JPH08143571A - Thieno(2,3-d)pyrimidin-4-one derivative - Google Patents

Abstract

PURPOSE: To obtain a thieno[2,3-D]phrimidin-4-one derivative useful as treating hypertension, angina pectoris and cardiac insufficiency failure, having inhibitory action on strong cyclic GMP specific phosphodiesterase, comprising a prescribed one skeleton. CONSTITUTION: This compound is shown by formula I [R<1> is a 1-4C alkyl; X is phenoxy, morpholino, piperidino, pyrrolidino, 4-carbethoxypiperidino, 4-(2- hydroxyethyl)piperazino or R<2> R<3> N (R<2> and R<3> are each H, a 1-4C alkyl or a 2-4C hydroxyalkyl)] such as 4-methyl-2-(5-nitro-2-propoxybenzoylamido) thiophene-3-carboxamide. For example, the compound is preferably obtained by reacting a 2-aminothiophene-3-carboxamide of formula II with a compound of formula III in the presence of a base such as triethylamine in an organic solvent such as N,N-dimethylformamide at 0 deg.C to the reflux temperature and treating the prepared compound of formula IV with a base such as NaOH.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a thieno [2,3-d] pyrimidin-4-one derivative having a cyclic GMP-specific phosphodiesterase inhibitory activity.

[0002]

2. Description of the Related Art Conventionally, as a cyclic GMP-specific phosphodiesterase inhibitor having a thienopyrimidine skeleton, the compound of JP-A-2-56484 has been known, but its inhibitory action was weak.

[0003]

The object of the present invention is to provide a compound having a strong cyclic GMP-specific phosphodiesterase inhibitory action, and by extension, hypertension, angina, heart failure, myocardial infarction, arteriosclerosis, asthma, It is useful for treating chronic reversible obstructive pneumonia such as bronchitis, atopic dermatitis and allergic rhinitis.

[0004]

Means for Solving the Problems As a result of diligent studies of compounds having a cyclic GMP-specific phosphodiesterase inhibitory effect, the present inventors have found that certain thieno [2,3
It was found that a compound having a -d] pyrimidin-4-one skeleton satisfies the object, and based on this finding, the present invention was completed.

That is, the present invention is

[0006]

Embedded image

[In the chemical formula 3, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and X represents a phenoxy group, a morpholino group, a piperidino group, a pyrrolidino group, a 4-carbethoxypiperidino group, 4- ( 2-hydroxyethyl) piperazino group or R ² R ³ N group is shown. Here, R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group having 2 to 4 carbon atoms. ] The thieno [2,3-d] pyrimidin-4-one derivative represented by these, and its salt,

[0008]

[Chemical 4]

[In the chemical formula 4, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and Y represents an amino group or a nitro group. ] Thieno [2,3-d] pyrimidine-
It is a 4-one derivative and its salt.

In the present invention, the alkyl group having 1 to 4 carbon atoms is a linear or branched alkyl group such as methyl group, ethyl group, propyl group, isopropyl group,
The hydroxyalkyl group having 2 to 4 carbon atoms means 2-
Hydroxyethyl group, 3-hydroxypropyl group, 2-
A linear or branched hydroxyalkyl group such as a hydroxypropyl group and a 2-hydroxy-2-methylpropyl group. The compound of the present invention can be produced, for example, by the production scheme shown in Chemical formula 5.

[0011]

Embedded image

[In the chemical formula 5, R ¹ , R ² and R ³ have the same meanings as described above. ] 2-Aminothiophene-3-carboxamide represented by Chemical Formula 6 as a starting material

[0013]

[Chemical 6]

And

[0015]

[Chemical 7]

[In chemical formula 7, R ¹ has the same meaning as described above. ]
The compound represented by is reacted in the presence of a base,

[0017]

Embedded image

[In the chemical formula 8, R ¹ has the same meaning as described above. ]
A compound represented by

Here, the base is triethylamine,
An organic base such as pyridine can be used, and a solvent such as N, N-dimethylformamide, tetrahydrofuran, acetone, chloroform, or dichloromethane can be used alone or in combination as a reaction solvent. The reaction temperature is from 0 ° C to the reflux temperature.

Then, by treating the compound represented by Chemical formula 8 with a base,

[0021]

[Chemical 9]

[In Chemical Formula 9, R ¹ has the same meaning as described above. ]
By obtaining the compound represented by and reducing the nitro group of

[0023]

[Chemical 10]

[In Chemical Formula 10, R ¹ has the same meaning as described above. ] The compound represented by this is obtained.

Here, an inorganic base such as potassium hydroxide or sodium hydroxide can be used as the base, an alcohol solvent such as methanol or ethanol can be used as the reaction solvent, and hydrogen peroxide can be used. Water can be added. The reaction temperature is from room temperature to reflux temperature.

As the reducing agent, palladium carbon-hydrogen, nickel chloride-sodium borohydride, iron-acetic acid or the like can be used, and the reaction solvent is methanol, ethanol, tetrahydrofuran, acetic acid or the like. They can be used alone or as a mixture. The reaction temperature is from 0 ° C to the reflux temperature.

Then, the compound represented by Chemical formula 10 is reacted with phenyl chloroformate in the presence of a base,

[0028]

[Chemical 11]

[In chemical formula 11, R ¹ has the same meaning as described above. ] The compound represented by this is obtained.

Here, an organic base such as triethylamine or pyridine can be used as a base, and a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone can be used as a reaction solvent.
The reaction temperature is from room temperature to reflux temperature.

Then, the compound represented by Chemical formula 11 and 1 to
5 equivalents of the formula R ² R ³ NH (I) [In the formula I, R ² and R ³ are as defined above. ] By reacting an amine represented by

[0032]

[Chemical 12]

[In the chemical formula 12, R ¹ , R ² and R ³ have the same meanings as described above. ] The compound represented by these can be obtained.

Here, as the reaction solvent, a solvent such as N, N-dimethylformamide, tetrahydrofuran or acetone can be used. The reaction temperature is from 0 ° C to the reflux temperature.

[0035]

The object of the present invention is to provide a strong cyclic GM.
A compound having a P-specific phosphodiesterase inhibitory effect is provided, and by extension, chronic reversible obstructive pneumonia such as hypertension, angina, heart failure, myocardial infarction, arteriosclerosis, asthma, bronchitis, atopic dermatitis and allergic rhinitis. It is useful for treatment such as.

[0036]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples.

The structural formulas of the compounds prepared in Examples 2 to 10 and 12 to 18 are shown in Tables 1 and 2.

Example 1 4-Methyl-2- (5-nitro-2-propoxybenzo)
Ilamido) thiophene-3-carboxamide 2-amino-4-methylthiophene-3-carboxamide 3.12 g of N, N-dimethylformamide 40 ml
To the solution was added 2.22 g (1.1 equivalent) of triethylamine, 4.87 g (1.0 equivalent) of 5-nitro-2-propoxybenzoyl chloride was added dropwise under ice cooling, and the mixture was stirred for 1 hour. After standing overnight, the reaction solution was poured into water, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (3.97 g). This product was used in the next reaction without purification.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
0.95 (3H, t, J = 7Hz), 1.96 (2H,
sext, J = 7 Hz), 2.37 (3H, s), 4.
47 (2H, t, J = 7Hz), 6.75 (1H,
s), 7.20 (1H, bs), 7.53 (1H, d,
J = 8 Hz), 7.65 (1H, bs), 8.43 (1
H, dd, J = 2,8 Hz), 8.80 (1 H, d, J
= 2 Hz), 12.75 (1 H, s).

Example 2 3,4-dihydro-5-methyl-2- (5-nitro-2)
- propoxyphenyl) thieno [2,3-d] pyrimidine
N- 4 -one 4-methyl-2- (5-nitro-2-propoxybenzoylamide) thiophen-3-carboxamide 3.69
g of methanol in 20 ml suspension, potassium hydroxide 1.
A solution of 72 g (3.0 equivalents) in 20 ml of water was added and refluxed for 6 hours. The reaction solution was poured into water, acidified with hydrochloric acid, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.97 g of the title compound. This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
22 (3H, t, J = 7Hz), 2.09 (2H, se
xt, J = 7 Hz), 2.62 (3H, s), 4.33
(2H, t, J = 7Hz), 6.89 (1H, s),
7.18 (1H, d, J = 8Hz), 8.36 (1H,
dd, J = 2, 8 Hz), 9.41 (1H, d, J = 2)
Hz), 10.95 (1H, bs).

Example 3 2- (5-Amino-2-propoxyphenyl) -3,4
-Dihydro-5-methylthieno [2,3-d] pyrimidi
3,4-dihydro-5-methyl- was added to a solution of 2.62 g (2.0 equivalents) of n-4-one nickel chloride hexahydrate in 30 ml of methanol.
2- (5-Nitro-2-propoxyphenyl) thieno [2,3-d] pyrimidin-4-one (1.90 g) and tetrahydrofuran (70 ml) were added, and sodium borohydride 0.82 g (4.0 equivalents) was added under ice cooling. Was added little by little.
The reaction solution was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in 2N hydrochloric acid (60 ml) solution, neutralized with an aqueous ammonia solution under ice cooling, extracted with ethyl acetate and dried. The solvent was distilled off under reduced pressure to obtain 1.45 g of the title compound. This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
15 (3H, t, J = 7Hz), 1.98 (2H, se
xt, J = 7 Hz), 2.61 (3H, s), 4.10
(2H, t, J = 7Hz), 6.7 to 7.0 (3H,
m), 7.83 (1H, d, J = 2Hz), 11.44
(1H, bs).

Example 4 3,4-Dihydro-5-methyl-2- [5- (phenoxy
Cycarbonylamino) -2-propoxyphenyl] thie
No [2,3-d] pyrimidin-4-one 2- (5-amino-2-propoxyphenyl) -3,4
0.52 g of triethylamine was added to a solution of 1.34 g of -dihydro-5-methylthieno [2,3-d] pyrimidin-4-one in 20 ml of N, N-dimethylformamide.
Equivalent) was added, and phenyl chloroformate 0.80 g under ice cooling
(1.2 eq) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure and the obtained residue was washed with ethyl acetate-
Crystallized with hexane. The obtained crystals were collected by filtration and dried to obtain 1.22 g of the title compound. This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
17 (3H, t, J = 7Hz), 2.01 (2H, se
xt, J = 7 Hz), 2.61 (3H, s), 4.18
(2H, t, J = 7Hz), 6.81 (1H, s),
7.0-7.5 (7H, m), 7.85 (1H, dd,
J = 2,8Hz), 8.37 (1H, d, J = 2H
z), 11.31 (1H, bs).

Example 5 3,4-Dihydro-5-methyl-2- [5- (morpholin
Nocarbonylamino) -2-propoxyphenyl] thie
[2,3-d] pyrimidin-4-one 3,4-dihydro-5-methyl-2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4 300 mg of morpholine (3.0 equivalents) was stirred in a solution of 500 mg of -one in 20 ml of N, N-dimethylformamide at 80 ° C for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to obtain 343 mg of the title compound.

M. p. 184-186 ° C.

¹ H-NMR (CDCl ₃ ) δ ppm;
17 (3H, t, J = 7Hz), 2.00 (2H, se
xt, J = 7 Hz), 2.60 (3H, s), 3.50
(4H, t, J = 5Hz), 3.77 (4H, t, J =
5 Hz), 4.17 (2H, t, J = 7 Hz), 6.4
9 (1H, s), 6.79 (1H, s), 7.01 (1
H, d, J = 8 Hz), 7.85 (1H, dd, J =
2,8Hz), 8.14 (1H, d, J = 2Hz), 1
1.34 (1H, bs).

Example 6 3,4-dihydro-5-methyl-2- [5- (piperidi
Nocarbonylamino) -2-propoxyphenyl] thie
No [2,3-d] pyrimidin-4-one 3,4-dihydro-5-methyl-as described in Example 5.
2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4
The title compound was obtained from -one and piperidine.

M. p. 218-221 ° C.

¹ H-NMR (CDCl ₃ ) δ ppm;
16 (3H, t, J = 7Hz), 1.5 to 1.7 (6
H, m), 2.00 (2H, sext, J = 7Hz),
2.60 (3H, s), 3.4 to 3.5 (4H, m),
4.16 (2H, t, J = 7Hz), 6.51 (1H,
s), 6.78 (1H, s), 7.00 (1H, d, J
= 8 Hz), 7.89 (1H, dd, J = 2, 8H
z), 8.11 (1H, d, J = 2Hz), 11.37
(1H, bs).

Example 7 3,4-dihydro-2- [5-[[4- (2-hydroxy
Ciethyl) piperazino ] carbonylamino] -2-pro
Poxyphenyl] -5-methylthieno [2,3-d] pi
Limidin-4-one as in Example 5, 3,4-dihydro-5-methyl-
2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4
The title compound was obtained from -one and 1-piperazine ethanol.

M. p. 169-171 ° C.

¹ H-NMR (CDCl ₃ ) δ ppm;
17 (3H, t, J = 7Hz), 2.00 (2H, se
xt, J = 7 Hz), 2.5 to 2.7 (6H, m),
2.61 (3H, s), 3.55 (4H, t, J = 5H
z), 3.68 (2H, t, J = 5Hz), 4.17.
(2H, t, J = 7Hz), 6.49 (1H, s),
6.78 (1H, s), 7.01 (1H, d, J = 8H
z), 7.85 (1H, dd, J = 2, 8 Hz), 8.
14 (1H, d, J = 2Hz), 11.34 (1H, b
s).

Example 8 3,4-dihydro-2- [5-[[N- (2-hydroxy
Ciethyl) -N-methylamino] carbonylamino]-
2-propoxyphenyl] -5-methylthieno [2,3
-D] Pyrimidin-4-one 3,4-dihydro-5-methyl-as in Example 5.
2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4
The title compound was obtained from -one and N-methylethanolamine.

M. p. 197-199 ° C.

¹ H-NMR (CDCl ₃ ) δ ppm;
13 (3H, t, J = 7Hz), 1.97 (2H, se
xt, J = 7 Hz), 2.61 (3H, s), 3.05
(3H, s), 3.52 (2H, t, J = 5Hz),
3.75 (1H, t, J = 5Hz), 3.89 (2H,
q, J = 5 Hz), 4.09 (2H, t, J = 7H
z), 6.76 (1H, s), 6.89 (1H, d, J
= 8 Hz), 7.75 (1H, s), 7.77 (1H,
dd, J = 2,8 Hz), 7.98 (1H, d, J = 2)
Hz), 11.32 (1H, s).

Example 9 2- [5-[[bis (2-hydroxyethyl) amino]]
Carbonylamino] -2-propoxyphenyl] -3,
4-dihydro-5- methylthieno [2,3-d ] pyrimi
Zin-4-one 3,4-dihydro-5-methyl-as in Example 5
2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4
The title compound was obtained from -one and diethanolamine.

M. p. 205-207 ° C.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.00 (3H, t, J = 7Hz), 1.77 (2H,
sext, J = 7 Hz), 2.50 (3H, s), 3.
43 (4H, t, J = 5Hz), 3.57 (4H, q,
J = 5 Hz), 4.05 (2H, t, J = 7 Hz),
5.00 (2H, t, J = 5Hz), 7.12 (1H,
d, J = 8 Hz), 7.16 (1H, s), 7.60
(1H, dd, J = 2, 8Hz), 7.88 (1H,
d, J = 2 Hz), 8.62 (1H, s), 11.88
(1H, bs).

Example 10 2- [5-[[(2-hydroxyethyl) amino] calcal
Bonylamino] -2-propoxyphenyl] -3,4-
Dihydro-5-methylthieno [2,3-d] pyrimidine
-4-one 3,4-dihydro-5-methyl-as in Example 5.
2- [5- (phenoxycarbonylamino) -2-propoxyphenyl] thieno [2,3-d] pyrimidine-4
The title compound was obtained from -one and ethanolamine.

M. p. 225-228 ° C.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
0.99 (3H, t, J = 7Hz), 1.76 (2H,
sext, J = 7 Hz), 2.50 (3H, s), 3.
15 (2H, q, J = 5Hz), 3.44 (2H, q,
J = 5 Hz), 4.04 (2H, t, J = 7 Hz),
4.73 (1H, t, J = 5Hz), 6.11 (1H,
t, J = 5 Hz), 7.10 (1H, d, J = 8H
z), 7.16 (1H, s), 7.53 (1H, dd,
J = 2,8 Hz), 7.91 (1H, d, J = 2H
z), 8.63 (1H, s), 11.73 (1H, b
s).

Example 11 2- (2-Ethoxy-5-nitrobenzoylamide)-
4-Methylthiophene-3-carboxamide In the same manner as in Example 1, the title compound was obtained from 2-amino-4-methylthiophene-3-carboxamide and 2-ethoxy-5-nitrobenzoyl chloride. This product was used in the next reaction without purification.

Example 12 3,4-dihydro-2- (2-ethoxy-5-nitrof
Phenyl) -5-methylthieno [2,3-d] pyrimidine
-4-one In the same manner as in Example 2, the title compound was obtained from 2- (2-ethoxy-5-nitrobenzoylamide) -4-methylthiophene-3-carboxamide. This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
68 (3H, t, J = 8Hz), 2.62 (3H, d,
J = 2 Hz), 4.44 (2H, q, J = 8 Hz),
6.88 (1H, bs), 7.17 (1H, d, J = 9)
Hz), 8.37 (1H, dd, J = 3,9 Hz),
9.39 (1H, d, J = 3Hz), 10.92 (1
H, bs).

Example 13 2- (5-amino-2-ethoxyphenyl) -3,4-
Dihydro-5-methylthieno [2,3-d] pyrimidine
-4-one In the same manner as in Example 3, 3,4-dihydro-2- (2-ethoxy-5-nitrophenyl) -5-methylthieno [2,3-d] pyrimidin-4-one gave the title compound. It was This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
56 (3H, t, J = 8Hz), 2.60 (3H, d,
J = 2 Hz), 3.62 (2H, bs), 4.21 (2
H, q, J = 8 Hz), 6.78 (1H, bs), 6.
82 (1H, dd, J = 3,9Hz), 6.89 (1
H, d, J = 9 Hz), 7.82 (1H, d, J = 3H)
z), 11.43 (1H, bs).

Example 14 3,4-Dihydro-2- [2-ethoxy-5- (pheno
Xycarbonylamino ) phenyl] -5-methylthieno
[2,3-d] Pyrimidin-4-one 2- (5-Amino-2-ethoxyphenyl) -3,4-dihydro-5-methylthieno [2,3-d] pyrimidin-as in Example 4. The title compound was obtained from 4-one and phenyl chloroformate. This product was used in the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ ppm;
58 (3H, t, J = 7Hz), 2.62 (3H, d,
J = 2Hz), 4.26 (2H, q, J = 7Hz),
6.80 (1H, q, J = 2Hz), 7.02 (1H,
d, J = 9 Hz), 7.1-7.5 (6H, m), 7.
7 to 7.9 (1H, m), 8.36 (1H, d, J = 3)
Hz), 11.28 (1H, bs).

Example 15 3,4-dihydro-2- [2-ethoxy-5- (morpho
Reno carbonylamino) phenyl] -5-methylthieno
[2,3-d] Pyrimidin-4-one 3,4-dihydro-2- [2-ethoxy-5- (phenoxycarbonylamino) phenyl] thieno [2,3-d] pyrimidine as in Example 5. The title compound was obtained from -4-one and morpholine.

M. p. 222-224 ° C.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.37 (3H, t, J = 7Hz), 2.49 (3H,
d, J = 2 Hz), 3.4 to 3.5 (4H, m), 3.
6 to 3.7 (4H, m), 4.14 (2H, q, J = 7)
Hz), 7.12 (1H, d, J = 9 Hz), 7.17
(1H, q, J = 2Hz), 7.67 (1H, dd, J
= 3,9 Hz), 7.93 (1H, d, J = 3 Hz),
8.58 (1H, bs), 11.91 (1H, bs).

Example 16 3,4-Dihydro-2- [2-ethoxy-5- (piperi
Dinocarbonylamino ) phenyl] -5-methylthieno
[2,3-d] Pyrimidin-4-one 3,4-dihydro-2- [2-ethoxy-5- (phenoxycarbonylamino) phenyl] thieno [2,3-d] pyrimidine as in Example 5. The title compound was obtained from -4-one and piperidine.

M. p. 199-202 ° C.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.37 (3H, t, J = 7Hz), 1.4 to 1.7
(6H, m), 2.49 (3H, d, J = 2Hz),
3.4-3.5 (4H, m), 4.13 (2H, q, J
= 7 Hz), 7.08 (1H, d, J = 9 Hz), 7.
16 (1H, q, J = 2Hz), 7.66 (1H, d
d, J = 3,9 Hz), 7.95 (1H, d, J = 3H
z), 8.50 (1H, s), 11.90 (1H, b
s).

Example 17 3,4-dihydro-2- [2-ethoxy-5- (pyrroli
Dinocarbonylamino ) phenyl] -5-methylthieno
[2,3-d] Pyrimidin-4-one 3,4-dihydro-2- [2-ethoxy-5- (phenoxycarbonylamino) phenyl] thieno [2,3-d] pyrimidine as in Example 5. The title compound was obtained from -4-one and pyrrolidine.

M. p. 234-237 ° C.

¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.37 (3H, t, J = 7Hz), 1.8 to 2.0
(4H, m), 2.50 (3H, d, J = 2Hz),
3.3-3.5 (4H, m), 4.14 (2H, q, J
= 7 Hz), 7.09 (1H, d, J = 9 Hz), 7.
16 (1H, q, J = 2Hz), 7.73 (1H, d
d, J = 3,9 Hz), 7.99 (1H, d, J = 3H
z), 8.20 (1H, s), 11.92 (1H, b)
s).

Example 18 2- [5-[(4-carbetoxypiperidino) carboni
Lumino] -2-ethoxyphenyl] -3,4-dihydride
Ro-5-methylthieno [2,3-d] pyrimidine-4-
On in the same manner as in Example 5, the title compound was obtained from 3,4-dihydro-2- [2-ethoxy-5- (phenoxycarbonylamino) phenyl] thieno [2,3-d] pyrimidin-4-one and ethyl isonipecotate. Got

¹ H-NMR (DMSO-d ₆ ) δ ppm;
1.19 (3H, t, J = 7Hz), 1.37 (3H,
t, J = 7 Hz), 1.4 to 1.6 (2H, m), 1.
8 to 1.8 (2H, m), 2.49 (3H, d, J = 2)
Hz), 2.5 to 2.7 (1H, m), 2.8 to 3.0
(2H, m), 4.0-4.2 (2H, m), 4.08
(2H, q, J = 7 Hz), 4.14 (2H, q, J =
7 Hz), 7.10 (1H, d, J = 9 Hz), 7.1
5 (1H, q, J = 2Hz), 7.66 (1H, dd,
J = 3,9 Hz), 7.94 (1H, d, J = 3H
z), 8.58 (1H, s), 11.88 (1H, b
s).

[0082]

[Table 1]

[0083]

[Table 2]

Test Example 1 [Phosphodiesterase inhibitory action] The phosphodiesterase isozyme was purified from the soluble fraction of dog aorta by the FRLC system using a MonoQHR5 / 5 column. That is, the excised tissue was treated with 25 mM Tris-HCl buffer, 250 mM sucrose, 2 mM magnesium chloride, 1 mM ethylene glycol bis (β-aminoethyl ether) N, N, N ′, N′-tetraacetic acid, 1 m.
After homogenization in the presence of M dithiothreitol and various protease inhibitors, the protein fractions were eluted with a salt gradient, and the phosphodiesterase activity of each fraction was measured to determine the calcium / calmodulin-dependent phosphodiesterase and cyclic GMP.
A mixed fraction of specific phosphodiesterase was obtained. Further, both were separated and purified by calmodulin affinity chromatography.

Phosphodiesterase activity is measured by S. M
atsushima et al. Biochem. Biophy
s. Res. Commun. , Vol. 148, No. 1468
For the canine aortic cyclic GMP-specific phosphodiesterase, 0.2 mM ethylene glycol bis (β-aminoethyl ether) N, N, N ', N'-tetraacetic acid was used as an activator according to the method described on page (1987). In the presence, 0.4 μM [ ³ H] cyclic GMP was measured as a substrate.

The test drug was dissolved in 100% dimethyl sulfoxide and then used as a 10% dimethyl sulfoxide solution. The final concentration in the reaction solution was 1% dimethyl sulfoxide.

The results are shown in Table 3.

[0088]

[Table 3]

(The sample is the compound of the example number corresponding to each sample number.)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/505 ABX ACD ADA ADD 31/535 ABM (72) Inventor Katsuo Hatayama 3 Takada, Toshima-ku, Tokyo 24-24-1 Taisho Pharmaceutical Co., Ltd.

Claims (2)

[Claims] Claims: [Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms, X represents a phenoxy group, a morpholino group, a piperidino group,
Pyrrolidino group, 4-carbetoxypiperidino group, 4-
(2-Hydroxyethyl) piperazino group or R ² R ³ N
Indicates a group. Here, R ² and R ³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or 2 carbon atoms.
~ 4 hydroxyalkyl groups are shown. ] The thieno [2,3-d] pyrimidin-4-one derivative represented by these, and its salt. 2. [Chemical formula 2] [In Chemical Formula 2, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and Y represents an amino group or a nitro group. ] The thieno [2,3-d] pyrimidin-4-one derivative represented by these, and its salt.