JPH0761986A - Condensed thiophene derivative - Google Patents

Abstract

PURPOSE:To obtain a new condensed thiophene derivative useful as a therapeutic agent for circulatory diseases such as hypertension, heart diseases, cerebral hemorrhage, etc., and having a strong antagonistic activity to angiotensin II and vasodepressor activity. CONSTITUTION:This condensed thiophene derivative is expressed by the formula I {W is the formula II or the formula III; R<1> and R<2> are each H, halogen, cyano, nitro, acylamino, (substituted) hydrocarbon residue; R<3> is H, a (substituted) alkyl, COD [D is H, an alkoxy, OH, halogen or (substituted)amino]; R<4> is H, halogen or nitro; R<5> is a group capable of forming an anion; R<6> is H or alpha(substituted)alkyl; R<7> is a (substituted)hydrocarbon residue; A is phenylene and phenyl which are directly bound or bound through a spacer having <=2 atom chain; n is 1 or 2}. E.g., 2-ethyl-7-[(2'-cyanobiphenyl-4-yl-methyl]-4--oxo-4,7- dihydrothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thienopyridone derivative having excellent pharmacological action and a synthetic intermediate thereof.

More specifically, the present invention has a strong angiotensin II antagonistic action and a hypotensive action, and is of a general formula useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke.

[Chemical 2] And R ² may be the same or different and each represents hydrogen, a halogen, a cyano group, a nitro group, an acylamino group or an optionally substituted hydrocarbon residue, and R ³ is hydrogen or an optionally substituted alkyl group. Group or formula-CO
A group represented by D (in the formula, D represents hydrogen, an alkoxy group, a hydroxyl group, halogen or an amino group which may be substituted), R ⁴ represents hydrogen, halogen or a nitro group, and R ⁵ represents R ⁶ represents hydrogen or an optionally substituted alkyl group, R ⁷ represents an optionally substituted hydrocarbon residue, and A represents 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.

[0003]

2. Description of the Related Art The renin-angiotensin system, together with the aldosterone system, is involved in homeostatic control functions such as systemic blood pressure, body fluid volume and electrolyte balance. Further, the relationship between the renin-angiotensin system and hypertension has been clarified by the development of an angiotensin II converting enzyme inhibitor (anti-ACE drug) having a strong vasoconstrictor action. Since angiotensin II raises blood pressure through angiotensin II receptor on the cell membrane, its antagonist is anti-ACE.
Like drugs, it can be used to treat hypertension caused by angiotensin. It has been reported so far that many angiotensin II analogues, such as salaracin [Sar ¹ , Ile ⁸ ] AII, have a strong angiotensin II antagonistic action. However, peptidic antagonists have been reported to have a short duration of action when administered parenterally and are ineffective when given orally [MA Ondetti and D. W. Cushman, Ann.
ual Reports in Medicinal Chemistry, 13 , 82-91 (197
8)]. Non-peptide angiotensin II antagonists are disclosed in JP-A-56
-71073, JP-A-56-71074, JP-A-57-
92270, JP-A-58-157768, JP-A-62-
240683, JP-A-63-23868, EP-032
3841 and Japanese Patent Laid-Open No. 11-11787, AT Chiu et al., Eur. J. Pharm., 157 , 13 (198).
8), PC Wonget al., J. Pharmcol. Exp. Ther., 24
7 , 1 (1988) and PC Wong et al., Hypertension,
13 , 489 (1989) and the like disclose imidazole derivatives having angiotensin II antagonistic activity. However, it is completely unknown that the fused thiophene derivative has an angiotensin II antagonistic action.

[0004]

DISCLOSURE OF THE INVENTION The present invention is to provide a novel fused thiophene derivative which has a potent angiotensin II antagonistic action and a hypotensive action and can be put into practical use as a medicine.

[0005]

[Means for Solving the Problems] As a result of intensive investigations by the present inventors, a compound having an angiotensin II antagonistic action and useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke was found to be excellent. In addition, we succeeded in producing a condensed thiophene derivative having angiotensin II antagonistic effect, and further researched the present invention to complete the present invention. That is, the invention has the formula

[Chemical 3] And R ² may be the same or different and each represents hydrogen, a halogen, a cyano group, a nitro group, an acylamino group or an optionally substituted hydrocarbon residue, and R ³ is hydrogen or an optionally substituted alkyl group. A group or an alkenyl group, or a group represented by the formula —C OD (wherein D represents hydrogen, an alkoxy group, a hydroxyl group, halogen or an amino group which may be substituted), and R ⁴ represents hydrogen or halogen. Or a nitro group, R ⁵ is a group capable of forming an anion or a group capable of being modified into it, R ⁶ is hydrogen or an optionally substituted alkyl group or alkenyl group, and R ⁷ is a substituted group. Represents a hydrocarbon residue which may be present, A represents that the phenylene group and the 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 halogen as R ¹ and R ² include F, Cl, Br and the like.

An acylamino group as R ¹ and R ² is
Wherein, R ⁸ represents a hydrogen or a hydrocarbon residue] wherein R ⁸ CONH- a group represented by. 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-pep
Benzyl, hexyl, heptyl, octyl, etc.), 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 a lower alkynyl group having about 2 to 8 carbon atoms (eg, ethynyl, 2-
Acyclic hydrocarbon residue such as butynyl, 2-pentynyl, 2-octynyl, etc., or alicyclic hydrocarbon residue having about 3 to 8 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclohexene- 1-yl,
Cyclooctyl) and cyclic hydrocarbon residues such as aromatic hydrocarbon residues having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.) and the like.

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, pentyl, i-pentyl, hexyl, heptyl, octyl, etc.), carbon number 2
~ 8 lower alkenyl groups (eg vinyl, allyl (all
yl), isopropenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-octenyl, etc.) and a lower alkynyl group having about 2 to 8 carbon atoms (eg, ethynyl, 2-
Acyclic hydrocarbon residue such as butynyl, 2-pentynyl, 2-octynyl, etc., or alicyclic hydrocarbon residue having about 3 to 8 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclohexene-1) -Ill,
Cyclooctyl) and cyclic hydrocarbon residues such as aromatic hydrocarbon residues having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.) and the like.

Hydrocarbon residues as R ¹ , R ² and R ⁷ include hydroxyl group, lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, etc.), lower (C _1-4 ) alkyl group (eg, , Methyl, ethyl, etc.), halogen (eg, F, Cl, Br, etc.), nitro, optionally substituted amino group (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 optionally having a substituent such as halogen, nitro, lower (C _1-4 ) alkoxy, lower (C _1-4 ) alkyl etc. 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 residue 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, and the alkyl group has an unsaturated bond. , Methyl, ethyl,
Examples thereof include vinyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, etc., and the alkyl group is a hydroxyl group, optionally substituted amino group (eg, amino etc.), halogen, 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.), and halogen includes: Examples thereof include Cl and Br, and the amino group which may be substituted includes, for example, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, alkyl at 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, and lower (C _1-4 ) alkyl.
(P-fluoro) phenylpiperazinyl or the like optionally substituted N-lower (C _1-4 ) alkylamino and the like),
N, N-di-lower (C _1-4 ) alkylamino (eg, dimethylamino etc.), N-arylamino (eg, phenylamino etc.), alicyclic amino (eg, morpholino, piperidino,
Piperazino, N-phenylpiperazino, etc.) and the like.

The compound in which D represents halogen is useful as a raw material for synthesizing the compound in which D represents an alkoxy group or an optionally substituted amino group.

R ⁴ represents hydrogen, halogen (eg Cl, Br, etc.) or 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, etc., which may be any group capable of forming an anion or a group capable of converting to an anion under biological conditions, that is, physiological conditions, R ⁵
The substitution position of is preferably the ortho position.

Further, a compound in which R ⁵ is a group capable of chemically forming an anion or a group capable of changing to a group (for example, cyano) is useful as a synthetic intermediate.

A indicates that the adjacent phenylene group and phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less. As the spacer having an atomic chain of 2 or less,
Any divalent chain in which the number of atoms constituting the straight chain portion is 1 or 2 may be used, 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

[Chemical 4] [In the formula, R ¹ represents lower (C _1-8 ) alkyl, R ³ is hydrogen or formula-COD (in the formula, D is lower (C _1-4 ) alkoxy group, hydroxyl group or optionally substituted) Amino groups (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

[Chemical 5] [In the formula, R ¹ is a lower (C _1-8) an alkyl, R ⁷ is hydrogen, an optionally substituted aryl group or an optionally substituted amino (e.g., amino, N- lower (C _{1 -4} ) Alkylamino, N, N-di-lower (C _1-4 ) alkylamino, phenylamino, benzylamino, morpholino, piperidino, piperazino, N-phenylpiperazino, etc.) Lower optionally substituted ( C _1-8 ) alkyl group or formula COD (wherein D is lower (C _1-4 ) alkoxy, hydroxyl group, optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino) , N, N-dilower 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)

[Chemical 6] [In the formula, R ¹ , R ² , R ⁴ , R ⁵ , A, W and n have the same meanings as described above. X represents halogen. ] Reaction (b)

[Chemical 7] [Wherein R ¹ , R ² , R ⁴ , A, W and n have the same meanings as described above. ] Reaction (c)

[Chemical 8] [In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A and n have the same meanings as described above. R ⁹ represents a lower (C _1-4 ) alkyl group. ] Reaction (d)

[Chemical 9] [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁹ , A and n have the same meanings as described above. R ¹⁰ and R ¹¹ represent hydrogen or a hydrocarbon residue. ] Reaction (e)

[Chemical 10] [In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A and n have the same meanings as described above. X represents halogen. ] Reaction (f)

[Chemical 11] [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)

[Chemical 12] [Wherein R ¹ , R ² , R ⁴ , A, W and n have the same meanings as described above. R ¹² represents a protecting group. ]

In the reaction (a), an alkylating agent is allowed to act in the presence of a base to carry out alkylation. Compound (I
I) Using 1 to 3 moles of a base and 1 to 3 moles of an alkylating agent, usually dimethylformamide,
Perform in a solvent such as dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone.

As such a base, sodium hydride, t
-Use potassium butoxy, cesium carbonate, potassium carbonate and sodium carbonate.

As the alkylating agent, substituted halides (eg chloride, bromide and iodide), substituted sulfonates (eg p-toluene sulfonate, methane sulfonate, etc.) are used.

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

Azide compound 1 to 1 mol of compound (IV)
It is used in an amount of about 10 to about 10 mol and is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene and benzene.

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

When an organotin azide compound is used, it is reacted in toluene or benzene while heating under reflux for about 10 to 30 hours. When reacting hydrazoic acid, add sodium azide and ammonium chloride to the compound (IV) at 5%.
Use approximately twice the molar amount, and use 100 to 13 in dimethylformamide.
The reaction is carried out at about 0 ° C for about 1 to 10 days. During this period, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride.

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

Alkali 1 to 1 mol relative to 1 mol of the compound (VI)
Using about 3 mol, it is usually carried out in a solvent such as alcohols containing water (methanol, ethanol, methyl cellosolve, etc.). As the alkali, sodium hydroxide, potassium hydroxide or the like is used. Further, the reaction conditions are preferably room temperature to about 100 ° C. and about 5 minutes to 10 hours.

The reaction (d) includes amines and esters (VI).
To give an amide compound (VIII).

2-5 amines per mole of compound (VI)
It is used in an amount of about 0 mol, usually in a solvent such as alcohols (methanol, ethanol, etc.) or without solvent at room temperature to 20
Perform by heating to 0 ° C.

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

The reaction (e) is to obtain an acid halide (IX) from a carboxylic acid (VII) with a halogenating agent.

Usually, halogenated hydrocarbons (eg, CHCl ₃ , CH ₂ Cl ₂ , ClCH ₂ CH ₂ Cl, etc.) are used in an amount of about 1 to 5 moles of a halogenating agent with respect to 1 mole 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.

Further, the reaction conditions are room temperature to about 100 ° C.,
It is preferably carried out for about 1 to 10 hours.

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

2 to 5 amines per 1 mol of compound (IX)
About 0 mol is used, usually alcohols (eg, methanol,
Ethanol etc.) and ethers (eg ethyl ether,
Tetrahydrofuran, dioxane, etc.).

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

The reaction (g) is to obtain the compound (V) by deprotecting the appropriately protected tetrazole derivative (X).

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

Thus, the compound (I) produced from the reaction (a) to the reaction (g) can be separated and purified from the reaction solution by an ordinary separation and purification means such as 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 and the like.

Further, these compounds (I) can be obtained by a conventional method in the form of salts with physiologically acceptable acids or bases, for example, salts with inorganic acids such as hydrochlorides, sulfates and nitrates, and depending on the compound, acetates and oxalic acids. 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, 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 the like or a method analogous thereto.

Further, among the starting compound (III), the compound (IIIa) in which n is 1 is disclosed in JP-A-63-23868 and JP-A-1.
-1187676 and EP-0323841, the compound (X), which is commercially available or synthesized by a method known in the literature, can be obtained according to the reaction (h).
For example, AA Vansheidt et al., Khim. Nauka i Pro
It can also be easily obtained by halogenomethylation according to the method described in m., 2 , 799 (1957). Reaction (h)

[Chemical 13] [In the formula, each symbol has the same meaning as described above. ]

Further, among the starting compound (III), n
The compound (IIIb) in which is 2 can be obtained by reacting the compound (IIIa) according to the reaction (i). Reaction (i)

[Chemical 14] [In the formula, each symbol has the same meaning as described above. ]

The compound (I) and its salt thus produced have a low toxicity and strongly suppress the angiotensin II-induced vasoconstriction and blood pressure-increasing actions, and are particularly effective in animals, particularly mammals (eg, humans, dogs, rabbits, rats). 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 drug, compound (I) and a salt thereof are mixed with themselves or an appropriate pharmacologically acceptable carrier, excipient, diluent to obtain powder, granules, tablets, capsules, injections. Can be administered orally or parenterally.

The dose varies depending on the target disease, symptom, administration subject, administration method, etc., but when administered as an adult essential hypertension therapeutic agent, the daily dose is about 10 to 10 by oral administration.
It is preferable to administer 100 mg by intravenous injection in a daily dose of about 5 to 50 mg in 2 to 3 divided doses.

[0047]

EXAMPLES The present invention will be described in more detail below with reference to Examples, Formulation Examples, Experimental Examples and Reference Examples, 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
Elute at (3: 1) to give the title compound as colorless crystals, 80 mg (31%)
Obtained. Melting point: 156-158 ° C IR (KBr) cm ^-1 : 1700,1595,1520 NMR (CDCl ₃ ) δ: 1.05 (6H, d, J = 6.6Hz), 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 Actual measurement Value: 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. The reaction mixture was stirred at 60 ° C for 3 hr, cooled in an ice bath, and the deposited precipitate was collected by filtration and washed with benzene. The obtained precipitate (223 mg) was dissolved in a mixture of 2-methoxyethanol (0.3 ml) and CH ₂ Cl ₂ (5 ml), and triethylamine (0.7 ml) was added thereto under ice cooling and the mixture was stirred for 30 minutes. The reaction mixture was poured into chloroform, washed it with 1N hydrochloric acid, dried (MgSO ₄₎ and the solvent was evaporated under reduced pressure. The obtained residue was purified by flash column chromatography using silica gel. Elution with ethyl acetate / hexane / chloroform (1: 1: 1) and then chloroform / methanol (9: 1) gave 200 mg (41%) of the title compound as colorless powder. IR (KBr) cm ^-1 : 1700,1590,1530,1480 NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.4Hz), 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
The solution dissolved in 0 ml) was cooled to −5 ° C., and a solution prepared by dissolving sodium nitrate (370 mg, 4.3 mmol) in concentrated sulfuric acid (5 ml) was added dropwise thereto. The reaction mixture was stirred at -3 ° C to -5 ° C for 1 hr, poured into ice water, the deposited precipitate was collected by filtration, and washed with cold water and then ethanol. The obtained precipitate was dissolved in chloroform, washed with saturated saline, and dried (MgSO ₄ ). The solvent was evaporated under reduced pressure, and the obtained yellow solid was washed with a mixed solvent of ether / hexane and dried to give the title compound (960 mg, 81%). Melting point: 194-201 ° C (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 value: C ₁₂ H ₁₂ N ₂ O ₅ S Calculated value: C, 48.64; H, 4.08; N, 9.45 Measured value: 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)
, Oily sodium hydride (60%) (160 mg) was added, and the mixture was stirred for 10 minutes. 4- [2 ′-(N-triphenylmethyltetrazol-5-yl) phenyl] benzyl bromide (2.23 g, 4 mmol) was added thereto, and the mixture was heated with stirring at 90 ° C. for 1 hour. The reaction solution was poured into water, 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 2.24 g (77%) of colorless crystals of the title compound. Melting point: 195-198 ° C IR (KBr) cm ^-1 : 1730,1705,1620 NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 9.6Hz), 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 a known method such as (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 the same method as Reference Example 1, 2, or 3.

[Table 1]

[Table 2] The following compounds (Reference Examples 18-32) were synthesized by the same method 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-carvone 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) was added to 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 hr. 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 the title compound as crystals, 254 mg (60%). NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 6Hz), 1.39 (3H, t, J = 6Hz), 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. Elute with chloroform / methanol (9: 1), 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 = 8.6Hz), 7.21 (1H, s), 7.28 (2
H, d, J = 8.6Hz), 7.5-7.7 (4H, m), 8.75 (1H, s) Further eluting with chloroform / methanol (9: 1) 2-ethyl-7-[[2 '-( 7 mg (2.7%) of a colorless solid of [1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid] was obtained. IR (KBr) cm ^-1 : 1650,1605,1580,1540,1505 NMR (CD ₃ OD) δ: 1.34 (3H, t, J = 7.6Hz), 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 hr. 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 NMR and IR spectra with the compound obtained in Example 1B. Mp: 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 a similar manner to 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-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 ethyl ester (600 mg, 1.235 mmol) in 1N sodium hydroxide solution (6 m
It was dissolved in l) and heated with stirring at 100 ° C. for 20 minutes. 1 after cooling
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 NMR and IR spectra with the compound obtained in Example 1B. Melting point: 153-157 ° C Elemental analysis: C ₂₄ H ₁₉ N ₅ O ₃ S ・ 3.5H ₂ 0 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 further at 100 ° C for 1 hour. After cooling, the reaction solution was poured into water, 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 to give the title compound crystals (258 mg, 62%). 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 (200 mg, 0.39 mmol) obtained in Example 11A 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 evaporated under reduced pressure. This operation was performed twice more, and 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 = 7.4Hz), 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 mmo
l) and benzylamine (2 ml) were stirred at 60 ° C. for 3 days.
After cooling, the reaction solution was poured into chloroform and washed twice with 1N hydrochloric acid,
It was dried (MgSO ₄ ) and concentrated, and the resulting residue was purified by flash column chromatography on silica gel. Elution with chloroform / methanol (19: 1 to 9: 1) gave 63 mg (45%) of crystals of the title compound. Melting point: 177-180 ° C IR (KBr) cm ^-1 : 1650,1590,1550,1500 NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7.4Hz), 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 a similar manner to 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] Pyridin-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 added to acetic anhydride (6 ml), acetic acid (6 ml), dioxane (4 ml) and tetrahydrofuran (5 ml). ) And heat to 70 ℃,
Zinc dust (85 mg) was added thereto, and the mixture was stirred for 2 hours. The filtrate obtained by removing the insoluble matter by filtration was concentrated under reduced pressure. The obtained oily substance was dissolved in a mixture of trifluoroacetic acid (8 ml) and water (1 ml), and the mixture was stirred at room temperature for 5 hr. 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, and the obtained residue was purified by flash column chromatography using silica gel. Elution with chloroform / methanol (20: 1) gave 59 mg (4%) of colorless crystals of the title compound.
2%) obtained. Melting point: 163-166 ° C IR (KBr) cm ^-1 : 1720,1700,1615,1550,1510 NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.4Hz), 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 Found: 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 by the same method 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 Example 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. Capsule (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 1 capsule 180 mg (1), (2), (3) and 1 of (4) After mixing / 2, granulate. The rest (4) is added to this and the whole is enclosed 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 1 tablet 230 mg (1), (2), (3), After mixing 2/3 of (4) and 1/2 of (5), granulate. The rest of (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-carboxylic acid ethyl ester sodium salt 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2), (3) distilled water for injection to a total volume of 2 ml Dissolve in, and put in an ampoule. All steps are performed aseptically.

Experimental Example 1 Angiotensin-II binding inhibitory effect on angiotensin receptor [Experimental method] Douglas et al. [Endocrinology, 102 , 685]
-696 (1978)] by modifying angiotensin II (A-II)-
Receptor binding inhibition experiments were performed. From the cortex of bovine adrenal gland A
-II receptor membrane fraction was prepared. The 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. Filters bound and free ¹²⁵ I-A-II (Whatman GF / B filter)
The radioactivity of ¹²⁵ IA-II bound to the receptor was measured. [Experimental Results] Experimental results relating to the compounds 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 anesthesia with pentobarbital Na, the femoral artery and vein were indwelled with a cannula, and kept under conditions of fasting and free intake of water until just 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. Before administration of the drug A-II (100ng
/ Kg) was measured for pressor response by intravenous administration. The drug was orally administered, and thereafter, A-II was intravenously administered at each measurement point, and the pressor response was similarly determined, and the inhibition rate was determined by comparing the reactions before and after drug administration. [Experimental Results] Table 19 shows the experimental results concerning the compounds of the present invention.

[0062]

[Table 19] ──────────────────────────── Example AII binding inhibitory effect Pressor suppressive effect 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 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; Unmeasured * ^b (% Inhibition) ++ ≧ 70%> + ≧ 50%

Claims (1)

[Claims] 1. A formula And R ² may be the same or different and each represents hydrogen, a halogen, a cyano group, a nitro group, an acylamino group or an optionally substituted hydrocarbon residue, and R ³ is hydrogen or an optionally substituted alkyl group. Group or formula-CO
A group represented by D (in the formula, D represents hydrogen, an alkoxy group, a hydroxyl group, halogen or an amino group which may be substituted), R ⁴ represents hydrogen, halogen or a nitro group, and R ⁵ represents R ⁶ represents hydrogen or an optionally substituted alkyl group, R ⁷ represents an optionally substituted hydrocarbon residue, and A represents 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.