KR790001066B1 - Process for preparing 6,11-dihydro-11-oxodibenz(b,e)oxepin alkanoic acids and esters thereof - Google Patents

Abstract

Title compd. (I; R = H or C1-4 alkyl, R1 = H, halogen, C1-4 alkoxy, C1-14 alkyl or acidic fluoromethyl, n = 1-3) and its ester, having good antiinflammatory activity, was prepd. Thus, alkyl ester (II) and hydroxypheny lacetic alkyl ester (III) was reacted to obtain diester(IV) in the presence of solvent or acid acceptor at 0-120≰C for 5min-20hr, and saponificated, cyclized, or reacted with thionyl halide and phosphorous halide to make 2-acid halide, the reaction product was cyclized by heating at 80-120≰C, and hydrolyzed, to giveI.

Description

6, 11-dihydro-11-oxodibenz [b, e] oxepin alkanoic acid and its manufacturing method

The present invention provides W- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) alkanoic acid and its esters with anti-inflammatory salts, pharmaceutically acceptable acid addition salts It is about a method. The compound of the present invention also exhibits analgesic action.

The compounds of the present invention have not been known to date. The anti-inflammatory 6, 11-dihydro-11-oxodibenz [b, e] oxepin acetates are described in US Patent Application No. 459, filed April 10, 1974 with Helsley, McFadden and Hoffman. 3- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) propionic acid is described in the above U.S. Patent Application but has anti-inflammatory or analgesic effects. There is no Therefore, it was not expected that the compounds of the present invention exhibit activity unlike propionic acid analogs.

The compound of the present invention has the following structural formula.

Where R is hydrogen or alkyl of 1-4

R ¹ is hydrogen or halogen, alkoxy having 1 to 4 carbons, alkyl having 1 to 4 carbons, or methyl fluoride, and n is 1-3.

Also included are salts prepared from physiologically possible bases. Good compounds are those in which R is hydrogen, R ¹ is hydrogen and n is 1, 2, or 3.

The compounds of the present invention can be prepared as follows:

Method A

1. An alkyl ester of hydroxyphenylalkanoic acid having m of the following structural formula 1-5 is prepared by a known method.

A preferred method is to react W- (hydroxyphenyl) alkanophosphoric acid in the presence of an acid such as sulfuric acid, hydrochloric acid or P-toluenesulfonic acid for 15 minutes to 20 hours between the alcohol and the boiling temperature of the alcohol.

2. An alkyl ester of the formula wherein Z is alkyl having 1-4 carbons

m is an integer of 1-5 and reacted with an alkyl ester of hydroxyphenylalkanoic acid of the following structure:

In the presence or absence of a solvent such as acetone, butanone, ethanol, dimethylformamide and an acid acceptor such as potassium carbonate or sodium ethoxide, for 5 minutes to 20 hours at 0-120 ° C., with or without a reaction inducer such as sodium iodide. Reaction gives the substituted carboxybenzyloxyphenyl alkanophosphoric acid of the following desired structure.

3. The diester is saponified with sodium thorium hydroxide or potassium in the presence of a solvent such as an ethanol / water mixture at ambient temperature to 125 ° C. for 15 minutes to 24 hours to prepare dicarboxylic acid in the following structure.

4. The dicarboxylic acid is reacted with a dehydrogenating agent such as polyphosphoric acid, ethanol-phosphorous pentoxide, sulfuric acid, or phosphorus pentachloride at 50-125 ° C. in the presence or absence of a solvent such as tetramethylene sulfone or acetic acid for 15 minutes to 12 hours. This minority compound of the present invention is prepared.

Method B

1.The dicarboxylic acid of the second step of Method A is treated with a reagent layer such as cionyl halide or phosphorus pentahalide at ambient temperature or boiling temperature of the reaction mixture in the presence or absence of solvent and reacted for 15 minutes to 4 hours. Obtain the diacid halide of the following structural formula.

X is chlorine, bromine or fluorine.

2. The modified condition of the Friedel-Crafts reaction of the diacid halide means a heat-closing reaction of heating the diacid halide to 80-125 ° C. for 10 minutes to 24 hours.

A compound in which R prepared according to Production Process A) or B) is hydrogenated is esterified to give its corresponding ester wherein R is alkyl having 5 carbon atoms. A good method is to use W- (6,11-dihydro-11-oxodibenz [be] oxepin-2-yl) alkanoic acid with alcohol in the presence of an acid such as sulfuric acid, hydrochloric acid or P-tontuene sulfonic acid. Between the boiling point of the alcohol and the senile acid in the presence of an acid such as sulfuric acid, hydrochloric acid or P-tontoene sulfonic acid for 15 minutes to 20 hours between the alcohol and the boiling point of the alcohol.

As experts know, the reaction time is correlated with the reaction temperature, so it takes a short time at high temperatures.

The compounds of the present invention are useful as anti-inflammatory agents that suppress inflammation in mammals. The activity of this compound can be seen in anti-inflammatory assays that induced edema with carrageenin in the sole of rats.

(Proc. Soc. Exptl. Biol. Med., 544 (1962); J. Pharmacol. Exp. Ther., 141, 369 (1963))

For example, 10 mg / kg 4- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid and 4- (6,11-dihydro-11-oxodi Benz [b, e] oxepin-2-yl) -butylate 50% edema is suppressed at 50 mg / kg. These data make the compounds of the present invention useful as anti-inflammatory agents at doses of about 0.1-100 mg / kg.

The compounds of the present invention are also useful as analgesics for eliminating mammalian pain. The use of some chemicals as analgesics of the present invention is measured by inducing torsion of mice with 2-phenyl-1,4-quitone, the standard assay for analgesics.

(Proc. Soc. Exptl. Biol. Ned., 45, 729 (1957)).

Thus, for example, a torsion inhibiting 50% dose of 4- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid is 16 mg / kg orally. From these data the compounds of the present invention are useful as analgesics at 0.5-50 mg / kg.

Examples of compounds of the present invention are as follows:

Methyl-6- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caproate;

Isopropyl-8- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caprylate;

Ethyl-4- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) butyrate;

n-butyl-6- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caproate;

t-butyl-8- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caprylate;

4- (6, 11-dihydro-9-n-butoxy-11-oxodibenz [b, e] oxepin-2-yl) butyric acid;

4- (6, 11-dihydro-8-n-butyl-11-oxodibenz [b, e] oxepin-2-yl) butyric acid.

The compounds of the present invention are useful as pharmaceuticals and veterinary drugs and are administered to patients orally, intramuscularly, intravenously, subcutaneously, intraperitoneally. A good route of administration is oral administration with inert diluents or edible carriers or as gelatin capsules or tablets.

For oral administration, the active ingredient of the present invention is administered in combination with excipients used in tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like.

Such formulations should contain at least 0.5% of active compound, but depend on the formulation and are usually 7-90%. Suitable formulation is selected according to the amount of active ingredient. Good compositions and formulations are preferred for oral formulations containing 5-500 mg of active ingredient.

Tablets, pills, capsules, troches and the like also contain the following ingredients: binders such as tragacanth gum or gelatin; Excipients such as starch or lactose, and sealing agents such as alkynic acid or potato starch; Lubricants such as magnesium stearate; Sweeteners such as sucrose and saccharin, and flavoring agents such as peppermint, methyl salicylate, and orange flavors contain liquid carriers such as fatty acids in addition to those mentioned above. Other formulations contain many other substances, such as epidermal agents. Thus tablets or pills can be coated with sugar-cellac or rumble. The syrup includes sweeteners, preservatives, dyes, colored papers, fragrances, and the like as a sweetener. The materials used to prepare these various compositions must be pharmaceutically pure and non-toxic in the amounts employed.

For parenteral administration, the active compounds of the present invention are used as solutions or suspensions. Such formulations should contain at least 0.1% active ingredient but should be 0.5-30% by weight. For such compositions the amount of active compound should be in a suitable dose. Good compositions and formulations contain 0.5-100 mg of active ingredient in unit doses.

Liquids or suspensions contain the following components: sterile diluents, such as distilled water for injection, saline, nonvolatile oil, polyethylene glycol, other synthetic solvents; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid and sodium hyposulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffers such as acetates, citrates, and phosphates, osmotic agents such as salt or glucose, and parenteral preparations are filled in ampoules, disposable syringes, and vials for use in glass or plastic.

The physiologically possible bases used for preparing the salts of the compounds of the present invention include inorganic bases containing sodium, potassium, calcium, and the like as cations, and organic bases such as ethanolamine, diethanolamine, and dimethylethanolamine.

The following examples further illustrate the present invention.

Example 1

A. A mixture of 28.8 g of ethyl 4- (hydroxyphenyl) butyrate, 33.6 g of ethyl α-bromo-2-toluate, 81.7 g of potassium carbonate, 580 ml of 2-butanone, and 1.8 g of sodium iodide was refluxed for 17 hours. Let's do it. The reaction solution is cooled, filtered and washed with ether to remove the solvent in vacuo to dissolve the yellow oil obtained in ether. The ether solution is washed successively with water, 5% sodium hydroxide solution, water, dried, filtered and the ether removed in vacuo to give a pale yellow oil. This oil is dissolved in a mixture of potassium hydroxide, ethanol and water and refluxed for 17 hours. The solution is cooled and the brown semisolid material obtained by vacuum evaporation of the solvent is dissolved in water and extracted with ether. The oil obtained by adjusting the medium of the aqueous layer to 2 with concentrated hydrochloric acid is left to obtain a solid. The solid material was collected by filtration, washed with water and recrystallized with acetonitrile to obtain 4- (4- (carboxybenzyloxy) phenyl) butyric acid having a melting point of 149-150 ° C. as a pale yellow solid.

Analysis: C ₁₈ H ₁₈ O ₅

Calc .: C 68.77%; H 5.77%

Found: C 68.52%; H 5.69%

In a similar manner 4- (4- (2-carbox 4-fluoro benzyloxy) phenyl) butyric acid and 4- (4- (2-carbox 4-5-chloro benzyloxy) phenyl) butyric acid and 4- (4- (2-carbox-3--3-benzyloxy) phenyl) butyric acid may be prepared.

B. Add 22.5 g of polyphosphoric acid to a 5.0 g solution of 4- (4- (2-carboxybenzyloxy) phenyl) butyric acid in 17.5 ml glacial acetic acid and stir at 95 ° C for 3 hours. After the solution is cooled, water is added to precipitate a precipitate which is collected by filtration. Recrystallization with benzene yields gray 4- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid with a melting point of 116-118 ° C.

Analysis: C ₁₈ H ₁₆ O ₄

Calc .: C 72.95%; H 5.44%

Found: C 72.79%; H 5.44%

In a similar manner 4- (6, 11-dihydro-9-fluoro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid, 4- (6, 11-dihydro-8- Chloro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid and 4- (6, 11-dihydro-10-methyl-11-oxodibenz [b, e] oxepin-2 -Yl) butyric acid can be prepared.

Example 2

Amberlite IR-120 H.C.P. in 2.6 g of 4- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) butyric acid (Example 1) and 25 ml of metalol. 0.8 g of the mixture is refluxed for 16 hours, cooled, diluted with ether and filtered. The filtrate was washed successively with 5% caustic soda solution, water, dried, filtered and concentrated in vacuo to recrystallize the residue with methanol, to give methyl 4- (6, 11-dihydro-11-, an off-white crystal with a melting point of 83-85 ° C. Oxodibenz [b, e] oxepin-2-yl) butyrate.

Analysis: C ₁₉ H ₁₈ O ₄

Calc .: 73.53% C; H 5.85%

Found: C 73.61%; H 5.92%

Example 3

A. 25.0 g of ethyl 6- (4-hydroxyphenyl) caproate at a boiling point of 148-150 ° C. (0.15 mm), 32.0 g of α-bromo-2-toluate, 72.0 g of anhydrous potassium carbonate; A mixture of 600 g of 2-butanone of 1.0 g of sodium thorium iodide was refluxed for 16 hours, cooled, filtered and washed with ether to concentrate the filtrate under vacuum to give a yellow oil. The oil is dissolved in 100 ml of 95% ethanol and 20 ml of water, and 23.5 g of 85% potassium hydroxide is added to reflux the mixture for 14 hours. The semisolid obtained by vacuum concentration of this solution was dissolved in water, washed with ether and acidified with ice-cold concentrated hydrochloric acid to give a white solid, which was collected and recrystallized with acetonitrile to give 6- (4- (2-carboxybenzyloxy) phenyl) caprophosphate is obtained.

Analysis: C ₂₀ H ₂₂ O ₅

Calc .: C 70.16%; H 6.48%

Found: C 70.22%; H 6.57%

6- (4- (2-carboxy-4-trifluoromethyl benzyloxy) phenyl) caproic acid and 6- (4- (2-carboxy-5-methoxy benzyloxy) phenyl) caproic acid in a similar manner can do.

B. 8.8 g of phosphorus pentachloride was added to a solution of 7.0 g of 6- (4- (2-carboxybenzyloxy) phenyl) caproic acid in 80 ml of cooled benzene, after all of the phosphorus pentachloride was dissolved, the ice bath was removed and the resulting yellow solution was added for 4 hours. Stir and remove benzene at 80 ° C. in vacuo. The residue amber oil is dissolved in 80 ml of methylene chloride, cooled, the dark solution formed by adding 10.9 g of tin with chloride is stirred at ambient temperature for 72 hours, hydrolyzed with 80 ml of 1N hydrochloric acid and then for another 36 hours. The organic layer is separated and concentrated from this mixture, and the residual rubbery material is dispersed in chloroform to be concentrated to dryness to obtain a solid. Recrystallization of this solid with acetonitrile gives 6- (6, 11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caproic acid as an off-white product with a melting point of 98-100 ° C.

Analysis: C ₂₀ H ₂₀ O ₄

Calc .: 74.05% C; H 6.22%

Found: C 73.85%; H 6.29%

In a similar manner 6- (6,11-dihydro-11-oxo-9-trifluoro methyldibenz [b, e] oxepin-2-yl) caproic acid and 6- (6,11-dihydro- 8-methoxy-11-oxodibenz [b, e] oxepin-2-yl) caproic acid can be prepared.

Example 4

A. Ethyl 8- (4-hydroxyphenyl) capryltate prepared according to Preparation A) was treated in the same manner as in Example 3A) to give 8- (4- (2-) as colorless crystals having a melting point of 116-118 ° C. Carboxybenzyloxy) phenyl) caprylic acid is obtained.

Analysis: C ₂₂ H ₂₆ O ₅

Calc .: C 71.32%; H 7.07%

Found: C 71.26%; H 7.14%

In a similar manner, 9- (4- (2-carboxy-5-chlorobenzyloxy) phenyl) caprylic acid can be prepared.

B. 3.4 g of polyphosphoric acid was added to a 1.0 g suspension of 8- (4- (2-carboxybenzyloxy) phenyl) caprylic acid in 2.63 ml of glacial acetic acid under nitrogen gas, stirred at 100 ° C. for 4 hours, diluted with water and cooled Filtered. The filter cake was combined with chloroform extract, washed with water, dried, and the residue obtained by removing chloroform was recrystallized with acetonitrile. Then, 8- (6, 11-dihydro-11-oxodibenz [b, e] having a melting point of 68-70 ° C was obtained. Oxepin-2-yl) caprylic acid is obtained.

Analysis: C ₂₂ H ₂₄ O ₄

Calc .: 74.97% C; H 6.86%

Found: C 74.67%; H 7.03%

In a similar manner 8- (6, 11-dihydro-8-chloro-11-oxodibenz [b, e] oxepin-2-yl) caprylic acid can be prepared.

Claims (1)

The alkyl ester of formula (A) and the hydroxyphenyl acetate acetate ester of formula (B) are reacted for 5 minutes to 20 hours at 0-120 ° C. in the presence of a solvent and an acid acceptor to obtain a diester of formula (C), which is saponified. And then ring closed, or reacted with thionyl halide or phosphorus halide (where the halide is bromine, chlorine or fluorine) to produce a diacid halide which is ring closed under Friedel-Craft standard conditions or heated at 80-125 ° C. A method for producing W- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) alkanoic acid and its esters of formula (D) by ring closure to hydrolysis.

Where R is hydrogen or alkyl of 1-4 carbons, R ¹ is hydrogen or halogen, alkoxy 1-4 alkoxy, alkyl having 1-4 carbons, trifluoromethyl, n is 1, 2 or 3 Z is alkyl having 1-4 carbons, m is an integer of 1-5.