NO132989B - - Google Patents

Description

This invention relates to a process for the preparation of new 2-(substituted phenyl)-propionic acids and salts, esters, amides and alcohols derived therefrom which have been found to possess valuable biological properties.

According to the invention, a method for the production of compounds with the general formula is thus provided

IN

where

R is halogen;

R 2 and R are each selected from hydrogen and halogen, wherein

at least one of which is hydrogen;

Y is COOH; ^GONH or CH 2 OH;

and pharmaceutically acceptable esters, inorganic salts and organic salts of de^or compounds where Y is COOH.

Similar 2-(substituted phenyl)-propionic acid derivatives are produced according to our Norwegian patent no. 131.50 7.

In the following description, the symbol RQ shall mean

According to the invention, the new compounds are produced as follows:

Acids

1. Hydrolysis of Rq

Z, where Z is cyano, carbamoyl,

or CO0R4 where R4 is an ester-forming group, especially lower alkyl.

The hydrolysis can be carried out by methods well known in the art, e.g. by using acid or alkali in water, in an organic, liquid reaction medium or in a mixture thereof, and a treatment temperature of 15-150°C is appropriate. Preferably, the hydrolysis is carried out by reflux treatment in the presence of an alkali metal hydroxide or of a mineral acid, and the organic, liquid reaction medium is a lower alkanol.

The starting materials can e.g. are prepared from the substituted acetophenones R^^-CO-CH^ in the usual way, and other methods

includes the methods described below under "esters" and

"amides".

2. Decarboxylation of Rq

This can be done by heating the compound with

about. 200°C.

The starting materials can be suitably produced on

usual way, e.g. by reacting an alkyl ester of an acid R -

CH-COOH with an alkyl carbonyl and an alkali metal alkoxide to give

an alkali metal derivative of a compound of the formula RQ-CH=C00alkyl)^,

methylation of this and hydrolysis of the product.

3. Oxidation of

The oxidation can be carried out using any suitable oxidizing agent1 such as permanganates, chromic acid, dichromates, peracids, hydrogen peroxide, nitric acid, hypochlorites, silver oxide or oxygen. A very suitable method involves oxidation in aqueous ethanol with alkali (eg an alkali metal hydroxide) and silver oxide.

The starting materials can be prepared by the methods described for related compounds in our British

patent 1,160,725.

4. Hydrogenation of

Typical methods include hydrogenation over a common catalyst such as e.g. palladium, palladium oxide or platinum in an inert solvent such as a lower alkanol, benzene, toluene, xylene, tetrahydrofuran, dioxane and acetic acid, at a temperature of about 0 C up to the return temperature of the system.

The starting materials can be produced in the usual way such as

e.g. according to the following reaction scheme:

5. Using the Ullmann reaction: i.e.

where one of the groups A and B is OH and the other is halogen. Preferably, A is OH and B is halogen. This reaction is normally carried out by heating a metal derivative (e.g. an alkali metal derivative, especially a potassium derivative) of the hydroxy compound with the halogen compound (especially an iodine or bromine compound) at 100-350°C in the presence of a metal catalyst, especially copper powder or copper --bronze.

6. Hydrolysis., of

wherein "alkyl" is preferably methyl. Typical hydrolysis conditions are described under method (1).

The starting materials can be prepared using methods similar to those described by Meyers and Temple. Esters

1. Esterification of the acids in the usual way, e.g. -

2. Using methods (4) and (5) as described under "acids", but starting with the desired ester instead of the acid. 3. By alcoholysis of the oxazolidines described under "acids" (6).

Amides

3. Using method (4) as described under "acids" but by starting with the amide instead of the acid.

Salts

1. Reaction of the acids with organic or inorganic bases. 2. Alkaline hydrolysis of

Alcohols

1. Reduction of the acids or preferably of the esters (especially the alkyl esters). Use of lithium aluminum hydride in a suitable solvent, e.g. ether, followed by acidification, is an example. Alternatively, hydrogenation in the presence of a copper/chromium oxide catalyst can be used. Esters can be reduced with sodium in a lower alkanol.

2. Using method (5) described under "acids", med

by starting with a protected alcohol instead of the acid.

the hole can be protected by means of a conventional, easily removable group, e.g. benzyl, which is removed after the first synthesis steps.

The compounds of the general formula I are in possession

of anti-inflammatory action and are useful in the treatment of inflammatory disorders. They also have analgesic and anti-pyretic properties and are useful in the treatment of pain conditions and pyretic conditions. They are useful in treating these three conditions individually or in any combination. A particularly notable and important feature of the compounds is their long-lasting effect. This feature allows

that a relatively high blood level is achieved for a long period after administration of a single dose (as long as approx. 24 hours in many cases), in contrast to short-acting compounds, e.g. 2-(4-isobutylphenyl)propionic acid, with which there is no significant amount of the compound in the blood after only a short time after administration of a single dose, e.g. 3-6 hours for 2-(4-isobutyl-phenyDpropionic acid. The compounds prepared according to the invention therefore only need to be administered once or sometimes twice, per day, while the short-acting compounds require administration at least three times and often four times per day.

The activity of the new compounds produced according to the invention has been determined on experimental animals using pharmacological tests which are known to be able to characterize compounds that have aspirin's therapeutic properties, namely anti-inflammatory, analgesic and antipyretic activity. Long- . lasting effect is confirmed by blood count-forsdk.

A preferred group of compounds are also those where Y is COOH. It is believed that when the salts, esters,. the amides and alcohols derived from these acids are used instead of the acids, these derivatives are metabolized in the body and converted there into the corresponding acids. One of the best methods for demonstrating the long-term anti-inflammatory effect of compounds is by means of the rat adjuvant arthritis test, in which compounds are administered chronically.

Hielpstoffartritt - phoeven

Groups of 6 CSE male common-strain rats, each with a yeké of 120-150 g, were given a. intradermal injection into the tail of 0.1 ml of a fine suspension in liquid paraffin B.P., of dead tubercle bacilli derived from human strains PN, DT and C (6 mg/ml. The test compounds were administered orally, suspended in an acacia matrix. Control animals received only acacia. Dosing was continued for 3 weeks after which the degree of arthritis in each hind paw was assessed by a trained observer and given a grading of 0 - 4,

the maximum grading for each rat being thus 8. Different doses were given in increasing amounts, each dose being three times greater than the previous dose, and the maximum dose being 27 mg of agent per kg animals. In this way, the ED^0 for each compound could be determined. The ED50 is the dose of a compound which reduces the arthritis by half compared to the controls. When ED^0 is expressed as a range of doses, the lower dose has reduced the arthritis by less than half and the upper dose has reduced the arthritis by more than half. ED50v^

then be between these two doses. When ED^Q is indicated as above

27 mg/kg,, this means that a half reduction of the arthritis does not

was achieved with the relevant connection.

The acute, non-steroidal, anti-inflammatory activity of the test compounds was determined using the sample with erythema "induced by ultra-violet light..

Ultraviolet light called erythema test

The test was carried out by the method according to Adams and Cobb, - Nature -, 1958, 181, 773. Female marsvih (Tuck strain) weighing 500-900 g: were fasted overnight, and on an area of the back the hairs were removed on the morning of the test. The animals were dosed with the compounds under test or with aspirin, which was used as the standard agent; and' 30 minutes later, eri portion of the 'area from which the hairs had been removed was exposed for 20 seconds to ultra-violet radiation from a Hanovia "Kromåyer" lamp, which was placed directly on the skin.

Two hours later, the degree of erythema (redness) was assessed visually bg

given a rating of 0, 1, 2, 3 or 4 by a trained observer who was unaware of the dosing schedule. Sufficient numbers of guinea pigs were used for each dose level and for the aspirin standards to ensure reproducibility of our results.

The results obtained with each compound under test are compared with aspirin which was examined at the same time/ whereby the activity of the compound expressed as the activity of aspirin can be calculated.

The following examples shall serve to further illustrate the invention.

Example 1

Ethyl 2-[4-(4-fluorophenoxy)phenyl]-2-methylmalonate (19.6 g)

was refluxed for 1 hour with a mixture of 2.5N aqueous sodium hydroxide (114 ml) and ethanol (57 ml). After cooling and acidifying with 5N hydrochloric acid, the resulting oil was extracted into ether. The extract was washed with water, dried, and the ether was distilled. The residue of impure 2-[4-(4-fluorophenoxy)phenyl] -2-methylmalonic acid was decarboxylated by heating for 20 minutes at 220° C. The product was recrystallized several times from benzene/

petroleum ether k.p. 62-68°c to give 2-[4-(4-fluorophenoxy)phenyl]propionic acid., m.p. 84-86°C.

The starting material was prepared as follows: An Ullmann reaction using p-fluorophenol and p-bromoacetophenone gave 41 - (4-fluorophenoxy)acetophenone, m.p. 65-67°C. This compound was subjected to the Willgerodt reaction using morpholine-cg sulfur, followed by hydrolysis, to give impure 4-(4-fluorophenoxy)-phenylacetic acid, which was esterified to give ethyl 4-(4-fluorophenoxy)-phenylacetate, m.p. 139-142°c/0.3 mm Hg. This ester was treated conventionally with diethyl carbonate and sodium ethoxide and then with dimethyl sulfate to give the desired ethyl 2-[4-(4-fluorophenoxy)-phenyl]-2-methylmalonate, m.p. 174-182°C/0.7 mm Hg..

Example 2

Ethyl 2-[4-(4-chlorophenoxy)phenyl]-2-methylmalonate (b.p. 186-187°C/0.3 mm Hg) was treated by the procedure of Example 1 to give 2-[4-(4- chlorophenoxy)phenyl]propionic acid, m.p. 105-107°C.

The starting material was prepared by the method according to example 1 from 4'-(4-chlorophenoxy)acetophenone (C.A., 62, 14581) via ethyl 4-(4-chlorophenoxy)phenylacetate, b.p. 167-168°C/0.4 mm Hg.

Example 3

Potassium hydroxide (3.4 g) was melted at 180°C with water

(1 mL), and 2,4-difluorophenol (5.2 g) was added. 2-(4-iodophenyl)-v propionic acid (5.5 g) and copper bronze (0.2 g) were then added to the melt, and the resulting mixture was stirred at 160-170°C for 2 hours. The cooled solid was extracted with methylene chloride containing some dilute hydrochloric acid, filtered, and the solution was extracted with dilute potassium carbonate solution. The aqueous extract was washed with ether and acidified with dilute hydrochloric acid, the resulting oil was isolated in ether and evaporated to dryness. The resulting solid was purified by preparative thin layer chromatography using 5% acetic acid/petroleum ether, b.p. 62-68°c and elution with ethyl acetate. Recrystallization from petroleum ether b.p. 80-100°C gave 2-1 4-r(2,4-difluorophenoxy)phenyl]-propionic acid, m.p. 105-106°C.

Example 4

The following compounds were prepared by Ullmann-

the reaction in a similar way as described in example 3: 2-14-(2,4-dichlorophenoxy)phenyl]propionic acid, m.p. 77-80 C. 2-[4-(4-chloro-2-fluorophenoxy)phenyl]propionic acid, m.p. 80-83 C. 2-[4-(4-fluorophenoxy)phenyl]propionic acid, m.p. 84-86C.

Example

Ethyl 3-chloro-4-(4-fluorophenoxy)phenyl-2-methylmalonate

(b.p. 198-202°C/1.2 mm Hg) was treated by the method of Example 1 to give 2-[3-chloro-4-(4-fluorophenoxy)phenyl]propionic acid,

sm.p. 59-61°C.

The starting material was prepared by the method according to example 1 from p-fluorophenol and 4'-bromo-3'-nitroacetophenone via 4'-(4-fluorophenoxy)-3'-nitroacetophenone, m.p. 96-98°C, 3'-amino-4'-(4-fluorophenoxy)acetophenone, m.p. 83-85°C, 3'-chloro-4'-(4-fluorophenoxy)-acetophenone, m.p. 68-70°C and ethyl-3-chloro-4-(4-fluorophenoxy)phenyl-

acetate, b.p. 171-174°c/0.8 mm Hg. 4'-bromo-3'-nitroacetophenone,

sm.p. 114-116°C was prepared by nitration of 4'-bromoacetophenone.

Example 6

2-[4-(4-fluorophenoxy)phenyl]propionic acid (2.32 g) in ethanol

(16 mL) containing concentrated sulfuric acid (0.5 mL) was refluxed for 5 h, and the alcohol was removed. After pre-

dilution with water, the product was isolated in ether and distilled to

give ethyl 2-[4-(4-fluorophenoxy)-phenylJpropionate, m.p.<j>169-171°C/2 mm Hg.

Example 7

Ethyl 2-[4-(4-fluorophenoxy)phenyl]propionate (1.3 g) in dry

ether (5 mL) was added dropwise to lithium aluminum hydride (200 mg) in dry ether (5 mL). After refluxing for 1 hour, excess hydride was cleaved with dilute sulfuric acid, and the ether layer was distilled to give -,-2^ [4-(4-fluorophenoxy)phenyl]propanol,

k.p. 151-152°C/0.6 mm Hg.

Example 8

A mixture of 2-[4-(2,4-difluorophenoxy)phenyl]propionic acid

(2 g) and thionyl chloride (10 ml) were refluxed for 10

minutes. Excess thionyl chloride was distilled, and the residue in ether (10 ml) was added dropwise to ammonium hydroxide (b.p. 0.88,

20 ml) chilled in ice. After 15 minutes, the ether layer was separated and evaporated. The resulting solid was purified by preparative layer chromatography using 5% acetic acid/toluene and eluting with ethyl acetate. Recrystallization from petroleum ether b.p. 100-120°c gave 2-[4-(2,4-difluorophenoxy)phenyl]propionamide/ m.p. 10 7-110°C.

Example 9

2-[4-(4-chlorophenoxy)phenyl]propionic acid (740mg) and ben zvi-amine (300mg) were mixed in ether. The precipitated solid was recrystallized from alcohol/ether to give the benzylamine salt of 2-[4-(4-chlorophenoxy)phenylpropionic acid, m.p. 138-139°c. Example lo

2-[4-(4-chlorophenoxy)phenyl]propionamide (1.0 g), water

(7 ml) and caustic soda (1 ml 18N) were refluxed with stirring for 24 hours. The solution was cooled, acidified with dilute hydrochloric acid, and the acid was isolated in ether and extracted into 2.5% potassium carbonate solution. The alkaline extracts were acidified with dilute hydrochloric acid, the acid was isolated again in ether, washed with water, dried and evaporated to dryness. The residue was recrystallized from light petrol (boiling point 80-100°C). Yield 0.644 g (64%), m.p. 109-110°C.

Example n

Methyl 2-[4-(4-chlorophenoxy)phenyl]propionate (1.2 g), sodium hydroxide (10 ml 2.5N) and 95% ethanol (5 ml) were refluxed for 1 hour. Alcohol was distilled off under reduced pressure, and the residue was acidified with dilute hydrochloric acid, the precipitate was isolated in ether, washed with water, dried and evaporated to dryness. The residue was recrystallized from light petrol (boiling point 80-100°C). The product was 2-[4-(4-chlorophenoxy)"phenylpropionic acid. Yield 0.85 g m.p. 104-106°C.

Example 12

2-[4-(4-chlorophenoxy)phenyl]propionitrile (310 mg), water

(7 ml) and caustic soda (1 ml 18N) were refluxed and stirred for 24 hours. The solution was cooled, acidified with dilute hydrochloric acid, the acid was isolated in ether and extracted into 2.5% potassium carbonate solution. The alkaline solution was acidified with dilute hydrochloric acid, and the acid was isolated again in ether,

washed with water, dried, evaporated to dryness and recrystallized from light petrol (boiling point 80-100°c). Yield 163 mg (48%)/sm.p. 107-109°C. The product was 2-[4-(4-chloropyroxy)phenyl]-propionic acid.

Example 13

Silver nitrate (6.8 g) in water (8 ml) was stirred and treated dropwise with a mixture of potassium hydroxide (3.04 ml 13.2N) and water (7.3 ml). The slurry was diluted with 9 mL of 95% ethanol and a solution of 2-[4-(4-chlorophenoxy)phenyl]-propionaldehyde (5.0 g) in 17 mL of 95% ethanol, and washing was done by slowly adding 95% ethanol (8 ml). The temperature reached 40°C. After stirring for 15 minutes, potassium hydroxide (1.8 ml 13.2N) and water (1.8 ml) were added over 1 hour. while the temperature was maintained at 43-45°C. The mixture was then stirred at 40°C for 30 minutes, the silver was collected and washed well with water. Ethanol was removed from the filtrate by distillation under reduced pressure, and the residue was acidified with dilute hydrochloric acid. The product was isolated in ether, extracted with 5% sodium carbonate solution, and the combined extracts were washed with ether, acidified with dilute hydrochloric acid, isolated again in ether, washed with water, dried and evaporated to dryness and recrystallized from light gasoline (boiling point 80-100 <o>C): The product was 2-[4-(4-chlorophenoxy)phenyl]propionic acid. Yield 3.29 g (62%), m.p. 98-105°C.

Example 14

A solution of 2-[4-(4-chlorophenoxy)phenyl]acrylic acid (400 mg) in ethyl acetate (25 ml) was hydrogenated at room temperature over 10% palladium on charcoal (100 mg). The theoretical amount of hydrogen (35 ml) was taken up immediately and the solution was then filtered fc>g. evaporated to give the crude propionic acid (390 mg); Recrystallization from gasoline with a boiling point of 80-100°C gave'^40 mg of small colorless needles (97% yield) of m.p. 102-104°C. The product was 2-[4-(4-chlorophenoxy)phenyl]propionic acid.

Example 15

2-[1-(4-(4•-chlorophenoxy)phenyl)ethyl]-4,4-dimethyl-2-oxazoline (0.95 g) and 3N hydrochloric acid (8 ml) were heated on a steam bath for 2 hours . The reaction mixture was extracted with ether, and

acidic material was isolated by extraction with 5% potassium carbonate solution. Acidification with dilute hydrochloric acid and isolation again with ether gave, after evaporation, a solid residue of 2-[4-(4-chlorophenoxy)phenylpropionic acid which was recrystallized from light petrol (boiling point 80-100°C). Yield 0.476 g (60%),

sm.p. 108-111°C.

Claims (1)

Analogous process for the preparation of therapeutically active compounds of the general formula I where is halogen; R 2 and R 1 are each selected from hydrogen and halogen, at least one of which is hydrogen; Y is COOH, C0NH2 or CH2OH, and the pharmaceutically acceptable esters, inorganic salts and organic salts of the compounds of formula i where Y is COOH, characterized by (1) hydrolysis of a compound of the general formula II where z is cyano, carbamoyl or COOR^ where R4 is an ester-forming group, or (2) decarboxylation of a compound of the general formula III or .(3) oxidation of a compound of the general formula V (4) hydrogenation of a compound of the general formula VII -' or an ester or an amide thereof, or (5) reaction of a compound of the general formula IX with a compound of the general formula x or an ester or alcohol derived therefrom, in which formulas one of the groups A and B (preferably A) is OH and the other (preferably B) is halogen, or (6) hydrolysis or alcoholysis of a connection with .-- the general formula XIII whereR^, fc^ ^6#-'R^i ;j,f6) "hair the -i • irigrefs seni angi ete ber interpretation, v after which the. compounds of formula I where Y is COOH are optionally converted to esters of variable n >^te^v or ..'/ \ possibly dmdaTiries to salts in ordinary mhjte, or optionally converted to dé"'-corresponding alcohols where Y is CH2OH by reduction in the usual way, or of" e-ve-niuelt omdaJinés":: .tili.de corresponding-; -amides* whbV Y is CONH2 by transfer of the acid to acid halide and conversion with ammonia, or byjhydrolysis of the corresponding hytril.