl-3-pentyloxy is preferred. The number of substituents in the R ² group is preferably 1 to 3,
~ 2 are particularly preferred. The alkyl group represented by R ³ is preferably a C _1-6 alkyl group, and specific examples thereof include the same ones as described above. Among them, C _1-4 alkyl and C _1-3 alkyl are preferable, and methyl and ethyl are particularly preferable.

In the above formula, examples of the C _1-8 alkanoylamino group represented by R ¹ include, for example, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, Hexanoylamino,
Heptanoylamino, octanoylamino and the like. As the alkanoylamino group represented by R ¹ , a C _3-5 alkanoylamino group is preferable, and isobutyrylamino is particularly preferable. The group represented by R ¹ is preferably substituted with one or two phenyl groups substituted at the 2-position of thienopyrimidine, and particularly preferably substituted with one phenyl group at the 4-position of the phenyl group. preferable. Preferred examples of the alkanoylamino group in the group R ¹ include a C _3-5 alkanoylamino group; a C _3-4 alkanoylamino group; and a C ₃ alkanoylamino group. Particularly preferred is isobutyryl. An amino group is mentioned.

[0028] where X is O in the formula -X-R ^43, R ⁴³
Is a branched alkyl group optionally having a substituent, is a branched alkoxy group optionally having a substituent, and is a branched alkoxy group optionally having a substituent. As the branched alkoxy group in the alkoxy group, a C _3-13 branched alkoxy group is preferable, and examples thereof include, for example, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, sec-pentyl Oxy, tert
-Pentyloxy, 3-pentyloxy, neopentyloxy, isohexyloxy, sec-hexyloxy, te
rt-hexyloxy, isooctyloxy, sec-octyloxy, tert-octyloxy, indanyloxy,
4-piperidinyloxy and the like. Examples of the branched alkoxy group include a C _3-9 branched alkoxy group, a C _3-8 branched alkoxy group, and a C _3-7
Are preferred, especially isopropoxy, sec-butoxy, 3-pentyloxy or 2,4-
Dimethyl-3-pentyloxy is preferred. Formula -XR
^When X in ⁴³ is O, the branched alkyl group in R ⁴³ which may have a substituent for R ⁴³ is preferably a C _3-13 branched alkyl group. Is 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, and a C _3-9 branched alkyl group, a C _3-8 branched alkyl group, a C _3-7 branched alkyl group, C _3-6 branched alkyl groups are preferred. As the substituent on the branched alkyl group, the same substituents as those described above for R ⁴¹ can be mentioned. Specific examples of the branched alkyl group which may have a substituent include, for example, 1,3-difluoro-2-propyl, 1,3-bis (dimethylamino) -2-propyl, 1,3-dimethoxy -2-propyl and the like, and further include 2-indanyl, 4-piperidinyl, N-methyl-4-piperidinyl, and dicyclohexylmethyl.

[0029] where X is O in the formula -X-R ^43, R ⁴³
Examples of the cycloalkyl group in the cycloalkyl group which may have a substituent and the substituent thereof include the same as those described for R ⁴¹ and R ⁴² above. Specific examples of the cycloalkyl group which may have a substituent include, for example, 2.6-dimethyl-1-cyclohexyl, 3,5-dimethyl-1-cyclohexyl, 4-
Methyl-1-cyclohexyl, 4-ethylcyclohexyl, 4-amino-1-cyclohexyl are also included.

Examples of the oxygen-containing 6-membered heterocyclic group include pyranyl, tetrahydropyranyl, dioxanyl,
Oxazinyl, isoxazinyl and the like can be mentioned. These hydrogenated products may be used. Examples of the substituent on 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, te
rt-butoxy, etc.), (3) carbamoyl group, (4) halogen (eg, fluorine, chlorine, bromine, iodine), (5) oxo group,
(6) hydroxyl group, (7) amino, (8) mono- or di-C _1-4
Alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), (9) nitro, (10) cyano, (11) Mercapto, (12) sulfo, (13) sulfino, (14) C _1-6 alkylthio (eg, methylthio,
Ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.). The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2. Preferred substituents on the heterocyclic group include halogen, nitro, amino, mono- or di-C _1-4 alkylamino, oxo, hydroxy, C _1-6 alkyl (among others,
C _1-4 alkyl), C _1-6 alkoxy (among others, C _1-4
Alkoxy) and C _1-6 alkylthio (among others, C _1-4 alkylthio). And X is S in Formula -X-R ^43, the alkyl group and the substituent R ⁴³ is the alkyl group which may have a substituent, the above R ⁴¹
Alternatively, those described in ^R42 , ^R43 or R
⁴⁴ and the like. And X is S in Formula -X-R ^43, the cycloalkyl group R ⁴³ is the cycloalkyl group which may have a substituent, and examples of their substituents, wherein the R ⁴¹ or R ⁴² above The same ones as mentioned above can be mentioned. X in the formula -XR ⁴³ is S, and R ⁴³ is an oxygen-containing 6-membered heterocyclic group in the oxygen-containing 6-membered heterocyclic group which may have a substituent; R ⁴³
Or include the same as those described in R ^44.

The group preferred are ^{R 2, (E) (1} ) formula -X-R ⁴⁴ (wherein, X is which may have, respectively, a R ⁴⁴ substituent when O C _3-13 Branched alkyl group, C _3-10
X represents S, a cycloalkyl group or a 6-membered oxygen-containing heterocyclic group.
In the formula, R ⁴² represents a C _1-13 which may have a substituent.
An alkyl group, a C _3-10 cycloalkyl group or a 6-membered oxygen-containing heterocyclic group) or (2) a hydroxyl group; (F) (1) a formula —O—R ⁵ (wherein R ⁵ Is (i) a C _3-8 branched alkyl group optionally having a C _1-4 alkyl as a substituent, (ii) a C _3-8 cycloalkyl group, or (iii) an oxygen-containing 6
(2) a group represented by the formula -SR
⁶ (wherein, R ⁶ is (i) C _1-6 alkyl group, (ii) C _3-8 cycloalkyl group or (iii) shows the oxygen-containing 6-membered heterocyclic group) group, or represented by (3) Hydroxyl group; (G) formula -OR
⁵¹ (wherein, R ⁵¹ represents a C _3-7 branched alkyl group or an oxygen-containing 6-membered heterocyclic group). Further, as a preferable example of R ² , a compound represented by the formula —X—R ⁴⁴ (wherein X is O, and R ⁴⁴ is a C _3-13 branched alkyl group or a substituted A group representing an oxygen 6-membered heterocyclic group is preferable, and R ² is preferably a group represented by the formula —X—R ⁴⁴ (wherein X is O and R ⁴⁴ is (1) C
C _3-13 branched alkyl group optionally substituted with _1-3 alkyl or halogen, or (2) halogen, C _1-4
An oxygen-containing 6-membered heterocyclic group which may be substituted with alkoxy, C _1-4 alkyl or C _1-4 alkylthio). Further, R ⁴⁴ is preferably a C _3-7 branched alkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent. R ⁴⁴
Is (1) a C _3-13 branched alkyl group optionally substituted with C _1-3 alkyl or halogen, or (2) halogen, C
_An oxygen-containing 6-membered heterocyclic group which may be substituted by _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio is preferred.

Examples of the substituent in the C _3-13 branched alkyl group or the C _1-13 alkyl group which may have a substituent represented by R ⁴⁴ include halogen, amino, mono- or di-C _{1. -4} alkylamino, C _1-4 alkoxy or C _3-7 cycloalkyl is preferred. Examples of the substituent in the C _3-10 cycloalkyl group which may have a substituent represented by R ⁴⁴ include halogen, nitro, C _1-4 alkyl, C _1-4 alkoxy, amino or mono- or di-. C _1-4 alkylamino is preferred. The substituent of the oxygen-containing 6-membered heterocyclic group which may have a substituent represented by R ^44, halogen, nitro, oxo, hydroxy, amino, mono- - or di -C _1-4 alkylamino, C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio are preferred. _{Examples of the} branched alkyl group in the C _3-13 branched alkyl group which may have a substituent represented by R ⁴⁴ include isopropoxy, sec-butoxy,
3-pentyloxy or 2,4-dimethyl-3-pentyloxy is preferred.

As R ² , ethoxy, isopropoxy, sec-butoxy, 3-pentyloxy 2,4
-Dimethyl-3-pentyloxy, tetrahydropyranyloxy, ethylthio, isopropylthio, tetrahydropyranylthio are particularly preferred. Among them, isopropoxy, sec-butoxy, 3-pentyloxy or 2,4
-Dimethyl-3-pentyloxy is preferred. The number of substituents in the R ² group is preferably 1 to 3,
~ 2 are particularly preferred. Specific examples of the alkyl group for R ³ include the same as those described above.
Among them, a C _1-4 alkyl group and a C _1-3 alkyl group are preferable, and methyl and ethyl are particularly preferable.

Specific examples of the groups represented by R ¹¹ , R ¹² and R ¹³ are the same as the specific examples of the groups represented by R ¹ . R ^{21 to} R ²⁹ described above and below
Specific examples of each group in are the same as the specific examples of those groups in R ² described above. Specific examples of the alkyl group according to R ³¹ include the same as those of the embodiment in R ^3. Specific examples of each group in R ^{41 to} R ⁴⁵ include the same as the specific examples of those groups in R ⁴ . Specific examples of each group in R ⁵ , R ⁵¹ and R ⁶ include the same as the specific examples of those groups in R ⁴ . The following compounds are also disclosed herein. Ethyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4 -Oxo-thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. Ethyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl)
-6-ethyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof.

The compound of the present invention can be produced by a method known per se, for example, the method described in PCT International Publication WO95 / 28405, the method described below, a method similar thereto, or a combination of these methods Thus, it can be manufactured.

Production method 1: Compound represented by the above formula (I)
In (I), the 2-position is a phenyl group substituted with an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl optionally substituted with alkyl. , 7-Dihydro-4-oxothieno [2,3-b] pyridine derivative or its salt is represented by P
A 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative which is a phenyl group substituted at the 2-position obtained by a method similar to the method described in CT International Publication WO95 / 28405 or The salt and the general formula R
^12- Y wherein R ¹² has the same meaning as described above. Y represents a halogen atom (eg, iodine, bromine, fluorine, chlorine). [E.g., allyl bromide, cyclopropylmethyl chloride, 1-bromo-2-butene, 1-bromo-3-butene, crotyl bromide (that is, 1-bromo-
2-methyl-2-propene), 2,2,2-trifluoroethyl iodide, etc.] or a salt thereof. Examples of the alkyl group represented by R ¹² include the same groups as the alkoxy group represented by R ¹ except for the oxygen atom (that is, the alkyl group). This reaction is usually performed in a solvent. Examples of such a solvent include amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, ethyl ether, dioxane, dimethoxyethane, and the like.
Ethers such as tetrahydrofuran and the like are used. In this reaction, the starting compound is dissolved in these solvents, a compound represented by the general formula R ¹² -Y (wherein R ¹² and Y each have the same meaning as described above) or a salt thereof is added, and a base is added. The reaction is carried out under a neutral condition (eg, by adding potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydride, thallium hydroxide, triethylamine, etc. to make it basic). The reaction temperature is about 0-100 ° C, more preferably about 0-40 ° C. Reaction time is about 1-20
0 hours, preferably about 1 to 48 hours. The reaction is
Stirring can be performed efficiently.

Production method 2: Compound represented by the above formula (I)
In (I), 4,7-dihydro-4-oxothieno [2,3-] wherein the 2-position is an alkanoylamino-phenyl group
b] A pyridine derivative or a salt thereof is obtained from PCT International Publication W
No. 2 produced by the method described in O95 / 28405
A 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative or a salt thereof, which is a phenyl group substituted at the amino position, with a general formula R ¹³ -Y wherein R ¹³ is C
_{A 1-8} alkanoyl group (specific examples include the same alkanoyl groups as those described above for “alkanoylamino” in R ^1. Specific examples include isobutyl chloride and the like.) Y is a halogen atom ( (Specific examples are the same as above.)
Is shown. Or a salt thereof. This reaction is usually performed in a solvent. Examples of the solvent include halogenated solvents such as anhydrous methylene chloride, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and ethers such as tetrahydrofuran, ethyl ether, dioxane, and dimethoxyethane. In this reaction, the starting compounds are dissolved in these solvents,
The formula R ¹³ -Y (wherein, R ¹³ and Y each have the same meaning as above) compound represented by or a salt thereof and a basic compound (e.g., potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride , Triethylamine, potassium-t-butoxide, thallium hydroxide, etc.)
This is done by adding The reaction temperature of this reaction is about 0
-100 ° C, more preferably about 0-40 ° C. The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 2 hours.
Time. This reaction can be carried out efficiently by stirring.

Production method 3: Compound represented by the above formula (I)
In (I), the 5-position is a formula -CO-R ²⁷ (wherein R ²⁷ is an alkyl group or an aryl group, thieno [2,3-b]
Pyridine derivatives are first described in PCT International Publication WO95 / 2
The ester group of a thieno [2,3-b] pyridine derivative in which the 5-position is an ester group, which is produced by a method similar to that described in JP-A-8405, is converted to a carboxylic acid amide derivative. By reacting a Grignard reagent with the resulting compound. These methods can be carried out in the same manner as the method described in PCT International Publication WO95 / 28405.

Production method 4: Compound represented by the above formula (I)
In (I), R ² is a branched alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, or a heterocyclic group which may have a substituent. The 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative is a 5-linear alkoxycarbonyl-4 produced by a method similar to the production method described in PCT International Publication WO95 / 28405. in 7-dihydro-4-oxothieno [2,3-b] pyridine derivative or a salt thereof with the general formula R ²⁴ -H [wherein, R ²⁴ has the same meaning as defined above. ]
By reacting with a compound represented by the formula (I) or a salt thereof, and performing transesterification. This reaction is usually performed in a reaction solvent. As such a solvent, for example, alcohols such as methanol, ethanol, isopropyl alcohol, and 3-pentyl alcohol are used. In this reaction, the starting compound is dissolved in these solvents, and the compound is added to the solvent by the general formula Ti (R ²⁸ ) ₄ [wherein R ²⁸ represents an alkoxy group which may have a substituent. (E.g., titanium (IV) isopropoxide and the like). The reaction temperature of this reaction is about 0
To 120 ° C, more preferably about 0 to 40 ° C, or about 10 to 20 ° C. The reaction time is about 1 to 24 hours, preferably about 1 to 12 hours, or about 1 to 6 hours. This reaction can be carried out efficiently by stirring.

Production method 5: Compound represented by the above formula (I)
In (I), R ² is a group of the formula —SR ²⁵ (wherein R ²⁵ is an alkyl group (including a branched alkyl group) which may have a substituent, a cycloalkyl group or a heterocyclic group). 4,7-dihydro-4-oxothieno [2,3-b] pyridine derivative, which is a group represented by the following formula, is produced by the same method as the production method described in PCT International Publication WO95 / 28405. wherein the compound represented by (I) -CO-R ² is a straight-chain alkoxy groups in (I) - is a carbonyl group or a carboxy group (R ² is a hydroxyl group) 4,7
Dihydro-4-oxothieno [2,3-b] pyridine derivative or a salt thereof and a compound represented by the general formula: R ²⁵ -SH wherein R ²⁵ has the same meaning as described above. Or a salt thereof. Examples of each group represented by R ²⁸ include the same groups as those described above for R ² . This reaction is usually performed without a solvent or in a reaction solvent. As such a solvent, for example, a halogenated solvent such as dichloromethane is used. In this reaction, Vilsmeier prepared from dimethylformamide and phosphorus oxychloride under basic conditions (eg, N, N-dimethylaminopyridine, etc.)
The condensation is carried out in the presence of a reagent. The reaction temperature of this reaction is about 0 to 200 ° C, more preferably about 0 to 120 ° C. The reaction time is about 1 to 24 hours, preferably about 2 to 12 hours. This reaction can be carried out efficiently by stirring.

Production method 6: Compound represented by the above formula (I)
In (I), 4,7-dihydro-4-oxothieno [2,3] wherein -CO-R ² is a carboxy group (R ² is a hydroxyl group).
-B] pyridine derivatives or salts thereof are, for example, PCT
4,7-Dihydro-4-oxothieno [2,3-] wherein R ² is an alkoxy group produced by the method described in International Publication WO95 / 28405 or a method similar thereto.
b] It can be produced by subjecting a pyridine derivative or a salt thereof to a hydrolysis reaction. The hydrolysis reaction is
Performed in a solvent. Examples of the solvent include ethers such as tetrahydrofuran and dioxane, and alcohols such as ethyl alcohol and methyl alcohol. In this reaction, an acid (eg, an inorganic acid such as hydrochloric acid; 2
This reaction is carried out efficiently in the presence of an aqueous solution of N) or an aqueous alkaline solution (eg, a 1 to 4N aqueous solution of an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like). Reaction temperature is about 10
To 100 ° C, preferably 20 to 60 ° C. The reaction time is about 1 to 4 hours, preferably 2 to 4 hours.
The reaction can be efficiently performed by stirring.

Production method 7: Compound represented by the above formula (I)
In (I), R ² is an optionally substituted alkoxy group (including an optionally substituted branched alkoxy group), and an optionally substituted cycloalkyl-oxy group Alternatively, the thieno [2,3-b] pyridine derivative which is a heterocyclic-oxy group optionally having substituent (s) is obtained by adding -CO at the 5-position in the above formula (I) produced by the above-mentioned production method 5. A thieno [2,3-b] pyridine-5-carboxylic acid derivative or a salt thereof in which -R ² is a carboxy group (R ² is a hydroxyl group) has a formula R ²⁹ -OH (wherein R ²⁹ represents a substituent, An alkyl group (including a branched alkoxy group), a cycloalkyl group or a heterocyclic group which may be present)
Alcohols represented by (eg, isopropanol,
2,4-dimethyl-3-pentanol). Examples of each group represented by R ²⁹ include the same groups as those described above for R ² .
This reaction is performed without a solvent or in a solvent. As the solvent, for example, a halogenated solvent such as dichloromethane is used. This reaction is carried out by adding a base such as N, N-dimethylaminopyridine to a Vilsmeier reagent prepared from dimethylformamide and phosphorus oxychloride. This reaction is carried out at room temperature to heating (about 100 ° C.).
More preferably, it is 0 to 120 ° C. The reaction time is about 1 to 12 hours, more preferably 4 to 12 hours. This reaction can be carried out efficiently by stirring.

Production method 8: Compound represented by the above formula (I)
In (I), thieno in which the 6-position is an alkyl group [2,3
-B] The pyridine derivative (IX) or a salt thereof is produced by a method similar to the production method described in PCT International Publication WO95 / 28405 or by a method similar to the above production methods 1 to 5. The thieno [2,3-b] represented by the above formula (VIII), wherein the position is a formula -XR ⁴ (wherein X and R ⁴ have the same meanings as described above), and R ³ is unsubstituted. The reaction can be carried out by reacting the pyridine derivative (VIII) or a salt thereof with a compound represented by the formula R ³¹ -Z (wherein R ³¹ and Z have the same meanings as described above). Examples of the metal in the compound represented by R ³¹ -Z include magnesium and lithium. Examples of the halogen include chloride and bromide. Examples of the metal halide include Grignard (Gr.) Such as methyl magnesium chloride and ethyl magnesium bromide.
ignard) reagents, lithium chloride and the like. The reaction is performed in a solvent. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran, ethyl ether, dioxane, and dimethoxyethane. In this reaction,
When a copper salt (eg, copper iodide or the like) is added to the reaction system, the reaction can be efficiently promoted. The reaction temperature is about 0 to 80
° C, more preferably 0 to 40 ° C. The reaction time is about 0.5 to 24 hours, more preferably 0.5 to 24 hours.
5 to 2 hours. The reaction can be efficiently performed by stirring.

The compound (I) of the present invention thus obtained may form a salt. The salt is preferably a physiologically acceptable acid addition salt. Examples of such a salt include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, etc.). For example, salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used. Further, when the compound of the present invention has an acidic group such as —COOH, an inorganic base (eg, an alkali metal salt or an alkaline earth metal such as sodium, potassium, calcium, magnesium, or the like, ammonia or the like) or an organic base ( For example, salts may be formed with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like.
The compound (I) or a salt thereof of the present invention may be a hydrate or a non-hydrate. Examples of the hydrate include a monohydrate, a 1.5-hydrate and a 2-hydrate. The thus-obtained compound (I) or a salt thereof of the present invention can be isolated and purified by a conventional separation means such as recrystallization, distillation, chromatography and the like. When the compound (I) of the present invention is obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto. It can be converted to a free form or another salt by an analogous method. When the compound (I) of the present invention is an optically active compound, it can be separated into d-form and l-form by a usual optical resolution means.

Compound (I) of the present invention or a salt thereof [hereinafter sometimes referred to as the compound of the present invention. Has extremely excellent GnRH antagonism and low toxicity. Moreover, it is excellent in oral absorbability and sustained action. It also has the property of being stable in blood plasma. Therefore, the compound of the present invention can be used as a warm-blooded mammal (eg, human, monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc.).
In the above, by suppressing the secretion of gonadotropin by GnRH receptor antagonism and controlling the sex hormone concentration in the blood, the treatment of male or female hormone-dependent diseases and the treatment of diseases caused by excess of these hormones It can be used safely and advantageously in therapy. That is, the compound of the present invention is used for sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, uterine fibroids, endometriosis, precocious puberty, amenorrhea, It is useful for treating premenstrual syndrome, multilocular ovary syndrome, acne, etc. The compounds of the present invention are also useful for regulating reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The compounds of the present invention can further be used as contraceptives for men or women and as ovulation inducers for women. The compound of the present invention can be used for the treatment of infertility by utilizing the rebound effect after drug withdrawal.
Further, the compound of the present invention is useful in the field of animal husbandry for regulating estrus in animals, improving meat quality for meat, and promoting animal growth. The compound of the present invention is also useful as a spawning promoter for fish. Although the compound of the present invention can be used alone, it is also effective to use it in combination with a steroidal or nonsteroidal antiandrogen or antiestrogen. The compound of the present invention may be used in combination with a chemotherapeutic agent for cancer. Preferred specific examples of the combination include ifosfamide, UF and UF for prostate cancer.
T, Adriamycin, Pepromycin (P
Chemotherapeutic agents such as eplomycin) and cisplatin can be used in combination with the compound of the present invention. In addition, for breast cancer, cyclophosphamide (Cyclophospamid)
e), 5-FU, UFT, Methotrexat
e), Adriamycin, Mitomycin C
A chemotherapeutic agent such as (Mitomycin C) and mitoxantrone (Mitoxantrone) can be used in combination with the compound of the present invention.

The compound of the present invention can be used to prevent or prevent the above diseases.
When used as a therapeutic agent, according to a method known per se,
Any of oral administration or parenteral administration is possible, mixed with a pharmaceutically acceptable carrier, and is usually orally administered as a solid preparation such as tablets, capsules, granules and powders, or intravenously, subcutaneously, It is parenterally administered as an injection, suppository, sublingual tablet, or the like intramuscularly. Further, it may be administered sublingually, subcutaneously or intramuscularly as a sustained release preparation such as sublingual tablets and microcapsules. The daily dose varies depending on the degree of symptoms; age, sex, body weight, sensitivity difference of administration subject; timing of administration, interval, nature of pharmaceutical preparation, preparation, type; type of active ingredient, and is not particularly limited. Usually, the amount is about 0.1 to 30 mg, preferably about 0.1 to 3 mg, more preferably 0.1 to 1 m per kg of the mammal.
g, usually administered in 1 to 4 divided doses per day.
When the compound of the present invention is used as a prophylactic / therapeutic agent for the above-mentioned diseases in the animal husbandry or fishery field, according to a method known per se, in the animal husbandry field, granules, orally as a solid preparation such as powder, subcutaneous, It is used as an injection for intramuscular injection, and in the field of marine products, it is molded into solid preparations such as granules and powders. The dosage for use in this manner is also the same as described above, but is preferably about 0.01 to 5 mg, preferably about 0.03 to 3 mg per kg body weight of the organism to be administered.
Is usually administered once to three times a day.

As the above-mentioned pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, such as excipients, lubricants, binders and disintegrants in solid preparations; , Dissolution aids, suspending agents,
It is blended as a tonicity agent, a buffer, a soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferred examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferable examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-
Mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferred examples of the solvent include, for example, distilled water for injection, alcohol,
Propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Examples include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferred examples of the tonicity agent include:
For example, glucose, sodium chloride, glycerin, D-mannitol, D-sorbitol and the like can be mentioned. Preferred examples of the buffer include phosphate, acetate, and the like.
Buffers such as carbonates and citrates are included. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of the preservative include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

A suspending agent, a solubilizing agent,
Stabilizing agents, isotonic agents, preservatives, and the like are added to obtain intravenous, subcutaneous, or intramuscular injections by a method known per se. At that time, if necessary, a freeze-dried product can be obtained by a method known per se. When the compound of the present invention or a salt thereof is administered to, for example, a human, the compound itself or an appropriate pharmacologically acceptable carrier, excipient, or diluent is mixed, and the compound is orally or parenterally administered as a pharmaceutical composition. It can be administered safely. Examples of the pharmaceutical composition include oral preparations (eg, powders, granules, capsules, tablets), injections, drops, external preparations (eg, intranasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process.

The compound of the present invention or a salt thereof is used as a dispersant (eg,
Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., preservatives (eg, methylparaben, propylparaben, benzyl alcohol, etc.), isotonic Agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) and aqueous injections, or olive oil,
It can be dissolved, suspended or emulsified in vegetable oils such as sesame oil, cottonseed oil and corn oil, propylene glycol and the like, molded into an oily injection, and used as an injection. In order to prepare a preparation for oral administration, the compound of the present invention can be prepared by, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg,
Add starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and press-mold to produce granules for tablets I do. Then, if necessary, the preparation can be made into an oral administration preparation which is coated by a method known per se for the purpose of taste masking, enteric coating or sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, and Bruronic F6.
8. Cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, copolymerization of methacrylic acid / acrylic acid), pigments (eg, bengara, titanium dioxide, etc.) are used. In the case of an enteric preparation, an intermediate layer is preferably provided between the enteric layer and the drug-containing layer by a method known per se for the purpose of separating the two layers.

In order to prepare an external preparation, the compound of the present invention can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid, the compound of the present invention may be used as it is or as an excipient (eg,
Mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) are added and mixed to form a powdery composition. The liquid is almost the same as the injection, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred. In addition, all of these are pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. For example, in order to prepare a suppository, the compound of the present invention can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.) and intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) Such〕,
Alternatively, vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like can be mentioned. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

[0051]

The present invention will be described in more detail with reference to the following Reference Examples and Examples, which should not be construed as limiting the present invention. ^{The 1} H-NMR spectrum was measured using JEOL LAMBDA 30 using tetramethylsilane as an internal standard.
It was measured with a 0 (300 MHz) type spectrometer, and all δ values were shown in ppm. The symbols and abbreviations used in this specification have the following meanings. s: singlet, d: doublet, t: triplet, d
t: double triplet, m: multiplet, br: wide. mp: melting point.

Reference Example 1 (1) 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3-methyl-4
Preparation of -oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: PCT International Publication WO95 / 2
Compound obtained according to Example 3 (10) of 8405: 7- (2,6-difluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3
-B] pyridine-5-carboxylic acid ethyl ester (3.0
g, 6.39 mmol) was dissolved in dichloromethane (30 ml) and added dropwise to a dichloromethane solution (40 ml) of aluminum chloride (4.27 g, 32 mmol) and dimethyl disulfide (2.88 ml, 32 mmol) under ice cooling. After stirring at the same temperature for 4 hours, the reaction solution was concentrated to dryness. The obtained residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with water and concentrated to dryness to obtain a solid, which was recrystallized from ethanol-ethyl acetate to give the title compound as pale yellow powdery crystals. Obtained (1.64
g, 56%). mp 244-246 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2H
z), 2.64 (3H, s), 4.40 (2H, q, J = 7.2Hz), 5.26 (2H,
s), 6.96-7.02 (4H, m), 7.25-7.28 (2H, m), 7.31-7.46
(1H, m), 8.40 (1H, s).

(2) 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl)
Preparation of ethyl-3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylate: The compound (1.6 g, 3.51 mmol) obtained in Reference Example 1 (1) was converted to dimethylformamide. (20 ml), and sodium hydride (0.154 g, 3.86 mmol) was added thereto under ice cooling to give 30 ml.
Stirred for minutes. Chloromethyl methyl ether at the same temperature
(0.324 ml, 4.21 mmol), and the mixture was further stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Ethanol (10 ml) was added to the reaction solution, which was concentrated to dryness. The obtained residue was partitioned between dichloromethane and saturated saline, and the organic layer was washed with water and concentrated to dryness to give a solid, which was purified by a silica gel column to give the title compound as an amorphous (1.63 g,
93%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2H
z), 2.65 (3H, s), 3.50 (3H, s), 4.40 (2H, q, J = 7.2H
z), 5.22 (2H, s), 5.25 (2H, s), 7.00 (2H, t, J = 8.3H
z), 7.10 (2H, d, J = 6.8Hz), 7.33-7.41 (3H, m), 8.37
(1H, s).

(3) 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl)
-3- (N-benzyl-N-methylaminomethyl) -4-
Production of oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester: The compound (5.60 g, 11.2 mmol) obtained in Reference Example 1 (2) was suspended in carbon tetrachloride (100 ml). To give N-bromosuccinimide (2.19 g, 1
2.3 mmol) and α, α`-azobisisobutyronitrile
(0.37 g, 2.24 mmol) was added and the mixture was heated under reflux for 2 hours. Return to room temperature and add dichloromethane (100 ml)
Was added, and the mixture was washed with saturated saline, dried and then dried to obtain a solid.
The obtained solid was dissolved in dimethylformamide (100 ml), and ethyldiisopropylamine (2.10 ml, 1
2.3 mmol) and N-methylbenzylamine (1.59 mmol)
(12.3 mmol) and stirred for 2 hours. The reaction was concentrated to dryness. The obtained residue was partitioned between dichloromethane and water, and the organic layer was washed with saturated saline, dried and concentrated to dryness to obtain a solid. Purification on a silica gel column gave the title compound as an amorphous (6.35 g, 92%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2H
z), 2.20 (3H, s), 3.51 (3H, s), 3.93 (2H, s), 4.20 (2
H, s), 4.40 (2H, q, J = 7.2Hz), 5.23 (2H, s), 5.27 (2
H, 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
m), 8.37 (1H, s).

(4) 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-methoxymethoxyphenyl)
-3- (N-benzyl-N-methylaminomethyl) -4-
Preparation of oxothieno [2,3-b] pyridine-5-N-methyl-O-methylhydroxamic acid: N-methyl-O-
Methylhydroxylamine hydrochloride (4.98 g, 151 m
mol) and N-ethyldiisopropylamine (8.73 m
l, 151 mmol) in dichloromethane solution (100 ml) was added to trimethylaluminum (1.5N solution, 20.4 ml,
(130.6 mmol) was added under ice cooling. After stirring at the same temperature for 30 minutes, the mixture was further stirred at room temperature for 30 minutes. A dichloromethane solution (100 ml) of the compound (6.30 g, 10.2 mmol) obtained in Reference Example 1 (3) was added under ice cooling, and the mixture was further stirred at the same temperature for 2 hours. The reaction solution was poured into water, extracted with chloroform, washed with saturated saline, dried and concentrated to dryness to obtain the title compound as an amorphous substance (5.73 g, 89%). 1H-NMR (300 MHz, CDCl ₃ ) δ: 2.21 (3H, s), 3.34 (3
H, 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-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3-
Production of (N-benzyl-N-methylaminomethyl) -5-benzoyl-4-oxothieno [2,3-b] pyridine: The compound obtained in the above Reference Example 1 (4) (5.20 g, 8.
20 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), and phenylmagnesium bromide (1M solution, 2
4.6 ml, 24.6 mmol) were added under ice cooling. 3 at the same temperature
After stirring for 6 hours, 6N hydrochloric acid was added under ice cooling to adjust the pH to 2 or less. Then, the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized, poured into water, extracted with ethyl acetate, washed with saturated saline, dried and concentrated to dryness to obtain the title compound as an amorphous substance (3.37 g, 68%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 3.91 (2H,
s), 4.30 (2H, s), 5.38 (2H, s), 6.98-7.05 (4H, m),
7.21-7.38 (5H, m), 7.43-7.48 (5H, m), 7.55-7.59 (1H,
m), 7.90 (2H, d, J = 7.1Hz), 8.06 (1H, s).

(6) 4,7-dihydro-7- (2,6-difluorobenzyl) -2- (4-hydroxyphenyl) -3-
Production of (N-benzyl-N-methylaminomethyl) -5-isobutyryl-4-oxothieno [2,3-b] pyridine: Using the compound obtained in Reference Example 1 (4) above as a raw material,
Using isopropylmagnesium chloride instead of phenylmagnesium bromide, the title compound was obtained as amorphous in the same manner as in Reference Example 1 (5) (2.
1 g, 51%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18 (6H, d), 2.10 (3
H, 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 2 The compound obtained in Reference Example 1 (3) was added with a small excess of 1N sodium hydroxide in tetrahydrofuran, and the mixture was added at room temperature.
The mixture is hydrolyzed by stirring for a period of time to convert into a compound having a carboxyl group at the 5-position. Next, the carboxylic acid derivative (carboxyl group at the 5-position) was added to dimethylformamide in N, N
Dimethylaminopyridine (large excess) and alcohols (eg, isopropanol, cyclohexanol, sec-butanol, 3-pentanol or 2,4-dimethyl-
3-pentanol) and dropwise addition of phosphorus oxychloride (10-fold amount) under ice-cooling to produce a compound in which the substituent at the 5-position is an ester. Further, by subjecting the ester derivative to a commonly used deprotection reaction using dilute hydrochloric acid, compounds 2 (1) to 2 (5) obtained by elimination of the methoxymethyl group in the methoxymethoxy group were converted to the following [Table 1]. ]
Shown in Further, by subjecting the compound obtained in Reference Example 1 (3) to a commonly used deprotection reaction using dilute hydrochloric acid,
Compound 2 (6) obtained by removing the methoxymethyl group in the methoxymethoxy group is shown in Table 1 below.

Reference Example 3 4,7-dihydro-7- (2,6-difluorobenzyl)-
Production of ethyl 2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylate: PCT International Publication Compound prepared according to Example 27 of WO 95/28405: 4,7-
Dihydro-7- (2,6-difluorobenzyl) -2- (4
-Aminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester was added with a small excess of isobutyryl chloride in pyridine. The mixture was stirred at room temperature for 2 hours to produce the title compound. m.p 185-186 ° C. Elemental _{analysis: C 36 H 35 F 2 N} 3 O 4 S · HCl · 1.5H 2 O
As ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8H)
z), 1.39 (3H, t, J = 7.1Hz), 2.12 (3H, s), 2.54 (1H,
m), 3.56 (2H, s), 4.16 (2H, s), 4.40 (2H, q, J = 7.1H
z), 5.26 (2H, s), 7.01 (2H, t, J = 8.1Hz), 7.10-7.30 (5
H, m), 7.41 (1H, m), 7.62 (2H, d, J = 8.5Hz), 7.81 (2H,
d, J = 8.5Hz), 8.35 (1H, s).

The structures of the compounds obtained by the methods of Reference Examples 1 (3) to 1 (6), Reference Examples 2 and 3 are shown in Table 1 below.

[0061]

[Table 1]

Example 1 3- (N-methyl-N-benzylaminomethyl) -4,7
-Dihydro-7- (2,6-difluorobenzyl) -2-
Preparation of (4-allyloxyphenyl) -5-benzoyl-4-oxothieno [2,3-b] pyridine hydrochloride: dimethyl of the compound (0.12 g, 0.2 mmol) obtained in Reference Example 1 (5) To a formamide (3 ml) solution were added potassium carbonate (0.055 g, 0.4 mmol) and allyl iodide (37 μm) under ice-cooling.
1,0.4 mmol) was added. After stirring at room temperature for 2 hours,
The residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and saturated saline. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless oil. To a solution of this oil in ether (4 ml) was added 1N ethereal hydrochloric acid (0.2 ml) under ice cooling.
ml) and stirred at the same temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-ether to give the title compound (Compound No. 1) as white crystals (0.068 g, 50%). The structure of the obtained compound is shown in Table 2 below. mp 120-122 ° C. Elemental analysis value C ₃₉ H ₃₂ F ₂ N ₂ O ₃ S.HCl.1.5H ₂ O.
0.1CHCl ₃ ¹ H-NMR (300MHz, DMSO-d6) δ: 2.83 (3H, s), 4.32
-4.63 (6H, m), 5.31-5.49 (4H, m), 6.02-6.14 (1H, m),
7.01-7.09 (4H, m), 7.24-7.63 (11H, m), 7.95 (2H, d, J
= 7.8Hz), 8.16 (1H, s), 11.95 (1H, brs).

Example 2 Using the compound obtained in Reference Example 1 (5) as a raw material,
Compound 2 prepared in the same manner as described in
(1), 2 (2), 2 (3) and 2 (4) are shown in Table 2 below.

Example 3 Using the compound obtained in Reference Example 1 (6) as a raw material,
Compound 3 prepared in the same manner as described in
(1), 3 (2), 3 (3), 3 (4), 3 (5) and 3 (6) are shown in [Table 2].

[0065]

[Table 2]

Example 4 Using the compound obtained in Reference Example 2 as a raw material, Compounds 4 (1) to 4 (4) produced in the same manner as described in Example 1
(22) is shown in [Table 3].

[0067]

[Table 3]

Example 5 4,7-Dihydro-7- (2,6-difluorobenzyl)-
Production of 2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester hydrochloride: above Compound obtained in Reference Example 3
(1.29 g, 2.0 mmol) in isopropyl alcohol solution (50 ml) was added to titanium (IV) isopropoxide (0.284).
g, 1.0 mmol) was added dropwise under ice cooling (0 ° C.). After the addition, the mixture was stirred at room temperature for 12 hours. The reaction solution was chloroform (200 m
l) and water. The aqueous layer is chloroform (200m
After extraction in 1), the extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless amorphous (1.08 g, 82%). The obtained amorphous was dissolved in chloroform, 10N hydrochloric acid-ethanol solution was added to form a salt, and the salt was recrystallized from chloroform-ether to give the title compound as colorless needles (0.86).
g, 74%). The structure of the obtained compound is shown in Table 4 below. mp 168-170 ° C. Elemental analysis _{C 37 H 37 F 2 N 3} O 4 S · HCl · 0.5H 2 O
As ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8H
z), 1.36 (6H, d, d = 6.3Hz), 2.10 (3H, s), 2.57 (1H,
m), 3.65 (2H, s), 4.16 (2H, s), 5.23 (1H, m), 5.23 (2
H, s), 7.00 (2H, dd, J = 8.1Hz), 7.10-7.26 (5H, m), 7.
38 (1H, m), 7.63 (2H, d, J = 8.3Hz), 7.78 (2H, d, J = 8.6H
z), 8.29 (1H, m).

Example 6 Using the compound obtained in Reference Example 3 as a raw material, Example 5
Compounds 6 (1), 6 (2), 6 (3) and 6 (4) shown in [Table 4] were produced in the same manner as described in Table 4.

[Table 4]

Example 7 4,7-dihydro-7- (2,6-difluorobenzyl)-
Production of 2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid: The obtained compound (1.2 g) was added to ethanol (10 g).
ml), and cooled to 0 ° C while adding 5N potassium hydroxide (5 ml). After returning to room temperature and stirring for 5 hours, 0.2N hydrochloric acid (200 ml) and chloroform (200 ml) were added.
l). Crystals were obtained from the organic layer, and ethyl acetate-
Recrystallization from ethanol gave the title compound as colorless powders (1.0 g, 81%). The structure of the obtained compound is shown in Table 5 below. mp 212-214 ° C.

Example 8 4,7-Dihydro-7- (2,6-difluorobenzyl)-
2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid (2,4-dimethyl-3 Preparation of (-pentyl) ester hydrochloride: Compound (0.062 g, 0.1 mmol) obtained in Example 7 above, N,
N-dimethylaminopyridine (0.489 g, 4.00 mm
ol) and a solution of 2,4-dimethyl-3-pentanol (2 ml) in dimethylformamide (1 ml).
(0.153 g, 1.0 mmol) was added dropwise under ice cooling (0 ° C.).
After the dropwise addition, the mixture was heated under reflux for 12 hours. The reaction solution is chloroform
(200 ml) and water. Chloroform aqueous layer
(200 ml), the extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless amorphous (1.08 g, 82%).
The obtained amorphous was dissolved in chloroform, and 10
N hydrochloric acid-ethanol solution was added to make a salt, which was recrystallized from chloroform-ether to give the title compound as colorless powdery crystals. The structure of the obtained compound is shown in Table 5 below. mp 174-175 ° C.

Example 9 4,7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -5- (4-tetrahydropyranylthio) carbonyl-4-oxothieno [2,
3-b] Preparation of pyridine hydrochloride: 4-mercaptotetrahydrofuran (470 mg, 4.00 mmole) was dissolved in dichloromethane (2 ml), and trimethylaluminum was added thereto.
(15%, 0.48 ml, 1.00 mmol) in hexane (1
5 ml) was added dropwise under ice cooling. After stirring at the same temperature for 1 hour, the compound obtained in the above Reference Example 3 (129 mg, 0.20 mm
ole) in dichloromethane (1 ml) was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 1 hour, poured into 200 ml of distilled water, extracted with chloroform, washed with saturated saline, and dried (Na ₂ SO ₄ ).
Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow amorphous (30 m
g, 11%). The obtained amorphous was dissolved in chloroform, 10N hydrochloric acid-ethanol solution was added to make a salt, and the salt was recrystallized from chloroform-ether to obtain the title compound as yellow powdery crystals. The structure is shown in Table 5 below.
Shown in mp 174-176 ° C. Elemental _{analysis: C 39 H 39 N 3 O} 4 S 2 F 2 · HCl · 2.5H 2 O
As ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8H)
z), 1.75-1.87 (2H, m), 1.97-2.04 (2H, m), 2.11 (3H,
s), 2.56 (1H, m), 3.54-3.61 (2H, m), 3.66 (2H, s), 3.
87 (1H, m), 3.96-4.01 (2H, m), 4.19 (2H, s), 5.30 (2H,
m), 7.01 (2H, dd, J = 8.1Hz), 7.12-7.32 (5H, m), 7.42
(1H, m), 7.62 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6H
z), 8.37 (1H, s).

Example 10 Using the compound obtained in Example 7 as a raw material and treating in the same manner as in Example 9 above, Compound 1 shown in the following [Table 5] was obtained.
0 (1) and 10 (2) were prepared.

[0074]

[Table 5]

Example 11 4,7-Dihydro-7- (2,6-difluorobenzyl)-
3- (N-methyl-N-benzylaminomethyl) -2-
(4-isobutyrylaminophenyl) -6-methyl-4-
Preparation of oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester hydrochloride: The compound obtained in Example 5 (1.98 g, 2.78 mmole) was dissolved in anhydrous tetrahydrofuran (50 ml), and methylmagnesium was added. Bromide in diethyl ether (3.0 M, 4.63 ml, 1
A mixture of 3.9 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, 1
N 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 0.1
The mixture was poured into 500 ml of N potassium hydroxide solution, extracted with chloroform, washed with saturated saline, dried (Na ₂ SO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to be colorless amorphous (1.80 g, 96%).
I got Sodium hydride in tetrahydrofuran (15m
l) and suspended in the amorphous (1.8) obtained above.
0g, 2.67 mmole) in tetrahydrofuran (15 ml)
Was added dropwise at room temperature. After the reaction solution was stirred at 50 ° C. for 0.5 hour, phenylselenyl chloride (1.02 g, 5.34 mmol) was added.
e) tetrahydrofuran solution (5 ml) was added dropwise, and 5
Stirred at 0 ° C. overnight. Pour the reaction solution into 500 ml of distilled water,
Extract with chloroform, wash with saturated saline and dry (Na ₂ SO
₄ ) After that, the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography to give a colorless amorphous
(1.00 g, 86%). The obtained amorphous was dissolved in chloroform, 10N hydrochloric acid-ethanol solution was added to form a salt, and the salt was recrystallized from chloroform-ether.
The title compound was obtained as white powdery crystals. The structure of the obtained compound is shown in [Table 6] below. mp 163-165 ° C. Elemental _{analysis: C 38 H 39 N 3 O} 4 SF 2 · HCl · 1.5H 2 O
As ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23 (6H, d, J = 6.8H)
z), 1.38 (6H, d, J = 6.8Hz), 2.10 (3H, s), 2.45 (3H,
s), 2.54 (1H, m), 3.63 (2H, s), 4.13 (2H, s), 5.30 (1
H, m), 5.34 (3H, s), 6.93 (2H, dd, J = 8.1Hz), 7.14-7.
39 (6H, m), 7.59 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6H
z).

Example 12 Reference Example 3, Example 6 (2), Example 6 (3) or Example 6
Using the compound obtained in (4) as a raw material and treating in the same manner as in Example 11, the compound 1 shown in [Table 6] described below was obtained.
2 (1), 12 (2), 12 (3) and 12 (4) were produced.

Example 13 The compound obtained in Reference Example 3 was used as a starting material, and treated in the same manner as in Example 11 except that ethylmagnesium bromide was used instead of methylmagnesium chloride in Example 11 described above. Compound 13 shown in Table 6 was produced.

Example 14 The compound obtained in Example 4 (1) or 4 (22) was used as a starting material, and treated in the same manner as in Example 11 to obtain a compound 14 (1) shown in Table 6 below. ) Or compound 14 (2), respectively. Further, Examples 4 (2), 4 (3), 4 (6),
Using the compound obtained in 4 (7) or 4 (8) as a raw material, the same treatment as in Example 11 was carried out, and the following [Table 6]
Compounds 14 (3) to 14 (7) shown below are produced.

[0079]

[Table 6]

Example 15 Prepared in Example 3 (1) or Example 5 (100 m
g), lactose 165 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg are used to produce tablets in a conventional manner.

Example 16 Compound (5 g) prepared in Example 3 (1) or Example 5
Was dissolved in distilled water for injection to make a total volume of 100 ml. This solution was aseptically filtered using a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Sartorius), dispensed into washing-sterilized vials in a volume of 2 ml each, and lyophilized by a conventional method to obtain 100 mg / ml. Produce lyophilized injections in vials.

Example 17 The compound prepared in Example 9 (100 mg), crystalline cellulose 50 mg, low-substituted hydroxypropylcellulose-31 (30 mg), hydroxypropylcellulose-L (6 mg) and magnesium stearate 1 mg
Is used to produce tablets in a conventional manner.

Example 18 The compound prepared in Example 11 (100 mg), lactose 1
Tablets are produced by a conventional method using 50 mg, croscarmellose sodium 30 mg, hydroxypropylcellulose 6 mg and magnesium stearate 1 mg.

Example 19 Using the compound (100 mg) produced in Example 12 (1), lactose 165 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg, tablets are produced in a conventional manner.

Example 20 The compound (100 mg) produced in Example 14 (1), lactose 150 mg, low-substituted hydroxypropylcellulose-31 (30 mg), polyvinylpyrrolidone 10 mg and magnesium stearate 1 mg were used in a conventional manner. To produce tablets.

Example 21 Using the compound (100 mg) produced in Example 14 (2), lactose 150 mg, carboxymethylcellulose calcium 30 mg, hydroxypropylcellulose 6 mg and magnesium stearate 1 mg, tablets are produced in a conventional manner.

Example 22 (1) Compound 5 g prepared by the method described in Example 3 (1) or Example 5 (2) Lactose / crystalline cellulose (grain) 330 g (3) D-mannitol 29 g (4) Low substituted hydroxypropylcellulose 20 g (5) Talc 25 g (6) Hydroxypropylcellulose 50 g (7) Aspartame 3 g (8) Dipotassium glycyrrhizinate 3 g (9) Hydroxypropylmethylcellulose 2910 30 g (10) Titanium oxide 3.5 g (11 ) Yellow iron sesquioxide 0.5 g (12) Light anhydrous silicic acid 1 g (1), (3), (4), (5), (6), (7) and (8) suspended in purified water or Dissolve and coat the core particles of (2) to produce fine particles. (9) to (11) are coated on the fine particles to form coated fine particles, and mixed with (12) to obtain fine particles 1 of the compound produced in Example 3 (1) or Example 5.
%, 500 g. This is packaged in 500 mg portions.

Example 23 (1) 100 g of the compound prepared in Example 3 (4), 9, 11, 12 (1), 14 (1) or 14 (2) (2) Lactose 234 g (3) Corn starch 150 g (4) 15 g of hydroxypropylcellulose (5) 1 g of light anhydrous silicic acid (500 g in total) (1), (2) and (3) were mixed in a fluidized bed granulator and dissolved in purified water to obtain (4). Spray, Example 3 (4), 9, 11, 1
Fine granules of the compound produced in 2 (1), 14 (1) or 14 (2) are obtained. After mixing with (5), pack 500 mg each.

Test Example 1 (1) Preparation of ¹²⁵ I-leuprorelin: 10 μl of 3 × 10 ^-4 M leuprorelin aqueous solution, and 0.01 mg / ml
Take lactoperoxidase (10 μl) into a tube and add N
10 μl (37 MBq) of a ¹²⁵ I solution was added, and after stirring,
10 μl of 0.001% H ₂ O ₂ was added and reacted at room temperature for 20 minutes. The reaction was stopped by adding 700 μl of a 0.05% TFA solution and purified by reverse phase HPLC. HPL
The condition of C is shown below. ¹²⁵ I-leuprorelin eluted with a retention time of 26-27 minutes. Column: TSKgel ODS-80 ^™ (TM is a registered trademark) CTR (4.6 mm × 10 cm) Eluent: Solvent A (0.05% TFA) Solvent B (40% CH ₃ CN-0.05) % TFA) 0 minutes (100% solvent A) -3 minutes (100% solvent A) -7 minutes (50% solvent A + 50% solvent B) -40 minutes (100% solvent B) Elution temperature: room temperature Elution rate: 1 ml / min

(2) C containing human GnRH receptor
Preparation of HO (Chinese Hamster Ovary) Cell Membrane Fraction: Human GnRH Receptor Expressing CHO Cells (10
⁹ mM) with 5 mM EDTA (ethylenediaminetetraacetic acid)
-Buffered physiological saline (PBS-EDTA)
And centrifuged at 100 × g for 5 minutes. A cell homogenate buffer (10 mM NaH
10 ml of CO ₃ , 5 mM EDTA, pH 7.5) was added and homogenized using a Polytron homogenizer. The mixture was centrifuged at 400 × g for 15 minutes, and the supernatant was collected in an ultracentrifuge tube and centrifuged at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. This precipitate was suspended in 2 ml of assay buffer and centrifuged at 100,000 × g for 1 hour. The membrane fraction collected as a precipitate was resuspended in 20 ml of assay buffer, aliquoted, stored at -80 ° C, and thawed at each use.

(3) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate: The human membrane fraction prepared in the above section (2) was diluted with assay buffer to 200 μg / ml, and 188 μl was dispensed into tubes. did. 2 μl of 2 mM compound dissolved in 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin were added simultaneously. To determine the maximum binding, 2 μl of 60% DMSO and 38 nM
Was added to 10 μl of ¹²⁵ I-leuprorelin. In order to measure the amount of non-specific binding, a reaction solution containing 2 μl of 100 μM leuprorelin dissolved in 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin was simultaneously prepared. 25
The reaction was performed at ゜ C for 60 minutes. After the reaction, the reaction solution was subjected to suction filtration using a polyethylene imine-treated Whatman glass filter (GF-F). After filtration, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper was measured using a γ-counter.

The following formula: (TB-SB) / (TB-NSB) × 100 (where, SB: radioactivity when a test compound is added, T
B: maximum binding radioactivity, NSB: non-specific binding radioactivity. ) Is calculated to determine the binding inhibition rate (%) of the test compound, and then the concentration of the test compound is changed to determine the inhibition rate. The concentration of the test compound that inhibits 50% binding (IC ₅₀
Value) was calculated from the Hill plot. Example 3 above
The compound obtained in (4) was used as a test compound, and the IC ₅₀ value obtained by the above measurement method is shown in Table 7 below.

[0093]

[Table 7]

[0094]

The compounds of the present invention have excellent gonadotropin-releasing hormone antagonism, are highly soluble in various organic solvents, and are extremely excellent in oral absorption. It is also excellent in stability and action continuity, and is stable in blood plasma. Therefore, it can be used, for example, as an agent for preventing or treating hormone-dependent diseases. Specifically, for example, as a medicine, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, uterine fibroids, endometriosis, precocious puberty, amenorrhea syndrome It is effective as a prophylactic or therapeutic agent for multilocular ovarian syndrome, acne, etc., or as a pregnancy regulator (eg, contraceptive, etc.), a fertility treatment agent, a menstrual regulator, and in the animal husbandry field, animal estrus It is also effective as a fish spawning promoter in the field of regulation of fish, improvement of meat quality for meat, regulation of animal growth, and fisheries.

──────────────────────────────────────────────────続 き Continuing on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication A61K 31/435 AEX A61K 31/435 AEX (72) Inventor Nobuhiro Suzuki 1077 Yatabe, Oji, Tsukuba, Ibaraki Prefecture 50 (72) Inventor Gi Imada 2-11-11 Sengen, Tsukuba, Ibaraki 16-16 Eminence Domine 701

Claims (29)

[Claims] 1. A compound of the general formula (I) [Wherein (A) R ¹ is an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ² is (1) an alkyl group, (2) aryl Group, (3)
(Wherein, R ⁴¹ is a cycloalkyl group which may have an alkyl group or a substituted group may have a substituent group, X represents O or S) wherein -X-R ⁴¹ represented by R ³ represents a hydrogen atom or an alkyl group, respectively; (B) R ¹ represents a C _1-8 alkanoylamino group, and R ² represents
X-R ⁴³ (wherein, when X is O, R ⁴³ has a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent. Oxygen containing 6 which may be
R ³ represents a hydrogen atom or an alkyl group. Or a salt thereof. Wherein R ¹ is (i) a halogen, a C _1-6 alkoxy group substituted by a group selected from (ii) C _3-10 cycloalkyl and (iii) C _2-9 alkenyl, R ² Is (1) C _1-6 alkyl, (2) C _6-14 aryl, (3) Formula —X—R ⁴² (wherein R ⁴²
_{Represents a} C _1-13 alkyl group or a C _3-10 cycloalkyl group which may have a substituent, and X represents O or S. The compound according to claim 1, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group. (3) a group in which R ⁴² is (1) halogen which may be substituted by C _1-4 alkoxy or C _3-8 cycloalkyl;
_1-13 alkyl group or (2) halogen, C _1-4 alkoxy or compound of claim 2, wherein optionally substituted with C _1-4 alkyl is also optionally C _3-10 cycloalkyl group. 4. The compound according to claim 2, wherein R ¹ is a C _1-3 alkoxy group substituted by vinyl. 5. The compound according to claim 2, wherein R ¹ is an allyloxy group. 6. The method according to claim 1, wherein R ² is substituted with (1) a C _1-3 alkyl group, (2) a C _6-14 aryl group, (3) halogen, C _1-3 alkyl or C _1-3 alkoxy. 3. A compound according to claim 2 which is a good _C3-7 alkoxy group. 7. The compound according to claim 2, wherein R ² is isopropyl, phenyl or isopropoxy. (8) R ¹ is a C _1-8 alkanoylamino group,
R ² is a group represented by the formula (1) -X-R ⁴⁴ (wherein, when X is O, R ⁴⁴ has a C _3-13 branched alkyl group which may have a substituent or a substituent; X represents an optionally substituted C _3-10 cycloalkyl group or an optionally substituted oxygen-containing 6-membered heterocyclic group,
In the formula, R ⁴⁴ represents a C _1-13 alkyl group which may have a substituent, a C _3-10 cycloalkyl group which may have a substituent or an oxygen-containing group 6 which may have a substituent. R ³ represents a hydrogen atom or C _1-6, or a group represented by (2) a hydroxyl group).
The compound according to claim 1, which is an alkyl group. (1) When X is O, R ⁴⁴ is C _1-4 alkyl,
C _3-13 branched alkyl optionally substituted by halogen, amino, mono- or di-C _1-4 alkylamino, C _1-4 alkoxy or C _3-7 cycloalkyl, halogen, nitro, C C _3-10 cycloalkyl group optionally substituted with _1-4 alkyl, C _1-4 alkoxy, amino or mono- or di-C _1-4 alkylamino, or halogen, nitro, oxo, hydroxy, amino , Thing-
Or di-C _1-4 alkylamino, C _1-4 alkoxy,
(2) When X is S, halogen, amino, mono- or di-C _1-4 represents an oxygen-containing 6-membered heterocyclic group which may be substituted by C _1-4 alkyl or C _1-4 alkylthio; A C _1-13 alkyl group optionally substituted with alkylamino, C _1-4 alkoxy or C _3-7 cycloalkyl, or
6-membered oxygen-containing group optionally substituted by halogen, nitro, oxo, hydroxy, amino, mono- or di-C _1-4 alkylamino, C _1-4 alkoxy, C _1-4 alkyl or C _1-4 alkylthio 9. The compound according to claim 8, which represents a heterocyclic group. 10. The compound according to claim 8, wherein R ¹ is a C _3-5 alkanoylamino group. 11. The compound according to claim 8, wherein R ¹ is isobutyrylamino. 12. When X is O, R ⁴⁴ is a C _3-7 branched alkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent. The compound according to claim 8, which is 13. When X is S, R ⁴⁴ represents a C _1-7 alkyl group which may have a substituent or an oxygen-containing 6-membered heterocyclic group which may have a substituent. The compound according to claim 8, which is the compound according to claim 8. (14) 2- (4-allyloxyphenyl) -4,
7-dihydro-7- (2,6-difluorobenzyl) -3
-(N-benzyl-N-methylaminomethyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine, 2- [4- (2-methyl-2-propen-1-yl-oxy ) Phenyl) -4,7-dihydro-7- (2,6
-Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -5-isobutyryl-4-oxo-thieno [2,3-b] pyridine, isopropyl [2- (4
-Allyloxyphenyl) -4,7-dihydro-7- (2,
6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate], ethyl [2- (4 -Allyloxyphenyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -6-methyl-4-
The compound according to claim 1, which is oxo-thieno [2,3-b] pyridine-5-carboxylate] or a salt thereof. 15. An isopropyl [4,7-dihydro-7-
(2,6-difluorobenzyl) -3- (N-benzyl-N
-Methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], sec-butyl [4,7-
Dihydro-7- (2,6-difluorobenzyl) -3- (N
-Benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,
3-b] pyridine-5-carboxylate], cyclohexyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4- Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 3-pentyl [4,7-dihydro-7- (2,
6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-
5-carboxylate], tetrahydropyranyl [4,
7-dihydro-7- (2,6-difluorobenzyl) -3
-(N-benzyl-N-methylaminomethyl) -2- (4
-Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 4,
7-dihydro-7- (2,6-difluorobenzyl) -3
-(N-benzyl-N-methylaminomethyl) -2- (4
-Isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid, 2,4-dimethyl-3-pentyl [4,7-dihydro-7- (2,6-
Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4-oxo-thieno [2,3-b] pyridine-5-
Carboxylate], isopropyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6 -Methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate], cyclohexyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N -Methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6
-Methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 3-pentyl [4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-
Benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylate], 4-tetrahydropyranyl [4,7-dihydro-
7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4-oxo-thieno [2,
3-b] pyridine-5-carboxylate] or a salt thereof. (16) 4,7-dihydro-7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -4
The compound according to claim 1, which is -oxo-5- (4-tetrahydropyranylthiocarbonyl) thieno [2,3-b] pyridine or a salt thereof. 17. An ethyl [4,7-dihydro-7- (2,6
-Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-methyl-4-oxo-thieno [2,3-b] pyridine-5 -Carboxylate] or a salt thereof. (18) Ethyl [4,7-dihydro-7- (2,6
-Difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -2- (4-isobutyrylaminophenyl) -6-ethyl-4-oxo-thieno [2,3-b] pyridine-5 -Carboxylate] or a salt thereof. (A) General formula (II) [Wherein, R ²¹ represents (1) an alkyl group, (2) an aryl group or
(3) Formula -X-R ⁴¹ (wherein, R ⁴¹ represents an alkyl group or a cycloalkyl group each of which may have a substituent, and X represents O
Or S, respectively, and R ³ represents a hydrogen atom or an alkyl group.]
I) or a salt thereof and a compound represented by the formula R ¹² -Y, wherein R ¹² is an alkyl group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkylalkenyl, and Y is a halogen atom Is shown. With a compound represented by the general formula (III): [Wherein, R ¹¹ represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ²¹ and R ³ have the same meaning as described above. Or a salt thereof, or (b) a compound of the general formula (IV): ^{Wherein, R 13} is a C _1-8 alkanoylamino group, R ²³
Represents a linear alkoxy group, and R ³ represents a hydrogen atom or an alkyl group. A compound represented by the formula: R ^24- OH wherein R ²⁴ is a branched alkyl group, a cycloalkyl group or a 6-membered oxygen-containing heterocyclic group which may have a substituent. Shows a ring group. Or a salt thereof or a compound represented by the formula R ²⁵ -SH, wherein R ²⁵ represents an alkyl group, a cycloalkyl group or an oxygen-containing 6-membered heterocyclic group which may have a substituent. By reacting with a compound represented by the formula
(V) [Wherein, R ¹³ is as defined above, and R ²² is a group represented by the formula (1) -XR
⁴³ (wherein, when X is O, R ⁴³ is a branched alkyl group, cycloalkyl group or oxygen-containing 6-membered heterocyclic group which may have a substituent, and when X is S, R ⁴³ is An alkyl group, a cycloalkyl group, or an oxygen-containing 6-membered heterocyclic group which may have a substituent) or (2) a hydroxyl group. A compound represented by the formula
(V) or a salt thereof, or (c) a compound represented by the general formula: Wherein, R ¹ is (1) (i) halogen, (ii) cycloalkyl and (iii) an alkoxy group or substituted by a group selected from alkenyl (2) C _1-8 alkanoylamino group, R ³
Represents a hydrogen atom or an alkyl group, respectively. Or a salt thereof represented by the formula: R ²⁷ -H wherein R ²⁷ is a group represented by the formula -XR ⁴ (wherein R ⁴ is an alkyl group which may have a substituent, , A cycloalkyl group or a 6-membered oxygen-containing heterocyclic group, and X represents O or S). With the compound represented by the general formula (VII): [Wherein (A) R ¹ represents an alkoxy group substituted by a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ²⁶ represents (1) an alkyl group, (2) aryl Group,
(3) Formula -X-R ⁴¹ (wherein, R ⁴¹ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and X represents O or S) Wherein R ³ represents a hydrogen atom or an alkyl group, respectively, or (B) R ¹ represents a C _1-8 alkanoylamino group, and R ²⁶ represents a group represented by the formula -X
-R ⁴⁵ (wherein, when X is O, R ⁴⁵ represents a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. Or a 6-membered oxygen-containing heterocyclic group which may be represented by the following formula: A method for producing the compound (I) or a salt thereof by producing the compound (VII) or a salt thereof represented by the formula: (20) a compound represented by the general formula (VIII): [Wherein (A) R ¹ represents an alkoxy group substituted with a group selected from (i) halogen, (ii) cycloalkyl and (iii) alkenyl, and R ² represents a formula -XR ⁴¹ (wherein R ⁴¹ represents an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and X represents O or S)
The a group represented by either indicating R ³ is a hydrogen atom or an alkyl group, respectively, the (B) R ¹ is C _1-8 alkanoylamino group, R ² is the formula -X
-R ⁴⁵ (wherein, when X is O, R ⁴⁵ represents a branched alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or a substituent And when X is S, R ⁴³ has an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. Or a 6-membered oxygen-containing heterocyclic group which may be substituted). And a salt thereof, and a compound represented by the formula: R ³¹ -Z wherein R ³¹ represents an alkyl group. Z represents a metal which may be halogenated. Or a salt thereof, which is represented by the general formula (IX): [Wherein, R ¹ , R ² and R ³¹ have the same meaning as described above. ]
A method for producing the compound (IX) or a salt thereof represented by the formula: 21. The compound according to claim 1, which has high oral absorbability. 22. The compound according to claim 1, which is stable in plasma, or a salt thereof. [23] a pharmaceutical comprising the compound or a salt thereof according to the above [1]; 24. The medicament according to claim 23, which is a therapeutic / prophylactic agent for a sex hormone-dependent disease. 25. The medicament according to claim 24, wherein the sex hormone-dependent disease is prostate cancer, uterine cancer, breast cancer, or pituitary tumor. (26) The sex hormone-dependent disease is benign prostatic hyperplasia,
25. Endometriosis, uterine fibroids, precocious puberty.
The medicament according to claim. 27. A pregnancy regulator comprising the compound according to claim 1 or a salt thereof. 28. A menstrual cycle regulator comprising the compound according to claim 1 or a salt thereof. 29. The pregnancy regulator according to claim 27, which is used for contraception.