JPS6411022B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel spiro compounds useful as pharmaceuticals and methods for producing the same.

More specifically, the present invention relates to the general formula This invention relates to a novel spiro compound represented by and a method for producing the same.

Regarding the above formula (), the 1-hydroxyethyl group may be substituted at any substitutable position on the benzene ring, and is preferably substituted at the 5th or 7th position.

The spiro compound () of the present invention may be, for example, a compound of the formula It can be produced by reducing the compound represented by This reaction is carried out in a suitable solvent, and any solvent may be used as long as it does not inhibit the reaction, but usually ether, tetrahydrofuran, dioxane, dimethoxyethane, methylene chloride, pyridine, isopropyl alcohol, etc., or a mixture thereof. A solvent is used. As the reducing agent in the reduction reaction, metal borohydride compounds such as sodium borohydride and potassium borohydride are conveniently used. The reaction temperature is usually about -70 to +40℃, especially about -
A temperature of about 15 to +20°C is convenient, but the reaction may be carried out at a lower or higher temperature for the purpose of suppressing the reduction of the carbonyl group at the 3-position and controlling the reaction rate.

The target compound () produced in this way can be purified by ordinary separation and purification means (e.g. distillation, chromatography).
It can be isolated and purified from the reaction mixture by . Compound () has optical isomers based on asymmetric carbon atoms, and these are naturally included in the scope of the present invention.

The spiro compound () of the present invention can be used, for example, in mammals (e.g., humans, rats, mice, guinea pigs,
It has suppressive effects on gastric juice secretion, anti-inflammatory effects, and analgesic effects on dogs and pigs, and is useful as an anti-ulcer agent, anti-inflammatory agent, and analgesic for diseases such as gastric/duodenal ulcers, acute chronic gastritis, low back pain, and arthritis. It is. For example, a spiro compound (2007) having a 1-hydroxyethyl group at the 5-position caused gastric mucosal damage in rats at 50 mg in a test according to the method of Robert et al. [Gastroenterology, 77 , 433 (1979)]. /Kg, and has low toxicity. When used as the above-mentioned medicine, the compound () can be safely administered orally or parenterally as it is or in an appropriate dosage form such as tablets, powders, capsules, injections, and suppositories with known excipients. can do.
The dosage varies depending on the subject, symptoms, administration route, etc., but when administered orally as a treatment for gastric/duodenal ulcers or acute chronic gastritis in adults,
A single dose of the compound () is approximately 1 to 20 mg/Kg body weight,
It is convenient to administer about 1 to 3 times a day.

The starting compound () used in the production of the compound () of the present invention can be produced, for example, by the method described in JP-A-55-2623 or in accordance therewith.

The present invention will be explained in more detail below using reference examples and examples, but the scope of the present invention is not limited thereto.

Reference example 1 3-acetylsalicylic acid methyl ester 5.8g
and α-bromo-γ-butyrolactone while stirring 10.4 g of potassium carbonate in 200 ml of acetone.
12.5 g was added dropwise, and the reaction solution was then heated under reflux for 11 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure.
The residue was subjected to silica gel chromatography,
Elute with chloroform to obtain α-[(6-acetyl-2
-methoxycarbonylphenyl)oxy]-γ-
Butyrolactone is obtained as a pale yellow oil.

Infrared absorption spectrum ν ^film _nax cm ^-1 : 1780 (γ-lactone), 1720 (COOCH ₃ ), 1690 (COCH ₃ ) Elemental analysis C ₁₄ H ₁₄ O ₆ Calculated value C60.43; H5.07 Actual value C60. 21; H5.02 Reference example 2 α-[(6-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone 3.5 g,
0.14 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 1.1 g of sodium chloride were mixed with N,N
-5 at 150-160°C in 66.5 ml of dimethylformamide
Stir the time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. Wash the ethyl acetate solution with water,
dry. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. The target product eluted with methylene chloride is recrystallized from chloroform-hexane to obtain 7-acetylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as colorless needles. Melting point 114-115℃.

Elemental analysis C ₁₂ H ₁₀ O ₃ Calculated value C71.28; H4.99 Actual value C71.39; H4.96 Reference example 3 α-[(4-acetyl-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone 2.8g,
0.056 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 0.6 g of sodium chloride were mixed with N,N
- Heat in 28 ml of dimethylformamide at 150-155°C for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. Wash the ethyl acetate solution with water and dry. The solvent is distilled off under reduced pressure and the resulting residue is subjected to silica gel chromatography. The fraction eluted with methylene chloride was recrystallized from ethanol.
-acetylspiro[benzo[b]furan-2
1.15 g of (3H), 1'-cyclopropane]-3-one are obtained as colorless crystals. Melting point 100-103℃. Infrared absorption spectrum ν ^KBr _nax cm ^- 1: 1700, 1680 (CO,
_COCH3 ). Nuclear magnetic resonance spectrum ( _CDCl3 ) δ:
1.70 (4H, q, J=7Hz, CH ₂ ), 2.62 (3H, s,
COCH ₃ ), 7.20 (1H, d, J=9Hz, aromat,
H), 8.27, 8.30 (1H, dd, J=9Hz, aromat.
H), 8.29 (1H, d, J=2Hz, aromat.H) Elemental analysis C ₁₂ H ₁₀ O ₃ Calculated value C71.28; H4.99 Actual value C71.07; H4.82 Example 1 5-acetylspiro [benzo[b]furan-2
(3H), 1'-cyclopropane]-3-one is dissolved in a mixture of 25 ml of tetrahydrofuran and 3 ml of isopropyl alcohol, and while stirring at -50°C, 0.9 g of sodium borohydride is added little by little. After stirring at room temperature for 30 minutes, the reaction solution was diluted with ice water and neutralized with an aqueous ammonium chloride solution. Extract the aqueous solution with ethyl acetate. Wash the extract with water and dry. The residue obtained by distilling off the solvent is subjected to silica gel chromatography and eluted with chloroform. The product was subjected to vacuum distillation to give 5-(1-hydroxyethyl)spiro[benzo[b]furan-2(3H),1'-cyclopropane]-
3-one is obtained as a colorless oil. bp110℃ (bath temperature) (0.05mmHg) Infrared absorption spectrum ν ^film _nax cm ^-1 : 3350 (OH),
1710 (CO). Nuclear magnetic resonance spectrum (deuterochloroform) δ; 1.45 (3H, d, J=6Hz, CH ₃ ), 1.62
(4H, q, J = 3Hz, CH ₂ ), 3.33 (1H, b,
OH), 4.83 (1H, q, J=6Hz, CH), 6.97 (1H,
d, J=9Hz, aromatic ring H), 7.55 (2H, m, aromatic ring H) Elemental analysis C ₁₂ H ₁₂ O ₃ Calculated value C70.57; H5.92 Actual value C70.47; H6.05 Example 2 7-Acetylspiro[benzo[b]furan-2
-(3H),1'-cyclopropane]-3-one was reacted in the same manner as in Example 1, and 7-(1-hydroxyethyl)spiro[benzo[b]furan-2(3H),
1'-cyclopropane]-3-one is obtained.

Infrared absorption spectrum ν ^film _nax cm ^-1 : 3400 (OH),
1700 (CO) Elemental analysis C ₁₂ H ₁₂ O ₃ Calculated value C70.57; H5.92 Actual value C70.36; H5.89

Claims (1)

[Claims] 1 formula A spiro compound represented by 2 formulas A formula characterized by reducing the compound represented by A method for producing a spiro compound represented by