JP3035745B2 - Condensed thiophene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel thienopyridone derivative having excellent pharmacological action and an intermediate for synthesizing the same.

More specifically, the present invention has a general angiotensin II antagonistic action and a blood pressure lowering action, and is useful as a therapeutic agent for circulatory diseases such as hypertension, heart disease and stroke.

Embedded image And R ² may be the same or different and each represents hydrogen, halogen, cyano, nitro group, acylamino group or an optionally substituted hydrocarbon residue, and R ³ is hydrogen, optionally substituted alkyl Group or formula -CO
D (wherein, D is hydrogen, an alkoxy group, a hydroxyl group, a halogen or an optionally substituted amino group) a group represented by, R ⁴ represents hydrogen, halogen or nitro group, R ⁵ is R ⁶ represents hydrogen or an alkyl group which may be substituted; R ⁷ represents a hydrocarbon residue which may be substituted; A represents phenylene; And the phenyl group is bonded directly or via a spacer having an atomic chain of 2 or less, and n represents an integer of 1 or 2.] or a salt thereof.

[0003]

2. Description of the Related Art The renin-angiotensin system is
Systemic blood pressure, fluid volume, electrolyte balun in combination with sterones
And is involved in homeostatic functions such as Also Renin
Strong relationship between angiotensin system and hypertension
Inhibition of vasoconstrictor angiotensin II converting enzyme
This has been clarified by the development of harmful drugs (anti-ACE drugs). A
Angiotensin II is an angiotensin II receptor on cell membrane
Raises blood pressure via anti-ACE
Treatment of hypertension caused by angiotensin as well as drugs
Can be used for treatment. Many angiotensins II so far
Relatives such as Saralasin [Sar¹, Ile⁸AII etc.
Has strong angiotensin II antagonist activity
It has been tell. However, peptide antagonists are administered parenterally
May have a short duration of action and be ineffective with oral administration
M. A. Ondetti and D. W. Cushman, Ann
ual Reports in Medicinal Chemistry,13, 82-91 (197
8)]. Non-peptide angiotensin II antagonists are disclosed in
71073, JP-A-56-71074, JP-A-57-10774
92270, JP-A-58-157768, JP-A-62-157.
240683, JP-A-63-23868, EP-032
3841 and Japanese Patent Application Laid-Open No. 1-111787.
A. T. Chiu etal., Eur. J. Pharm.,157, 13 (198
8), P.C.Wonget al., J. Pharmcol. Exp.Ther.,twenty four
7, 1 (1988) and P.C.Wong et al., Hypertension,
13, 489 (1989), etc.
One imidazole derivative is disclosed. But
Condensed thiophene derivative antagonizes angiotensin II
It is not known at all to have any use.

[0004]

An object of the present invention is to provide a novel condensed thiophene derivative which has a potent angiotensin II antagonistic action and a blood pressure lowering action and can be put to practical use as a medicament.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have intensively studied a compound having an angiotensin II antagonistic activity and useful as a therapeutic agent for circulatory diseases such as hypertension, heart disease and stroke. The inventors succeeded in producing a fused thiophene derivative having angiotensin II antagonistic activity, further advanced the research, and completed the present invention. That is, the present invention uses the formula

Embedded image And R ² may be the same or different and each represents hydrogen, halogen, cyano, nitro group, acylamino group or an optionally substituted hydrocarbon residue, and R ³ is hydrogen, optionally substituted alkyl R ⁴ represents hydrogen, halogen or an alkenyl group, or a group represented by the formula —C OD (wherein D represents hydrogen, an alkoxy group, a hydroxyl group, a halogen or an amino group which may be substituted). R ⁵ represents a group capable of forming an anion or a group capable of forming an anion; R ⁶ represents hydrogen or an optionally substituted alkyl group or alkenyl group; and R ⁷ represents a substituted group. A represents a hydrocarbon residue which may be bonded, A represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less;
n represents an integer of 1 or 2], or a salt thereof.

With respect to the general formula (I), examples of the halogen as R ¹ and R ² include F, Cl, and Br.

An acylamino group as R ¹ and R ² is
And a group represented by the formula R ⁸ CONH-, wherein R ⁸ represents hydrogen or a hydrocarbon residue. The hydrocarbon residue as R ⁸ is, for example, a lower alkyl group having about 1 to 8 carbon atoms (eg,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pe
Methyl, hexyl, heptyl, octyl, etc.) and lower alkenyl groups having about 2 to 8 carbon atoms (eg, vinyl, allyl (a
llyl), isopropenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-octenyl, etc.) and lower alkynyl groups having about 2 to 8 carbon atoms (eg, ethynyl, 2-ethenyl).
Acyclic hydrocarbon residues such as butynyl, 2-pentynyl and 2-octynyl) or alicyclic hydrocarbon residues having about 3 to 8 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclohexene-) 1-yl,
And cyclic hydrocarbon residues such as aromatic hydrocarbon residues having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.).

The hydrocarbon residue as R ¹ , R ² and R ⁷ is, for example, a lower alkyl group having about 1 to 8 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl). -Butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, etc.), carbon number 2
About 8 lower alkenyl groups (eg, vinyl, allyl (all
yl), isopropenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-octenyl, etc.) and lower alkynyl groups having about 2 to 8 carbon atoms (eg, ethynyl, 2-
Acyclic hydrocarbon residues such as butynyl, 2-pentynyl, 2-octynyl and the like, or alicyclic hydrocarbon residues having about 3 to 8 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclohexene-1) -Il,
And cyclic hydrocarbon residues such as aromatic hydrocarbon residues having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.).

The hydrocarbon residue represented by R ¹ , R ² and R ⁷ is a hydroxyl group, a lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, etc.), a lower (C _1-4 ) alkyl group (eg, , Methyl, ethyl, etc.), halogens (eg, F, Cl, Br, etc.), nitro, optionally substituted amino groups (eg, amino, methylamino, dimethylamino, phenylamino, benzylamino, morpholino, piperidino, Piperazino, N-phenylpiperazino, N- (m-methoxy)
Phenylpiperazino, etc.), acyloxy (eg, lower
(C _1-4 ) alkanoyloxy, benzoyloxy, etc.),
Phenyl (eg, phenyl which may have a substituent such as halogen, nitro, lower (C _1-4 ) alkoxy, lower (C _1-4 ) alkyl at any position on the benzene ring),
Formula -COD 'wherein D' is a hydroxyl group, a lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, etc.) or an optionally substituted amino (eg, amino, methylamino, dimethylamino, phenyl) Amino, benzylamino, morpholino, piperidino, piperazino, N-phenylpiperazino, etc.]]. The hydrocarbon residues represented by R ¹ and R ² may form a ring.

The alkyl group or alkenyl group as R ³ and R ⁶ is a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched. The alkyl group has an unsaturated bond. Such as methyl, ethyl,
Vinyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and the like, wherein the alkyl group is a hydroxyl group, an optionally substituted amino group (eg, amino), a halogen, a lower (C _1-4 ) alkoxy group (Eg, methoxy, ethoxy, etc.), lower (C _1-4 ) alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.) and the like.

Examples of the alkoxy group represented by D in the group represented by the formula —COD as R ³ include a lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, etc.). Examples of the amino group which may be substituted include, for example, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, alkyl is any position on the benzene ring, Phenyl, naphthyl, pyridyl, piperidinyl, piperazinyl, N- which may have a substituent such as halogen, nitro, lower (C _1-4 ) alkoxy, lower (C _1-4 ) alkyl
(N-lower (C _1-4 ) alkylamino and the like which may be substituted with (p-fluoro) phenylpiperazinyl and the like),
N, N-di-lower (C _1-4 ) alkylamino (eg, dimethylamino), N-arylamino (eg, phenylamino), alicyclic amino (eg, morpholino, piperidino,
Piperazino, N-phenylpiperazino and the like).

A compound in which D represents a halogen is useful as a raw material for synthesizing a compound in which D represents an alkoxy group or an amino group which may be substituted.

R ⁴ represents hydrogen, halogen (eg, Cl, Br, etc.) or a nitro group, which may be substituted at the ortho or meta position.

Examples of a group capable of forming an anion as R ⁵ or a group capable of changing to an anion include carboxyl, lower (C _1-4 ) alkoxycarbonyl, cyano, tetrazolyl, trifluoromethanesulfonic acid amide (—NHSO
₂ CF _3), phosphoric acid, sulfonic acid and the like, may be any group capable of converting thereinto or a group capable of forming an anion under biological conditions i.e. under physiological conditions, R ⁵
Is preferably an ortho position.

A compound in which R ⁵ is a group capable of chemically forming an anion or a group capable of being converted to an anion (eg, cyano) is useful as a synthetic intermediate.

A represents that the adjacent phenylene group and phenyl group are bonded directly or via a spacer having an atom chain of 2 or less.
Any linear chain may be used as long as it is a divalent chain having 1 or 2 atoms, and may have a side chain. Specifically, lower (C _1-4 ) alkylene, — (CO) —, —O
-,-(NH)-, -S-,-(CO)-(NH)-, -O-
_{(CH 2) -, - S-} (CH 2) -, - (CH) = (CH) - and the like, such as.

Among the compounds represented by the above formula (I),
formula

Embedded image [Wherein, R ¹ represents lower (C _1-8 ) alkyl, R ³ represents hydrogen or a formula —COD (D is a lower (C _1-4 ) alkoxy group, a hydroxyl group or optionally substituted. Amino group (eg,
Amino, N- lower (C _1-4) alkylamino, N, N- di-lower (C _1-4) alkylamine amino shows a shows a phenylamino, etc.)), in R ⁵ represents a carboxyl or tetra Zoriru] The compounds represented or salts thereof are preferred. Also

Embedded image [Wherein, R ¹ represents lower (C _1-8 ) alkyl; R ⁷ represents hydrogen, an optionally substituted aryl group or an optionally substituted amino (eg, amino, N-lower (C _{1 -4} ) lower (optionally substituted with alkylamino, N, N-di-lower (C _1-4 ) alkylamino, phenylamino, benzylamino, morpholino, piperidino, piperazino, N-phenylpiperazino) A C _1-8 ) alkyl group or a formula COD (where D is lower (C _1-4 ) alkoxy, hydroxyl group, optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino) , N, N-di-lower alkyl (C _1-4 ) amino, phenylamino, benzylamino, etc.), (C _3-8 ) cycloalkyl, optionally substituted aryl group (eg, halogen, etc.), R ⁵ shows the carboxyl or tetrazolyl .] Or a salt thereof is preferred.

The compound of the above general formula (I) can be produced, for example, by the following method. Reaction (a)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , R ⁵ , A, W and n are as defined above. X represents a halogen. Reaction (b)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , A, W and n are as defined above. Reaction (c)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A and n are as defined above. R ⁹ represents a lower (C _1-4 ) alkyl group. Reaction (d)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁹ , A and n are as defined above. R ¹⁰ and R ¹¹ represent a hydrogen or hydrocarbon residue. Reaction (e)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A and n are as defined above. X represents a halogen. Reaction (f)

Embedded image [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ , R ¹¹ , X,
A and n are as defined above. Reaction (g)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , A, W and n are as defined above. R ¹² represents a protecting group. ]

In the above reaction (a), alkylation is carried out by the action of an alkylating agent in the presence of a base. Compound (I
I) 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent are used per 1 mol of dimethylformamide,
The reaction is performed in a solvent such as dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, and ethyl methyl ketone.

Such bases include sodium hydride, t
Using potassium butoxy, cesium carbonate, potassium carbonate and sodium carbonate;

As the alkylating agent, substituted halides (eg, chloride, bromide, iodide, etc.), substituted sulfonic esters (eg, p-toluenesulfonic acid ester, methanesulfonic acid ester, etc.) are used.

The reaction conditions vary depending on the combination of the base and the alkylating agent used, but are usually 1 to 100 ° C. under ice cooling.
It is preferably performed in about 10 hours. In the reaction (b), the cyano group substituted on the benzene ring is reacted with various azides to convert the cyano group into a tetrazole compound (V).

Azide compound 1 per mole of compound (IV)
It is usually used in a solvent such as dimethylformamide, dimethylacetamide, toluene, benzene or the like.

Examples of such azide compounds include trialkyltin or triphenyltin azide, hydrazic acid and salts thereof.

When an organic tin azide compound is used, the reaction is carried out for about 10 to 30 hours while heating and refluxing in toluene or benzene. When reacting hydrazoic acid, sodium azide and ammonium chloride are added to compound (IV) in an amount of 5%.
About 13 times the molar amount of dimethylformamide
The reaction is carried out at about 0 ° C. for about 1 to 10 days. During this time, the reaction is preferably promoted by adding appropriate amounts of sodium azide and ammonium chloride.

The reaction (c) is carried out in the presence of an ester (V
The carboxylic acid (VII) is obtained by hydrolyzing I).

The alkali (1) is added to 1 mole of the compound (VI).
Using about 3 moles, it is usually carried out in a solvent such as an alcohol containing water (methanol, ethanol, methylcellosolve, etc.). As the alkali, sodium hydroxide, potassium hydroxide or the like is used. Further, the reaction conditions are preferably performed at room temperature to about 100 ° C. for about 5 minutes to about 10 hours.

The reaction (d) is carried out by reacting an amine with an ester (VI).
To obtain the amide compound (VIII).

Amines 2 to 5 per mole of compound (VI)
About 0 mol, usually in a solvent such as alcohols (methanol, ethanol, etc.) or without solvent, at room temperature to 20
Heat to 0 ° C.

Examples of such amines include ammonia, alkylamine (eg, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, butylamine, etc.), aralkylamine (eg, benzylamine, phenethylamine, etc.), and arylamine (eg, Aniline, N-methylaniline, etc.) and alicyclic amines (morpholino, piperidino, piperazino, N-phenylpiperazino, etc.).

The reaction (e) is for obtaining an acid halide (IX) from a carboxylic acid (VII) by a halogenating agent.

The halogenated hydrocarbons (eg, CHCl ₃ , CH ₂ Cl ₂ , ClCH ₂ CH ₂ Cl, etc.) are usually used by using about 1 to 5 mol of the halogenating agent per 1 mol of the compound (VII). Ethers (eg, tetrahydrofuran, dioxane, etc.)
And in a solvent such as aromatics (eg, benzene, toluene, etc.).

Examples of the halogenating agent include oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like.

The reaction conditions are room temperature to about 100 ° C.
It is preferable to carry out in about 1 to 10 hours.

In the reaction (f), the acid halide (IX) is reacted with an amine to obtain an amide compound (VIII).

Amines 2 to 5 per mole of compound (IX)
About 0 mol is used, and usually alcohols (eg, methanol,
Ethanol, etc., and ethers (eg, ethyl ether,
(Eg, tetrahydrofuran, dioxane).

Examples of such amines include ammonia, alkylamines (eg, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, butylamine, etc.), aralkylamines (eg, benzylamine, phenethylamine, etc.), and arylamines (eg, Aniline, N-methylaniline, etc.) and alicyclic amines (eg, morpholino, piperidino, piperazino, N-phenylpiperazino, etc.).

In the reaction (g), the compound (V) is obtained by deprotecting the appropriately protected tetrazole derivative (X).

In this reaction, conditions for deprotection vary depending on the protecting group (R ¹² ) used. R ¹² is triphenylmethyl,
In the case of 2-tetrahydropyranyl, methoxymethyl and ethoxymethyl, etc., in a hydroalcoholic solution containing about 0.5N to 2N hydrochloric acid or acetic acid (eg, methanol, ethanol, etc.) or a mixture of trifluoroacetic acid and water : 2-5), it is convenient and convenient to react at room temperature for about 1 to 10 hours.

The compound (I) thus produced from the reaction (a) by the reaction (g) can be separated and purified from the reaction solution by a usual separation and purification means, for example, distillation of the reaction solvent, extraction with water or an organic solvent, concentration, neutralization, It can be easily isolated as crystals or oil by recrystallization, distillation, column chromatography, or the like.

These compounds (I) can be used in the conventional manner in the form of salts with physiologically acceptable acids or bases, for example, salts with inorganic acids such as hydrochloride, sulfate, nitrate, etc. It can be led to salts with organic acids such as salts, succinates and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts.

Among these compounds, the starting compound (II) is, for example, (1) P. Blaszkiewicz, H. Vorbruggen and HJ Kesle
r (Schering AG): DOS 2, 447,477 (15.4.76); Chem. Abs
t., 85, 46627 (1976) (2) Y. Kuwada, K. Meguro, Y. Sato and T. Fugono (T
akeda Chem.): DOS 2,435,025 (6.25.75); Chem. Abst.,
82, 156252 (1975) or a method analogous thereto.

Among the starting compound (III), the compound (IIIa) wherein n is 1 is described in JP-A-63-23868 and JP-A-Hei.
Compound (X), which is obtained by the method described in JP-117876 and EP-0323841 and is commercially available or synthesized by a method known in the literature, is prepared according to reaction (h).
For example, AA Vansheidt et al., Khim. Nauka i Pro
m., 2 , 799 (1957) and the like, and can be easily obtained by halogenomethylation according to the method described in, for example, M., 2 , 799 (1957). Reaction (h)

Embedded image [Wherein the symbols are as defined above. ]

Further, among the starting compounds (III), n
Is a compound (IIIb) obtained by reacting the compound (IIIa) according to the reaction (i). Reaction (i)

Embedded image [Wherein the symbols are as defined above. ]

The compound (I) and the salt thereof thus produced are low toxic, strongly suppress the vasoconstriction and blood pressure increasing effects of angiotensin II, and are useful for animals, particularly mammals (eg, humans, dogs, rabbits, rats, etc.). It has an antihypertensive effect on the blood and is useful not only as a therapeutic agent for hypertension but also as a therapeutic agent for cardiovascular diseases such as heart disease and stroke. When used as such a medicament, compound (I) or a salt thereof is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and is used as a powder, granule, tablet, capsule, or injection. And can be administered orally or parenterally.

The dosage varies depending on the target disease, symptoms, administration target, administration method, and the like. When administered as a therapeutic agent for essential hypertension in adults, the daily oral dose is about 10 to 10 days.
It is preferable to administer a daily dose of about 5 to 50 mg in two or three divided doses of 100 mg or intravenously.

[0047]

EXAMPLES The present invention will be described in more detail with reference to Examples, Preparation Examples, Experimental Examples and Reference Examples below, but it goes without saying that these do not limit the present invention.

Reference Example 1 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid isobutyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid (200 mg, 0.9 mmol) and boron trifluoride ethyl ether (47%) (0.5 ml) were added to isobutyl alcohol (10 ml), and the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was concentrated to dryness, and the obtained residue was purified by flash column chromatography using silica gel. Chloroform / ethyl acetate
80 mg (31%) of the title compound as colorless crystals eluted with (3: 1)
Obtained. Melting point: 156-158 ° C IR (KBr) cm ^-1 : 1700, 1595, 1520 NMR (CDCl ₃ ) δ: 1.05 (6H, d, J = 6.6 Hz), 1.40 (3H, t, J = 7.4H)
z), 2.0-2.2 (1H, m), 2.94 (2H, q, J = 7.4,15.0Hz), 4.20 (2H,
d, J = 6.6Hz), 7.16 (1H, s), 8.84 (1H, s) Elemental analysis: C ₁₄ H ₁₇ NO ₃・ H ₂ O Calculated: C, 63.38; H, 5.70; N, 15.84 Values: C, 63.70; H, 5.44; N, 15.50

Reference Example 2 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid 2-methoxyethyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid (380 mg, 1.7 mmol) and DMF (0.13 ml, 1.7 mmol) were added to benzene (5 ml) and heated to 60 ° C., to which thionyl chloride (0.15 ml, 2.1 mmol) was added. After stirring the reaction solution at 60 ° C. for 3 hours, the mixture was cooled in an ice bath, and the deposited precipitate was collected by filtration and washed with benzene. The resulting precipitate (223 mg) 2-methoxyethanol (0.3 ml) and dissolved in a mixture of CH ₂ Cl ₂ (5ml), was stirred added thereto under ice-cooling triethylamine (0.7 ml) 30 min. The reaction solution was poured into chloroform, washed with 1N hydrochloric acid, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography using silica gel. Elution with ethyl acetate / hexane / chloroform (1: 1: 1) followed by chloroform / methanol (9: 1) gave 200 mg (41%) of the title compound as a colorless powder. IR (KBr) cm ^-1 : 1700, 1590, 1530, 1480 NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.4 Hz), 2.94 (2H, q, J = 7.4, 1
5.0Hz), 3.45 (3H, s), 3.7-3.8 (2H, m), 4.5-4.6 (2H, m), 7.17
(1H, s), 8.87 (1H, s) Elemental analysis: C ₁₃ H ₁₅ NO ₄ S Calculated: C, 55.50; H, 5.37; N, 4.98 Found: C, 55.47; H, 5.38; N, 4.95

Reference Example 3 2-Ethyl-4-hydroxy-3-nitrothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5 −
Carboxylic acid ethyl ester (1.0 g, 4.0 mmol) was added to concentrated sulfuric acid (1
0ml) was cooled to -5 ° C, and a solution of sodium nitrate (370mg, 4.3mmol) dissolved in concentrated sulfuric acid (5ml) was added dropwise. The reaction solution was stirred at -3 ° C to -5 ° C for 1 hour, poured into ice water, and the deposited precipitate was collected by filtration, and washed with cold water and then with ethanol. The obtained precipitate was dissolved in chloroform, washed with saturated saline, and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow solid was washed with a mixed solvent of ether / hexane and dried to obtain 960 mg (81%) of the title compound. Mp: 194-201 ℃ ^{(decomposition) IR (KBr) cm -1:} 1700,1600,1590,1530 NMR (CDCl 3) δ: 1.42 (3H, t, J = 7.4Hz), 1.47 (3H ,, t, J = 7.2H
z), 3.05 (2H, q, J = 7.4,15.0Hz), 4.50 (2H, q, J = 7.2,14.4H
z), 8.93 (1H, s ) Elemental _{analysis: C 12 H 12 N 2 O} 5 S Calculated: C, 48.64; H, 4.08 ; N, 9.45 Found: C, 48.48; H , 4.01; N, 9.28

Reference Example 4 2-ethyl-7-[[2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxylic acid ethyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid ethyl ester (1.00 g, 4 mmol) in DMF (20 ml)
And oily sodium hydride (60%) (160 mg) was added thereto, followed by stirring for 10 minutes. To this was added 4- [2 ′-(N-triphenylmethyltetrazol-5-yl) phenyl] benzyl bromide (2.23 g, 4 mmol), and the mixture was heated with stirring at 90 ° C. for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained residue was purified by flash column chromatography using silica gel. Elution with ethyl acetate / dichloromethane (1: 1) gave 2.24 g (77%) of the title compound as colorless crystals. Melting point: 195-198 ° C IR (KBr) cm ^-1 : 1730, 1705, 1620 NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 9.6 Hz), 1.39 (3H, t, J = 6.8H)
z), 2.72 (2H, q, J = 8.9,15.0Hz), 4.38 (2H, q, J = 7.2,13.8H
z), 5.02 (2H, s), 6.80-8.0 (9H, m), 8.29 (1H, s) Elemental analysis: C ₄₅ H ₃₇ N ₅ O ₃ S Calculated: C, 74.26; H, 5.12; N , 9.62 Found: C, 74.09; H, 5.18; N, 9.50

The following compound (II) can be prepared by known methods, for example, (1) P. Blaszkiewicz, H. Vorbruggen and HJ Kesle
r (Schering AG): DOS 2,447, 477 (15.4.'76); Chem. Ab
st., 85, 46627 (1976), (2) Y. Kuwada, K. Meguro, Y. Sato and T. Fugono (Ta
keda Chem.): DOS 2, 435,025 (6.25.'75); Chem. Abs
t., 82, 156252 (1975), (3) RK Russell, JB Press, RA Rampulla, J.
J. McNally, R. Falotico, JA Keiser, DA Brig
ht and A. Tobia, J. Med. Chem., 31 , 1786 (1988), (4) M. Sugiyama, T. Sakamoto, K. Tabata, K. Endo,
K. Ito, M. Kobayashi and H. Fukumi, Chem. Pharm. B
ull., 37 , 2091 (1989), (5) M. Sugiyama, T. Sakamoto, K. Tabata and H. Fuk
umi, Chem. Pharm. Bull., 37 , 2717 (1989), (6) GD Madding and MD Thompson, J. Heterocyc
lic Chem., 24 , 581 (1987), (7) J. Barker, PR Huddleston and D. Holmes, J.
Chem. Research (S), 1985 , 214, (8) J. Barker, PR Huddleston and D. Holmes, J.
Chem. Research (S), 1986, 122, (9) MA Khan and AE Guarsoni, J. Heterocyclic
Chem., 14 , 807 (1977), (10) K. Ogawa, I. Yamawaki, Y. Matsusita, N. Nomur
a, and I. Okazaki, WO89 / 02432 or by a method similar to Reference Example 1, 2 or 3.

[Table 1]

[Table 2] The following compounds (Reference Examples 18-32) were synthesized in the same manner as in Reference Example 4.

[Table 3] The following compounds (Reference Examples 33-40) were synthesized in the same manner as in Reference Example 4.

[Table 4]

Example 1 A: 2-Ethyl-7-[(2'-cyanobiphenyl-4-yl) methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic Acid ethyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid ethyl ester (250 mg, 1 mmol), 4- (2'-
(Cyanophenyl) benzyl chloride (250 mg, 1.1 mmol) with N,
It was dissolved in N-dimethylformamide (DMF) (5 ml), potassium carbonate (150 mg) was added thereto, and the mixture was stirred at 90 ° C. for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained residue was purified by flash column chromatography using silica gel. Elution with ethyl acetate / dichloromethane (1: 1) gave 254 mg (60%) of the title compound as crystals. NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 6 Hz), 1.39 (3H, t, J = 6 Hz), 2.8
1 (2H, q, J = 6,15Hz), 4.40 (2H, q, J = 6,13.5Hz), 5.27 (2H, s),
7.25-8.0 (9H, m), 8.37 (1H, s) B: 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester and 2-ethyl-7-[[2 '-(1H-tetrazole- 5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid The compound obtained in Example 1A (250 mg, 0.59 mmol), sodium A solution of azide (390 mg, 5.9 mmol) and ammonium chloride (300 mg, 5.9 mmol) in DMF (15 ml) was stirred at 110 ° C. for 10 days. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained residue was purified by flash column chromatography using silica gel. Elution with chloroform / methanol (9: 1) gave 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno. 37 mg (13%) of pale yellow powder of [2,3-b] pyridine-5-carboxylic acid ethyl ester was obtained. IR (KBr) cm ^-1 : 1720,1600,1550,1505 NMR (CD ₃ OD) δ: 1.31 (3H, t, J = 7.6Hz), 1.36 (3H, t, J = 7.0H)
z), 2.85 (2H, q, J = 7.6,15.0Hz), 4.33 (2H, q, J = 7.0,14.2H
z), 5.45 (2H, s), 7.15 (2H, d, J = 8.6 Hz), 7.21 (1H, s), 7.28 (2
H, d, J = 8.6 Hz), 7.5-7.7 (4H, m), 8.75 (1 H, s), and further eluted with chloroform / methanol (9: 1) to give 2-ethyl-7-[[2 '-( 7 mg (2.7%) of a 1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid] colorless solid was obtained. IR (KBr) cm ^-1 : 1650, 1605, 1580, 1540, 1505 NMR (CD ₃ OD) δ: 1.34 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 8.6, 1
5.0Hz), 5.47 (2H, s), 7.15 (2H, d, J = 8.2Hz), 7.24 (1H, s), 7.
28 (2H, d, J = 8.2Hz), 7.5-7.7 (4H, m)

Example 2 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b Pyridine-5-carboxylic acid ethyl ester The compound (727 mg, 1 mmol) obtained in Reference Example 4 was added to a solution (20 ml) of trifluoroacetic acid / water (1: 3), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained residue was purified by flash column chromatography using silica gel. Elution with chloroform / methanol (9: 1) gave 1.28 g (86%) of colorless crystals of the title compound. This product was identified by comparing the compound obtained in Example 1B with NMR and IR spectra. Melting point: 161-164 ° C Elemental analysis: C ₂₆ H ₂₃ N ₅ O ₃ S ・ H ₂ O Calculated: C, 62.01; H, 5.00; N, 13.91 Found: C, 62.05; H, 4.59; N, 13.78 The compounds listed in Table 5 were prepared in the same manner as in Example 2.

[Table 5]

Example 10 2-Ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b ] Pyridine-5-carboxylate 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3- b] Pyridine-5-carboxylic acid ethyl ester (600 mg, 1.235 mmol) was added to a 1N sodium hydroxide solution (6 m
l) and stirred under heating at 100 ° C. for 20 minutes. After cooling, add 1
An N hydrochloric acid solution (7 ml) was added, and the mixture was extracted with chloroform. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained crystals were washed with dichloromethane and dried to obtain 550 mg of colorless crystals of the title compound. This product was identified by comparing the compound obtained in Example 1B with NMR and IR spectra. Melting point: 153-157 ° C Elemental analysis: C ₂₄ H ₁₉ N ₅ O ₃ S ・ 3.5H ₂₀ Calculated: C, 55.38; H, 5.03; N, 13.48 Found: C, 54.75; H, 3.93; N , 13.15

Example 11 A: 2-Ethyl-7-[(2'-t-butoxycarbonylbiphenyl-4-yl) methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine- 5-carboxylic acid ethyl ester 2-ethyl-4-hydroxythieno [2,3-b] pyridine-5-
Carboxylic acid ethyl ester (200 mg, 0.8 mmol), 4- (2-
(t-butoxycarbonylphenyl) benzyl bromide (300
mg, 0.9 mmol) and cesium carbonate (650 mg, 2.0 mmol) in DMF (10 m
In addition to l), the mixture was stirred at 60 ° C for 3 hours and at 100 ° C for 1 hour. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with water, dried (MgSO ₄ ) and concentrated to dryness. The obtained residue was purified by flash column chromatography using silica gel to obtain 258 mg (62%) of crystals of the title compound. IR (KBr) cm ^-1 : 1720,1705,1690,1510 NMR (CDCl ₃ ) δ: 1.20 (9H, s), 1.32 (3H, t, J = 7.6Hz), 1.41 (3
H, t, J = 7.2Hz), 2.81 (2H, q, J = 7.6,14.6Hz), 4.40 (2H, q, J =
7.2,14.2Hz), 5.23 (2H, s), 7.2-7.5 (8H, m), 7.81 (1H, dd, J =
1.6,7.6Hz), 8.42 (1H, s ) Elemental analysis: C ₃₀ H ₃₁ NO ₅ S Calculated: C, 69.61; H, 6.04 ; N, 2.71 Found: C, 69.85; H, 6.15 ; N, 2.37 B: 2-ethyl-7-[(2'-carboxybiphenyl-4-yl) methyl] -4-oxo-4,7-dihydrothieno [2,3-b]
Pyridine-5-carboxylic acid ethyl ester The compound obtained in Example 11A (200 mg, 0.39 mmol) and anisole (0.1 ml) were added to trifluoroacetic acid (5 ml) under ice cooling to give 2.5%.
Stir for hours. The reaction solution was concentrated to dryness under reduced pressure, dichloromethane was added to the residue, and the solvent was distilled off under reduced pressure. This operation was performed twice more, ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain 167 mg (93%) of a pale yellow powder of the title compound. IR (KBr) cm ^-1 : 1715,1680,1605 NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J = 7.4 Hz), 1.29 (3H, t, J = 7.2H)
z), 2.80 (2H, q, J = 7.4, 15.0Hz), 4.23 (2H, q, J = 7.2, 13.8H
z), 5.49 (2H, s), 7.11 (1H, s), 7.3-7.6 (7H, m), 7.73 (1H, d, J
= 7.4Hz), 8.77 (1H, s) Elemental analysis: C ₂₆ H ₂₃ NO ₅ S ・ 0.3H ₂ O Calculated: C, 66.88; H, 5.09; N, 3.00 Actual: C, 67.03; H, 5.14; N, 2.95

Example 12 2-Ethyl-5- (N-benzylcarbamoyl) -7-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-
b] pyridine Compound obtained in Example 2 (123 mg, 0.25 mmol)
l) and benzylamine (2 ml) were stirred at 60 ° C for 3 days.
After cooling, pour the reaction mixture into chloroform, wash twice with 1N hydrochloric acid,
It was dried (MgSO ₄ ) and concentrated, and the obtained residue was purified by flash column chromatography on silica gel. Elution with chloroform / methanol (19: 1 to 9: 1) gave 63 mg (45%) of the title compound as crystals. Melting point: 177-180 ° C IR (KBr) cm ^-1 : 1650, 1590, 1550, 1500 NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7.4 Hz), 2.83 (2H, q, J = 7.4,
14.2Hz), 4.56 (2H, d, J = 5.8Hz), 5.57 (2H, s), 7.0-7.7 (14H,
m), 8.95 (1H, s) Elemental analysis: C ₃₁ H ₂₆ N ₆ O ₂ S Calculated: C, 68.11; H, 4.79; N, 15.37 Found: C, 68.06; H, 4.79; N, 15.17 The compounds listed in Table 6 were prepared in the same manner as in Example 12.

[Table 6]

Example 17 3-Acetylamino-2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [ 2,3-b] Pyridine-5-carboxylic acid ethyl ester 2-ethyl-3-nitro-7-[[2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]- 4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester (200 mg, 0.26 mmol) was treated with acetic anhydride (6 ml), acetic acid (6 ml), dioxane (4 ml) and tetrahydrofuran (5 ml). ) And heated to 70 ° C,
To this was added zinc dust (85 mg) and stirred for 2 hours. The filtrate obtained by filtering off insolubles was concentrated under reduced pressure. The obtained oil was dissolved in a mixture of trifluoroacetic acid (8 ml) and water (1 ml) and stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with water, dried (MgSO ₄ ), concentrated to dryness, and the obtained residue was purified by flash column chromatography using silica gel. Elution with chloroform / methanol (20: 1) gave 59 mg of the title compound as colorless crystals (4
2%). Melting point: 163-166 ° C IR (KBr) cm ^-1 : 1720,1700, 1615, 1550, 1510 NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.4 Hz), 1.29 (3H, t, J = 7.0H
z), 2.03 (3H, s), 2.63 (2H, q, J = 7.4,15.0Hz), 4.23 (2H, q, J =
7.0, 14.2Hz), 5.45 (2H, s), 7.13 (2H, d, J = 8.2Hz), 7.28 (2H,
d, J = 8.2Hz), 7.5-7.7 (4H, m), 8.74 (1H, s), 9.66 (1H, bs) Elemental _{analysis: C 28 H 26 N 6 O} 4 S · H 2 O Calculated: C, 59.99; H, 5.03; N, 14.9.
9 Observed value: C, 59.50; H, 4.56; N, 14.76 The following compounds (Examples 18 to 20) were synthesized in the same manner as in Example 2.

[Table 7] The following compounds (Examples 21 to 36) were synthesized in the same manner as in Example 12.

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

Formulation Examples When the compound (I) of the present invention is used as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke, it can be used, for example, by the following formulation. 1. Capsules (1) 2-Ethyl-7-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3- b] Pyridine-5-carboxylic acid ethyl ester 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg One of (1), (2), (3) and (4) After mixing, granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 2. Tablets (1) 2-Ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3- b] Pyridine-5-carboxylic acid ethyl ester 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg (1), (2), (3), After mixing 2/3 of (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets. 3. Injection (1) 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3- b] pyridine-5-carvone
Sodium acid ethyl ester 10mg (2) Inosit 100mg (3) Benzyl alcohol 20mg 1 ampule 130mg Dissolve (1), (2), (3) in distilled water for injection to make a total volume of 2ml and enclose in an ampoule. . All steps are performed under aseptic conditions.

Experimental Example 1 Angiotensin-II binding inhibitory effect on angiotensin receptor [Experimental method] The method of Douglas et al. [Endocrinology, 102 , 685]
-696 (1978)] to modify angiotensin II (A-II)-
Receptor binding inhibition experiments were performed. A from bovine adrenal cortex
A -II receptor membrane fraction was prepared. Compound of the present invention (10 ^-9
−3 × 10 ⁻⁵ M) and ¹²⁵ I-angiotensin-II (
¹²⁵ I-AII) (1.85 kBq / 50 μl) was added to the receptor membrane fraction and incubated for 1 hour at room temperature. A bond with a free ¹²⁵ I-A-II filter (Whatman GF / Bfilter)
And the radioactivity of ¹²⁵ IA-II bound to the receptor was measured. [Experimental results] The experimental results of the compound of the present invention are shown in Table 19.

Experimental Example 2 Inhibitory effect of the compound of the present invention on A-II pressor response [Experimental method] Jcl: SD rats (9 weeks old, male) were used. The day before the experiment,
Under pentobarbital Na anesthesia, the femoral artery and vein were placed with an indwelling cannula and kept under fasting and free access to water until immediately before the experiment. On the day of the experiment, the arterial cannula was connected to a blood pressure transducer and the mean blood pressure was recorded on a polygraph. Prior to drug administration, control A-II (100 ng)
/ Kg) by intravenous administration. The drug was orally administered, and then A-II was intravenously administered at each measurement point. Similarly, the pressor response was determined and the response before and after drug administration was compared to determine the inhibition rate. [Experimental results] The experimental results of the compound of the present invention are shown in Table 19.

[0062]

[Table 19] Example AII binding inhibitory action Antihypertensive action IC ₅₀ (μM) 30 mg / kg, po ──────────────────────────── 2 0.05 NT * ^a 3 0.07 NT 4 0.20 NT 5 0.05 NT 6 0.09 NT 7 0.17 NT 8 0.01 NT 10 0.04 ++ * ^b 11 0.21 NT 12 0.06 ++ 13 0.02 NT 14 0.13 NT 15 0.05 NT 160 .12 ++ 20 0.67 NT 21 0.25 ++ 23 0.17 ++ 24 0.19 ++ 25 0.78 ++ 26 0.21 ++ 28 0.22 + 29 0.12 ++ 30 0.02 ++ ────────────────────────── * ^a NT; not measured * ^b (% Inhibition) ++ ≧ 70%> + ≧ 50%

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/12 A61P 9/12 43/00 116 43/00 116 (56) References JP-A-2-225485 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 495/04 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] [Chemical Formula 1] And R ² may be the same or different and each represent a hydrogen, a halogen, a cyano, a nitro group, an acylamino group or a hydrocarbon residue which may be substituted, and R ³ may be hydrogen or a substituent; An alkyl group optionally having an unsaturated bond or a compound of the formula -COD (where D is hydrogen,
An alkoxy group, a hydroxyl group, a halogen or an optionally substituted amino group), R ⁴ represents a hydrogen, a halogen or a nitro group, and R ⁵ represents a group capable of forming an anion or R ⁶ represents a hydrogen or an optionally substituted alkyl group which may have an unsaturated bond; R ⁷ represents an optionally substituted hydrocarbon residue; Represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n represents an integer of 1 or 2.] or a salt thereof. 2. R ¹ and R ² are each (1) hydrogen,
(2) halogen, (3) cyano, (4) nitro group,
(5) Formula R ⁸ CONH— wherein R ⁸ is hydrogen and has 1 to 1 carbon atoms.
A lower alkyl group having 8 carbon atoms, a lower alkenyl group having 2 to 8 carbon atoms, a lower alkynyl group having 2 to 8 carbon atoms, an alicyclic hydrocarbon residue having 3 to 8 carbon atoms, or an aromatic hydrocarbon having 6 to 12 carbon atoms Indicates a residue] or (6) (a) hydroxyl group, (b) lower
(C _1-4 ) alkoxy group, (c) lower (C _1-4 ) alkyl group,
(D) Halogen, (ho) nitro, (he) amino, (to) methylamino, (thi) dimethylamino, (li) phenylamino, (nu)
Benzylamino, (ru) morpholino, (o) piperidino,
(W) piperazino, (f) N-phenylpiperazino, (yo) N
-(M-methoxy) phenylpiperazino, (t) lower (C
_1-4 ) Alkanoyloxy, (le) benzoyloxy, (so)
Halogen, nitro, lower at any position on the benzene ring
Phenyl which may have a substituent selected from (C _1-4 ) alkoxy and lower (C _1-4 ) alkyl, and (Z) a compound of the formula —COD ′ wherein D ′ is a hydroxyl group, a lower ( C _1-4 ) represents an alkoxy group, amino, methylamino, dimethylamino, phenylamino, benzylamino, morpholino, piperidino, piperazino, or N-phenylpiperazino]. (I) a lower alkyl group having 1 to 8 carbon atoms, (ii) a lower alkenyl group having 2 to 8 carbon atoms, and (iii) a 2 to 8 carbon atoms.
A lower alkynyl group, (iv) an alicyclic hydrocarbon residue having 3 to 8 carbon atoms or (v) an aromatic hydrocarbon residue having 6 to 12 carbon atoms, wherein R ³ is (1) hydrogen, (2) ) (A) hydroxyl group,
It may have a substituent selected from (b) amino, (c) halogen, (d) lower (C _1-4 ) alkoxy and (e) lower (C _1-4 ) alkoxycarbonyl (i ) 1 to 1 carbon atoms
A lower alkyl group of 8 or (ii) a lower alkenyl group having 2 to 8 carbon atoms, or (3) a formula -COD (where D is (a) hydrogen, (b) a lower (C _1-4 ) alkoxy group, (C)
Hydroxyl group, (d) halogen, (e) amino, (f) halogen, nitro, lower (C _1-4 )
The alkyl moiety has a substituent selected from phenyl, naphthyl, pyridyl, piperidinyl, piperazinyl and N- (p-fluoro) phenylpiperazinyl which may have alkoxy or lower (C _1-4 ) alkyl. Optionally N-lower (C _1-4 ) alkylamino, (g) N, N-
Dilower (C _1-4 ) alkylamino, (h) phenylamino, (i) morpholino, (j) piperidino, (k) piperazino, or (l) N-phenylpiperazino)
R ⁴ is hydrogen, halogen, or nitro; R ⁵ is carboxyl, lower (C _1-4 ) alkoxycarbonyl, cyano, tetrazolyl, trifluoromethanesulfonamide, R ⁶ is (1) hydrogen or (2) (a) hydroxyl, (b) amino, (c) halogen, (d) lower (C _1-4 ) alkoxy, E) optionally having a substituent selected from lower (C _1-4 ) alkoxycarbonyl; (i) a lower alkyl group having 1 to 8 carbon atoms; or (ii) a lower alkyl group having 2 to 8 carbon atoms.
Wherein R ⁷ is (a) a hydroxyl group, (b) a lower (C _1-4 ) alkoxy group, (c) a lower (C _1-4 ) alkyl group,
(D) Halogen, (ho) nitro, (he) amino, (to) methylamino, (thi) dimethylamino, (li) phenylamino, (nu)
Benzylamino, (ru) morpholino, (o) piperidino,
(W) piperazino, (f) N-phenylpiperazino, (yo) N
-(M-methoxy) phenylpiperazino, (t) lower (C
_1-4 ) Alkanoyloxy, (le) benzoyloxy, (so)
Halogen, nitro, lower at any position on the benzene ring
Phenyl which may have a substituent selected from (C _1-4 ) alkoxy and lower (C _1-4 ) alkyl, and (Z) a compound of the formula —COD ′ wherein D ′ is a hydroxyl group, a lower ( C _1-4 ) represents an alkoxy group, amino, methylamino, dimethylamino, phenylamino, benzylamino, morpholino, piperidino, piperazino, or N-phenylpiperazino]. (I) a lower alkyl group having 1 to 8 carbon atoms, (ii) a lower alkenyl group having 2 to 8 carbon atoms, and (iii) a 2 to 8 carbon atoms.
A lower alkynyl group, (iv) an alicyclic hydrocarbon residue having 3 to 8 carbon atoms or (v) an aromatic hydrocarbon residue having 6 to 12 carbon atoms, wherein A is a phenylene group and a phenyl group ((1) )
Directly or (2) (a) lower (C _1-4 ) alkylene, (b)-
(CO)-, (c) -O-, (d)-(NH)-, (e) -S-,
(F) - (CO) - (NH ) -, ( DOO) -O- (CH ₂₎ -, (h)
-S- (CH ₂ )-and (li)-(CH) = (CH)-, which are bonded via a spacer having an atomic chain of 2 or less, wherein n is an integer of 1 or 2. The compound according to claim 1, which is 3. A compound of the formula [Wherein, R ¹ represents lower (C _1-8 ) alkyl, R ³ represents hydrogen or a formula —COD (D represents a lower (C _1-4 ) alkoxy group, a hydroxyl group, amino, N-lower ( C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamino or phenylamino), and R ⁵ represents carboxyl or tetrazolyl], or a salt thereof. 4. A compound of the formula [Wherein, R ¹ represents lower (C _1-8 ) alkyl, R ⁷ represents (1) hydrogen, (2) (a) halogen (nitro), lower (C _1-4 ) at any position on the benzene ring. ) Alkoxy and lower (C
_1-4 ) phenyl which may have a substituent selected from alkyl, (b) amino, (c) N-lower (C _1-4 ) alkylamino, (d) N, N-di lower ( C _1-4 ) alkylamino, (ho) phenylamino, (he) benzylamino, (to) morpholino, (thi) piperidino, (li) piperazino, (nu) N-
Phenylpiperazino, and the formula (CO)
D 'is lower (C _1-4 ) alkoxy, hydroxyl, amino, N
Having a substituent selected from the group _{consisting of} lower (C _1-4 ) alkylamino, N, N-di-lower alkyl (C _1-4 ) amino, phenylamino and benzylamino. Lower (C _1-8 ) alkyl groups, (3)
(C _3-8 ) cycloalkyl or (4) (a) a hydroxyl group,
(B) lower (C _1-4 ) alkoxy group, (c) lower (C _1-4 ) alkyl group, (d) halogen, (ho) nitro, (he) amino, (to) methylamino, (h) Dimethylamino, (li) phenylamino, (nu) benzylamino, (ru) morpholino, (o) piperidino, (wa) piperazino, (f) N-phenylpiperazino,
(Y) N- (m-methoxy) phenylpiperazino, (T) lower (C _1-4 ) alkanoyloxy, (R) benzoyloxy,
At any position on the (so) benzene ring, halogen, nitro,
Phenyl optionally having a substituent selected from lower (C _1-4 ) alkoxy and lower (C _1-4 ) alkyl, and
(T) Formula -COD 'wherein D' is a hydroxyl group, lower (C _1-4 )
Alkoxy, amino, methylamino, dimethylamino, phenylamino, benzylamino, morpholino, piperidino, piperazino, or N-phenylpiperazino]. A good aromatic hydrocarbon residue having 6 to 12 carbon atoms;
⁵ represents carboxyl or tetrazolyl. Or a salt thereof. (5) 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-
4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid
Ethyl ester, 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine- 5-carboxylic acid, 2-ethyl-7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b] Pyridine-5-carboxylic acid methoxyethyl ester, 2-ethyl-5- (N-benzylcarbamoyl) -7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4- Oxo-4,7-dihydrothieno [2,3-b] pyridine, 2-ethyl-5- (N-phenylcarbamoyl) -7-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl ] Methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine, 2-ethyl-5- (N-2-
Pyridylmethylcarbamoyl) -7-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-4,7-dihydrothieno [2,3-b] pyridine, or a mixture thereof salt. 6. An angiotensin II receptor antagonist comprising the compound according to claim 1 or a salt thereof. 7. A compound of the formula Wherein R ¹ , R ² and W are as defined in claim 1. ]
Or a salt thereof and a compound of the formula [Wherein, R ⁴ , R ⁵ , A and n are as defined above. X represents a halogen. ] A compound represented by or reacting a salt thereof, optionally, (i) compound wherein R ⁵ is cyano group or a protected tetrazolyl group or a salt thereof R ⁵
Wherein R ³ is a tetrazolyl group or a salt thereof; (ii) converting a compound or a salt thereof wherein R ³ is a lower (C _1-4 ) alkoxycarbonyl group or a halogenocarbonyl group, wherein R ³ is a carboxyl group or a substituted group; (Iii) converting a compound or a salt thereof in which R ³ is a carboxyl group to a compound or a salt thereof in which R ³ is a halogenocarbonyl group, and / or Or (iv)
2. The method for producing a compound according to claim 1 or a salt thereof, comprising a step of converting the compound according to claim 1 which is a free form into a salt.