WO2013037862A1 - Specific phosphatidylcholines as modulators of platelet activation factor activity - Google Patents

Abstract

The present invention relates to a pharmaceutical composition or a medicament for use in preventing or treating a PAF-related disease, comprising a phosphatidylcholine of formula (I), and also to the use of such a compound as a medicament or as a modulator of PAF activity.

Description

 Specific Phosphatidylcholines as Modulators of Platelet Activating Factor Activity

The present invention relates to the use of specific phosphatidylcholines as modulators of platelet activating factor activity, also called PAF. It also relates to a pharmaceutical composition or a medicament for preventing or treating diseases related to the activity of PAF.

 Some compounds modulating the activity of PAF are known. However, these compounds may exhibit unsatisfactory activity, undesirable side effects, be expensive, difficult to obtain, to synthesize, have an unsatisfactory delivery, and / or have insufficient stability.

 The object of the invention is therefore to obtain compounds that modulate the activity of PAF, or the use of such compounds, in order to solve all or part of the problems mentioned above or in the present description.

 The application WO 94/12170 describes unsaturated fatty acid-based medicaments, and more specifically based on docosahexaenoic acid (also called DHA or 22: 6n-3). This document teaches that these compounds make it possible to bring an essential fatty acid to the brain with a particularly high efficiency. Moreover, it also discloses that these compounds exhibit antithromboxane A2 activity.

Compounds exhibiting anti-thromboxane activity are normally inactive against platelet aggregation agonists that do not occur via the arachidonic acid cascade (cascade that ends with the generation of thromboxane A ₂ ).

This anti-thromboxane activity is quite different from that of Platelet Activation Factor (PAF), generated during inflammatory conditions, which leads to platelet aggregation independently of thromboxane A ₂ generation.

 Surprisingly, therefore, the inventors have found that polyacetyl-2-docosahexaenoyl-glycerophosphocholine (AceDoPC) can modulate, and in particular inhibit, PAF activity.

According to a first aspect, the invention relates to the use of a phosphatidylcholine of formula (I) below:

 Formula (I)

in which :

R 1 represents an acyl group, in particular acetyl,

 X represents O, S or NH, and

R ₂ represents an unsaturated fatty acyl comprising at least two carbon-carbon double bonds,

its pharmaceutically acceptable salts and its enantiomers,

as modulator, in particular inhibitor, of PAF activity.

 In particular, this use is carried out in vitro or ex vivo.

 According to another of its aspects, the subject of the invention is a phosphatidylcholine of Formula (I) for its use as a medicament for preventing and / or treating:

- a disease in which PAF activity, and in particular high PAF activity, contributes to the disease state and / or symptoms of the disease, and / or

- PAF-related illness and / or symptoms, particularly related to "abnormal" PAF activity, particularly related to "strong" PAF activity, such as allergic asthma, thrombosis and / or inflammation, especially allergic inflammation.

 According to another of its aspects, the invention relates to a composition pharm ace uti q ue or a ed ed com m ent com com, or cons ista nt in phosphatidylcholine of Formula (I) for its use to prevent and / or or to treat PAF-related illness and / or symptoms, particularly related to abnormal PAF activity, particularly related to high PAF activity, for example in the case of allergic asthma, thrombosis and / or inflammation, especially allergic inflammation.

 In particular, the phosphatidylcholine of Formula (I) is the active substance of the composition or the medicament.

According to another of its aspects, the invention relates to a composition pharm ace uti q ue or un ed ed com m ent com com, or cons ista nt in u u phosphatidylcholine of Formula (I) for use in preventing and / or treating a disease in which PAF activity, particularly abnormal activity, and more particularly high PAF activity, contributes to the disease state and / or or the symptoms of the disease.

 The present invention also relates to phosphatidylcholine of Formula (I) as an active substance.

 The invention also relates to the use of the phosphatidylcholine of Formula (I) for the preparation of a pharmaceutical composition or a medicament, in particular as defined in the present description.

 According to yet another of its aspects, the subject of the invention is a method for treating and / or preventing PAF-related diseases and / or symptoms, in particular related to the PAF activity, in particular to an abnormal activity of the PAF. PAF, and more particularly related to a high activity of PAF, said method comprising the administration to a subject of an effective amount of phosphatidylcholine of Formula (I).

 According to another of its aspects, the subject of the invention is a method for treating and / or preventing diseases in which PAF activity, in particular abnormal activity of PAF, and more particularly a high activity of PAF, contributes pathology and / or symptom of the disease, said method comprising administering to a subject an effective amount of phosphatidylcholine of Formula (I).

 "Abnormal PAF activity" means an activity that is significantly different from a reference sample and / or a median value. This significant difference can be 10%, in particular 20% or even 30%.

 "Strong PAF activity" means higher activity than a reference sample or a threshold value. This activity can be higher by 10%, in particular by 20% or even 30%.

 In formula (I), R 1 represents an acyl group. This group R 1 can comprise from 2 to 6 carbon atoms. In particular, Ri is chosen from -COMe, -COEt, -COnPr, -COiPr, -COnBu, -COsBu and -COtBu.

In Formula (I), R ₂ represents unsaturated fatty acyl, in particular comprising at least two carbon-carbon double bonds. More particularly this group R ₂ is chosen from:

 the conjugated dienes or trienes, in particular chosen from:

the dienes EE, ZZ, ZE and EZ, in particular ZZ, and the EZE, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE and ZZZ trienes, in particular EZE and ZZZ,

 the polyunsaturated fatty acyls comprising 2, 3, 4, 5 or 6 carbon-carbon double bonds separated by a carbon atom, in particular the carbon-carbon double bonds are all Z, and more particularly the fatty acyl corresponds to an acid fat n-3 or n-6,

 - their derivatives, and

 - their metabolites.

In particular, R ₂ represents a fatty acyl triene EZE conjugated or corresponds to an acyl fatty n-3 or n-6, in particular chosen from DHA, also called docosahexaenoic acid, EPA, also called eicosapentaenoic acid, DPA, also called acid docosapentaenoic, ARA, also called arachidonic acid, LNA, also called alpha-linolenic acid, and LA, also called linoleic acid.

 By "fatty acyl" is meant an acyl corresponding to a fatty acid, that is to say a carboxylic acid having a linear aliphatic chain, unbranched, saturated or unsaturated. The fatty acyl may comprise from 4 to 28 carbon atoms.

 In the present invention, the fatty acyl may comprise from 12 to 28 carbon atoms, in particular from 16 to 26 carbon atoms, and most preferably from 18 to 24 carbon atoms.

 By "polyunsaturated fatty acyl" is meant a fatty acyl comprising at least 2 non-conjugated carbon-carbon double bonds, in particular at least 2 carbon-carbon double bonds separated by a carbon atom, and more particularly in which all the double bonds are separated by a carbon atom. In particular, the polyunsaturated fatty acyl comprises at least 3 carbon-carbon double bonds.

 By "polyunsaturated fatty acyl all Z" is meant a fatty acyl comprising carbon-carbon double bonds all having a Z configuration, in particular these double bonds are separated by a carbon atom.

 By "diene fatty acyl or conjugated triene" is meant a fatty acyl comprising:

 - 2 conjugated carbon-carbon double bonds which have an EE, EZ, ZE or ZZ configuration or

- 3 conjugated carbon-carbon double bonds which have an EZE, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE or ZZZ configuration. In particular, fatty acyl comprises the structure -CH (OR ₅ ) -CH = CH-CH = CH-CH = CH-CH (OR ₆ ) -, in which:

 the double bonds have an EZE, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE or ZZZ configuration, in particular EZE, and

R 5 and R ₆ represent, independently of one another, H or an alkyl group comprising from 1 to 3 carbon atoms.

 "Derivatives" means compounds which may be substituted, in particular by at least one substituent chosen from halogens, alkyl groups, in particular C 1 -C 10 alkyl, aryl groups, in particular C 6 -C 10 alkyl groups, alkyl ethers, aryl ethers, alkylamines, arylamines, alkylthioethers, arylthioethers, alkyl esters, aryl esters, alkylamides and arylamides.

 By "metabolite" is meant a compound derived from the unsaturated fatty acid metabolism corresponding to unsaturated fatty acyl as described in Formula (I), or a derivative thereof, in the body of an animal or animal. a human.

 According to a particular embodiment, the unsaturated fatty acyl comprises at least two, in particular at least three, carbon-carbon double bonds which can be conjugated, in particular the fatty acyl comprises three carbon-carbon double bonds having an EZE configuration. .

 According to another particular embodiment, the unsaturated fatty acid comprises at least two, in particular at least three, carbon-carbon double bonds which are separated by a carbon atom, more particularly the acyl comprises 2 carbon-carbon double bonds. separated by a carbon atom. In particular unsaturated fatty acyl corresponds to an n-3 or n-6 fatty acid.

 In particular, the fatty acyl is chosen from the acyls corresponding to DHA, EPA, DPA, ARA, LNA or LA.

 Especially the compound of Formula (I) is AceDoPC or 1-acetyl-2-docosahexaenoyl-glycerophosphocholine.

 The composition or the medicament may further comprise an antioxidant, in particular Vitamin E.

 According to one embodiment, the pharmaceutical composition or the medicament may further comprise a lipid-lowering compound or a lipase inhibitor, in particular tetrahydrolipstatin.

The composition or the drug may comprise, in addition to the compound of formula (I), and optionally another active ingredient, at least one excipient and / or a pharmaceutically acceptable carrier, in particular water. In particular, the composition or the medicament comprises one or more compounds making it possible to obtain the formulation in the desired form, for example of capsule, granule, tablet, gel, suppository, solution, suspension, emulsion. , of cream ...

 The compound of formula (I) may be used at a daily dose of 0.1 to 15 mmol per subject, in particular in the case of a human being, and more particularly from 0.2 to 10 mmol, or even about 0 5 mmol.

 The composition, drug or method may involve oral or parenteral administration, particularly intravenous or infusion.

 According to a particular embodiment, when the composition, the medicament in which the method involves a phosphatidylcholine-type compound comprising docosahexaenoic acid in position sn-2, and in particular of formula (I) in which F 1 corresponds to DHA, then the compound, composition, drug or method may not be used for its platelet anti-aggregation activity, and in particular is not intended to be used for its effect against cardiovascular diseases, including atherosclerosis and against deficiencies or deficiencies in essential fatty acids, especially in the brain.

Of course, the various features of the invention presented in the present description can be combined with each other.

The following examples are intended to illustrate the invention and in no way to limit it. EXAMPLE

 In order to demonstrate the effect of a compound according to the invention on PAF activity, the following example has been realized.

 Plasma-isolated human platelets placed in the presence of Platelet Activating Factor (PAF) at a final concentration of 100 nM to induce platelet aggregation.

 In the following cases acetyl docosahéxanoyl phosphatydylcholine (AceDoPC) was preincubated for 1 minute, and the following results were measured:

 AceDoPC 1 μΜ inhibition 15.5% (n = 3)

AceDoPC 10 μΜ inhibition 51.2% (n = 4) AceDoPC 50 μM inhibition 74.2% (n = 1)

 AceDoPC 100 μΜ inhibition 100% (n = 1)

These results show that AceDoPC has an IC ₅₀ of about 10 μΜ and therefore a significant modulation effect, in this case a strong inhibition, of PAF activity.

Claims

1. A pharmaceutical composition or a medicament comprising a phosphatidylcholine of Formula (I):

 Formula (I) in which:  R 1 represents an acyl group, in particular acetyl,  X represents O, S or N H, and R ₂ represents an unsaturated fatty acyl comprising at least two carbon-carbon double bonds,  and pharmaceutically acceptable salts and enantiomers thereof, for use in preventing and / or treating PAF disease and / or symptoms. 2. A pharmaceutical composition or a medicament comprising a phosphatidylcholine of Formula (I):

 Formula (I) in which: R 1 represents an acyl group, in particular acetyl, X represents O, S or NH, and R ₂ represents an unsaturated fatty acyl comprising at least two carbon-carbon double bonds, and its pharmaceutically acceptable salts and enantiomers, in its use for preventing and / or treating a disease in which PAF activity contributes to the disease state and / or symptoms of the disease. Pharmaceutical composition or drug according to claim 1 or 2, characterized in that R 1 comprises from 2 to 6 carbon atoms, and in particular is selected from -COMe, -COEt, -COnPr, -COiPr, -COnBu, -COsBu and COtBu. Pharmaceutical composition or medicament according to any one of Claims 1 to 3, characterized in that R ₂ represents an unsaturated fatty acyl, in particular comprising at least two carbon-carbon double bonds, very particularly chosen from:  the conjugated dienes or trienes,  polyunsaturated fatty acyls comprising 2, 3, 4, 5 or 6 carbon-carbon double bonds separated by a carbon atom,  - their derivatives and,  - their metabolites. Pharmaceutical composition or medicament according to any one of Claims 1 to 4, characterized in that R ₂ represents an unsaturated fatty acyl radical comprising at least two carbon-carbon double bonds chosen from:  the conjugated dienes EE, ZZ, ZE and EZ, in particular ZZ, and  the conjugated trienes EZE, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE and ZZZ, in particular EZE and ZZZ. Pharmaceutical composition or drug according to any one of claims 1 to 5, characterized in that R ₂ represents a fatty acyl comprising the structure -CH (OR ₅ ) -CH = CH-CH = CH-CH = CH-CH (OR ₆ ) -, in which: the double bonds have an EZE, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE or ZZZ configuration, in particular EZE and, R 5 and R ₆ represent, independently of one another, H or an alkyl group comprising from 1 to 3 carbon atoms. 7. The pharmaceutical composition or medicament according to any one of claims 1 to 6, characterized in that R ₂ represents a polyunsaturated fatty acyl comprising 2, 3, 4, 5 or 6 carbon-carbon double bonds separated by a carbon atom and wherein the carbon-carbon double bonds are all Z. 8. Pharmaceutical composition or drug according to any one of claims 1 to 7, characterized in that R ₂ represents a fatty acyl chosen from acyls corresponding to DHA, EPA, DPA, ARA, LNA or LA. 9. Pharmaceutical composition or medicament according to any one of claims 1 to 6, characterized in that it is used to prevent and / or treat a disease selected from allergic asthma, thrombosis and / or inflammation, in particularly allergic inflammation. 10. Use of a Phosphatidylcholine of Formula (I)

 Formula (I) in which:  R 1 represents an acyl group, in particular acetyl,  X represents O, S or N H, and R ₂ represents an unsaturated fatty acyl comprising at least two carbon-carbon double bonds, its pharmaceutically acceptable salts and its enantiomers, as a modulator, in particular an inhibitor, of the PAF activity, in particular in vitro or ex vivo.