GB2055363A

GB2055363A - Alkanoic acid derivatives

Info

Publication number: GB2055363A
Application number: GB8019834A
Authority: GB
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1979-06-18
Filing date: 1980-06-17
Publication date: 1981-03-04
Also published as: DE3022599A1; JPS5639039A; PT71405A; FR2459219B1; IT1128163B; IT8048996A0; IT8048995A0; GR68764B; PT71405B; CH646935A5; ES492556A0; GB2055363B; IT1143921B; FR2459219A1; US4362891A; ES8105254A1

Description

1

GB 2 055 363 A

1

SPECIFICATION Alkanoic acid derivatives

5 This invention relates to alkanoic acid derivatives more particularly to a 2 - (4 - alkenylphenyl) alkanoic acid compound its salts and esters, processes for their preparation and their uses.

A class of compounds consisting of phenyl alkane 10 derivatives is known to have therapeutic properties. This class of compounds includes within its scope, inter alia, compounds of the general formula (I)

OH

15

r1

f

$ ^—CH—X

(I)

20 wherein R1 represents ethyl, propyl, butyl, alkenyl (C2-C4), pentyl (except/7-pentyl), alkoxy (C2-C3), allyloxy, phenoxy, phenylthio orcycloalkyl (Cs-C7) optionally substituted by methyl or ethyl in the 1 -position, Rz represents hydrogen or methyl and X 25 represents the radical COOH, COOR3 wherein R3 represents alkyl (Ct-Cs) or optionally N-alkylated aminoalkyl (C2-C8), COOM wherein M represents the ammonium ion or a single equivalent of a non-toxic metallic cation, COOH.B wherein B represents a 30 non-toxic organic base, CONH2, CH2NH2 orthe group CH2OR4 where R4 represents hydrogen or lower alkanoyl (C1-c3).

These phenyl alkane derivatives are known to have anti-inflammatory activity.

35 We have now found a compound which falls within this class of phenyl alkane derivatives which has surprisingly good therapeutic properties and, in particular, good anti-inflammatory activity as well as marked antipyretic and analgesic activity.

40 Thus, the present invention provides 2 - (4 -

dimethylvinylphenyl) propionic acid of formula (II):

45

ch3

(ch3)2c=ch (; ')—ch—cooh

(I)

50 and its physiologically acceptable "salts" (as herein defined) and "esters" (as herein defined).

The physiologically acceptable "salts" are defined herein as the alkali and alkaline earth metal salts, particularly the sodium and calcium salts and the 55 lysine, arginine and N-methyl-glucamine salts.

The physiologically acceptable "esters" are defined herein as the C^ alkyl esters, particularly methyl or ethyl, or a C2._5 alkanoyloxy methyl ester such as pivaloyloxy methyl oracetoxymethyl. 60 Preferred compounds according to the invention are the free acid of formula II, the calcium salt and the DL-lysine salt.

The acid of formula (II) and esters thereof may be prepared by dehydration of the compound of for-65 mula (III):

ch3

(ch3)2ch—ch—k /)—ch—coor

70 (EI)

wherein R represents a hydrogen atom or a C,-C4 alkyl group or an alkanoyloxymethyl group.

The dehydration may conveniently be effected 75 using p-toluene sulphonic acid or a derivative thereof, for example, p-toluene sulphonyl chloride or sulphuric acid in a high boiling, inert solvent such as toluene or halobenzenes for example dichloroben-zene, at elevated temperature.

80 In a modification of this process, the compound of general formula (III) in which R = H, may be dehydrated as just described but with the addition of a CrC4 alkanol, for example methanol or ethanol, to produce an ester of the general formula (IV):

85

ch3

(ch3)2c=ch—f \>—ch—coor

90

(ed where R is a C,-C4 alkyl group.

The ester (IV) can be hydrolysed by conventional techniques to produce the acid (II). For example, the ester (IV) may be treated with a base, for example, 95 sodium or potassium hydroxide, preferably at an elevated temperature.

The compounds of general formula (III) used as intermediate forthe preparation of the compounds of formula (II) may be produced by reduction of the 100 isobutyryl compound of formula (V):

105

(ch3)2ch (3d

O '

ch3

chcoor where R is as previously defined followed by hydrolysis where appropriate.

The reduction may be performed with a reducing 110 agent, such as sodium borohydride, or by catalytic hydrogenation for example using platinum, palladium or Raney nickel.

The 2 - (4 - isobutyrylphenyl) propionic acid starting material of formula (V) in which R = H may be 115 prepared by reacting a 4 - isobutyrylhalobenzene of general formula (VI):

120

(ch3)2chco-(3ze)

jT\

•x where X is a halogen atom, e.g. fluorine, with a dialkylmethylmalonate of general formula (VII):

125

130

coor5

J

ch-ch3

I

coor5

(VII)

2

GB 2 055 363 A

2

where Rs is a C,-C6 alkyl group.

The malonate of general formula (VII) may be reacted in the form of an alkali metal salt, preferably the sodium salt.

5 This reaction is followed by hydrolysis and decarboxylation where necessary. Hydrolysis may be carried out under alkaline conditions followed by acidification or under acidic conditions.

Another possibility of preparing the compound of 10 formula (III) is to hydrolyse with a base such as sodium hydroxide the product of the reaction of a compound of formula (VI) with a compound of formula (VII) followed by reduction of the basic hydrolysis product in the presence of a reducing agent 15 preferably sodium borohydride, or by catalytic hyd-rogenation for example using platinum palladium or Raney nickel.

The 4 - isobutyrylhalobenzene of general formula (VI) may be prepared, for example, by a conventional 20 Friedel-Crafts reaction between an isobutyrylhafide and a halobenzene in the presence of, for example, aluminium trichloride.

The physiologically acceptable salts and esters of the compound of formula (II) may be prepared by 25 conventional methods from the acid of formula (II). Thus salts may be prepared by treating the acid of formula II with a suitable base in the presence of a solvent such as water or aqueous acetone or water and an alkanol e.g. ethanol. Alkyl esters may be pre-30 pared from the reaction of the acid with a CTC4

alkanol in the presence of a suitable acid catalyst e.g. concentrated sulphuric acid or a sulphonic acid e.g. p-toluene sulphonic acid.

Alternatively esters may be prepared by treating a 35 salt of the acid (II) with an appropriate alkyl halide or alkanoyloxymethyl halide in a suitable solvent e.g. toluene.

The compound of formula II (and its "salts" (as herein defined) and "esters" (as herein defined) 40 have an anti-inflammatory activity which is unexpectedly greaterthan that of its nearest known analogues belonging to the class of phenyl alkane derivatives referred to above, namely 2 - (4 -isobutylphenyl) propionic acid (ibuprofen) and 2 - (4 45 - methylvinylphenyl) propionic acid. The free acid also has an unexpectedly higher antipyretic and analgesic activity than the latter compound.

The following tests were performed to determine the anti-inflammatory activity of the compound (II). 50 1. Carrageenan induced edema in the rat

A modification of the method described by C. A. Winter et al. (Proc. Soc. Exp. Biol. Med., 111,544, 1962) was followed, using groups of female CD-COBS rats Charles River) of 150-170 g. 55 The compounds, suspended in 0.5% gum acacia, were orally administered in a fixed volume of 10 ml/KG. One hour laterthe inflammation was induced injecting 0.1 ml of a 1% suspension of carrageenan in 0.9 NaCI solution into the subplantar tissue of the 60 right hindpaw of each rat. The paw volume was measured by means of a mercury displacement device supplied by U. Basile (Milano) at 0 time and again 3 hours afterthe carrageenan injection.

Edema volume was calculated as the difference 65 between the paw volume after and before the induction of inflammation.

Percentage inhibition of the edema was calculated for each group as compared with control groups and statistical analysis was performed by means of the 70 Dunnetttest.

2. Freund adjuvant arthritis

Adjuvant arthritis (Pearson, C. M., Proc. Soc. Exp. Biol. Med., 91,95,1956) was induced in female rats weighing 150-175 g by intradermal injection into the 75 tail of 0.1 ml of a fine suspension of Mycobacterium butyricum in liquid paraffin (Smg/ml).

After 14 days animals were chosen on the basis of their arthritic score and groups of 5 rats were made. Test compounds, suspended in gum acacia, were 80 orallyadministered once a day for 14 days; at the end ofthis period animals were scored again and percentage inhibition versus first score was calculated. Comparisons with controls were performed by the Dunnetttest.

85 Analgesic activity was determined by the Randall-Selitto test.

In this test analgesic activity in rats was evaluated applying to the inflammed paw an increasing pressure (Randall, L. O., Selitto, J. J., Arch. int. Phar-90 macodyn., 111,409,1957) and recording pain threshold by means of an analgesimeter. Groups of 6 female CD-COBS rats were used for the experiment. Drugs were administered orally two hours afterthe injection of 0.1 ml of a 7.5% suspension of 95 brewer's yeast into the plantartissue of the right hind paw. Pain threshold was measured immediately before treatment and again two hours later and results were expressed as pain threshold increase in comparison with a control group. (Dunnetttest). 100 Antipyretic activity was determined bythe Yeast induced pyrexia test in rats.

This test w°as performed according to the method of Niemegeersefa/: (Arzneim. Forsch.,25,10,1519, 1975), using female CD-COBS rats (Charles River, 105 Italy) of 150-160 g. Pyrexia was induced injecting 15 ml/kg of a 20% brewer's yeast suspension sub-cutaneously in rats fasted overnight. The animals were moved into the laboratory one day before the experiment in orderto maintain their body tempera-110 ture constant. On the day of the experiment only aminals whose esophageal temperature ranged between 35.5°C and 37°C were used. 4 hours after the injection of the brewer's yeast rats with a temperature 3=37.5°C were chosen and split into groups of 115 7. Suspensions of the test compound were then administered by gavage and the esophageal temperature was recorded 1,2,3 and 24hours after treatment. Results were expressed as "temperature index" which was obtained calculating the total area 120 lying between the temperature curves and a baseline value, corresponding to 36.5°C. Comparisons with controls were performed by the Dannett test.

The following results obtained are shown in Tables I and II, the compounds being identified as 125 follows:

1. 2 - (4 -dimethylvinylphenyl) propionic acid (compound of invention)

2. 2 - (4 - methylvinylphenyl) propionic acid

3. Ibuprofen.

3

GB 2 055 363 A

3

TABLE 1

1

2

3

Activity and Test

Oral dose mg kg-1

% inhibition

Oral dose mg Kg"1

% inhibition

Oral dose mg Kg-1

% inhibition

ANTIINFLAMMATORY Rat carrag-ceenan

Rat adjuvant arthritis

3

30

9

16

3

16

9

35

9

13

25

23

TABLE 2

1

2

Activity and Test

Oral dose mg Kg"1

% inhibition

Oral dose mg Kg-1

% inhibition

ANALGESIC Randall Selitto Test

25 50

3Sa) 7Sa)

25 50

2fa)

28fa)

ANTIPYRETIC

Brewer

Yeast pyrexia-rat

5.00

42

5

13

(a) = % pain threshold increase

Tests performed using the Sodium, Calcium, L-and DL-lysine, L- and DL-arginine and N-methyl - D -glucamine salts and methyl, ethyl and pivaloylox-ymethyl esters established that these have a level of 5 anti-inflammatory activity which issimilartothatof the compound (II) itself.

The invention also provides a pharmaceutical composition comprising 2 - (4-dimethylvinylphenyl) propionic acid and/or a physiologically acceptable 10 salt or ester thereof together with a physiologically acceptable carrier or excipient.

The compounds according to the invention may be formulated in conventional manner for administration by any convenient route for example, fororal, 15 rectal, topical, intravenous and intramuscular administration.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions 20 prepared by conventional means with physiologically acceptable excipents. We have found that the physiologically acceptable salts of the compound (II) are soluble in water and hence particularly useful for the preparation of compositions for oral administra-25 tion.

The compounds of the invention may be formulated for rectal administration for example, in the form of suppositories using a conventional sup-

poritory excipent. The compositions may also take 30 such forms as creams, ointments and lotions for topical administrations.

Physiologically acceptable salts may be formulated for intravenous or intramuscular administration in dry form for reconstitution before use, or as a 35 sterile solution.

A proposed daily dose for administration to man is 100 mg to 1.6 g e.g. 500 mg to 1 g which may be conveniently administered in two orthree doses per day.

40 The invention is further illustrated by the following Examples. All temperatures are in °C. The abbreviation DMF is used for dimethyl formamide. All melting points given are uncorrected.

Example 1

45 2-(4- Dimethylvinylphenyl) propionic acid a) Anhydrous aluminium trichloride (44 g) was slowly added to a stirred solution of fluorobenzene (84.1 g) and isobutyrylchloride (23.4 g) over a period of 30 minutes at a temperature of 10°to 15°. The 50 reaction mixture was refluxed for 3 hours and, after cooling, poured into an ice/concentrated hydrochloric acid mixture. The mass was vigorously stirred and extracted twice with 200 ml portions of ether.

The collected ethereal extracts were washed with 55 two 150 ml portions of a 10% solution of NaOH,then with water and subsequently dried over Na2S04. The

4

GB 2 055 363 A

4

solvent was evaporated and the residue was distilled under reduced pressure to give 4 -fluoroisobutyryl-benzene (31.5 g) b.p. 55-56°C (4-5 mm). Chemical and structural analyses were consistent with the 5 formula of this product.

b) Freshly distilled diethylmethylmalonate (62.84 g) was added dropwise to a stirred mixture of sodium hydride (8.86 g) and anhydrous DMF (500 ml) under a slight flow of nitrogen at room tempera-

10 ture.

The mixture was stirred for 30 minutes and treated dropwise with 4 -fluoroisobutyrylbenzene (30.4 g). The gaseous flow was stopped and the reaction mixture heated at 115°to 120° for 24 hours. After evap-15 oration of most of the DMF the residue was treated with water (500 ml) and extracted with three 200 ml portions of ether. The combined ethereal extracts were washed twice with 200 ml portions of water and subsequently dried over Na2S04. 20 Evaporation of the solvent gave a yellow oily mass which was distilled under reduced pressure (39-42°C, 5mm) to leave an oily residue.

c) The above residue (34 g) was mixed with a solution of NaOH (8 g) in 1:1 methanol : water (140 ml) at

25 room temperature. The stirred solution was heated at 45° to 55° for six hours. After removing methanol (60 ml approx) by evaporation, the cooled mixture was treated with water (200 ml) and extracted twice with 200 ml portion of ether. The aqueous phase was 30 acidified with concentrated hydrochloric acid and again extracted twice with 200 ml portions of ether. The last collected ethereal extracts were dried over Na2S04 and evaporated to give pure 2 - (4 -isobutyrylphenyl) - propionic acid (21.4 g). The melt-35 ing point after recrystallisation from ether-ligroin was 78-80°.

Found: C%70.75 (Calc. 70.88); H%7.36 (7.32)

d) 2 - (4 - Isobutyrylphenyl) propionic acid (14.4 g) was mixed with a 3% solution of NaOH (320 ml) at

40 room temperature and stirred for 20 minutes until dissolution had ocurred, then treated with sodium borohydride (2.6 g) and stirred again for 2 hours. The mixture was extracted twice with 150 ml portions of ether and the aqueous phase was cooled to 0.5°. It 45 was cautiously acidified with dilute hydrochloric acid and again extracted with three 150 ml portions of ether. The collected ethereal extracts were dried over Na2S04 and evaporated under reduced pressure. The residue was further dried at 60° in a vac-50 uum oven for two hours to give a product (14.4 g). Crystallisation from ethyl acetate gave 2 -[4 - (1 -hydroxy - 2 - dimethylethyl) phenyl] propionic acid as a white solid m.p. 99-101°.

e) A solution of p -toluenesulphonic acid monohy-55 drate (8.4 g) in o - dichlorobenzene (60 ml) was heated at 110° to 120° and treated dropwise with a previously prepared solution of 2 -[4 - (1 - hydroxy -2 - dimethylethyl) phenyl] propionic acid (9g)ino -dichlorobenzene (40 ml) over a period of 20 minutes 60 at the same temperature. The reaction mixture was rapidly cooled to room temperature, poured into water and extracted several times with ether. The combined ethereal extracts were washed with water and then treated with a 5% solution of NaOH. The 65 separated aqueous phase was acidified with a 10%

solution of hydrochloric acid and extracted again with ether and the organic phase was separated.

The solvent was removed to give an oily product which was crystallised from ligroin to give the title 70 compound (3.5 g) m.p. 53-54°.

The residual ligroin solution was chromatog-raphed on an inactivated (10% water) silica gel column (450 g) using a 1,1,1 -trichloroethane/ether/ methanol mixture (10:3:1) an eluantto give a further 75 3.5 g of the pure title compound.

Found C% 76.43 (Calc. 76.44); H% 7.88 (7.90). Example 2

Sodium 2-(4- dimethylvinylphenyl) propionate Stoichiometric amounts of 2 - (4 - dimethylvinyl-80 phenyl) propionic acid and 1N aqueous sodium hydroxide were stirred at room temperature for 30 minutes. The mixture was washed with 2 x 50 ml portions of ether and the aqueous solution evaporated to dryness to give the title compound as a 85 white solid, m.p. 166-168°. I.R. C= 0 stretch 1550-1560 cm"1.

Example 3

Calcium -2-[4- dimethylvinylphenyl)propionate Calcium (0.34 g) in 30 ml of anhydrous ethanol 90 was added to a stirred solution of 2 - (4 - dimethylvinylphenyl) propionic acid (4g) in 50 ml of ethanol at room temperature. After refluxing for 1 hour, the clear reaction mixture was cooled and maintained at 0° for 10 hours. The title salt was collected by suction 95 filtration and dried under reduced pressure to yield a white crystalline solid (3.85 g) m.p. 120-122°. I.R. C = 0 stretch 1550 -1560 cm-1.

Example 4

2-(4- Dimethylvinylphenyl) propionic acid, D,L-100 lysine salt.

A solution of DL-lysine (7.17 g) in 30 ml water was added to a solution of 2 - (4-dimethylvinylphenyl) propionic acid (10 g) in ethanol (100 ml) at room temperature. The reaction mixture was refluxed for 2 105 hours, cooled and treated with activated charcoal until clear. The solvent was partially removed under vacuum and the title salt precipitated by addition of acetone, to give a crystalline powder (12.7 g) which was dried at 50° in a vacuum stove for 2 hours, m.p. 110 175-177°.

The experiment was repeated using L-lysine in place of D, L-lysine to obtain the L-lysine salt, m.p. 154-158°. I. R. Both salts showed the disappearance of the characteristics NH stretching band of the free 115 NH2 group at 3350 cm-1.

Example 5

2-(4- Dimethylvinylphenyl) propionic acid, D, L-arginine salt A saturated solution of DL-arginine (4.26 g) in 120 water was added to a stirred solution of 2 - (4 -

dimethylvinylphenyl) propionic acid (5 g) in acetone (20 ml) and water (5 ml). After stirring for 1 hour at room temperature the solvent was removed and the residue crystallized from acetoneethanol to yield the 125 title compound (8.25 g) m.p. 168-189°C.

The experiment was repeated using L-arginine in place of D, L-arginine to yield the L-arginine salt as an amorphous solid, m.p. 105-107° I.R. Both salts showed the disappearance of the characteristic NH 130 stretching band of the free NH2 group at 3350cm"1.

5

GB 2 055 363 A

5

Example 6

2-(4- Dimethylvinylphenyl) propionic acid, N -methyl -D- glucamine salt

A solution of 2 - (4-dimethylvinylphenyl) prop-5 ionic acid (3 g)and N - methyl - D-glucamine (2.86 g) in anhydrous ethyl alcohol (35 ml) was refluxed for 1 hour. The solvent was partially removed under vacuum and the title salt precipitated by addition of acetone to yield a crystalline product (3 g) which was 10 dried at 50° in a vacuum stove for 1 hour. m.p. 128-130°C I. R. C = 0 stretch 1550 -1560 cm-1. Example 7

2 -(4- Dimethylvinylphenyl) propionic acid a) Freshly distilled diethylmethylmalonate (80 ml) 15 was added dropwise to a stirred mixture of sodium hydride (13.4 g) and anhydrous DMF (170 ml) under a slight flow of nitrogen at room temperature. The mixture was stirred for 30 minutes and treated dropwise with 4 -fluoroisobutyrylbenzene (58 g) 20 prepared as in Example I.The gaseous flow was stopped and the reaction mixture heated at 118-120° for 24 hours. After evaporation of most of the DMF, the residue was treated with water (100 ml) and then evaporated to remove all the DMF. The residue was 25 hydrolysed with a solution of NaOH (40.5 g) in water (1.1 1)and methanol (200 ml), and the resulting mixture boiled and stirred for 5 hours and then concentrated by evaporation of 360 ml of solvent.

The aqueous solution was then extracted twice 30 with 120 ml portions of methylene chloride. A freshly prepared solution of sodium borohydride in 2%

NaOH was added dropwise over 30 minutes to the aqueous solution at room temperature and stirred for 2 hours. It was cautiously acidified with concen-35 trated hydrochloric acid (130 ml) and then concentrated to half volume.

A solution of 10N NaOH was added to reach a pH value of about 6 and the mixture extracted with ethyl acetate (3 x 200 ml). Evaporation of the solvent gave 40 51 g of crude 2-[4 - (1 - hydroxy-2-dimethylethyl) phenyl] propionic acid.

b) A solution of the acid (51 g) prepared in (a) in anhydrous methanol (160 ml) was added dropwise to a boiling solution ofp -toluenesulphonic acid (27

45 g)ino -dichlorobenzene (400ml)and methanol (160 ml.). The methanol was distilled off and the solution was heated for 45 minutes at 110°. The reaction mixture was rapidly cooled to room temperature and treated with solution of NaHC03 (35 g) in water (400 50 ml).

The upper phase was separated and the water phase was extracted twice with methylene chloride (50 ml x 2).

The combined organic phases were washed with 55 water and after evaporation of the solvent the residue was distilled under reduced pressure (105°; 0.6 mm) to yield 35 g. of the title compound, methyl ester.

A solution of NaOH (10 g) in methanol (ml 150) and 60 water (370 ml) was added to the ester and the resulting mixture was boiled for 3 hours. The methanol was evaporated, the cooled mixture was extracted with methylene chloride, and the separated water phase acidified with dilute HC1 until pH 3 and then 65 extracted with methylene chloride (4 x 100 ml). After evaporation of the organic phase the residue was crystallised from ligroin to give the title compound (25 g) m.p. 55-56°.

Example 8

70 2-(4- Dimethylvinylphenyl) propionic acid, ethyl ester

A solution of 2 - (4 - dimethylvinylphenyl) propionic acid (11.5 g) in anhydrous ethanol (250 ml) and 2.5 ml 98% H2S04 was refluxed for 4 hours. After 75 cooling the solvent was removed and the oily residue was treated with a saturated NaHC03 solution, extracted with two 100 ml portions of ether and dried over Na2S04. Evaporation of the solvent gave a white oil which was dried at 40° in a vacuum stove 80 for 3 hours to yield the title ester (12.5 g)as an oily product. Found: C%75.65 (Calc75.44); H%8.26 (8.42).

Example 9

2-(4- Dimethylvinylphenyl) propionic acid, methyl 85 ester

The title compound was prepared according to the method of Example 8 except that methanol, not ethanol, was reacted with the starting acid to yield an oily product. Found: C% 76.87 (Calc. 77.03); H% 90 8.22(8.31).

Example 70

2-(4- Dimethylvinylphenyl) propionic acid, pivaloyloxymethyl ester

A solution of sodium 2 - (4 - dimethylvinylphenyl) 95 propionate (3 g) and chloro-methyl pivalate (3.9 g) in toluene (50 ml) was refluxed for 6 hours. After cooling, 50 ml of ethyl ether were added and the mixture was washed with 10% NaHC03. The solvent was removed, and the residue dried at 60°for 3 hours in a 100 vacuum stove to yield the title ester as an oily product (2 g). Found: C%71.5 (Calc. 71.66); H%8.2 (8.23). PHARMACEUTICAL EXAMPLES:

TABLETS mgltablet

(i)

105 Active ingredient 250.0

Lactose 101.9

Maize Starch 49.5

Pregelatinised Maize Starch 27.0

Polyvinyl Pyrrolidone 3.6

110 Sodium Carboxymethylcellulose 13.5

Colloidal Silicon dioxide 4.5

Weight

450.0

115

(ii)

Active ingredient Microcrystalline cellulose Colloidal Silicon dioxide 120 Magnesium Stearate

CAPSULES 125 Active ingredient

Microcrystalline cellulose Colloidal Silicon dioxide Magnesium Stearate

130

Weight

Fill Weight

250.0 93.0 3.5 3.5

350.0

mglcapsule 250.0 93.0 3.5 3.5

350.0

6

GB 2 055 363 A

6

SUPPOSITORIES Active ingredient Suppository base*

mg/suppository 500.0 2500.0

5 Weight 3000.0

* Any conventional base may be used INJECTIONS Active ingredient 200 mg Water for injections B.P. to 2 ml.

10 Sodium chloride may be added to adjust the tonicity of the solution.

The active ingredient in each of the above examples is 2 - (4 - dimethylvinylphenyl) propionic acid. CLAIMS

15 1. 2-(4-Dimethylvinylphenyl) propionic acid of formula (II):

ch3

20

(ch3 )2 c=ch —ch—cooh

(I)

and its physiologically acceptable "salts" (as herein defined) and "esters" (as herein defined).

25 2. 2 - (4-Dimethylvinylphenyl) propionic acid.

3. A compound according to claim 1, which is the calcium or DL-lysine salt.

4. A process forthe preparation of 2 - (4 -dimethylvinylphenyl) - propionic acid of formula II as

30 defined in claim 1 or a physiologically acceptable "ester" (as herein defined) thereof which comprises dehydrating a compound of general formula (III):

oh

35 (ch3)2ch—ch' (H)

40

45

ch3 /=\ |

h—ch—coor wherein R is a hydrogen atom or a C,-C4 alkyl group or an alkanoyloxymethyl group, and if desired, converting the resulting acid of formula (II) to a physiologically acceptable "salt" (as herein defined) thereof.

5. A process forthe preparation of a compound according to claim 1, which comprises dehydrating a compound of formula (III), as defined in claim 2 where R is a hydrogen atom, in the presence of C,-C4 alkanol to produce an ester of formula (IV):

defined) thereof together with a physiologically acceptable carrier or excipient.

7. A pharmaceutical composition according to claim 6, formulated for oral administration.

8. A pharmaceutical composition according to claim 6 or 7 in unit dosage form and containing from about 30 mg to about 800 mg of active ingredient.

Printed for Her Majesty's Stationery Office byTheTweeddale Press Ltd., Berwick-upon-Tweed, 1981.

Published at the Patent Office, 25 Southampton^ Buildings, London, WC2A1AY, from which copies may be obtained.

50

55

60

65

ch3

ch—coor ced where R is a C,-C4 alkyl group if desired, hydrolysing the resulting ester (IV) to form the compound of formula (II) and, if desired converting the compound of formula (II) to a physiologically acceptable "salt" (as herein defined (thereof.

6. A pharmaceutical composition which comprises as active ingredient 2 - (4 - dimethylvinylphenyl) propionic acid and/or a physiologically acceptable "salt" (as herein defined) thereof and/or a physiologically acceptable "ester" (as herein