AU651216B2 - Use of 9, 12, 15-octadecatriene-6-ynoic acid - Google Patents

Use of 9, 12, 15-octadecatriene-6-ynoic acid Download PDF

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AU651216B2
AU651216B2 AU18459/92A AU1845992A AU651216B2 AU 651216 B2 AU651216 B2 AU 651216B2 AU 18459/92 A AU18459/92 A AU 18459/92A AU 1845992 A AU1845992 A AU 1845992A AU 651216 B2 AU651216 B2 AU 651216B2
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dicranine
octadecatriene
ynoic acid
acid
treatment
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AU1845992A (en
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Christian Borel
Michel Guichardant
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Societe des Produits Nestle SA
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Societe des Produits Nestle SA
Nestle SA
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

1 651216
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ft
S*
*r
ORIGINAL
/c Name of Applicant: Actual Inventors: Address for Service: Invention Title: SOCIETE DES PRODUITS NESTLE S.A.
Christian Borel and Michel Guichardant SHELSTON WATERS 55 Clarence Street SYDNEY NSW 2000 "USE OF 9, 12, 15-OCTADECATRIENE-6-YNOIC ACID"
C
a. ab The following statement is a full description of this invention, including the best method of performing it known to us:- This invention relates to the use of 9(Z),12(Z),15(Z)octadecatriene-6-ynoic acid which will be referred to hereinafter as "dicranine".
Dicranine is a polyunsaturated fatty acid of which the methyl ester can be extracted from the moss Ceratodon purpureus, as shown in the Article by J. Gellerman et al.
published in Biochemistry (1977), Vol. 16, 7, 1258-1262.
It has surprisingly been found that dicranine has therapeutic properties, more particularly anti-aggregating and anti-inflammatory properties and also anti-bacterial properties.
Accordingly, the present invention relates to the use of dicranine as a therapeutically active substance. More particularly, the present invention relates to the use of 15 dicranine as an anti-aggregating, anti-inflammatory and anti-bacterial agent.
The present invention also relates to a pharmaceutical composition containing dicranine as its therapeutically active substance in conjunction with a pharmaceutically 20 inert excipient.
The pharmaceutical composition according to the invention may be formulated, for example, as an injectable solution or as tablets.
The present invention also relates to a cosmetic 25 composition containing dicranine.
The cosmetic composition according to the invention may be formulated, for example, as a cream, ointment or lotion.
The present invention is illustrated by the following Examples in which the following abbreviations are used: 13-IIODE 13-hydroxyoctadecadienoic acid 12-HETE 13-hydroxyeicosatetraenoic acid 5-HETE 5-hydroxyeicosatetraenoic acid HHT 12-hydroxyheptadecatrienoic acid 12-HPETE 12-hydroperoxyeicosatetraenoic acid
LTB
4 (5S,12R)-5,12-dihydroxy-6,14-cis-8,10-transeicosatetraenoic acid
PGG
2 15-hydroperoxy-9a,lla-peroxidoprosta-5,13dienoic acid
PGH
2 15-hydroxy-9a,lla-peroxidoprosta-5,13dienoic acid.
Example 1 describes a process for the synthesis of dicranine.
Examples 2 to 6 demonstrate the anti-inflammatory, anti-aggregating and anti-bacterial properties of dicranine.
*"Example 1 a) 50 mg Fe(N0 3 3 and 10.9 g metallic sodium are added to 15 200 ml liquid NH 3 After stirring for 1 hour at ambient temperature, ml propargyloxytetrahydropyran are added dropwise. After stirring for another hour, 30 ml ethyl iodide are added.
Stirring is continued for 12 hours to allow the ammonia to 20 escape. Sulfuric acid is then added to a pH value of approximately 4, after which the mixture is extracted with ether.
The ether phase is recovered and the solvent is evaporated. The residue is dissolved in 50 ml methanol, 25 10 ml 25% sulfuric acid is added to the resulting solution and, after stirring for 1 hour, the mixture is diluted with water. The diluted mixture is then extracted with ether.
The ether phase is recovered and dried over magnesium sulfate, after which the solvent is evaporated under reduced pressure. The residue is distilled and 22 g 2pentine-l-ol are obtained.
b) 0.5 ml pyridine is added to a solution of 10.5 g 2pentine-l-ol in 150 ml ether, after which 4.2 ml phosphorus tribromide are added dropwise.
The mixture is heated under reflux for 3 hours, after which ice is added.
The mixture is then extracted with ether. The ether phase is washed with a potassium carbonate solution and dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is distilled and 9.75 g l-bromo-2-pentyne are obtained.
c) 25.5 g ethyl bromide are added with stirring to a solution of 100 ml THF containing 5.0 g magnesium.
The mixture is cooled to 0°C and a solution of 6.0 g propargyl alcohol in 10 ml tetrahydrofuran (THF) is gently added.
The mixture is stirred for 2 hours at 20°C and then 15 cooled to 0°C. 0.5 g cuprous chloride and a solution of 9.7 g l-bromo-2-pentyne in 15 ml THF are then added in that order. The mixture is heated under reflux for 19 hours, after which an excess of cuprous chloride is added and heating is continued for 5 hours. A mixture of ice and 20 sulfuric acid is then added and the resulting mixture is extracted with ether. The ether phase is washed with a potassium carbonate solution and dried over magnesium sulfate and the solvent is removed under reduced pressure.
The residue is distilled and 6.8 g 2,5-octadiyne-l-ol are 25 obtained.
d) 6.5 g 2,5-octadiyne-l-ol and 2 ml phosphorus tribromide in 75 ml ether are reacted in the same way as described in b) to obtain 6.3 g e) 3.6 ml propargyl alcohol and 6.0 g diyne are added to 9.6 ml ethyl bromide and 2.8 g magnesium in 50 ml THF in the same way as described in c).
4.5 g 2,5,8-undecatriyne-l-ol are obtained in the form 4 of a white solid.
f) 0.5 ml pyridine and 1.0 g Lindlar catalyst are added to a solution of 2.0 g 2,5,8-undecatriyne-l-ol in ml ethyl acetate. The mixture is placed under hydrogen at 1 bar for 24 hours.
The catalyst is recovered by filtration and the solvent is evaporated under reduced pressure.
Distillation of the residue gives 0.8 g 2,5,8-undecatriene-l-ol.
g) A mixture of 0.8 g 2,5,8-undecatriene-l-ol and 0.3 ml phosphorus tribromide in 20 ml ether is heated under reflux for 30 minutes in the same way as described in 15 Distillation gives 0.52 g l-bromo-2,5,8-undecatriene.
h) Bromine is added a solution of 5.0 g 6-heptenoic acid in 70 ml ether to obtain the dibrominated compound 20 (verified by NMR).
A solution of 5 g sodium in 150 ml liquid NH3 is added to this mixture which is then stirred for 12 hours to allow the ammonia to escape. 10.0 g solid ammonium chloride and 200 ml water are then added. The mixture is acidified by addition of 6 N HC1 and is then extracted with ether. The ether phase is washed with water and dried over magnesium sulfate and the solvent is evaporated under reduced pressure. Distillation of the residue gives 3.5 g heptyne-6oic acid.
i) 550 mg heptyne-6-oic acid in 5 ml THF are added dropwise to a solution of ethyl magnesium bromide prepared from 0.21 g magnesium and 0.97 g ethyl bromide in 50 ml THF.
The mixture is stirred for 1 hour at 20*C, after which mg CuCN and 500 mg l-bromo-2,5,8-undecatriene are added in that order. The mixture is heated under reflux for 6 hours, cooled and, after addition of ice, is acidified with dilute HC1.
The mixture is extracted with ether, the ether phase is recovered and dried over magnesium sulfate, the residual solvents are evaporated under pressure and a yellow oil is obtained.
Column chromatography and distillation give 260 mg of a colourless oil which is indentified by NMR of the carbon and proton and by mass spectrometry as being 9(Z),12(Z),15- (Z)-octadecatriene-6-ynoic acid.
-Example 2 15 This Example tests the effect of dicranine on the lipoxygenase and the cyclooxygenase of isolated human blood platelets.
Platelets are isolated from human blood on an anticoagulant of the ACD type (Lagarde et al., Thrombos. Res.
20 (1979) 17, 581-588). Dicranine solubilized in ethanol is added to the platelets in suspension in a physiological buffer (Hepes) in a quantity of approx. 3.105 cells/il to obtain a dicranine concentration of 10 4 or 10- 6
M.
The platelets are incubated for 10 minutes at 37"C and 25 are then stimulated by addition of an arachidonic acid solution to obtain an arachidonic acid concentration of 10 5
M,
followed by incubation for another 10 minutes at 37°C. The whole is then acidified to pH 3 by addition of 3N HC1. The total lipids are extracted with ethyl ether and the monohydroxylated fatty acids are separated therefrom by thinlayer chromatography using the method described by Guichardant et al. in Biochem. Biophys. Acta, (1985), 836, 210- 214.
The monohydroxylated fatty acids are measured by highperformance liquid chromatography (HPLC) and are quantified by comparison with the standard 13-HODE under the assumption that they all have the same molar extinction coefficient at 3.104 M 1 cm 1 During activation of the platelets, two metabolic pathways of the arachidonic acid are activated, namely: the lipoxygenase pathway which leads to the formation of 12-HPETE which is reduced to 12-HETE, the cyclooxygenase pathway which forms the metabolites responsible for platelet aggregation, namely:: the endoperoxides PGGg, PGH 2 and the thromboxan A 2
(TXA
2 which stabilizes into TXB 2 the prostaglandins of series 2 and a monohydroxylated fatty acid, HHT.
Determination of the 12-HETE enables the lipoxygenase activity to be estimated. Determination of HHT enables the cyclooxygenase activity to be estimated.
The following results are obtained: Dicranine Visually Increase in Reduction 20 concentration observed effect 12-HETE in HHT relative to relative to the control the control Control Aggregation 10-6 M Slight inhibition 40% 18% 4 M Inhibition of platelet aggregation 654% 31% Very strong activation of the lipoxygenase pathway and a reduction in the cyclooxygenase pathway are observed for a dicranine cocnentration of 10' M. This result shows that the increase in 12-HETE is not associated with greater availability of the arachidonic acid which is less well utilized by the cyclooxygenase. Accordingly, dicranine is effective in increasing the 12-HETE. Now, it is known that 12-HETE is involved in the regulation of immunological processes. Accordingly, dicranine may be assumed to have an immunological effect.
The same effect is observed, albeit less strongly, for a dicranine concentration of 10-6 M.
Example 3 This Example tests the anti-agglomerating properties of dicranine on isolated human blood platelets. The test used is based on Born's turbidimetric method described in Nature (1962), 194, 927-929.
Several inductors each acting specifically at various levels of the action of arachidonic acid were used, namely: 15 thrombin which takes into account the entire enzymatic mechanism resulting in aggregation, arachidonic acid, a direct substrate of cyclooxygenase which forms the mediators responsible for aggregation, namely the endoperoxides PGG 2
PGH
2 and thromboxan A.
20 (TXA 2 S 9-methano-PGH 2 (structural analog of PGH 2 reference U46619) which causes aggregation on its own.
~The following results were obtained for a dicranine concentration of 10- M: S1 i. Without preliminary incubation of the dicranine: When thrombin (0.1 unit/ml) or arachidonic acid (5.10 M) is used as inductor, normal aggregation of the platelets is observed (no inhibition). When 9-methano-PCH 2 (1 gg/ml) is used as inductor, aggregation is completely inhibited. Accordingly, it may be concluded that dicranine does not act at the level of the enzymes phospholipase or cyclooxygenase; on the contrary, it seems to act directly on the receptor site of PGH 2
/TXA
2 to inhibit aggregation.
If a second dose of 9-methano-PGH 2 (1 gg/ml) is added, no 8 aggregation is observed. Accordingly, the inhibition process appears to be irreversible.
2. With incubation of dicranine: After incubation for 10 minutes at 37*C, aggregation is slightly inhibited when thrombin is used as inductor.
After incubation for 20 minutes at 37*C, aggregation is inhibited to a far greater extent with thrombin. One explanation may be that the inhibition of aggregation necessitates the formation of a metabolite of dicranine which takes place by slow kinetics.
The results are set out in the following Table: Inductors Level of aggregation 15 Control Dicranine 4
M)
4444 4 4 4* 4 4* 25 Thrombin Without incubation 65 10 Mins. 70 69 20 Mins. 68 44 Arachidonic acid Without incubation 70 9-Methano-PGH, Without incubation 66 0 This effect may also arise out of the fact that the synthesis of 12-HETE, which is known as an inhibitor of platelet aggregation, is considerably increased in the presence of dicranine. The same applies to the synthesis of 12-HPETE, its precursor.
It may be concluded from the present Example that, in a concentration of at least 10- 4 M and after incubation, dicranine has anti-aggregating properties towards human blood platelets.
In addition, the dicranine appears to act through its metabolites (monohydroxylated fatty acids) rather than directly.
Example 4 One of the principal metabolites of dicranine was isolated by HPLC, namely 13-hydroxy-9(Z),12(Z),15(Z)octadecatriene-6-ynoic acid.
The anti-aggregating properties of this metabolite were studied in accordance with Example 3 using thrombin as inductor in a quantity of 0.1 unit per ml.
Slow inhibition of platelet aggregation induced by thrombin is observed at a metabolite concentration of 10-M both without incubation and after incubation for 15 minutes.
Example The object of this Example is to test the effects of dicranine on isolated human leucocytes.
Human leucocytes are isolated by the method described by Guichardant et al. in Biochem. J. (1988), 256, 79-883.
The leucocytes are then optionally incubated for 30 minutes at 37°C in the presence of dicranine in a concentration of 10 4 or 10'M in ethanol, after which the optionally incubated leucocytes are stimulated by addition of arachidonic .acid in a concentration of 10-5M and ionophoric calcium (Oven A23187-Sigma) in a concentration of 2.10- 6 M and are then left for 10 minutes at 37*C. The whole is then acidified to pH 3 by addition of 3N hydrochloric acid. The total lipids are extracted with a mixture of ethanol and chloroform after which the lipids extracted are separated by two-dimensional thin-layer chromatography.
The monohydroxylated fatty acids are developed in the first dimension with a solvent mixture of hexane, ethyl ether and glacial acetic acid in a ratio by volume of 59:40:1, the dihydroxylated fatty acids remaining at the beginning of the plate. The monohydroxylated fatty acids are collected from the plate together with the 13-HODE and are extracted with ethyl ether. After evaporation of the solvent under nitrogen, they are separated by inverse-phase HPLC with an elution solvent mixture of methanol and aqueous acetic acid, pH 3, in a ratio by volume of 73:27.
They are detected by UV spectroscopy at a wavelength of 234 nm and are quantified by comparison with the standard 13- HODE on the assumption that they all have the same molar extinction coefficient at 3 x 104 M-cm The dihydroxylated fatty acids remaining at the beginning of the plate are then developed in the second dimension perpendicularly to the first using a solvent 15 mixture of hexane, ethyl ether and glacial acetic acid in a ratio by volume of 25:74:1. They are collected, extracted and separated as described above except that the elution solvent mixture used for the HPLC is methanol/aqueous acetic acid, pH 3, in a ratio by volume of 66:34. PGB 2 is used as the quantitative evaluation standard for the dihydroxylated fatty acids according to their respective maximum UV absorptions (wavelength 280 nm and molar extinction coefficient 2.8 x 104 M-cmi' for PGB 2 wavelength 270 nm and molar extinction coefficient 5 x 10 4 M-'cm 1 for the dihydroxylated derivatives).
It is known that stimulation of the leucocytes by ionophoric calcium in the presence of arachidonic acid activates 5-lipoxygenase and that this activation translates into a significant synthesis of 5-HETE and leucotrienes, such as LTB 4 This is observed for the control leucocytes which were not incubated in the presence of dicranine.
In the case of the leucocytes incubated in the presence of 10 4 M dicranine, the activation of is inhibited. This inhibition causes a significant reduction in the synthesis of 5-HETE and LTB 4 This reduction is of the order of 50% for their synthesis by comparison with the control which is significant at 5% for LTB 4 according to the Student-Fischer paired test.
In the case of the leucocytes incubated in the presence of 10 6 M dicranine, the activation of is not inhibited. In this concentration, dicranine is not active.
In a concentration of 10 4 M, dicranine inhibits the synthesis of leucotrienes which are the mediators of inflammation. Accordingly, dicranine has anti-inflammatory properties.
Example 6 15 These Examples describe the anti-bacterial properties of dicranine towards the following bacteria: Bacillus stearothermophilus Bacillus cereus Bacillus subtilis 20 Staphylococcus aureus Streptococcus faecalis Example a *e 3 ml nutrient gelose (SNA) inoculated with 1% of a culture of the bacterium in question previously incubated for 16 to 18 hours are applied to a Petri dish of 15 ml S"gelose (PCA). A certain quantity of dicranine in the form of a solution in ethanol is applied to a 6.5 mm or 13 mm diameter disc of sterile filter paper. After evaporation of the solvent, the disc is placed at the centre of the Petri dish.
The whole is then incubated for 24 hours at a temperature of 30 to 37°C for the mesophilic bacteria and at a temperature of 55*C for the thermophilic bacteria. Visually, it can be seen that, in a zone surrounding the paper 12 disc, the microorganism has not developed. The diameter in mm of this inhibition zone is measured, the following results being obtained: Dicranine concentration (jg/disc) 25 50 75 100 125 250 500 1000 B. stearoth. 0 9 11 14 16 17 26 32 B. cereus 0 9 10 11 15 16 19 22 B. subtilis 0 8 11 13 13 14 16 19 St. aureus 0 10 11 12 16 17 21 22 23 Str. faecalis 6 10 12 13 Not determined 35 Accordingly, inhibition of the development of the bacteria is observed from 25 jg dicranine per disc or even for Str. faecalis from 10 pg dicranine/disc.
Example b 200 il of an infusion based on brain and heart containing 0 to 200 Ag/ml dicranine in the form of its sodium *.salt are introduced into each cup of a 96 cup plate and il of an aqueous suspension containing 103 to 10 5 germs per 25 ml are added. The whole is then incubaced at the tempera- 25 tures mentioned in Example a.
Samples (100 4l) are taken after 0, 2, 4, 6, 8 and 24 hours and are diluted with 900 pl physiological salt solution containing 0.85% sodium chloride and 0.1% tryptone to obtain approximately 10 to 300 bacteria per gelose plate. After incubation for 24 hours, the colonies formed are counted. The following results are obtained: a) number of B. Stearothermophilus still viable per ml solution (logarithmic value): Dicranine concentration (Ag/ml) Control 10 50 100 150 200 0 Hour 2 Hours 4 Hours 6 Hours 8 Hours 24 Hours 3.699 4.009 5.826 6.975 7.975 7.484 3.699 3.845 6.628 8.312 7.628 3.724 3.806 6.439 7.161 7.366 3.699 3.176 3.146 3.263 3.845 5.866 3.711 2.736 2.816 2.766 2.602 2.093 3.699 2.477 1.937 1.544 1.454 0.004 .4 4* 4 4 4 4 4*4 4**4 *444 .4 4**4 4. 4 4.
.4 4* 4.
b) Number of B.cereus till viable per ml solution (logarithmic value): Dicranine concentration (Ag/ml) Control 10 50 100 150 200 0 Hour 25 2 Hours 4 Hours 6 Hours 8 Hours 24 Hours 3.699 3.900 6.591 8.238 7.544 3.628 3.628 3.415 3.146 2.826 3.699 3.602 3.149 2.107 0.875 2.924 2.049 0.041 6.337 5.734 2.778 1.648 0.176 7.945 6.301 2.767 1.439 0.301 7.544 7.0 6.071 1.124 0.041 1 14 c) Number of B. subtilis still viable per ml solution (logarithmic value): Dicranine concentration (Ag/ml) Control 10 50 100 150 200 0 Hour 2 Hours 4 Hours 6 Hours 8 Hours 24 Hours 4.301 4.439 6.954 8.423 7.724 4.301 4.301 4.204 3.903 3.740 6.851 3.732 7.756 3.991 7.484 4.114 4.000 3.954 2.204 3.748 3.716 1.342 3.556 3.699 1.079 3.665 3.618 1.021 3.782 3.679 0.301 3.342 3.277 0.001 .9 9 99 9 9 9*9* 15 Accordingly, it can be seen that, in concentration of 150 Ag/ml, dicranine is bactericidal towards the mesophilic bacteria B. cereus and B. subtilis. In a concentration of 100 gg/ml, a bacteriostatic effect is observed for 4 hours.
Dicranine is bactericidal towards the thermophilic bacterium B. stearothermophilus from 200 gg/ml. In concentration of 50 to 150 ig/ml, a bacteriostatic effect is observed for 4 hours.

Claims (8)

1. A pharmaceutical composition comprising a therapeutically or antibacterially effective amount of 12(Z), 15(Z)-octadecatriene-6-ynoic acid and a pharmaceutically acceptable excipient or carrier.
2. A method for the treatment of prophylaxis of blood aggregation, inflammation, and/or bacterial infection, the method comprising administering to a patient in need of such treatment an effective amount of 12(Z), 15(Z)-octadecatriene-6-ynoic acid, optionally together with a pharmaceutically acceptable excipient or carrier.
3. A method according to claim 2 for the treatment or prophylaxis of blood aggregation.
4. A method according to claim 2 for the treatment or prophylaxis of inflammation.
5. A method according to claim 2 for the treatment or prophylaxis of bacterial infection.
6. A cosmetic composition in the form of a lotion, ointment or cream and comprising 12(Z), 15(Z)-octadecatriene-6-ynoic acid and a cosmetically S 20 acceptable excipient or carrier.
7. A pharmaceutical composition according to claim 1 and substantially as described in this specification with reference to any one of Examples 2 to 6. DATED this 10th day of May 1994 e o SOCIETE DES PRODUITS NESTLE S.A. Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia Sof SHELSTON WATERS I I 16 Abs tact Uses of 9(Z) ,15(Z)-ootadecatrierie-6-ynoic acid The invention relates to the use of 9(Z),12(Z),15(Z)- octadecatriene-6-ynoic acid as a therapeutically active substance. 0 S 000:0, of 0
044. S S .00.
AU18459/92A 1991-08-20 1992-06-22 Use of 9, 12, 15-octadecatriene-6-ynoic acid Ceased AU651216B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH2450/91A CH682542A5 (en) 1991-08-20 1991-08-20 Uses of octadécatriène-9 (Z), 12 (Z), 15 (Z) -ynoïque-6.
CH2450/91 1991-08-20

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AU1845992A AU1845992A (en) 1993-03-04
AU651216B2 true AU651216B2 (en) 1994-07-14

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EP (1) EP0528135A1 (en)
JP (1) JPH05238933A (en)
AU (1) AU651216B2 (en)
CA (1) CA2073138A1 (en)
CH (1) CH682542A5 (en)
IE (1) IE922599A1 (en)
NO (1) NO922638L (en)
NZ (1) NZ243365A (en)
ZA (1) ZA924899B (en)

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CH682542A5 (en) 1993-10-15
ZA924899B (en) 1993-04-28
CA2073138A1 (en) 1993-02-21
EP0528135A1 (en) 1993-02-24
AU1845992A (en) 1993-03-04
NO922638D0 (en) 1992-07-03
IE922599A1 (en) 1993-02-24
NO922638L (en) 1993-02-22
JPH05238933A (en) 1993-09-17
NZ243365A (en) 1993-11-25

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