GB1560629A

GB1560629A - 6,11-dihydro-11 - oxodibenzyloxepinealkanoic acids and esters

Info

Publication number: GB1560629A
Application number: GB31436/76A
Authority: GB
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1975-07-30
Filing date: 1976-07-28
Publication date: 1980-02-06
Also published as: CH627752A5; PT65421A; GR70328B; AT359066B; ES450125A1; ZA764557B; SE426320B; NO147561C; AU512130B2; FI63569C; ATA559976A; SE7608546L; NO762647L; PT65421B; DK342476A; FI63569B; NO147561B; FR2319339B1; FR2319339A1; NL7608203A

Abstract

6,11-Dihydro-11-oxodibenz[b,e]oxepinealkanoic acids of the formula I, their C1- to C4-alkyl esters and the pharmacologically compatible salts are prepared. An alpha -bromo-2-toluylic ester which is optionally substituted by halogen, C1- to C4-alkoxy, C1- to C4-alkyl or trifluoromethyl is reacted with an alkyl ester of a hydroxyphenylacetic acid. The resulting diester is hydrolysed, cyclised and, where appropriate, converted into the corresponding alkyl ester. The resulting compounds can be used as anti-inflammatory and analgesic agents. <IMAGE>

Description

(54) 6,11-DIHYDRO-II -OXODIBENZ[B,E]- OXEPINEALKANOIC ACIDS AND ESTERS (71) We, HOECHST AKTIENGESELL SCHAFT, a body corporate organized according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to certain w (6,11 - dihydro - 11 - oxodibenz[b,e]oxepin 2 - yl) alkanoic acids, esters and salts. The compounds of the invention have antiinflammatory activity, and analgesic activity has also been demonstrated.

6,11 - dihydro - 11 - oxodibenz[b,e]oxepineacetic acids having antiinflammatory activity are described in British Patent 1,481,866. However, 3 - (6,11 - dihydro - 11 oxodibenz [b,e] oxepin - 2 - yl) propionic acid, suggested by the aforementioned specification, demonstrated no antiinfiammatory or analgesic activity. It is therefore unexpected that the compounds of the present invention, unlike the propionic acid analogue, exhibit such activity.

The present invention provides a compound of the tormula I:

wherein: R represents a hydrogen atom or an un substituted or substituted alkyl radical; R' represents a hydrogen atom, a halogen atom, an unsubstiuted or substituted alkoxy radical, or an unsubstituted or substituted alkyl radical; and alkyl radical; and n is an integer of from 1 to 3.

Preferred compounds of the invention are those in which R represents a hydrogen atorn or an alkyl radical having from 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, and R' represents a hydrogen atom, a halogen atom, an alkoxy radical having from 1 to 4 carbon atoms, an alkyl radical having from 1 to 4 carbon atoms, or a trifluoro - methyl radical.

Among this group compounds are preferred in which R' represents a fluorine or chlorine atom or a methyl, methoxy or trifluoromethyl radical, or, in particular, a hydrogen atom.

Compounds in which both R and R' represent hydrogen atoms are especially preferred.

The invention further provides salts, especially physiologically tolerable salts, of the compounds of the formula I defined above in which R is hydrogen.

The compounds of the invention may be prepared by cyclisation of the corresponding dicarboxylic acids of the formula II:

There are two preferred methods for effecting cyclisation, described below in further detail under the headings "Method A" and "Method B".

METHOD A Ring closure is effected in a single stage by treatment with a dehydrating agent, for example, polyphosphoric acid, sulphuric acid, ethanol - phosphorus pentoxide or phosphorus pentachloride, to yield a compound of the formula Ia, i.e. a compound of the formula I wherein R represents a hydrogen atom:

The reaction may, if desired, be carried out in a solvent such as tetramethylene sulphone or acetic acid; the temperature is preferably within the range of from 50 to 125eC and the duration of the reaction is preferably from 15 minutes to 12 hours.

The acid of the formula Ia may, if desired, be converted to an ester of the formula I wherein R is an unsubstituted or substituted alkyl group, preferably an alkyl group having from 1 to 5, more preferably 1 to 4, carbon atoms. In a preferred procedure, the acid is reacted with an alcohol ROH in the presence of an acid, for example, sulphuric, hydrochloric or p - toluenesulphonic acid. The temperature is advantageously within the range of from 500C to the boiling point of the alcohol ROH and the reaction duration is advantageously from 15 minutes to 20 hours; the higher the temperature, the shorter the reaction time.

METHOD B The dicarboxylic acid of the formula II is converted to the corresponding dihalide of the formula III, wherein X represents a florine, chlorine or bromine atom:

This step may be effected by treating the dicarboxylic acid with a halogenating agent, for example, a thionyl halide or a phosphorus pentahalide. The reaction may be carried out in the presence or absence of a solvent, the temperature preferably being within the range of from ambient to the boiling point of the reaction mixture and the reaction time preferably being from 15 minutes to 4 hours.

The dihalide of the formula III is then cyclised to form a halide of the formula IV:

The ring dosure may be carried out under standard or modified FriedelCrafts conditions; "modified Friedel-Crafts conditions" means a thermal cyclisation effected, for example, by heating the dihalide of the formula III at a temperature of from 80 to 1250C for a period of from 10 minutes to 24 hours.

The halide of the formula IV may be hydrolysed to yield the corresponding acid of the formula Ia, which may, if desired, be esterified as described above under Method A.

Alternatively, the esters may be prepared directly from the halide of the formula IV.

Preparation of the Starting Material The dicarboxylic acid of the formula H may be prepared by the reaction between an alkyl ester of the formula V:

wherein Z represents an unsubstituted or substituted alkyl radical, preferably an alkyl radical having from 1 to 4 carbon atoms and R' is as defined above, and a hydroxyphenylalkanoic acid ester of the formula VI:

wherein T represents an unsubstituted or substituted alkyl radical, preferably one of the formula VIII: CmH2m Fl (\/EI) wherein m is an integer from 1 to 5, and n is as defined above.

The product of this reaction is a diester of the formula VII:

The reaction may be carried out in a suitable solvent, for example, acetone, butanone, ethanol or dimethylformamide, and in the presence of an acid scavenger, for example, potassium carbonate or sodium ethoxide. A reaction initiator, for example, sodium iodide, may be used if desired. The reaction temperature is preferably from 0 to 1200C and the reaction time is preferably from 5 minutes to 20 hours.

The diester of the formula VII is then converted to the corresponding dicarboxylic acid of the formula II, for example by saponification using a base such as sodium or potassium hydroxide, in a solvent, for example, an ethanol - water mixture. The reaction time is advantageously from 15 minutes to 24 hours and the temperature is preferably from ambient to 125oC.

The starting hydroxyphenylalkanoic ester of the formula VI may be prepared by any suitable method. In a preferred procedure, the corresponding Iw-(-hydroxyphenyl-)- alkanoic acid is reacted with an alcohol in the presence of an acid, for example, sulphuric, hydrochloric or p - toluenesulphonic acid, preferably at a temperature of from 500C to the boiling point of the alcohol and for a period of from 15 minutes to 20 hours.

Examples of compounds of the invention are: 4 - (6,11 - dihydro - 11 - oxodibenz[b,e]- oxepin - 2 - yl)butyric acid; methyl 4 - (6,11 - dihydro - 11 - oxodibenz- [b,eloxepin - 2 - yl) butyrate; methyl 6 - (6,11 - dihydro - 11 oxodibenz [b,e] oxepin - 2 - yl) caproate; isopropyl 8 - (6,11 - dihydro - 11 - oxodi benz [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 - oxodi benz [b,e] oxepin - 2 - yl) caproate; t - butyl 8 - (6,11 - dihydro - 11 - oxodi benz[b,e]oxepin - 2 - yl) caprylate; 4 - (6,11 - dihydro - 9 - n - butoxy - 11 oxodibenz [b,e] oxepin - 2 - yl) butyric acid; and 4 - (6,11 - dihydro - 8 - n - butyl - 11 oxodibenz [b,e] oxepin - 2 - yl) butyric acid.

The compounds of the formula I of the invention and the physiologically tolerable salts of those compounds of formula I in which R is hydrogen show an ability to suppress inflammation in mammals, the preferred does being from 0.1 to 100 mg/kg body weight. These compounds and their physiologically tolerable salts also show an ability to alleviate pain in mammals, the preferred dosage for this purpose being from 0.5 to 50 mg/kg body weight The compounds of the formula I and the physiologically tolerable salts referred to are accordingly valuable as pharmaceutical and veterinary products and may be administered to a patient by any convenient route, for example, orally, intramuscularly, intravenously, subcutaneously, or intraperitoneally.

The present invention further provides a pharmaceutical preparation comprising, as active ingredient, at least one compound of the formula I and/or at least one physiologically tolerable salt as referred to, in admixture or conjunction with a pharmaceutically suitable carrier. The amount of active ingredient is preferably from 7 to 70 per cent by weight of the composition.

The invention still further provides a method of combating inflammation and/or alleviating pain in a non-human mammal, which comprises administering to the mammal a compound of the formula I, a physiologically tolerable salt as referred to, or a pharmaceutical preparation as defined above, preferably in the dosages mentioned above.

The preferred route of administration is oral, for example, with an inert diluent or with an edible carrier or in gelatin capsules or tablets. For the purpose of oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form, for example, of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or chewing gum. These preparations preferably contain at least 0.5 / of active compound, but may be varied depending upon the particular form and may conveniently be from 7,' to 90'. by weight of the unit. The amount of active ingredient in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are so prepared that an oral dosage unit form contains between 5 and 500 milligrams of the active ingredient.

The tablets, pills, capsules, troches, and other oral dosage forms may also contain additional ingredients, for example, the following: a binder, for example, gum tragacanth or gelatin; an excipient, for example, starch or lactose; a disintegrating agent, for example, alginic acid or potato starch; a lubricant, for example, magnesium stearate; and a sweetening agent, for example, sucrose or saccharin, or a flavouring agent, for example, peppermint, methyl salicylate, or orange flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Other dosage unit forms may contain other materials which modify the physical form of the dosage unit, for example, coatings. Thus, tablets or pills may, for example, be coated with sugar, shellac or both. A syrup may, for example, contain, in addition to the active ingredients, sucrose as a sweetening agent, and certain preservatives, dyes and colourings, and flavours. Material used in preparing these various compositions must, of course, be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations preferably contain at least 0.1% O/o of the active ingredient, preferably from 0.5 to 30 of the total weight.

The amount of the active ingredient in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are so prepared that a parenteral dosage unit contains between 0.5 to 100 milligrams of the active ingredient.

The solutions or suspensions may also include other components for example, the following; a sterile diluent, for example, water, for injection; saline solution, fixed oils, poly ethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, for example, benzyl alcohol or methyl p hydroxybenzoate; antioxidants, for example, ascorbic acid or sodium bisulphite; chelating agents, for example, ethylenediaminetetraacetic acid; buffers, for example, acetates, citrates or phosphates; and agents for the adjustment of toxicity, for example, sodium chloride or dextrose. The parenteral preparations may, for example, be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Physiologically tolerable bases useful for generating salts of the compounds of the formula I in which R is hydrogen include inorganic bases, for example, those containing the cations sodium, potassium or calcium, and various organic bases, for example, ethanolamine, diethanolamine and dimethylethanolamine.

The invention is further illustrated by the following Examples.

EXAMPLE 1 A. A mixture of 28.8 g of ethyl 4 (hydroxyphenyl) - butyrate, 33.6 g of ethyl ek bromo - 2 - toluate, 81.7 g of potassium car bonate, 580 ml of 2 - butanone and 1.8 g of sodium iodide was refluxed for 17 hours. The reaction mixture was cooled, filtered, and washed with diethyl ether, the solvent was re moved in vacuo and the resulting yellow oil was dissolved in diethyl ether. The ethereal solution was washed successively with water, a 5% aqueous sodium hydroxide solution and water, dried, filtered and the ether was re moved in vacuo, leaving a light yellow oil.

The oil was dissolved in a mixture of potas sium hydroxide, ethanol and water and re fluxed for 17 hours. The solution was cooled, the solvent was removed in vacua and the re sulting brown semi-solid was dissolved in water and extracted with diethyl ether. The oil, formed by adjusting the pH of the aqueous layer to 2 with concentrated hydrochloric acid, solidified upon standing. The solid was col lected by filtration, washed with water and re crystallised from acetonitrile to give a light tan solid, of melting point, 149 to 1500C, which was 4 - [4 - (2 - carboxybenzyloxy) - phenyl] butyric acid.

Analysis: Calculated for Ci,HisOa: C 68.77::;68.77%; 68.77::;68.77%; H 5.77%.

Found: C 68.52%; H 5.69 '.

In a similar manner there were prepared 4 [4 - (2 - carboxy - 4 - fluorobenzyloxy) phenyl]butyric acid, 4 - [4 - (2 - carboxy 5 - chlorobenzyloxv)phenyl]butyric acid and 4 - [2 - (2 - carboxy - 3 - methylbenzvloxyj phenl]butyric acid.

B. 22.5 g of polyphosphoric acid were added to a solution of 5.0 g of 4 - [4 - car boxybenzyloxy)phenyl]butyric acid in 17.5 ml of glacial acetic acid and the solution was stirred at 950C for 3 hours. The solution was permitted to cool and water was added to effect a precipitate which is collected by filtration.

Recrystallisation from benzene gave an off white solid, of melting point 116 to 118 C, which was 4 - (6,11 - dihydra - 11 - oxodi benz[b,e]oxepin - 2 - yl)butyric acid.

Analysis: Calculated for C MHIG04: C 72.96 ; H 5.44Q!, Found: C 72.79-; H 5.44'.'.5.44 . 5.44'.'.5.44 .

In a similar manner there were prepared 4 - (6,11 - dihydro - 9 - fluoro - 11 - oxodibenz - [b,e]oxepin - 2 - yl)butyric acid, 4 (6,11 - dihydro - 8 - chioro - 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.

EXAMPLE 2 A mixture of 2.6 g of 4 - (6,11 - dihydro 11 - oxodibenz[b,e]oxepin - 2 - yl)butyric acid (Example 1) and 0.8 g of Amberlite (Registered Trade Mark) It120 It120 H.C.P. in 25 ml of methanol was refluxed for 16 hours, cooled, diluted with ether and filtered. The filtrate was washed successively with a 5% aqueous sodium hydroxide solution and water, dried, filtered, and concentrated in vacua, leaving a solid which was recrystallised from methanol to give off-white crystals, of melting point 83 to 850C, of methyl 4 - (6,11 - dihydro - 11 oxodibenztb,e]oxepin - 2 - yl)butyrate.

Analysis: Calculated for C19H18O4: C 73.53% H 5.85%.

Found: C 73.61%; H 5.92%.

EXAMPLE 3 A. A mixture of 25.0 g of ethyl 6 - (4 hydroxyphenyl) - caproate, bp 148 to 1500C (0.15 mm), prepared as described in the general description, 32.0 g of ethyl fr- - bromo - 2 - toluate, 72.0 g of anhydrous potassium car bonate and 1.0 g of sodium iodide in 600 ml of 2 - butanone was reflexed for 16 hours. The mixture was cooled, filtered, and washed with diethyl ether, and the filtrate was concentrated in vacuo, leaving a yellow oil. The oil was dissolved in 100 ml of 95% ethanol and 20 ml of water and 23.5 g of 85% potassium hydroxide were added and the mixture was refluxed for 14 hours. The solution was concentrated in vacua, leaving a semi-solid which was dissolved in water. The aqueous solution was washed with diethyl ether and acidified with ice-cold concentrated hydrochloric acid to yield a white solid which was collected and recrystallised from acetonitrile to provide white crystals, of melting point 138 to 1400C, of 6 - [4 - (2 - carboxybenzyloxy)phenyl]- caproic acid.

Analysis: Calculated for C2,H22Or,: C 70.16%; H 6.48%.

Found: C 70.22so; 70.22so; H 6.57%.

In a similar manner there were prepared 6 - [4 - (2 - carboxy - 4 - trifluoromethyl benzyloxy)phenyl] caproic add and 6 - [4 (2 - carboxy - 5 - methoxybenzyloxy)phenyl]caproic acid.

B. 8.8 g of phosphorous pentachloride were added to an ice-bath-cooled solution of 7.0 g of 6 - [4 - (2 - carboxyloxy)phenyl]caproic acid in 80 ml of benzene. After all the phosphorus pentachloride had dissolved, the ice-bath was removed and the resulting yellowish solution was stirred for 4 hours and the benzene was removed in vacua at 80 C, leaving an amber oil. The oil was dissolved in 80 ml of methylene chloride, the solution was cooled and 10.9 g of stannic chloride were added, resulting in a dark solution which was stirred for 72 hours at ambient temperature, hydrolysed with 80 ml of IN hydrochloric acid, and stirred for an additonal 36 hours.

The mixture was separated and the organic phase was concentrated, leaving a gum which was triturated with chloroform, dried and concentrated to give a solid. The solid was recrystallised from acetonitrile to give an offwhite product, of melting point 98 to 1000 C, which was 6 - (6,11 - dihydro - 11 - oxodibenz[b,e]oxepin - 2 - yl)caproic acid.

Analysis: Calculated for C20H2604: C 74.05%; H 6.22%.

Found: C 73.85%; H 6.29%.

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

EXAMPLE 4 A. A sample of ethyl 8 - (4 - hydroxyphenyl)caprylate, prepared as described in the general description, was treated according to the procedure described in Example 3A to produce colourless crystals, of melting point 116 to 1180C, of 8 - [4 - (2 - carboxybenzyl oxy)phenyl I caprylic acid.

Analysis: Calculated for C22H26%: C 71.32%; H 7.07%.

Found: C 7126%; H 7.14%.

In a similar manner there was prepared 8 [4 - (2 - carboxy - 5 - chlorobenzyloxy) phenyl]caprylic acid.

B. 3.4 g of polyphosphoric acid were added to a suspension under nitrogen of 1.0 g of 8 [4 - (2 - carboxybenzyloxy)phenylj caprylic add in 2.63 ml of glacial acetic acid. The reaction mixture was stirred at 1000C for 4 hours, then diluted with water, and allowed to cool and filtered. The filter cake was dissolved in chloroform, the filtrate was extracted with chloroform and the chloroform solutions were combined, washed with water, dried and the chloroform was removed, leaving a solid which was recrystallised from acetonitrile to give a solid, of melting point 68 to 70 C, which was 8 - (6,11 - dihydro - 11 - oxodi benz[b,e]oxepin - 2 - yl)caprylic acid.

Analysis: Calculated for C.2H.24O,: C 74.97 .,; H 6.86 Found: C 74.67; H703Dr.

In a similar manner there was prepared 8 (6,11 - dihydro - 8 - chloro - 11 - oxodi benz[b,e]oxepin - 2 - yl)caprylic acid.

WHAT WE CLAIM IS: 1. A compound of the formula I:

wherein: R represents a hydrogen atom or an unsub stituted or substituted alkyl radical; R' represents a hydrogen atom, a halogen atom an unsubstituted or substituted alkoxy radical, or an unsubstituted or substituted alkyl radical; and n is an integer of from 1 to 3.

2. A compound as claimed in claim 1, wherein R represents an alkyl radical having from 1 to 5 carbon atoms.

3. A compound as claimed in claim 2, wherein R represents an alkyl radical having from 1 to 4 carbon atoms.

4. A compound as claimed in any one of claims 1 to 3, wherein R' represents an alkyl radical having from 1 to 4 carbon atoms.

5. A compound as claimed in claim 4, wherein R' represents a methyl radical.

6. A compound as claimed in any one of claims 1 to 3, wherein R' represents an alkoxy radical having from 1 to 4 carbon atoms.

7. A compound as claimed in claim 6, wherein R' represents a methoxy radical.

8. A compound as claimed in any one of claims 1 to 3, wherein R' represents a fluorine or chlorine atom.

9. A compound as claimed in any one of claims 1 to 3, wherein R' represents a trifluoromethyl group.

10. 4(6,11- dihydro - 11 - oxodibenz[b,e]- oxepin - 2 - yl)butyric acid.

11. Methyl 4 - (6,11 - dihydro - 11 - oxodi benz [b,e] oxepin - 2 - yl)butyrate.

12. 6 - (6,11 - dihydro - 11 - oxodibenz [b,e]oxepin - 2 - yl)caproic acid.

13. 8 - (6,11 - dihydro - 11 - oxodibenz [b,e]oxepin - 2 - yl)caprylic acid.

14. A compound as claimed in daim 1, which is specifically mentioned herein.

15. A salt of a compound as daimed in any one of claims 1 to 14 in which R is hydrogen.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. B. 8.8 g of phosphorous pentachloride were added to an ice-bath-cooled solution of 7.0 g of 6 - [4 - (2 - carboxyloxy)phenyl]caproic acid in 80 ml of benzene. After all the phosphorus pentachloride had dissolved, the ice-bath was removed and the resulting yellowish solution was stirred for 4 hours and the benzene was removed in vacua at 80 C, leaving an amber oil. The oil was dissolved in 80 ml of methylene chloride, the solution was cooled and 10.9 g of stannic chloride were added, resulting in a dark solution which was stirred for 72 hours at ambient temperature, hydrolysed with 80 ml of IN hydrochloric acid, and stirred for an additonal 36 hours. The mixture was separated and the organic phase was concentrated, leaving a gum which was triturated with chloroform, dried and concentrated to give a solid. The solid was recrystallised from acetonitrile to give an offwhite product, of melting point 98 to 1000 C, which was 6 - (6,11 - dihydro - 11 - oxodibenz[b,e]oxepin - 2 - yl)caproic acid. Analysis: Calculated for C20H2604: C 74.05%; H 6.22%. Found: C 73.85%; H 6.29%. In a similar manner there were prepared 6 - (6,11 - dihydro - 11 - oxo - 9 - trifluoro methyldibenz [b,ej oxepin - 2 - yl) caproic acid and 6 - (6,11 - dihydro - 8 - methoxy - 11oxodibenz[b,e]oxepin - 2 - yl) caproic acid. EXAMPLE 4 A. A sample of ethyl 8 - (4 - hydroxyphenyl)caprylate, prepared as described in the general description, was treated according to the procedure described in Example 3A to produce colourless crystals, of melting point 116 to 1180C, of 8 - [4 - (2 - carboxybenzyl oxy)phenyl I caprylic acid. Analysis: Calculated for C22H26%: C 71.32%; H 7.07%. Found: C 7126%; H 7.14%. In a similar manner there was prepared 8 [4 - (2 - carboxy - 5 - chlorobenzyloxy) phenyl]caprylic acid. B. 3.4 g of polyphosphoric acid were added to a suspension under nitrogen of 1.0 g of 8 [4 - (2 - carboxybenzyloxy)phenylj caprylic add in 2.63 ml of glacial acetic acid. The reaction mixture was stirred at 1000C for 4 hours, then diluted with water, and allowed to cool and filtered. The filter cake was dissolved in chloroform, the filtrate was extracted with chloroform and the chloroform solutions were combined, washed with water, dried and the chloroform was removed, leaving a solid which was recrystallised from acetonitrile to give a solid, of melting point 68 to 70 C, which was 8 - (6,11 - dihydro - 11 - oxodi benz[b,e]oxepin - 2 - yl)caprylic acid. Analysis: Calculated for C.2H.24O,: C 74.97 .,; H 6.86 Found: C 74.67; H703Dr. In a similar manner there was prepared 8 (6,11 - dihydro - 8 - chloro - 11 - oxodi benz[b,e]oxepin - 2 - yl)caprylic acid. WHAT WE CLAIM IS:

1. A compound of the formula I:

5. A compound as claimed in claim 4, wherein R' represents a methyl radical.

7. A compound as claimed in claim 6, wherein R' represents a methoxy radical.

10. 4(6,11- dihydro - 11 - oxodibenz[b,e]- oxepin - 2 - yl)butyric acid.

12. 6 - (6,11 - dihydro - 11 - oxodibenz [b,e]oxepin - 2 - yl)caproic acid.

13. 8 - (6,11 - dihydro - 11 - oxodibenz [b,e]oxepin - 2 - yl)caprylic acid.

14. A compound as claimed in daim 1, which is specifically mentioned herein.

16. A physiologically tolerable salt of a com

pound as claimed in any one of claims 1 to 14 in which R is hydrogen.

17. A process for the preparation of a compound of formula I as claimed in claim 1, in which R is hydrogen, by effecting cyclisation of a compound of the formula II:

wherein R' and n have the meanings given in claim 1, by reacting with a dehydrating agent.

18. A process as claimed in claim 17, wherein the dehydrating agent comprises polyphosphoric acid, ethanol - phosphorus pent oxide, sulphuric acid or phosphorus penta chloride.

19. A process as claimed in claim 17 or claim 18, wherein the reaction is carried out in tetramethylene sulphone or acetic acid.

20. A process as claimed in any one of claims 19 to 21, wherein the reaction is carried out at a temperature within the range of from 50 to 1250C.

21. A process as claimed in any one of claims 17 to 20, wherein the duration of the reaction is within the range of from 15 minutes to 12 hours.

22. A process for the preparation of a compound of formula I as claimed in claim 1, wherein: (a) a compound of the formula II is reacted with a halogenating agent to yield a diacid halide of the formula m:

wherein X represents chlorine, bromine, or fluorine, and (b) effecting cyclisation of the compound of the formula III to yield a compound of the formula IV:

and (c) converting the compound of the formula IV to a compound of the fomula I.

23. A process as claimed in claim 22, wherein the halogenating agent used in step (a) comprises a thionyl halide or a phosphorus pentahalide.

24. A process as claimed in daim 22 or claim 23, wherein step (a) is carried out at a temperature within the range of from ambient to the boiling point of the reaction mixture.

25. A process as claimed in any one of claims 22 to 24, wherein the duration of step (a) is within the range of from 15 minutes to 4 hours.

26. A process as claimed in any one of claims 22 to 25, wherein step (b) is effected by means of a Friedel-Crafts reaction.

27. A process as claimed in any one of claims 22 to 25, wherein step (b) is effected by heating the compound of the formula m at a temperature of from 80 to 1250C for from 10 minutes to 24 hours.

28. A process as claimed in any one of claims 22 to 27, wherein step (c) comprises hydrolysing the compound of the formula IV to yield a compound of the formula Ia:

29. A process for the preparation of a compound of the formula I as claimed in claim 1 wherein R does not represent a hydrogen atom, which comprises reacting the compound of the formula Ia with an alcohol of the formula ROH, wherein R represents an unsubstituted or substituted alkyl radical.

30. A process as claimed in daim 29, wherein the reaction is carried out under acid conditions.

31. A process as claimed in claim 30, wherein the reaction is carried out in the presence of sulphuric acid, hydrochloric acid, or p - tolu enesulphonic acid.

32. A process as claimed in claim 30 or claim 31, wherein the reaction is carried out at a temperature within the range of from 50 C to the boiling point of the alcohol ROH.

33. A process as claimed in any one of claims 30 to 32, wherein the duration of the reaction is within the range of from 15 minutes to 20 hours.

34. A process as claimed in any one of claims 17 to 33, carried out substantially as described in any one of the Examples herein.

35. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 17 to 34.

36. A pharmaceutical preparation which comprises as active ingredient at least one compound as claimed in any one of claims 1 to 14 and 35 and/or at least one physiologically tolerable salt as claimed in claim 16, in admixture or conjunction with a pharmaceutically suitable carrier.

37. A pharmaceutical preparation as claimed in claim 36, containing from 7 to 70 per cent by weight, in total of the compound(s) as claimed in any one of claims 1 to 14 and 35 and/or slat(s) as claimed in claim 16.

38. A pharmaceutical preparation as claimed in claim 36 or claim 37, is dosage unit form.

39. A pharmaceutical preparation as claimed in claim 36, in the form of an oral dosage unit containing from 5 to 500 mg of the active ingredient.

40. A pharmaceutical preparation as claimed in claim 37, in the form of a parenteral dosage unit containing from 0.5 to 100 mg of the active ingredient.

41. A pharmaceutical preparation as claimed in any one of claims 36 to 40, which is solid.

42. A method of combating inflammation and/or alleviating pain in a non-human mammal, which comprises administering thereto a compound as claimed in any one of claims 1 to 14 and 35 or a salt as claimed in claim 16 or a pharmaceutical preparation as claimed in any one of claims 36 to 41.

43. A method as claimed in claim 42, wherein an amount of from 0.1 to 100 mg/kg body weight of active ingredient is administered.

44. A method as claimed in claim 42, wherein an amount of from 0.5 to 50 mg/kg body weight of active ingredient is administered.