NO154838B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE SPIROBENZOFURANON COMPOUNDS. - Google Patents

Description

The present invention relates to the production of spirobenzofuranone compounds with a therapeutic effect and with the formula:

The 1-hydroxyethyl group in the above formula I can be in any position in the benzene ring,

and a preferred position is the 5 or 7 position.

According to the invention, the compound of formula I is prepared by reducing a compound of the formula:

The reduction is normally carried out in a suitable solvent. While any solvent that does not interfere with the reaction may be used, examples of solvents include ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, pyridine, isopropyl alcohol, etc., and

mixtures thereof. The reduction is preferably carried out using a reducing agent such as metal borohydride (eg sodium borohydride or potassium borohydride). The reaction temperature is normally from approx. -70°C to +40°C, preferably from -15°C to +20°C, although the reaction can be carried out at higher or lower temperatures if this is desired to prevent reduction of the carbonyl group in the 3-position and to regulate the reaction rate .

The compound of formula I prepared as indicated above can be isolated from the reaction mixture and purified by conventional methods (eg, distillation, column chromatography, etc.). The compound with formula I has optical isomers based on its asymmetric carbon atom, and the production of these isomers is covered by the present invention.

The spiro compounds of formula I are new compounds

which have gastric secretion-inhibiting, anti-inflammatory and analgesic effects, as well as other effects in mammals (eg human, rat, mouse, guinea pig, dog and pig); the compound of formula I which has the 1-hydroxyethyl group in the 5-position, shows e.g. strong protective effect against gastric mucosal erosion in rats at a dose of 50 mg/kg by the method according to Robert et al. (Gastroenterology, 11_, 433

(1979)), and they are less toxic.

The compounds are therefore valuable as antiulcer, anti-inflammatory, analgesic agents and as drugs for the treatment of peptic ulcer, acute or chronic gastritis, lumbago, arthritis and other diseases. Treatment of peptic ulcer includes both prophylactic administration of the spiro compounds of formula I to prevent the outbreak of an ulcer in a patient who is predisposed to this, as well as treatment of an existing peptic ulcer. In such medical applications, each compound of formula I can be safely administered orally or parenterally, either alone or formulated with per se known pharmaceutically acceptable carriers or diluents, in suitable dosage forms such as tablets, powders, capsules, injections and suppositories. Although the recommended dose depends on the patient, condition, route of administration, etc., the normal oral dose for the treatment of peptic ulcer or acute or chronic gastritis is about 1-20 mg as compound I per kg body weight per dose, which should be given 1 to 3 times a day.

The starting compound of formula II used

by the present method can be produced as described in European patent publication no. 3084, or any analogous method.

Followed reference examples and design examples further illustrate the invention.

Reference example 1

To a mixture of methyl 3-acetylsalicylate (5.8 g) and potassium carbonate (10.4 g) in acetone (200 ml) was added α-bromo-γ-butyrolactone (12.5 g) with stirring and the mixture was refluxed for 11 hours. The soluble substances were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on silica gel and elution was carried out with chloroform. By the above method, α-[(6-acetyl-2-methoxycarbonyl-phenyl)oxy]-γ-butyrolactone was obtained as a pale yellow oil. Infrared absorption ion spectrum: (IR) v^"""^111 cm : max 1780 (γ-lactone), 1720 (COOCH3), 1690 (COCH3)

Elemental analysis for c^4H^4°<g>

Calculated: C 60.43; H 5.07

Found: C 60.21; H 5.0 2

Reference example 2

A mixture of α-[(6-acetyl-2-methoxycarbonylphenyl)-oxy]-γ-butyrolacetone (3,5), 1,8-diazabicyclo[5,4,0]-7-undecene (0.14 g) and sodium chloride (1.1 g) in N,N-dimethylformamide (66.5 ml) was stirred at 150-160°C for 5 hours. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. The fraction eluted with dichloromethane was recrystallized from CHCl3~hexane to give 7-acetylspiro[benzo[b]furan-2(3H),1'-cyclopropan]-3-one (0.22 g) as colorless needles melting at 114 -115°C.

Elemental analysis for C^2H10°<3>

Calculated: C 71.28; H 4.99

Found: C 71.39; H 4.96

Reference example 3

A mixture of ot-[(4-acetyl-2-methoxycarbonylphenyl)-oxy]-γ-butyrolacetone (2.8 g), 1,8-diazabicyclo[5,4,0]-7-undecene (0.056 g), sodium chloride (0.6 g) and N,N-dimethylformamide (28 ml) were heated at 150-155°C for 4 hours. The solvent was removed in vacuo and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried. The residue obtained by removing the solvent in vacuo was chromatographed on silica gel. The fraction eluted with dichloromethane was crystallized from ethanol to give 5-acetylspiro[benzo[b]furan-2(3H),1<1->cyclopropan]-3-one (1.15 g) as colorless crystals .

IRvKBf cm"1: 1700, 1680 (CO, COCHo). NMR (CDC10)6: max 3 3

1.70 (4H, q. J=7Hz, CH2), 2.62 (3H, s, COCH3), 7.20 (1H, d, J=9Hz, aromatic.H), 8.27, 8.30 (1H, dd, J=9Hz, aromatic.H),

8.29 (1H, d, J=2Hz, aromatic.H).

Example 1

To a well-stirred solution of 5-acetylspiro[benzo-[b]furan-2(3H), 1'-cyclopropan]-3-one (1 g) in tetrahydrofuran (25 ml) and isopropanol (3 ml) was added portions added NaBH^ (0.9 g) while cooling at -50°C. The reaction mixture was then stirred at room temperature for 30 minutes, followed by dilution with ice water, which was neutralized with aqueous ammonium chloride. The aqueous solution was extracted with ethyl acetate. The extract was washed with water and dried. The residue obtained by removal of the solvent was chromatographed on silica gel and eluted with CHCl 2 . The product was distilled under reduced pressure to give 5-(1-hydroxyethyl)spiro[benzo[b]furan-2(3H), 1<1->cyclopropane]-3-one as a colorless oil. k.p. 0.05 mmHg:

110°C (bath temperature). IRv^^cm"1: 3350 (OH) ,

1710 (CO). NMR (CDCl 3 ) 6 : 1.45 (3H, d, J=6Hz, CH 3 ),

1.62 (4H, q, J=3Hz, CH2), 3.33 (1H, b, OH), 4.83 (1H, q,

J=6Hz, CH), 6.97 (1H, d, J=9Hz, aromatic.H), 7.55 (2H, m, aromatic.H)

Elemental analysis for C^2H12°3

Calculated: C 70.57; H 5.92

Found: C 70.47; H 6.05

Example 2

By a method similar to that of Example 1, 7-acetylspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one was reacted to give 7-(1-hydroxyethyl)spiro[benzo [b]furan-2(3H), 1'-cyclopropan]-3-one.

IRvmax cm~<1>: 3400 (OH)' 1700 (CO).

Elemental analysis for C^H^O-j

Calculated: C 70.57; H 5.92

Found: C 70.36; H 5.89

Comparison experiment

The following comparative data have been obtained for a compound of formula I and for known compounds:

The experiment was carried out in the same way as stated in Norwegian patent application no. 801290.

Claims (1)

Analogous process for the preparation of therapeutically effective spirobenzofuranone compounds of the formula: characterized by reducing a compound with the formula: