JPH09110873A - Thienopyrimidine derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative containing an (esterified) carboxyl group and an anion-forming group or a group convertible to the group in the molecule, exhibiting excellent endothelin antagonistic action and useful as a vasoconstrictor, an endothelin antagonistic agent, etc. SOLUTION: This new thieno[2,3-d]pyrimidine derivative has an (esterified) carboxyl group and an anion-forming group or a group convertible to the forming group (excluding carboxyl group) and is expressed by formula I [R<1> and R<2> are each H or a (substituted) hydrocarbon group; R<3> is a 1-6C alkoxy- carbonylated 1-6C alkyl or a sulfoamidated 1-6C alkyl; R<4> is a (substituted) hydrocarbon group or a (substituted) heterocyclic group; W is bond or an intervening group; (n) is 1-3], etc. It has endothelin antagonistic action and is useful for vasoconstrictor, endothelin antagonistic agent, etc. The compound can be produced either by reacting a compound of formula II (R<3> ' is a halogenated or cyanated 1-6C alkyl) with a sulfonamide compound or hydrolyzing the CN group of the compound to an ester group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a thieno [2,3-d] pyrimidine derivative having an endothelin antagonistic activity,
The present invention relates to a method for producing the same and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art It is suggested that endothelin may be involved in cerebral infarction, angina, myocardial infarction, renal failure and liver injury caused by ischemia among the adult diseases which have been increasing in recent years. Has been done. Endothelin is a peptide consisting of 21 amino acids produced from endothelial cells, and endothelin-1, endothelin-2 and endothelin-3 are known. Hereinafter, in this specification,
These endothelin groups are collectively referred to as "endothelin". It has been reported that endothelin has the strongest and lasting vasoconstrictor action, blood pressure elevation activity, and contractile force enhancing action on myocardium among the in-vivo substances or synthetic substances found so far. It is believed that the action of these peptides is mediated by endothelin receptors, which are thought to exist in vascular smooth muscle membranes and others. As endothelin receptors, endothelin-A receptors and endothelin-B receptors (hereinafter, both are collectively referred to as "endothelin receptors") are known. Therefore, compounds that show an affinity for endothelin receptors and show endothelin antagonism are effective against diseases caused by ischemia (eg, cerebral infarction, angina, myocardial infarction, renal failure and liver injury).・ Treatment is possible and its development is highly expected. Heretofore, compounds obtained by synthesis that have an endothelin antagonism include, for example, E
P-A-510526, EP-A-526708, PC
T. WO-9308799, Journal of Medicinal Chemistr
y), 37, pp. 1553-1557 (1994). A thieno [2,3-d] pyrimidine derivative having an endothelin antagonism is EP-
A-640,606.

[0003]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a thieno [2,3-d] pyrimidine derivative having a superior endothelin antagonism, a method for producing the same, and a pharmaceutical composition containing the same. To do.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have found that the thieno [2,3-
Further examination of the d] pyrimidine derivative showed that it was a thieno [2,3-d] pyrimidine derivative, and
Optionally esterified carboxyl group and (2)
It has been found that a derivative having a group capable of forming an anion or a group capable of changing it (excluding a carboxyl group) has a superior endothelin antagonism. The present inventors have conducted further research based on this finding,
The present invention has been completed.

In the present invention, (1) a carboxyl group which may be esterified in the molecule and (2) a group capable of forming an anion or a group which can be changed to that group (excluding the carboxyl group) are included. The thieno [2,3-d] pyrimidine derivative (I) having (2) a group capable of forming an anion or a group which can be changed thereto is a tetrazolyl group, an optionally substituted sulfonamide group, or phosphoric acid. A group or a sulfonic acid group, which is a group which may be further substituted with an alkyl group or an acyl group, (3) the general formula

Embedded image (In the formula, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ is a C _1-6 alkoxy-carbonyl group or a formula —NH—SO ₂ —R ⁵ ( wherein the C _1-6 alkyl group R ⁵ has a group represented by halogen showing an optionally substituted C _1-6 alkyl group or a C _6-14 aryl group) as a substituent, R ⁴ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, W is a bond or an intervening group,
(n represents an integer of 1 to 3) or a salt thereof, (4) the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ is C The compound according to (3) above, which is a _1-20 hydrocarbon group, (5) wherein the C _1-20 hydrocarbon group is C _1-10 alkyl, C _3-10 cycloalkyl, C _2-10 alkenyl, C _{6 -14} is a compound described in the above item (4) which is an aryl or C _7-20 aralkyl group, (6) the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ is C _{7- 20.} The compound according to the above (4) which is an aralkyl group, (7) wherein the substituent in the hydrocarbon group represented by R ¹ may be (1) halogen, (2) nitro, (3) cyano, (4) optionally substituted hydroxyl group, (5) formula —S (O) f—R ⁶ (in the formula, f is an integer of 0 to 2, R ⁶ is a hydrogen atom or a substituent) It A hydrocarbon group which may optionally be present), (6) optionally substituted amino group, or (7) optionally substituted heteroatom of oxygen, sulfur or nitrogen of 1 to 4 The compound according to the above item (3) which is a 5- to 6-membered heterocyclic group containing (8) a hydrocarbon group represented by R ¹ which may have a substituent, wherein the substituent is halogen or C ₁ (4) The compound according to the above item (3) which is _-4 alkylthio, (9) wherein the hydrocarbon group in the hydrocarbon group which may have a substituent represented by R ² is a C _1-20 hydrocarbon group. (3) The compound according to the item (10), wherein the C _1-20 hydrocarbon group is C _1-10 alkyl, C _3-10
The compound according to the above item (9), which is a cycloalkyl, C _2-10 alkenyl, C _6-14 aryl or C _7-20 aralkyl group, (11) a carbon atom which may have a substituent represented by R ^2. The hydrocarbon group in the hydrogen group is a C _1-10 alkyl group, the compound according to the above item (3), (12) the hydrocarbon group which may have a substituent represented by R ² has a substituent , (1) halogen, (2) nitro, (3)
Cyano, (4) optionally substituted hydroxyl group, (5)
Formula -S (O) f-R ⁶ group (wherein, f is the integer of 0 to 2, R ⁶ is a hydrogen atom or an optionally substituted hydrocarbon group.) Represented by, (6) The compound according to the above item (3), which is an optionally substituted amino group or (7) a 5- or 6-membered heterocyclic group optionally containing 1 to 4 heteroatoms of oxygen, sulfur and nitrogen. (13) The substituent in the optionally substituted hydrocarbon group represented by R ² is (1) a halogen atom, (2) nitro,
(3) hydroxy, (4) cyano, (5) C _1-4 alkylthio,
(6) C _1-4 alkoxy, (7) C _1-6 alkyl-carbonyloxy or (8) C _3-6 cycloalkyloxy-carbonyloxy, the compound according to the above (3), (14) R ² Is a hydrogen atom or a C _1-6 alkyl-carbonyloxy or C _3-6 cycloalkyloxy-carbonyloxy optionally substituted C _1-6 alkyl group, the compound according to the above (3), (15) R ³ is a group represented by C _1-6 alkoxy-carbonyl or the formula —NH—SO ₂ —R ⁵ ′ (wherein R ⁵ ′ represents a C _1-6 alkyl group or a C _6-14 aryl group). the compounds according to (3) above, wherein a C _1-6 alkyl group having as a substituent, (16) R ³ is wherein -NH-SO ₂ -R ⁵ (wherein, R ⁵ is a halogen A C _1-6 alkyl group or a C _6-14 aryl group which may be substituted) The compound according to (3) above, which is a C _1-6 alkyl group having as a substituent, (17) R ³ has the formula —NH—SO ₂ —R ⁵ ′ (wherein R ⁵ ′ is C _{1 -6} alkyl group or C _6-14 aryl group), which is a C _1-6 alkyl group having as a substituent a compound represented by the above (3),

(18) R ⁴ may have a C _1-20 hydrocarbon group which may have a substituent or may have a substituent,
1 to 4 selected from oxygen atom, sulfur atom and nitrogen atom
A 5- to 13-membered heterocyclic group having 4 heteroatoms
(19) The compound described in (3) above, (19) The compound described in (3) above, wherein the hydrocarbon group represented by R ⁴ which may have a substituent is a C _6-14 aryl group. 20) Substituents in the optionally substituted hydrocarbon group represented by R ⁴ include (1) halogen, (2) nitro, (3) cyano, (4) C _1-6 alkoxy, carboxyl, halogen,
C _1-6 alkyl-carbamoyl or C _1-6 alkoxy group optionally substituted with a nitrogen-containing 5 to 7-membered heterocycle-carbonyl, (5) C _7-13 aralkyloxy, (6) C _1-3 alkoxy A C _1-4 alkyl group which may be substituted with (7) C
_1-6 alkanoyl group, (8) C _1-4 alkylthio, (9) C _2-6
Alkenyloxy, (10) C _1-6 alkoxy-carbonyl or (11) C _1-6 alkyl-carbamoyl as above
(21) The compound as described in the item (3), (21) the hydrocarbon group which may have a substituent represented by R ⁴ , wherein the substituent is (1) C _1-6 alkoxy, (2) carboxyl, (3) Halogen, (4) C _1-6 alkyl-carbamoyl, (5) halogen or (6) nitrogen-containing 5 to 7-membered heterocycle-a C _1-6 alkoxy group optionally substituted by carbonyl (3) (22) The intervening group represented by W is (1) C _1-4 alkylene,
(2) C _2-6 alkenylene, (3) - (CH ₂₎ cNR ⁷ - wherein, c is an integer of 0 to 3, R ⁷ represents hydrogen or C _1-6 alkyl] expressed in Group, (4) -CO-, (5) formula-CON
R ⁷ - (wherein, R ⁷ is of the same meaning as defined above) a group represented by, (6) -O -, ( 7) formula -S (O) f- (wherein, f is 0-2
An integer of), a group represented by (8) -NR ⁷ S (O) e- (wherein, e is an integer of 0 to 2, R ⁷ have the same meaning as defined above) The compound according to the above item (3), (23) the compound according to the above item (3) in which W is a bond, (24) R ¹ substitutes the (1) halogen atom or (2) C _1-4 alkylthio group. A benzyl group which may have as a group,
R ² is hydrogen or C _1-4 alkyl - carbonyloxy or C _3-6 cycloalkyl - good C _1-4 alkyl group which may have a oxycarbonyloxy as a substituent, R ³
Is (1) C _1-6 alkoxy-carbonyl group or (2) formula -N
A group represented by H—SO ₂ —R ⁵ ″ (in the formula, R ⁵ ″ represents a C _1-3 alkyl group optionally substituted with a halogen atom or a phenyl group) as a substituent. _Playing C _1-6
An alkyl group, R ⁴ is (1) C _1-6 alkoxy, carboxy, C _1-6 alkyl - carbamoyl, piperazinecarbonyl or optionally substituted C _1-4 alkoxy group with a halogen, (2) C _{7- 8} aralkyloxy, (3) C _1-3 alkoxy optionally substituted C _1-4 alkyl, (4) C
_1-6 alkanoyl, (5) C _2-4 alkenyloxy, (6) C _1-6
The above shows a phenyl group substituted with an alkoxy-carbonyl or (7) C _1-6 alkyl-carbamoyl, respectively.
(3) The compound according to the item (25) 2,4 (1H, 3H) -dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno. [2,
3-d] pyrimidine-3-acetic acid or a salt thereof. (26) 2,4 (1H, 3H) -dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl) thieno [2,
3-d] pyrimidine-3-acetic acid or a salt thereof. (27) 2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -1- (2-methylthiobenzyl) -5-
(Methanesulfonamidomethyl) thieno [2,3-d]
Pyrimidine-3-acetic acid or a salt thereof. (28) 2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -1- (2-methylthiobenzyl)-
5- (Carboxymethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.

(29) General formula

Embedded image (In the formula, R ¹ , R ² , n and R ⁴ have the same meanings as those described in the above item (3). R ³ 'represents a halogenated or cyanated C _1-6 alkyl group). In the case where (1) R ³ 'is a halogenated C _1-6 alkyl group, the compound or a salt thereof is subjected to a nucleophilic substitution reaction with a sulfonamide, and (2) R ³ ' is a cyano group. In the case of a compound having a _modified C _1-6 alkyl group, a method for producing the compound or salt thereof according to the above (3), characterized by subjecting to an alkaline hydrolysis reaction and then an esterification reaction, (30) above (1) ), (3) or a pharmaceutical composition containing the salt or a salt thereof according to (28), (31) The pharmaceutical composition according to (30) above, which is a vasoconstrictor, (32) cerebral blood vessels, coronary arteries The pharmaceutical composition according to the above (31), which is a coronary vein or pulmonary vasoconstrictor, (33) endothelin The pharmaceutical composition according to the above (30) which is an anti-drug, (34) the pharmaceutical composition according to the above (33) which is a therapeutic agent for acute renal failure, myocardial infarction and / or liver injury, (35) surgery of an organ or The pharmaceutical composition according to the above (33), which is a preventive or therapeutic agent for functional deterioration of organs caused by transplantation, and (36) the pharmaceutical composition according to the above (35), wherein the organ is the liver.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Thieno [2,3-d] pyrimidine, which is the skeleton of the compound of the present invention in the present specification, is represented by the following formula.

Embedded image Examples of the optionally esterified or amidated carboxyl group in the thienopyrimidine derivative of the present invention include, for example, the formula —CO-D (wherein D is a (1) hydroxyl group, and the (2) formula —O—R ⁸ (In the formula, R ⁸ represents a hydrocarbon group which may have a substituent) or (3) an optionally substituted amino group. ). } The group represented by these is mentioned. Examples of the group capable of forming an anion or a group capable of changing to an anion (excluding a carboxyl group which may be esterified or amidated) include, for example, tetrazolyl and a sulfonamide group which may have a substituent { Example, a group represented by the formula: —NH—SO ₂ —R ⁵ (wherein R ⁵ represents a C _1-6 alkyl group or a C _6-14 aryl group which may be substituted with a halogen atom), and phosphoric acid And sulfonic acid groups, each of which further includes 1 to 2 C _1-6 alkyl or acyl (eg, C _2-5 alkanoyl (eg, acetyl, propionyl, butyryl, valeryl), C _6-14 aryl). Carbonyl (eg, benzoyl)}. Among these, preferably, the general formula

Embedded image (In the formula, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ is a C _1-6 alkoxy-carbonyl group or a formula —NH—SO ₂ —R ⁵ ( wherein the C _1-6 alkyl group R ⁵ has a group represented by halogen showing an optionally substituted C _1-6 alkyl group or a C _6-14 aryl group) as a substituent, R ⁴ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, W is a bond or an intervening group,
n represents an integer of 1 to 3) or a salt thereof.

In R ⁸ in the above definition of D, R ¹ , R ² and R ^{4 in} the general formula (I ′) and the optionally substituted hydrocarbon group represented by R ⁶ described later. As the hydrocarbon group, a C _1-20 hydrocarbon group is preferable. As the hydrocarbon group, for example, a C _1-10 alkyl group (eg,
Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Among them, C
_1-6 alkyl groups are preferred. ), A C _3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc. Among them, a C _3-6 cycloalkyl group is preferable), C _7-10 bicyclo. Alkyl group (eg, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3,2,1] octyl, bicyclo [3,2,1] nonyl, bicyclo [4,2] , 1] nonyl, bicyclo [4,3,1] decyl, etc. Among them,
Cyclopentyl and cyclohexyl are preferred. ), C
_2-10 alkenyl group (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl, etc. Among them, C _2-6 alkenyl group is preferable), C _{6- 14} aryls (eg phenyl,
Naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc. Among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. ), C _7-20 aralkyl {eg, benzyl, phenethyl, benzhydryl, trityl, etc. Of these, C _7-8 aralkyl (eg, benzyl, phenethyl) is preferable. ｝.

The substituent which the hydrocarbon group may have is, for example, (1) halogen (eg, fluorine, chlorine, bromine, iodine), (2) nitro, (3) nitroso, (4) cyano. ,
(5) Substituent {eg, (i) C _1-6 alkyl (hydroxyl group, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkoxy, C _1-3 alkylthio, oxy-C _1-3 alkoxy) , Carboxy,
It may have carbamoyl, C _1-6 alkyl-carbamoyl, a nitrogen-containing 5- to 7-membered heterocyclic group or halogen as a substituent. ), (Ii) C _1-4 acyl, (iii) C _7-20 aralkyl (this group is halogen, C _1-3 alkoxy or C
_1-4 alkyl may have a substituent), (iv)
C _6-14 aryl (which may have halogen as a substituent), (v) C _2-6 alkenyl, (vi) C _3-7 cycloalkyl, (vii) C _1-3 alkoxy-carbonyl, ( viii) Mono-
Or di-C _1-6 alkylamino, (ix) C _1-3 alkoxy-carbonyl, (x) C _1-6 alkylcarbonyl, (xi) C
_3-6 cycloalkyloxycarbonyl or (xii) trifluorosulfonyl} optionally hydroxyl,
(6) ^{-S (O) f-R 6} { wherein, f is an integer of 0 to 2, R
⁶ is a hydrocarbon group which may have a hydrogen atom or a substituent (eg, halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano-C _6-14 aryl, halogeno C _6-14 aryl, etc.) . As the hydrocarbon group, C
_1-20 hydrocarbon groups, especially C _1-6 alkyl, C _6-14 aryl, C _7-20 aralkyl are preferred. )}, (7) optionally substituted amino group [eg, formula —NR ⁹ R ¹⁰ {wherein R ⁹
And R ¹⁰ are the same or different and each is an amino represented by a hydrogen atom, a hydrocarbon group (as defined above), a C _1-6 acyl or a 5- to 13-membered heterocyclic group (examples are the same as those described later)}. Group], (8) optionally substituted carboxyl group [eg, formula —CO—R ¹¹ {in the formula, R ¹¹ is (i) hydrogen atom, (i)
i) hydroxy, (iii) C _1-6 alkyl, (iv) C _1-6 alkoxy, (v) C _3-6 cycloalkyl, (vi) C _6-14 aryl,
(vii) C _7-20 aralkyl, (viii) optionally substituted amino group (examples are the same as the above) or (ix) 5 to 13 membered heterocyclic group (the examples are the same as those described later). } Group], (9) 5- to 13-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (the heterocyclic group is (i) halogen). Atom, (ii) C
_It may be substituted with _1-4 alkyl, (iii) C _1-3 alkoxy, (iv) C _1-4 alkylthio, and (v) phenoxy which may be substituted with halogen. ｝, (10) Sulfo, (11) C
_6-14 aryl (eg phenyl, naphthyl, anthryl,
Phenanthryl, acenaphthyl, anthracenil, etc. ), (12) C _3-7 cycloalkyl, (13) C _1-6 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy, etc.), (14) Oxo, (15) thioxo, (16) C _3-4 alkynyl (eg, propargyl, 2-butynyl, etc.), (17) C _3-10
Cycloalkyl group, (18) C _2-10 alkenyl group (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl, etc., among them.
A C _2-6 alkenyl group is preferred. ), (19) C _7-20 aralkyl (examples are the same as above), (20) amidino, (21) azide and the like. When the hydrocarbon group is a cycloalkyl, cycloalkenyl, aryl or aralkyl group, it has 1 to 3 C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl etc.) as a substituent. This C _1-6 alkyl may further be 1 to
It may be substituted with 3 hydroxy, oxo, C _1-3 alkoxy (eg, methoxy, ethoxy, ethoxy, n-propoxy, isopropoxy, etc.), C _1-3 alkylthio, halogen, carbamoyl and the like. The substituted C
_1-6 alkyl as formyl (methyl substituted by oxo), carboxyl (methyl substituted by oxo and hydroxy), C _1-6 alkoxycarbonyl (methyl substituted by oxo and alkoxy) (Eg, C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl), hydroxy C _1-6 alkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl,
Hydroxypropyl etc.), C _1-3 alkoxy-C _1-6 alkyl (eg, methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, propoxyhexyl, etc.) and the like. The number of the substituents in the above is 1 to 6, preferably 1 to 5, more preferably 1 to 3, and most preferably 1 to 2. The number of substituents that the substituent may further have is preferably 1 to 3, and particularly preferably 1 to 2. The above n represents an integer of 1 to 3, preferably 1 or 2, and particularly preferably 1.

[0011] C _1-6 alkoxy represented by R ³ - C in C _1-6 alkyl group having a group represented by a carbonyl group or the formula -NH-SO ₂ -R ⁵ as a substituent _1-6 Examples of alkyl groups include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, sec-butyl, t
-Butyl, pentyl, hexyl and the like. Particularly, methyl and ethyl are preferable. C _1-6 alkoxy represented by R ³ - C _1-6 The alkoxy in a carbonyl group, methoxy, ethoxy, propoxy, isopropoxy, n- butoxy, isobutoxy, t-butoxy, pentoxy, hexyloxy and the like. Of these, C _1-4 alkoxy is preferable. Examples of the C _1-6 alkyl group in the C _1-6 alkyl group which may be substituted with halogen represented by R ⁵ include the same ones as described above. Particularly, methyl and ethyl are preferable. Examples of the halogen include fluorine, chlorine, bromine and iodine, and among them, fluorine and chlorine are preferable. The number of substituents is preferably 1 to 3, and particularly preferably 1 or 3. Examples of the C _6-14 aryl group represented by R ⁵ include phenyl, naphthyl and anthryl, and phenyl is particularly preferable.

The heterocyclic group in the optionally substituted heterocyclic group represented by R ⁴ and the above-mentioned heterocyclic group include, for example, as atoms (ring atoms) constituting a ring,
A 3 to 13 membered ring having 1 to 4 heteroatoms selected from oxygen (O), sulfur (S), and nitrogen (N),
Preferable one is a 5- to 13-membered aromatic heterocyclic group, or a saturated or unsaturated non-aromatic heterocyclic group. Suitable examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, pyrrolinyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
Oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazinyl, 1,2,3-triazolyl, 1,2,
Aromatic monocyclic heterocyclic groups such as 4-triazolyl, triazolidinyl tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-
Benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,
β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,
2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-
a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4, 3-
b] Aromatic condensed heterocyclic groups such as pyridazinyl. The non-aromatic heterocyclic group is preferably, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl,
Examples thereof include thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolino and hexamethylamino. The heterocyclic group preferably has 5 to 7 members, more preferably 5 to 6 members. Further, the heterocyclic group may have one or more, preferably 1 to 3 appropriate substituents, and examples of the substituent include the same substituents as the above-mentioned hydrocarbon group. .

The intervening group represented by W is, for example,
(1) C _1-4 alkylene (eg, methylene, ethylene, etc.),
(2) C _2-6 alkenylene (eg, vinylene, butadienylene, etc.), (3) Formula — (CH ₂ ) cNR ⁷ — [In the formula, c is an integer of 0 to 3, R ⁷ is hydrogen or C _{1- 6} alkyl (eg, methyl,
Ethyl, propyl, butyl, etc.)],
(4) -CO -, (5 ) formula -CONR ⁷ - (wherein, R ¹⁰ is of the same meaning as defined above) a group represented by, (6) -O -, ( 7) formula -
A group represented by S (O) f- (in the formula, f represents an integer of 0 to 2), (8) Formula —NR ⁷ S (O) e- (in the formula, e is an integer of 0 to 2) R ⁷ has the same meaning as defined above, and the like.

The preferred hydrocarbon group in the hydrocarbon group which may have a substituent represented by R ¹ is a C _1-20 hydrocarbon group, among which a C _1-10 alkyl group is preferable. , C _3-10 cycloalkyl, C _2-10 alkenyl,
More preferred is C _6-14 aryl or C _7-20 aralkyl. R ¹ is most preferably a C _7-20 aralkyl group which may have a substituent. Preferred substituents in the hydrocarbon group which may have a substituent represented by R ¹ include (1) halogen, (2) nitro, (3) cyano,
(4) optionally substituted hydroxyl group, (5) formula-S
(O) f-R ⁶ (wherein, f is an integer of 0 to 2, R ⁶ is a hydrogen atom or an optionally substituted hydrocarbon group.)
(6) An optionally substituted amino group or (7) a optionally substituted 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms of oxygen, sulfur and nitrogen. In addition, as a preferable example of the group R ¹ , the formula — (CH ₂ ) mQ (in the formula, m is 0 to
In the integer of 3, Q is a C _6-14 aryl group which may have a substituent, a C _3-10 cycloalkyl group which may have a substituent or an optionally substituted 5 Is a 13-membered heterocyclic group. ). Substituents in the C _6-14 aryl group which may have a substituent represented by Q include (1) halogen, (2) nitro, (3) cyano, (4) amino, and (5) substituent A carboxyl group optionally having (6) C _1-6 alkylenedioxy, (6) C _1-6 alkylthio or (7) formula —A—R ¹² (wherein A is the above-mentioned W
And an intervening group similar to R ¹² represents C _1-6 alkyl. ) The group represented by is mentioned. The above-mentioned carboxyl group which may have a substituent is represented by the above formula -C.
It has the same meaning as the group represented by OR ¹¹ . Especially,
Preferred examples of the substituent in the C _6-14 aryl group which may have a substituent represented by Q include (1) halogen, (2) C _1-6 alkylthio, and (3) C _1-6 alkoxy. Or
(4) A group represented by the formula —A—R ¹² (in the formula, A and R ¹² have the same meanings as described above). Above all, Q
Preferred examples of the substituent in the C _6-14 aryl group which may have a substituent represented by are halogen, C
_1-6 alkylthio and C _1-6 alkoxy are mentioned. In C _6-14 aryl group in good C _6-14 aryl group optionally having a substituent represented by Q, phenyl being most preferred. The group R ¹ is most preferably a C _7-20 aralkyl group which may have a substituent. Preferred examples of the substituent include a halogen atom, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkylthio and C _1-4 alkoxy. Among them, the most preferred are substituents, a halogen atom, C _1-4 alkylthio. Particularly, include C _1-4 alkylthio. As the group R ¹ , a benzyl group which may have a substituent is most preferable. The optionally substituted amino group represented by the group R ⁸ is represented by the formula: —NR ⁹ R ¹⁰ {in the formula, R ⁹
And R ¹⁰ are the same or different and represent a hydrogen atom, a hydrocarbon group (examples are the same as above), a C _1-6 acyl or a heterocyclic group (examples are the same as those described later)}. To be

Preferable examples of the substituent of the optionally substituted hydrocarbon group represented by R ² include, for example, the substituent of the optionally substituted hydrocarbon group of the group R ¹ . The same thing as a preferable thing is mentioned. Preferred examples of the group R ² include a hydrogen atom and an optionally substituted C _1-10 alkyl group. As the optionally substituted C _1-10 alkyl group, an _optionally substituted C _1-6 alkyl group is more preferable, and among them, an optionally substituted C _1-4 alkyl group is most suitable. Is. Preferred substituents for the hydrocarbon group which may have a substituent represented by R ² include (1) halogen, (2) nitro, (3) cyano and (4) optionally substituted Hydroxyl group, formula (5) --S (O) f--R
⁶ (in the formula, f represents an integer of 0 to 2, R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group), (6) optionally substituted amino group or (7) substituted 5 to 1 to 4 optionally containing heteroatoms of oxygen, sulfur and nitrogen
A 6-membered heterocyclic group can be mentioned. The most suitable substituents for the optionally substituted hydrocarbon group represented by R ² are (1) halogen atom, (2) nitro, (3) hydroxy, (4) cyano, ( 5) C _1-4 alkylthio, (6) C
_1-4 alkoxy, (7) C _1-6 alkyl-carbonyloxy or (8) C _3-6 cycloalkyloxy-carbonyloxy are mentioned, and among them, C _1-6 alkyl-carbonyloxy or C _3-6 Cycloalkyl-oxycarbonyloxy is preferred.

In the above formula (I), the group represented by R ³ is preferably (a) (1) C _1-6 alkoxy-carbonyl or (2) formula -NH-SO ₂ -R ⁵ '( wherein, R ⁵ 'has a group a substituent represented by C _1-6 an alkyl group, or a C _6-14 aryl group) C _1-6
Alkyl group, (b) formula -NH-SO ₂ -R ⁵ (wherein, R ⁵
Represents a (1) C _1-6 alkyl group optionally substituted by halogen or (2) represents a C _6-14 aryl group) as a substituent, a C _1-6 alkyl group, Expression (c)-
NH-SO ₂ -R ⁵ '(wherein, R ^5' is C _1-6 alkyl group or a C _6-14 aryl group indicates a) C _1-6 alkyl group a group represented by and has as a substituent , (D) Formula-NH-S
C ₁ having a group represented by O ₂ -R ⁵ ″ (wherein R ⁵ ″ represents a C _1-3 alkyl group optionally substituted with halogen or a phenyl group) as a substituent _-3 alkyl group, a group represented by the formula (e) —NH—SO ₂ —R ⁵ ′ ″ (wherein R ⁵ ′ ″ represents a C _1-3 alkyl group or a phenyl group) as a substituent. Has a C _1-3 alkyl group,
(F) Formula —NH—SO ₂ —R ⁵ ″ ″ (wherein R ⁵ ″ ″ is C
A C _1-3 alkyl group having a group represented by _1-6 alkyl group) as a substituent, or (g) the formula —NH—
C _1-6 having a group represented by SO ₂ —R ⁵ ″ ″ ″ (wherein R ⁵ ″ ″ ″ represents a C _1-3 alkyl group) as a substituent
And an alkyl group.

In the above formula, preferable examples of the group R ⁴ include a C _6-14 aryl group which may have a substituent, a C _7-20 aralkyl group which may have a substituent and a substituent. A C _3-10 cycloalkyl group which may have the formula, —CO—R
1 to 4 heteroatoms selected from the optionally substituted carboxyl group represented by ¹¹ (examples are the same as above), optionally substituted oxygen atom, sulfur atom and nitrogen atom. A 5- to 13-membered heterocyclic group having
A ~ 6 membered heterocyclic group is preferred. Is preferred. Examples of the substituent which may have the above-mentioned substituent include the same substituents as the above-mentioned hydrocarbon group. Among these substituents, preferred are (1) halogen, (2)
Nitro, (3) cyano, (4) C _1-6 alkoxy, carboxyl, halogen, C _1-6 alkyl-carbamoyl or nitrogen-containing 5 to 7-membered heterocycle-C _1-6 alkoxy optionally substituted with carbonyl Group, (5) C _7-13 aralkyloxy,
(6) C _1-4 alkyl group optionally substituted by hydroxy, oxo or C _1-3 alkoxy, (7) C _1-6 alkanoyl group, (8) C _1-4 alkylthio, (9) C _{2 -6} alkenyloxy, (10) C _1-6 alkoxy-carbonyl, (11) C _1-6 alkyl-aminocarbonyl. Preferred examples of the group R ⁴ include a C _6-14 aryl group which may have a substituent, a C _3-10 cycloalkyl group which may have a substituent, and a group represented by the formula —CO—R ¹¹ . A 5- to 13-membered heterocyclic group having 1 to 4 heteroatoms selected from a carboxyl group which may have a substituent, an oxygen atom, a sulfur atom and a nitrogen atom which may have a substituent. Can be mentioned.
The most preferable example of the group R ⁴ is a C _6-14 aryl group which may have a substituent. The most preferable substituents are C _1-6 alkoxy, carboxyl, halogen, C _1-6 alkyl-aminocarbamoyl, nitrogen-containing 5 to 7-membered heterocycle-carbonyl or C ₁ which may be substituted with halogen. _-6 alkoxy groups can be mentioned. Preferable examples of the group R ⁴ may have (1) a halogen or C _1-6 alkoxy optionally C _1-6 alkoxy or optionally substituted by (2) C _1-6 alkylthio substituent A _C6-14 aryl group is mentioned. Preferred as the group R ⁴ is C _6-, which may be substituted with optionally substituted C _1-6 alkoxy (particularly, C _1-6 alkoxy optionally substituted with C _1-6 alkoxy). Examples include ₁₄ aryl groups. As a preferred group R ⁴ ,
(1) C _1-6 alkoxy, carboxyl, C _1-6 alkyl-
Carbamoyl, piperazinecarbonyl or a C _1-4 alkoxy group optionally substituted with halogen, (2) C _7-8
Aralkyloxy, (3) hydroxy, oxo or C
_1-3 Good C _1-4 alkyl group optionally substituted by alkoxy, particularly, optionally substituted by C _1-3 alkoxy C
_1-4 alkyl group, (4) C _1-6 alkanoyl group, (5) C _2-4 alkenyloxy, (6) C _1-6 alkoxy-carbonyl or (7) C _1-6 alkyl-carbamoyl substituted And a phenyl group which may be present.

[0018] In the above formulas, W, (. Wherein, f is indicating an integer of 0 to 2) bond or the formula -S (O) f-,, formula -CO- or formula -CONR ⁷ - [ In the formula, R ⁷ is C _1-4
An alkyl group (eg, methyl, ethyl, propyl, butyl, etc.) is shown. ] The intervening group represented by As W, a bond is particularly preferable.

Examples of C _2-6 alkenyl in the definition of the above radicals are, for example, vinyl, allyl, isopropenyl, butenyl, hexatrienyl. Examples of C _2-4 alkenyl include vinyl, allyl, isopropenyl and butenyl. Examples of C _6-14 aryl in the definition of the above groups include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl. Of these, phenyl is preferred. Examples of C _7-8 aralkyl in the definition of the above groups include benzyl and phenethyl. Examples of C _1-6 alkoxy in the definition of the above groups include, for example, methoxy, ethoxy, propoxy,
Examples include isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Examples of C _1-4 alkoxy include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy. Halogen in the definition of the above groups includes fluorine, chlorine, bromine and iodine.

C _1-6 alkyl in the above definition of the group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-.
Butyl, pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned. As C _1-4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, t-butyl. C _1-3 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl. Examples of C _3-10 cycloalkyl in the definition of the above group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. As C _3-7 cycloalkyl, for example, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl and cycloheptyl are mentioned. Examples of C _3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C _1-6 in the definition of the above groups
Examples of the acyl include formyl and the formula —CO—R.
C _2-6 alkanoyl represented by ¹³ (in the formula, R ¹³ represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl). Examples of C _1-4 acyl in the above definition of the group include a group represented by formyl and the formula —CO—R ¹³ ′ (wherein R ¹³ ′ represents methyl, ethyl, propyl or isopropyl). To be 5-7 above
The member nitrogen-containing heterocyclic group, for example, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,
Triazolyl, tetrazolyl, flazanyl, tetrahydrofuryl, pyridyl, pyrimidinyl, pyridazinyl, oxadiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,3,2,3,2,3.
1,2,3-triazolidinyl, 1,2,3-triazolyl,
1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethylene aminyl, oxazolidinyl, thiazolidinyl and the like can be mentioned. Of these, a 5- or 6-membered heterocyclic group is preferable. Among the 5- or 6-membered heterocyclic groups, especially,
Pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl are preferred. In the above definition, the number of substituents is preferably 1 to 3, and more preferably 1 or 2.

The above compound (I), compound (I ') or a salt thereof can be produced by a method known per se. For example, it can be manufactured as follows. (A) General formula (II ')

Embedded image (In the formula, R ² 'is a hydrocarbon residue which may have a substituent, R ³ , R ⁴ , W and n have the same meanings as described above, and R ¹⁴ has a hydrogen atom or a substituent. Optionally represented by a hydrocarbon residue) represented by a compound (II ') or a salt thereof,
A ring closure reaction is carried out by treating with a base to produce a compound (IV ′) in which R ¹ is hydrogen and R ² is a hydrocarbon residue which may have a substituent in the compound (I ′) or a salt thereof. can do. This reaction is carried out in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol,
Examples include ethers such as dioxane and tetrahydrofuran. Examples of the base include sodium methylate,
Alkali metal alkoxides such as sodium ethylate and sodium isopropoxide, and alkali metal hydrides such as sodium hydride are used. The amount of base used is
The compound (II ′) or a salt thereof is used in an amount of about 1.1 to 5 equivalents, preferably about 1.5 to 3 equivalents. The reaction temperature is about 10 ° C to heating reflux temperature, preferably about 25 ° C to heating reflux temperature. The reaction time is a few minutes to a few days, preferably about 10 minutes to 2 days. Compound (I) of the present invention
For example, 4 of the thiophene compound represented by the above formula (II ′)
A compound in which R ³ or WR ^{4 at the} 5th or 5th position is a group capable of forming an anion or a group capable of being converted into the anion can be produced by subjecting it to a ring closure reaction similar to the above.

(B) The following general formula (III)

Embedded image [In the formula, R ² 'is a hydrocarbon residue which may have a substituent, R ³ has the same meaning as described above, and R ¹⁴ is hydrogen or a hydrocarbon residue which may have a substituent. , N is an integer of 1 to 3, respectively. ] The compound (III) represented by or a salt thereof is treated with a base to carry out a ring closure reaction,
Then, by subjecting it to a reaction for introducing a group represented by the formula —WR ⁴ (wherein W and R ⁴ have the same meanings as described above),
In the compound (I ′), R ¹ is hydrogen, R ² is an optionally substituted hydrocarbon group, and R ³ and WR ⁴ are compounds (IV ′) or salts thereof having the same meanings as described above. Can be manufactured. The ring closure reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane and tetrahydrofuran.
As the base, for example, alkali metal alkoxides such as sodium methylate, sodium ethylate, and sodium isopropoxide, and alkali metal hydrides such as sodium hydride are used. The amount of base used is about 1.1-5 equivalents, preferably about 1.5-3 equivalents, relative to 1 equivalent of compound (III). The reaction temperature is about 10 ° C to heating reflux temperature, preferably about 25 ° C to heating reflux temperature.
The reaction time is a few minutes to a few days, preferably about 10 minutes to 2 days. Specific examples of the reaction for introducing the group —WR ⁴ include (1) acylation reaction (eg, reaction using acid chloride-aluminum chloride), (2) formylation reaction (eg,
Reaction using phosphorus oxychloride-dimethylformamide or N-methylformanilide), (3) halogenation reaction (eg, reaction using N-bromosuccinimide, bromine-pyridine, sulfuryl chloride) and functional group substitution reaction, ( 4) Nitration reaction (eg, reaction using fuming nitric acid-concentrated sulfuric acid, sodium nitrate-concentrated sulfuric acid) and functional group substitution reaction. Specifically, it is performed under the following conditions, for example. (1) Acylation reaction: alkanoyl chloride (eg,
Acetyl chloride, propionyl chloride, etc.) and a solvent that does not adversely affect the reaction (eg, nitrobenzene, nitromethane, carbon disulfide, etc.), using a Lewis acid catalyst (eg, aluminum chloride, titanium tetrachloride, etc.), and about 0-100 ℃
Done in (2) Formylation reaction: phosphorus oxychloride-N,
N-dimethylformamide, N-methylformanilide, oxalyl chloride-N, N-dimethylformamide, N-methylformanilide, thionyl chloride-N, N
-Dimethylformamide, N-methylformanilide is used, and a solvent that does not adversely influence the reaction (eg, benzene,
Toluene, xylene, tetrahydrofuran, dioxane, 1,2-dichloroethane, etc.) or without solvent,
It is performed at about 15 to 130 ° C. (3) Halogenation reaction: Sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide, bromine, chlorine, iodine, and a solvent that does not adversely affect the reaction (eg, dichloromethane, chloroform, carbon tetrachloride) 1,2-dichloroethane, pyridine, benzene, toluene, xylene, etc.), about 15 to 1
Performed at 30 ° C. (4) Nitration reaction: It is carried out in fuming nitric acid-concentrated sulfuric acid, sodium nitrate-concentrated sulfuric acid, potassium nitrate-concentrated sulfuric acid at about 0 to 80 ° C. The nitro group, halogen, etc. introduced by the electrophilic substitution reaction as described above are further subjected to a functional group conversion reaction. As the functional group conversion reaction, a functional group conversion reaction known per se is used. Specifically, for example, reduction reaction, acylation reaction, sulfonylation reaction, alkylation reaction, diazo coupling reaction, Wittig reaction, reaction between halogen and Grignard reagent, organozinc reagent, organoboron reagent or organotin reagent. And a reaction represented by the following (e) and (f). The compound (I) of the present invention is, for example, a compound in which R ³ or WR ^{4 at} the 4-position or 5-position of the thiophene compound represented by the above formula (II ′) is a group capable of forming an anion or a group capable of being converted into it. , Or the above formula (II
A compound in which R ^{3 at} the 4-position of the thiophene compound represented by I) is a group capable of forming an anion or a group capable of being converted into it.
It can be produced by subjecting it to a reaction similar to the ring closure reaction shown in (a) or (b) above.

(C) Compound (IV ') or a salt thereof prepared in the above (a) and (b) and the general formula (V'): R ¹ ″ —
By reacting with a compound represented by X (V ′) (in the formula, R ¹ ″ is a hydrocarbon residue which may have a substituent, and X is halogen) or a salt thereof. A compound (VI) in which R ¹ in the compound (I ′) is a hydrocarbon residue which may have a substituent and R ² is a hydrocarbon residue which may have a substituent; Salts can be produced. The hydrocarbon residue which may have a substituent represented by R ¹ ″ has the same meaning as defined for R ¹ . Halogen represented by X is fluorine, chlorine, bromine and iodine. The reaction is carried out in a solvent that does not adversely influence the reaction. Examples of the solvent include tetrahydrofuran,
Examples thereof include ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and dimethyl sulfoxide. The reaction is under basic conditions (for example, in the presence of potassium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, etc.)
Is preferable. The amount of compound (V ′) to be used is about 1-5 equivalents, preferably about 1.1-2.5 equivalents, relative to 1 equivalent of compound (IV ′). When a base is used, the amount used is about 1-5 equivalents relative to 1 equivalent of compound (IV ′),
It is preferably about 1.1 to 3 equivalents. The reaction temperature is about 1
The temperature is from 0 ° C to the heating reflux temperature, preferably about 20 to 130 ° C. The reaction time is a few minutes to a few days, preferably about 15 minutes to 2
Day.

(D) The hydroxyl group in the molecule can be substituted with various groups. The reaction is carried out in a suitable solvent such as dimethylformamide (DMF), acetonitrile, acetone, etc., in a halide (eg, alkyl halide (eg, propyl iodide, isobutyl iodide, ethyl acetate), aralkyl halide (eg, benzyl chloride). } Is added. The reaction is carried out by stirring the mixture at 0-40 ° C. for 2-18 hours. For example, when ethyl acetate is used, the acetic acid ester obtained is treated with an appropriate solvent and base (eg, 1N NaOH in ethyl alcohol).
Is reacted at room temperature for 2 to 12 hours. The acetic acid compound is dissolved in a suitable solvent {eg, tetrahydrofuran (THF)}, isobutyl chloroformate is added in the presence of a suitable base (eg, triethylamine), and the reaction is conducted at 0 ° C.
For 1 to 4 hours. Suitable amine compound for reaction solution (eg, methylamine, propylamine, piperidine, etc.)
Is added and the reaction is performed at 0 ° C. to room temperature for 1 to 12 hours. In addition,
The compound having a hydroxyl group in the molecule, which is the above-mentioned raw material compound, can be prepared, for example, by subjecting a compound having an alkoxy group in the molecule to acid hydrolysis.
The acid hydrolysis is carried out by adding 1N hydrochloric acid in a commonly used method, for example, a suitable solvent {eg, alcohols (eg, methanol, ethanol)}, and reacting at 0 ° C. to room temperature for 1 to 10 hours.

(E) In the compound (I ') of the present invention, W
A compound in which R ⁴ is an alkanoyl-phenyl group can be produced by introducing an alkanoyl-phenyl group into a compound in which the 6-position is halogenated (eg, WR ⁴ = corresponding to bromine). In order to introduce an alkanoyl-phenyl group, first, a raw material compound having 6-position unsubstituted (corresponding to WR ⁴ = H) is subjected to a halogenation reaction to obtain a halogenated compound. The halogenation is carried out by adding N-bromosuccinimide and a catalytic amount of 2,2′-azobis (isobutyronitrile) and reacting in a suitable solvent (eg, carbon tetrachloride, chloroform).
The reaction is carried out at 100 to 120 ° C. for 1 to 4 hours. Introduction of the alkanoyl-phenyl group is performed in a suitable solvent (eg, dimethoxyethane (DME)). Alkanoyl solution - phenyl borate is added palladium compound _{{example, Pd (PPh 3) 4,} Ph = phenyl} a and sodium carbonate _{(2M, Na 2 CO 3)} . The reaction is carried out under an inert gas stream at room temperature to about 120 ° C. for about 1 to 12 hours. In addition, the production of alkanoyl-phenyl borate is carried out by using alkanoyl-phenyl bromide and a boric acid compound {eg, (i-PrO) ₃ B, Pr = propyl} in the presence of a suitable base (eg, BuLi, Bu = butyl). To do.

(F) W in the compound (I ') of the present invention
The compound in which R ⁴ is an alkyl-phenyl group can be prepared by the same reaction using alkyl-phenyl borate instead of alkanoyl-phenyl borate in the above method (e). Further, the introduction of other groups in the compound of the present invention can be carried out using a method known per se.

(G) In the compound (I ') of the present invention, R ³
A compound in which is an alkoxycarbonyl group can be produced by introducing a cyano group into a raw material compound and then esterifying the obtained compound. The reaction for introducing a cyano group is carried out by dissolving the starting compound in an appropriate solvent (eg, dimethyl sulfoxide (DMSO)), adding sodium cyanate to the solution, and reacting at 40 to 60 ° C. for 2 to 12 hours. The subsequent esterification reaction is carried out using a starting compound and an alcohol solution (eg, ethyl alcohol) in a suitable solvent (eg, ethyl alcohol). Those saturated with hydrochloric acid. ｝ At 80 to 120 ° C. for 12 to 48 hours.

(H) In the compound (I ') of the present invention, R ³
Is of the formula —NH—SO ₂ —R ⁵ (wherein R ⁵ is as defined above)
A compound which is an alkyl group substituted with a group represented by can be halogenated, and then subjected to a nucleophilic substitution reaction with sulfonamides. The halogenation can be accomplished by using N-bromosuccinimide or a catalytic amount of 2,2'-in a suitable solvent (eg, carbon tetrachloride).
Add azobis (isobutyronitrile), add 100-12
The reaction is carried out at 0 ° C. for 1 to 4 hours. The nucleophilic substitution reaction can be carried out under the same conditions as the reaction conditions of the compound (IV ′) and the compound (V ′) shown in the above item (c). For example, sodium hydride and a sulfonamide derivative (eg, methanesulfonamide, ethanesulfonamide, benzenesulfonamide) washed with n-hexane in a suitable solvent {eg, N, N-dimethylformamide (DMF)} are used. In addition, the reaction is performed at 0 to 40 ° C. for 1 to 24 hours.

[0029] (i) compound prepared above (IV ') or (VI) or a salt thereof, subjected to a reaction of converting the R ² to hydrogen, the compound (I' R ² is a hydrogen) Compound (VII) or (VII ′) or a salt thereof can be produced. Examples of the reaction for converting R ² into hydrogen include an alkaline hydrolysis reaction. The hydrolysis reaction is carried out in a solvent that does not adversely affect the reaction of compound (IV ′)
Alternatively, it is carried out by reacting (VI) or a salt thereof with a base. As the solvent, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and dioxane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and dimethylsulfoxide are used.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, and alkali metal carbonates such as potassium carbonate and sodium carbonate. Are used. The amount of the base used is about 1-10 equivalents, preferably about 1.5-5 equivalents, relative to 1 equivalent of compound (IV ′) or (VI). The reaction temperature is about 10 ° C to the boiling point temperature of the solvent used, preferably about 15 to 100 ° C.
The reaction time is a few minutes to a few days, preferably about 15 minutes to 2 days. The compound described in the item (28) can be produced, for example, by subjecting the compound (I ′) in which R ³ is alkoxycarbonyl-methyl as a raw material to the above alkali hydrolysis reaction.

(J) In the compound (I ') of the present invention, R ²
A hydrocarbon group which may be substituted, such as pivaloyloxymethyl or 1- (cyclohexyloxycarbonyloxy) ethyl, is a starting compound (I ′, R ² = H)
And chloride reagents {eg, pivaloyloxymethyl chloride,
1- (cyclohexyloxycarbonyloxy) ethyl-1-chloride or the like} or an acid anhydride compound (eg, pivalic anhydride) in a suitable solvent {eg, dimethylformamide (DMF)} in a suitable base (eg, K ₂ C
O ₃ ) and potassium iodide, the reaction is carried out at 0 to room temperature for 2 to 24 hours.

Raw material compound (I
I ′), (III) and salts thereof can be produced, for example, by the following method A or B. 1. Method A: General formula (VIII)

Embedded image (Wherein R ³ , R ⁴ , R ¹⁴ , W and n have the same meanings as described above) or a salt thereof, or the general formula (VIII ′)

Embedded image (In the formula, R ³ and R ¹⁴ have the same meanings as described above.) A method of reacting a compound or a salt thereof with an isocyanate ester derivative. The isocyanate ester derivative has, for example, the formula R ¹⁴ OOC- (CH ₂ ) n-NCO.
(In the formula, R ¹⁴ and n have the same meanings as described above). The reaction of the compound (VIII), (VIII ') or a salt thereof with an isocyanate derivative does not adversely affect the reaction (eg, tetrahydrofuran, pyridine, dioxane,
Benzene, dichloromethane, 1,2-dichloroethane,
In toluene, xylene) at about 15-130 ° C, preferably about 25-130 ° C. The isocyanate derivative is used in about 1-5 equivalents, preferably about 1.1-2.5 equivalents, relative to 1 equivalent of compound (VIII) or (VIII ').
The reaction time is a few minutes to a few days, preferably about 15 minutes to about 2
Day.

2. Method B: produced by reacting compounds (VIII), (VIII ') and salts thereof with phosgene or its equivalent [eg, triphosgene such as bis (trichloromethyl) carbonate, diphosgene such as trichloromethylchloroformate] An amine [eg, a compound represented by the formula R ¹⁴ OOC- (CH ₂ ) n-NH ₂ (wherein R ¹⁴ and n have the same meanings as described above)] to the isocyanate derivative. Method. Compound (VIII), (VI
II ′) and a salt thereof with phosgene or an equivalent thereof, in a solvent that does not adversely influence the reaction (eg, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform),
It is carried out at about 15 to 130 ° C, preferably about 25 to 130 ° C. Phosgene or its equivalent is compound (VIII)
Alternatively, about 0.5 to 2 equivalents, preferably about 0.9 to 1.1 equivalents are used with respect to 1 equivalent of (VIII '). The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days. The addition reaction of an amine is a solvent that does not adversely influence the reaction (eg, pyridine, tetrahydrofuran, dioxane, benzene,
Dichloromethane, 1,2-dichloroethane, toluene,
Xylene) in about 15 to 130 ° C., preferably about 25 to 130 ° C.
It is carried out at 130 ° C. The amine is used in about 1-5 equivalents, preferably about 1.1-3 equivalents, relative to 1 equivalent of compound (VIII) or (VIII ′). The reaction time ranges from minutes to days,
It is preferably about 15 minutes to about 2 days.

The compound used in the above reaction (VII
I) or its salt can be prepared as follows. A ketone having an active methylene group [eg, formula R ³ —CO—CH ₂ —W
R ⁴ (in the formula, R ³ , R ⁴ and W have the same meanings as described above)] to the method of Karl Gevaert et al., Chem. Ber. 99 . 94-
According to the method described in 100 (1966) (K. Gewald, E. Schinke and H. Bettcher), a cyanoacetic acid ester derivative and sulfur can be reacted to convert to compound (VIII) or a salt thereof. That is, the ketone is added to a cyanoacetic acid ester derivative in the presence of acetic acid and ammonium acetate in a solvent that does not adversely affect the reaction (eg, benzene, toluene, etc.),
After heating to reflux and once forming an alkylidene cyanoacetic acid ester derivative, a solvent that does not adversely affect the reaction in the presence of sulfur and a base (eg, organic base such as triethylamine, ethyldiisopropylamine, dimethylaminopyridine, etc.) (eg, The 2-aminothiophene derivative [compound (VIII)] can be obtained by heating (eg, about 50 to 80 ° C.) in methanol, ethanol or the like). In addition, the compound (VIII ') is obtained by the method of Karl Gewald et al.
Berichte (Chem. Ber.), 98 , 3571-3577 (1965) (K.Gew
ald), Chemiste Berichte (Chem. Ber.), 99 , 271
2-2715 (1966) (K. Gewald and E. Schinke).

The compound of the present invention thus obtained [compound (I), compound (I ') and the compound of the above item (28) are collectively referred to as "the compound of the present invention". ]
As the salt of, a physiologically acceptable acid addition salt is preferable. Examples of such salts include inorganic acids (eg, hydrochloric acid,
Salts with hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid) , Methanesulfonic acid, benzenesulfonic acid, etc.) and the like. Further, when the compound of the present invention has an acidic group such as —COOH, the compound of the present invention is an inorganic base (eg, alkali metal salt or alkaline earth metal salt such as sodium, potassium, calcium, magnesium, ammonia, etc.). Or an organic base (eg,
Trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) to form a salt. The thus-obtained compound of the present invention or a salt thereof can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. Thus, when the compound of the present invention is obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se or It can be converted into an educt or other salt by a similar method. Compounds (II) to (IX)
The same salt as the salt of the compound of the present invention is used as the salt of. When the compound of the present invention or a salt thereof is an optically active substance, it can be separated into a d-form and an l-form by an ordinary optical resolution means.

The compound of the present invention has low toxicity and can be used safely. Since the endothelin antagonist of the present invention has an extremely excellent endothelin antagonistic action,
For example, mammals (eg, rat, mouse, rabbit, cat,
Can be used as an endothelin antagonist for dogs, cows, horses, humans, etc.). Specifically, for example, acute renal failure, myocardial infarction, liver disorder, angina, cerebral infarction, cerebral vasospasm,
As a therapeutic agent for diseases such as hypertension, renal disease, asthma, variant angina, Raynaud's syndrome, pulmonary hypertension, surgical shock, chronic heart failure, arteriosclerosis, cardiac hypertrophy, migraine, etc. of organs (eg, liver) It can be safely used as a prophylactic or therapeutic agent for functional deterioration of organs caused by surgery or transplantation, and as a prophylactic agent for vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA). Especially acute renal failure, myocardial infarction, liver damage,
Organs (eg, liver) for the treatment of hypertension and pulmonary hypertension
It is effective as a prophylactic or therapeutic agent for the functional deterioration of organs caused by surgery or transplantation, and as a prophylactic agent for vascular restenosis after PTCA. Furthermore, the compound of the present invention can be used as a vasoconstriction inhibitor, for example, a cerebrovascular system, coronary artery, coronary vein or pulmonary vasoconstriction inhibitor.

When the compound of the present invention or a salt thereof is administered to, for example, a human, it may be mixed with itself or with a suitable pharmacologically acceptable carrier, excipient, diluent, and orally as a pharmaceutical composition. It can be safely administered parenterally. Examples of the pharmaceutical composition include oral agents (eg, powders, granules, capsules, tablets), injections, drip infusions, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process. The compound of the present invention or a salt thereof is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HOC 60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), a preservative (eg, Methylparaben, propylparaben, benzyl alcohol, etc.), an isotonic agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) with an aqueous injection, vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc. Can be dissolved, suspended or emulsified in to form an oil-based injection, which can be used as an injection.

In order to prepare a preparation for oral administration, the compound (I) or a salt thereof according to the present invention can be prepared by a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, Calcium carbonate, etc., binders (eg,
Starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.)
Etc. are added to the mixture, the mixture is compression-molded, and then, if necessary, coated by a method known per se for the purpose of taste masking, enteric coating or sustainability, to give an oral administration preparation. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm Corporation). Made in Germany, methacrylic acid / acrylic acid copolymerization) and dyes (eg red iron oxide,
Titanium dioxide etc.) is used. In the case of an enteric-coated preparation, it is preferable to provide an intermediate phase between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

As an external preparation, the compound (I) of the present invention or a salt thereof can be made into a solid, semisolid or liquid external preparation according to a method known per se. For example, as the above solid, the compound of the present invention or a salt thereof is used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose). Derivatives, acrylic acid polymers, etc.) are added and mixed to form a powdery composition.
The liquid is almost the same as the injection, and is an oily or aqueous suspension. If it is semi-solid,
Aqueous or oily gels or ointments are preferred. In addition, all of these are pH adjusting agents (eg, carbonic acid,
Phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc., preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) and the like may be added. For example, to make a suppository, according to a method known per se,
The compound (I) of the present invention or a salt thereof can be made into an oily or aqueous solid, semisolid or liquid suppository.
Examples of the oily base used in the above composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) Or vegetable oils (eg sesame oil, soybean oil,
Cottonseed oil). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers and acrylic acid polymers.

The daily dose of the compound of the present invention depends on the degree of symptoms; age, sex, body weight, sensitivity difference of patient; timing of administration,
Interval, property of pharmaceutical preparation, preparation, kind; different depending on kind of active ingredient and the like, but not particularly limited, usually about 0.01 to 10 mg, preferably about 0.03 to 3 mg per kg body weight of a mammal, Preferably about 0.1-1
mg, which is usually administered in 1 to 4 divided doses per day. The compound of the present invention has a particularly high degree of action as an endothelin antagonist. Moreover, it is excellent in oral properties and duration of action.

[0040]

The present invention will be described in more detail with reference to the following examples, but the present invention should not be limited thereto. ¹ H-NMR spectrum was measured using Varian GEMINI 200 (200M) using tetramethylsilane as an internal standard.
Hz) type spectrum meter or Brooker AM-500
Measured with a (500MHz) type spectrometer, total δ
Values are given in ppm. The symbols used below have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dt: double triplet,
m: multilet, br: wide range, J: coupling constant.

Reference Example 1 2-amino-4-methyl-5- (4-methoxyphenyl)
Preparation of thiophene-3-carboxylic acid ethyl ester: 4-
Methoxyphenylacetone (16.5 g, 0.10 mol),
Ethyl cyanoacetate (12.2 g, 0.10 mol), ammonium acetate (1.55 g, 20 mmol), acetic acid (4.6 ml, 8
A mixture of 0 mmol) and benzene (20 ml) was heated to reflux for 24 hours while removing water produced by the Dean Stark apparatus. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was washed with brine dried (MgSO _4), and the solvent was distilled off under reduced pressure. To the resulting residue in ethanol (30 ml) was added sulfur (3.21 g,
0.10 mol) and diethylamine (10.4 ml, 0.10 mol)
Was added, and the mixture was stirred at 50 to 60 ° C. for 2 hours, the reaction solution was concentrated, and the residue obtained was extracted with ethyl acetate. The extract was washed and dried with brine (MgSO _4), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from ether-hexane to give pale yellow plate crystals (11.5 g, 40%). mp: 79-
80 ° C. ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1Hz),
2.28 (3H, s), 3.83 (3H, s), 4.31 (2H, q, J = 7.1Hz),
6.05 (2H, brs), 6.91 (2H, d, J = 8.8Hz), 7.27 (2H, d,
J = 8.8Hz). IR (KBr): 3426, 3328, 1651, 1586, 1550, 1505, 1485
cm ^-1 . FAB-MS m / z: 291 (M ⁺ ).

Reference Example 2 (1). 2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) thieno [2,3-d] pyrimidine-3-
Production of ethyl acetate: 2-amino-4-methyl-5- (4-methoxyphenyl) thiophene-3-carboxylic acid ethyl ester obtained in Reference Example 1 (8.00 g, 2
Ethyl isocyanate acetate (4.54 ml, 40.5 mmol) was added dropwise to a solution of 7.0 mmol) in pyridine (30 ml).
The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was concentrated to dryness, and the obtained residue was partitioned between ethyl acetate and aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, the extracts were combined, washed with brine and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was suspended in ethanol (100 ml), and potassium tert.-butoxide (6.06 g, 5
(4.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid (50 ml) was added to the reaction solution under ice cooling, and ethanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration, washed with water-ethanol, and dried over phosphorus pentoxide under reduced pressure to give a white powder (11.
0 g, 96%) was obtained. As a sample for elemental analysis,
The obtained powder was recrystallized from ethanol to give colorless crystals. mp: 164-165 ° C. (2). Using 2, amino-4-methylthiophene-3-carboxylic acid ethyl ester in the same manner as in Reference Example 2 (1), 2,4 (1H, 3H) -dioxo-5-methylthieno [2,3- d] Pyrimidine-3-acetic acid ethyl ester was obtained. Yield: 94%, amorphous. (3). 2,4 (1H, 3H) -dioxo-5-methylthieno [2,3-d] pyrimidine-obtained in the above item (2)
N-Bromosuccinimide was added to a chloroform solution of 3-acetic acid ethyl ester, and the mixture was refluxed for 2 hours and then 2,4 (1H,
3H) -dioxo-5-methyl-6-bromothieno [2,
3-d] pyrimidine-3-acetic acid ethyl ester was obtained.
Yield: 86%, amorphous.

Reference Example 3 2,4 (1H, 3H) -Dioxo-6- (4-hydroxyphenyl) -5-methylthieno [2,3-d] pyrimidine-
Preparation of 3-acetic acid ethyl ester: Aluminum chloride (2.
90g, 21.7mmol) and methyl disulfide (2.45m)
(2,27.2 mmol) and dichloromethane (60 ml) under ice-cooling, and the compound obtained in Reference Example 2 (2.0 g, 5.34 mmol).
A solution of dichloromethane (40 ml) was added dropwise. 20 at room temperature
After stirring for a period of time, the reaction mixture was poured into ice water, and dichloromethane was distilled off under reduced pressure. The obtained suspension was extracted with ethyl acetate, the extract was washed with brine and dried (MgSO ₄
After that, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a white powder (1.
64 g, 85%) was obtained. As a sample for elemental analysis, the obtained powder was recrystallized from ethyl acetate to give colorless crystals. mp: 240-242 ° C. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7.1H
z), 2.37 (3H, s), 4.15 (2H, q, J = 7.1Hz), 4.59 (2H,
s), 6.85 (2H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.6Hz),
9.73 (1H, s), 12.39 (1H, s). IR (KBr): 3356, 2992, 1720, 1690, 1667, 1611, 1593,
1568, 1537, 1502 cm ^-1 .

Reference Example 4 2,4 (1H, 3H) -Dioxo-6- (4-hydroxyphenyl) -1- (2-methylthiobenzyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid Production of ethyl ester: Compound obtained in Reference Example 3 (0.60 g,
To a solution of 1.66 mmol) in pyridine (8 ml) was added acetic anhydride (3 m
(3, 1.8 mmol) was added and the mixture was stirred at room temperature for 3 hours.
The residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white amorphous substance (0.57 g). Potassium carbonate (0.38 g, 2.75 mmol) and 2-methylthiobenzyl chloride (0.65 g, 4.15 mmol) were added to the obtained dimethylformamide (5 ml) solution of amorafas, and the mixture was stirred at room temperature for 22 hours. The residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white amorphous substance (0.60 g). This amorphous was added to methanol (18 ml) and tetrahydrofuran (12 ml).
Dissolved in a mixed solvent of potassium carbonate (0.313).
g (2.26 mmol) in water (8 ml) was added dropwise. 3 at room temperature
After stirring for 0 minutes, 1N hydrochloric acid (5 ml) was added to the reaction solution under ice cooling.
And extracted with ethyl acetate. The extract was washed and dried with brine (MgSO _4), and the solvent was distilled off under reduced pressure. The residue was crystallized with ether to give colorless crystals (4.33 g, 7
8%). mp: 177-178 ° C. ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2Hz),
2.45 (3H, s), 2.52 (3H, s), 4.28 (2H, q, J = 7.2Hz),
4.87 (2H, s), 5.28 (2H, s), 5.75 (1H, s), 6.78 (2
H, d, J = 8.6Hz), 6.97-7.14 (4H, m), 7.21-7.34 (2H,
m). IR (KBr): 3346, 2978, 1752, 1700, 1651, 1613, 159
1, 1564, 1535, 1481 cm ^-1 .

Reference Example 5 (1). Using the compound obtained in Reference Example 3 and reacting with 2-chloro-6-fluorobenzyl chloride instead of 2-methylthiobenzyl chloride in the same manner as in Reference Example 4, 2,4 (1H , 3H) -Dioxo-6-
(4-Hydroxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester was prepared. Yield: 5
9%, amorphous. (2). Using the compound obtained in Reference Example 2 (3), Reference Example 4
2,4 (1H, 3H) -Dioxo-1- (2-methylthiobenzyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester was prepared in the same manner as described in 1. Yield: 87%, amorphous.

Reference Example 6 2,4 (1H, 3H) -Dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5-
Preparation of methyl thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester: sodium hydride (60% oil; 5
00mg, 12.5mmol) dimethylformamide (20ml)
The compound obtained in Reference Example 4 in a suspension under an ice-cold nitrogen stream.
(2.0 g, 3.7 mmol) of dimethylformamide (30 ml)
The solution was added dropwise. After stirring at the same temperature for 30 minutes, chloromethyl methyl ether (1.0 g, 12.4 mmol) was added dropwise. The reaction solution was stirred at room temperature for 16 hours, and the residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, the extracts were combined, washed with brine and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane to give colorless crystals (1.05 g, 59%). mp: 13
3-134 ° C. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1Hz),
1.43 (3H, t, J = 7.0Hz), 2.49 (3H, s), 3.87 (3H, s),
4.05 (2H, q, J = 7.0Hz), 4.25 (2H, q, J = 7.1Hz), 4.83
(2H, s), 5.24 (2H, s), 6.86-6.94 (4H, m), 7.09-7.
14 (1H, m), 7.22-7.31 (3H, m). IR (KBr): 2984, 1758, 1707, 1665, 1607, 1562, 153
5, 1477 cm ^-1 .

Reference Example 7 Using the compound obtained in Reference Example 5, in the same manner as in Reference Example 6, 2-chloro-6-fluorobenzyl was reacted instead of chloromethyl methyl ether,
2,4 (1H, 3H) -dioxo-6- (4-isobutoxyphenyl) -1- (2-chloro-6-fluorobenzyl)
-5-Methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester was prepared. Yield: 29%, amorphous.

Reference Example 8 2,4 (1H, 3H) -dioxo-5-bromomethyl-
1- (2-methylthiobenzyl) -6- (4-methoxymethoxyphenyl) thieno [2,3-d] pyrimidine-
Production of 3-acetic acid ethyl ester Compound obtained in Reference Example 6 (1.20 g, 2.22 mmol), N
-Bromosuccinimide (0.4 g, 2.25 mmol), α, α '
-A mixture of azobisisobutyronitrile (50 mg) and carbon tetrachloride (50 ml) was heated to reflux for 4 hours. After cooling, the insoluble matter was removed by filtration, and the filtrate was diluted with dichloromethane. The organic layer was washed with brine and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure to give a yellow amorphous substance (2.0 g). ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.2Hz),
2.53 (3H, s), 3.50 (3H, s), 4.26 (2H, q, J = 7.2Hz),
4.80 (2H, s), 4.89 (2H, s), 5.22 (2H, s), 5.36 (2
H, s), 7.00-7.50 (8H, m).

Reference Example 9 2,4 (1H, 3H) -Dioxo-6- (4-methoxyphenyl) -1- (2-methylthiobenzyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid Production of ethyl ester: Compound obtained in Reference Example 2 (2.0 g, 5.3
5 mmol) in dimethylformamide (25 ml), potassium carbonate (1.1 g, 7.98 mmol), potassium iodide (catalytic amount) and 2-methylthiobenzyl chloride (1.2 g, 6.96 mmo)
l) was added and the mixture was stirred at room temperature for 18 hours. The residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography,
A pale yellow amorphous (1.8 g, 66%) was obtained. Crystallization with ether gave colorless crystals. mp: 144-1
45 ° C.

Reference Example 10 2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -using the compound obtained in Reference Example 2 as a starting material and in the same manner as in Reference Example 9. 1- (2-chloro-6
-Fluorobenzyl) -5-methylthieno [2,3-d]
Pyrimidine-3-acetic acid ethyl ester was prepared. Yield: 95%, amorphous.

Reference Example 11 Using the compounds obtained in Reference Examples 9 and 10 as starting materials, the following compound was prepared in the same manner as in Reference Example 8. Compound (1): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-methylthiobenzyl)-
5-Bromomethylthieno [2,3-d] pyrimidine-3
-Acetic acid ethyl ester. Yield: 95%, amorphous. Compound (2): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5-bromomethylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 100%, amorphous. Compound (3): 2,4 (1H, 3H) -dioxo-6- (4-
Isobutoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5-bromomethylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 60%, amorphous.

Reference Example 12 2,4 (1H, 3H) -in the same manner as in Reference Examples 6 and 8.
Dioxo-5-bromomethyl-1- (2-methylthiobenzyl) -6- (4-propoxyphenyl) thieno [2,3
-D] Pyrimidine-3-acetic acid ethyl ester was obtained as an amorphous.

Reference Example 13 2,4 (1H, 3H) -dioxo-5-methyl-1- (2-
Preparation of methylthiobenzyl) -6- (4- (2-methoxyethyl) phenyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester: Reference Example 5 dissolved in 1,2-dimethoxyethane (50 ml). (2) obtained in (2)
(1H, 3H) -Dioxo-6-bromo-5-methyl-1
-(2-Methylthiobenzyl) thieno [2,3-d] pyrimidin-3-yl} acetic acid ethyl ester (1.0 g, 2.
07 mmol), 4- (methoxyethylphenyl) boric acid (1.0 g, 5.56 mmol) and 2M sodium carbonate (5.2 ml, 10.4 mmol) in a mixture of Pd (PP
h ₃ ) ₄ (Ph = phenyl) (358 mg, 0.31 mol) was added under a stream of argon. The mixture was stirred at reflux for 5 hours and filtered through Celite. The furnace liquid was partitioned between ethyl acetate and brine. The aqueous phase was separated and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over MgSO _4, and vacuum dried. The residue is ethyl acetate-n-hexane (1: 5-1:
Silica gel chromatography was performed using 3) to obtain the title compound as a colorless amorphous substance (860 mg, 77).
%). Recrystallization using ethyl acetate-n-hexane gave the title compound (594 mg) as a colorless powder. mp12
6-128 ° C.

Reference Example 14 2,4 (1H, 3H) -dioxo-5-bromomethyl-1-
(2-Methylthiobenzyl) -6- (4- (2-methoxyethyl) phenyl) thieno [2,3-d] pyrimidine-3
-Production of acetic acid ethyl ester: the compound obtained in Reference Example 13 (600 mg, 1.11 mmol), N-bromosuccinimide (198 mg, 1.11 mol) and 2,2'-azobisisobutyronitrile (18 mg, 0). 0.11 mmol) was dissolved in chloroform (30 ml) and refluxed with stirring for 1.5 hours. The mixture was partitioned with dichloromethane and brine. The organic phase was separated, washed with brine, dried over MgSO ₄ , then dried in vacuo to give the title compound as a pale yellow amorphous (730 mg, 44% pure).

Reference Example 15 2,4 (1H, 3H) -Dioxo-6- (4-methoxyphenyl) -1- (2-methylthiobenzyl) -5- (cyanomethyl) thieno [2,3-d] pyrimidine- Production of 3-acetic acid ethyl ester: Compound (0.1%) obtained in Reference Example 11 (1).
67 g, 1.0 mmol) was added to dimethyl sulfoxide (DMSO)
Sodium cyanide (50 mg, 1.0)
mmol) was added and the mixture was stirred at 60 ° C. for 6 hours. After cooling, the reaction solution was poured into ice water (100 ml) and extracted with ethyl acetate (50 ml) and methylene chloride (100 ml, twice). The extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain a pale yellow amorphous substance (0.20 g, 38%). ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.1Hz),
2.52 (3H, s), 3.82 (3H, s), 3.94 (2H, s), 4.25 (2
H, q, J = 7.1Hz), 4.88 (2H, s), 5.38 (2H, s), 6.95
(2H, d), 7.05 (1H, d), 7.17 (1H, t), 7.34 (2H, d),
7.20-7.40 (2H, m) .IR (KBr): 2978, 2254, 1676, 160
7, 1568, 1539, 1483, 1257 cm ^-1 . The compounds shown in the above reference examples are listed in the following [Table 1] and [Table 2].

[0056]

[Table 1]

[0057]

[Table 2]

Example 1 2,4 (1H, 3H) -Dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5-
Preparation of (Methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester: Sodium hydride (60% oil; 60 mg, 1.5 mmol) in dimethylformamide (10 ml) suspension in ice. Reference example 8 under a cold nitrogen stream
The compound obtained in (0.6 g, 1.0 mmol) and methanesulfonamide (0.11 g, 1.2 mmol) were added. The reaction solution was stirred at room temperature for 16 hours, and the residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, the extracts were combined, washed with brine and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give a pale yellow amorphous substance (0.36 g, 59%).
I got ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.1Hz),
2.53 (3H, s), 2.88 (3H, s), 3.48 (3H, s), 4.28 (2
H, q, J = 7.1Hz), 4.37 (2H, d, J = 6.3Hz), 4.85 (2H,
s), 5.19 (2H, s), 5.36 (2H, s), 6.07 (1H, t), 7.0-
7.20 (4H, m), 7.25-7.40 (4H, m).

Example 2 2,4 (1H, 3H) -Dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5-
(Benzenesulfonamidomethyl) thieno [2,3-d]
Production of pyrimidine-3-acetic acid ethyl ester: Reference Example 8
By using the compound (0.6 g) obtained in 1. above and reacting benzenesulfonamide in place of methanesulfonamide by the method described in Example 1, a pale yellow amorphous (0.56 g) was obtained.
g, 83%). ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.34 (3H, t, J = 7.1Hz),
2.52 (3H, s), 3.50 (3H, s), 4.30 (2H, q, J = 7.1Hz),
4.27 (2H, m), 4.82 (2H, s), 5.21 (2H, s), 5.26 (2
H, s), 6.63 (1H, t), 6.97 (1H, d), 7.08 (2H, d),
7.17 (1H, dt), 7.25-7.45 (6H, m), 7.51 (1H, t), 7.
66 (2H, dd), 7.94 (1H, d).

Example 3 Using the compound obtained in Reference Example 8, 11, 12, 13 or 14, the following compound was prepared in the same manner as in Example 1. Compound (1): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-methylthiobenzyl)-
5- (methanesulfonamidomethyl) thieno [2,3-
d] Pyrimidine-3-acetic acid ethyl ester. Yield: 91
%,amorphous. Compound (2): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.
Yield: 33%, amorphous. Compound (3): 2,4 (1H, 3H) -dioxo-6- (4-
Isobutoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 29%, amorphous. Compound (4): 2,4 (1H, 3H) -dioxo-6- (4-
Propoxyphenyl) -1- (2-methylthiobenzyl)
-5- (Methanesulfonamidomethyl) thieno [2,3
-D] pyrimidine-3-acetic acid ethyl ester. Yield: 8
5%, amorphous. Compound (5): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.
Yield: 89%, mp 153-155 ° C. Compound (6): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (propanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.
Yield: 85%, mp 122-123 ° C.

Compound (7): 2,4 (1H, 3H) -dioxo-6- (4-propoxyphenyl) -1- (2-methylthiobenzyl) -5- (isopropanesulfonamidomethyl) thieno [2, 3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 60%, amorphous. Compound (8): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (trifluoromethanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 58%, amorphous. Compound (9): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (isopropanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 93%, amorphous. Compound (10): 2,4 (1H, 3H) -dioxo-6- (4
-Propoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl) thieno [2,
3-d] pyrimidine-3-acetic acid ethyl ester. yield:
84%, mp 132-134 ° C. Compound (11): 2,4 (1H, 3H) -dioxo-6- (4
-(2-Methoxyethyl) phenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl)
Thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 59%, m.p. p. 131-134 ° C.

Example 4 2,4 (1H, 3H) -Dioxo-6- (4-methoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethoxycarbonylmethyl) thieno [2,3-d] Pyrimidine-3
-Production of acetic acid ethyl ester: The compound (0.11 g, 0.21 mmol) obtained in Reference Example 15 was dissolved in ethanol (20 ml), and saturated hydrogen chloride ethanol solution (10.5 N) was added.
(4 ml) was added and the mixture was heated under reflux for 48 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate solution.
(30 ml). The aqueous layer was again ethyl acetate (30 ml)
Extracted. The extracts are combined, washed with brine and dried (M
After gSO ₄ ) the solvent was evaporated under reduced pressure. The obtained residue was crystallized from methanol to give colorless crystals (0.10 g, 84
%). mp: 117-118 ° C. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1Hz),
1.29 (3H, t, J = 7.1Hz), 2.53 (3H, s), 3.82 (3H, s),
3.84 (2H, d), 4.19 (2H, q, J = 7.0Hz), 4.22 (2H, q,
J = 7.1Hz), 4.82 (2H, s), 5.34 (2H, s), 6.89 (2H, s)
d), 7.05 (1H, d), 7.15 (1H, t), 7.25 (2H, d), 7.32
(2H, t).

Example 5 2,4 (1H, 3H) -Dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5-
Preparation of (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid: compound obtained in Example 1
(0.5 g, 0.83 mmol) in tetrahydrofuran (10 ml)
And dissolved in methanol (2 ml) and 1N aqueous sodium hydroxide solution (2 ml) was added. The mixture was stirred at room temperature for 4 hours, 1N aqueous hydrochloric acid solution (2 ml) was added, the reaction mixture was concentrated, and the obtained residue was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, the extracts were combined, washed with brine and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain a pale yellow solid (0.55 g). Recrystallized from ethyl acetate-isopropyl ether to give pale yellow crystals (0.40
g, 76%). mp: 208-209 ° C. ¹ H-NMR (300MHz, DMSO) δ: 2.55 (3H, s), 2.87 (3H,
s), 3.41 (3H, s), 4.30 (2H, s), 4.41 (2H, s), 5.21
(2H, s), 5.24 (2H, s), 6.91 (1H, t), 7.02 (1H, d),
7.11 (2H, d), 7.15 (1H, d), 7.33 (1H, t), 7.42 (2
H, d). The potassium salt of the title compound was prepared by reacting the title compound with potassium carbonate in water and ethanol.

Example 6 2,4 (1H, 3H) -Dioxo-6- (4-isobutoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3- d] Preparation of pyrimidine-3-acetic acid ethyl ester: 2,4 (1H, 3H) -dioxo-6- (4-methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5 obtained in Example 1.
-(Methanesulfonamidomethyl) thieno [2,3-d]
Pyrimidine-3-acetic acid ethyl ester was dissolved in tetrahydrofuran, 1N hydrochloric acid was added, and the mixture was reacted at room temperature for 3 hours,
2,4 (1H, 3H) -dioxo-6- (4-hydroxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid Ethyl ester (0.30 g) was obtained. This was dissolved in 25 ml of dimethylformamide (DMF), isobutyl iodide (0.30 g) and potassium carbonate (0.3 g) were added, and the mixture was reacted at room temperature for 24 hours. The reaction mixture is dried under vacuum, the residue is partitioned between ethyl acetate (50 ml) and aqueous ammonia chloride (30 ml), the organic phase is separated off, N
After drying with a ₂ SO ₄ and vacuum drying, a yellow amorphous substance was obtained. This was chromatographed on silica gel to give the title compound as a yellow amorphous (0.11 mg).

Example 7 Using the compound obtained in Example 1, the following compound was produced in the same manner as in the method described in Example 6. Compound (1): 2,4 (1H, 3H) -dioxo-6- (4-
Carboxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.
Yield: 70%, amorphous. Compound (2): 2,4 (1H, 3H) -dioxo-6- (4-
Allyloxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,
3-d] pyrimidine-3-acetic acid ethyl ester. yield:
84%, amorphous. Compound (3): 2,4 (1H, 3H) -dioxo-6- (4-
Butoxyphenyl) -1- (2-methylthiobenzyl)-
5- (methanesulfonamidomethyl) thieno [2,3-
d] Pyrimidine-3-acetic acid ethyl ester. Yield: 82
%,amorphous. Compound (4): 2,4 (1H, 3H) -dioxo-6- [4-
(2,2,2-trifluoroethoxyphenyl) -1- (2
-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester.

Example 8 2,4 (1H, 3H) -Dioxo-6- (4-methylaminocarbonylmethoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2, Preparation of 3-d] pyrimidine-3-acetic acid ethyl ester: The compound of Example 7 (1) was treated with isobutylchloroform and triethylamine in tetrahydrofuran at 0 ° C.
The reaction was carried out for 3 hours to obtain an acid anhydride. This was reacted with methylamine to obtain the title amide compound. Yield: 100%, amorphous.

Example 9 Using the compound obtained in Reference Example 7, the following compound was prepared in the same manner as in Example 8. Compound (1): 2,4 (1H, 3H) -dioxo-6- (4-
Propylaminocarbonylmethoxyphenyl) -1- (2
-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 95%, amorphous. Compound (2): 2,4 (1H, 3H) -dioxo-6- (4-
Piperazinocarbonylmethoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 66%, amorphous.

Example 10 (1). Pivaloyloxymethyl 2,4 (1H, 3H) -dioxo-6- (4-methoxymethoxyphenyl) -1-
Preparation of (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetate: 2,4 (1H, 3H) -dioxo-6 obtained in Example 5. -(4-Methoxymethoxyphenyl) -1-
(2-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester (0.25 g, 0.413 mmol), potassium carbonate (86 mg, 0.622 mmol) and Potassium iodide (83 mg, 0.50 mmol) was added to dimethylformamide (8 m
l) dissolved in chloromethyl pivalate (72 ml,
0.50 mmol) was added dropwise. After stirring for 22 hours at 0 ° C. to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was separated with ethyl acetate and brine. The aqueous phase was separated and extracted with ethyl acetate. Extracts were combined, washed with brine, dried over MgSO _4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (4: 6).
Elution with -1: 1) gave the title compound as a colorless syrup (0.24g, 80.8%). Ethyl acetate-ether-
Recrystallization from hexane gave the title compound as white crystals (0.203 g, 72.6%). (2). Using the compound obtained in Example 5 as a starting material, the following compound is produced in the same manner as in the method described in Example 10 (1). (R, S) -1- (Cyclohexyloxycarbonyloxy) ethyl 2,4 (1H, 3H)
-Dioxo-6- (4-methoxymethoxyphenyl) -1
-(2-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetate.

Example 11 Using the compound obtained in Example 2, 3, 4, 6, 7, 8 or 9, the following compound is produced in the same manner as in Example 5. Compound (1): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (benzenesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 68%,
mp: 120-125 ° C. Compound (2): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-methylthiobenzyl)-
5- (methanesulfonamidomethyl) thieno [2,3-
d] Pyrimidine-3-acetic acid. Yield: 76%, mp: 20
8-209 ° C. Compound (3): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-methylthiobenzyl)-
5- (Carboxymethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 65%, m
p: 243-245. Compound (4): 2,4 (1H, 3H) -dioxo-6- (4-
Methoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 57%,
amorphous. Compound (5): 2,4 (1H, 3H) -dioxo-6- (4-
Isobutoxyphenyl) -1- (2-chloro-6-fluorobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 30
%,amorphous. Compound (6): 2,4 (1H, 3H) -dioxo-6- (4
-Isobutoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Compound (7): 2,4 (1H, 3H) -dioxo-6- (4
-Propoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 84%,
amorphous. Compound (8): 2,4 (1H, 3H) -dioxo-6- (4
-Butoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 85%,
amorphous. Compound (9): 2,4 (1H, 3H) -dioxo-6- (4
-Propoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. amorphous. Compound (10): 2,4 (1H, 3H) -dioxo-6- (4
-(2-Methoxyethyl) phenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl)
Thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 7
3%, mp: 167-168 ° C.

Compound (11): 2,4 (1H, 3H) -dioxo-6- (4-methoxymethoxyphenyl) -1- (2-
Methylthiobenzyl) -5- (isopropanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 64%, mp: 112-114 ° C. Compound (12): 2,4 (1H, 3H) -dioxo-6- (4
-Methylaminocarbonylmethoxyphenyl) -1- (2
-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. Yield: 58%, amorphous. Compound (13): 2,4 (1H, 3H) -dioxo-6- (4
-Propylaminocarbonylmethoxyphenyl) -1-
(2-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 81%, amorphous. Compound (14): 2,4 (1H, 3H) -dioxo-6- (4
-Piperazinocarbonylmethoxyphenyl) -1- (2-
Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 84%, amorphous. Compound (15): 2,4 (1H, 3H) -dioxo-6-
(4-propoxyoxyphenyl) -1- (2-methylthiobenzyl) -5- (isopropanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 84%, amorphous. Compound (16): 2,4 (1H, 3H) -dioxo-6-
(4-Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl)
Thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 8
0%, mp 125-128 ° C. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.4Hz),
2.53 (3H, s), 2.96 (2H, q, J = 7.4Hz), 3.48 (3H, s), 4.3
5 (2H, d, J = 6.6Hz), 4.92 (2H, s), 5.19 (2H, s), 5.36
(2H, s), 6.05 (1H, t, J = 6.6Hz), 7.01-7.37 (8H, m). IR (KBr): 1702, 1649, 1543, 1487 cm ^-1 Mass spectrum: 620.1 (MH ⁺ ) Compound (17): 2,4 (1H, 3H) -dioxo-6-
(4-Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (propanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 93%, mp 123-124 ° C. Compound (18): 2,4 (1H, 3H) -dioxo-6-
(4-Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (trifluoromethanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid. Yield: 52%, amorphous. Compound (19): 2,4 (1H, 3H) -dioxo-6-
[4- (2,2,2-trifluoroethoxyphenyl)]
-1- (2-Methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-
3-acetic acid.

The compounds shown in the above examples are listed in the following [Table 3], [Table 4] and [Table 5].

[0072]

[Table 3]

[0073]

[Table 4]

[0074]

[Table 5]

Example 12 Compound (100 mg) prepared in Example 1, lactose 1
Using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg,
A tablet is produced by a conventional method.

Example 13 The compound (5 g) prepared in Example 1 is dissolved in distilled water for injection to make a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius) and 2 m in a washed and sterilized vial.
Dispense by l and freeze-dried by standard method to obtain 100mg
/ Produce lyophilized injections of vials.

Example 14 Compound (100 mg) prepared in Example 5, lactose 1
Using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg,
A tablet is produced by a conventional method.

Example 15 The compound (5 g) produced in Example 5 was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius) and 2 m in a washed and sterilized vial.
Dispense by l and freeze-dried by standard method to obtain 100mg
/ Produce lyophilized injections of vials.

Example 16 A tablet is produced by a conventional method using the compound (100 mg) produced in Example 3 (5), 165 mg lactose, 25 mg corn starch, 4 mg polyvinyl alcohol and 1 mg magnesium stearate.

Example 17 The compound (5 g) produced in Example 3 (5) is dissolved in distilled water for injection to make a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml aliquots into washed and sterilized vials, and freeze-dried by a conventional method to obtain 10
0 mg / vial of lyophilized injection is prepared.

Example 18 A tablet is prepared by a conventional method using the compound (100 mg) prepared in Example 11 (16), 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate.

Example 19 The compound (5 g) produced in Example 11 (16) was dissolved in distilled water for injection to make a total volume of 100 ml. 0.22 of this liquid
Aseptic filtration using a μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed into wash-sterilized vials in 2 ml aliquots, freeze-dried by a conventional method,
A lyophilized injection of 100 mg / vial is prepared.

Experimental Example 1 Inhibitory activity test for binding of endothelin to endothelin A receptor expressed by CHO cells: Method: Cells: CHO cells expressing human endothelin A (ET _A ) receptor, that is, ET _A 24 cells. Medium: DMEM 10%, FCS, Gln, amino acid, penicillin, streptomycin. 2 × 10 ⁵ cells / well in 12 wells of a 24-well plate
Cells were seeded in wells (1 ml medium / well). The next day, [ ³ H] arachidonic acid was added to each well at 250 nCi (nanocurie) / ml. The next day, in order to remove unincorporated arachidonic acid and floating cells, 0.5 ml of the medium was added after aspirating the medium using an aspirator, and this operation was repeated again. 3
After leaving still for 0 minutes with a CO ₂ incubator, the medium was quickly replaced. The compound obtained in Example 5 or the compound obtained in Example 11 (16) was diluted with 3.15 × 10 ⁻⁸ M endothelin-1 in a diluting buffer (20 mM Tris, 5 mM).
Mg (AcO) ₂ , 2 mM EGTA, 0.03% NaN ₃ , 0.0.
It was serially diluted with 1% BSA, 0.05% CHAPS), and 10 μl was added to each well (endothelin-1 final concentration 6.3 × 10 ⁻¹⁰ M). Maximum reaction value is 3.15 x 10
^-8 M endothelin-110 μl (final concentration 6.3 × 10 ^-10
Estimated by adding M). The radioactivity without stimulation was estimated by adding a buffer for dilution. After leaving still for 30 minutes in a CO ₂ incubator, the whole medium was collected and the radioactivity derived from the released [ ³ H] arachidonic acid was measured by a liquid scintillation counter. The IC ₅₀ value was calculated by Hill plot from each sample concentration and the relative reaction value. IC ₅₀
The values are the binding amount (B) at the time of adding the sample and the maximum binding amount (B
₀ ) and the amount of non-specific binding (NSB) were measured and calculated according to the following formula, and Percent MaximunBinding (PM
B) was calculated. The concentration giving PMB = 50% is I
It was determined as a C ₅₀ value. PMB = [(B-NSB) / (B 0 -NSB) ] × 10
0

Abbreviations: DMEM: Dulbecco's Modified Eagle Medium. FCS: fetal bovine serum. AcO: acetyloxy EGTA: ethylene glycol bis (2-aminoethyl ether) tetraacetic acid. BSA: Bovine Serum Albumin CHAPS: 3-[(3-chloroamidopropyl) dimethylammonio] -1-propanesulfonate Result: The obtained IC ₅₀ value is shown in the following [Table 6].

[0085]

[Table 6]

Experimental Example 2 Inhibitory activity test for binding of endothelin to endothelin B receptor expressed by CHO cells: Method: Cells: CHO cells expressing human endothelin B (ET _B ) receptor, that is, ET _B 24 cells Medium: DMEM 10%, FCS, Gln, amino acid, penicillin, streptomycin. 2 × 10 ⁺⁵ cells in 12 wells of a 24-well plate
The cells were seeded so that each well had 1 ml medium / well. The next day, [ ³ H] arachidonic acid was added to each well at 250 nCi / ml. The next day, in order to remove unincorporated arachidonic acid and floating cells, 0.5 ml of medium was added after aspirating the medium using an aspirator,
This operation was repeated again. After leaving still for 30 minutes in a CO ₂ incubator, the medium was quickly replaced. Example 5
The compound obtained in Example 11 or the compound obtained in Example 11 (16) was added to a dilution buffer containing 3.15 × 10 ⁻⁸ M endothelin-1 (20 mM Tris, 5 mM Mg (AcO) ₂ , 2 mM E).
GTA, 0.03% NaN ₃ , 0.1% BSA, 0.05
% CHAPS) serially diluted to each well 10 μl
(Endothelin-1 final concentration 6.3 × 10 ⁻¹⁰ M).
The maximum reaction value is 3.15 × 10 ^-8 M endothelin-11
The estimation was performed by adding 0 μl (final concentration 6.3 × 10 ⁻¹⁰ M). The radioactivity without stimulation was estimated by adding a buffer for dilution. After leaving it in the CO ₂ incubator for 30 minutes,
Radioactivity derived from [ ³ H] arachidonic acid released from the whole medium was measured by a liquid scintillation counter. The IC ₅₀ value was calculated by Hill plot from each sample concentration and the relative reaction value. Results: The obtained IC ₅₀ values are shown in the following [Table 7].

[0087]

[Table 7]

Experimental Example 3 Inhibitory activity test on binding between endothelin and endothelin A receptor expressed in porcine heart coronary artery: Method: Remove fat and connective tissue of coronary artery extracted from porcine heart, and remove from vehicle group from adjacent site, A ring specimen with a width of 3 mm was obtained for the drug treatment group. Suspend the sample in a Magnus tube filled with Krebs solution and apply a static tension of 2 g to 1.
Stabilized for 5 hours. Potassium chloride (KCl) (60 mM)
It was shrunk for 10 minutes to obtain the maximum reaction, and then washed and allowed to stand for 1 hour. The compound obtained in Example 5 or the compound obtained in Example 11 (16) or vehicle (H ₂
O) was pretreated (30 minutes) and then endothelin-1 (3n
M) was added and maximum contraction was observed. The contraction rate of endothelin-1 (% KCl) was calculated by setting the contraction of KCl in each sample to 100%. Further, the inhibition rate was calculated from the contraction rate of each drug-treated group with the contraction rate of the vehicle group being 100%. Results: The results obtained are shown in the following [Table 8].

[0089]

[Table 8]

As is clear from [Table 8], in the ring specimen of the porcine coronary artery expressing the ET _A receptor,
ET _A receptor agonist or endothelin-1 (3n
It can be seen that the compound of the present invention suppresses the action of contracting blood vessels (smooth muscle) by M). Thus, the compound of the present invention
It was confirmed to be an _A receptor antagonist.

Experimental Example 4 Inhibitory activity test on binding between endothelin and endothelin B receptor expressed in porcine heart coronary vein method: Method: Fat and connective tissue of coronary vein isolated from porcine heart were removed, and vehicle from adjacent site A ring specimen having a width of 3 mm was obtained for the group and the drug-treated group. The sample was suspended in a Magnus tube filled with Krebs solution, and resting tension was applied for 0.5 hour to stabilize for 1.5 hours. Potassium chloride (KCl) (60m
M) was contracted for 10 minutes to obtain the maximum reaction, and then washed, and then a stable period was maintained for 1 hour. The compound obtained in Example 5 or the compound obtained in Example 11 (16) or vehicle (H ₂ O) was pretreated (30 minutes), and then S6c (1n
M) (S6C: saraphotoxin S6C. Peptide snake venom consisting of 21 amino acids. The structure is similar to endothelin, and its action is a selective agonist for the ET _B receptor), and maximum contraction was observed. The contraction rate of S6c (% KC
1) was calculated. In addition, the contraction rate of the vehicle group is 100
The inhibition rate was calculated from the contraction rate of each drug treatment group as%. Results: The results are shown in the following [Table 9].

[0092]

[Table 9]

As is clear from [Table 9], in the ring preparation of porcine coronary vein expressing the ET _B receptor,
It can be seen that the compound of the present invention suppresses the vascular (smooth muscle) contracting action of the agonist of the ET _B receptor, ie, S6c (1 nM). Thus, it was confirmed that the compound of the present invention is an ET _B receptor antagonist.

Experimental Example 5 Inhibitory activity test on binding between endothelin and endothelin A receptor expressed by insect cell Sf9: Method: A membrane fraction of insect cell Sf9 expressing human endothelin-A receptor was used as an assay buffer [20 mM Tris. -Hydrochloric acid, 2 mM EGTA, 5 mM magnesium acetate 0.1% BSA, 0.03% NaN ₃ 0.5% phenylmailsulfonyl fluoride, 20 μg / m
1 leupeptin, 4 μg / ml E-64 (manufactured by Peptide Laboratories), 1 μg / ml pepstatin (H7.2)], and the insect cell Sf9 membrane fraction expressing human endothelin-A receptor was 1.4 μg. / Ml. 100μ
g / ml was dispensed and 5 nM [ ¹²⁵ I] endothelin-1
(2 μl) was added. A solution of the test compound in dimethylsulfoxide (3 μl) was added, and inating was carried out at 25 ° C. for 60 minutes. Further, in order to measure the maximum binding amount (B ₀ ) and the non-specific binding amount (NSB), a dimethyl sulfoxide solution (3 μl) containing dimethyl sulfoxide (3 μl) or endothelin-1 (10 ⁻⁵ M) was added. The lot was incubated. 0.05% CHAPS-assay buffer (1.5 ml) was added, the mixture was filtered through GF / F glass fiber filter paper (trade name, manufactured by Whatman, UK), and further washed with the same buffer (1.5 ml).
[ ¹²⁵ I] of the filtrate was measured with a γ-counter, and Experimental Example 1
The Percent Maximun Binding (PMB) was determined in the same manner as in. The concentration giving PMB = 50% was determined as the IC ₅₀ value. Results: The IC ₅₀ values for the compounds of the invention are given in the following [Table 1
0].

[0095]

[Table 10]

Experimental Example 6 Inhibitory activity test on binding of endothelin to endothelin B receptor expressed by insect cell Sf9: Method: A membrane fraction of insect cell Sf9 expressing human endothelin-B receptor was used as an assay buffer [20 mM Tris. -Hydrochloric acid, 2 mM EGTA, 5 mM magnesium acetate 0.1% BSA, 0.03% NaN ₃ 0.5% phenylmailsulfonyl fluoride, 20 μg / m
1 leupeptin, 4 μg / ml E-64 (manufactured by Peptide Institute), 1 μg / ml pepstatin (H7.2)], and the insect cell Sf9 membrane fraction expressing human endothelin-B receptor was 1.4 μg. / Ml. 100μ
g / ml was dispensed and 5 nM [ ¹²⁵ I] endothelin-1
(2 μl) was added. A solution of the test compound in dimethylsulfoxide (3 μl) was added, and inating was carried out at 25 ° C. for 60 minutes. Further, in order to measure the maximum binding amount (B ₀ ) and the non-specific binding amount (NSB), a dimethyl sulfoxide solution (3 μl) containing dimethyl sulfoxide (3 μl) or endothelin-1 (10 ⁻⁵ M) was added. The lot was incubated. 0.05% CHAPS-assay buffer (1.5 ml) was added, and the mixture was filtered through GF / F glass fiber filter paper (trade name, manufactured by Watma Ltd., UK) and further washed with the same buffer (1.5 ml). [ ¹²⁵ I] of the filtrate was measured with a γ-counter, and Percent Maximun Binding (PMB) was determined in the same manner as in Experimental Example 1. The concentration giving PMB = 50% was determined as the IC ₅₀ value. Results: The IC ₅₀ values for the compounds of the invention are given in the following [Table 1
1].

[0097]

[Table 11]

[0098]

The thienopyrimidine derivative (I) of the present invention
Has an extremely excellent endothelin antagonism, and therefore, the endothelin antagonist containing the thienopyrimidine derivative of the present invention can be used for acute renal failure, myocardial infarction, liver injury, angina, cerebral infarction, cerebral vasospasm, hypertension, Kidney disease, asthma,
Variant angina, Raynaud's syndrome, pulmonary hypertension, surgical shock, chronic heart failure, arteriosclerosis, cardiac hypertrophy, migraine, etc. as a preventive or therapeutic agent, or prevention of functional deterioration of organs caused by surgery or transplantation of organs Alternatively, it can be advantageously used as a therapeutic agent, as a preventive agent for vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA), and as a contraction inhibitor for cerebral blood vessels, coronary arteries, coronary veins or pulmonary blood vessels.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/505 ABS A61K 31/505 ABS ABU ABU ABX ABX ACD ACD ACS ACS ACV ACV AED AED

Claims (36)

[Claims] 1. A thieno [2, which has in its molecule (1) a carboxyl group which may be esterified and (2) a group capable of forming an anion or a group which can be changed to that (excluding a carboxyl group). 3-d] pyrimidine derivative (I). 2. A group capable of forming an anion or a group capable of changing to an anion is a tetrazolyl group, a sulfonamide group optionally having a substituent, a phosphoric acid group or a sulfonic acid group, which are further alkyl. The derivative according to claim 1, which is a group which may be substituted with a group or an acyl group. 3. A general formula: (In the formula, R ¹ and R ² are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ is a C _1-6 alkoxy-carbonyl group or a formula —NH—SO ₂ —R ⁵ ( wherein the C _1-6 alkyl group R ⁵ has a group represented by halogen showing an optionally substituted C _1-6 alkyl group or a C _6-14 aryl group) as a substituent, R ⁴ is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, W is a bond or an intervening group,
n represents an integer of 1 to 3) or a salt thereof. 4. The compound according to claim 3, wherein the hydrocarbon group represented by R ¹ in the optionally substituted hydrocarbon group is a C _1-20 hydrocarbon group. 5. A C _1-20 hydrocarbon group is C _1-10 alkyl, C
The compound according to claim 4, which is a _3-10 cycloalkyl, C _2-10 alkenyl, C _6-14 aryl or C _7-20 aralkyl group. 6. The compound according to claim 4, wherein the hydrocarbon group represented by R ¹ in the optionally substituted hydrocarbon group is a C _7-20 aralkyl group. 7. A hydrocarbon group which may have a substituent represented by R ¹ , wherein the substituent is (1) halogen, (2) nitro,
(3) cyano, (4) optionally substituted hydroxyl group,
In (5) ^{-S (O) f-R 6} ( wherein, f is an integer of 0 to 2, R
⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group. ), A (6) optionally substituted amino group or (7) optionally substituted oxygen, sulfur,
The compound according to claim 3, which is a 5- or 6-membered heterocyclic group containing 1 to 4 nitrogen heteroatoms. 8. The compound according to claim 3, wherein the substituent in the optionally substituted hydrocarbon group represented by R ¹ is halogen or C _1-4 alkylthio. 9. The compound according to claim 3, wherein the hydrocarbon group represented by R ² which may have a substituent is a C _1-20 hydrocarbon group. 10. A C _1-20 hydrocarbon group is a C _1-10 alkyl group,
The compound according to claim 9, which is a C _3-10 cycloalkyl, C _2-10 alkenyl, C _6-14 aryl or C _7-20 aralkyl group. 11. The compound according to claim 3, wherein the hydrocarbon group represented by R ² which may have a substituent is a C _1-10 alkyl group. 12. A hydrocarbon group which may have a substituent represented by R ² , wherein the substituent is (1) halogen, (2) nitro, (3) cyano or (4) And a hydroxyl group of formula (5) —S (O) f—R ⁶ (in the formula, f represents an integer of 0 to 2 and R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group). A group represented by, (6) optionally substituted amino group or (7) optionally substituted oxygen,
The compound according to claim 3, which is a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms of sulfur and nitrogen. 13. A hydrocarbon group which may have a substituent represented by R ² , wherein the substituent is (1) halogen atom, (2) nitro, (3) hydroxy, (4) cyano, ( The compound according to claim 3, which is 5) C _1-4 alkylthio, (6) C _1-4 alkoxy, (7) C _1-6 alkyl-carbonyloxy or (8) C _3-6 cycloalkyloxy-carbonyloxy. . 14. R ² is a hydrogen atom or C _1-6 alkyl-
The compound according to claim 3, which is a C _1-6 alkyl group which may be substituted with carbonyloxy or C _3-6 cycloalkyloxy-carbonyloxy. 15. R ³ is C _1-6 alkoxy-carbonyl or the formula —NH—SO ₂ —R ⁵ ′ (wherein R ⁵ ′ is a C _1-6 alkyl group or a C _6-14 aryl group. 4. The compound according to claim 3, which is a C _1-6 alkyl group having a group represented by the formula 4) as a substituent. 16. R ³ is of the formula —NH—SO ₂ —R ⁵ (wherein
R ⁵ is claim 3 is a C _1-6 alkyl group as a substituent a group represented by halogen showing an optionally substituted C _1-6 alkyl group or a C _6-14 aryl group) The described compound. 17. R ³ is the formula —NH—SO ₂ —R ⁵ ′ (wherein
R ⁵ 'is C _1-6 alkyl group or a C _6-14 compound of claim 3 wherein the group represented by aryl group shows a) a C _1-6 alkyl group as a substituent. 18. R ⁴ is C which may have a substituent.
_{A 1 to 20} hydrocarbon group or a 5 to 13 membered heterocyclic group optionally having a substituent and having 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
A compound as described. 19. The compound according to claim 3, wherein the hydrocarbon group represented by R ⁴ which may have a substituent is a C _6-14 aryl group. 20. A hydrocarbon group which may have a substituent represented by R ⁴ , wherein the substituent is (1) halogen, (2) nitro,
(3) Cyano, (4) C _1-6 alkoxy, carboxyl, halogen, C _1-6 alkyl-carbamoyl or nitrogen-containing 5
~ 7-membered heterocycle-C optionally substituted with carbonyl
_1-6 alkoxy group, (5) C _7-13 aralkyloxy, (6) C
_1-3 alkoxy optionally substituted C _1-4 alkyl group, (7) C _1-6 alkanoyl group, (8) C _1-4 alkylthio,
The compound according to claim 3, which is (9) C _2-6 alkenyloxy, (10) C _1-6 alkoxy-carbonyl or (11) C _1-6 alkyl-carbamoyl. 21. In the optionally substituted hydrocarbon group represented by R ⁴ , the substituent is (1) C _1-6 alkoxy, (2)
Carboxyl, (3) halogen, (4) C _1-6 alkyl-carbamoyl, (5) halogen or (6) nitrogen-containing 5 to 7-membered heterocycle-a C _1-6 alkoxy group optionally substituted by carbonyl A compound according to claim 3. 22. The intervening group represented by W is (1) C _1-4 alkylene, (2) C _2-6 alkenylene, (3) formula — (CH ₂ ) cNR ⁷ —
[Wherein c represents an integer of 0 to 3 and R ⁷ represents hydrogen or C _1-6 alkyl], (4) -CO-, (5) formula-C
ONR ⁷ - (wherein, R ⁷ is of the same meaning as defined above) a group represented by, (6) -O -, ( 7) formula -S (O) f- (wherein, f is 0
A group represented by the formula (8) -NR ⁷ S
The compound according to claim 3, which is a group represented by (O) e- (in the formula, e represents an integer of 0 to 2 and R ⁷ has the same meaning as described above). 23. The compound according to claim 3, wherein W is a bond. 24. R ¹ is (1) a halogen atom or (2) a benzyl group optionally having a C _1-4 alkylthio group as a substituent, and R ² is hydrogen or C _1-4 alkyl-carbonyloxy. Alternatively, R ³ is a C _1-4 alkyl group which may have C _3-6 cycloalkyl-oxycarbonyloxy as a substituent, and R ³ is (1) a C _1-6 alkoxy-carbonyl group or (2)
A group represented by the formula —NH—SO ₂ —R ⁵ ″ (wherein R ⁵ ″ represents a C _1-3 alkyl group optionally substituted with a halogen atom or a phenyl group) is a substituent. the by which C _1-6 alkyl group optionally having as a, R ⁴ is (1) C _1-6 alkoxy, carboxy, C _1-6 alkyl - carbamoyl, optionally substituted piperazine carbonyl or halogen C _1-4
Alkoxy group, (2) C _7-8 aralkyloxy, (3) C _1-3 optionally substituted alkoxy C _1-4 alkyl, (4) C
_1-6 alkanoyl, (5) C _2-4 alkenyloxy, (6) C _1-6
Alkoxy - carbonyl or (7) C _1-6 alkyl - a compound according to claim 3, wherein respectively a phenyl group substituted with carbamoyl. 25. 2,4 (1H, 3H) -dioxo-6- (4
-Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (methanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid or a salt thereof. 26. 2,4 (1H, 3H) -dioxo-6- (4
-Methoxymethoxyphenyl) -1- (2-methylthiobenzyl) -5- (ethanesulfonamidomethyl) thieno [2,3-d] pyrimidine-3-acetic acid or a salt thereof. 27. 2,4 (1H, 3H) -dioxo-6- (4
-Methoxyphenyl) -1- (2-methylthiobenzyl)
-5- (Methanesulfonamidomethyl) thieno [2,3
-D] Pyrimidine-3-acetic acid or a salt thereof. 28. 2,4 (1H, 3H) -dioxo-6- (4
-Methoxyphenyl) -1- (2-methylthiobenzyl) -5- (carboxymethyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester. 29. A general formula: (Wherein R ¹ , R ² , n and R ⁴ have the same meanings as those in claim 3. R ³ 'represents a halogenated or cyanated C _1-6 alkyl group) or In the case of a compound in which (1) R ³ 'is a halogenated C _1-6 alkyl group, the salt is subjected to a nucleophilic substitution reaction with a sulfonamide, and (2) R ³ ' is cyanated. The method for producing a compound or a salt thereof according to claim 3, wherein the compound having a C _1-6 alkyl group is subjected to an alkali hydrolysis reaction and then an esterification reaction. 30. A pharmaceutical composition comprising the compound according to claim 1, 3 or 28 or a salt thereof. 31. The pharmaceutical composition according to claim 30, which is a vasoconstrictor. 32. The pharmaceutical composition according to claim 31, which is a cerebral blood vessel, coronary artery, coronary vein or pulmonary vasoconstrictor. 33. The pharmaceutical composition according to claim 30, which is an endothelin antagonist. 34. The pharmaceutical composition according to claim 33, which is a therapeutic agent for acute renal failure, myocardial infarction and / or liver injury. 35. The pharmaceutical composition according to claim 33, which is a preventive or therapeutic agent for functional decline of organs caused by surgery or transplantation of organs. 36. The pharmaceutical composition according to claim 35, wherein the organ is the liver.