Thienopyridine derivatives, their production and use

The present thienopyridine derivatives and composition having gonadotropin-releasing hormone antagonistic activity are useful as prophylactic or therapeutic agents for the prevention or treatment of several hormone dependent diseases, for example, a sex hormone dependent cancer (e.g. prostatic cancer, cancer of uterine cervix, breast cancer, pituitary adenoma), benign prostatic hypertrophy, myoma of the uterus, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne vulgaris; is effective as a fertility controlling agent in both sexes (e.g. a pregnancy controlling agent and a menstrual cycle controlling agent); is useful as a contraceptive of male or female, as an ovulation-inducing agent of female; is useful as an infertility treating agent by using a rebound effect owing to a stoppage of administration thereof; is useful as modulating estrous cycles in animals in the field of animal husbandry, as an agent for improving the quality of edible meat or promoting the growth of animals; is useful as an agent of spawning promotion in fish.

TECHNICAL FIELD 
The present invention relates to novel 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and salts thereof. The 
present invention further relates to method for manufacturing these 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and salts thereof, and 
pharmaceutical composition containing these 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and salts thereof. 
BACKGROUND ART 
Secretion of anterior pituitary hormone undergoes the control by peripheral 
hormone secreted from target organs for the respective hormones and by 
secretion-accelerating or secretion-inhibiting hormone from hypothalamus, 
which is the upper central organ of anterior lobe of pituitary (in this 
specification, these hormones are collectively called "hypothalamic 
hormone"). At the present stage, as hypothalamic hormones, nine kinds of 
hormones including, for example, thyrotropin releasing hormone (TRH) or 
gonadotropin releasing hormone {GnRH: sometimes called as LH-RH 
(luteinizing hormone releasing hormone)} are confirmed their existence. 
These hypothalamic hormones are assumed to show their actions via the 
receptor which is considered to exist in the anterior lobe of pituitary, 
and observational studies of receptor genes specific to these hormones, 
including cases of human, have been developed. Accordingly, antagonists or 
agonists specifically and selectively control the action of hypothalamic 
hormone by acting on these receptors and control the secretion of anterior 
pituitary hormone. As the results, they are expected to be useful for 
prophylactic and therapeutic agents of anterior pituitary hormone 
dependent diseases. 
As compounds having such GnRH antagonistic activity, a number of compounds 
including, for example, derivatives of GnRH such as straight-chain 
peptides (U.S. Pat. No. 5,140,009, U.S. Pat. No. 5,171,835), cyclic 
hexapeptide derivatives (Japanese Patent Application Laid-open 
No.S61(1986)-191698) or bicyclic peptide derivatives (Journal of Medicinal 
Chemistry, Vol.36, pp.3265-3273, 1993). Furthermore, as non-peptide 
compounds having such GnRH antagonistic activity, compounds described in 
PCT International Publication No. WO 95/28405 are known. 
Such peptide compounds leave many problems including, for example, oral 
administrability, dosage form, stability of the drug, durability of 
actions, stability on metabolism. It has been desired to obtain GnRH 
antagonists which have excellent characteristics of high GnRH antagonistic 
activity, oral administrability, stability in plasma of blood and 
durability of actions. 
The object of the invention lies in providing novel 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives having excellent 
gonadotropin releasing hormone antagonistic activity. 
DISCLOSURE OF INVENTION 
The present invention provides 4,7-dihydro-4-oxo-thieno[2,3-b]pyridine 
derivatives having excellent properties of high GnRH antagonistic 
activity, oral administrability, stability in plasma in blood, and 
durability of actions. 
The present invention is directed to: 
1. A compound represented by the formula (I): 
##STR1## 
wherein (A)R.sup.1 is (1)an alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl, R.sup.2 is (1)an alkyl group, (2)an aryl group, (3)a group 
of the formula: --X--R.sup.41, wherein R.sup.41 is an optionally 
substituted alkyl group or an optionally substituted cycloalkyl group and 
X is O or S, and R.sup.3 is a hydrogen atom or an alkyl group; or 
(B)R.sup.1 is a C.sub.1-8 alkanoylamino group, R.sup.2 is (1)a group of the 
formula: --X--R.sup.43, wherein when X is O, R.sup.43 is an optionally 
substituted branched alkyl group, an optionally substituted cycloalkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group, and when X is S, R.sup.43 is an optionally substituted 
alkyl group, an optionally substituted cycloalkyl group or an optionally 
substituted 6-membered oxygen-containing heterocyclic group or (2)a 
hydroxyl group, and R.sup.3 is a hydrogen atom or an alkyl group, or a 
salt thereof. 
2. A compound according to the item 1, wherein R.sup.1 is a C.sub.1-6 
alkoxy group which is substituted with a group selected from the group 
consisting of (i)halogen, (ii)C.sub.3-10 cycloalkyl and (iii)C.sub.2-9 
alkenyl, R.sup.2 is a group of the formula: --X--R.sup.42, wherein 
R.sup.42 is an optionally substituted C.sub.1-13 alkyl group or an 
optionally substituted C.sub.3-10 cycloalkyl group, and X is O or S, and 
R.sup.3 is a hydrogen atom or an C.sub.1-6 alkyl group. 
3. A compound according to the item 2, wherein R.sup.42 is (1)C.sub.1-13 
alkyl which may optionally be substituted with halogen, C.sub.1-4 alkoxy 
or C.sub.3-8 cycloalkyl or (2)C.sub.3-10 cycloalkyl which may optionally 
be substituted with halogen, C.sub.1-4 alkoxy or C.sub.1-4 alkyl. 
4. A compound according to the item 2, wherein R.sup.1 is a C.sub.1-3 
alkoxy group which is substituted with vinyl. 
5. A compound according to the item 2, wherein R.sup.1 is allyloxy. 
6. A compound according to the item 2, wherein R.sup.2 is (1)C.sub.1-3 
alkyl group, (2)C.sub.6-14 aryl group or (3)C.sub.5-7 alkoxy group which 
may optionally be substituted with halogen, C.sub.1-3 alkyl or C.sub.1-3 
alkoxy. 
7. A compound according to the item 2, wherein R.sup.2 is isopropyl, phenyl 
or isopropoxy. 
8. A compound according to the item 1, wherein R.sup.1 is a C.sub.1-8 
alkanoylamino group, R.sup.2 is (1)a group of the formula: --X--R.sup.44, 
wherein when X is O, R.sup.44 is an optionally substituted C.sub.3-13 
branched alkyl group, an optionally substituted C.sub.3-10 cycloalkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group, and when X is S, R.sup.44 is an optionally substituted 
C.sub.1-13 alkyl group, an optionally substituted C.sub.3-10 cycloalkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group, or (2)a hydroxyl group, and R.sup.3 is a hydrogen atom 
or a C.sub.1-6 alkyl group. 
9. A compound according to the item 8, wherein (1) when X is O, R.sup.44 is 
a C.sub.3-13 branched alkyl group which may optionally be substituted with 
C.sub.1-4 alkyl, halogen, amino, mono- or di-C.sub.1-4 alkylamino, 
C.sub.1-4 alkoxy or C.sub.3-7 cycloalkyl; a C.sub.3-10 cycloalkyl group 
which may optionally be substituted with halogen, nitro, C.sub.1-4 alkyl, 
C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino; or a 6-membered 
oxygen-containing heterocyclic group which may optionally be substituted 
with halogen, nitro, oxo, hydroxy, amino, mono- or di-C.sub.1-4 
alkylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or C.sub.1-4 alkylthio; or 
(2) when X is S, R.sup.44 is a C.sub.1-13 alkyl group which may optionally 
be substituted with halogen, amino, mono- or di-C.sub.1-4 alkylamino, 
C.sub.1-4 alkoxy or C.sub.3-7 cycloalkyl; or a 6-membered 
oxygen-containing heterocyclic group which may optionally be substituted 
with halogen, nitro, oxo, hydroxy, amino, mono- or di-C.sub.1-4 
alkylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or C.sub.1-4 alkylthio. 
10. A compound according to the item 8, wherein R.sup.1 is a C.sub.3-5 
alkanoylamino group. 
11. A compound according to the item 8, wherein R.sup.1 is isobutyrylamino. 
12. A compound according to the item 8, wherein X is O, and R.sup.44 is an 
optionally substituted C.sub.3-7 branched alkyl group or an optionally 
substituted 6-membered oxygen-containing heterocyclic group. 
13. A compound according to the item 8, wherein X is S and R.sup.44 is an 
optionally substituted alkyl group, or a 6-membered oxygen-containing 
heterocyclic group which may optionally be substituted. 
14. A compound according to the item 1, which is 
2-(4-allyloxyphenyl)-4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-meth 
ylaminomethyl)-5-isobutyryl-4-oxothieno[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-oxothieno[2,3-b]pyridine; 
isopropyl 
[2-(4-allyloxyphenyl)-4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-met 
hylaminomethyl)-6-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate]; ethyl 
(2-(4-allyloxyphenyl)-4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-met 
hylaminomethyl)-6-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate), or a 
salt thereof. 
15. A compound according to the item 1, which is isopropyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxylate]; sec-butyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxylate]; 
cyclohexyl [4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminome 
thyl)-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxylate] 
; 3-pentyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxylate]; 
tetrahydropyranyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxylate]; 
4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4-i 
sobutyrylaminophenyl)-4-oxothieno[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-oxothieno[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-oxothieno[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-oxothieno[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-oxothieno[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-oxothieno[2,3-b]pyridine-5-carboxylate], 
or a salt thereof. 
16. A compound according to the item 1, which is 
4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4-i 
sobutyrylaminophenyl)-4-oxo-5-(4-tetrahydropyranyl-thiocarbonyl)thieno[2,3- 
b]pyridine, or its salt. 
17. Ethyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-6-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate] 
or its salt. 
18. Ethyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-6-ethyl-4-oxothieno[2,3-b]pyridine-5-carboxylate] or 
its salt. 
19. A method for producing a compound of the formula (I) or a salt thereof, 
which comprises (a) reacting a compound of the formula (II): 
##STR2## 
wherein R.sup.21 is (1)an alkyl group, (2)an aryl group, (3) a group of 
the formula: --X--R.sup.41, wherein R.sup.41 is an optionally substituted 
alkyl group or an optionally substituted cycloalkyl group and --X-- is O 
or S, or its salt, with a compound of the formula: 
EQU R.sup.12 --Y 
wherein R.sup.12 is an alkyl group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl, and Y is a halogen atom, to produce a compound of the 
formula (III): 
##STR3## 
wherein R.sup.11 is an alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl, and R.sup.3 is a hydrogen atom or an alkyl group, or a salt 
thereof, 
(b) reacting a compound of the formula (IV): 
##STR4## 
wherein R.sup.13 is a C.sub.1-8 alkanoylamino group, R.sup.23 is a 
straight-chain alkoxy group, and R.sup.3 is a hydrogen atom or an alkyl 
group, with a compound of the formula: 
EQU R.sup.24 --OH 
wherein R.sup.24 is an optionally substituted branched alkyl group, an 
optionally substituted cycloalkyl group or an optionally substituted 
6-membered oxygen-containing heterocyclic group, or with a compound of the 
formula: 
EQU R.sup.25 --SH 
wherein R.sup.25 is an optionally substituted alkyl group, an optionally 
substituted cycloalkyl group or an optionally substituted 6-membered 
oxygen-containing heterocyclic group, or alternatively subjecting the 
compound (IV) to hydrolysis, to produce a compound of the formula (V): 
##STR5## 
whereion R.sup.13 has the same meaning as defined above, R.sup.22 is (1)a 
group of the formula: --X--R.sup.43, wherein when X is O, R.sup.43 is an 
optionally substituted branched alkyl group, an optionally substituted 
cycloalkyl or an optionally substituted 6-membered oxygen-containing 
heterocyclic group, and when X is S, R.sup.43 is an optionally substituted 
alkyl group, an optionally substituted cycloalkyl group or an optionally 
substituted 6-membered oxygen-containing heterocyclic group or (2) a 
hydroxyl group, or a salt thereof, or 
(c)reacting a compound of the formula (VI): 
##STR6## 
wherein R.sup.1 is (1)an alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl, or (2) C.sub.1-8 alkanoylamino group, and R.sup.3 is a 
hydrogen atom or an alkyl group, with a compound of the formula: 
EQU R.sup.27 --H 
wherein R.sup.27 is a group of the formula: --X--R.sup.4, whererin R.sup.4 
is an optionally substituted alkyl group, an optionally substituted 
cycloalkyl group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group and X is O or S, to produce a compound of the formula 
(VII): 
##STR7## 
wherein (A)R.sup.1 is (1)an alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii) cycloalkyl and 
(iii) alkenyl, R.sup.26 is (1) an alkyl group, (2)an aryl group, (3)a 
group of the formula: --X--R.sup.41, wherein R.sup.41 is an optionally 
substituted alkyl group or an optionally substituted cycloalkyl group and 
X is O or S, and R.sup.3 is a hydrogen atom or an alkyl group; or 
(B)R.sup.1 is a C.sub.1-8 alkanoylamino group, R.sup.26 is (1)a group of 
the formula: --X--R.sup.43, wherein when X is O, R.sup.43 is an optionally 
substituted branched alkyl group, an optionally substituted cycloalkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group and when X is S, R.sup.43 is an optionally substituted 
branched alkyl group, an optionally substituted cycloalkyl group or an 
optionally substituted 6-member ed oxygen-containing heterocyclic group, 
and R.sup.3 is a hydrogen atom or an alkyl group. 
20. A method for producing a compound of the formula (IX): 
##STR8## 
wherein (A)R.sup.1 is (1)an alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl, R.sup.2 is (1)an alkyl group, (2)an aryl group, (3)a group 
of the formula: --X--R.sup.41, wherein R.sup.41 is an optionally 
substituted alkyl group or an optionally substituted cycloalkyl group and 
X is O or S, and R.sup.3 is a hydrogen atom or an alkyl group; or 
(B)R.sup.1 is a C.sub.1-8 alkanoylamino group, R.sup.2 is (1)a group of the 
formula: --X--R.sup.45, wherein when X is O, R.sup.45 is an optionally 
substituted branched alkyl group, an optionally substituted cycloalkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group, and when X is S, R.sup.45 is an optionally substituted 
alkyl group, an optionally substituted cycloalkyl group or an optionally 
substituted 6-membered oxygen-containing heterocyclic group, and R.sup.3 
is a hydrogen atom or alkyl group, or a salt thereof, which comprises 
reacting a compound of the formula (VIII): 
##STR9## 
wherein R.sup.1 and R.sup.2 have the same meanings as defined above with a 
compound of the formula: 
EQU R.sup.32 --Z 
wherein R.sup.32 is an alkyl group and Z is a metal optionally be 
halogenated, or its salt. 
21. A compound according to the item 1, which has a chracteristic of high 
bioavailability when orally administered. 
22. A compound according to the item 1, which is stable in plasma of blood. 
23. A pharmaceutical composition, which comprises a compound as defined in 
the item 1 and a carrier, excipient or diluent therefor. 
24. A pharmaceutical composition according to the item 23, which is a 
composition for treating or preventing a sex hormone dependent disease. 
25. A pharmaceutical composition according to the item 24, wherein the sex 
hormone dependent disease is prostatic cancer, uterus cancer, breast 
cancer or pituitary adenoma. 
26. A pharmaceutical composition according to the item 25, wherein the sex 
hormone dependent disease is prostatauxe, endometriosis, myoma uteri or 
precocious puberty. 
27. A pregnancy controlling composition, which comprises a compound or a 
salt thereof as defined in the item 1 and a carrier, excipient or diluent 
therefor. 
28. A menstrual cycle controlling composition, which comprises a compound 
or a salt thereof as defined in the item 1 and a carrier, excipient or 
diluent therefor. 
29. A composition according to the item 27, which is a composition for 
contraception. 
30. A method for treating a mammal suffering from a gonadotropin-releasing 
hormone derived disorder, which comprises administering an effective 
amount of a compound as defined in the item 1 to the mammal. 
31. Use of a compound as defined in the item 1 for producing a 
pharmaceutical composition for antagonizing gonadotropin-releasing hormone 
activity in a mammal suffering from a sex hormone dependent disease. 
The nucleus of the present compound, 
4,7-dihydro-4-oxo-thieno[2,3-b]pyridine, is shown in the following formula 
(X): 
##STR10## 
As the alkoxy group in the "alkoxy group substituted with a group selected 
from (i)halogen, (ii)cycloalkyl and (iii)alkenyl" in R.sup.1 of the above 
formulae, an C.sub.1-6 alkoxy group is preferable. The examples of the 
C.sub.1-6 alkoxy group are exemplified by methoxy, ethoxy, propoxy, 
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy and 
hexyloxy. Among others, C.sub.1-4 alkoxy group or C.sub.1-3 alkoxy group 
is preferable, and methoxy is especially preferable. 
As the examples of the halogen, which is a substituent on the alkoxy group, 
mention is made of fluorine, chlorine, bromine and iodine. Among them, 
fluorine is preferable. 
As the cycloalkyl group, which is a substituent on the alkoxy group, 
C.sub.3-10 cycloalkyl group is preferable, and which is exemplified by 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl 
and cyclononyl. Among them, C.sub.3-6 cycloalkyl is preferable, and 
cyclopropyl is especially preferable. 
As the alkenyl group, which is a substituent on the alkoxy group, 
C.sub.2-10 alkenyl group is preferable, and which is exemplified by vinyl, 
allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, hexatrienyl and 
3-octenyl. Among them, C.sub.2-6 alkenyl group is preferable, and 
C.sub.2-4 alkenyl group is more preferable. 
The alkenyl group may have an alkyl group as a substituent, and the alkenyl 
group which has an alkyl group as a substituent is also called as "alkenyl 
group". As the alkyl, C.sub.1-6 alkyl is preferable, and which is 
exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl and hexyl. Among them, C.sub.1-4 alkyl is 
more preferable, C.sub.1-3 alkyl is still more preferable, and methyl is 
especially preferable. 
Examples of the "alkenyl group substituted with alkyl" include C.sub.2-13 
alkenyl group, preferably C.sub.2-9 alkenyl group, preferably C.sub.2-7 
alkenyl group. 
Preferable examples of the "alkenyl group substituted with alkyl" include 
2-methyl-allyl. 
The number of substituents in R.sup.1 is preferably l to 3, especially 1 to 
2. 
In the compound (I), as preferable examples of the group R.sup.1, mention 
is made of (1)C.sub.1-6 alkoxy group which is substituted with a group 
selected from the group consisting of (i)halogen, (ii)C.sub.3-10 
cycloalkyl and (iii)C.sub.2-10 alkenyl; (2)C.sub.1-6 alkoxy group which is 
substituted with a group selected from the group consisting of (i)halogen, 
(ii)C.sub.3-10 cycloalkyl and (iii)C.sub.2-6 alkenyl; (3)C.sub.2-6 alkoxy 
group which is substituted with a group selected from the group consisting 
of (i)halogen, (ii)C.sub.3-6 cycloalkyl and (iii)C.sub.2-6 alkenyl; 
(4)C.sub.1-4 alkoxy group which is substituted with C.sub.2-6 alkenyl. As 
especially preferable examples, mention is made of (5)vinyl-C.sub.1-3 
alkoxy group and allyloxy. 
As the alkyl group shown by R.sup.2, C.sub.1-6 alkyl group is preferable, 
and is exemplified by methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl and hexyl. Among them, C.sub.1-4 alkyl group 
is preferable and C.sub.1-3 alkyl group is more preferable. Furthermore, 
C.sub.3 alkyl group (n-propyl, isopropyl) is especially preferable. 
As the aryl group shown by R.sup.2, C.sub.6-14 aryl group is preferable, 
and which is exemplified by phenyl, naphthyl, anthryl, phenanthryl, 
acenaphthyl and anthracenyl. Among them, phenyl and naphthyl are 
preferable. 
As the alkyl group of the optionally substituted alkyl group of R.sup.41 in 
--X--R.sup.41, wherein X is O or S, R.sup.41 includes C.sub.1-13 alkyl 
group is preferable and which includes straight-chain or branched alkyl 
group. The straight-chain alkyl group includes methyl, ethyl, n-propyl, 
n-buthyl, n-pentyl, n-hexyl and n-octyl. The branched alkyl includes 
isopropyl, isobuthyl, sec-buthyl, tert-buthyl, isopentyl, sec-pentyl, 
tert-pentyl, 3-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, 
iso-octyl, sec-octyl and tert-octyl. Preferable examples of the alkyl 
group include C.sub.1-9 alkyl group, C.sub.1-7 alkyl group and C.sub.1-6 
alkyl group. Preferble examples of the branched alkyl group include 
branched C.sub.3-13 alkyl group, branched C.sub.3-9 alkyl group, branched 
C.sub.3-8 alkyl group, branched C.sub.3-7 alkyl group and branched 
C.sub.3-6 alkyl group. 
As the alkoxy group represented by the group --X--R.sup.41, in which X is O 
and R.sup.41 is the optionally substituted alkyl, C.sub.1-13 alkoxy group 
is preferable, and the examples of the alkoxy group include 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. As preferable examples 
of the alkoxy group, mention is made of C.sub.1-10 alkoxy group, C.sub.1-9 
alkoxy group, C.sub.1-8 alkoxy group, C.sub.1-7 alkoxy group. Among 
others, C.sub.3-9 alkoxy group, C.sub.3-8 alkoxy group, C.sub.3-7 alkoxy 
group and C.sub.3 alkoxy group (i.e. n-propoxy, isopropoxy) are more 
preferable. 
As the substituents on the alkyl group in the optionally substituted alkyl 
group (which includes the optionally substituted branched alkyl group) 
shown by R.sup.41 in --X--R.sup.41 of R.sup.2 and the substituents on the 
cycloalkyl group in the optionally substituted cycloalkyl group of 
R.sup.41 in the group --X--R.sup.41 of R.sup.2, mention is made of 
(1)halogen, (2)alkoxy, (3)alkyl, (4)cycloalkyl, (5)alkylthio, (6)amino, 
(7)mono- or di-C.sub.1-4 alkylamino, (8)nitro, (9)hydroxyl, (10)oxo, 
(11)carbamoyl, (12)cyano, (13)mercapto and (14)sulfo. 
The number of the substituents is preferably 1 to 6, more preferably 1 to 3 
and still more preferably 1 or 2. As more preferable examples of the 
substituents include halogen, nitro and amino. 
As the alkoxy group represented by the group --X--R.sup.41 wherein X is O 
and R.sup.41 is an optionally substituted alkyl group, it includes 
2-indanyloxy, 4-piperidinyloxy, tetrahydro-4H-pyra-4-nyloxy. 
The halogen is exemplified by fluorine, chlorine, bromine and iodine. Among 
them, fluorine and chlorine are preferable. 
As the alkoxy, C.sub.1-4 alkoxy is preferable, and is exemplified by 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and 
tert-butoxy. Among others, methoxy is especially preferable. 
As the alkyl, C.sub.1-4 alkyl is preferable, and is exemplified by methyl, 
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 
Among them, methyi and ethyl are especially preferable. 
As the cycloalkyl, C.sub.3-8 cycloalkyl is preferable, and is exemplified 
by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 
cyclooctyl. Among others, C.sub.3-7 cycloalkyl is preferable. 
As the mono-alkylamino, mono-C.sub.1-4 alkylamino is preferable. Examples 
of the mono-C.sub.1-4 alkylamino include N-methyamino, N-ethylamino, 
N-propylamino, N-n-butylamino and N-isobutylamino. As the di-alkylamino, 
di-C.sub.1-4 alkylamino is preferable. The di-C.sub.1-4 alkylamino 
includes N,N-dimethyamino, N,N-diethylamino and N,N-dipropylamino. 
As the alkylthio, C.sub.1-4 alkylthio is preferable. Examples of the 
C.sub.1-4 alkylthio includes methylthio, ethylthio, n-propylthio, 
isopropylthio, n-butylthio and isobutylthio. 
As the substituents on the alkyl or cycloalkyl, C.sub.1-4 alkyl is 
preferable. 
The number of the substituents on the alkoxy group is 1 to 3, more 
preferable 1 or 2. 
As the cycloalkyl group shown by R.sup.41 in the group --X--R.sup.41 of 
R.sup.2, C.sub.3-10 cycloalkyl group is preferable. Examples of the 
C.sub.3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 
cyclohexyl, cycloheptyl and cyclooctyl. Among others, C.sub.3-8 cycloalkyl 
group and C.sub.3-7 cycloalkyl group are preferable. The cycloalkyl group 
may form a bicyclic condensed ring group. Examples of the bicyclic 
condensed ring group includes indanyl. As the substituents on the 
cycloalkyl group, mention is made of the same group as those substituted 
on the alkyl group as described in the above. 
Preferable substituents in the optionally substituted C.sub.1-13 alkyl 
group of R.sup.41 include halogen, C.sub.1-4 alkoxy or C.sub.3-8 
cycloalkyl. Preferable substituents in the optionally substitued 
C.sub.3-10 cycloalkyl group of R.sup.41 include halogen, C.sub.1-4 alkoxy 
or C.sub.1-4 alkyl. 
Preferable examples of the group R.sup.2 include (A)(1) C.sub.1-6 alkyl 
group, (2) C.sub.6-14 aryl group or (3) a group of the formula: 
--X--R.sup.42, wherein R.sup.42 is an optionally substituted C.sub.1-13 
alkyl group or an optionally substituted C.sub.3-10 cycloalkyl group, and 
X is O or S; (B)(1) C.sub.1-6 alkyl group, (2) C.sub.6-14 aryl group or 
(3) a group of the formula: --X--R.sup.42, wherein R.sup.42 is an 
optionally substituted C.sub.1-9 alkyl group or an optionally substituted 
C.sub.3-8 cycloalkyl group and X is O or S; (C)(1)C.sub.1-6 alkyl group, 
(2)C.sub.6-14 aryl group, (3)C.sub.1-9 alkoxy group which may optionally 
be substituted with C.sub.1-4 alkyl and (D) C.sub.1-6 alkoxy group. 
As the group R.sup.2, (1)an C.sub.1-3 alkyl group, (2)C.sub.6-14 aryl 
group, (3)C.sub.3-7 alkoxy group which may optionally be substituted with 
halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy. 
As the group R.sup.2, isopropyl, phenyl, ethoxy, isopropoxy, sec-butoxy, 
3-pentyloxy, 2,4-dimethyl-3-pentyloxy, ethylthio and isopropylthio are 
more preferable. Furthermore, as the group R.sup.2, isopropyl, phenyl, 
isopropoxy, sec-butoxy, 3-pentyloxy, 2,4-dimethyl-3-pentyloxy are still 
more preferable. 
The number of the substituents in the group R.sup.2 is 1 to 3, more 
preferably 1 or 2. 
As the alkyl group in R.sup.3, C.sub.1-6 alkyl group is preferable, and the 
examples of it is the same as those mentioned above. In particular, 
C.sub.1-4 alkyl and C.sub.1-3 alkyl are more preferable, and methyl and 
ethyl are still more preferable. 
In the above formulae, examples of the C.sub.1-8 alkanoylamino group shown 
by R.sup.1 include formylamino, acetylamino, propionylamino, butyrylamino, 
isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, 
hexanoylamino, heptanoylamino and octanoylamino. As the alkanoylamino 
group shown by R.sup.1, C.sub.3-5 alkanoylamino is preferable, and 
isobutyrylamino is especially preferable. 
The number of substituents of R.sup.1 on the phenyl group at 2-position is 
one to two, especially one. 
As preferable examples of the alkanlylamino group, C.sub.3-5 alkanlylamino 
grooup is mentioned. Further, C.sub.3-4 alkanlylamino group is more 
preferable, and isobutyrylamino is especialy preferable. 
As the alkoxy group represented by the group --X--R.sup.43 wherein X is O 
and R.sup.43 is the optionally substituted branched alkyl group, a 
branched C.sub.3-13 alkoxy group is preferable, and the examples of the 
branched alkoxy group include isopropoxy, isobutoxy, sec-butoxy, 
tert-butoxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, 3-pentyloxy, 
neopentyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, isooctyloxy, 
sec-octyloxy, tert-octyloxy, indanyloxy, 4-piperidinyloxy. As preferable 
examples of the branched alkoxy group, mention is made of C.sub.3-9 
branched alkoxy group, C.sub.3-8 branched alkoxy group and C.sub.3-7 
branched alkoxy group. Among them, isopropoxy, sec-butoxy, 3-pentyloxy and 
2,4-dimethyl-3-pentyloxy are especially preferable. 
As the branched alkyl group in the formula: --X--R.sup.43, wherein X is O, 
mention is made of C.sub.3-13 branched alkyl group which includes 
isopropyl, isobuthyl, sec-buthyl, tert-buthyl, isopentyl, sec-pentyl, 
tert-pentyl, 3-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, 
iso-octyl, sec-octyl and tert-octyl. Preferble examples of the branched 
alkyl group include branched C.sub.3-9 alkyl group, branched C.sub.3-8 
alkyl group, branched C.sub.3-7 alkyl group and branched C.sub.3-6 alkyl 
group. 
As the substituents on the branched alkyl group, mention is made of those 
mentioned above in the group of R.sup.41. Examples of the optionally 
substituted branched alkyl group include 1,3-difluoro-2-propyl, 
1,3-bis(dimethylamino)-2-propyl, 1.3-dimethoxy-2-propyl. Furthermore, 
examples of the optionally substituted branched alkyl group include 
2-indanyl, 4-piperidinyl, N-methyl-4-piperidinyl, dicyclohexylmethyl. 
As the cycloalkyl group in the optionally substituted cycloalkyl group of 
R.sup.43 in the group of --X--R.sup.43 wherein X is O, and substituents on 
the cycloalkyl, mentions are made of those described in the group R.sup.41 
and R.sup.42. 
Examples of the optionally substituted cycloalkyl group include 
2,6-dimethyl-1-cyclohexyl, 3,5-dimethyl-1-cyclohexyl, 
4-methyl-1-cyclohexyl, 4-ethylcyclohexyl, 4-amino-1-cyclohexyl. 
Examples of the 6-membered oxgen-containing heterocyclic group shown in the 
above includes pyranyl, tetrahydropyranyl, dioxanyl, oxazinyl and 
isoxazinyl. The heterocyclic group includes an hydrogen additive. 
Examples of substituents, which the heterocyclic groups may have, 
(1)C.sub.1-6 alkyl, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, 
isobutyl, sec-butyl, tert-butyl; (2)C.sub.1-6 alkoxy, e.g. methoxy, 
ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, 
tert-butoxy; (3)carbamyol; (4)halogen, e.g. fluorine, chlorine, bromine, 
iodine; (5)oxo; (6)hydroxy; (7)amino, (8)mono- or di-C.sub.1-4 alkylamino, 
e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, 
dimethylamino, diethylamino, dipropylamino, diisopropylamino, 
dibutylamino; (9)nitro; (10)cyano; (11)mercapto; (12)sulfo; (13)sulfino; 
(14)C.sub.1-6 alkylthio, e.g. methylthio, ethylthio, propylthio, 
isopropylthio, n-butylthio, sec-butylthio, tert-butylthio. The numbers of 
the substituents are preferably 1 to 6, more preferably 1 to 3, still more 
preferably 1 or 2. 
As preferable examples of substituents on the heterocyclic group, mention 
is made of halogen, nitro, amino, mono- or di-C.sub.1-4 alkylamino, oxo, 
hydroxy, C.sub.1-6 alkyl (especially, C.sub.1-4 alkyl), C.sub.1-6 alkoxy, 
(especially, C.sub.1-4 alkoxy), C.sub.1-8 alkylthio (especially, C.sub.1-4 
alkylthio). 
As the alkyl group in the optionally substituted alkyl group of R.sup.43 in 
the group of --X--R.sup.43 wherein X is S, and substituents on the alkyl, 
mentions are made of those described in the group R.sup.41, R.sup.42, 
R.sup.43 and R.sup.44. 
As the cycloalkyl group in the optionally substituted cycloalkyl group of 
R.sup.43 in the group of --X--R.sup.43 wherein X is S, and substituents on 
the cycloalkyl, mentions are made of those described in the group R.sup.41 
and R.sup.42. 
As the 6-membered oxgen-containing heterocyclic group in the optionally 
substituted 6-membered oxgen-containing heterocyclic group of R.sup.43 in 
the group of --X--R.sup.43 wherein X is S, and substituents on the 
heterocyclic group, mentions are made of those described in the group 
R.sup.43 and R.sup.44. 
In the compound (I), as preferable examples of the group R.sup.2, mention 
is made of (E) a group of the formula: --X--R.sup.44, wherein when X is O, 
R.sup.44 is an optionally substituted branched C.sub.3-13 alkyl group, an 
optionally substituted C.sub.3-10 cycloalkyl group or an optionally 
substituted 6-membered oxygen-containing heterocyclic group, and when X is 
S, R.sup.44 is an optionally substituted C.sub.1-13 alkyl group, an 
optionally substituted C.sub.3-10 cycloalkyl group or an optionally 
substituted 6-membered oxgen-containing heterocyclic group, or (2)a 
hydroxyl group; 
(F)(1) a group of the formula: --O--R.sup.51, R.sup.51 is (1)a branched 
C.sub.3-8 alkyl group which may be substituted with C.sub.1-4 alkyl, (ii) 
a C.sub.3-8 cycloalkyl or (iii) a 6-membered oxygen-containing 
heterocyclic group, (2) a group of the formula: --S--R.sup.6, wherein 
R.sup.6 is (1) a C.sub.1-6 alkyl group, (ii) a C.sub.3-8 cycloalkyl group 
or (iii) a 6-membered oxgen-containing heterocyclic group or (3) hydroxyl 
group; (G)a group of the formula: --O--R.sup.51, wherein R.sup.51 is a 
branched C.sub.3-7 alkyl group or a 6-membered oxygen-containing 
heterocyclic group. 
Furthermore, in the compound (I), as preferable examples of the group 
R.sup.2, mention is made of a group of the formula: --X--R.sup.44, wherein 
X is O, R.sup.44 is an optionally substituted branched C.sub.3-13 alkyl 
group or an optionally substituted 6-membered oxygen-containing 
heterocyclic group; a group of the formula: --X--R.sup.44, wherein X is O, 
R.sup.44 is a branched C.sub.3-13 alkyl group which may optionally be 
substituted with C.sub.1-3 alkyl or halogen or (2) a 6-membered 
oxygen-containing heterocyclic group which may optionally be substituted 
with halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or C.sub.1-4 alkylthio. 
In addition to the above, preferable example of the group R.sup.44 is 
mentioned as optionally substituted branched C.sub.3-7 cycloalkyl group or 
an optionally substituted 6-membered oxygen-containing heterocyclic group. 
Preferable example of the group R.sup.44 includes (1)a branched C.sub.3-13 
alkyl group substituted with C.sub.1-3 alkyl or halogen atom or (2)a 
6-membered oxygen-containing heterocyclic group substituted with halogen, 
C.sub.1-4 alkoxy, C.sub.1-4 alkyl or C.sub.1-4 alkylthio. 
Preferable substituents on the C.sub.1-13 branched alkyl group of R.sup.44 
or on the C.sub.1-13 alkyl group of R.sup.44 include C.sub.1-4 alkyl, 
halogen, amino, mono- or di-C.sub.1-4 alkylamino, C.sub.1-4 alkoxy or 
C.sub.3-7 cycloalkyl. Preferable substituents on the C.sub.3-10 cycloalkyl 
group include halogen, nitro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino or 
mono- or di-C.sub.1-4 alkylamino. Preferable substituents on the 
optionally suibstituted 6-membered oxygen-containing heterocyclic group 
include halogen, nitro, oxo, hydroxy, amino, mono- or di-C.sub.1-4 
alkylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or C.sub.1-4 alkylthio. 
Specifically preferable examples of the optionally substituted C.sub.3-13 
branched.alkyl is isopropoxy, sec-butoxy, 3-pentyloxy, or 
2,4-dimethyl-3-pentyloxy. 
As the group R.sup.2, specifically preferable examples include ethoxy, 
isopropoxy, sec-butoxy, 3-pentyloxy, 2,4-dimethyl-3-pentyloxy, 
tetrahydropyranyloxy, ethylthio, isopropylthio, tetrahydropyranylthio. 
Among others, isopropoxy, sec-butoxy, 3-pentyloxy, 
2,4-dimethyl-3-pentyloxy are more specifically preferable. 
The number of the substituents in the group R.sup.2, 1 to 3 is preferable 
and 1 to 2 is more preferable. 
As the alkyl group in R.sup.3, C.sub.1-6 alkyl group is preferable, and the 
examples of it is the same as those mentioned above. In particular, 
C.sub.1-4 alkyl and C.sub.1-3 alkyl are more preferable, and methyl and 
ethyl are still more preferable. 
Concrete examples of the groups R.sup.11, R.sup.12 and R.sup.13 include 
those mentioned as R.sup.1. Concrete examples of the groups R.sup.21 to 
R.sup.29 include those mentioned as R.sup.2. Concrete examples of the 
alkyl group in R.sup.31 include those mentioned as R.sup.3. Concrete 
examples of the groups R.sup.41 to R.sup.45 include those mentioned as 
R.sup.4. Concrete examples of the groups R.sup.5, R.sup.51 and R.sup.6 
include those mentioned as R.sup.4. 
In the present specification, the following compounds are disclosed: Ethyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-6-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate] 
or its salt. Ethyl 
[4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-benzyl-N-methylaminomethyl)-2-(4- 
isobutyrylaminophenyl)-6-ethyl-4-oxothieno[2,3-b]pyridine-5-carboxylate] or 
its salt. 
The compound of this invention can be produced by a per se known methods, 
for example, the methods disclosed in PCT International Publication No. WO 
95/28405, the methods mentioned below, analogous methods thereto, or a 
combination of these method. 
Production Method 1: 
The compound (I), wherein the group at the 2-position is a phenyl group 
which is substituted with an alkoxy group substituted with a group 
selected from the group consisting of (i)halogen, (ii)cycloalkyl and 
(iii)alkenyl which may optionally be substituted with alkyl, is produced 
by allowing a 4,7-dihydro-4-oxo-thieno[2,3-b]pyridine derivative, wherein 
the 2-position is a phenyl group which is substituted with a hydroxyl 
group, to react with a compound represented by the formula R.sup.12 --Y, 
wherein R.sup.12 is the same meaning as defined above, i.e. an alkyl group 
optionally substituted with (i) halogen, (ii) cycloalkyl or (iii)alkenyl 
which may optionally be substituted with alkyl and Y stands for a halogen 
atom, or a salt thereof. 
The starting compound can be produced by a method analogous to the method 
disclosed in PCT International Publication No. WO 95/28405, As examples of 
the compound represented by the formula R.sup.12 --Y, mention is made of 
allyl bromide, cyclopropylmethyl chloride, 1-bromo-2-butene, 
1-bromo-3-butene, crotyl chloride (i.e. 1-bromo-2-methyl-2-propene), 
2,2,2-trifluoroethyl iodide, and so on, or a its salt. 
As the alkyl group of R.sup.12, mention is made of a group which have a 
structure that an oxygen atom has been eliminated from the alkoxy group 
shown by R.sup.1. 
This reaction is conducted usually in a solvent, as exemplified by amides 
such as dimethylformamide, dimethylacetamide, etc., nitrites such as 
acetonitrile, etc., and ethers such as ethylether, dioxane, 
dimethoxyethane, tetrahydrofuran. 
This reaction is conducted by dissolving the starting compound in any of 
these solvents and by adding to the solution a compound represented by the 
formula R.sup.12 --Y or a salt thereof and a basic compound, e.g. 
potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium 
hydride, thallium hydride or triethylamine. 
The reaction temperature ranges from about 0 to 100.degree. C. preferably 
from about 0 to 40.degree. C. The reaction time ranges from about 1 to 200 
hours, preferably from about 1 to 48 hours. This reaction can be 
efficiently carried out by stirring. 
Production Method 2: 
The present compound (I) of the formula (I) mentioned in the above, wherein 
the group R.sup.1 is alkanoylamino-phenyl group, is produced by allowing a 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivative wherein the 2-position 
is a phenyl group substituted with an amino group to react with a compound 
represented by the formula R.sup.13 '--Y, wherein R.sup.13 ' stands for 
C.sub.1-8 alkanoyl group, the alkanoyl group being that in the 
"alkanoylamino" group mentioned above and Y stands for a halogen atom, or 
a salt thereof. 
The starting compound can be produced by a method analogous to the method 
disclosed in PCT International Publication No. WO 95/28405. 
This reaction is conducted usually in a solvent, as exemplified by a 
halogenated solvent such as anhydrous methylene chloride, amides such as 
dimethylformamide, dimethylacetamide, nitriles such as acetonitrile, 
ethers such as tetrahydrofuran, ethyl ether, dioxane and dimethoxy ethane. 
This reaction is conducted by dissolving the starting compound in any of 
these solvents and by adding to the solution a compound represented by the 
formula R.sup.13 '--Y, wherein R.sup.13 and Y have the same meaning as 
defined above or a salt thereof, and a basic compound, e.g. potassium 
carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydride, 
triethylamine, potassium-t-butoxide or thallium hydroxide. 
The reaction temperature ranges from about 0 to 100.degree. C. preferably 
from about 0 to 40.degree. C. The reaction time ranges from about 10 
minutes to 24 hours, preferably from about 30 minutes to 2 hours. This 
reaction can be conducted efficiently by stirring. 
Production Method 3: 
The present compound (I), which has a group of the formula: --CO--R.sup.27, 
wherein the group R.sup.27 is an alkl group or an aryl group, is produced 
by allowing a 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivative wherein 
the 5-position is an ester group to a reaction in which the ester compound 
is converted to a carboxylic acid amide derivative, and then thus obtained 
carboxylic acid amide derivative is reacted with a Grignard reagent. These 
reactions are carried out with the similar procedures described in PCT 
International Publication No. WO 95/28405. 
Production Method 4: 
The compound (I) wherein R.sup.2 stands for an optionally substituted 
branched alkoxy group, an optionally substituted cycloalkyl group or an 
optionally substituted heterocyclic group, is produced by subjecting a 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivative which has straight-chain 
alkoxycarbonyl group at 5-position to an ester interchange reaction with a 
compound of the formula: R.sup.24 --H, wherein R.sup.24 has the same 
meaning as defined above. 
This reaction is conducted usually in a solvent, as exemplified by alcohols 
such as methanol, ethanol, isopropyl alcohol, 3-pentyl alcohol. 
This reaction is carried out by dissolving the starting compound in any of 
these solvents and then by adding to the solution a compound represented 
by the formula Ti(R.sup.28 ).sub.4, wherein R.sup.28 is an optionally 
substituted alkoxy group (Examples of which has the same as those 
mentioned above.). Examples of the compound are titan(IV)tetraisopropoxide 
and so forth. 
The reaction temperature ranges from about 0 to 120.degree. C. preferably 
from about 0 to 40.degree. C., more preferably from about 10 to 20.degree. 
C. The reaction time ranges from about 1 to 24 hours, preferably from 
about 1 to 12 hours, more preferably from about 1 to 6 hours. This 
reaction can be conducted efficiently by stirring. 
Production Method 5: 
The compound (I) wherein R.sup.2 stands for a group of the formula: 
--S--R.sup.25, wherein R.sup.25 is optionally substituted alkoxy group 
(which includes branched alkoxy group), an optionally substituted 
cycloalkyl group or an optionally substituted heterocyclic group, is 
produced by reacting a 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivative 
which has the group --CO--R.sup.2, wherein R.sup.2 is a straight-chain 
alkoxy group or a hydroxyl group, at 5-position or a salt thereof with a 
compound of the formula: R.sup.25 --SH, wherein R.sup.25 has the same 
meaning as defined above. 
This reaction is conducted with or without a solvent. As the solvent, 
halogenated solvents such as dichloromethane and so forth are exemplified. 
This reaction is carried out in the presence of Vilsmeier reagent, which 
has been prepared from dimethylformamide and phosphorous oxychloride, 
under basic conditions such as by adding for example 
N,N-dimethylaminopyridine. 
The reaction temperature ranges from about 0 to 200.degree. C., preferably 
from about 0 to 120.degree. C. The reaction time ranges from about 1 to 24 
hours, preferably from about 2 to 12 hours. 
This reaction can be conducted efficiently by stirring. 
Production Method 6: 
The compound (I) wherein --CO--R.sup.2 is carboxyl group, is produced by 
subjecting the compound (I) wherein R.sup.2 is alkoxy group or a salt 
thereof, which is produced by the method disclosed in the PCT 
International Publication WO 95/28405 or an analogous method thereto, to 
hydrolysis. 
The hydrolysis is conducted in a solvent such as ethers, e.g. 
tetrahydrofuran and dioxane, alcohols, e.g. ethyl alcohol, methyl alcohol. 
In this reaction, it proceeds smoothly in the presence of an acid, e.g. 
inorganic acid such as hydrochloric acid (e.g. 2N aqueous solution is 
preferable) or an aqueous alkaline solution, e.g. an aqueous solution of 
alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or 
lithium hydroxide (a 1N to 4N aqueous solution of the alkali is 
preferable). 
The reaction temperature ranges from about 10 to 100.degree. C. preferably 
20 to 60.degree. C. The reaction time ranges from about 1 to 4 hours, 
preferably 2 to 4 hours. The reaction is conducted efficiently by 
stirring. 
Production Method 7: 
The compound (I) wherein R.sup.2 stands for an optionally substituted 
alkoxy group (which includes branched alkoxy group), an optionally 
substituted cycloalkyl-oxy group or an optionally substituted heterocyclic 
group-oxy group, is produced by reacting a 
4,7-dihydro-4-oxothieno[2,3-b]pyridine derivative which has the group 
--CO--R.sup.2, wherein --CO--R.sup.2 is carboxyl group, at 5-position or a 
salt thereof with a compound of the formula: R.sup.29 --OH, wherein 
R.sup.29 is an optionally substituted alkyl group (which includes branched 
alkyl group), an optionally substituted cycloalkyl group or an optionally 
substituted heterocyclic group, for example isopropanol, 
2,4-dimethyl-3-pentanol. 
This reaction is conducted with or without a solvent. As the solvent, 
halogenated solvents such as dichloromethane and so forth are exemplified. 
This reaction is carried out in the presence of Vilsmeier reagent, which 
has been prepared by dimethylformamide and phosphorous oxychloride, under 
basic conditions by adding for example N,N-dimethylaminopyridine. The 
reaction temperature ranges from room temperature to heating (about 
100.degree. C.) preferably from about 0 to 120.degree. C. The reaction 
time ranges from about 1 to 12 hours, preferably from about 4 to 12 hours. 
This reaction can be conducted efficiently by stirring. 
Production Method 8: 
The compound (IX), in which the group R.sup.3 is an alkyl group, is 
produced by reacting a compound of 4,7-dihydro-4-oxothieno[.sub.2,3 
-b]pyridine derivative (VIII) wherein R.sup.2 is a group of the formula: 
--X--R.sup.4, wherein X and R.sup.4 have the same meanings as defined 
above, R.sup.3 is hydrogen, or its salt, with a compound of the formula: 
R.sup.32 --Z, wherein R.sup.32 and Z have the same meanings as defined 
above. 
Examples of metals of the group Z in the compound of the formula: R.sup.32 
--Z include magnesium and lithium. The halogen includes chloride, bromide. 
The halogenated metals include Grignard reagents (e.g. methylmagnesium 
chloride, ethylmagnesium chloride), and lithium chloride. 
This reaction is conducted usually in a solvent, as exemplified by 
halogenated hydrocarbons, e.g. dichloromethane, ethers, e.g. 
tetrahydrofuran, ethylether, dioxane, dimethoxyethane. This reaction 
proceeds smoothly in the presence of copper salt, e.g. copper iodide. 
The reaction temperature ranges from about 0 to 80.degree. C. preferably 0 
to 40.degree. C. The reaction time ranges from about 0.5 to 24 hours, 
preferably 0.5 to 2 hours. The reaction is conducted efficiently by 
stirring. 
As salts of the present compound (I), physioloigically acceptable acid 
addition salts are preferable. Examples of such salts includes those with 
an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, nitric acid, 
sulfuric acid and phosphoric acid, or those with an organic acid, e.g. 
formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, 
tartaric acid, maleic acid, citric acid, succinic acid, malic acid, 
methanesulfonic acid, benzenesulfonic,acid, and p-toluenesulfonic acid. 
Further, when the compound (I) has an acid group such as --COOH, the 
compound (I) may form a salt with an inorganic base, e.g. an alkali metal 
or alkaline earth metal such as sodium, potassium, calcium and magnesium; 
ammonia, or an organic base, e.g. trimethylamine, triethylamine, pyridine, 
picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine 
and N,N'-dibenzylethylenediamine. The present compound (I) or its salt may 
also be in the form of hydrates thereof, e.g. 1 hydrate, 1.5 hydrates or 2 
hydrates. 
The present compound (I), its salt or their hydrates produced thus above 
can be isolated and purified by a conventional separating and/or purifying 
means such as recrystallization, distillation and chromatography. In the 
case where the compound (I) is produced in a free form, it can be 
converted to a salt thereof by a per se conventional means or a method 
analogous thereto. On the contrary, when it is obtained in the form of a 
salt, it can be converted to its free form or to any other salt. In the 
case where the compound or a salt thereof of the present invention is an 
optically active compound, it can be separated into d-compound and 
l-compound by means of a conventional optical resolution. 
Since the compound (I) or its salt of this invention, hereinafter it is 
sometimes abbreviated as "the present compound", have a GnRH antagonistic 
activity and excellent properties such as oral administrabilty (namely, 
high bioavailability when orally administered), stability in plasma of 
blood and durability of actions as well as less toxicity, the present 
compound can be safely used for the therapy of male hormone or female 
hormone dependent diseases as well as the therapy of diseases caused by 
excess secretion of these hormones, in mammals, e.g. human, monkey, cow, 
horse, dog, cat, rabbit, rat and mouse, suppressing the secretion of 
gonadotropic hormone by the action of GnRH receptor antagonistic action. 
More specifically, the present compound is effective as a prophylactic or 
therapeutic agent for the prevention or treatment of several hormone 
dependent diseases, for example, a sex hormone dependent cancer (e.g. 
prostate cancer, cancer of the uterine cervix, breast cancer, pituitary 
adenoma), benign prostatic hypertrophy, myoma of the uterus, 
endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, 
polycystic ovary syndrome and acne vulgaris. And, the present compound is 
also effective as a fertility controlling agent in both sexes, e.g. 
pregnancy controlling agents and menstrual cycle controlling agents. The 
present compound can be further used as a contraceptive of male or female 
and, as an ovulation-inducing agent of female. The present compound can be 
used as an infertility treating agent by using a rebound effect owing to a 
stoppage of administration thereof. Further, the present compound is 
useful as modulating estrous cycles in animals in the field of animal 
husbandry, and as an agent for improving the quality of edible meat or 
promoting the growth of animals. Besides, the present compound is useful 
as an agent of spawning promotion in fish. 
While the present compound can be used singly, they can also effectively be 
used by administering in combination with a steroidal or non-steroidal 
antiandrogenic agent. The present compound can effectively be used by 
administering in combination with a chemotherapeutic agent for cancer. In 
treatment of prostate cancer, examples of the chemotherapeutic agent 
include Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin and the like. 
In treatment of breast cancer, examples of the chemotherpeutic agent 
include Cyclophosphamide, 5-FU, UFT, Methotrexate, Adriamycin, Mitomycin 
C, Mitoxantrone and the like. 
When the present compound is employed as prophylactic and/or therapeutic 
agents of the above-mentioned diseases, the present compound can be 
administered orally or parenterally in accordance with per se known means. 
It is mixed with a pharmaceutically acceptable carrier, excipient or 
diluent therefor and usually administered orally as a solid preparation 
such as tablet, capsule, granule or powder, or parenterally as 
intravenous, subcutaneous or intramuscular injection, or as suppository or 
sublingually administrable tablet. Further, it is sublingually, 
subcutaneously or intramuscularly administered as a sustained release 
formulation such as sublingually administrable tablets, or microcapsules. 
The daily dose of the present compound varies with the degree of 
affliction; age, sex, body weight and difference of sensitivity of the 
subject to be administered; the time and intervals of administration, 
properties,-dosage forms and kinds of the medicinal preparation; and kinds 
of the effective components, and it ranges usually, though not 
specifically limited, from about 0.1 to 30 mg, preferably from about 0.1 
to 3 mg, more preferably from about 0.1 to 1 mg, relative to 1 kg body 
weight of the mammals, which is administered usually once daily or by 2 to 
4 divided dosages. The daily dose when used in the field of animal 
husbandry or fishery varies with the conditions analogous to those 
mentioned above, it ranges, relative to 1 kg body weight of the subject 
animal or fish, from about 0.01 to 5 mg, preferably from about 0.03 to 3 
mg, once or 2 to 3 divided dosages. 
As the above-mentioned pharmaceutically acceptable carriers, excipients or 
diluents therefor, conventional various organic or inorganic carriers 
excipients or diluents are used, and they are incorporated as excipients, 
lubricants, binders and disintegrants in solid compositions; and as 
solvents, solubilisers, suspending agents, isotonizing agents, buffering 
agents and pain-easing agents in liquid or solid compositions. And, 
depending on necessity, further additives such as preservatives, 
anti-oxidants, coloring agents and sweeteners can also be used. 
Preferable examples of the above-mentioned excipients include lactose, 
sugar, D-mannitol, starch, crystalline cellulose and light anhydrous 
silicic acid. Preferable examples of above-mentioned lubricants include 
magnesium stearate, calcium stearate, talc and colloid silica. Preferable 
examples of the above-mentioned binders include crystalline cellulose, 
sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl 
cellulose, polyvinyl pyrrolidone and polyethylene glycol. Preferable 
examples of the above-mentioned disintegrants include starch, 
carboxymethyl cellulose, carboxymethyl cellulose calcium, low substituted 
hydroxypropyl cellulose, cross carmelose sodium and carboxymethyl starch 
sodium. 
Preferable examples of the above-mentioned solvents include water for 
injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. 
Preferable examples of the above-mentioned solubilizers include 
polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, 
ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate 
and sodium citrate. Preferable examples of the above-mentioned suspending 
agents include surfactants such as stearyl triethanolamine, sodium lauryl 
sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, 
benzetonium chloride and monostearic glyceryl ester; and hydrophilic 
polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium 
carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, 
hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable examples of 
the above-mentioned isotonizing agents include sodium chloride, glucose, 
glycerin, D-mannitol and D-sorbitol. Preferable examples of the 
above-mentioned buffering agents include buffer solutions such as 
phosphate, acetate, carbonate and citrate. Preferable examples of the 
above-mentioned pain-easing agents include benzyl alcohol. Preferable 
examples of the above-mentioned preservatives include para-hydroxybenzoic 
acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, 
dehydroacetic acid and sorbic acid. Preferable examples of the 
above-mentioned anti-oxidants include sulfite and ascorbic acid. 
Preferable examples of the above coloring agent include red iron oxide and 
titanium oxide. 
To the compound of this invention, are added, for example, a suspending 
agent, a solubilizer, a stabilizer, an isotonizing agent and a 
preservative, then the mixture is formulated, in accordance with a per se 
known method, into an intravenous, subcutaneous or intramuscular 
injection. These injections can be processed into lyophilized 
preparations, when necessary, by a per se known method. Examples of the 
above-mentioned pharmaceutical composition are orally administering 
agents, e.g. diluted powders, granules, capsules and tablets; injections; 
dropping injections; external agents, e.g. transnasal preparations, 
percutaneous preparations, etc.; ointments, e.g. rectal ointment, vaginal 
ointment, etc. and the like. Such pharmaceutical compositions can be 
manufactured by a per se known method commonly used in preparing 
pharmaceutical compositions. 
Concretely, the present compound can be made into injections either in a 
form of an aqueous injection together with dispersing agents, e.g. Tween 
80 (Atlas Powder, U.S.A.), HCO 60 (Nikko Chemicals, Japan), polyethylene 
glycol, carboxymethylcellulose, sodium alginate, etc., preservatives, e.g. 
methyl paraben, propyl paraben, benzyl alcohol, etc., isotonizing agents, 
e.g. sodium chloride, mannitol, sorbitol, glucose, etc. and the like or in 
a form of an oily injection by dissolving, suspending or emulsifying in 
plant oil, e.g. olive oil, sesame oil, cotton seed oil, corn oil, etc.; 
propylene glycol and the like. In preparing a pharmaceutical composition 
for oral use, the present compound is molded by compressing, for example, 
with excipients, e.g. lactose, sucrose, starch, etc.; disintegrating 
agents, e.g. starch, calcium carbonate, etc.; binders, e.g. starch, gum 
arabic, carboxymethylcellulose, polyvinylpyrrolidone, 
hydroxypropylcellulose, etc.; or lubricants, e.g. talc, magnesium 
stearate, polyethylene glycol 6000, etc. and the like. 
If necessary, the present composition is coated by a per se known method 
with an object of masking the taste, enteric coating or long-acting 
sustained release. Examples of the coating agent therefore are 
hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, 
hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F 68, 
cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, 
hydroxymethylcellulose acetate succinate, Eudragit (a copolymer of 
methacrylic acid with acrylic acid; manufactured by Rohm, Germany), 
coloring agent, e.g. red iron oxide, titanium oxide and the like. 
Subcoating layer may be provided between the enteric coating and the core 
according to a per se known method. 
In preparing an external composition, the present compound as it is or a 
salt thereof is subjected to a per se known method to give a solid, 
semisolid or liquid agent for external use. For example, the solid 
preparation is manufactured as follows. The present compound as it is or 
after adding/mixing excipients, e.g. mannitol, starch, microcrystalline 
cullulose, etc., thickeners, e.g. natural gums, cellulose derivatives, 
acrylic acid polymers, etc. and the like thereto/therewith is made into a 
powdery composition. With respect to the liquid composition, an oily or 
aqueous suspension is manufactured by the manner nearly the same as in the 
case of the injection. In the case of a semisolid composition, the 
preferred one is an aqueous or oily gel or an ointment. Each of them may 
be as compounded with a pH adjusting agent, e.g. carbonic acid, phosphoric 
acid, citric acid, hydrochloric acid, sodium hydroxide, etc., an 
antiseptic agent, e.g. p-hydroxybenzoates, chlorobutanol, benzalkonium 
chloride, etc. and the like. In the manufacture of an ointment for zori 
example, the present compound can be made into an oily or an aqueous 
solid, semisolid or liquid ointment. Examples of the oily base material 
applicable in the above-mentioned composition are glycerides of higher 
fatty acids, e.g. cacao butter, Witepsols (manufactured by 
Dynamite-Nobel), etc., medium fatty acids, e.g. Miglyols (manufactured by 
Dynamite-Nobel), etc.; and plant oil, e.g. sesame oil, soybean oil, cotton 
seed oil, etc. and the like. Examples of the aqueous base material are 
polyethylene glycols and propylene glycol and those of the base material 
for aqueous gel are natural gums, cellulose derivatives, vinyl polymers, 
acrylic acid polymers, etc.

BESST MODE FOR CARRYING OUT THE INVENTION 
By way of the following Reference Examples and Examples, the present 
invention will be described in more detail, but they are not intended to 
limit the scope of the invention. 
.sup.1 H-NMR spectra were taken with JEOL LAMBDA 300 (300 MHz) type 
spectrometer, employing tetramethylsilane as the internal standard. All 
data values were expressed in ppm. 
The symbols used in the present specification have the following meanings: 
s: singlet, d: doublet, t: triplet, dt: double triplet, m: multiplet, br: 
broad. 
REFERENCE EXAMPLE 1 
(1) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-hydroxyphenyl)-3-methyl-4-oxothien 
o[2,3-b]pyridine-5-carboxylic acid ethyl ester: 
The compound produced in accordance with Working Example 3(10) of PCT 
International Publication No. WO 95/28405, i.e. 
7-(2,6-difluorobenzyl)-2-(4-methoxyphenyl)-3-methyl-4-oxothieno[2,3-b]pyri 
dine-5-carboxylic acid ethyl ester (3.0 g, 6.39 mmol), was dissolved in 
dichloromethane (30 ml), and to which was added dropwise, under 
ice-cooling, a dichloromethane solution (40 ml) of aluminum chloride (4.27 
g, 32 mmol) and dimethyl disulfide (2.88 ml, 32 mmol). The mixture was 
stirred for 4 hours at the same temperature, then the reaction mixture was 
concentrated to dryness. The concentrate was partitioned between ethyl 
acetate and a saturated aqueous solution of sodium hydrogen carbonate. The 
organic layer was washed with water, followed by concentration to dryness. 
The concentrate was recrystallized from ethanol-ethyl acetate to give the 
titled compound as pale yellow powdery crystals (1.64 g, 56%). 
m.p. 244-246.degree. C. 
Elemental Analysis for C.sub.24 H.sub.19 F.sub.2 NO.sub.4 S.0.2H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 62.79; 4.26; 3.05 
Found: 62.80; 4.11; 3.14 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.40(3H,t,J=7.2 Hz), 2.64(3H,s), 
4.40(2H,q,J=7.2 Hz), 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) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-methoxymethoxyphenyl)-3-methyl-4-o 
xothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester: 
The compound produced in Reference Example 1(1) (1.6 g, 3.51 mmol) was 
dissolved in dimethylformamide (20 ml). To the solution was added, under 
ice-cooling, sodium hydride (0.154 g, 3.86 mmol), and the mixture was 
stirred for 30 minutes. To the reaction mixture was added, at the same 
temperature, chloromethyl methylether (0.324 ml, 4.21 mmol). The mixture 
was stirred for 30 minutes at the same temperature and, then, for 2 hours 
at room temperature. To the reaction mixture was added ethanol (10 ml), 
which was concentrated to dryness. The concentrate was partitioned between 
dichloromethane and a saturated aqueous sodium chloride solution. The 
organic layer was washed with water and concentrated to dryness. The 
concentrate was purified by means of a silica gel column chromatography to 
give the titled compound as an amorphous product (1.63 g, 93%). 
Elemental Analysis for C.sub.26 H.sub.23 F.sub.2 NO.sub.5 S.0.38H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 61.67; 4.73; 2.77 
Found: 61.42; 4.57; 3.07 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.41(3H,t,J=7.2 Hz), 2.65(3H,s), 
3.50(3H,s), 4.40(2H,q,J=7.2 Hz), 5.22(2H,s), 5.25(2H,s), 7.00(2H,t,J=8.3 
Hz), 7.10(2H,d,J=6.8 Hz), 7.33-7.41(3H,m), 8.37(1H,s). 
(3) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-methoxymethoxyphenyl)-3-(N-benzyl- 
N-methylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid ethyl 
ester: 
The compound produced in the above-mentioned Reference Example 1(2) (5.60 
g, 11.2 mmol) was suspended in carbon tetrachloride (100 ml). To the 
suspension were added N-bromosuccinic acid imide (2.19 g, 12.3 mmol) and 
.alpha.,.alpha.'-azobisisobutyronitrile (0.37 g, 2.24 mmol). The mixture 
was heated for 2 hours under refluxing. The reaction mixture was cooled to 
room temperature, to which was added dichloromethane (100 ml). The mixture 
was washed with a saturated aqueous saline solution and dried, followed by 
concentration to dryness. The concentrate was dissolved in 
dimethylformamide (100 ml). To the solution were added ethyl 
diisopropylamine (2.10 ml, 12.3 mmol) and N-methylbenzylamine (1.59 ml, 
12.3 mmol). The mixture was stirred for two hours, followed by 
concentration to dryness. The concentrate was partitioned between 
dichloromethane and water. The organic layer was washed with a saturated 
aqueous sodium chloride solution, dried and concentrated to dryness to 
give a solid matter, which was purified by means of a silica gel column 
chromatography to give the titled compound as an amorphous product (6.35 
g, 92%). 
Elemental Analysis for C.sub.34 H.sub.32 F.sub.2 N.sub.2 O.sub.5 
S.0.5H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 65.06; 5.30; 4.46 
Found: 65.28; 5.22; 4.49 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.39(3H,t,J=7.2 Hz), 2.20(3H,s), 
3.51(3H,s), 3.93(2H,s), 4.20(2H,s), 4.40(2H,q,J=7.2 Hz), 5.23(2H,s), 
5.27(2H,s), 7.00(2H,t,J=8.3 Hz), 7.10(2H,d,J=6.8 Hz), 7.18-7.26(5H,m), 
7.36-7.44(1H,m), 7.72-7.75(2H,m), 8.37(1H,s). 
(4) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-methoxymethoxyphenyl)-3-(N-benzyl- 
N-methylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-N-methyl-O-methyl-hydroxa 
mic acid: 
To a dichloromethane solution (100 ml) of N-methyl-O-methylhydroxylamine 
hydrochloride (4.98 g, 151 mmol) and N-ethyl diisopropylamine (8.73 ml, 
151 mmol) was added, under ice-cooling, trimethyl alminium (1.5N solution, 
20.4 ml, 130.6 mmol). The mixture was stirred for 30 minutes at the same 
temperature, then for further 30 minutes at room temperature. 
To the reaction mixture was added, under ice-cooling, a dichloromethane 
solution (100 ml) of the compound produced in Reference Example 1(3) (6.30 
g, 10.2 mmol). The mixture was stirred for further 2 hours at the same 
temperature. The reaction mixture was poured into water, which was then 
subjected to extraction with chloroform. The extract was washed with a 
saturated aqueous sodium chloride solution, dried and concentrated to 
dryness to give the titled compound as an amorphous product (5.73 g, 89%). 
Elemental Analysis for C.sub.34 H.sub.33 F.sub.2 N.sub.3 O.sub.5 
S.1.2H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 62.32; 5.44; 6.41 
Found: 62.51; 5.49; 6.38 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 2.21(3H,s), 3.34(3H,s), 
3.54(3H,s), 3.72(2H,s), 3.76(3H,s), 4.19(2H,s), 5.23(2H,s), 5.30(2H,s), 
6.95(2H,t,J=8.3 Hz), 7.12(2H,d,J=6.8 Hz), 7.15-7.22(5H,m), 
7.33-7.41(1H,m), 7.70-7.74(2H,m), 8.33(1H,s). 
(5) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-hydroxyphenyl)-3-(N-benzyl-N-methy 
laminomethyl)-5-benzoyl-4-oxothieno[2,3-b]pyridine: 
The compound produced in the Reference Example 1(4) (5.20 g, 8.20 mmol) was 
dissolved in anhydrous tetrahydrofuran (100 ml). To the solution was 
added, under ice-cooling, phenyl magnesium bromide (1M solution, 24.6 ml, 
24.6 mmol). The mixture was stirred for 3 hours at the same temperature, 
to which was added, under ice-cooling, 6N hydrochloric acid to adjust the 
pH to not higher than 2, followed by stirring for one hour at room 
temperature. The reaction mixture was neutralized and, then, poured into 
water, which was then subjected to extraction with ethyl acetate. The 
extract was washed with a saturated aqueous sodium chloride solution, 
dried and concentrated to dryness to give the titled compound as an 
amorphous product (3.37 g, 68%). 
Elemental Analysis for C.sub.36 H.sub.28 F.sub.2 N.sub.3 O.sub.5 S: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 71.27; 4.65; 4.62 
Found: 71.20; 4.58; 4.70 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 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=7.1 Hz), 8.06(1H,s). 
(6) Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-hydroxyphenyl)-3-(N-benzyl-N-methy 
laminomethyl)-5-isobutyryl-4-oxothieno[2,3-b]pyridine: 
Employing the compound produced in Reference Example 1(4) as the starting 
material, the titled compound was produced as an amorphous product (2.1 g, 
51%) by substantially the same procedure as in Reference Example 1(5) 
using isopropyl magnesium chloride in place of phenyl magnesium bromide. 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.18(6H,d), 2.10(3H,s), 
3.61(2H,s), 4.1-4.2(3H,m), 5.26(2H,s), 6.90(2H,d), 6.99(2H,t), 
7.1-7.2(6H,m), 7.40(1H,m), 7.65(2H,d), 8.28(1H,s). 
REFERENCE EXAMPLE 2 
The compound produced in Reference Example 1(3) is subjected to hydrolysis 
in tetrahydrofuran by adding a little excess amount of 1N sodium hydroxide 
while stirring for 2 hours at room temperature, to thereby convert the 
compound into a compound whose substituent at 5-position is carboxyl group 
(a carboxylic acid derivative). 
The carboxylic acid derivative is mixed, in dimethylformamide, with 
N,N-dimethylaminopyridine (large excess amount) and alcohol (e.g. 
isopropanol, cyclohexanol, sec-butanol, 3-pentanol or 
2,4-dimethyl-3-pentanol). To the mixture is added dropwise, under 
ice-cooling, phosphorus oxychloride (10 times as much volume) to produce a 
compound whose substituent at 5-position is an ester. 
The ester derivative is subjected to a conventional deprotection reaction 
by using a diluted hydrochloric acid to give the compound 2(1), 2(2), 
2(3), 2(4) and 2(5) shown in the below-mentioned Table 1. 
The compound obtained by the method of Reference Example 1(3) is subjected 
to a conventional deprotection reaction by using a diluted hydrochloric 
acid to give a compound wherein the methoxymthyl group in the 
methoxymethoxy group of the starting compound is eliminated. The structure 
of thus obtained compound is shown in the below-mentioned Table 1. 
REFERENCE EXAMPLE 3 
Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-isobutyrylaminophenyl)-3-(N-methyl 
-N-benzylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid ethyl 
ester: 
To the compound produced in accordance with Working Example 27 described in 
PCT International Publication No. WO95/28405, i.e. 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-aminophenyl)-3-(N-methyl-N-benzyla 
minomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, was 
added, in pyridine, a little excess amount of isobutyryl chloride. The 
mixture was stirred for 2 hours at room temperature to give the titled 
compound. 
m.p. 185-186.degree. C. 
Elemental Analysis for C.sub.36 H.sub.35 F.sub.2 N.sub.3 O.sub.4 
S.HCl.1.5H.sub.2 O: 
C(%) H(%) N(%) 
Calcd.: 61.14; 5.56; 5.94 
Found: 61.00; 5.60; 5.87 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.28(6H,d,J=6.8 Hz), 
1.39(3H,t,J=7.1 Hz), 2.12(3H,s), 2.54(1H,m), 3.56(2H,s), 4.16(2H,s), 
4.40(2H,q,J=7.1 Hz), 5.26(2H,s), 7.01(2H,t,J=8.1 Hz), 7.10-7.30(5H,m), 
7.41(1H,m), 7.62(2H,d,J=8.5 Hz), 7.81(2H,d,J=8.5 Hz), 8.35(1H,s). 
The structures of compounds which were obtained in Reference Examples 1(3) 
to 1(6) and in Reference Examples 2 and 3 are shown in the following Table 
1. 
TABLE 1 
______________________________________ 
#STR11## 
Ref. No. R.sup.1 R.sup.2 
______________________________________ 
1(3) methoxymethoxy 
ethoxy 
1(4) methoxymethoxy N-methyl-O-methylhydroxylamino 
1(5) hydroxy phenyl 
1(6) hydroxy isopropyl 
2(1) hydroxy isopropoxy 
2(2) hydroxy cyclohexyloxy 
2(3) hydroxy sec-butoxy 
2(4) hydroxy 3-pentoxy 
2(5) hydroxy 2,4-dimethyl-3-pentoxy 
2(6) hydroxy ethoxy 
3 isobutyrylamino ethoxy 
______________________________________ 
EXAMPLE 1 
Production of 
3-(N-methyl-N-benzylaminomethyl)-4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-a 
llyloxyphenyl)-5-benzoyl-4-oxothieno[2,3-b]pyridine hydrochloride: 
To a solution of the compound produced in Reference Example 1(5) (0.12 g, 
0.2 mmol) in dimethylformamide (3 ml) were added, under ice-cooling, 
potassium carbonate (0.055 g, 0.4 mmol) and allyl iodide (37 .mu.l, 0.4 
mmol). The mixture was stirred for 2 hours at room temperature, which was 
then concentrated. The concentrate was partitioned between ethyl acetate 
and a saturated aqueous sodium chloride solution. The aqueous layer was 
subjected to extraction with ethyl acetate. 
The organic layers were combined and dried (MgSO.sub.4), followed by 
distilling off the solvent under reduced pressure. The residue was 
purified by means of a silica gel column chromatography to give a 
colorless oily product. To a solution of this oily product in ether (4 ml) 
was added, under ice-cooling, 1N hydrogen chloride in ether (0.2 ml). The 
mixture was stirred for 10 minutes at the same temperature. The reaction 
mixture was concentrated under reduced pressure. The concentrate was 
crystallized from ethyl acetate-ether to give the titled compound as a 
white crystalline product (0.068 g, 50%). The structure of thus obtained 
compound is shown in the below-mentioned Table 2. 
m.p. 120-122.degree. C. 
Elemental Analysis for C.sub.39 H.sub.32 F.sub.2 N.sub.2 O.sub.3 
S.HCl.1.5H.sub.2 O.0.1CHCl.sub.3 : 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 65.03; 5.04; 3.88 
Found: 65.05; 4.80; 3.81 
______________________________________ 
.sup.1 H-NMR (300 MHz, DMSO-d.sub.6).delta.: 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=7.8 Hz), 8.16(1H,s), 11.95(1H,brs). 
EXAMPLE 2 
Employing the compound produced in Reference Example 1(5) as the starting 
material, substantially the same procedure as described in Example 1 is 
conducted to give compounds 2(1), 2(2), 2(3) and 2(4), whose structures 
are shown in the below-mentioned Table 2. 
EXAMPLE 3 
Employing the compound produced in Reference Example 1(6) as the starting 
material, substantially the same procedure as described in Example 1 was 
conducted to give compounds 3(1), 3(2), 3(3), 3(4), 3(5) and 3(6), whose 
structures are shown in the following Table 2. 
TABLE 2 
______________________________________ 
#STR12## 
Ex. No. R.sup.1 R.sup.2 
yield (%) 
m.p. (.degree. C.) 
______________________________________ 
1 allyloxy phenyl 50 120-122 
(hydrochloride) 
2(1) cyclopropylmethoxy phenyl 
2(2) 2-buten-1-yloxy phenyl 
2(3) 2-methyl-2-propen- phenyl 
1-yloxy 
2(4) 3-buten-1-yloxy phenyl 
3(1) allyloxy isopropyl 46 182-184 
(hydrochloride) 
3(2) cyclopropylmethoxy isopropyl 58 152-155 
(hydrochloride) 
3(3) 2-buten-1-yloxy isopropyl 34 126-130 
(hydrochloride) 
3(4) 2-methyl-2-propen- isopropyl 60 175-177 
1-yloxy (hydrochloride) 
3(5) 3-buten-1-yloxy isopropyl 12 141-144 
(hydrochloride) 
3(6) 2,2,2-trifluoro- isopropyl 3 128-130 
ethoxy (hydrochloride) 
______________________________________ 
EXAMPLE 4 
Employing the compound produced in Reference Example 2 as the starting 
material, substantially the same procedure as described in Example 1 is 
conducted to give compounds 4(1) to 4(22), whose structures are shown in 
the following Table 3. 
TABLE 3 
______________________________________ 
#STR13## 
- yield 
Ex. No. R.sup.1 R.sup.2 (%) m.p. (.degree. C.) 
______________________________________ 
4(1) allyloxy isopropoxy 63 167-169 
(hydrochloride) 
4(2) cyclopropylmethoxy isopropoxy 
4(3) 2-buten-1-yloxy isopropoxy 
4(4) 2-methyl-2-propen- isopropoxy 
1-yloxy 
4(5) 3-buten-1-yloxy isopropoxy 
4(6) allyloxy cyclohexyloxy 
4(7) cyclopropylmethoxy cyclohexyloxy 
4(8) 2-buten-1-yloxy cyclohexyloxy 
4(9) 2-methyl-2-propen- cyclohexyloxy 
1-yloxy 
4(10) allyloxy sec-butoxy 
4(11) cyclopropylmethoxy sec-butoxy 
4(12) 2-buten-1-yloxy sec-butoxy 
4(13) 2-methyl-2-propen- sec-butoxy 
1-yloxy 
4(14) allyloxy 3-pentoxy 
4(15) cyclopropylmethoxy 3-pentoxy 
4(16) 2-buten-1-yloxy 3-pentoxy 
4(17) 2-methyl-2-propen- 3-pentoxy 
1-yloxy 
4(18) allyloxy 2,4-dimethyl- 
3-pentoxy 
4(19) cyclopropylmethoxy 2,4-dimethyl- 
3-pentoxy 
4(20) 2-buten-1-yloxy 2,4-dimethyl- 
3-pentoxy 
4(21) 2-methyl-2-propen- 2,4-dimethyl- 
1-yloxy 3-pentoxy 
4(22) allyloxy ethoxy 
______________________________________ 
EXAMPLE 5 
Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-isobutyrylaminophenyl)-3-(N-methyl 
-N-benzylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid 
isopropyl ester hydrochloride: 
To an isopropyl alcohol solution (50 ml) of the compound obtained in 
Reference Example 3 (1.29 g, 2.0 mmol) was added dropwise, under 
ice-cooling (0.degree. C.), titan(IV)isopropoxide (0.284 g, 1.0 mmol). The 
mixture was stirred for 12 hours at room temperature. The reaction mixture 
was partitioned between chloroform (200 ml) and water. The aqueous layer 
was subjected to extraction with chloroform (200 ml). The extract 
solutions were combined, washed with an aqueous sodium chloride solution 
and dried (Na.sub.2 SO.sub.4), followed by distilling off the solvent 
under reduced pressure. The residue was purified by means of a silica gel 
column chromatography to give a colorless amorphous product (1.08 g, 82%). 
The amorphous product thus obtained was dissolved in chloroform. To the 
solution was added a 10N hydrogen chloride in ethanol solution to form a 
corresponding salt, which was recrystallized from chloroform-ether to give 
the titled compound as colorless crystalline needles (0.86 g, 74%). The 
structure of the compound thus obtained is shown in the below-mentioned 
Table 4. 
m.p.168-170.degree. C. 
Elemental Analysis for C.sub.37 H.sub.37 F.sub.2 N.sub.3 O.sub.4 
S.HCl.0.5H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd..: 63.19; 5.59; 5.98 
Found: 63.33; 5.70; 6.09 
______________________________________ 
.sup.1 H-NMR (300 MHz, CDCl.sub.3).delta.: 1.28(6H,d,J=6.8 Hz), 
1.36(6H,d,J=6.3 Hz), 2.10(3H,s), 2.57(1H,m), 3.65(2H,s), 4.16(2H,s), 
5.23(1H,m), 5.23(2H,s), 7.00(2H,dd,J=8.1 Hz), 7.10-7.26(5H,m), 7.38(1H,m), 
7.63(2H,d,J=8.3 Hz), 7.78(2H,d,J=8.6 Hz), 8.29(1H,m). 
EXAMPLE 6 
Employing the compound obtained in Reference Example 3 as the starting 
material, the compounds 6(1), 6(2), 6(3) and 6(4) were produced in 
substantially the same manner as described in Example 5. The structure of 
these compounds are shown in Table 4. 
TABLE 4 
______________________________________ 
#STR14## 
- yield m.p. (hydrochloride) 
Ex. No. R.sup.2 (%) (.degree. C.) 
______________________________________ 
5 isopropyloxy 74 168-170 
6(1) sec-butyloxy 82 171-173 
6(2) cyclohexyloxy 73 177-179 
6(3) 3-pentyloxy 78 194-195 
6(4) 4-tetrahydropyranyloxy 64 165-167 
______________________________________ 
EXAMPLE 7 
Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-2-(4-isobutyrylaminophenyl)-3-(N-methyl 
-N-benzylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid: 
The compound obtained in Reference Example 3 (1.2 g) was dissolved in 
ethanol (10 ml), to which was added 5N potassium hydroxide (5 ml) while 
cooling at 0.degree. C. The reaction mixture was warmed to room 
temperature, which was stirred for 5 hours, followed by shaking together 
with 0.2N hydrochloric acid (200 ml) and chloroform (200 ml). From the 
organic layer, a crystalline product was obtained, which was 
recrystallized from ethyl acetate-ethanol to give the titled compound as 
colorless powdery crystals (1.0 g, 81%). The structure of thus obtained 
compound is shown in the below-mentioned Table 5. 
m.p. 212-214.degree. C. 
Elemental Analysis for C.sub.34 H.sub.31 F.sub.2 N.sub.3 O.sub.4 
S.2.5H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 61.81; 5.49; 6.36 
Found: 61.61; 5.41; 6.34 
______________________________________ 
EXAMPLE 8 
Production of 
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-pentyl) ester hydrochloride: 
To dimethylformamide solution (1 ml) of the compound obtained in Example 7 
(0.062 g, 0.1 mmol), N,N-dimethylaminopyridine (0.489 g, 4.00 mmol) and 
2,4-dimethyl-3-pentanol (2 ml) was added dropwise, under ice-cooling 
(0.degree. C.), phosphorus oxychloride (0.153 g, 1.0 mmol). The mixture 
was then heated for 12 hours under refluxing. The reaction mixture was 
partitioned between chloroform (200 ml) and water. The aqueous layer was 
subjected to extraction with chloroform (200 ml). The extract solutions 
were combined, washed with an aqueous sodium chloride solution and dried 
(Na.sub.2 SO.sub.4), followed by distilling off the solvent under reduced 
pressure. The residue was purified by means of a silica gel column 
chromatography to give a colorless amorphous product (1.08 g, 82%). The 
product was dissolved in chloroform. To the solution was added a iON 
hydrogen chloride in ethanol to form a corresponding salt, which was 
recrystallized from chloroform-ether to give the titled compound as 
colorless crystalline powders. The structure of the compopund thus 
opbtained is shown in the below-mentioned Table 5. 
m.p. 174-175.degree. C. 
Elemental Analysis for C.sub.41 H.sub.45 F.sub.2 N.sub.3 O.sub.4 
S.HCl.H.sub.2 O: 
______________________________________ 
C (%) H (%) N (%) 
______________________________________ 
Calcd.: 64.09; 6.30; 5.47 
Found: 64.31; 6.13; 5.48 
______________________________________ 
EXAMPLE 9 
Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-methyl-N-benzylaminomethyl)-2-(4-i 
sobutyrylaminophenyl)-5-(tetrahydropyranylthio)carbonyl-4-oxo-thieno[2,3-b] 
pyridine hydrochloride: 
In 2 ml of dichloromethane was dissolved 4-mercaptotetrahydrofuran (470 mg, 
4.00 mmole), and to the solution was added dropwise a hexane solution (15 
ml) of trimethyl aluminium (15%, 0.48 ml, 1.00 mmole) under ice-cooling. 
After one hour stirring at the same temperature, to the mixture 
dichloromethane solution (1 ml) of the compound (129 mg, 0.20 mmole) 
obtained in the above Reference Example 3 was added dropwise under 
ice-cooling. The reaction mixture was stirred for one hour, and then 
poured into 200 ml of distilled water. The resultant was subjected to 
extraction with chloroform, dried with a saturated aqueous solution of 
sodium chloride and dried (Na.sub.2 SO.sub.4), followed by distilling off 
the solvent under reduced pressure. The residue thus obtained was 
subjected to a purification procedure of silica gel column chromatography 
to give a yellow amorphous product (30 mg, 11%). Thus obtained amorphous 
product was dissolved in chloroform, and to the solution was added 10N 
hydrogen chloride in ether to give a salt, and was recrystallized from 
chloroform-ether to give the titled compound as yellow crystals. The 
structure of the compound is shown in the below-mentioned Table 5. 
m.p. 174-176.degree. C. 
Elemental Analysis for C.sub.39 H.sub.39 N.sub.5 O.sub.4 S.sub.2 
F.sub.2.HCl.2.5H.sub.2 O 
C H N 
Calcd.: 58.75; 5.69; 5.27 (%); 
Found: 58.77; 5.59; 5.54 (%) 
.sup.1 H-NMR(300 MHz, CDCl.sub.3).delta.: 1.28(6H,d,J=6.8 Hz), 
1.75-1.87(2H,m), 1.97-2.04(2H,m), 2.11(3H,s), 2.56(1H,m), 3.54-3.61(2H,m), 
3.66(2H,s), 3.87(1H,m), 3.96-4.01(2H,m), 4.19(2H,s), 5.30(2H,m), 
7.01(2H,dd,J=8.1 Hz), 7.12-7.32(5H,m), 7.42(1H,m), 7.62(2H,d,J=8.6 Hz), 
7.80(2H,d,J=8.6 Hz), 8.37(1H,s). 
EXAMPLE 10 
Employing the compound produced in Example 7 as the starting material, a 
procedure substantially the same as described in Example 9 was carried out 
to give compounds 10(1) and 10(2), whose structures are shown in the 
following Table 5. 
TABLE 5 
______________________________________ 
#STR15## 
- yield 
m.p. 
Ex. No. R.sup.2 (%) (.degree. C.) 
______________________________________ 
7 hydroxy 81 212-214 
8 2,4-dimethyl-3-pentyloxy 82 174-175 
(hydrochloride) 
9 4-tetrahydropyranylthio 11 174-176 
(hydrochloride) 
10(1) ethylthio 53 251-253 
(hydrochloride) 
10(2) isopropylthio 56 139-141 
(hydrochloride) 
______________________________________ 
EXAMPLE 11 
Production of 
4,7-dihydro-7-(2,6-difluorobenzyl)-3-(N-methyl-N-benzylaminomethyl)-2-(4-i 
sobutyrylaminophenyl)-6-methyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic 
acid isopropyl ester hydrochloride: 
To an anhydrous tetrahydrofuran solution (50 ml) of the compound obtained 
in Example 5 (1.98 g, 2.78 mmole) was added dropwise a mixture of 
diethylether solution of methyl magnesium bromide (3.0M, 4.63 ml, 13.9 
mmole) and copper iodide (529 mg, 2.78 mmole), under ice-cooling. The 
mixture was stirred for 0.5 hour at the same temperature, to the resultant 
was added 1N hydrogen chloride under ice-cooling to adjust to not more 
than pH 2, and then the mixture was stirred for 0.5 hour at room 
temperature. The reaction mixture was poured into a 500 ml aqueous 
solution of 0.1 N potassium hydroxide, the resultant was subjected to 
extraction with chloroform, dried with a saturated aqueous solution of 
sodium chloride and dried (Na.sub.2 SO.sub.4), followed by distilling off 
the solvent under reduced pressure. The residue thus obtained was 
subjected to a purification procedure of silica gel column chromatography 
to give a yellow amorphous product (1.80 g, 96%). 
To a tetrahydrofuran (15 ml) suspension of sodium hydride was added 
dropwise the tetrahydrofuran (15 ml) solution of the amorphous product 
(1.80 g, 2.67 mmole) obtained in the above at room temperature. After 
stirring the reaction mixture at 50.degree. C. for 0.5 hour, a 
tetrahydrofuran (5 ml) solution of phenylselenyl chloride (1.02 g, 5.34 
mmole) was added dropwise at 50.degree. C. for one overnight. The. 
reaction mixture was poured into 500 ml of distilled water, extracted with 
chloroform, dried with a saturated sodium chloride and dried (Na.sub.2 
SO.sub.4), followed by distilling off the solvent under reduced pressure. 
The residue was subjected to a purification procedure of silica gel column 
chromatography to give a colorless amorphous product (1.00 g, 86%). Thus 
obtained amorphous product was dissolved in chloroform, and to the 
solution was added 10N hydrogen chloride in ether to give a salt, and was 
recrystallized from chloroform-ether to give the titled compound as white 
powdery crystals. The structure of the compound is shown in the 
below-mentioned Table 6. 
m.p. 163-165.degree. C. 
Elemental Analysis for C.sub.38 H.sub.39 N.sub.3 O.sub.4 SF.sub.2.HCl. 
1.5H.sub.2 O 
______________________________________ 
C H N 
______________________________________ 
Calcd.: 62.07; 5.89; 5.71 (%) 
Found: 62.31; 5.81; 6.04 (%) 
______________________________________ 
.sup.1 H-NMR(300 MHz, CDCl.sub.3).delta.: 1.23(6H, d, J=6.8 Hz), 1.38(6H, 
d, J=6.8 Hz), 2.10(3H, s), 2.45(3H, s), 2.54(1H, m), 3.63(2H, s), 4.13(2H, 
s), 5.30(1H, m), 5.34(3H, s), 6.93(2H, dd, J=8.1 Hz), 7.14-7.39(6H, m), 
7.59(2H, d, J=8.6 Hz), 7.80(2H, d, J=8.6 Hz). 
EXAMPLE 12 
Employing the compound produced in Reference Example 3 as the starting 
material, Example 6(2), 6(3) or 6(4), a substantially the same procedure 
as described in Example 11 was conducted to give compounds 12(1), 12(2), 
12(3) and 12(4), whose structures are shown in the below-mentioned Table 
6. 
EXAMPLE 13 
Employing the compound produced in Reference Example 3 as the starting 
material, a substantially the same procedure as described in Example 11 
was conducted using ethylmagnesium bromide instead of methylmagnesium 
bromide to give the compound 13, whose structure is shown in the 
below-mentioned Table 6. 
EXAMPLE 14 
Employing the compound produced in Example 4(1) or 4(22) as a starting 
material, a substantially the same procedure as described in Example 11 
was conducted to give compounds 14(1) and 14(2), whose structures are 
shown in the following Table 6. 
Employing the compound produced in Example 4(2), 4(3), 4(6), 4(7) or 4(8) 
as a starting material, a substantially the same procedure as described in 
Example 11 was conducted to give compounds 14(3) to 14(7), whose 
structures are shown in the following Table 6. 
TABLE 6 
______________________________________ 
#STR16## 
- yield 
m.p. 
Ex. No. R.sup.1 R.sup.2 R.sup.3 (%) (.degree. C.) 
______________________________________ 
11 isobutyryl- 
isopropoxy methyl 
76 163-165 
amino (hydrochloride) 
12(1) isobutyryl- ethoxy methyl 32 179-181 
amino (hydrochloride) 
12(2) isobutyryl- cyclohexyl- methyl 18 158-160 
amino oxy (hydrochloride) 
12(3) isobutyryl- 3-pentyloxy methyl 35 157-159 
amino (hydrochloride) 
12(4) isobutyryl- 4-tetrahydro- methyl 34 170-172 
amino pyranyloxy (hydrochloride) 
13 isobutyryl- ethoxy ethyl 8 135-137 
amino (hydrochloride) 
14(1) allyloxy isopropoxy methyl 79 143-145 
(hydrochloride) 
14(2) allyloxy ethoxy methyl 95 amorphous 
14(3) 2-buten-1-yl- isopropoxy methyl 
oxy 
14(4) allyloxy cyclohexyloxy methyl 
14(5) cyclopropyl- cyclohexyloxy methyl 
methoxy 
14(6) 2-buten-1-yl- cyclohexyloxy methyl 
oxy 
14(7) cyclopropyl- isopropoxy methyl 
methoxy 
______________________________________ 
EXAMPLE 15 
Using the compound produced in Example 3(1) or in Example 5 (100 mg), 
lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and 
magnesium stearate (1 mg), tablets are prepared by a conventional method. 
EXAMPLE 16 
The compound produced in Example 3(1) or in Example 5 (5 g) is dissolved in 
distilled water for injection to make the whole volume 100 ml. This 
solution is subjected to sterilized filtration through 0.22 .mu.m membrane 
filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius 
Inc.), 2 ml each of which is divided into sterilized vials, followed by 
lyophilization to prepare a lyophilized injectable composition of 100 
mg/vial. 
EXAMPLE 17 
Using the compound produced in Example 3(4) (100 mg), crystalline cellulose 
(50 mg), low substituted hydroxypropylcellulose-31 (30 mg), 
hydroxypropylcellolose-L (6 mg) and magnesium stearate (1 mg), tablets are 
prepared by a conventional method. 
EXAMPLE 18 
Using the compound produced in Example 9 (100 mg), lactose (150 mg), cross 
carmelose sodium (30 mg), hydroxypropylcellulose (6 mg) and magnesium 
stearate (1 mg), tablets are prepared by a conventional method. 
EXAMPLE 19 
The compound produced in Example 11 (100 mg), lactose (165 mg), corn starch 
(25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), tablets 
are prepared by a conventional method. 
EXAMPLE 20 
Using the compound which is produced in Example 12(1) (100 mg), lactose 
(150 mg), low substituted hydroxypropylcellolose-31 (30 mg), 
polyvinylpyrrolidone (10 mg) and magnesium stearate (1 mg), tablets are 
prepared by a conventional method. 
EXAMPLE 21 
Using the compound which is produced in Example 14(1) or 14(2) (100 mg), 
lactose (150 mg), carboxymethylcellulose calcium (30 mg), 
hydroxypropylcellulose (6 mg) and magnesium stearate (1 mg), tablets are 
prepared by a conventional method. 
EXAMPLE 
______________________________________ 
(1) Compound produced in Example 3 (1) 
5 g 
or in Example 5 
(2) Lactose.crystalline cellulose (granules) 330 g 
(3) D-mannitol 29 g 
(4) Low-substituted hydroxypropyl cellulose 20 g 
(5) Talc 25 g 
(6) Hydroxypropyl cellulose 50 g 
(7) Aspartame 3 g 
(8) Glycyrrhizic acid dipotassium salt 3 g 
(9) Hydroxypropylmethyl cellulose 2910 30 g 
(10) Titanium oxide 3.5 g 
(11) Yellow iron sesquioxide 0.5 g 
(12) Light anhydrous silicic acid 1 g 
Total 500 g 
______________________________________ 
In pure water are suspended or dissolved (1), (3), (4), (5), (6), (7) and 
(8). The granule of (2) is coated with the suspension or solution to 
prepare raw fine granules, which are coated with (9) to (11) to prepare 
coated fine granules, which are mixed with (12), to give 500 g of fine 
granules containing 1% of the compound produced in Example 3(1) or Example 
5. 500 mg each of thus-prepared fine granules is packed. 
EXAMPLE 
______________________________________ 
(1) Compound produced in Example 3 (4), 9, 11, 
5 g 
12 (1), 14 (1) or 14 (2) 
(2) Lactose 330 g 
(3) Corn starch 150 g 
(4) Hydroxypropyl cellulose 15 g 
(5) Light anhydrous silicic acid 1 g 
Total 500 g 
______________________________________ 
The above (1), (2) and (3) are mixed in a fluidized-bed granulating 
machine, and an aqueous solution of (4) is sprayed to the mixture in the 
granulating machine to give fine granules. After mixing with the (5), 500 
mg each of thus prepared fine granules of the compound produced in Example 
3(4), 9, 11, 12(1), 14(1) or 14(2) are packed. 
EXPERIMENTAL EXAMPLE 1 
(1)Preparation of .sup.125 I-leuprorelin: 
Ten .mu.l of 3.times.10.sup.-4 M aqueous solution of leuprorelin and 10 
.mu.l of 0.01 mg/ml lactoperoxidase in 0.1M HEPES buffer (pH 7.4) were 
taken into a tube, to which was added 10 .mu.l (37 MBq in 0.1 M HEPES 
buffer (pH7.4)) of an Na.sup.125 I solution. The mixture was stirred, to 
which was added 10 .mu.l of 0.001% H2O.sub.2, then reaction was allowed to 
proceed for 20 minutes at room temperature. To the reaction mixture was 
added 700 .mu.l of a 0.05% TFA solution to cease the reaction. The product 
was purified by means of reversed phase HPLC. Conditions of HPLC are as 
follows. .sup.125 I-leuprorelin was eluted at a retention time of 26 to 27 
minutes. 
______________________________________ 
Column: TSK gel ODS-80 .TM.CTR (4.6 mm .times. 10 cm) 
Eluent: Solvent A (0.05% TFA) 
Solvent B (40% CH.sub.3 CN-0.05% TFA) 
0 minute (100% Solvent A) - 3 minutes (100% solvent 
A) - 7 minutes (50% solvent A + 50% solvent B) - 
40 minutes (100% solvent B) 
Elution temp.: Room temperature 
Flow rate: 1 ml/min. 
______________________________________ 
(2) Preparation of membrane fraction of CHO (Chinese Hamster Ovary) cells 
containing human GnRH receptors 
CHO cells (10.sup.9) expressing human GnRH receptors were suspended in a 
phosphate-buffered saline supplemented with 5 mM EDTA (ethylenediamine 
tetraacetate) (PBS-EDTA). The suspension was subjected to centrifugal 
separation for 5 minutes at 100.times.g. To the pellet of cells was added 
10 ml of a homogenate buffer for cells (10 mM NaHCO.sub.3, 5 mM EDTA, pH 
7.5), which was homogenated by using a Polytron homogenizer. Centrifugal 
separation was conducted for 15 minutes at 400.times.g. The supernatant 
was taken into an ultracentrifugal tube, which was subjected to centrifuge 
for one hour at 100,000.times.g to give precipitate of the membrane 
fraction. The precipitates was suspended in 2 ml of the assay buffer (25 
mM Tris-HCl, 1 mM EDTA, 0.1% BSA (bovine serum albumin), 0.25 mM PMSF, 1 
.mu.g/ml pepstatin, 20 .mu.g/ml leupeptin, 100 .mu.g/ml phosphoramide, 
0.03% sodium azide, pH 7.5), which was centrifuged for one hour at 
100,000.times.g. The membrane fraction recovered as precipitate was again 
suspended in 20 ml of the assay buffer, which was distributed to vials and 
stored at -80.degree. C. until used. 
(3)Determination of Inhibitory rate of .sup.125 I-leupororelin binding: 
Membrane fraction of CHO cells expressing human GnRH receptors preparation 
in the above (2) as diluted with an assay buffer to 200 .mu.g/ml and 188 
.mu.l each was distributed into tubes. 2 .mu.l of 2 mM of the compound 
dissolved in 60% DMSO and 10 .mu.l of 38 nM .sup.125 I-leuprorelin were 
added simultaneously to the CHO cell membrane fraction which expresses 
human GnRH receptors. For determining the amount of maximun binding, a 
solution for reaction supplemented with 2 .mu.l of 60% DMSO and 10 .mu.g 
of 38 nM .sup.125 I-leuprorelin was prepared. And, for determining the 
amount of non-specific binding, a solution for reaction supplemented with 
2 .mu.l of 100 .mu.M leuprorelin dissolved in 60% DMSO and 10 .mu.g of 38 
nM .sup.125 I-leuprorelin were also prepared simultaneously. 
The reaction was allowed to proceed at 25.degree. C. for 60 minutes. The 
reaction mixture were respectively subjected to filtration under sucking 
with Whatman glass filter (GF-F) processed with polyethyleneimine. After 
completion of the filtration, radioactivity of the .sup.125 I-leuprorelin 
remaining on the filter paper was measured with a .gamma.-counter. 
By calculation of the following formula, the binding inhibitory rate (PMB, 
%) of each test compound was determined. 
EQU PMB=(TB-SB)/(TB-NSB).times.100 
TB: Maximum binding radioactivity. 
SB: Radioactivity obtained when a compound was added. 
NSB: Non-specific binding ratio activity. 
Bisides, the inhibitory rates were determined by changing the 
concentrations of test compounds, and the concentration of a test compound 
inhibiting the (TB-NSB) by 50%, i.e. the concentration of PMB=50% 
(IC.sub.50 value), was calculated by way of Hill plot. 
The compound obtained in Example 3(4) was subjected to the above 
measurement methods, and obtained IC.sub.50 value shown in the following 
Table 7. 
TABLE 7 
______________________________________ 
.sup.125 I-leuprorelin binding inhibitory rate 
IC.sub.50 value (nM) 
Test compound Human GnRH receptor 
______________________________________ 
Compound of Example 3 (4) 
10 
______________________________________ 
INDUSTRIAL APPLICABILITY 
A gonadotropin-releasing hormone antagonistic compound of the present 
invention has excellent properties on oral absorbing, stability, 
durability of actions and stability on metabolism. Therefore, the present 
compound can be used as a prophylactic or therapeutic agent for the 
prevention or treatment of several hormone dependent diseases, for 
example, a sex hormone dependent cancer (e.g. prostatic cancer, cancer of 
uterine cervix, breast cancer, pituitary adenoma), benign prostatic 
hypertrophy, myoma of the uterus, endometriosis, precocious puberty, 
amenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne 
vulgaris; is effective as a fertility controlling agen t in both sexes 
(e.g. a pregnancy controlling agent and a menstrual cycle controlling 
agent); can be used as a contraceptive of male or female, as an 
ovulation-inducing agent of female; can be used as an infertility treating 
agent by using a rebound effect owing to a stoppage of administration 
thereof; is useful as modulating estrous cycles in animals in the field of 
animal husbandry, as an agent for improving the quality of edible meat or 
promoting the growth of animals; is useful as an agent of spawning 
promotion in fish.