CH627752A5 - Process for the preparation of 6,11-dihydro-11-oxodibenz[b,e]oxepinealkanoic acids and their esters - Google Patents

Description

The present invention relates to a process called 3- (6, l 1-dihydro-l 1-oxo-for the preparation of new 6,11-dihydro-l 1-oxo-dibenz [b, e] oxepin-2-yl) However, propionic acid showed neither dibenz [b, e] oxepin-alkanoic acids, their esters and physiological anti-inflammatory or analgesic effects. It is gisch tolerated salts with anti-inflammatory and therefore surprising that the compounds of the present also have an analgesic effect. Invention in contrast to the propionic acid analogue

6,11 -Dihydro-11-oxo-dibenz [b, e] oxepinetic acid with such an effect.

anti-ignition effect is disclosed in the US patent application.

459 774 from Helsley, McFadden and Hoffman of speaking of the formula 10.04.1974. The also in the above patent application 35

0

CH2 (CH2CH2) n-C02R.

in which R is a hydrogen atom or an alkyl group with 1 to The process according to the invention is carried out as in the patent

4 carbon atoms, R 'a hydrogen or halogen claims 1 and 8 specified.

atom, an alkoxy or alkyl group having 1 to 4 carbon. In the following some embodiments of the atoms or the trifluoromethyl group and n are a number of so invention.

1 to 3 mean. Preferred compounds are those in Process A

which R and R 'is a hydrogen atom and n is 1, 2 or 3 1. An alkyl ester of a hydroxyphenylalkanoic acid. formula

CH2- (0H2CH2) nC02CmH (2m + 1)

in which n has the meaning given above and m represents a number from 1 to 5, according to a preferred embodiment, reaction of an (o- (hydroxyphenyl) alkanoic acid with an alcohol in the presence of another acid, such as sulfuric acid, hydrochloric acid or p -Toluenesulfonic acid, at temperatures from 50 ° C to the boiling point of the alcohol used within 15 minutes to 20 hours.

2. An alkyl ester of the formula

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627752

CH2Br in which R 'has the meaning given above and Z represents an alkyl group having 1 to 4 carbon atoms, is reacted with an alkyl ester of a hydroxyphenylalkanoic acid of the formula 10

CH2- (CH2CH2) nC02Cm '.! F2n> fl)

in which n and m have the meanings given above, in with the addition of a catalyst such as sodium iodide, at temperature

Presence of suitable solvents such as acetone, butanone, temperatures from 0 to 120 ° C in a time from 5 minutes to 20

Ethanol or dimethylformamide and an acid binder for 2 hours to diester a substituted carboxybenzyloxy

such as potassium carbonate or sodium ethylate, optionally phenylalkanoic acid of the formula

R '

H2 (CH2CH2) nC02Cn) H (2nH.1)

in which R ', n and m have the meanings given above, implemented.

30 3. The diester thus obtained then becomes a dicarboxylic acid of the formula

.CH2 (CH2CH2) nC02H

in which R 'and n have the meanings mentioned above, 40 preferably saponified using a base such as sodium or potassium hydroxide in a solvent such as ethanol / water for 15 minutes to 24 hours at temperatures from room temperature to 125 ° C.

4. The dicarboxylic acid obtained is treated with 45 a dihydration agent such as polyphosphoric acid, ethanol-phosphorus pentoxide, sulfuric acid or phosphorus pentachloride, optionally in a solvent such as tetramethylene sulfone or acetic acid, at temperatures from 50 to 125 ° C. for 15 minutes to 12 hours an invention 50

cox cyclized compound in which R is hydrogen.

Procedure B

1. A dicarboxylic acid according to process A, 2 with an appropriate amount of a halogenating agent such as thionyl halide or phosphorus pentahalide, optionally in a solvent at temperatures from room temperature to the boiling point of the reaction mixture, for 15 minutes to 4 hours to a dicarboxylic acid halide of the formula

CH2 (CH2CH2) nC0X

in which R 'and n have the meanings given above and X denotes chlorine, bromine or fluorine.

2. The dicarboxylic acid halide thus obtained is cyclized either under the standard conditions or under modified conditions of the Friedel-Crafts reaction and then hydrolyzed to a compound of the formula I (R = H). Modified conditions of the Friedel-Crafts reaction are understood to mean thermal cyclization, which is carried out by heating a dicarboxylic acid halide over a period of 10 minutes to 24 hours to temperatures of 80 to 125 ° C.

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Procedure C

A compound (R = H) prepared by process A or B can be converted into a corresponding ester in which R denotes an alkyl group with 1-4 C atoms. According to a preferred embodiment, a co- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) alkanoic acid is mixed with an alcohol in the presence of an acid, such as sulfuric acid, hydrochloric acid or p- Toluenesulfonic acid, reacted at temperatures from 50 ° C to the boiling point of the alcohol in question for 15 minutes to 20 hours. Depending on

627752

Reaction temperature, the reaction times are of course correspondingly longer or shorter.

Because of their anti-inflammatory properties, the compounds produced according to the invention and their esters with 1 to 4 carbon atoms are valuable anti-inflammatory agents when administering doses between 0.1 and 100 mg / kg body weight. Some of them are also valuable analgesics due to their pain-relieving properties when doses of 0.5 to 50 mg / kg body weight are administered.

Examples of compounds obtainable according to the invention are:

4- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) butyric acid, 4- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2 -yl) -butyric acid- (methyl ester)

6- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -caproic acid methyl ester

8- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -caprylic acid isopropyl ester

4- (6, l 1-Dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -butyric acid ethyl ester

6- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -caproic acid n-butyl ester

8- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -caprylic acid tert-butyl ester

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

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

The compounds prepared according to the invention and their alkyl esters with 1 to 4 carbon atoms are valuable pharmaceutical and veterinary products and can be administered to the patient in effective amounts in various ways, e.g. oral, intramuscular, intravenous, subcutaneous or intraperitoneal, but preferably oral, e.g. with inert extenders, digestible carriers or in gelatin capsules or tablets.

The active substances of formula I and Ia can be administered orally, e.g. Use together with extenders or in the form of tablets, troches, capsules, elixirs, suspensions, syrups, waffles or chewing gums. The active substance content of this formulation should be at least 0.5%, but it can advantageously vary between 7 and about 90 percent by weight depending on the formulation. The oral dose units produced according to the invention preferably contain 5 to 500 mg of active substance.

The tablets, pills, capsules and lozenges can contain the following additives: binders such as gum tragacanth or gelatin, extenders such as starch or milk sugar, disintegrants such as alginic acid, potato starch, lubricants such as magnesium stearate and sweeteners such as sucrose or saccharin as well as taste-improving substances such as peppermint, methyl salicylate or orange flavoring. If capsules are selected as the dose unit, they can also contain liquid carriers such as fatty oils in addition to the substances mentioned above. In addition, other additives are possible, which change the external form of the dose unit, e.g. Covers. So tablets or pills can be provided with sugar, shellac or both. In addition to the active substances, syrup can contain sucrose as a sweetener and various preservatives, colors and flavorings.

For parenteral administration, the active ingredients of the formulas I and Ia can be incorporated in solutions or suspensions, the active ingredient content being at least 0.1%, but can also vary between 0.5 and about 30 percent by weight. The parenteral dose units preferably contain between 0.5 and 100 mg of active substance.

The solutions or suspensions can also contain the following additives: sterile diluents such as water for injections, salt solutions, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; anti-bacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffer substances such as acetates, citrates or phosphates and agents for adjusting the isotonicity such as sodium chloride or dextrose. The parenteral preparations can be filled into ampoules, disposable syringes or violets made of glass or plastic containing several cans.

Inorganic bases which contain sodium, potassium or calcium ions and various organic bases such as ethanolamine, diethanolamine and dimethylethanolamine are suitable as physiologically compatible bases for the salt formation of the compounds of the formula I.

example 1

A) A mixture of 28.8 g of ethyl 4- (4-hydroxyphenyl) -butter acid, 33.6 g of ethyl a-bromo-2-toluic acid, 81.7 g of potassium carbonate, 580 ml of 2-butanone and 1 , 8 g of sodium iodide is heated under reflux for 17 hours. It is cooled, filtered, washed with ether, the solvent is removed in vacuo and the yellow oil obtained is dissolved in ether. The ethereal solution is washed successively with water, an aqueous 5% sodium hydroxide solution and water, dried, filtered and the ether is removed in vacuo to give a light yellow oil. The oil is dissolved in a mixture of potassium hydroxide, ethanol and water and refluxed for 17 hours. The solution is cooled, the solvent is removed in vacuo and the brown, semi-solid residue obtained is dissolved in water and the solution is extracted with ether. The oil formed after adjusting the aqueous layer to pH 2 with concentrated hydrochloric acid is solid on standing, filtered off, washed with water and recrystallized from acetonitrile. 4- [4- (2-Carboxybenzyloxy) phenyl] -butyric acid is obtained as a light brown solid substance, mp. 149-150 ° C.

Analysis: CisHisOs Ber .: C 68.77% H 5.77%

Found: C 68.52% H 5.69%.

Similarly, the 4- [4- (2-carboxy-4-fluoro-benzyloxy) phenyl] butyric acid, which

4- [4- (2-carboxy-5-chlorobenzyloxy) phenyl] butyric acid and 4- [4- (2-carboxy-3-methylbenzyloxy) phenyl] butyric acid.

B) 22.5 g of polyphosphoric acid become a solution of 5.0 g of 4- [4- (2-carboxybenzyloxy) phenyl] butyric acid in

17.5 ml of glacial acetic acid were added and the mixture was stirred at 95 ° C. for 3 hours. The solution is allowed to cool and water is added to give a precipitate which is filtered off with suction. By recrystallization from benzene, 4- (6, l 1-dihydro-1 l-oxodibenz [b, e] oxepin-2-yl) -butyric acid is obtained as an off-white solid, mp. 116-118 ° C.

Analysis: CisHtóCU calc .: C 72.95% H 5.44%

Found: C 72.79% H 5.44%.

Similarly, the 4- (6, l-dihydro-9-fluoro-l 1-oxodibenz [b, e] oxepin-2-yl) butyric acid, the 4- (6, l 1-dihydro- 8-chloro-11-oxodibenz [b, e] oxepin-2-yl) -butyric acid and 4- (6, l 1-dihydro-10-methyl-l 1-oxodi-benz [b, e] oxepin-2 -yl) -butyric acid.

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Example 2

A mixture of 2.6 g of 4- (6, l 1-dihydro-l 1-oxodi-benz [b, e] oxepin-2-yl) butyric acid (Example 1) and 0.8 g of strongly acidic ion exchanger in 25 ml of methanol is refluxed for 16 hours, cooled, diluted with ether and filtered. The filtrate is washed successively with aqueous 5% sodium hydroxide solution and water, dried, filtered and concentrated in vacuo to a solid substance which is recrystallized from methanol. 4- (6, l 1-Dihydro-l 1-oxodibenz [b, e] oxepin-2-yl) -butyric acid methyl ester is obtained as whitish crystals of mp. 83-85 ° C.

Analysis: C19H18O4 Calc .: C 73.53% H 5.85%

Found: C 73.61% H 5.92%.

Example 3

A) A mixture of 25.0 g of 6- (4-hydroxyphenyl) -caproic acid ethyl ester, bp. 148-150 ° C. (0.15 mm Hg), which was prepared by process A), 32.0 g Ethyl a-bromo-2-toluic acid, 72.0 g of anhydrous potassium carbonate and 1.0 g of sodium iodidine 600 ml of 2-butanone are heated under reflux for 16 hours. It is cooled, filtered, washed with ether and the filtrate is concentrated in vacuo. A yellow oil is obtained which is dissolved in 100 ml of 95% ethanol and 20 ml of water, mixed with 23.5 g of 85% potassium hydroxide solution and heated to reflux for 14 hours. The solution is concentrated in vacuo and the semisolid substance obtained is dissolved in water. The aqueous solution is washed with ether and concentrated with ice-cold. Acidified hydrochloric acid. A white solid substance is obtained, which is filtered off with suction and recrystallized from acetonitrile. The 6- [4- (2-carboxy-benzyloxy) phenyl] -caproic acid is obtained in the form of white crystals of mp. 138-140 ° C.

Analysis: C20H22O5 Calc .: C 70.16% H 6.48%

Found: C 70.22% H 6.57%.

Similarly, the 6- [4- (2-carboxy-4-trifluoromethylbenzyloxy) phenyl] caproic acid and the 6- [4- (2-carboxy-5-methoxybenzyloxy) phenyl] caproic acid are obtained.

B) 8.8 g of phosphorus pentachloride are added to a solution of 7.0 g of 6- [4- (2-carboxybenzyloxy) phenyl] -caproic acid in 80 ml of benzene, cooled in an ice bath. After the phosphorus pentachloride has completely dissolved, the ice bath is removed, the yellowish solution obtained is stirred for 4 hours and the benzene is removed in vacuo at 80.degree. The amber oil obtained is dissolved in 80 ml of methylene chloride, cooled and mixed with 10.9 g of tin-IV chloride, giving a dark solution which is stirred at room temperature for 72 hours and hydrolyzed with 80 ml of 1N hydrochloric acid.

627 752

siert and stirred for a further 36 hours. The phases are separated and the organic phase is concentrated to a rubber-like substance which is triturated with chloroform, dried and concentrated to a solid substance. This is recrystallized from acetonitrile, and it becomes a whitish product with a melting point of 98-100 ° C. which contains the 6- (6, l 1-dihydro-1 l-oxodibenz [b, e] oxepin-2-yl) represents caproic acid.

Analysis: C20H20O4 Calc .: C 74.05% H 6.22%

Found: C 73.85% H 6.29%.

Similarly, the 6- (6, l 1-dihydro-l l-oxo-9-trifluoromethyldibenz [b, e] oxepin-2-yl) -caproic acid and the 6- (6, l 1-dihydro-8- methoxy-l l-oxodibenz [b, e] oxepin-2-yl) -caproic acid.

Example 4

A) 8- (4-Hydroxyphenyl) caprylic acid ethyl ester, which has been prepared by process A), is treated in the procedure described in Example 3 A). The 8- [4- (2-carboxybenzyloxy) phenyl] -caprylic acid is obtained in the form of colorless crystals with a melting point of 116-118 ° C.

Analysis: C22H26O5 Calc .: C71.32% H 7.07%

Found: C71.26% H 7.14%

8- [4- (2-Carboxy-5-chlorobenzyloxy) phenyl] caprylic acid is prepared in a similar manner.

B) 3.4 g of polyphosphoric acid are added to a suspension of 1.0 g of 8- [4- (2-carboxybenzyloxy) phenyl] caprylic acid in 2.63 ml of glacial acetic acid under nitrogen. The reaction mixture is stirred at 100 ° C for 4 hours, diluted with water, allowed to cool and filtered. The filter cake is dissolved in chloroform and the filtrate extracted with chloroform. The chloroform solutions are combined, washed with water, dried and the chloroform removed. The solid substance obtained is recrystallized from acetonitrile and the 8- (6, l 1-dihydro-l l-oxodibenz [b, e] oxepin-2-yl) -caprylic acid is obtained as a solid substance, mp. 68-70 ° C. .

Analysis: C22H24O4

Ber. C 74.97% H 6.86%

Found C 74.67% H 7.03%.

8- (6, l-dihydro-8-chloro-l 1-oxodibenz [b, e] oxepin-2-yl) -caprylic acid is prepared in a similar manner.

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Claims (13)

627752 1. Process for the preparation of new 6,11 -dihydro-11-oxodibenz [b, e] oxepin-alkanoic acids of the formula I. CH2 (CH2CH2) n-COOH (I), where n is an integer from 1 to 3 15 R 'is hydrogen, halogen, alkoxy having 1 to 4 carbon atoms, and their pharmaceutically acceptable atoms, alkyl having 1 to 4 carbon atoms or trifluoro salts, characterized in that an alkyl ester is methyl; and Formula II CH ^ Br '(II), wherein Z is alkyl having 1 to 4 carbon atoms, with an alkyl ester of a hydroxyphenylacetic acid of the formula III CH2- (CH2CH2) nC02CmH (2m + 1) (III), wherein m is an integer from 1 to 5, the resulting diester of formula IV R H2 (CH2CH2) nC02 ° mH (2m + l) (IV) saponified, the dicarboxylic acid of formula V thus obtained .COOH R! CH "(CH" CH ") COOH 2 2 2 n (V) cyclized to the corresponding co- (6, l 1-dihydro-l l-oxodibenz [b, e] -oxepin-2-yl) -alkanoic acid and, if necessary, the process products subsequently converted into their pharmaceutically acceptable salts. 2. The method according to claim 1, characterized in that one effects the cyclization with the aid of a dehydrating agent. 2nd PATENT CLAIMS 3rd 627 752 CH0 (CH0CH0) -COOK 2 2 2 n in which the symbols R 'and n have the meaning given in patent claim 1 and R denotes alkyl having 1 to 4 carbon atoms, characterized in that a compound is prepared by the process according to patent claim 1 (la), of formula I and esterified with an agent giving off the radical R. 3. The method according to claim 1, characterized in that a compound of formula I, wherein R 'is hydrogen, chlorine, fluorine, methyl, methoxy or trifluoromethyl, with hydrogen being preferred. 4. The method according to claim 1, characterized in that 4- (6, l 1-dihydro-l 1-oxo 60 produces dibenz [b, e] oxepin-2-yl) butyric acid. 5. The method according to claim 1, characterized in that 6- (6, l 1-dihydro-l 1-oxodibenz [b, e] oxepin-2-yl) -caproic acid is prepared. 6. The method according to claim 1, characterized marked-6S, which is 8- (6, l 1-dihydro-l 1-oxo dibenz [b, e] oxepin-2-yl) caprylic acid. 7. Process for the preparation of new 6,11-dihydro-l 1-oxodibenz [b, e] oxepin-alkanoic acid alkyl esters of the formula Ia 8. Process for the preparation of new 6,11-dihydro-l 1-oxodibenz [b, e] oxepin-alkanoic acids of the formula I. CH "(CH" CH ") -COOH 2 2 2 n (I), where n is an integer from 1 to 3 R 'is hydrogen, halogen, alkoxy having 1 to 4 carbon atoms, and their pharmaceutically acceptable atoms, alkyl having 1 to 4 carbon atoms or trifluoro salts, characterized in that an alkyl ester is methyl; and 30 of formula II (II), CH2Br where Z is alkyl having 1 to 4 carbon atoms, with an alkyl ester of a hydroxyphenylacetic acid of the formula III CH2- (CH2CH2) nC02CmH (2m + 1) (III), wherein m is an integer from 1 to 5, the resulting diester of formula IV H2 (CH2CH2) nC ° 2CmH (2m + l) R < (IV) saponified, the dicarboxylic acid of formula V thus obtained -CO OH R ' CH2 (CH2CH2) nCOOH (V) 627752 4 by reaction with a halogenating agent in the corresponding dicarboxylic acid halide of the formula VI R ' (VI), where X is chlorine, bromine or fluorine, converted this to the corresponding <»- (6,11-dihydro-l 1-oxodibenz [b, e] oxepin-2-yl) -alkanoic acid and the process products, if appropriate, subsequently in transferred their pharmaceutically acceptable salts. 9. The method according to claim 8, characterized in that one effects the cyclization with the aid of a dehydrating agent. 10. The method according to claim 8, characterized in that a compound of formula I, wherein R 'is hydrogen, chlorine, fluorine, methyl, methoxy or trifluoro 20th means methyl, with hydrogen being preferred. 11. The method according to claim 8, characterized in that 4- (6,11 -dihydro-11-oxodibenz [b, e] oxepin-2-yl) -butyric acid is prepared. 12. The method according to claim 8, characterized in that 6- (6, l 1-dihydro-l 1-oxodibenz [b, e] oxepin-2-yl) -caproic acid is prepared. 13. The method according to claim 8, characterized in that 8- (6, l 1-dihydro-l 1-oxodibenz [b, e] oxepin-2-yl) -caprylic acid is prepared.