JPS5951290A - Benzothienoimidazopyrimidinedione compound - Google Patents

Abstract

NEW MATERIAL:1,2,3, 5,6, 7,8,9-Octahydro[1]benzothieno[2,3-d]imidazo[1,2-a]-pyrimidine- 2,9-dione of formula I and its acid addition salt. USE:It has blood platelet coagulation suppressing activity and is useful for the remedy and prevention of vascular thrombosis, prevention of temporary local anemia, and prevention of blood platelet thrombosis during the use of artificial heart, artificial kidney, etc. It is administered preferably orally at a dose of 1-10mg daily. PROCESS:The objective compound can be prepared by (1) oxidizing the compound of formula II (R is lower alkyl) with chromic acid, (2) subjecting the resultant compound of formula III successively to dithioketalization and deacetylation to obtain the compound of formula V, (3) reacting the compound with benzoyl isocyanate and then Na-ethoxide, (4) reacting the obtained compound of formula VII with phosphorus oxychloride and then with sodium borohydride, (5) reacting the obtained compound of formula IX with bromoacetic acid lower alkyl ester in a mixture of concentrated aqueous solution of NaOH and methylene chloride to obtain the compound of formula X, (6) converting the compound to the compound of formula X I by heating with NH3 in ethanol in a sealed tube, and (7) refluxing the compound of formula X I in a solvent in the presence of concentrated hydrochloric acid, etc. in N2 stream.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has a platelet aggregation inhibiting effect and is expressed by formula (1) (1121:3+5,6171819-
Relating to octahydro[1]benzothieno(Z,a-a)imidazo[l,2-a)pyrimidine-2,9-dione.

The compounds of formula (I) according to the invention may also exist in tautomeric forms. Therefore, the present invention is not limited to the compounds of formula (1) shown herein, but rather the tautomers 1 such as formula (I
Tautomers of a) or formula (Ib) (TO, , ) (Ib) are also encompassed by the present invention.

The compounds of formula (1) according to the invention can be used as salts with physiologically harmless acids. Non-toxic pharmaceutically usable salts include salts with acids commonly used in the art such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, alkyl or allyl sulfonic acids, fumaric acid, maleic acid, succinic acid or citric acid. It's salt.

The compound of the present invention has an inhibitory effect on platelet aggregation and is therefore useful for the treatment and prevention of intravascular thrombosis, prevention of short-term local anemia, and prevention of platelet thrombosis when using prosthetic devices (artificial heart, artificial kidney). Useful.

The in vitro platelet aggregation inhibiting effect of the compound of formula (1) of the present invention is shown in Table 1. For example, when platelet-rich blood cells of U.S. and Toto are used, aggregation induced by collagen or ADPd) is inhibited by 50%. The C degree is 0.32 μM and 4.9 μM, respectively, and 0.32 μM and 4.9 μM, respectively, and 0.2 μM in human platelet-rich blood.
．． 66 μM and 2.5 μM.

In addition, for AD Pi-induced aggregation of dog platelet-rich plasma, 1
It is 3 μM.

Furthermore, nine compounds of the present invention were orally administered to rats, and the rats were collected 2 hours later, and the rate of inhibition of aggregation of platelet-rich plasma against collagen and ADP islet transport is shown in the table.

Ox vivo platelet aggregation inhibitory effect* p<o, o 5 , jujube WI P (0,01 can be produced).

(VN) (VN) (X]:) (1) (In the formula, R represents lower alkyl.) The starting material is Gewald (Hemische Berichina Vol. 99, 9
4, 1966) as a compound of formula (n),
This is converted into chromium R[' to give a compound (support)), which is then washed and converted into a dithioketal, followed by deacetylation to obtain a compound (V). Next, compound (V) is reacted with benzoyl isocyanate to obtain compound (2).9 This is then heated with sodium ethoxide in ethanol to obtain compound (2).

Next, according to a conventional method, the compound (vIO is treated with phosphorus oxychloride to form a chlorinated compound (one powder is 1τ). Then, the compound (1 powder is reacted with sodium borohydride to obtain compound (IX), When this is reacted with a phase transfer catalyst 2 in a mixed solvent of an aqueous solution and methylene chloride, the compound (3
) is obtained. When this is heated in a sealed tube with ammonia in 1 liter, the compound (to) is obtained, and finally the compound (
9) is heated under reflux with concentrated hydrochloric acid or hydrobromic acid in a lower alcohol such as methanol or ethanol, water, or a mixed solvent thereof under a nitrogen atmosphere to obtain the formula (1) of the present invention.
) is obtained.

The compounds of formula (1) according to the invention, their tautomers and their physiologically compatible acid addition salts are compatible with carriers 2 such as organic or inorganic inert carriers such as lactose, starch, Tablets with magnesium stearate or talc.

It can be made into solid preparations such as capsules or powders.

The compounds of formula (1) according to the invention are preferably administered orally.

It is sufficient to administer 1 to 1 (119) doses per day.

The invention will now be illustrated by detailed examples.

Example 1 2-acetylamino-4,51617-tetrahydro (
1) Ethyl benzothio7ene-3-carboxylate 10.8
ii' and 27 g of pyridinium chlorochromate are added to dry pyridine 120- and stirred overnight at 40-50°C. The solvent is distilled off under reduced pressure, the residue is treated with water and chloroform, and the chloroporum extract layer is separated. After washing the extract with water.

Wash with 2N hydrochloric acid and distill off the chloroform.

The residue was prepared with silica gel 1009 to yield 22-acetylamino-7-oxo-4. 5.6 points were obtained.

Example 2 2-acetylamino-7-oxo-4,5,G, 7-
Add 2.81 ml of ethyl tetrahydro(1)penzodiophene-3-carboxylate to 150 ml of wood vinegar.

This is mixed with ethanedithiol 4., 79 and boron fluoride Nieteller) 0.5- and stirred at room temperature for 10 minutes. The reaction solution was poured into water and extracted with chloroborm. After washing the extract with water and an aqueous N-sodium hydroxide solution, chloroform was distilled off, resulting in 2-acedelamino-4,
2.809
Obtained.

2-acetylamino-41,5,6,7-tetrahydrospiro[[1]benzothiophene-7,2'-(1,3
) 10.4 g of ethyl didiolan]-3-carboxylate is suspended in 100 g of ethanol while hot, and a solution of 1.7 g of potassium hydroxide dissolved in 3.5 g of water is added while stirring. After stirring the reaction solution at room temperature for 15 minutes, the solvent was dried under reduced pressure.・Extract the residue with chloroporum, wash the chloroform layer with water, and distill off the chloroform to obtain 2-amino-4,5
,6,7-tetrahydrospiro((1)benzothiophene-7,2'-(1,3)dithiolane)-3-carboxylic acid (melting point 133-135°C) was obtained in an amount of 7.639.

Example 4 2-amino-4,5,6,7-tetrahydrospiro [[
1] ethyl benzothiophene-7,2'-(1,3)dithiolane]-8-carboxylate 4.282 to benzene 8o
- suspended in penzoyl isocyaner) 2.32
Add 9. After the reaction solution was stirred at room temperature for 30 minutes, the deposited precipitate was collected by filtration.

When washed with methanol, 2-(3-benzoylureido)-
4,5,G,7-tetrahydrospiro[[1]benzothiophene-7,2'-(1,3)dithiolanthi-3-carboxylic acid ethyl 5.30(1-(points 251-253)
°C) was obtained.

Example 5 2-(3-benzoylureido)-4,,5,(3,
7-tetrahydrospiro ((1) benzothiophene-7
, 5.02 ethyl 2'-(1,3)dithiolanthi-3-carboxylate, 2.59 sodium metal in ethanol/L
Add to the solution dissolved in 120 tnl and stir under heating under reflux for 3 hours. Cool, filter the precipitated crystals, and wash with ethanol.

Then dissolve this in water.

Neutralize to p+13-4I using concentrated hydrochloric acid at 50-60°C. When the precipitated crystals are collected by filtration, 1.2.3.4゜5
, 6.7.8-octahydrospiro[[ribenzocheno(2,3-d)pyrimidine-8,2'-(1,3)dithiolane)-2,4-dione (melting point 280°C or higher) is 2
．． 5g was obtained.

Example 6 1,2.3.4.5.6.7.8-octahydrospiro[(υbenzocheno(2,a-a)pyrimidine-8,2
'-(1,3)dithiolane)-2,4-dione 1.9
5g of phosphorus oxychloride 3- and dimethylaniline 3-
Add to the mixture and stir overnight under heating. The solvent was distilled off under reduced pressure, the residue was added to ice water, and extracted with chloroform. The chloroform layer is 2N-hydrochloric acid.

After washing with water, chloroform is then distilled off.

The residue was purified using silica gel 309 to obtain 2,4-dichloro-5,0,7,8-tetrahydrospiro [(1) benzocheno(2,3-6)pyrimidine-8,2'-(+, a
) dithiolane] (melting point 210-215°C) is 0.9!
Ml was obtained.

Example 7 2.4-dichloro-5,6,7,8-tetrahydrospiro [(1) benzoche/(2,a-d)pyrimidine-8
.
Stir overnight at room temperature. The reaction solution was dried under reduced pressure, the residual aroma was thoroughly treated with water, and the non-4") fraction was filtered to yield 2-chloro-3,
4・+ 51 G, 7.8・−hexahydrosubilo (
(1) Benzocheno (2,3-(1)pyrimidine-8,
2'-(1,3) Giti A run] (1; points 202-20
4°C) was 0.789 A).

Example 8 2-chloro-3,4,5,G,7,8-hexahydrosubilo((1)benzocheno(2,3-a)pyrimidine-8,2'-(1,,'l) dithiolane) ■, 9o9
．． Ethyl bromoacetate 1. ．． 18 g of tetrabutylammonium iodide, 0.159 g of tetrabutylammonium iodide, and 6 rnl of 10N sodium hydroxide are mixed and stirred in 15 QmJ of methylene chloride at room temperature under a nitrogen stream. After 20 minutes, separate the organic layer and wash thoroughly with water. When the solvent was distilled off under reduced pressure, the residual aroma crystallized and solidified into 2-chloro-3,4,5,6,7,8-hegizuhydrospiro((
1) Benzocheno(2,3-d)pyrimidine-8,2'
-(1,3)dithiolanthi-3-ethyl acetate (melting point 16
3-165°C) was obtained at 1.602.

Example 9 2-Chloro-3,4,5,6,7,8-hexylhydrospiro((1)benzocheno(2,a-a)pyrimidine-8,2'-(1,3)dithiolancy 3- 1.90!7 of ethyl acetate was mixed with 10% ammonia-ethanol solution 60-2 in a sealed tube at 120-130°C under nitrogen flow for 15-2.
Heat for 0 hours. After cooling, the precipitate is collected by filtration. The solid solution is dried under reduced pressure, the residual aroma is treated with ethanol, and the insoluble matter is filtered off. Combine this filtration) 5v product with the above d and υ removal products and thoroughly wash with water. Suspend this in methanol and add concentrated hydrochloric acid to pi+2
As step 3, insoluble matter is removed by filtration. When the filtrate is dried under reduced pressure, 1
,2゜3,5. G, 7.8,9-octahydrospiro([l]benzocheno(2,3-d)imidazo(1,
2-a) Pyrimidine-9,2'-(1,3) didiolan]-2-one hydrochloride (melting point 255-258°C) is 1.0
09 Obtained Power Bow Example 1, 2.8.5.6.7.8. '9-mectahhydrospiro[[l]benzocheno(2,a-d)imidazo(1
, 2-a) Pyrimidine-9,2'-(1,3)dithiolanthi-2-one hydrochloride (8.009 g) was added to 250 ml of concentrated hydrochloric acid under a nitrogen stream! and 100° C. of water, and heated at a bath temperature of 130 to 150° C. for 3 to 4 hours.

After cooling, the reaction mixture was washed with ether, and the aqueous layer was treated with activated carbon and then concentrated under reduced pressure to deposit a precipitate.

When the precipitate is collected up to the second crystal, 1.2.3.5.6.7.
8.9-octahydro[1]benzothieno(2,a-d
) 3.709 imidazo(l+2-a)pyrimidine-2,9-dione hydrochloride were obtained. Melting point 206-208°C
(decomposition point).

IR ShiKBrcrn-': 3100~2500,17
90°ax 1640.1610 IH-NMR (DMSO-d6) δ:

Claims (1)

[Claims] 1+ 2.3.5. (i, ?, 8.9-octahydro(1)benzocheno(2,3-a)imidazo(11
2-a) Pyrimidine-2,9-dione and zono nb kokika salt