FI63569C - FREQUENCY REQUIREMENT FOR PHARMACEUTICAL FRAMEWORK 6,11-DIHYDRO-11-OXODIBENZ (B E) OXEPINALKYLKARBOXYLSYROR OCH DEAS ESTRAR - Google Patents

Description

Γβ1 Μ4Χ NOTICE OF PUBLICATION, 7γ, λ jAfft ^ ^ utlAggninosskrift 63569 C Patent granted on 11 07 1983 (45) Patent neddelat ^ T ^ <(51) ICv.lk?/lnt.CL3 C 07 D J13 / 12 FINLAND — FINLAND (ii) ρκ «μμ« ιιμ-ρμιιιιμ ^ 76215 ^ (22) H * k «nlip« y «—Amatahifidii 28.07.76 * '(M) AikvpUvI — GlMgtatadaf 28.07.76 (41) Tullut) ulkiMksi - Blhrlt offantDf γγ

Pstanttl-jm registry managed (44) MM '** »». ^ ^ FltMlt- och rtfilttratynlNn' AnaMcan Uttafd och utl-tkrtfun pubUcorad 31.UJ.03 (32) (33) (y) ^ yy4 «« y eaiollcm · - * «« Lrd prioriut 30.07.75 USA (US) 600210 (71) Hoechst Aktiengesellschaft, Postfach 80 03 20, 6230 Frankfurt (Main) 80,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Arthur Raymond McFadden, East Brunswick, New Jersey,

Daniel Eugene Aultz, Middlesex, New Jersey, USA (US) (7 * 0 Oy Kolster Ab (5M Method for the preparation of pharmaceutically acceptable 6,11-dihydro-11-oxodibenz-Zb, §7oxepine alkylcarboxylic acids and their esters - Förfarande för framställning av farmaceutisk The present invention relates to a process for the preparation of pharmaceutically acceptable salts of 6,11-dihydro-11-oxodibenz [b] q7-oxepine alkylcarboxylic acids of the formula I, their esters and their derivatives.

H2 (CH2CH2) n -COOK

CCCX

wherein R is hydrogen or lower alkyl, and n is an integer of 1, 2 or 3. The compounds of formula (I) have been found to have anti-inflammatory activity as well as analgesic activity.

Compounds of formula I have not previously been described in the literature * 6,1-dihydro-11-oxodibenz [1 / e] oxepine acetic acid having anti-inflammatory activity is described in U.S. Patent No. 2,63569, 459,774. (6,11-Dihydro-11-oxodibenz [p, e] oxepin-2-yl) propionic acid mentioned in the aforementioned U.S. patent application has not been shown to have anti-inflammatory or analgesic activity. Therefore, it is unexpected that the compounds of this invention, in contrast to propionic acid analogs, have such an effect.

The compounds of this invention are prepared by any of the process alternatives described below, wherein nsn and R are as defined above.

Method option a

Step 1. An alkyl ester of formula

a CO-Z

(II) CH 2 Br wherein Z is alkyl of 1 to 4 carbon atoms is reacted with an alkyl ester of hydroxyphenylalkylcarboxylic acid having the formula ': nV> -CH 2 - (CH 2 CH 2) n CO 2 CmH (2nil) (III)

HO

wherein m is an integer from 1 to 5; in the presence or absence of a suitable solvent such as acetone, butanone, ethanol or dimethylformamide and an acid scavenger such as potassium carbonate or sodium ethylate in the presence or absence of the reaction initiator, sodium iodide, at a temperature of 0-120 ° C for 5 minutes to 20 hours to give the formula Substituted carboxy-benzyloxyphenylalkylcarboxylic diester according to N, N2CH2 (CH2CH2) nCO2CmH (2m + 1) CO2 "(IV).

Step 2. Diester IV is saponified to give a dicarboxylic acid of formula 3,63569

aCO 2 H (CHOCHO) CO, H

I 2 2 2n 2 co2-o «V * preferably using a base such as sodium or potassium hydroxide in a solvent such as ethanol / water for 15 minutes to 24 hours at room temperature to 125 ° C.

Step 3. The dicarboxylic acid V is cyclized by treatment with a dehydrating agent such as polyphosphoric acid, ethanol-phosphorus pentoxide, sulfuric acid or phosphorus pentachloride without solvent or with a solvent such as tetramethylene sulfone or acetic acid at 50-125 ° C for 12 hours at 50-125 ° C. to give a compound of the invention wherein R is hydrogen. The starting material, hydroxyphenylalkylcarboxylic alkyl ester of formula III, wherein m is an integer from 1 to 5, is prepared by methods known in the art. The preferred procedure is to react the IV- (hydroxy-phenyl) alkylcarboxylic acid with an alcohol in the presence of an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid at a temperature between 50 ° C and the boiling point of the alcohol for 15 minutes to 20 hours.

Method option b

Step 1. The dicarboxylic acid obtained from step 2 of process variant a is treated with a sufficient amount of e.g. thionyl halide or phosphorus pentahalide in the presence or absence of a solvent at a temperature between room temperature and the boiling point of the reaction mixture for 15 minutes to 4 hours to form a diacid halide

r ^ Jr- CH2 (CH2CH2) nCOX

wherein X is chlorine, bromine or fluorine.

(VI) 4 63569

Step 2. The di-acid halide VI is cyclized under either standard or modified Friedel-Crafts conditions and then hydrolyzed to give a compound of the invention wherein R is hydrogen. By modified Friedel-Crafts conditions is meant thermal cyclization performed by heating the diacid halide for 10 minutes to 24 hours at 80-125 ° C. additional reaction

A compound of formula I wherein R is hydrogen prepared by the process of the invention and prepared according to either process variant a or b is esterified to give the corresponding ester wherein R is alkyl of 1 to 5 carbon atoms. Preferably (6,11-dihydro-11-oxodibenz / 5,7-oxepin-2-yl) -alkylcarboxylic acid is reacted with an alcohol in the presence of an acid such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid at a temperature between 50 ° C and the boiling point of the alcohol. 15 minutes to 20 hours.

The compounds of formula I are useful anti-inflammatory agents due to their ability to arrest inflammation in mammals at doses of 0.1 to 100 mg per kilogram of body weight.

The compounds of formula I are also useful as analgesics due to their ability to relieve pain in mammals at doses of 0.5 to 50 mg per kilogram of body weight.

The following table shows the anti-inflammatory properties of the compounds of formula I. The experiment has studied carrageenan-induced paw swelling in rats (carrageenan paw edema test).

Test compound (Formula I)

Example ED50 or n_n_R_% Inhibition_ 1 B 1 H 10.1 3 B 2 H 18.2 4 B 3 H 11.7 2 1 CH3 31.7%

It was very surprising that the compounds of formula I which contain a relatively long side chain compared to the compounds known from BE patent 818 055 and U.S. patent application 459 774 have such effective anti-inflammatory activity.

5,63569

Therapeutic comparative experiments were also performed using the compound of Example 1 of the present application (4- (6,11-dihydro-11-oxodibenz [b, 7-oxepin-2-yl) butyric acid) and 6,11-dihydro as known from U.S. Patent Application No. 459,774. ll-oxodibenz / &, e7oksepiini-acetic acid. A carrageenan-induced rat paw swelling test was used as an experiment. The results were as follows:

Anti-inflammatory activity (ED ... mg / kg, oral) 50 6.11-dihydro-11-oxodibenz- [5,7] oxepine-acetic acid 6,4 4- (6,11-dihydro-11-oxodibenz- [5], (7-oxepin-2-yl) butyric acid 10.1

The same compounds were also determined to have a gastrointestinal irritant effect as well as a therapeutic index. The results were as follows:

Gastrointestinal irritant activity (ED5q mg / kg, oral) 6.11-dihydro-11-oxodibenz- [F, 7] oxepine-acetic acid 106.6 4- (6,11-dihydro-11-oxodibenz- / hfe / oxepin-2- yl) butyric acid 217.7

Therapeutic index 6.11-dihydro-11-oxodibenz-2H-oxepine-acetic acid 16.7 4- (6,11-dihydro-11-oxodibenz- [E, e] oxepin-2-yl) -butyric acid 21.6

The results show that the compound of the present application tested and the reference compound known from the said U.S. patent application have approximately the same order of anti-inflammatory activity. However, the compound of the present application irritates the gastrointestinal tract substantially less than the reference compound, so that it has a higher therapeutic index.

β 63569

The compounds of formula I may be administered to a patient by any conventional route, such as orally, intramuscularly, intravenously by subcutaneous injection or intraperitoneally, preferably orally. For the purpose of oral administration, the active compounds of this invention may be incorporated with conventional excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, waffles, chewing gum and the like.

For the purpose of parenteral therapeutic administration, the active compounds of formula I may be incorporated into a solution or suspension.

Physiologically acceptable bases useful in the preparation of salts of the compounds of formula I include inorganic bases, such as those in which the cation is sodium, potassium or calcium, as well as various organic bases, such as ethanolamine, diethanolamine and dimethylethanolamine.

The invention is illustrated by the following examples.

Example 1 A. A mixture of 28.8 g of ethyl 4- (4-hydroxyphenyl) butyrate 33.6 g of ethyl o (bromo-2-toluate, 81.7 g of potassium carbonate, 580 ml of 2-butanone and 1.8 g of sodium iodide are boiled for 17 hours, the reaction mixture is cooled, filtered, washed with ether, the solvent is removed in vacuo and the yellow oil obtained is dissolved in ether.The ether solution is washed successively with water, 5% aqueous sodium hydroxide solution, water, dried, filtered and ether. removed in vacuo to leave a pale yellow oil, the oil is dissolved in a mixture of potassium hydroxide, ethanol and water and the solution is boiled for 17 hours.The solution is cooled, the solvent is removed in vacuo and the resulting brown semi-solid is dissolved in water and extracted with ether. to 2 with solid hydrochloric acid, solidifies on standing, the solid is collected by filtration, washed with water and recrystallized from acetonitrile to give a pale tan solid, m.p. 149-150 ° C, 4- [4- (2-carboxybenzyloxy) -phenyl] -butyric acid.

Analysis:

Calculated for c 18 H 18 O 5:% C; 5.77% H.

Found: 68.52% C; 5.69% H.

63569 B. 22.5 g of polyphosphoric acid are added to a solution of 5.0 g of 4- (4-carboxybenzyloxy) phenyl] butyric acid in 17.5 ml of glacial acetic acid, and the solution is stirred at 95 ° C for 3 hours. The solution is allowed to cool, and water is added to precipitate and the precipitate is collected by filtration Recrystallization from benzene gives an off-white solid, mp 116-118 ° C, 4- (6,11-dihydro-11-oxodibenz / b,% 70% yl) butyric acid.

Calculated for C 18 H 16 O 4: 72.95% C; 5.44% H.

Found: 72.79% C; 5.44% H.

Example 2

A mixture of 2.6 g of 4- (6,11-dihydro-11-oxodibenz [b, e7-oxepin-2-yl) butyric acid (Example 1) and 0.8 g of the ion exchanger AMBERLITE IR-120 HC.P . In 25 ml of methanol, boil for 16 hours, cool, dilute with ether and filter. The filtrate is washed successively with 5% aqueous sodium hydroxide solution and water, dried, filtered and concentrated in vacuo to leave a solid which is recrystallized from methanol to give off-white crystals, m.p. 83-85 ° C, methyl 4- (6,11-dihydro-11-oxodibenz [1H] oxepin-2-yl) butyrate.

Analysis:

Calculated for C 18 H 28 N 2 O 3: 73.53% C; 5.85% H.

Found: 73.61% C; 5.92% H.

Example 3 A. A mixture of 25.0 g of ethyl 6- (4-hydroxyphenyl) caproate, m.p. 148-150 ° C (0.15 mm), 32.0 g of ethyl N-bromo-2-trifluoroate, 72.0 g of dry potassium carbonate and 1.0 g of sodium iodide in 600 ml of 2 -butanone, boil for 16 hours. = The mixture is cooled, filtered, washed with ether and the filtrate is concentrated in vacuo to leave a yellow oil, the oil is dissolved in 100 ml of 95% ethanol and 20 ml of water and 23.5 g of 85% ethanol are added. potassium hydroxide, and the mixture is boiled for 14 hours. The solution is concentrated in vacuo to leave a semi-solid which is dissolved in water. The aqueous solution is washed with ether and acidified with ice-cold concentrated hydrochloric acid to give a white solid which is collected and recrystallized from acetone to give white crystals, m.p. 138-140 ° C »6- [4- (2-carboxybenzyloxy) phenyl / caproic acid.

Analysis ^

Calculated for C 20 H 22 O 5: 70.16% C; 6.48% H.

Found: 70.22% C; 6.57% H.

B. 8.8 g of phosphorus pentachloride are added to an ice-cooled solution of 7.0 g of (6- / 4- (2-carboxybenzyloxy) phenyl] -caproic acid in 80 ml of benzene, and all the phosphorus pentachloride is dissolved in an ice bath and the resulting yellowish solution is stirred. hours and the benzene is removed in vacuo at 80 ° C to leave a golden brown oil (6- / 4- (2-carboxybenzyloxy) -phenyl] -caproic acid diacid chloride), the oil is dissolved in 80 ml of methylene chloride, the solution is cooled and 10.9 g are added. stannous chloride, resulting in a dark solution which is stirred for 72 hours at room temperature, hydrolyzed with 80 ml of 1N hydrochloric acid and stirred for a further 36 hours, the mixture is separated and the organic phase is concentrated to leave a resin which is triturated with chloroform. , dried and concentrated to give a solid, which is recrystallized from acetonitrile to give an off-white product, mp 98-100 ° C, 6- (6,11-dihydro-11). -oxodibenz [b, e7oxepin-2-yl] caproic acid. Analysis:

Calculated for C 20 H 22 O 4: 74.05% C; 6.22% H.

Found: 73.85% C; 6.29% H.

Example 4 A. A sample of ethyl 8- (4-hydroxyphenyl) caprylate prepared according to process variant a is treated according to the embodiment described in Example 3A to give colorless crystals, m.p. 116-118 ° C, 8- [4- (2-carboxybenzyloxy) phenyl] caprylic acid.

Analysis:

Calculated for <22H26t ^ 5: 71.32% C; 7.07% H.

Found: 71.26% C; 7.14% H.

B. 3.4 g of polyphosphoric acid are added under nitrogen protection to a suspension of 1.0 g of 8- [4- (2-carboxybenzyloxy) phenyl] caprylic acid in 2.63 ml of glacial acetic acid. The reaction mixture is stirred at 100 ° C for 4 hours, then diluted with water and allowed to cool and filtered. The filter cake is dissolved in chloroform, the filtrate is extracted with chloroform and the chloroform solutions are combined, washed with water, dried and the chloroform removed to leave a solid which is recrystallized from acetonitrile to give a solid, m.p. 68-70 ° C, 8- (6,11-dihydro-11-oxodibenz [b, e] oxepin-2-yl) caprylic acid. Analysis:

Calculated for C 22 H 24 O 4: 74.97% C; 6.86% H.

Found: 74.67% C; 7.03% H.

Claims (1)

A process for the preparation of therapeutically useful 6/11-dihydro-11-oxodibenz, b / oxepinalkyl carboxylic acids, their esters and pharmaceutically acceptable salts thereof, wherein R-CH 2 (CH 2 CH 2) n -COOR wherein R is hydrogen or lower alkyl, and n is an integer of 1, 2 or 3, characterized in that a) (1) an alkyl ester of the formula CC 'CH 2 Br wherein Z is alkyl of 1 to 4 carbon atoms is reacted with an alkyl ester of hydroxyphenylalkylcarboxylic acid the formula is (CH2CH2) (CH2CH2) nCO2CmH (2mtl) (II1) hoA ^ 1 where n is as defined above and m is an integer from 1 to 5 to give a diester of the formula aCO2Z CO2 -O (IV) (2) obtained the diester is saponified to give a dicarboxylic acid of the formula α2 - CH2 (CH2CH2) nCO2H and (3) cyclized to give the corresponding dicarboxylic acid to give the corresponding u> - (6,11-dihydro-11-oxodibenz [b, e7oxepin-2-yl) α-alkylcarboxylic acid of formula 11 6 3569 jL CH0- (CH-CH0) cclh j V / ^ I c ί ί n & \ I (Ia) or b) the dicarboxylic acid obtained from process variant a) (2) is treated with a halogenating agent to give a diacid halide of formula a COX -CH_ (CHOCHO) COX - wherein X is chlorine, bromine or iodine, and the diacid halide thus obtained is cyclized and hydrolyzed to give the corresponding t * # - (6,11 "dihydro-11'-oxodibenz [b, e7oxynin-2-yl) -alkylcarboxylic acid and the N- (6-yl-dihydro-11-oxo-dibenz, S-oxepin-2-yl) -alkylcarboxylic acid obtained from process variant a) or b) is malidally esterified to give (N- (6,11-dihydro-11-oxodibenz / E). (E7-oxepin-2-yl) -alkylcarboxylic acid ester of the formula O, CH0 (CH_CH0) -CO ~ R αίσ. wherein R is lower alkyl. 12. 63569 For the preparation of a therapeutically active compound 6,11-dihydro-11-oxodibenz / B, e7oxepinalkylcarboxylic acid, with the formula I, esters and pharmaceuticals containing the same, O -COOR (I) in the form of an alkyl derivative R is selected from the group consisting of 1 to 2 or 3 of the same solvent, att (a) (1) to the alkyl ester of the formula, / Vc02Z (ID L 1 color Z to the alkyl of 1-4 cholatomers, to the alkyl ester of the hydroxyphenylalkylcarboxylic acid of the form ^ YCH2- (CH2CH2) nCO2CmH (2m + 1) (III) HO color is defined as 1-5, for the diester of formula 0 / CO22 and CH2CH2> CO2CmH (2m + 1) ^ CO (IV) (2) to give the same ester as the dicarboxylic acid of formula 6 35 6 9 ν '2 (CH0CH_) C0HH I j ^ ^ Ä Π ^ ^ AcHj-O-Vy (v) and (3) the cyclic dicarboxylic acid cyclone is selected from the group consisting of (6, H-dihydro-11-oxodibenz [E, 7-oxepin-2-yl) alkylcarboxylic acid with the formula ch2- (CH2CH2) nCO2H <ia) or b) den i point (2) of the first alternative a) dicarboxylic acid is used as a halogenated form for the treatment of disyrohalides with the form <CH2 (ch2ch2) nCOX 2 (VI) color X is chlorine, bromine or iodine and the like hydrolysers for the preparation of solution J) - (6-yl-dihydro-11-oxodibenz (F, 7-oxepin-2-yl) -alkylcarboxylic acid and the alternative alternatives a) or b) optionally) J- (6,11-di-hydro -11-oxodibenz (b, b / oxepin-2-yl) alkylcarboxylic acid is optionally esterified to give (6,11-dihydro-11-oxodibenz [b, e7-oxepin-2-yl) alkylcarboxylic acid ester with formula