LU85138A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING CAMPHO-METHYLIDENE CINNAMIC ACID DERIVATIVES - Google Patents

Description

t * 1 1

Pharmaceutical compositions containing derivatives of cinnamic csapho-methylidene acid.

; The present invention relates to the use, as medicaments, of derivatives of csmpho-methylidene cinnamic acid.

The Applicant has indeed discovered that certain derivatives of camphoromethylidene cinnamic acid have enhanced activity in the topical and systemic treatment of acne, psoriasis and other dermatoses or dermatological, inflammatory and allergic conditions as well! 10 than antitumor activity.

| The subject of the invention is therefore a pharmaceutical composition containing, as active ingredient, a compound having the formula:

Pb ®l> n (îÇ— in which:! R ^ denotes a linear or branched C 1 -C 4 alkyl radical or a C 1 -C 4 alkoxy radical, n being an integer ranging from 0 to 4; when n is equal to or greater than 2, the radicals R ^ may be the same or different; R ^ denotes a hydrogen atom, a C 1 -C 4 alkyl radical, an aryl radical optionally substituted by atoms of halogen or by R, C 1 -C 4 alkyl or alkoxy groups, a radical -CH, -COOR 4 or -CO-N 4 1> Xp7 | 'and R 4 denotes a radical -COOR 4, -C0- N / -CHOj-CHCORg) ^ or -Cf ^ OR ^; ! · ‘Nr7 î R ^ and R,., Identical or different, being alkyl, alkenyl, cycloalkyl or aralkyl radicals containing at most 20 carbon atoms, optionally-

Only substituted with hvdroxv, alkoxy, amine or quaternary ammonium groups,

Rg and R ^, identical or different, denoting a hydrogen atom or alkyl, alkenyl, cycloalkyl or aralkyl radicals containing a maximum of 35 carbon atoms, optionally substituted by hydroxyl, alkoxy, amine or quaternary ammonium groups; p? |: r> î

U

/ 2 ♦ *

Rg denotes a hydrogen atom or an alkyl, cycloalkyl or aralkyl radical containing at most 20 carbon atoms; or else when denotes a hydrogen atom, an alkyl radical or an optionally substituted aryl radical, R ^ may represent a radical 5 or M is a hydrogen jitome, an alkali metal or the group ^ (Rg) ^ "R8 denoting hydrogen or a C 1 -C 4 alkyl or hydroxyalkyl group; the two radicals -CH = and camphor methylidene being in the para or meta position relative to each other on the aromatic nucleus, in a non-toxic support or excipient.

Among the preferred radicals R ^, R,., R ^, R ^ and R ^, mention may be made of methyl, ethyl, propyl, butyl, hexyl, 2-ethylhexyl, menthyl, oleyl, benzyl, p-methoxy benzyl radicals. A preferred aryl radical for R 1 is the phenyl radical.

In general, the compounds of formula (I) can be prepared by known methods, consisting in condensing malonic acid or one of its derivatives on an aromatic aldehyde according to the following reaction scheme: CH3 (R1) n x1 ““ -J] -CHO + CH £ - ^ 25 CH3 (Rl) n

dx - X

n, R ^, R3 and R3 having the above meanings.

The compounds of formula (I) more particularly used in the pharmaceutical composition of the invention are the following compounds (1) to (16): "/ m Ji i; ; I i * m m i co r- ~ ÎbO bt „^ n co ττ1 σ 'a) οι' -

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The procedures (A) to (N) used for the preparations of the compounds (1) to (16) are explained below.

Procedure A

In a flask fitted with 250 ml, place: 5 22 g of malonic acid 40 ml of dry pyridine

The mixture is stirred until complete dissolution. 1 ml of pipiridine is then added, then 27 g of 4'-formyl-3-benzylidlne camphor and the whole is gradually heated to 110 ° C. There is a gas evolution which stops after approximately 1 hour 30 of heating.

The solution is then cooled and acidified by adding 100 ml of 6N hydrochloric acid. The precipitate formed is filtered, washed with water until neutral, dried under vacuum.

30 g of compound (1) are obtained (yield = 96%)

15 Procedure B

In a 1-liter flask, 69 g of 2-ethyl hexyl malonate 2 ml of pipiridine 500 ml of 20 'ethanol 54 g of 4'-formyl-3-henzylidene camphor are placed.

The mixture is heated at reflux for 24 hours. An additional 2 ml of piperidine is then added and the mixture is brought to reflux for 6 hours.

The solution is cooled and concentrated in vacuo. The residue is taken up. in 500 ml of toluene. The organic phase is washed several times with water, dried and concentrated in vacuo.

The oil obtained is chromatographed on silica (eluent: acetone / hexane (1/9).

55 g of compound (2) are obtained (yield: 47%).

To prepare compounds (4) and (7), the 2-30 ethylhexyl malonate is replaced, respectively, with ethyl malonate and men-thyl malonate.

7

Procedure C

In a 250 ml equipped flask, place: 10.6 ml of ethyl cyanoacetate 150 ml of absolute ethanol and 5 1.5 g of potassium fluoride as catalyst.

To this mixture is added in small portions, 27 g of 4’-formyl-3 ben-zylidene camphor. The reaction mixture becomes pasty, 125 ml of absolute ethanol are then introduced and the mixture is left to stir at 50 ° C. for 1 hour.

The mixture is cooled and the precipitate is drained, washed with 200 ml of etha-1q nol then 200 ml of water and finally dried under vacuum.

32.7 g of compound (3) are obtained (yield: 90%).

To obtain compound (6), the ethyl cyanoacetate is replaced by 2'-ethylhexyl cyanoacetate.

Procedure D

15 In a 2-liter equipped reactor, place: 56 g of p- (2-oxo 3-bornylidene methyl) cinnamic acid (compound 1) 27 g of butanol 800 ml of dry benzene and 4 ml of concentrated sulfuric acid .

The mixture is heated at reflux for 4 hours, separating the water formed using a Dean-Stark apparatus.

The solution is then cooled and then washed with water, dried and evaporated to dryness.

The residue is recrystallized from ethanol.

25 g of compound (5) are obtained (yield = 76%).

Procedure E

. In a 500 ml equipped reactor, place: 31 g of p- (2-oxo 3-bornylidene methyl) cinnamic acid (compound 1) 200 ml of dry toluene and 24 g of thionyl chloride.

The mixture is brought to reflux for 2 hours. The excess thionyl chloride is removed and the toluene is distilled under vacuum.

The residue is recrystallized from a 40/60 toluene-hexane mixture.

After drying, 26 g of p- (2-oxo 3-borny-35 lidene methyl) cinnamic acid chloride are obtained (yield = 80%).

where kr

i Operating mode F

I In a fitted 250 ml talion, place ï

I 10 g of acid chloride obtained in E

I 3.9 g of 2-ethyl hexylamine 15 4.2 ml of triethylamine and 100 ml of methylene chloride.

The mixture is brought to reflux for 2 hours. After cooling, * the organic phase is washed with water, dried, filtered and concentrated to dryness.

The oily residue is dried under vacuum to give an amorphous solid.

• jq 12.2 g of compound (8) are thus obtained (yield = 96%).

Operating mode G

In a 100 ml equipped flask, place: 4.15 g of p-methoxybenzyl alcohol, 20 ml of pyridine 15 and 9.9 g of acid chloride obtained at E are introduced in small portions, at room temperature.

I The reaction is slightly exothermic.

At the end of the addition, the mixture is brought to 70cC for 1 hour.

After cooling, the solution is then poured into a mixture of 20,200 ml of ice and 30 ml of concentrated hydrochloric acid.

The precipitate formed is filtered, washed with water and recrystallized from the Acetone. 6.8 g of compound (9) are obtained (yield = 52%).

Procedure H

I. In a 2 liter reactor equipped, place: 25 300 ml of dry benzene [200 ml of dry toluene 228 g of oleic alcohol 13.2 ml of concentrated sulfuric acid then 45 g of p- (2-oxo acid Cinnamic 3-bornylidene methyl) (compound 1).

The mixture is heated at reflux for 5 hours, separating the water formed using a Dean Stark apparatus.

The solution is then cooled and then washed with water, dried and evaporated to dryness. The residue is distilled under 0.1 mmHg at 160-174 ° C to remove excess oleic alcohol. The expected ester is isolated by column chromatography in the presence of silica gel and choroform (10 1 CHCl 2 + 2 kg of silica gel).

D 9

The chloroform part containing the p- (2-cxo-3-bornyli-methylene) oleyl cinnamate is concentrated and 40 g of compound (10) are obtained (yield 40%).

Procedure I

K - - - - îj ^ Heated for 2 hours at 180-190 ° C a mixture containing 17.4 g (0.1

Imole) of potassium phenylacetate, 5 g (0.035 mole) of potassium carbonate, 0.5 ml of pyridine, 26.8 g (0.1 mole) of 4'-formyl-3-benzylidene camphor and 15.3 g (0.15 mole) acetic anhydride. A nitrogen flow is maintained during the heating time.

After cooling, 300 ml of ice are added and then 50 ml of 6N potassium hydroxide. Extraction is carried out with 50 ml of ether, then the aqueous phase is acidified. The precipitate is recrystallized from 100 ml of 50% ethyl alcohol. 15.2 g of compound (11) are obtained.

Operating mode J

In a flask fitted with a Dean Stark, a solution of 7.72 g (0.02 mol) of the compound (11) obtained according to procedure I, 5 ml of hexanol, 50 ml of reflux is heated. toluene and 3 drops of concentrated sulfuric acid, d: · After 3 hours at reflux, the reaction mixture is concentrated. The i; I residue is recrystallized from ethanol. 5.9 g of pale yellow product (12) are obtained.

Operating mode K

To a 250 ml flask are added 5 ml (10 ^ mole) of ethyl 2-ethylphos-phono-propionate, 5.4 g of 4'-formyl 3-benzylidene camphor (2.10 ^. Mole), 40 ml of '' a saturated solution of potassium carbonate and 40 ml of water. After 24 hours of vigorous stirring at room temperature, extraction is carried out with 3 times 50 ml of toluene. The organic phase is washed with water, distilled! lees, dried and then evaporated to yield 8 g of a yellowish oil which crystallizes when cold. Recrystallization from bexane is carried out, which leads to 5.2 g of white crystals of the compound (13).

30 Operating mode L

In a 100 ml flask, 1 g of pulverized potassium hydroxide is placed in suspension in 30 ml of dioxane. A solution of 1.12 g (5.10 mole) of ethyl diethylphosphonoacetate and -3 1.34 g of 3'-formyl 3-benzylidene camphor (5.10 mole) in 30 ml is added dropwise. dioxane. After 1 hour of stirring, the reaction mixture is diluted with 40 ml of S 10 toluene. After filtration and evaporation of the solvents, an oil is obtained which crystallizes when cold. After recrystallization from hexane, a product is obtained which melts at 85.5 ° C (14).

Operating mode M

3 5 Cooled to -30 ° C under argon 250 cm of ether. 3.8 g of lithium aluminum hydride are added. 33.8 g of 4 ′ - / 2-ethoxycarbonyl-trans-ethen7-yl-trans-benzylidene-camphor obtained according to procedure D are slowly added at this temperature, replacing butanol with ethanol. The reaction mixture is allowed to slowly return to room temperature, then

J

10 100 μl of ethyl acetate is added. We dilute with water and filter on icëlite. The organic phase is decanted and the solvent is distilled under reduced pressure.

3

The residue is dissolved in 160 cm of ether. This solution is added to a suspension of 50 g of activated manganese dioxide in 160 cm of hexane.

The mixture is stirred for two hours at room temperature and then filtered. The solvent is evaporated. The product is purified by chromatography on Ijj gel. silica using a toluene-ethyl acetate 95: 5 mixture as solvent,

Then recrystallized from isopropyl ether (compound 15).

Procedure E

• 3 3 20 To a boiling solution of 0.3 cm of 30% sodium hydroxide in 10 cm of methanol, a hot solution of 8 g of 4'-formyl-3 3 3-benzylidene-camphor and 10 is added dropwise. cm of propane in 70 cm of methanol. The mixture is heated under reflux for 1 hour, then cooled and the reaction mixture is poured into water. After extraction with ether and evaporation, 3.7 g of pale yellow crystals of compound (16) are obtained by recrystallization from isopropyl ether.

The alcohols of formula (I) in which R ^ denotes -C ^ OH can be obtained, for example by reduction of the corresponding aldehydes in which R ^ denotes -CHO.

The acetals of formula (I) in which R ^ denotes -CHiOR ^^ are derived from aldehydes by adding thereto alkanols, cycloalkanols or aralkyl alcohols in an acid medium. They can also be obtained by adding aldehydes to the alcohols of formula (I) in which R ^ denotes in an acid medium.

if I * 11 *

The ethers of formula (I) in which R ^ denotes -CI ^ ORg are obtained (from the alcohols of formula (I) in which R ^ denotes -CH ^ OH per% action of an alkyl halide, of cycloalkyl or aralkyl.

"Tests carried out on rats and mice have made it possible to demonstrate the very low toxicity of the compounds according to the invention, the oral LD50 of which is generally greater than 3 g / kg.

The compounds of formula (I) have an activity in the topical and systemic treatment of benign or malignant neoplasias, premalignant lesions as well as in the systemic and topical prophylaxis of these affections.

! 10 They are also suitable for the treatment of dermatoses such as acne or psoriasis. They can also be used orally to treat certain rheumatic conditions such as for example chronic arthritis.

The compounds of formula (I) are generally administered orally at a daily dose of about 2 pg to 5 mg per kg, and preferably from 10 µg to 2 mg per kg.

As a support for the pharmaceutical composition of the invention, any conventional non-toxic excipient can be used, the active compound being either in the soluble state or in the state dispersed in the support.

The excipients can consist of organic or mineral substances, for example water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, alkanols, glycols, polyalkylene glycols, oils, waxes, fatty acid esters, etc.

The administration can be carried out by enteral, parenteral or topical route. Via the enteral route, medicines can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions or suppositories. Parenterally, the compositions may be in the form of solutions for infusion or for injection.

30 Topically, the pharmaceutical compositions based on the compounds according to the invention are in the form of ointments, tinctures, creams, solutions, lotions, gels, sprays or even suspensions.

The topical compositions preferably contain from 0.0005¾ to about 5% by weight of compound according to the invention.

it {12 I ·

These topical compositions can be in anhydrous form or in aqueous form depending on the clinical indication and can contain other ingredients, in particular anti-oxidant agents.

The pharmaceutical compositions according to the invention are illustrated by the following nonlimiting examples.

EXAMPLE 1 Capsule

0.3 g of powder having the following composition is used:

Para- (2-oxo-3-hornylidene methyl) cinnamic acid 50 mg 1q Corn starch 0.06 g

Lactose q.s.p. 0.3 g

The powder is packaged in a capsule composed of gelatin, "titanium dioxide and a preservative.

These capsules are administered orally at the rate of 2 to 3 capsules / 15 days for the treatment of dermatoses.

Example 2

Ointment

An ointment for topical administration has the following composition: Butyl ester of para- (2-oxo 3-bornylidene methyl) cinnamic acid 1 g

Vaseline 49 g Ceresin 15 g

Vaseline oil 35 g

This ointment is used for the treatment of acne.

Claims (8)

13 1. Pharmaceutical composition characterized by the fact that it contains, as active ingredient, a derivative of cinnamic campho-methylidene acid of formula: !! 5 CH3 (Vn - I -f-CH = CC ^ CI) νΛ -— "X / I 3 H TO in which: R ^ denotes a C ^ -C ^ alkyl radical, linear or branched or a Cj alkoxy radical -C ^, n being an integer ranging from 0 to 4; when n is equal to or greater than 2, the radicals may be the same or different; denotes a hydrogen atom, a C 1 -C 4 alkyl radical, a radical 15 aryl optionally substituted by halogen atoms or by R. / 6 alkyl or C 1 -C 4 alkoxy groups, a CN-radical, -COOR 4 or -CO-N 3N 6 R 7 and R3 denotes a radical -COOR ^, -CO-N "', -CHO, -CHCORg) ^ or-C ^ OR ^; R7 R ^ and R, -, identical or different, being alkyl, alkenyl, cycloalkyl or aralkyl radicals containing at most 20 carbon atoms, optionally substituted by hydroxy, alkoxy, amine or quaternary ammonium groups, R and R, identical or different, denoting a hydrogen atom or _ 6 7. alkyl, alkenyl, cycloalkyl or aralkyl radicals containing at most I 20 carbon atoms, optionally substituted by hydroxy, alkoxy, amine or quaternary ammonium groups; 3Q Rg denotes a hydrogen atom or an alkyl, cycloalkyl or aralkyl radical containing at most 20 carbon atoms; or when R2 denotes a hydrogen atom, an alkyl radical or an optionally substituted aryl radical, Rg can represent a COif'li 'radical ^ where M is a hydrogen atom, an alkali metal or the group ^ (Rg) ^, Rg 55 denoting hydrogen or a C 1 -C 4 alkyl or hydroxyalkyl group; ji j 14! R2 the two radicals -CH = C and methylidene camphor being in: ’^ * 3 para or meta position relative to each other on the aromatic nucleus, in a non-toxic support or excipient. 2. Pharmaceutical composition according to claim 1, characterized in that it contains, as active ingredient, a compound of formula ï ICH3 W, in which n = 0 and the group -CH = is eïl position 15 meta and denotes - CH = CH - C02 ethyl or in the para position and denotes: H j; - ch = c; - ^ co2h C02 - 2-ethylhexyl - CH = C ^ C02 - 2-ethylhexyl CN 25 CH = C; C0 „-ethyl” J- C 0 2 ~ é thy 1 e -CH = 30 ^ '' "'" CO ^ ethyl -ch = cb-co2 (ch2) 3-ch3 i If 1 * I 15 ♦ ^^ CN -CH = C ^ C02—2 — é thj'lh exyl e S ___- C02-menthyl -CH = CC ^ C02-Eîenthyle -CH = CH-C0NH-2-éthyIhexyle 10 -ch = ch-co2-ch2 —— och3 -ch = ch-co2- (CH2) g-CH = CH- (CH2) 7-CH3 ^ CO „H 15 2 -CH = ^^ phenyl l ^ -C02C6H13 -CH = ^" "- phenyl 20 C02“ ethyl -CH - h ^ ch3 -CH "CH - CHO 25 ch3 d -CH" 3. Pharmaceutical composition according to claim 1, characterized by; 30 the fact that it contains para- (2-oxo 3-bornylidene methyl) cinnamic acid as an active ingredient. 4. Pharmaceutical composition according to claim 1, characterized in that it contains, as active ingredient, the butyl ester of para (2-oxo 3-bornylidene methyl) cinnamic acid. / il il i 16 ♦ i i 5. Pharmaceutical composition for the treatment and prophylaxis of neoplasias and of dermatological and rheumatic affections, characterized in that it contains, as active ingredient, a campho-methylidene cinnamic acid derivative of formula (I) according to the claim 1, in a non-toxic carrier or excipient. 6. Pharmaceutical composition for the treatment and propylaxis of neoplasias and dermatological and rheumatic diseases, characterized in that it contains, as active ingredient, a camphomethylidene cinnamic acid derivative according to claim 2 in a non-toxic carrier or excipient. 7. Pharmaceutical composition for the treatment and prophylaxis of | neoplasias and dermatological and rheumatic diseases, characterized in that it contains, as active ingredient, para- (2-oxo 3-bornylidene methyl) cinnamic acid, in a non-toxic carrier or excipient. 8. Pharmaceutical composition for the treatment and prophylaxis of neoplasias and dermatological and rheumatic diseases characterized in that it contains, as active ingredient, the butyl ester of para- (2-oxo-3 acid) -bornylidene methyl) cinnamic in a support or - non-toxic excipient. Drawings: ......... * £ 1 boards _ / S ^ psgss including ....... 4 ....... pa? E ce cçs ^ ds. l · .. y ce c cc.ription ..... 4 · of claim. A description i Luxsîr.br-vr b U B & ts *. '·· I 0. imm V i E I iJt i t t * ί i i a «fdie Alain, / ^ / ks / fina,. û VjM