NO132689B - - Google Patents

Description

This invention relates to a method for producing

ling of novel 3- and 4-phenoxyphenylalkanoic acids, their pharmaceutically acceptable cationic salts, and the corresponding esters, amides and 3- and 4-phenoxyphenylalkanols with anti-inflammatory activity and mild, aspirin-like analgesic and antipyretic activity.

Many people and animals suffer from various rheumatic diseases that include inflammation, swelling, tenderness, reduced mobility, pain and fever. Although there are a number of available anti-inflammatory agents which have been found to be effective in the symptomatic treatment of such disorders as rheumatoid arthritis, rheumatoid spondylitis and degenerative joint disease (osteoarthritis) of the hip, such agents have many undesirable side effects. Research to find improved anti-inflammatory agents therefore continues.

according to the invention, a manufacturing

discovery of new compounds which are excellent anti-inflammatory agents, and which, in addition to their anti-inflammatory activity, exhibit mild, aspirin-like analgesic and anti-pyretic activity.

The new compounds produced according to the invention have the formula

and the pharmaceutically acceptable acid addition salts of the compounds which are basic; where Y 1 and Y 2 are the same or different and mean hydrogen, halogen, methyl, ethyl or C 1 - - alkoxy, since both and Y 2 cannot be hydrogen when R is hydrogen or methyl and the group

is in paraposition,

is hydrogen or lower alkyl,

n is 0 or 1, and

Z is

A) -COOR2. where R 2 is hydrogen, lower alkyl, an alkali metal, an equivalent of an alkaline earth metal, or an ammonium group,

where each R^ is equal or different and is

hydrogen, hydroxy, lower alkyl or -CH2-COOH, or

C) OR^i where R^ is hydrogen or lower alkanoyl, in racemic,

d- or l-shape.

The new (3- or 4-phenoxyphenyl)-alkanoic acids,_ their_- — pharmaceutically acceptable cationic salts and the esters, amides and

The (3- or 4-phenoxyphenyl)-alkanols are useful in pharmaceutical preparations for the treatment of inflammation, pain and fever in humans and animals. Some of the compounds also enhance to a large extent the analgesic activity of a number of painkillers.

The term "alkali metal" is understood here to mean sodium, potassium and lithium.

The term "alkaline earth metal" is to be understood as calcium, magnesium and barium.

The term "acid addition salts" refers to salts produced by reacting the free amine with an organic or inorganic acid. Representative salts are hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate and napsylate (salt of 2-naphthalenesulfonic acid).

"Halogen" includes chlorine, fluorine, bromine and iodine.

"C₁-C₁ alkoxy" means methoxy, ethoxy and propoxy.

The compounds of general formula I are excellent anti-inflammatory agents, and many of them have an ED^<q> of from 0.2 to 1.0 mg/kg in the erythema blocking test. All compounds are useful in the treatment of inflammation in mammals, and the acids and amines are particularly preferred. In addition to their anti-inflammatory activity, the compounds also have mild analgesic and anti-pyretic activity. The compounds are used as an active ingredient in pharmaceutical preparations together with a pharmaceutically acceptable diluent or carrier. The compounds are generally administered to mammals in doses of from 0.2 to 50.0 mg/kg body weight daily, either in a single dose or in multiple doses over a period of 24 hours.

It should be understood that both the d- and 1- isomers of the -alkyl compounds are covered by formula I. E.g. The cari -alkyl acids are split into fine d- and 1-isomers by known methods. Both the d- and 1- isomers have been found to have almost identical activity. Thus, either the racemic mixture or the d- and 1-isomer can be used in the treatment of inflammation, pain and fever in mammals.

Some of the compounds of formula I, especially those in which Y1 and Y2 are hydrogen, n is °' Ri is hydrogen, methyl or ethyl, and Z is. COOH, or a salt thereof, has surprisingly been found to enhance the analgesic effect achieved by certain analgesics, such as esters of i,2-diferiyl-2-hydroxy-3-methyl-(substituted 4-amino)butanef, particularly -d-propoxyphene (identified chemically as -d-1,2-diferiyl-2-propionoxy-3-methyl-4-dimethylaminobutane), and certain narcotic analgesics such as morphine, codeine, etc., when administered together with these.

Reinforcement of the pain-relieving effect is achieved when approx. 1 part by weight of a compound of formula I is administered approximately simultaneously with or is administered from 1 hour before to 1 hour after the administration of from 0.005 to 20 parts by weight of the analgesic. In order to achieve a high degree of analgesic effect, generally from 0.5 to 50 mg/kg of a compound of formula I is administered together with the usual therapeutic dose of the analgesic.

Representative compounds prepared according to the invention include the following: 2-(2,5-Dichloro-3-phenoxyphenyl)acetic acid 2-(2,5-Dimethyl-3-phenylthiophenyl)acetic acid

2-(2-Fluoro-5-ethyl-3-phenoxyphenyl)acetic acid 2-(2,5-Dibromo-3-phenylthiophenyl)butyric acid 2-(4-Ethoxy-3-phenoxyphenyl)propionic acid d-2-(3-Phenoxyphenyl) )propionic acid 2-(l-Pentyl)-2-(3-phenoxyphenyl)acetic acid 2-(3-Phenoxyphenyl)acetic acid 2-(3-Phenoxyphenyl)propionic acid, sodium salt, dihydrate 2-(3-Phenoxyphenyl)propionic acid, calcium salt, dihydrate 2-(4-Methyl-3-phenoxyphenyl)acetic acid 2-(4-Methoxy-3-phenoxyphenyl)acetic acid 2-(4-Chloro-3-phenoxyphenyl)propionic acid 2-(4-Chloro-3-phenoxyphenyl)acetic acid 1- 2-(3-Phenoxyphenyl)propionic acid, sodium salt 2-(5-Chloro-3-phenoxyphenyl)acetic acid 2-(2-Chloro-3-phenoxyphenyl)acetic acid 2-(2-Methyl-5-phenoxyphenyl)acetic acid 2-(3 -Phenoxyphenyl)propionic acid 2-(2-Fluoro-5-phenoxyphenyl)acetic acid 2-(2-Ethyl-3-phenoxyphenyl)propionic acid, calcium salt 2-(5-Chloro-3-phenoxyphenyl)propionic acid 2-(3-Phenoxyphenyl)propanol Methyl 2-(3-phenoxyphenyl)propionate Ethyl 2-(3-phenoxyphenyl)acetate Ethyl 2-(3-phenoxyphenyl)propionate 2-(3-Phenoxyphenyl)propionamide 2-(3-Phenoxyphenyl)ethylcarbamate N-Methyl- 2-(3-phenoxyphenyl)propionam id N-Methyl-2-(3-phenoxyphenyl)propylcarbamate

N,N-Dimethyl-2-(3-phenoxyphenyl)propionamide N,N-pimethyl-2-(3-phenoxyphenyl)-n-pentyl carbamate N-Methyl-2-(3-phenoxyphenyl)propylamine sulfate 2 -(3-Phenoxyphenyl)butyric acid

2-(3-Phenoxyphenyl)valeric acid 2-(3-Phenoxyphenyl)caproic acid

2-(3-Phenoxyphenyl)heptanoic acid

3-(3-Phenoxyphenyl)butyric acid

Ethyl 3-(3-phenoxyphenyl)butyrate 3-(3-Phenoxyphenyl)butanol

3 -(3-Phenoxyphenyl)butyl acetate

2-(3-Phenoxyphenyl)propyl propionate 4-(3-Phenoxyphenyl)valeramide

5-(3-Phenoxyphenyl)caproic acid, aluminum salt 2-(2,3-Dimethyl-4-phenoxyphenyl)propionic acid 2-(3,5-Dimethyl-4-phenoxyphenyl)propionic acid, sodium salt 2-(3-Methoxy-4-phenoxyphenyl) )propionic acid 2-(3-Methoxy-4-phenoxyphenyl)acetic acid 2-(2-Methoxy-4-phenoxyphenyl)acetic acid t-Butyl-2-(2-methyl-4-phenoxyphenyl)propionate 2-(3-Methyl-4 -phenoxyphenyl)acetic acid Ethyl 2-(3-bromo-4-phenoxyphenyl)propionate 2-(3-Methyl-4-phenoxyphenyl)propionic acid 2-(2,3-Dimethyl-4-phenoxyphenyl)acetic acid 2-(2,3 -Dimethyl-4-phenoxyphenyl)propionic acid 2-(3,5-Dimethyl-4-phenoxyphenyl)acetic acid 2-(2,5-Dimethoxy-4-phenoxyphenyl)acetic acid 2-(2-Fluoro-4-phenoxyphenyl)propionic acid Methyl- 2-(2-Fluoro-4-phenoxyphenyl)propionate 2-(3-Methyl-4-phenoxyphenyl)propionamide 2-(2-Chloro-4-phenoxyphenyl)propionamide N-methyl-2-(2-fluoro-4- phenoxyphenyl)propionamide N,N-Dimethyl-2-(3-ethyl-4-phenoxyphenyl)propionamide

According to the invention, the compounds of formula I can be prepared by methods known per se for the production of phenylacetic acids, phenylpropionic acids and derivatives thereof. Although various methods can be used to obtain the compounds of formula I, a number of the preferred reaction processes are indicated and described in the following. In formulas and references, R is as defined under formula I, and "Ar" means the group

in Formula I.

A. Acids

I. Ar-CH3 NBS Ar-CH2~Br NaCN Ar-CH2"C<N> H^O Ar-CH2-COOH

The methyl group in a suitable methyl diaryl ether is halogenated by the action of N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride or a similar halogenating agent, with a suitable catalyst such as benzoyl peroxide or azo-bis-iso-butyronitrile, in an inert solvent such as carbon tetrachloride, or another halogenated hydrocarbon. The resulting halomethyl diaryl ether is reacted with sodium or potassium cyanide, suitably in dimethyl sulfoxide solution. The nitrile thus formed is hydrolysed to the corresponding carboxylic acid by the action of either acidic or basic agents by well-known methods.

As illustrated in the preceding reaction schemes, the nitrile can be alkylated with an aliphatic halide (R^X2) in liquid ammonia in the presence of sodium amide to give an -aliphatic substituted nitrile. The alkylated nitrile is hydrolyzed as above to give the corresponding carboxylic acid (reaction IIa).

In a similar way, an arylacetic acid can be alkylated in the o-position

to the carboxyl group, as shown in reaction IIb.

By another method, as illustrated in the reactions lic

and Ild, an aryl acetate ester, which like the ethyl ester, or an aryl acetonitrile, can be converted into the corresponding malonic acid ester or cyanoacetic acid ester by the action of metallic sodium and diethyl carbonate. Any of these derivatives can then be alkylated. Such alkylation is usually carried out by reacting the malonic acid ester or the cyanoacetic acid ester with a strong basic agent, such as sodium ethoxide, sodium methoxide, potassium tert-butoxide or sodium hydride, whereby a carban ion is formed on the α-carbon atom. Subsequent treatment of the carbanion intermediate with an alkylating agent such as an alkyl halide or tosylate (R^X2) gives the corresponding α-alkyl malonic acid ester or cyanoacetic acid ester derivative. Either of these can be hydrolyzed to the corresponding α-alkylarylmalonic acid, which is then decarboxylated by well-known methods to give the desired α-alkylarylacetic acid.

The nitrile prepared according to reaction I can optionally be methylated by following the following procedure (reaction III): The nitrile is condensed with ethyl formate under basic conditions, e.g. in the presence of sodium hydride or sodium methoxide in an inert hydrocarbon solvent such as benzene. The resulting hydroxymecylene derivative is benzoylated by reaction with either benzoic anhydride or benzoyl chloride and pyridine, and then the benzoic ester is hydrogenated in the presence of a noble metal catalyst to give the desired α-methylarylacetonitrile, which is then hydrolyzed as above.

The desired o-methylarylacetonitrile can optionally be prepared by the following reaction (reaction IV): Aryloxy-aceto-phenone (prepared by an Ullman ether synthesis) is reduced either with hydrogen in the presence of a noble metal catalyst or with a metal hydride, such as lithium aluminum hydride , lithium or sodium borohydride to the corresponding carbinol. Conversion of this carbinol to the corresponding bromide can be carried out by treating the carbinol with phosphorus tribromide, preferably in an inert solvent such as chloroform, benzene or carbon tetrachloride. The bromide thus formed is reacted with sodium cyanide, suitably in a dimethyl sulphoxide solution, to give a nitrile which is hydrolysed as indicated above to the desired carboxylic acid.

The α-alkyl acids thus obtained can be split into their d- and 1-isomers by known methods.

The desired phenoxyphenylalkanoic acids can also be prepared by the Willgerodt reaction (reaction V). In this reaction, a suitable phenoxyphenyl alkyl ketone is heated with e.g. morpholine and sulfur, and the resulting thioamide is hydrolyzed to give the desired alkanoic acid derivative which can be alkylated by treatment with two equivalents of sodium amide in liquid ammonia, followed by addition of alkyl halide (R^X2) as illustrated in reaction 11b.

The acids of formula I where n is different from 0 can be prepared by well-known methods with the known Wittig reaction as shown in reactions Via and VIb. The unsaturated ester intermediates as in Vila) or nitriles (as in VIb) can be hydrogenated in the presence of a noble metal catalyst, such as platinum and the resulting saturated esters and nitriles can be hydrolysed as indicated above to the desired carboxylic acids.

C. Esters

The carboxylic acids produced by the methods described in the above reactions are converted to the corresponding esters by well-known methods, such as e.g. by heating the acid with an alcohol in the presence of a mineral acid (Villa), or by converting the acid into the corresponding acid chloride, followed by reaction of said acid chloride with an alcohol, preferably in the presence of an HCl iron ing forge 1 (VHIb ).

D. Amides

The amides are obtained by reacting the above-mentioned acid chloride with an amine. This reaction is normally carried out in an inert solvent such as chloroform, benzene or carbon tetrachloride, in the presence of an acid scavenger such as pyridine or K 2 CO 2 , or in a tertiary amine solvent such as collidine, lutidine or triethylamine.

E. Alcohols

The above-described esters can be reduced with a metal hydride such as e.g. lithium aluminum hydride, to the corresponding alcohol by known methods.

F. Esters

The alcohols obtained above in reaction X can be converted into ester derivatives by well-known methods, such as e.g. treating the alcohol with an acid chloride or acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine.

Such a reaction using acetic anhydride gives e.g. the desired acetate ester.

G. Acid Hydroxamides

The esters prepared according to the reaction Villa and

VHIb can be converted to acid hydroxamides by treatment with

in

hydroxylamine by well-known methods.

The following examples shall serve to further illustrate the invention.

Example 1

Preparation of 2-(3-phenoxyphenyl)acetic acid

42.4 g of m-phenoxyacetophenone was added to 26 ml of morpholine

and 9.6 g of sulfur. The reaction mixture was refluxed with stirring for 20 hours. To the reaction mixture was then added 700 ml of a 15% aqueous potassium hydroxide solution and a small amount of ethyl alcohol. The reaction mixture was refluxed with stirring for a further 20 hours. About 200 ml of the solvent was distilled off. The remaining reaction mixture was filtered while hot, partially cooled with ice and acidified with concentrated hydrochloric acid, whereupon an oily precipitate formed and then crystallized. The crystalline precipitate was filtered, washed several times with water and dried to give 45.9 g of crude product as a yellow-orange solid. The crude product was suspended in boiling hexane, and ethyl acetate was added until the product disappeared.

in resolution. The solution was then treated with charcoal, filtered and cooled to give 22.7 g of white flakes of 2-(3-phenoxyphenyl)acetic acid, m.p. 84-86 C; pKg = 6.9.

Analysis: Calculated for C14H12<0>^ C 73.66; H 5.30.

Found: C 73.85; H 5.45.

Example 2-5

The following compounds were prepared by the method of Example 1 for the corresponding phenoxyacetophenone, using appropriate amounts of sulfur and morpholine.

2-(4-Methyl-3-phenoxyphenyl)acetic acid, m.p. 49-51°C;

pK s=7.0 from 4-methyl-3-phenoxyacetophenone.

Analysis: Calculated for C15H14°3: C 74.36; H 5.83.

Found: C 74.45; H 5.88. 2-(4-Methoxy-3-phenoxyphenyl)acetic acid, m.p. 85-87.5 oC; pK s =6.9, from 4-methoxy-3-phenoxyacetophenone.

Analysis: Calculated for C 15 H 14 O 4 : C 69.75; H 5.46

Found C 69.47; H 5.30 2-(2-Methoxy-5-phenoxyphenyl)acetic acid, m.p. 90-94°C;

pK s=7.4, from 2-methoxy-5-phenoxyacetophenone.

Analysis: Calculated for C 15 H 14 O 4 : C 69.75; H 5.46

Found: C 69.58; H 5.61 2-(2-Methyl-5-phenoxyphenyl)acetic acid, b.p. 153-163°c/ 0.16 mm Hg, pKg - 6.9, from 2-methyl-5-phenoxyacetophenone.

Analysis: Calculated for 15H14°3: C 74.36; H 5.83.

Found C 72.08; H 5.82.

Example 6

2-(4-Chloro-3-phenoxyphenyl)acetic acid

232.7 g of 3-phenoxy-4-chlorotoluene, 196 g of N-bromosuccinimide and 1.0 g of benzoyl peroxide were added to 1200 ml of carbon tetrachloride. The reaction mixture was stirred and refluxed for 24 hours, after which the reaction mixture was filtered and the solid was washed with carbon tetrachloride. The filtrate was evaporated to an oil and distilled to give fractions A, B and C of crude 4-chloro-3-phenoxybenzyl bromide.

Fractions B and C were combined and analyzed.

Analysis: Calculated for C13Hl0BrCl0: C 52.46; H 3.38.

Found: C 52.25; H 3.44.

The combined fractions B and C were redistilled through a Vigreux column to give fractions A, B, C, D and E. Nuclear magnetic resonance studies showed that fractions C and D contained 91 and 92% 4-chloro-3- phenoxyphenyl bromide.

For about. 400 ml of dimethyl sulfoxide was dissolved in 22.2 g of 95% sodium cyanide, and the reaction mixture was heated to approx. 50°C. The crude 4-chloro-3-phenoxybenzyl bromide (125 g) was added dropwise with stirring. The temperature was maintained at between 50 and 60°C during the bromide addition. A red color was immediately formed on the addition of the bromide. After the bromide addition was complete, the reaction mixture was heated to 60°C and stirred for 3 hours. The mixture was then cooled to room temperature and stirred overnight, after which it was poured onto ice and extracted with ethyl ether and then with hexane. The extracts were washed with water and dried over sodium sulfate. The solvents were evaporated to give a red-brown viscous oil which was distilled to give fractions A, B and C a<y> 2-(4-chloro-3-phenoxyphenyl)acetonitrile.

Analysis: Calculated for C14Hl0ClN0: C 68.99 H 4.13 N 5.74

Found : C 68.72 H 4.20 N 5.50

Acid hydrolysis of the nitrile gave the corresponding 2-(4-chloro-3-phenoxyphenyl)-acetic acid. 50.9 g of the above nitrile was added to 500 ml of concentrated hydrochloric acid. The reaction mixture was stirred and heated to 85°C for 24 hours. 500 ml of distilled water was added to the reaction mixture, which was then heated with stirring at 105°C for 4 hours (careful refluxing). The reaction mixture was then poured into a large volume of ice and

water. The reaction mixture was extracted twice with ethyl ether.

The combined ether phases were washed with water and extracted with dilute sodium carbonate. The extract was then washed with ethyl

ether and acidified by dropwise addition of 6N hydrochloric acid with stirring. The voluminous white precipitate thus obtained was filtered and washed with water and dried in vacuo to

give 34.2 g of white, crydallinic 2-(4-chloro-3-phenoxyphenyl)acetic acid, m.p. 77-80°C.

Example 7-8

The following compounds were prepared by the method of Example 14 from the corresponding toluenes using the appropriate amounts of N-bromosuccinimide, benzoyl peroxide and sodium cyanide.

2-{2-Chloro^5-phenoxyphenyl)acetic acid, m.p. 88-90°C; pK -6.8;

2-(2-Fluoro-5-phenoxyphenyl)acetic acid, m.p. 80-82 C; pK„ - 6.65;

Example 9

Preparation of 2-(3-phenoxyphenyl)propionic acid

A. 3- Phenoxyacetophehon. A mixture consisting of

908 g (6.68 mol) m-hydroxyacetophenone, 4500 g (28.6 mol) bromobenzene, 996 g (7.2 mol) anhydrous potassium carbonate and 300 g copper bronze were heated under reflux with re-

leading until the water evolution of complete, using a Dean-Stark water separator. The mixture was then stirred and refluxed for 24 hours. After cooling to room temperature, the reaction mixture was diluted with an equal volume of CHCl 2 °g filtered. The filtrate was washed with 5% HCl, then with 5% NaOH, with water, dried over Na 2 SO 4 and evaporated in vacuo.

The remaining oil was distilled through a 15 cm Vigreux-

column to give 918 g of 3-phenoxyacetophenone, k.å. 120-121 C

(0.09 mm Hg) , ii^5= 1.5868.

B. α-methyl-3-phenoxybenzyl alcohol. A stirred solution of 700 g of m-phenoxyacetophenone in 3000 ml of anhydrous methanol was cooled to 0°C in an ice-acetone bath. Sodium borohydride, 136 g (3.6 moles), was added to this solution in small portions at such a rate that the temperature never rose above 10 C. After the borohydride addition was complete, the reaction mixture was warmed to room temperature and stirred for 18 hours.

It was then stirred and refluxed for 8 hours.

About. 400 ml of methanol was distilled off, and the remaining solution was evaporated to approx. one third of its original volume in a vacuum and poured into ice water. This mixture was extracted twice with ether, acidified with 6N HCl and again extracted with ether. The ether extracts were collected, washed with saturated NaCl-oppr solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining oil was distilled through a 15 cm Vigreux column to give 666 g of α-methyl-3-phenoxybenzyl alcohol, b.p. 132-134°C, (0.35 mm Hg). n^<5> = 1.5809.

C. o— Methyl- 3-phenoxybenzyl bromide. A stirred solution

of 1357 g α-methyl-3-phenoxybenzyl alcohol in 5000 ml anhydrous CCl^

(dried over molecular sieve) was cooled to 0°C. To this was added• 1760 g of PBr^, and stirring and cooling were carried out at such a rate that the temperature remained: at 0-5°C during the addition. The reaction mixture was then warmed to room temperature and .

was stirred at room temperature overnight (about 12 hours). The reaction mixture was then poured into ice water, and the organic phase was separated. The aqueous phase was extracted with CCl^,

and the combined extracts were washed 3 times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 1702 g of α-methyl-3-phenoxybenzyl bromide as a heavy,

25

viscous oil, nD = 1.5993;

D. 2-(3- Phenoxyphenyl) propionitrile. A well-stirred suspension of 316 g of 98% sodium cyanide in 5000 ml of anhydrous dimethylsulfoxide (previously dried over molecular sieve) was heated to 50-60°C and held at this temperature while 1702 g of o-methyl-3-phenoxybenzyl bromide was slowly added. After the bromide addition was complete, the temperature was raised to 75°C, and the mixture was stirred at this temperature for 1/2 hour.

The mixture was then cooled to room temperature and stirred

overnight at room temperature and then poured into ice water. The resulting aqueous suspension was extracted twice with ethyl acetate and then with ether. The organic extract was washed twice with sodium chloride solution, once with water and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave an oily residue which was distilled through a 15 cm Vigreux column to give 1136 g of 2-(3-phenoxyphenyl)propionitrile, m.p. 141-148°C (0.1 mm Hg), n^<5> ■ 1.5678.

E. 2-(3- Phenoxyphenyl) propionic acid. A mixture of 223 g of 2-(3-phenoxyphenyl)propionitrile and 400 g of sodium hydroxide in 1600 ml of 50% ethanol was refluxed with stirring for 72 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The resulting solution was washed with ether, acidified with concentrated HCl and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The remaining oil was distilled to give 203.5 g (84%) of 2-(3-phenoxyphenyl)propionic acid as a viscous oil; k.p. 168-171°C (0.11 mm Hg), n^<5>= 1.5742, pKg = 7.3.

Example 10

2-( 3- Phenoxyphenyl) propionic acid, sodium salt, dihydrate

2-(3-Phenoxyphenyl)propionic acid (6460 g) was converted to the sodium salt by adding it portionwise to 26.7 moles of 2N sodium hydroxide with stirring and cooling. The aqueous solutions were then evaporated to near dryness in vacuo. The semi-dry residues were then stirred with ethyl acetate and again evaporated in vacuo. The white, solid residues were dissolved in the smallest possible amount of boiling ethyl acetate, filtered into a large container (about 18 1 solution) and allowed to stand at 7°C overnight. The resulting crystalline mass was filtered and dried in vacuo at room temperature to give 6954 g of pure sodium 2-(3-phenoxyphenyl)propionate, dihydrate, m.p. 76-78°C.

t

Example 11

2-(3- Phenoxyphenyl)propionamide

A solution of 0.5 M 2-(3-phenoxyphenyl)propionyl chloride in 300 ml of dry ethyl ether was added dropwise to 2 L of liquid ammonia with stirring. After the addition was complete, the reaction mixture was stirred for 1 hour, and 500 ml of diethyl ether was added. The reaction mixture was stirred overnight, whereby excess ammonia was evaporated. Dilute hydrochloric acid was added to the reaction mixture. The ether layer was separated, washed with sodium hydroxide, water and dried over sodium sulfate. Evaporation of the ether in vacuo gave a gummy residue which crystallized after rubbing with cold hexane. Recrystallization from ethyl acetate and hexane gave 76.2 g of 2-(3-phenoxyphenyl)propionamide, m.p. 67-69°C

Example 12

Methyl-2-(3-phenoxyphenyl)acetate

2-(3-Phenoxyphenyl)acetic acid was dissolved in chloroform, stirred, and thionyl chloride in chloroform was slowly added. The reaction mixture was carefully refluxed with stirring for 3 hours and then evaporated to dryness to give the corresponding acid chloride. The acid chloride was taken up in chloroform,

and the resulting solution was added dropwise with stirring to an excess of cold methyl alcohol. The reaction mixture was cooled to below 10°C and then warmed to room temperature. The solvent was removed on a rotary evaporator and the residue was distilled to give methyl 2-(3-phenoxyphenyl)acetate.

Example 13

N,N-Dimethyl-2-(3-phenoxyphenyl)propionamide

72.6 g of 2-(3-phenoxyphenyl)propionic acid and 36.9 g of thionyl chloride were added to 400 ml of dry chloroform. The reaction mixture was refluxed with stirring for approx. 3 hours. The chloroform was then evaporated, and the residue was distilled azeotropically 2 times with benzene. The residue was dissolved in ethyl ether and, with stirring and cooling, added to a solution of 45 g of dimethylamine in ethyl ether. The temperature was maintained at approx. 0°C

or lower during addition. The reaction mixture was warmed to room temperature, gently refluxed for 1 1/2 hours, poured into ice and water, acidified, and the ethyl ether layer separated. The aqueous layer was extracted with ethyl ether. The ether extracts were combined, washed with water, dried over sodium sulfate and evaporated to a white solid. The solid was dissolved in boiling hexane and cooled slowly to room temperature to give 67.8 g of N,N-dimethyl-2-(3-phenoxyphenyl)-propionamide, m.p. 73.5-76°C.

Example 14-15

The following compounds were prepared by the procedure of Example 13, using appropriate starting materials.

N-Methyl-2-(3-phenoxyphenyl)butyramide, m.p. 84-86°C.

Analysis: Calculated for C17HlgN02: C 75.81 H 7.11 N 5.20.

Found: C 75.60 H 7.11 N 5.00.

N-Methyl-2-(3-phenoxyphenyl)propionamide, m.p. 57-58 C.

Example 16

Cleavage of α-dl-2-(3-phenoxyphenyl)propionic acid

200 g of dl-2-(3-phenoxyphenyl)propionic acid, prepared according to Example 9, was dissolved in 3000 ml of hot ethyl acetate,

and 100 g of d-(+)-o-methylbenzylamine was added to the solution. A crystalline mass separated on cooling. This was filtered to give 229 g of dl-2-(3-phenoxyphenyl)propionic acid, d-(+)-α-methylbenzylamine salt, m.p. 115-126°C. Five successive recrystallizations from hot ethyl acetate gave 63.5 g of d-(+)-2-(3-phenoxyphenyl)propionic acid, d-(+)-α-methylbenzylamine salt, m.p. 142-144 C,

[ a]* 5 + 14.5° (C = 1%, GHCl 3 ), [ a]^ 5 + 3.74 (C = 1%, CB^ E) .

In a similar manner, l-(-)-2-(3-phenoxyphenyl)propionic acid, l-(-)-α-methylbenzylamine salt was prepared, m.p. 141-142°C, [α]^ 5 -3.63 (C = 1%, CH 3 OH).

52 g of d-(+)-2-(3-phenoxyphenyl)propionic acid, d-(+)-α-methylbenzylamine salt was suspended in 1.5 L H 2 O and 0.5 L Et 2 O

and acidified by the addition of 5N HCl. The ether layer was washed with water, dried over sodium sulfate and evaporated in vacuo to give d-(+)-2-(3-phenoxyphenyl)propionic acid, [<*]D 25 + 46.0 (C <=> 1%, CHC13 ).

Similarly, l-(-)-2-(3-phenoxyphenyl)propionic acid, [<*]p<5> -45.7 (C = 1%, CHCl3) was prepared from l-(-)-2-( 3-Phenoxyphenyl)propionic acid, l-(-)-α-methylbenzylamine salt.

Example 17

2-( 3- Phenoxyphenyl) butyric acid

A. 2-(3- Phenoxyphenyl) butyronitrile

23 g of sodium was added to 4 liters of liquid ammonia in a 5 liter flask containing a catalytic amount of ferric chloride. The reaction mixture was stirred for approx. 30 minutes. To the resulting mixture was added 209 g of 2-(3-phenoxyphenyl)acetonitrile, prepared according to reaction I. The reaction mixture was stirred for 30 minutes, and 187.2 g of ethyl iodide was added while stirring. The reaction mixture was then stirred overnight to allow the ammonia to evaporate. Anhydrous ethyl ether was added to the residue, and the mixture was acidified with 6N hydrochloric acid and stirred for approx. 1 hour. The reaction mixture was then extracted with ethyl ether. The ether layer was washed with water and sodium thiosulfate solution, and the ether was evaporated. The resulting oily residue was distilled to give 155.2 g of 2-(3-phenoxyphenyl)butyronitrile, m.p. 138-140°c/0.14 mm Hg.

B. 145 g of the 2-(3-phenoxyphenyl)butyronitrile prepared above was hydrolyzed to the corresponding acid by following the procedure of Example 9 E, to give 95.9 g of 2-(3-phenoxyphenyl)butyric acid, m.p. . 73-77°C.

Example 18

Ethyl-2-(3-phenoxyphenyl)propionate

200 g of 2-(3-phenoxyphenyl)propionic acid, prepared according to Example 9, was dissolved in 1500 ml of ethanol, and hydrogen chloride gas was introduced into the ethanolic solution until it was saturated. The reaction mixture was then refluxed with stirring overnight, after which a large portion of the ethanol was evaporated in vacuo, and the remaining reaction mixture was poured into ice water. The reaction mixture was basified with 10% sodium hydroxide and extracted twice with ethyl ether. The combined ether extracts were washed twice with water and dried over sodium sulfate. The ethyl ether was evaporated to give crude ethyl 2-(3-phenoxyphenyl)propionate as an oily residue. The preparation was repeated with a further 200 g of 2-(3-phenoxyphenyl)propionic acid. The crude residues were collected and distilled through a 15 cm Vigreux column to give 339.9 g of ethyl 2-(3-phenoxyphenyl)propionate, m.p. 128-134°C/0.15 mm Hg, n^ ^ 5453

Example 19

2-(3- Phenoxyphenyl) propanol

to 27.4 g of lithium aluminum hydride in a flame-dried, nitrogen-purged flask was added approximately 1 liter of ethyl ether. The mixture was stirred vigorously for 45 minutes. 300 g of ethyl 2-(3-phenoxyphenyl)propionate, prepared according to Example 18, dissolved in 500 ml of ethyl ether was then added dropwise to the lithium aluminum hydride suspension at such a rate that a slight reflux was constantly maintained. After the ester addition was complete, the reaction mixture was stirred and gently refluxed overnight. After cooling the reaction mixture to room temperature, resolution was achieved by careful dropwise addition of 44.5 ml of water, 33.3 ml of 20% sodium hydroxide and 155 ml of water. A large amount of water was then added, and an emulsion was formed. This was made clear by acidification. The reaction mixture was then extracted with ethyl ether, the ether layer was separated, and the aqueous layer was extracted again with ethyl ether. The ether extract

was collected, washed with water, dried over sodium sulfate and a little sodium carbonate. The dried ether solution was then evaporated to an oily residue. This was distilled to give 241.6 g of 2-(3-phenoxyphenyl)propanol, b.p. 128-131°C/0.1 mm Hg,

25

nf = 1.5771.

Example 20

2-(3- Phenoxyphenyl) propyl acetate

11.4 g of 2-(3-phenoxyphenyl)propanol, prepared according to example 19, 7 ml of acetic anhydride and approx. 100 ml of pyridine were mixed, refluxed with stirring for 18 hours. Most of the pyridine was evaporated in vacuo, and the residue was dissolved in chloroform, washed with dilute hydrochloric acid, water and dried over anhydrous sodium sulfate. The chloroform was removed by evaporation in vacuo and the resulting oily residue was distilled to give 10.6 g of 2-(3-phenoxyphenyl)pyridyl acetate, m.p. 138-145°C/0.1 mm Hg, nP = 1.5478.

Example 21

2-(3- Phenoxyphenyl)propylpropionate

2-(3-Phenoxyphenyl)propylpropionate was prepared in a similar manner using the appropriate starting materials, b.p. 142-149°C/0.1 mm Hg, n^<5> = 1.5420.

Example 22

2-(3- Phenoxyphenyl) propionic acid hydroxamide

Sodium methoxide was prepared by adding 5 g of sodium metal to 150 ml of methanol. A solution of 7 g of hydroxylamine hydrochloride dissolved in 100 ml of methanol was then added to the cooled sodium methoxide solution, and the precipitated sodium chloride was removed by filtration. 25.6 g of methyl 2-(3-phenoxyphenyl)propionate, prepared according to Example 18, was then added to the filtrate with stirring. The reaction mixture was stirred at room temperature for 1/2 hour and then refluxed with stirring for 1 1/2 hours. The reaction mixture was then cooled and acidified by dropwise addition of 6N hydrochloric acid. After partial removal of the solvent in vacuo, a yellow oil was formed which then crystallized. Recrystallization from a small amount of ethyl acetate and methylcyclohexane gave 12.2 g of 2-(3-phenoxyphenyl)-propionic acid hydroxyamide, m.p. 121-122°C.

Example 23

3-(3- Phenoxyphenyl)butyric acid

A. Ethyl-3-(3-phenoxyphenyl)crotonate. 224 g of triethylphosphonoacetate was slowly added to 48 g of a 50% sodium hydride dispersion suspended in 500 ml of monoglyme with stirring.

212 g of m-phenoxyacetophenone dissolved in 1500 ml of monoglyme were added

added dropwise and stirred for 1 hour. The reaction mixture was then refluxed overnight, cooled to room temperature and cleaved by the addition of water. After evaporation of the solvent in vacuo, the crude product was dissolved in ethyl acetate, washed twice with water and dried over sodium sulfate. Evaporation of ethyl acetate gave an oily residue which was distilled to give 52.6 g of ethyl 3-(3-phenoxyphenyl)crotonate, m.p. 163-170°C/0.2 mm Hg,

■ 25

n D = 1.5770.

B. Ethyl-3-(3-phenoxyphenyl)butyrate. 19 7 g of it

above prepared ethyl 3-(3-phenoxyphenyl) crotonate dissolved in 400 ml of ethanol was hydrogenated in the presence of 5 g of platinum oxide. The ethanol was evaporated in vacuo to give an oily residue

which was distilled to give 160 g of ethyl 3-(3-phenoxyphenyl)

butyrate, b.p. 137-139°C/0.6 mm Hg, n^<5> = 1.5401.

C. 3-(3-phenoxyphenyl)butyric acid. 160 g of the above-prepared ethyl 3-(3-phenoxyphenyl)butyrate was hydrolyzed by the method according to Example 9 E to give 117.2 g of 3-(3-phenoxyphenyl)butyric acid, b.p. 193-195°C/0.23 mm, n^<5> = 1.5687, pK - 7.2.

Example 24

Preparation of 2-(3-methoxy-4-phenoxyphenyl)acetic acid.

29.2 g of 3-methoxy-4-phenoxyacetophenone and 5.75 g of sulfur were added to 17 ml of morpholine. The reaction mixture was carefully refluxed with stirring for 20 hours. It was then diluted with 300 ml of 15% potassium hydroxide and 100 ml of ethyl alcohol and refluxed with stirring overnight. The reaction mixture was then poured into ice water and acidified with 6N HCl, whereupon a gummy precipitate, which partially crystallized, formed. The precipitate was filtered, washed with water and dried in vacuo. The dried precipitate was taken up in hexane with ethyl acetate, decolorized by boiling, filtered and cooled to give 18.4 g of dense, yellow-orange crystals of 2-(3-methoxy-4-phenoxyphenyl)acetic acid, m.p. 83-85°C. pK = 6.8.

Example 25-30

The following compounds were prepared by the method of Example 24 from the corresponding phenoxyacetophenone using appropriate amounts of sulfur and morpholine: 2-(2-Methyl-4-phenoxyphenyl)acetic acid, m.p. 71.5-74 C, pK = 6.9. 2-(3,5-Dimethyl-4-phenoxyphenyl)acetic acid, m.p. 124-126 C, pK - 7.45. 2-(3-Methyl-4-phenoxyphenyl)acetic acid, m.p. 89-91 c, pK = 7.1. 2-(2,3-Dimethyl-4-phenoxyphenyl)acetic acid, m.p. 106-108 C, pK = 7.1.

2-(2-Ethyl-4-phenoxyphenyl)acetic acid, m.p. 82-84 C,

PK = 7.0.

pp

2-(2-Methoxy-4-phenoxyphenyl)acetic acid, m.p. 105-107 c, pK = 7.4.

Example 31

Preparation of 2-(3-methyl-4-phenoxyphenyl)propionic acid.

To 500 ml of liquid ammonia containing a trace of iron (III) chloride, 2.48 g of sodium metal was added in portions. The resulting solution was stirred for 30 minutes, after which 11.8 g of 2-(2-methyl-4-phenoxyphenyl)acetic acid was added over a period of 30 minutes, and the dark green solution was stirred for 45 minutes. 11.3 g of methyl iodide were added dropwise to the solution. The reaction mixture was stirred for 2 1/2 hours, and then 500 ml of dry ethyl ether was added, and the reaction mixture was stirred overnight, and the ammonia was allowed to evaporate. The solution was acidified with dilute hydrochloric acid, ethyl ether was separated and extracted with 10% sodium hydroxide. This was washed with ethyl ether, acidified and extracted with ethyl ether. The ethyl ether extract was dried over sodium sulfate and evaporated. The resulting oil was distilled to give 5 g of 2-(2-methyl-4-phenoxyphenyl)propionic acid as a yellow, fluorescent oil, m.p. 185-188°C/0.08 mm Hg, pKg = 7.40.

Example 32-36

The following o-alkylated compounds were prepared by the method according to example 31 from the corresponding phenoxy-phenylacetic acid (or substituted phenoxyphenylacetic acid O and the corresponding alkyl halide.

2-(2-Methyl-4-phenoxyphenyl)propionic acid, m.p. 123.5-125°C, pK = 7.3.

2-(4-Phenoxyphenyl) valeric acid from 2-(4-phenoxyphenyl,) -

acetic acid and n-propyl iodide, m.p. 73-75°C, pK s =7.45.

2-(2,3-Dimethyl-4-phenoxyphenyl)propionic acid, m.p. 100-101°C. 2-(2-Fluoro-4-phenoxyphenyl)propionic acid, m.p. 92-94°C. 2-(3-Methoxy-4-phenoxyphenyl)propionic acid, m.p. 242-250°c/ 0.08 mm Hg.

Example 37.

Preparation of ethyl 2-(3-phenoxyphenyl)acetate.

Dry HCl gas was bubbled through a solution of 257 g of 2-(3-phenoxyphenyl)acetic acid, prepared by the method according to example 1, in 1500 ml of ethanol until it was saturated. The solution was refluxed with stirring for 3 hours and again saturated with HCl gas. The solution was refluxed overnight. After cooling, the reaction mixture was partially evaporated in vacuo and then poured into ice water. The oily product was extracted into ether. The ether solution was washed with water and 5% sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the ether in vacuo and distillation of the oily residue gave 256 g of ethyl 2-(3-phenoxyphenyl)acetate, b.p. 140-146°C/L0.1 mm Hg, n^<3>,<5> = 1.5520.

Example 38.

Preparation of diethyl 2-methyl-2-(3-phenoxyphenyl)malonate.

A mixture of 128 g of ethyl 2-(3-phenoxyphenyl)acetate and 300 ml of diethyl carbonate was stirred and heated to approx. 110°C while 11.5 g of sodium metal was added in pea-sized lumps over 1 1/2 hours. Some ethanol and diethyl carbonate distilled off from the reaction mixture during the sodium addition. When the sodium addition was complete, the reaction temperature was raised until the vapor temperature above the reaction mixture had reached 130°C. The reaction mixture was cooled to 15°C in an ice bath, and 60 ml of methyl iodide was added dropwise over 1/4 hour. The reaction mixture was heated to 80°C for 1 hour. After cooling, some water was added, and the injection mixture was poured into ice water and acidified with HCl and extracted with ether. The ether extract was dried over sodium sulfate and evaporated in vacuo. The remaining liquid was distilled through a 15 cm Vigreux column to give 100.2 g of diethyl 2-methyl-2-(3-phenoxyphenyl)malonate, m.p. 155-175°c/ 10.1 mm Hg, n^<3>,<5> = 1.5337.

Example 39

Preparation of 2-methyl-2-(3-phenoxyphenyl)malonic acid.

A solution of 57 g of diethyl 2-methyl-2-(3-phenoxyphenyl)-malonate and 40 g of sodium hydroxide in 300 ml of 50% (v/v) aqueous ethanol was stirred and refluxed overnight. The reaction mixture was poured into ice water and washed with ether to remove unhydrolyzed ester. The aqueous layer was acidified with concentrated HCl and extracted with ether. The ether extract was dried over sodium sulfate and evaporated in vacuo to give 44 g of 2-methyl-2-(3-phenoxyphenyl)malonic acid, m.p. 138-143°C, decomposition by evolution of gas.

Example 40

Preparation of 2-(3-phenoxyphenyl)propionic acid.

15 g of 2-methyl-2-(3-phenoxyphenyl)malonic acid, prepared according to Example 39, was heated to 130-160 C and stirred until the vigorous CO 2 evolution had ceased. After cooling to room temperature, 12.2 g of 2-(3-phenoxyphenyl)propionic acid were obtained, 24 rip = 1.5729, whose NMR spectrum was identical to the material prepared in example 9.

ANTI-INFLAMMATORY ACTIVITY

A modification of Winder et al. (1958) method [Winder, C.V., Wax, J., Burr, V. and Posiere, C.E.: "A Study of Pharmacological Influences on Ultraviolet Erythema in Guinea Pigs", Arch. Int. Pharmacodyn., 116, 261, 1958] was used to measure the anti-inflammatory activity of a number of compounds prepared according to the invention. In the following table, the oral ED5C 0 for the prevention of erythema is indicated in mg compound per kg. body weight.

Claims (1)

Analogy method for the production of therapeutically active phenylalkanoic acids of the general formula and the pharmaceutically acceptable acid addition salts of the compounds which are basic; where and Y 2 are the same or different and mean hydrogen, halogen, methyl, ethyl or - C 1 -C 6 -alkyloxy, since both Y^ and Y^ cannot be hydrogen when is hydrogen or methyl and the group is in paraposition, R is hydrogen or lower alkyl, n is 0 or 1, and Z is A) -COOR 2 , where R 2 is hydrogen, lower alkyl, an alkali metal, an equivalent of an alkaline earth metal or an ammonium group, , where each R^ is the same or different and is hydrogen, hydroxy, lower alkyl or -CH2-COOH, or C) OR^, where R^ is hydrogen or lower alkanoyl, in racemic, d- or l-form, characterized by , when Z must be COOH, a) hydrolysis of a nitrile with the formula where Ar in the above formula and in the following means the group from formula I; b) alkylation of an acid of the formula Ar-CH2"COOH to form a compound of formula I where n is 0; c) decarboxylation of a dicarboxylic acid of the formula: to form a compound of formula I wherein n is 0; d) heating a ketone of the formula: with s/ovel and morpholine and hydrolysis of the resulting thioamide to form a compound of formula wherein R, is hydrogen; or e) reaction of an aldehyde or ketone with the formula: with triethylphosphonoacetate, catalytic hydrogenation of the product thus formed, and hydrolysis of the resulting ester to form an acid where n is 1; and optionally reacting the formed acid or acid halide thereof with an alcohol of the formula R2OH, or optionally reacting the product obtained with a base containing an alkali metal, alkaline earth metal or ammonium cation, or optionally, reaction of the obtained acid or an acid halide thereof with an amine of the formula (R^) or optionally, reduction of the obtained acid or an ester thereof to form a compound where Z is OH, or optionally, reaction of the obtained ester with hydroxylamine, or optionally, reduction of the obtained acid or an ester thereof and reaction of the resulting alcohol with the acid anhydride or halide of a lower alkanoic acid, and/or converting the product into an acid addition salt, and possibly cleavage of a racemic product into its optical antipodes.