NO147561B - ANALOGUE PROCEDURES FOR THE PREPARATION OF 6,11-DIHYDRO-11-OXODODIBENZ (B, E) OCSEPINALKAN ACIDS, ESTERS AND SALTS THEREOF - Google Patents

Description

The invention relates to analogous methods for the production of w-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)alkane acids and esters as well as pharmaceutically acceptable salts thereof with anti-inflammatory action. In addition, the compounds produced according to the invention have shown an analgesic effect.

The compounds produced according to the invention are new. 6,11-dihydro-11-oxodibenz [b,e]oxepin-acetic acids which have anti-inflammatory activity are discussed in Norwegian patent no. 142,397. However, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid, disclosed in the above patent, showed no anti-inflammatory or analgesic effect. It is therefore unexpected that the compounds produced according to the invention, in contrast to propionsvreanalogen^ irtø_vex_ al i k ak.tj_vi.te.t-..

The compounds produced according to the invention have the following

formula:

where R means hydrogen or alkyl with from 1-4 carbon atoms, R' is hydrogen, halogen, alkoxy with from 1-4 carbon atoms, alkyl with from 1-4 carbon atoms or trifluoromethyl and n can vary from 1 to 3. The salts thereof prepared with physiologically tolerable bases are also covered. The preferred compounds are those in which R is hydrogen, R' is hydrogen and n is 1, 2 or 3.

The method according to the invention is characterized in that

a) a compound with formula

wherein R<1> and n have the above meaning, is cyclized in the presence of a water-attracting medium or

b) a compound of formula

in which R' and n have the above meaning and Z means halogen,

is cyclized under Friedel-Crafts conditions, and the formed oi-(6,11-dihydro-11-oxodibenz[b,e j-oxepin-2-yl)-alkanoic acid halide is hydrolyzed, and

possibly one is esterified. obtained u>- ( 6_,,_J_^djJiydro_-Ll--ak_3^

[b,e]-oxepin-2-yl)alkanoic acid to an alkyl ester with 1-4 carbon atoms in the alkyl group or optionally react w-{6,11-dihydro-11-oxodibenz[b-,e]oxepin-2-yl) the alkanoic acid with a physiologically tolerable base for salt formation.

An alkyl ester of hydroxyphenylalkanoic acid with the formula:

in which m is an integer from 1-5, is produced according to known methods. A preferred method is to react w-(hydroxyphenyl)alkanoic acid with an alcohol in the presence of an acid such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid at a temperature from 50°C to the boiling point of the alcohol for from 15 minutes to 20 hours.

An alkyl ester of formula:

wherein Z means alkyl with from 1-4 carbon atoms, is reacted with an alkyl ester of hydroxyphenylalkanoic acid of formula: in which m is an integer from 1-5, in the presence of a suitable solvent, such as acetone, butanone, ethanol or dimethyl -formamide, and an acid scavenger, such as potassium carbonate or sodium ethoxide, in the presence or absence of a reaction initiator such as sodium iodide, at a temperature from 0 - 120°C for a time from 5 minutes to 20 hours to provide a diester of a substituted carboxybenzyloxyphenylalkane- acid with formula:

The diester is saponified by giving a dicarboxylic acid with the formula:

preferably using a base, such as sodium or potassium hydroxide in a solvent, such as an ethanol-water mixture, for a time from 15 minutes to 24 hours at a temperature from room temperature to 125°C.

The dicarboxylic acid is cyclized by treatment with a dehydrating medium, such as a polyphosphoric acid, ethanol-phosphorus pentoxide, sulfuric acid or phosphorus pentachloride, with or without a solvent, such as tetramethylene sulfone or acetic acid, at a temperature from 50 - 125°C and for a time from 15 minutes to 12 hours to form a compound wherein R is hydrogen.

Eh dicarboxylic acid according to method A, step 2 is treated with a sufficient amount of a substance, such as thionyl halide or phosphorus pentahalide, in the presence or absence of a solvent, at a temperature from room temperature to the boiling point of the reaction mixture for from 15 minutes to 4 hours to form the diacid halide of formula:

where Z means chlorine, bromine or fluorine.

The diacid halide is cyclized either under standard or modified Friedel-Crafts conditions and then hydrolyzed to form a compound of the invention where R is hydrogen. Modified Friedel-Crafts conditions mean thermal cyclization which is carried out by heating a diacid halide from 10 minutes to 24 hours at a temperature from 80 - 125°C.

A compound in which R is hydrogen, prepared by either process A or B is esterified to form a corresponding ester in which R is alkyl with from 1-4 carbon atoms.

A preferred method is to react a u>-(6,11-dihydro-11-oxodibenz [b,e]oxepin-2-yl)alkanoic acid with an alcohol in the presence of an acid, such as sulfuric acid, hydrochloric acid or p- toluene-sulfonic acid at a temperature from 50°C to the boiling point of the alcohol for from 15 minutes to 20 hours.

As is well known, the reaction time is proportional to the reaction temperatures, so that a shorter reaction time is required when higher temperatures are used.

The compounds produced according to the invention are useful as anti-inflammatory substances due to their ability to suppress inflammation in mammals from 0.1 to 100 mg/kg body weight.

While the compounds produced according to the invention and the known acetic acid derivatives exert approximately the same anti-inflammatory activity, the compounds produced according to the invention show a lower effect with stomach irritation, an unwanted side effect which is currently associated with anti-inflammatory activity'. This effect, which is expressed as a higher therapeutic index (the ratio between the dose necessary to produce gastric irritation and the dose necessary to produce anti-inflammatory effects) for the compounds compared to the acetic acid derivatives, shows: _ove__leÆ[eriheta__ asr ælka-iisy-r.e-irer- .f reais:L"iTl-tr i±.ø_Lge invent- • the ice in relation to the known compounds.

The anti-inflammatory effect was determined by means of Carrageenan induced rat paw edema in rats, stomach irritation also in rats after oral administration of the compounds and necropsy of the animals to examine the stomach for single or multiple lesions (erosion, ulcer or perforation).

The results are the following:

The therapeutic index for the first compound (known) is thus 16.7, for the second compound according to the invention 21.6. The compounds produced according to the invention are also useful as analgesics due to their ability to relieve pain in mammals in doses of 0.5 - 50 mg/kg body weight.

The compounds of the invention are valuable as pharmaceuticals and veterinary products and can be administered to a patient by any conventional route such as orally, intramuscularly, intravenously, subcutaneously or intraperitoneally. The preferred method of administration is oral, e.g. with an inert diluent or with a digestible carrier or in gelatin capsules or tablets.

Physiologically tolerable bases useful for converting the compounds according to the invention into salts thereof include inorganic bases containing sodium, potassium or calcium cations, as well as various organic bases such as ethanolamine, diethanolamine and dimethylethanolamine.

The invention will be explained in more detail with the help of some examples.

Example IA

A mixture of 28.8 g of ethyl 4-(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 refluxed boiled for 17 hours. The reaction mixture is cooled, filtered, washed with ether, the solvent is removed in vacuo and the resulting yellow oil is dissolved in ether. The ethereal solution is washed successively with water, a 5% aqueous sodium hydroxide solution and water, dried, filtered and the ether removed in vacuo leaving a pale yellow oil. The oil is dissolved in a mixture of potassium hydroxide, ethanol and water and boiled under reflux 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. The oil is formed by adjusting the pH of the aqueous layer to 2 with concentrated hydrochloric acid and solidifies on standing. The solid is collected by filtration, washed with water and recrystallized from acetonitrile to give a faint brownish substance, mp 149-150°C with 4-[4-(2-carboxybenzyloxy)-phenyl]-butyric acid.

Analysis:

Calculated for C,0H,o0_ : 68.77% C, 5.77% H

lol io D

Found: 68.52% C, 5.69% H.

4-[4-(2-carboxy-4-fluoro-benzyloxy)-phenyl]butyric acid and 4-[2-(2-carboxy-3-methylbenzyloxy)phenyl]butyric acid are prepared in a similar manner.

Example IB

22.5 g of polyphosphoric acid is added to a solution of 5.0 g of 4- [4- (carhexybenzyloxyj £e_xyl_Lsm0.r_3.yre.. in_ 1.7 ,5 ml of glacial acetic acid,

and the solution is stirred at 95°C for 3 hours. The solution is cooled and water is added to cause precipitation which is collected by filtration. Recrystallization from benzene gives a white solid, mp 116 - 118°C, with 4-(6,11-dihydro-11-oxodibenz [b,e]oxepin-2-yl)butyric acid.

Analysis:

Calculated for C18H16°4 : 72.95% C, 5.44% H

Found: 72.79% C, 5.44% H.

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.

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 IR-120 H CP"

in 25 ml of refluxing methanol is boiled for 16 hours, cooled, diluted with ether and filtered. The filtrate is washed successively with a 5% aqueous sodium hydroxide solution and water, dried, filtered and concentrated in vacuo leaving a solid which is recrystallized from methanol to give white crystals, mp 83-85°C, with methyl 4-(6,11- dihydro-II-

oxodibenz[b,e]oxepin-2-yl)butyrate.

Analysis:

Calculated for Ci9E18°4 : 73.53% C, 5.85.% H

Found: 73.61% C, 5.92% H.

Example 3A

A mixture of 25.0 g ethyl 6-(4-hydroxyphenyl)-caproate, boiling point 148 - 150°C (0.15 mm) prepared according to method A,' 32.0 g ethyl-a-bromo-2-toluate, 72.0 g anhydrous potassium carbonate and

■1.0 g sodium iodide in 600 ml 2-butanone refluxed is boiled 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

85% potassium hydroxide is added, ag hl a nd i ng-en_.tilbakel.0pt... is boiled

for 14 hours. The solution is concentrated in vacuo leaving a semi-solid which dissolves 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 acetonitrile to form white crystals, mp 138-140°C, with 6-[4-(2- carboxybenzyloxy)phenyl]caproic acid Analysis:

Calculated for c2oH22°5 : 70'16% c'6'48% H

Found: 70.22% C, 6.57% H.

6-[4-(2-carboxy-4-trifluoromethylbenzyloxy)phenyl]caproic acid and 6-[4-(2-carboxy-5-methoxybenzyloxy)phenyl]caproic acid are prepared in a similar manner.

Example 3B

8.8 g of phosphorus pentachloride is added to an ice bath cooled solution of 7.0 g of 6-[4-(2-carboxybenzyloxy)phenyl]caproic acid in 80 ml of benzene. After the phosphorus pentachloride has dissolved, the ice bath is removed and the resulting yellowish solution is stirred for 4 hours and the benzene is removed in vacuo at 80°C leaving a yellowish oil. The oil is dissolved in 80 ml of methylene chloride, the solution is cooled and 10.9 g of stannous chloride is added, and a dark solution is formed which is stirred for 72 hours at ice temperature,

hydrolyzed with 80 ml of 1-normal hydrochloric acid and stirred for a further 36 hours. The mixture is separated and the organic phase. is concentrated leaving a gummy substance which is triturated with chloroform, dried and concentrated to give a solid. The solid is recrystallized from acetonitrile to give a white product, mp 98-100°C, with 6-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)caproic acid.

Analysis:

Calculated for C20H20°4 <:><7>4.05% C, 6.22% H

Found: 73.85% C, 6.29% H.

In a similar manner, 6-(6,11-dihydro-11-oxo-9-trifluoromethyldibenz[b,e]oxepin-2-yl)caproic acid and 6-(6,11-ddJiydrjo—a.rfflet^ are prepared

Example 4A

A sample of ethyl 8-(4-hydroxyphenyl) caprylate, prepared according to method A, is treated according to the treatment procedure outlined in Example 3A, to form colorless crystals, mp 116 - 118°C, of 8-[4-(2-carboxybenzyloxy) phenyl]-caprylic acid.

Analysis:

Calculated for C22H26°5 <:><7>1'32% c' 7'07% H

Found: 71.26% C, 7.14% H.

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

Example 4B

3.4 g of polyphosphoric acid are added to a suspension under nitrogen with 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 cooled 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 leaving a solid which is recrystallized from acetonitrile to give a solid, mp 68-70°C, with 8-( 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-caprylic acid.

Analysis:

Calculated for C22H24°4<:><7>4'97% c' 6.86% H

Found: 74.67% C, 7.03% H.

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

Claims (1)

1. Analogy method for the preparation of a therapeutically active compound of formula wherein R means hydrogen or alkyl of 1-4 carbon atoms, R' means hydrogen, halogen, alkoxy of 1-4 carbon atoms, alkyl of 1-4 carbon atoms or trifluoromethyl, and n is 1, 2 or 3, or a pharmaceutically acceptable salt of which, c a r a c t e r-in particular a) a compound with formula in which R' and n have the above meaning, is cyclized in the presence of a water-attracting medium, or b) a compound of formula in which R<1> and n have the above meaning and z means halogen, is cyclized under Friedel-Crafts conditions and the formed co-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-alkanoic acid -halide is hydrolyzed, and optionally an obtained co-(6,11-dihydro-llOxodibenz-[b,e]oxepin-2-yl)alkanoic acid is esterified to an alkyl ester with 1-4 carbon atoms in the alkyl group or optionally reacted with co-(6,11-dihydro- The 11-oxodibenz[b,e]oxepin-2-yl)alkanoic acid with a physiologically tolerable base for salt formation.