WO1993003040A1 - Thienopyrimidin-4-one derivative - Google Patents

Abstract

Object: to provide a new type of a compound having an angiotensin II receptor blocker activity, thus contributing to the therapy of hypertension and cardiac insufficiency. Constitution: a thienopyrimidin-4-one derivative represented by general formula (I) and a salt thereof, wherein (a) represents (b), (c) or (d), wherein R?1 and R2¿ represent each hydrogen, alkyl or phenyl, or alternatively when R1 is adjacent to R?2, R1 and R2¿ are combined together to represent alkylene; R3 represents alkyl or alkylthio; B represents a carbon-to-carbon single bond or -NHCO-; R4 represents carboxyl, sulfoxyl or tetrazol-5-yl; and X represents hydrogen or halogen.

Description

 Rui Akira

 Thienopyrimidine-1 4-one derivative

 Technical field

 The present invention relates to a thienovirimidine-141 derivative having angiotensin II receptor blocking activity. Conventionally, as an angiotensin II antagonist having a pyrimidine skeleton, Japanese Patent Application Laid-Open (JP-A) No. 3-115,711, European Patent Application Publication Nos. 407,342, and 419,048 However, the compound described in JP-A No. 4-45811 is known, but the compound having a chenovirimidine skeleton is not known.

 An object of the present invention is to provide a new compound having angiotensin Π receptor blocker action of evening eve, which is useful for treating hypertension, heart failure and high intraocular pressure.

Disclosure of the invention

 The invention relates to the formula

R3

[Where,

(In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a furyl group, or R 1 and R ² are adjacent to each other. In R ¹ and R ² come together to represent an alkylene group having 3 to 5 carbon atoms. R ³ represents an alkyl group having 1 to 7 carbon atoms or an alkylthio group having 1 to 7 carbon atoms, and B represents a carbon-carbon single bond or a formula—NHCO—. R ⁴ represents a carboxyl group, a sulfoxyl group or a tetrazole-5-yl group, and X represents a hydrogen atom or a halogen atom.] And a dithiopyridine derivative represented by the formula Salt.

 In the present invention, an alkyl group having 1 to 7 carbon atoms means a straight-chain or branched alkyl group such as a methyl group, a methyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. Say. The alkylthio group having 1 to 7 carbon atoms means a straight-chain or branched-chain alkylthio group such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, and isobutylthio group. Say. Halogen atoms refer to fluorine, chlorine, bromine and iodine. The salt of the compound of the formula (I) means a metal salt such as a sodium salt and a potassium salt. The compound of the present invention can be produced, for example, by the following method. That is, a compound which is known or can be obtained by a conventional method from a known compound,

R3 N. (π)

 H

(Wherein and R ³ have the same meanings as described above.)

After treating this compound with 1 to 3 equivalents of a base, 1 to 5 equivalents of the formula

[Wherein, R ⁵ represents a nitro group or a 2- (N-triphenylmethyl-tetrazol-1-yl) phenyl group, and X · represents a halogen atom. Is reacted with a 4-substituted benzyl halide represented by the formula R3

を製造することができる。 (Wherein, R ³ and R ⁵ are as defined above.)

Can be manufactured.

 Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. Examples of bases include metal hydrides such as sodium hydride, organic bases such as lithium lithium and lithium diisopropylamide, alcoholates such as sodium methoxide, and potassium hydroxide. Hydroxide or carbonate such as lime carbonate. As the organic solvent, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetate, and the like can be used. The reaction temperature is from 178 to the reflux temperature of the solvent.

Next, the compound of formula (式) wherein R ⁵ is 2- (N-triphenylmethyl-tetrazol-15-yl) phenyl group is deprotected with an acid in a solvent to obtain a compound of formula (R). In I), the compound of the present invention wherein B is a carbon-carbon single bond and R ⁴ is a tetrazol- _5- yl group can be produced.

 Hydrochloric acid, hydrochloric acid, p-toluenesulfonic acid and the like can be used as an acid in this reaction, and methanol, ethanol, tetrahydrofuran and the like can be used as a solvent. The reaction temperature is from room temperature to the reflux temperature of the solvent.

On the other hand, the compound of the formula (II) wherein R ^{5 is a} nitrogen atom can be treated as follows to obtain the compound of the present invention.

That is, first, in the formula <21), the nitro group of the compound in which R ^{5 is a} nitro group is reduced to an amino group.

Here, as the reducing agent, iron Z drunk acid, tin dichloride Z hydrochloric acid, nickel chloride Z hydrogenation Sodium boron, palladium / carbon hydrogen, and the like can be used. As the solvent, an alcohol such as methanol, ethyl sulphate, water or the like can be used. <The reaction temperature is from room temperature to the reflux temperature of the solvent.

 The amino compound is then converted to a compound of formula

Wherein X is as defined above, and R ⁶ represents a carbonyl group or a sulfonyl group c) by reacting with an acid anhydride represented by the following formula (I): The compound of the present invention can be produced wherein NHC is 0 and R ⁴ is a carbonyl group or a sulfoxyl group.

 This reaction can be performed in the presence of a base or in the absence of a base. As the base, an organic base such as pyridine, triethylamine, diisobu π-viramine or the like can be used. As the solvent, chloroform, dichloromethane, N, N-dimethylformamide or the like can be used. The reaction temperature is from room temperature to the reflux temperature of the solvent.

The compound of the present invention can be prepared orally or nonperiodically (for example, intravenously, rectally, or ocular mucosa) in the form of various dosage forms by conventional formulation techniques and administered. Here, as the dosage form of the microbial preparation, solid preparations such as tablets, granules and capsules, or liquid preparations such as solutions, fat emulsions and ribosome preparations can be used. As the dosage form of the preparation for intravenous administration, an aqueous or non-aqueous solution, an emulsifier, a suspension, or a solid preparation to be dissolved immediately before use can be used. Suppositories and the like can be used as the dosage form of the preparation for rectal administration. As the dosage form of the ophthalmic mucosal administration preparation, a solution, an emulsifier, a suspending agent, an ointment and the like can be used. The dose of the compound of the present invention in these administration methods varies depending on the patient's condition, disease type, age, body weight, etc., but when administered for hypertension or heart failure, it is usually from l to 100 per 1 B. 0 mg, given once or several times a day. Industrial applicability

 -The compounds of the present invention have an excellent angiotensin II receptor blocking effect and can be useful for treating hypertension, heart failure and high intraocular pressure.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.

Example 1.

 2-Provyl-1 3 — i Γ.2_ '-(Tetrazol-5-yl) biphen-1-4-ylmethyl} 1-5-Tilthieno {2,3-d] Birimidine-1 4 (3H) — ON (Compound 1)

 (1) 2-Amino-4-methyl-3 -thiophenecarboxyamide To a solution of 5 g of dichloromethan in 100 ml, add 9 ml (2 equivalents) of triethylamine, and add chlorate butyrate under ice-cooling. 4.3 ml (1.3 equivalents) was added dropwise over 10 minutes. After stirring at room temperature for 1 hour, water was added, and the mixture was extracted with π-methane. The organic layer was saturated with sodium hydrogen carbonate. After washing with an aqueous solution and saturated saline solution in that order, drying over magnesium sulfate, and distilling off the solvent, the residue was subjected to silica gel gel chromatography (elution solvent; hexane: ethyl ether = 7: 3). ) To give 5.62 g of 2-butyricamino-4-methyl-3-thiophenecarbodiamide.

 Dissolve 5.60 g of the compound obtained in 80 ml of methanol and add a solution of 1.96 g (1.2 equivalents) of potassium hydroxide in 30 ml of methanol. Heated and refluxed for 5 hours. After evaporating the solvent, water was added, and the pH was adjusted to 5 to 6 with 10% hydrochloric acid. The precipitated crystals were washed with water and recrystallized from dichloromethan-hexane to give colorless crystals of 2-propyl-5-methylthieno [2,3-d] birimidine-1 4 (3H) -one. 96 g were obtained.

 m.p. 2 2 0 ~ 2 2 2

 Ή-NMR (CDCls) δ p p m;

 1.03 (3 H, t, J = 7 H z),

 1. 8 8 (2 H, sext, J = 7 Hz),

2.58 (3 H, d, J = 1 Hz), 2.73 (2 H, t, J = 7 Hz), 6.77 (1 H, q, J = 1 Hz) , 1 1.48-: 1.1.7 8 (1 H, b) (2) 60% oily sodium hydride 3.66 g (1.1 equivalents) was washed twice with hexane (5 ml) and N, N-dimethylformamide (90 ml) was added. Under ice-cooling, 17.3 g of the compound obtained in (1), 200 ml of a solution of 0N, N-dimethylformamide was added dropwise. C. The mixture was stirred at room temperature for 1 hour, and then cooled with 110 to obtain N-trif. --Methyl-5- [2- (4, -bromomethylbiphenyl)] tetrazole 55.6 g (1.2 equivalents) of N, N-dimethylformamide 150m1 solution for 20 minutes After stirring at the same temperature for 4 hours, the mixture was stirred at room temperature overnight. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel force chromatography (elution solvent; hexane: ethyl ethyl acetate = 7: 1), and recrystallized from ethyl acetate-hexane to give 2-propyl-1 3 -— [[2 '-( N-triphenylmethyl-tetrazol-5-yl) biphen-1-yl] methyl} -1-5-methylthieno [2,3-d] birimidine-1 4 (3H) 29. & g.

 m.p.166-: L64. C (d e c.)

 JH-NMR (CDCI3) <!> P p m;

 0.90 (3 H, t, J = 7 H z),

 1, 72 (2 H, s ext, J = 7 H z),

 2.58 (3 H, d, J = 1 Hz), 2.59 (2 H, t, J = 7 Hz),

5.27 (2 H, b s), 6.77 (1 H, q, J = 1 H z),

 6.82 to 7.02 (8H, m), 7.11 (2H, d, J = 8Hz), 7.15 to 7.56 (12H, m), 7. 85 to 7.98 (1H, m)

(3) To a solution of 29.8 g of the compound obtained in (2) in 600 ml of tetrahydrofuran was added 60 ml of 4N hydrochloric acid, and the mixture was stirred at room temperature for one hour. After the reaction, an aqueous solution of sodium hydrogen carbonate was added to adjust the pH to 5 to 6, and the mixture was extracted with ethyl acetate and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off, and the residue was washed with a cross-sectional form to obtain 15.1 g of the title compound as colorless crystals.

mp 222-223 (de c.) H—NMR (DMS O—d ₆ ) 5 ppm;

 0.87 (3 H, t, J = 7 H z),

 1.65 (2 H, sext, J = 7 Hz),

 2.47 (3 H, d, J = 1 Hz), 2.68 (2 H, t, J = 7 Hz), 5.36 (2 H, bs), 7.09 ( 4 H, s),

 7.12 (1H, q, J = 1Hz), 7.50 to 7.76 (4H, m)

 2-Butyl-3 — ί_ [2 '-(Tetrazol-5-yl) biphen-1-yl] methyl} —5-Methylthieno “2,3-d] birimidine-1 4 (3H) -1 ON (Compound 2)

(1) To a solution of 20 g of 2-amino-4-methyl-3-thiophenecarboxyamide in 200 ml of dichloromethane was added 36 ml (3 equivalents) of triethylamine, and the mixture was cooled on ice. 19.8 ml (1.3 equivalents) of folic acid chloride was added dropwise over 10 minutes. After 3 hours under stirring at room temperature, and extracted with Axis n _D methane adding water, organic layer was washed successively with saturated bicarbonate Na Application Benefits um solution and saturated brine, dried over anhydrous magnesium sulfate, Solvent evaporated did. The residue was washed with isopropyl ether to obtain 26 g of 2-valeroylamino-4-methyl-3-thiophenecarboxyamide.

 The compound obtained here was dissolved in 210 ml of methanol, a solution of 9.2 g (1.3 equivalents) of hydroxide hydroxide in 50 ml of methanol was added, and the mixture was heated under reflux for 5 hours. After the solvent was distilled off, water was added, and the pH was adjusted to 5 to 6 with 10% hydrochloric acid. The precipitated crystals were washed with water and ethyl acetate to obtain 2-1.3 g of 2-butyl-5-methylthieno [2,3-d] pyrimidine-4 (3H) -crystal. The crystals were recrystallized from methanol to obtain colorless crystals.

 Melting point; 1 75-: at I 76

 Ή-NMR (DMS O-de) δ p p m;

 0.88 (3 H, t, J = 7 H z),

 1. 3 2 (2 H, sext, J = 7 Hz),

1. 6 7 (2 H, quint, J = 7 H z), 2.43 (3 H, d, J = 1 Hz), 2.58 (2 H, t, J = 7 Hz), 7.03 (1 H, Q, J = 1 Hz), 1 2.15 to; 1 2.35 (1 H, b)

(2) Wash 176 mg (l.1 equivalent) of 60% oily sodium hydride twice with 1 mi of hexane, then add 10 ml of N, N-dimethylformamide and cool on ice. compound 888 mg obtained under (1) N, N-dimethylformamide a Mi de 1 2 m 1 solution after 1 hour stirring at _c room temperature was added dropwise, one 1 0. C Under cooling, N-trifyl-nylmethyl-5- [2- (4'-promomethylbiphenyl)] tetrazole 2.46 g (1.1 equivalents) of N, N-dimethylformamide A 12 ml solution was added dropwise over 5 minutes, stirred at the same temperature for 4 hours, and then stirred at room temperature overnight. After the reaction, water was added and the mixture was extracted with sulfuric acid ether. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7: 1) to give 2-butyl-3-{[2'-I- (N-triphenylmethyl-tetrazol-5-yl). 1.41 g of crystals of biphen-1-yl] methyl} -1-methylthieno [2,3-d] pyrimidin-4 (3H) one were obtained. The crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals.

 m. p. 1 1 9-: 1 2 2 'C (d e c.)

 — NMR (CDC 13) 5 p p m;

 0.8 7 (3 H, t, J = 7 H z),

 1.30 (2 H, sext, J = 7 H 2),

 1.67 (2 H, q u int, J = 7 H z)

 2.59 (3 H, d, J = 1 H 2), 2.62 (2 H, t, J = 7 H z),

5.27 (2 H, b s), 6.76 (1 H, q, J = 1 H z),

 6.85 to 7.02 (8H, m), 7.11 (2H, d, J = 8Hz), 7.18--7.37 (10H, m), 7 . 3 7 ~ 7.54 (2 H, m),

7. 8 7— 7. 9 7 (1 H, m)

(3) To a solution of 1.40 g of the compound obtained in (2) in 28 ml of tetrahydrofuran was added 2.8 ml of 4 N hydrochloric acid, and the mixture was stirred at room temperature overnight. After the reaction, sodium bicarbonate water The solution is added to pH 5-6, extracted with ethyl acetate, the organic layer is washed with saturated saline _c , dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is purified by silica gel π The mixture was subjected to chromatography (elution solvent; dichloromethane: methanol = 99: 1) to obtain 0.79 g of crystals of the title compound. The crystals were recrystallized from a beef sac into a black hole form to obtain colorless crystals.

 m.p. 194-4: 197. C (d e c.)

_{^{J H- NMR (CDC 1 3)}} <5 ρ ρ m;

 0.92 (3 H, t, J = 7 H z),

 1.42 (2 H, sext, J = 7 H 2),

 1.87 (2 H, q u int, J = 7 H z),

 2.48 (3 H, d, J = 1 H z), 2.76 (2 H, t, J = 7 H 2),

5.33 (2H, s), 6.78 (1H, q, J = 1Hz),

 7.1 1 (2 H, d, J = 8 Hz), 7.16 (2 H, d, J = 8 Hz),

7.40 (1 H, d d, J = 2 Hz, 7 H z),

 7.5 2 (1 H, d t, J = 2 Hz, 7 Hz),

 7.59 (1 H, d t, J = 2 Hz, 7 H z),

 8.06 (1H, dd, J = 2Hz, 7Hz) Example 3.

 2—Ethyl 3— {“2 '-(Tetrazol 5—yl) Biffe _ ~ 4 一 1 L L Methyl) 1 5—Methyl thieno Γ2.3-d 1 3 H) One compound (Compound 3)

 (1) Example 2 In the same manner as in <1), 2-ethyl-5-methylthieno [2,3-d] birimidine 1-4 (3H) was obtained.

 m. p. 238-240. C

¹ H—NMR (CDC 13) δ ppm;

 I. 40 (3 H, t, J = 7 H z), 2.58 (3 H, d, J = 1 H z), 2.79 (2 H, q, J = 7 H 2) , 6.77 (1 H, q, J = 1 H z),

II. 8 3 (1 H, bs) (2) Using the compound obtained in (I), 2-ethyl-3 — {[2 ′ — (N-triphenylmethyl-tetrazol-5-yl) was obtained in substantially the same manner as in Example 2 (2). ) Biphen-1-yl) Methyl) 5-Methylthieno [2,3-d] birimidine-1

(3H)-got on.

_{! H-NMR (CDC 1 3} ) 5 p P m;

 1.18 3 H, t, J = 7 Hz), 2.60 (3 H, d, J = l Hz), 2.61 (2 H, q, J = 7 Hz), 5.2 7 (2 H, bs),

 6.78 (1H, q, J = 1Hz), 6.86-6.98 (7H, m), 7.11 (2H, d, J = 8Hz), 7.18 to 7.37 (11H, m),

7. 4 3 to 7.5 2 (2 H, m), 7.90 to 7.97 (1 H, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 2 (3).

 m.p. 2 40 ~ 2 42 (d e c *)

 iH-NMR (DMS O-de) <5 ppm;

 1.15 (3 H, t, J = 7 Hz), 2.48 (3 H, d, J = l Hz),

2.75 (2 H, q, J = 7 Hz), 5.35 (2 H, b s),

 7.02 to 7.38 (5H, m), 7.50 to 7.74 (4H, m)

 2-I-Tylthio 3— (“2 '— (Tetrazol-5-yl) biphen-1-yl} methyl} 1.5.6.7.8—Tetrahydro“ 11 Benzothieno II, 3— dl bilimijin 1 4 (3H) — ON

 (1) 2-Ethylthio-1,5,6,7,8-tetrahydro [1] benzothieno [2,3-d] birimidine-1 (3H) —one 2 In the same way as in (2), 2—ethylthio 3 — {[2'-I- (N-trifluoromethylate-trazol-5-yl) bif-n-4-1yl] methyl} -5,6,7,8 —Tetra Hydro

[1] benzothieno [2,3-d] birimidine 1 4 (3 H) 1one was obtained. ^J H-NMR (CDC la) 5 p P m;

 1.30 (3 H, t, J = 7 Hz), 1.7 to 2.0 (4 H, m),

 2.7 to 2.8 (2H, m), 2.9 to 3.1 (2H, m),

 3.13 (2H, q, J = 7Hz), 5.21 (2H, s),

 6.8 to 7.5 (22H, m), 7.89 (1H, dd, J = 1Hz, 8Hz)

(2) Using the compound obtained in (1), the title compound was obtained in substantially the same manner as in Example 2 (3).

^{J H - NMR (DM SO -} de) <5 PP m;

 1.28 (3 H, t, J = 7 H z), 1.7 to 2.0 (4 H, m),

 2. 7 to 3.0 (4 H, m), 3.16 (2 H, q, J = 7 Η ζ),

 5.25 (2 Η, s), 7.05 (2 Η, d, J = 8 Η ζ),

 7.14 (2 Η, d, J = 8 Η ζ), 7.5 to 7.8 (4 Η, m)

 2—Provirthio 3— “2,-(Tetrazol-5-yl) biphenyl-14-yl” I-methyl} 1-5,6.7,8—Tetrahydro “11-Benzoche / [2, 3-d] virimidin 1 4 (3 H) 1 on

 (1) 2-mercapto-1,5,6,7,8-tetrahydro [1] benzothieno [2,3-d] birimidine-1 4 (3H) -on potassium salt 2.0 To a suspension of 0 g of N, N-dimethylformamide in 20 ml of a suspension, 1.48 g (1.2 equivalents) of propyl iodide was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was washed with methanol and washed with methanol to give 2-hydropropylthio 5,6,7,8-tetrahydro [ 1] Benzothieno [2,3—d] birimidine-1 (3H) one crystal 0.62 g was obtained.

 m.p. 2 1 6 to 2 1 7 * C

 Ή-NMR (CD CI 3) <5 ppm;

 1.05 (3 H, t, J = 7 H z),

1.77 (2H, sext, J = 7Hz), 1.8 to 2.0 (4H, m), 2.7 to 2.8 (2 H, m), 2.9 to 3.1 (2 H, m),

3.2 1 (2 H, t, J = 7 Hz), 1 1.100 (1 H, b s)

(2) Using the compound obtained in (1), and in substantially the same manner as in Example 2 (2), 2-butyl birtio-3 -— [[2′-I- (N-trifluoromethyl-tetrazol-5-α) 1) biphen] 4-methyl] methyl 5, 1, 7, 8—tetrahydro [1] benzothieno [2,3-d] pyrimidine 1 4 (3H) Obtained.

_{Ή- NMR CDC 1 3) 5 p} P m;

 0.98 (3 H, t, J = 7 H 2),

 1.68 (2 H, se e t, J = 7 Hz), 1.73-1.96 (4 H, m),

2.68 to 2.84 (2H, m), 2.90 to 3.03 (2H, m),

 3.1 1 (2H, t, J = 7Hz), 5.22 (2H, bs>,

 6. 8 2 ~ 7, 0 0 (6 H, m), 7.07 (2 H, d, J = 8 H z),

7.13 (2H, d, J = 8Hz), 7.18 to 7, 52 (12H, m),

7.8.4 to 7.94 (1 H, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 2 (3).

^J H-NMR (DMS O-de) 5 ppm;

 0.93 (3 H, t, J = 7 H 2),

 1.66 (2H, sext, J = 7Hz), 1.68 ~: L. 9 1 (4H, m),

2.62 to 2.79 (2H, m), 2.79 to 2.94 (2H, m),

 3.16 (2 H, t, J = 7 Hz), 5.28 (2 H, b s),

7.07 (2 H, d _f J = 8 HZ), 7.13 (2 H, d, J = 8 Hz),

7, 4 8 to 7, 7 3 (4H, m) Example 6.

2—Provir-1 3— {“2 '— (Tetralu 5-Gol) Biphen 4-yl JJ Methyl j Thieno 3 2—d 1 Birimidine 1 4 (3H) —On (Compound 4 ) (1) In a solution of 2.2 g (3 equivalents) of sodium in 5 O ml of 2-methoxyethanol, methyl 3-amino-2-thiophenecarboxylate 5.O g and butamidine hydrochloride 4.3 g (1.1 equivalents) were sequentially added, and the mixture was refluxed for 5 hours. After the reaction, 10% hydrochloric acid was added to adjust to <14 to 5, the precipitated crystals were filtered, and the crude product was subjected to silica gel chromatography (elution solvent: dichloromethane: methanol = 99: The resulting product was subjected to 1) to obtain 1.64 g of a crystal of 2-provircheno [3,2-d] birimidine-1 4 (3H) -one. The crystals were recrystallized from methanol to obtain colorless crystals. mp 237-23 9. C

¹ H-NMR <DMS 0-d 6) δ (ppm);

 0.92 (3 H, t, J = 8 H z),

 1. 7 2 (2 H, sext, J = 8 Hz),

 2.60 (2 H, t, J = 8 Hz),

 7.3.4 (1 H, d, J = 5 H z),

 8. 1 4 (1 H, d, J = 5 H z), 1 2.2-: 1 2.5 (1 H, b)

(2) 86 mg (1.1 equivalents) of 60% sodium hydride in oil was washed with hexane; washed twice with Im1; 5 ml of N, N-dimethylformamide was added; 0.38 g 0N, N-dimethylformamide 4 ml solution of the compound obtained in 1) was added dropwise. After stirring at room temperature for 30 minutes, under ice-cooling, N-trifluoromethyl-5- [2- (4,1-bromomethylbifurnyl)] tetrazole 1.20 g (1.1 equivalent) of N, N —5 ml of a dimethylformamide solution was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic eyebrows were washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 2-propyl-1 3 — {[2'-1 (N-trifuyuni). 0.39 g of dimethyl-thitra [5-yl] bifu-n-41-yl] methyl} thieno [3,2-d] birimidine-l-4 (3H) -one was obtained.

¹ H-NMR (CDC ls) δ (ppm);

 0.92 (3 H, t, J = 8 Hz),

1. 7 3 (2 H, sext, J = 8 H z), 2.65 (2 H, t, J = 8 Hz), 5.32 (2 H, s),

6. 8 5~ 7. 55 (23 H , m), 7. 78 <1 H f d, J = 5 H z),

7.90 ~ 8.00 (1H, m)

(3) To a solution of 0.38 g of the compound obtained in (2) in 10 ml of tetrahydrofuran was added 1 ml of 4 N hydrochloric acid, and the mixture was stirred at room temperature with stirring at room temperature. An aqueous solution was added to adjust the pH to 5 to 6, extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give 0.33 g of crystals of the title compound. The crystals were recrystallized from dichloromethane to obtain colorless crystals.

mp 21 3-21 5 ^e C (ie c ..)

 ! H-NMR (DMS O-de) δ (ppm);

 0.88 (3 H, t, J = 8 H 2),

 1, 6 8 (2 H, sext, J = 8 Hz),

 2.72 (2H, t, J = 8Hz), 5.41 (2H, s),

 7.08 (2H, d, J = 8Hz), 7.10 (2H, d, J = 8Hz),

7.38 (1 H, d, J = 5 Hz), 7.48 to 7.75 (H, m),

 8.2 0 (1 H, d, J = 5 Hz) Example 7.

 2-Butyl 3-f "2,1 (tetrazol-5-yl) biphen-14-yl 1 methyl) thieno" 3.2-dl bilimidine-1 4 (3H) -one (compound Five )

(1) A solution of 5.0 g of methanol in 50 ml of methanol was mixed with 5.0 g of methyl 3-ha * -leloylamino-2 thiophene carbo silicate under ice-cooling, and stirred for 18 hours at room temperature. After the reaction, the solvent is distilled off, and the residue is purified by silica gel column chromatography.

(Elution solvent; hexane: diethyl ether-2: 1), and 2-butylthieno [3,2-d] pyrimidine-1 4 (3H) one and 3-valeroylamine 2-thiophenecarboxamide A mixture of compounds (NMR integral value ratio 2: 7) was obtained.

The mixture obtained here was dissolved in 70 ml of methanol, added with 1.19 β (1.2 equivalents) of a hydroxide, and stirred at room temperature at room temperature. After the reaction, add 10% hydrochloric acid The precipitated crystals were washed with water to obtain 2.79 g of crystals of 2-butylthieno [3,2-d] pyrimidine-14 (3H) -one. The crystals were recrystallized from methanol to obtain colorless crystals.

 m.p. 19 1 to 19 3

¹ H-NMR (DMS 0-de) δ (ρ ρ m);

 0.89 (3 H, t, J = 7 H z),

 1.3.3 (2 H, sext, J = 7 Hz),

 1.68 (2 H, q u int, J = 7 H z),

 2.63 (2 H, t, J = 7 H z),

 7.33 (1 H, d, J = 5 H z),

 8.13 (1 H, d, J = 5 Hz), 1 2.35 (1 H, b s)

(2) Wash 88 mg (l. 1 equivalent) of 60% oil-based sodium hydride twice with 1 ml of hexane, add 5 ml of N, N-dimethylformamide, and cool on ice. Below, a solution of the compound 4 (16 mg) obtained in (1) in N, N-dimethylformamide (5 ml) was added dropwise. After stirring at room temperature for 1 hour, the mixture was cooled at 110 and cooled under N-trifurylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazole 1.23 g (l. (1 equivalent) of an N, N-dimethylformamide solution (5 ml) was added dropwise over 5 minutes, stirred at the same temperature for 4 hours, and then stirred at room temperature for 1 hour. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate =: 1) to give 2-butyl-3 — {[2,1- (N-triflic acid). 5-Methyl) thieno [3,2-d] birimidine-1 4 (3H) 1-on (0.79 g) Was.

¹ H-NMR (CDC 13) 5 (ppm);

 0.87 (3 H, t, J = 7 Η ζ),

 1. 3 2 (2 Η, set, J = 7 Η ζ),

 1. 6 8 (2 Η, q u int, J = 7 Η ζ),

2.67 (2 Η, t, J = 7 Η ζ), 5.32 (2 Η, bs), 6.84 to 7.02 (8H, m), 7.10 (2H, d, J = 8Hz), 7.18 to 7.38 (11H, m), 7. 3 8 to 7.5 3 (2 H, 'm),

7, 7 8 (1 H, <1, J = 5 H z), 7.88 to 7.98 (1 H, m)

<3) To a solution of 0.7 Sg of the compound obtained in (2) in 15 ml of tetrahydrofuran was added 2 ml of 4N hydrochloric acid, and the mixture was stirred at room temperature for a while. After the reaction, an aqueous solution of sodium hydrogencarbonate was added to adjust the pH to 4 to 5, extracted with ethyl acetate, and the attached layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.66 g of the title compound.

 JH-NMR (DMS O-de) 5 (PPm);

 0.83 (3 H, t, J = 7 H z),

 1.29 (2 H, sext, J = 7 Hz),

 1. 6 3 (2 H, q u int, J = 7 H z),

 2.72 (2H, t, J = 7Hz), 5.41 (2H, s),

 7.08 (2H, d, J = 8Hz), 7.10 (2H, d, J = 8Hz),

7.38 (1H, d, J = 5Hz), 7.45 to 7.75 (4H, m),

8.2 0 (1 H, d, J = 5 Hz) Example 8.

 2—Probyl-1 —— {Γ2 · '— (Tetrazol-5-yl) biphen-1-yl1methyl} -17—MethylthienoΓ3.2-d1Birimidine-1 4 (3H) One-one (compound 6)

 (1) Methyl 3-amino-4 monomethyl 1-2-thiophenecarboxylate 5.

0 g of 4 N hydrogen chloride dioxane 50 ml solution was added to butyronitrile 2.8 ml (1.

(1 equivalent) and stirred at room temperature for 1 week. After adding water and washing with ethyl acetate, the aqueous layer was neutralized with potassium hydroxide and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (elution solvent; hexane: ^ ethyl = 3: 1). 0-26 g of crystals of —Brobilu 7-methylthieno [3,2-d] birimidine-1 4 (3H) —one was obtained. mp 2 16 ~ 2 17 ° C

 'H-NMR (DMS O-de) δ (ppm);

 0.93 (3 H, t, J = 7 H z),

 1.73 (2H, sext, J = 7Hz), 2.28 <3H, s),

 2.62 (2 H, t, J = 7 H z), 7.78 (1 H, s),

 1 2.25 to 12.40 (1 H, b)

(2) Using the compound obtained in (1), and in substantially the same manner as in Example 7 (2), the 2-p-pill-1-3 — {[2,1- (N-triphenylmethylethyl) Tolazole-5-yl) biphenyl-14-yl] methyl} -1-7-methylthieno [3,2-d] pyrimidine-14 (3H) -one was obtained.

 m.p. 185-187. C (d e c.)

 Ή-NMR (CDCI 3) δ (ρρm);

 0.93 (3 Η, t, J = 7 Η ζ),

 1. 7 6 (2 Η, sext, J = 7 Η ζ),

 2.39 (3Η, d, J = lHz), 2.64 (2Η, t, J = 7Η 7),

5.32 (2Η, b s), 6.85 to 7.02 (8Η, m),

 7.09 (2 Η, d, J = 8 Η ζ), 7.18 to 7.37 (10 0, m),

7. 3 8 to 7.5 2 (3 Η, m), 7.88 to 7.96 (1 Η, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3).

 "H-NMR (DMS O-de) δ (ρ p m);

 0.91 (3 H, t, J = 7 H z),

 1.70 (2 H, sext, J = 7 Hz),

 2.32 (3H, d, J = 1Hz), 2.72 (2H, t, J = 7Hz), 5.41 (2H, s), 7.08 (4 H, s),

7.48 to 7.73 (4H, m), 7.84 (1H, q, J = 1H2) Example 9.

 2—Butyl 3 — (“2'-I (Tetrazol-5-yl) Biphen-1-yl 1 Methyl} 1—7-Methithieno“ 3,2-d1 Pyrimidine 1 4 (3 H) One (compound 7)

(1) Substantially in the same manner as in Example 8 (1), ² -butyl-1-7-methylthieno [3,2-d] birimidine-14 (3H) -one was obtained.

 m.p.190-: 192. C

 JH-NMR (DMS O-d e) δ (ρ p m);

 0.9 Ό (3 Η, t, J = 7 Η ζ),

 1. 3 5 (2 Η, se χ t, J = 7 Η ζ),

 1. 7 0 (2 Η, q u int, J = 7 Η ζ),

 2.28 (3 Η, d, J = 1 Η ζ), 2.63 (2 Η, t, J = 7 Η ζ), 7.77 (1 Η, q, J = 1 Η ζ) , 1 2. 3 3 (1 Η, bs)

(2) Using the compound obtained in (1), and using substantially the same manner as in Example 7 (2), 2-butyl-3 — {[2'-I- (N-life-methylethyllutetrasol-5-) 1) Biphenyl 4-methyl] methyl} -17-methylthieno [3,2-d] birimidine-14 (3H) one was obtained.

 JH-NMR (CDC13) δ (ppm);

 0.8 8 <3 H, t, J = 7 H z),

 1 · 3 3 (2 H, sext, J = 7 Hz),

 1. 7 1 (2 H, q u int, J = 7 H,

 2.39 (3H, d, J = 1Hz), 2.67 (2H, t, J = 7Hz), 5.32 (2H, bs), 6.86 ~ 7. 00 (8 H, m),

 7.08 (2H, d, J = 8Hz), 7.18 to 7.50 <13H, m), 7. & 8 to 7.96 (1H, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3). mp 208-209 (dec.)

! H—NMR (DMS d- ₁ ) δ (ppm);

 0.83 (3 H, t, J = 7 H z),

 1.3.3 (2 H, sext, J = 7 Hz),

 1.67 (2 H, q u int, J = 7 H z), 2.31 (3 H, s),

 2.74 (2 H, t, J = 7 Hz), 5.41 (2 H, b s),

 7.0.0 (4H, s), 7.48 to 7.74 (4H, m),

 7.84 (1H, s) Example 10.

 2-butyl-3— {C2,1 (tetrazol-5-yl) biphen-1-yl] methyl} -1 6-t-butylthieno “3,2-d] birimidine-1 4 (3 H) — ON (Compound 8)

 (1) In the same manner as in Example 2 (1), 2-butyl-6-t-butylthieno [3,2-d] birimidine-14 (3H) one was obtained.

 m.p. 193-: 196. C

¹ H-NMR (DMS 0-d ₆ ) δ (ppm);

 0.88 (3 H, t, J = 7 H z),

 1.29 (2 H, sext, J = 7 Hz), 1.38 (9 H, s),

 1.67 (2 H, q u int, J = 7 H z),

 2.59 (2 H, t, J = 7 Hz), 7.13 (1 H, s),

 1 2.25 (1 H, b s)

(2) Using the compound obtained in (1), substantially in the same manner as in Example 7 (2), 2—butyl-3 — {[2′-I- (N-triphenylmethylthiol trazol-5 -Yl) biphen-l-yl] methyl} -l- 6-t-butylthieno [3,2-d] bilimidine-4 (3H)

_{^{1 H - NMR (CDC 1 3}} ) δ (ppm);

0.87 (3 H, t, J = 7 H z), I. 3 2 (2 H, sext, J = 7 H z), 1.6 (9 H, s),

 1, 6 6 (2 H, q u int, J = 7 H z),

 2.63 (2H, t, J = 7Hz), 5.31 (2H, bs),

 6.82 to 7.01 (9H, m), 7.07 (2H, d, J = 8Hz),

7.14 to 7.55 (12H, m), 7.88 to 7.98 (1H, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3).

 ! H—NMR (DMS O-") δ (ρ p m);

 0.82 (3 H, t, J = 7 H z),

 1.28 (2H, sext, J = 7Hz), 1.40 (9H, s>,

 1. 6 2 (2 H, q u int, J = 7 H z),

 2.70 (2 H, t, J = 7 Hz), 5.38 (2 H, b s),

 7.08 (4 H, s), 7.20 (1 H, s),

 7.47-7.74 (4H, m), Example 1 1.

 2-Butyl 3-{{2,1- (tetrazol-5-yl) biphen-4-yl-1methyl} -1-6-fuerthieno “3,2-d1Birimidine-1 4 (3H) -on (Compound 9)

 (I) In the same manner as in Example 2 (1), 2-butyl-6-phenylthieno [3,2-d] birimidine-14 (3H) one was obtained.

 m.p. 2 2 1 ~ 2 2 2 'C

^J H-NMR (DMS 0-d $) δ (ppm);

 0.91 (3 H, t, J = 7 H z),

 1. 3 4 (2 H, set, J = 7 H 2),

 1. 7 1 (2 H, q u int, J = 7 H z),

2.63 (2H, t, J = 7Hz), 7.42 to 7.58 (3H, m), 7.78 (1H, s), 7.78 to 7 . 9 3 (2 H, m), 1 2.38 (1 H, bs)

(2) Using the compound obtained in (1), substantially in the same manner as in Example 7 (2), 2-butyl-1 3-{[2,1 (N-triphenylmethylethyltetra Zol-5-yl) biphenyl-14-yl] methyl} -16-phenylthieno [3,2-d] pyrimidine-14 (3H) -one was obtained.

 'H-NMR (CDCls) δ (ppm);

 0.8.8 (3 Η, t, J = 7 Η ζ),

 1. 3 4 (2 Η, sext, J = 7 Η ζ),

 1. 7 0 (2 Η, q u int, J = 7 Η ζ),

 2.67 (2 Η, t, J = 7 Η ζ), 5.33 (2 Η, b s),

 6.80 to 7.60 (26 Η, m), 7.65 to 7.80 (2 Η, m),

7. 8 8 to 7.98 (1 mm, m)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3).

 m.p. 238-239. C (d e c.)

¹ H-NMR (DMS 0-d ₆ ) δ (ppm);

 0.84 (3 H, t, J = 7 H z),

 1. 3 2 (2 H, set, J = 7 H z),

 1.65 (2 H, q u int, J = 7 H z),

 2.75 (2 H, t, J = 7 Hz), 5.42 (2 H, s),

 7.08 (2H, d, J = 8H2), 7.13 (2H, d, J = 8Hz),

7.4 4 to 7.75 (7H, m), 7.82 to 7.95 (3H, m) Example 1 2.

 1-Propylthio-1 3— {Γ2,1 (tetrazol-5-yl) biphen-14-yl1methyl} thieno “3,2-d1 birimidine-1 4 (3H) One on

(1) 2—melkabuteno [3,2-d] birimidine 1 4 (3 H) — on 3. To a solution of 64 g N, N-dimethylformamide (50 ml) was added 1.1 g (1 equivalent) of a hydroxide of water and stirred for 1 hour. Next, 3.36 g (1 toddler) of provir iodide was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water, and the precipitated crystals were filtered and dried under reduced pressure to obtain 3.89 g of 2-bromothiocheno [3,2-d] birimidine-4 (3H) -one.

mp 16 1 to: 1 6 3 ^e C (de c.)

 H-NMR (DMSO-de) δ (ppm);

 0.99 (3 H, t, J = 7 H z),

 1. 7 1 (2 H, sext, J = 7 Hz),

3.18 (2 H, t _f J = 7 H z),

 7.30 (1 H, d, J = 5 H z),

 8.13 (1H, d, J = 5Hz), 12.72 (1H, bs)

<2> Using the compound obtained in (1), and in substantially the same manner as in Example 7 (2), 2-provothio-13-{[2'-i- (N-triphenylmethyl-tetrazol-5 —Il) Bifun 4Ill] METELL) Thieno [3,2-d] Bilimidin I 4 (3H) I got one.

Ή-NMR (CDCI ₃ ) δ (ppm);

 1. 0 0 (3 H, t, J = 7 H z),

 1. 7 1 (2 H, sext, J = 7 Hz),

 3.15 (2 H, t, J = 7 H z), 5.29 (2 H, s),

 6.90 to 7.50 (23H, m), 7.73 (1H, d, J = 5Hz),

7.90 (1 H, d d, J = 1 H z, 8 H 2)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3).

 ! H—NMR (DMS O-de) δ (ppm);

 0.96 (3 H, t, J = 7 H z),

1. 6 9 (2 H, sext, J = 7 H z), 3.20 (2H, t, 7Hz) 5.34 (2H, s),

7.06 (2 H, d, J = 8 Hz) 7.18 (2 H, d, J = 8 Hz)

7.34 (1H, d, = 5Hz) 7.50 to 7.70 (4H, m),

8.2 0 (1 H, d, = 5 H z) Example 1 3.

 2-Ethylthio-3— [J2 '-(Tetrazol-5-yl) Biphenyl-14-ylmethyl} Thieno “3.2-d1 Bilimidine-1 4 (3 H) — ON

 (1) 2-Ethylthiothieno [3,2-d] pyrimidine-1 (3H) one is used, and 2-ethylthiothieno is substantially the same as in Example 7 <2). {[2'-I (N-trifur-methyl-tetrazol-5-yl) bifu-un-1-4-yl] methyl} Thieno [3,2-d] birimidine-1 ( 3 H) I got one.

¹ H-NMR (CDC 1 a) δ (ppm);

 1.3.3 (3 H, t, J = 7 Hz), 3.17 (2 H, q, J = 7 Hz),

5.28 (2 H, s), 6.80 to 7.6 0 (23 H, m),

 7.74 (1 H, d, J = 5 Hz),

 7.90 (1 H, d d, J = l H z, 8 H z)

(2) Using the compound obtained in (1), the title compound was obtained in substantially the same manner as in Example 7 (3).

¹ H-NMR (DMS 0-d ₆ ) δ (ρ pm);

 1.31 (3H, t, J = 7Hz), 3.22 (2H, q, J = 7Hz), 5.33 (2H, s), 7.06 ( 2 H, d, J = 8 H z),

 7.18 (2 H, d, J = 8 Hz), 7.35 (1 H, d, J = 5 Hz), 7.50 to 7.70 (4 H, m), 8.2 0 (1 H, d, J = 5 Hz) Example 1 4.

2-butyltin 3 -— {“2,1- (tetrazol-5-H-biphenyl-1.4-yl; 1-methyl) thieno _3 _t 2 -d J bilimidine-1 4 C3 H ) One ON (1) 2-Mercaptocheno [3,2-d] pyrimidine-1 4 (3H) -one 5.52 g of a mixed solution of 60 ml of N, N-dimethylformamide and 60 ml of methanol To the mixture was added 1.68 g (1 equivalent) of potassium hydroxide, and the mixture was stirred at room temperature for 1 hour, and then 6.62 g (1.2 equivalents) of butyl iodide was added, and the mixture was stirred at room temperature for 1 minute. After the reaction, the solvent was distilled off, water was added, and the precipitated crystal was passed through, dried under reduced pressure, and crystallized of 2-butylthiothieno [3,2-d] pyrimidine-14 (3H) -one 5. Got 55 g o

 m.p. 13 9-14 1 'C

 H—NMR (DMS O-de) δ (ρ pm);

 0, 9 6 (3 Η, t, J = 7 Η ζ),

 1.49 (2 Η, sext, J = 7 Η ζ),

 1.76 (2 Η, q u int, J = 7 Η ζ),

 3.2 & (2 Η, t, J = 7 Η ζ), 7.26 (1 Η, d, J = 5 Η ζ), 7.79 (1 Η, d, J = 5 Η ζ), 1 1.73 (1 Η, bs)

(2) Using the compound obtained in (1) and substantially as in Example 7 (2), 2-butylthio-3-({[2 '-(N-tophenylmethyl-tetrazole-5-) Le) biphen-l-methyl] thieno [3,2-d] bilimidine-l 4- (3H) -one.

 'H-NMR (CD Cl s) δ (ρ ρ m);

 0.93 (3 H, t, J = 7 H 2),

 1.43 (2 H, set, J = 7 H 2),

 1.6 1 (2 H, q u i t, J = 7 H z),

 3.16 (2 H, t, J = 7 Hz), 5.28 (2 H, s),

6. 8 0~7. 50 (23 H r m), 7. 73 (1 H, d, J = 5 H 2),

7.89 (1 H, d d, J = 2 Hz, 8 Hz)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 7 (3). ^J H-NMR (DS 0-d ₆ ) δ (ppm):

 0.89 (3 H, t, J = 7 H z),

 1. 3 8 (2 H, sext, J = 7 Hz),

 1.65 (2 H, q u int, J = 7 H z),

 3.22 (2H, t, J = 7H2), 5.33 (2H, s),

 7.ϋ 6 (2 H, d, J = 8 Hz), 7.18 (2 H, d, J = 8 Hz),

7.3.4 (1H, d, J = 5Hz), 7.50 to 7.7.0 (4H, m),

8.2 0 (1 H, d, J = 5 Hz) Example 1 5.

 2—Brovirchio 3— “4- (2-carboxy-1.3.6—cyclohexyl benzoamide) Benzyl” 1 Thieno “3,2-d] Birimidin-1 4 (3H) —On

 (1) Substantially the same as Example 7 (2) using 2-bromothiothieno [3,2-d] pyrimidin-14 (3H) one obtained in Example 1 2 (1). Thus, 2-propylthio-3- (4-nitrobenzyl) thieno [3,2-d] birimidine-14 (3H) -one was obtained.

 m. ρ. 1 30 ~: 1 3 2 * C

¹ H-NMR (CDCI 3) δ (ppm);

 1. 0 2 (3 H, t, J = 7 H z),

 1.75 (2 H, sext, J = 7 Hz),

 3.23 (2 H, t, J = 7 Hz), 5.48 (2 H, s),

 7.23 (1 H, d, J = 5 Hz), 7.49 (2 H, d, J = 8 Hz),

7.78 (1 H, d, J = 5 Hz), 8.18 (2 H, d, J = 8 H 2)

(2) 1.3 ml of acetic acid and 0.60 g of iron were added to a solution of 1.10 g of the compound obtained in (1) in 100 ml of methanol, and the mixture was refluxed for 8 hours. The reaction solution was filtered through celite, the solvent was distilled off, water was added to the residue, and the mixture was neutralized with saturated sodium bicarbonate water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and then dried. After drying over magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (elution solvent; Xanthine: acid acid-9: 1) attached to 2-bromothio-1-3- (4-amino benzyl) thieno [3,2-d] bilimidine-1 (3H) -one 0.72 g of the crystal was obtained. The crystals were recrystallized from dichloromethane to obtain colorless crystals.

 m.p. 158-: I59. C

^! H-NMR (CDC 1 s) δ (ppm);

 1.03 (3 H, t, J = 7 H z),

 1.76 (2 H, se ext, J = 7 H z),

 3.30 (2 H, t, J = 7 Hz), 5.32 (2 H, s),

 6.81 (2 H, d, J = 8 Hz), 71.8 (1 H, d, J = 5 Hz),

7.28 (2 H, d, J = 8 Hz), 7.71 (1 H, d, J = 5 H 2)

(3) To a solution of 0.30 g of the compound obtained in (2) in 20 ml of methylene chloride was added 0.22 g (l. 1 equivalent) of anhydrous 3,6-dichlorophthalic acid and stirred at room temperature for 1 hour. did. The precipitated crystals were filtered to obtain 0.48 g of the title compound as crystals. The crystals were recrystallized from acetone-hexane to obtain colorless crystals.

 m. p. 1 53-: at I 54

^J H-NMR (DMS 0-d ₆ ) δ (ppm);

 0.97 (3 H, t, J = 7 H z),

 1.70 (2 H, se ext, J = 7 H z),

 3.20 (2 H, t, J = 7 H z), 532 (2 H, s),

 7, 24 (2 H, d, J = 8 Hz), 7.34 (1 H, d, J = 5 Hz),

7.58 (2H, d, J = 8H2), 7.67 (2H, s),

 8.19 (1H, d, J = 5Hz) Example 1 6.

 2-Propirthio-1-3- (2-sulfobenzamide) Benzyl 1 Che Γ3,2-d 1 Birimidine 1 4 (3H) 1-one

Using the compound obtained in Example 15 (2), the title compound was obtained in substantially the same manner as in Example 15 (3). ¹ H-NMR (DMS O—ds) δ (ppm);

 0.97 (3 H, t, J = 7 H z),

 1. 7 1 (2 H, sext, J = 7 Hz),

 3.20 (2H, t, J = 7Hz), 5.33 (2H, s),

 7.2 2 (2 H, ύ, J = 8 Hz), 7.3 4 (1 H, d, J = 5 Hz),

7.43 to 7.54 (2H, m), 7.60 (2H, d, J = 8Hz),

7.65 to 7.76 (1H, m), 7.84 to 7.93 (1H, m),

 8.19 (1H, d, J = 5Hz) Example 1 7.

 2-Provide-1 3 — {“2 '-(Tetrazol-5-yl) biphen-1-yl] methyl} Thieno“ 3,4-d] pyrimidine-1 4 (3 H) One compound (compound) 0) (1) 60% oily sodium hydride 42 g (l. 1 eq.) Was washed with 1 ml of hexane for 2 N, and then N, Ν-dimethylforma Add 15 ml of the amide, and add 2 ml of 2-propylbieno [3,4-d] birimidine-1 (3H) one under ice-cooling 1.85 g of N, N-dimethylformamide 25 ml Solution was added dropwise After stirring at room temperature for 1 hour, the mixture was cooled to 110 ° C and cooled to N-triphenylmethyl-1- (2-((4'-bromomethylbiphenyl))] tetrazole A solution of 6.37 g (1.2 equivalents) of N, N-dimethylformamide solution (20 ml) was added dropwise over 20 minutes, stirred at the same temperature for 4 hours, and then stirred at room temperature for one hour. After the reaction, add water and extract with ethyl acetate. After drying with magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluting solvent; hexane: ethyl acetate =: 1) to give a residue. —Provir-1 3 — {[2 '-(N—Trifluoromethyl-tetrazol-5-yl) -biphenyl-14-yl] methyl} thieno [3,4-d] bilimi The crystals obtained here were recrystallized from ethyl ethyl hexane to give colorless crystals.

mp 1 4 9-1 5 1 ^e C

^J H-NMR (CDC 13) <5 p P m;

 0.93 (3 H, t, J = 7 H z),

1. 7 2 (2 H, set, J = 7 H z), 2. 5 7 (2 H, t, J = 7 H z), 5.2 2 (2 H, bs),

 6.82 to 7.02 (8H, m), 7.09 (2H, d, J = 8Hz), 7.18 to 7.57 (13H, m), 7. 8 8 to 7.97 (1 H, m),

8.2 9 (1 H, d, J = 3 H z)

(2) To a solution of 5.12 g of the compound obtained in (1) in 100 ml of tetrahydrofuran was added 4 i) mI of 4N hydrochloric acid, and the mixture was stirred at room temperature for one minute. After the reaction, an aqueous solution of sodium hydrogen carbonate was added to adjust the pH to 5 to 6, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off, and the residue was washed with ethyl acetate to give 2.17 g of the title compound as colorless crystals.

m.ρ. 2 0 0 ~ 2 0 2 ^C C (de c.)

'H-NMR (DM SO-d ₆ ) δ pp

 0.8 8 (3 H, t, J = 7 H z),

 1. 6 7 (2 H, se ext, J = 7 H z),

 2.62 (2H, t, J = 7Hz), 5.30 (2H, bs),

 7.09 (4 H, S), 7.48 to 7.7 3 (4 H, m),

 7.77 (1H, d, J = 3Hz), 8.50 (1H, d, J = 3Hz)

Example 1 8.

 2-butyl-1-3-U2 '-(tetrazol-5-yl) biphenyl-4-yl-methyl) thieno "3,4-dl bilimidine-1 4C3 H) one (compound 11 1) (1) methyl Ammonia was saturated with a solution of 5.84 g of methanol in 60 ml of ice under ice-cooling, and the mixture was stirred for 6 hours at room temperature. The crystals were recrystallized from methanol to obtain 4.77 g of 3-valeroylamine 4-theofencarpoxyamide.

The compound 2.Og obtained here was dissolved in 40 ml of methanol, 0.70 g (1.2 equivalents) of a hydrating power was added, and the mixture was heated and refluxed for 10 hours. % Hydrochloric acid was added to adjust the pH to 7-8, and the precipitated crystals were washed with water and crystallized with 2-butylethyleno [3,4-1C!] Birimidine-1 4 (3H) -one 1,71 g This crystal was meta- It was recrystallized from an aqueous solution of ethanol to obtain colorless crystals.

 m. p. 1 85-: I 87 ° C

 1 H-N MR (DMSO-de) δ p p m;

 0.90 (3 H, t, J = 7 H z),

 1.3.3 (2 H, sext, J = 7 Hz),

 1.67 (2 H, q u int, J = 7 H z),

 2.53 (2H, t, J = 7Hz), 7.66 (1H, d, J = 3Hz), 8.41 (1H, d, J = 3Hz) , 11.44〜: 11.66 (1H, W>

(2) Using the compound obtained in <1), 2-butyl-3-({[2 '-(N-triphenylmethyl-methyl) -tetra] was obtained in substantially the same manner as in Example 17 (1). Zol-5-isole) biphenyl-1-methyl] thieno [3,4-d] birimidine-14 (3H) one was obtained.

¹ H-NMR (CDC 13) δ ppm;

 0.87 (3 H, t, J = 7 Η ζ),

 1. 3 2 (2 Η, sext, J = 7 Η ζ),

 1. 6 8 (2 Η, q u int, J = 7 Η ζ),

 2. 5 8 (2 Η, t, J = 7 Η ζ), 5.2 3 (2 Η, b s),

 6.82 to 7.02 (8Η, m), 7.08 (2 2, d, J = 8Η =),

7.17 to 7.58 (13 Η, m), 7.85 to 8.00 (1 Η, m),

8.2 9 (1 Η, d, J = 3 Η ζ)

(3) Using the compound obtained in (2), the title compound was obtained in substantially the same manner as in Example 17 (2).

^{J H - NMR (DM SO -} d 6) δ ppm;

 0.82 (3 H, t, J = 7 H z),

 1.30 (2 H, sext, J = 7 Hz),

 1. 6 2 (2 H, q u int, J = 7 H z),

2.63 (2 H, t, J = 7 Hz), 5.30 (2 H, bs), 7.08 (4 H, s), 7.48 to 7.73 (H, m),

7.76 (1 H, d, J = 3 Hz), 8.50 (1 H, d, J = 3 Hz)

Example 1 9.

 Neuve Mouth Building 1 3- ((2,-(tetrazol-5-yl) biphen-1-4-ylmethyl) thieno "3.4-d1 birimidine-1 4 (3H) -on Calcium salt 2-Probiyl-1 obtained in Example 17 3-{[2,1 (Tetrazol-5-yl) biphen-14-1yl] methyl} thieno [3,4-d] Bilimidine 4 (3H) -one 0.87 g of methanol in 10 ml of methanol, 114 mg (1 equivalent) of potassium hydroxide in 2 ml of methanol Then, 100 ml of ether was added under ice-cooling, and the precipitate was filtered to obtain 0.84 g of the title compound.

 H—NMR (DM S 0—) δ p p m;

 0, 9 1 (3 H, t, J = 7 H z),

 1.70 (2 H, sext, J = 7 Hz),

 2. 6 € (2 H, t, J = 7 H z), 5.26 <2 H, b s),

 6.97 (2H, d, J = 8Hz), 7.09 (2H, d, J = 8Hz),

7.23 to 7.40 (3H, m), 7.48 to 7.58 (1H, m), 7.75 (1H, d, J = 3Hz), 8 . 4 9 (1 H, d, J = 3 H z)

Example 20.

 2—Propyl-1-3- [2,1- (tetrazol-5-yl) biphen-1-yl 1-methyl} -1-5-Methylthieno Γ2,3-d1 Birimidine-1 4 (3H ) One-potassium lithium salt

2-Provyl-1 obtained in Example 1 3 — {[2 '— (Tetrazol-5-yl) biphen-14-yl] methyl} -1-5-Methylthieno [2,3-d] Birimidine mono 4 (3H) -one 1 4.9 g of methanol in 30 ml of methanol, 1.89 g (1 equivalent) of potassium hydroxide in methanol 20 ml Was added and stirred at room temperature for 1 hour. Under ice-cooling, 300 ml of ether was added, and the mixture was passed through the precipitate to obtain 14.8 g of the title compound. _{^{1 H - NMR (CD 3 0}} D) δ ppm;

 0.94 (3 H, t, J = 7 H z),

 1. 7 3 (2 H, sext, J = 7 Hz),

 2.52 (3 H, d, J = 1 Hz), 2.72 (2 H, t, J = 7 Hz),

5.32 (2 H, ti s), 6.98 (2 H, d, J = 8 Hz),

 7.09 (2H, d, J = 8Hz), 7.10 (1H, q, J = 1Hz),

7.25 to 7.40 (3H, m), 7.5h to 7.6 (1H, m)

 2-butyl-3-1-{[2 '-(tetrazol-5-yl) biphenyl-4-yl1 methinole} —5—methylthieno 2,3-d1 bilimidine One 4 (3H) —Onium salt

 2-butyl-3 obtained in Example 2 — {[2'-I (tetrazol-5-yl) biphenyl-4-yl] methyl} — 5-methylthiothieno [2,3-d] bi To a solution of 0.53 g of limidine-one 4 (3H) -one in 5 ml of methanol was added a 2 ml solution of 65 mg (1 equivalent) of lithium hydroxide in methanol, and the mixture was stirred at room temperature. Stir for 1 hour. Under ice cooling, 100 ml of ether was added, and the precipitate was filtered to obtain 0.48 g of the title compound.

 iH—NMR (C DsOD) δ p p m;

 0.89 (3 H, t, J = 7 Η ζ),

 1. 3 7 (2 Η, sext, J = 7 Η ζ),

 1. 6 8 (2 Η, q u int, J = 7 Η ζ),

 2.52 (3Η, d, J = lHz), 2.74 (2H, 't, J = 7ΗΗ), 5.38 (2Η, bs), 6.93 (1 Η, q, J = 1 Η ζ),

 7.02 (2 Η, d, J = 8 Η ζ), 7.11 (2 Η, d, J = 8 Η ζ), 7.35 to 7.56 (4 Η, m) test An example

The measurement of the angiotensin Π receptor binding reaction of the compound of the present invention can be carried out by the method described in J. Pharmacoco 1. Ex. Ther., Pp. 247, pp. 1 (1988, PC ong et al.) in the following manner.

 [Preparation of receptor sample]

 After decapitation of the rat, the adrenal gland was removed and the cortex was separated. 50 times the adrenal cortex

It was homogenized with 0 mM Tris-HCl buffer (ρH7.5). The homogenate was centrifuged at 1000 × g for 5 minutes and the supernatant was further ultracentrifuged at 480 × g for 10 minutes. The sediment was suspended in 50 mM toI;

 [Receptor binding reaction]

300 nM [ ³ H] angiotensin E in 1.0 ml of receptor standard

1 / mm o 1) an aqueous solution 1 0 # 1, and the specimen (the present compound) of 1 (J - ⁸ ~; was added I Y one ⁴ Micromax dimethylsulfoxide丰Cid solution 1 0 # 1, 0. 5 Micromax chloride Magnesium aqueous solution and 25% aqueous serum albumin solution were each added with 10 # 1 and reacted for 1 hour with 26. After completion of the reaction, the mixture was rapidly filtered through a glass filter (GFB Zittman) and filtered. The filter was washed three times with 3 ml of 50 mM Tris-HCl buffer (ρ Η 7.5) The radioactivity on the filter was determined by liquid scintillation with 10 ml of Aquasol 2 scintillation overnight Non-specific binding was 100 nM.

^[3 H] and angiopathy O Tianjin E solution 1 0 / i 1 count obtained in the presence, by subtracting this was determined specific binding at each瀵度analyte.

 [Data processing]

For the data, the ratio to the control was determined from the specific binding force obtained in the presence of the sample, and the inhibition rate of each test was calculated from this. The 50% inhibitory concentration (ICSB) was determined by a curve-fitting method using a computer. The results are shown in Table 1. Sample IC 50 value (β Μ) Compound 1 Ό. 0 3 4 Compound 2 0.0.29 Compound 3 0.0.03 7 Compound 4 0.0.19 Compound 5 0.0 2 2 Compound 6 0.0.0 18 Compound 7 0.04 9 Compound 8 0.05 2 Compound 90, 0 64 Compound 1 0 0.01 0 0 Compound 1 1 0.0.17

Claims

The scope of the claims  (1 set

[Where,

(In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a fluorine group, or when R ¹ and R ² are adjacent to each other, And R ¹ and R ² together represent an alkylene group having 3 to 5 carbon atoms.) Represents a group represented by the formula: wherein R ³ is an alkyl group or a carbon atom having 1 to 7 carbon atoms. indicates 1 to 7 alkylthio group, B represents a group represented by a carbon one-carbon single锆合or formula one NHCO-, R ⁴ represents a carboxyl group, sulfoxyl group or Tetorazoru 5 I group, X represents a hydrogen atom or a halogen atom.] And a salt thereof.