WO2017006047A1 - 1-alkyl,2-acylglycerophosphocholines for the treatment of inflammation or of intestinal cancer - Google Patents

Abstract

The invention relates to a compound of formula (I): where X and R are defined in claim i, or a drug or pharmaceutical composition comprising such a compound of formula (I) or any pharmaceutically acceptable hydrates, salts or solvates thereof, in the form of a pure isomer or a mixture of isomers in any proportion, for the use thereof in treating intestinal cancer or intestinal inflammation.

Description

 infestitmation of intestinal tract

 The present invention relates to a new therapeutic use of specific known 1-acetyl-1-acylglucophosphocholines.

 Inflammatory bowel diseases and intestinal cancers affect a large part of the population. Examples of compounds known for their anti-inflammatory and / or anti-tumor intestinal applications include, in particular, aspirin at low doses (this the last being haemorrhagic in high doses), 5 ~ amino ~ salicylic acid (derived from aspirin) and corticosteroids which act according to different mechanisms of action. Only aspirin inhibits Cyclooxygenase H (COX II also called COX-2) by acetylating the active site, which prevents access of arachictonic acid, hence production of pro-inflammatory prostaglandins. On the other hand, 5-amino-salicylic acid inhibits leukocyte chirniotactism and the synthesis of interleukin-8. Corticosteroids, on the other hand, inhibit inflammation via a downregulation of transcription of pro-inflammatory cytokines. The action of corticosteroids is upstream, and are therefore susceptible to side effects, especially on the immune system,

 One of the objectives of the invention is to provide an alternative to the treatments already proposed for inflammatory bowel diseases and intestinal cancers which would not have, in particular, the risk of side effects on the immune system that corticosteroids present,

In the context of the invention, the inventors have demonstrated, in a totally unexpected manner, that the ~ acetyl ~ 2 ~ docosabexaénGyl ~ glycerophosphochoiine (AceDoPC), and more generally that a compound of formula (I):

Formula (I)

in which :

 X represents O, S or 1MH, and

 R represents unsaturated fatty acyl comprising at least one carbon-carbon double bond, preferably at least two carbon-carbon double bonds;

or one of its pharmaceutically acceptable hydrates, salts or solvates, in the form of a pure isomer or a mixture of isomers in all proportions,

could be used for combating and / or preventing gut inflammation or intestinal cancer As ^an example ^of Intestinal inflammation include chronic inflammatory bowel diseases including ulcerative colitis and Crohn's disease, colonic diverticulosis ,. ..,

 Such compounds were known in the prior art and in particular described in applications WO 2013/037852 and WO 94/12170, but for very different therapeutic applications, in particular for platelet anti-aggregation activity, and in particular for their effect against cardiovascular diseases, including atherosclerosis and against deficiency or deficiency of essential fatty acids, particularly in the brain, or for activity modulating or inhibiting the activity of PAF,

In the context of the invention, the inventors have demonstrated that the compounds of formula (I), or one of their hydrates, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, in the form of a pure isomer or a mixture of isomers in all proportions, could be used, as a drug or active agent, for the treatment of intestinal inflammation or intestinal cancer,

 In the definition of the compounds used in the context of the invention, its terms used have the conventional meanings given below.

 By "isomer" is meant both an optical isomer and a geometrical isomer. In the remainder of the description, for reasons of simplicity, a compound of formula (I) will be named a compound of formula (I) which! either in the form of a pure isomer or a mixture ofomers in all proportions, unless otherwise specified, particularly in the definition of the fatty acyl group. If necessary, the compounds of formula (I) are isolated in the form of pure isomers or in a form enriched in an isomer by conventional separation techniques: it is possible to use, for example fractional recrystallizations, conventional chromatography techniques.

 By "solvates" is meant a form of the compound associated with one or more solvent molecules, especially used during its synthesis or during its purification, without being in solution in the latter. The solvent in question will be chemically acceptable.

 The salts of the compounds of formula (I) according to the present invention include those with acids or bases, depending on the substituents present. Pharmaceutically acceptable salts may be mentioned, such as sodium, potassium and calcium salts.

 By "hydrates" is meant a compound in hydrated form. By way of example, mention may be made of semihydrates, monohydrates and polyhydrates.

The term "fatty acyl" means an acyl corresponding to a fatty acid, that is to say to an carboxylic acid having a linear, unbranched allpbatic chain which in the definition of the compounds of formula (I) is unsaturated. . the fatty acyl in the formula (I) can in particular comprise from 4 to 28 carbon atoms, in particular from 12 to 28 carbon atoms, preferably from 16 to 26 carbon atoms, and preferably from 18 to 24 carbon atoms. By "unsaturated fatty acyl" is meant a fatty acyl comprising at least one double non-conjugated carbon-carbon home. By "polyunsaturated fatty acyl" is meant a fatty acyl comprising at least 2 non-conjugated carbon-carbon double bonds, particularly at least 2 carbon-carbon double bonds separated by a carbon atom, and more particularly wherein all the double bonds are separated by a carbon atom. In particular, a polyunsaturated fatty acyl comprises at least 3 carbon-carbon double bonds.

 By "fatty acyl dene or conjugated triene" means a fatty acyie including, in particular;

 in the case of dienes, 2 conjugated carbon-carbon double bonds which have an EE, EZ, ZE or ZZ configuration or

dans laquelle : in the case of trienes, 3 conjugated carbon-carbon double bonds which have a configuration of £ 2, EEZ, ZEE, ZZE, ZEZ, EZZ, EEE or ZZZ; in particular, the fatty acyl can comprise the structure ~ CH (OR *) -

in which :

* The double bonds have a configuration EZE, EEZ, ZEE, ZZE, 2EZ _f EZZ, EEA or ZZZ, particularly EZE and

 * ¾ and [¾, represent, independently of each other, H or an alkyl group comprising from 1 to 3 carbon atoms.

 In a particular embodiment, the unsaturated fatty acyl present in the formula (I) of the compounds used in the context of the invention comprises at least three carbon-carbon double bonds which may be conjugated, especially fatty acyls. includes 3 carbon-carbon double bonds with an EZE configuration.

According to another particular embodiment, the unsaturated fatty acid present in its formula (I) of the compounds used in the context of the invention comprises at least two, in particular at least three, carbon-carbon double bonds which are separated. by a carbon atom. In particular, the unsaturated fatty acyl corresponds to the acyl chain of a n-3 fatty acid (also known as omega 3) or n-6 (also called omega 6), in particular fatty acyl is chosen from acyls. corresponding to DHA (docosa exaenoic acid), EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid), ARA (arachidonic acid), LNA (alpha-linolenic acid) or LA (linoleic acid).

 In formula (I), R is preferably chosen from:

 your dienes or conjugated trienes, especially chosen from the dienes

EE, ΖΣ, ZE and ZZ EZ _t being preferred dienes and trienes EZE, EEZ _f ZEE, ZZE, ZEZ, £ ZZ, EEA and ZZZ, ZZZ and ies trienes EZE being preferred,

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

 * their derivatives, and their metabolites;

 in particular, R represents a fatty acyl triene EZE conjugated or corresponds to a n-3 or n-6 fatty acyl, in particular corresponds to the acyl part of DHA, ayssi called docosahexaenoic acid, to the acyl part of ΙΈΡΑ, also called acidic acid. eicosapentaenoic acid, to the acyl part of DPA, also called docosapentaenoic acid, to the acyl part of AA, also called arachidonic acid, to the acyl part of LNA, also called alpha-linolenic acid, or to the acyl part of LA, also called linoleic acid.

 By "derivatives" of a compound is meant said substituted compound, in particular with at least one substituent chosen from halogens (chlorine, bromine, fluorine or fluorine), alkyl groups, in particular C 1 -C 10 alkyl groups, aryl groups, especially C 10 -C 10 aryl groups, alkyl ethers, aryl ethers, alkylamines, arylamines, alkyl thioethers, arylthioethers, alkyl esters, aryl esters, alkylamides and arylamides.

By "alkyl" is meant a saturated, linear or branched hydrocarbon-based chain. By way of example of an alkyl group comprising from 1 to 6 carbon atoms, designated CC ₆ , mention may be made, in particular, of methyl, ethyl, propyl, isopropyl, t-butyl, tert-butyl, tert-butyl, n-pentyl, n-hexyl. By "aryl" is meant a mono-, b- or polycyclic carbocycle, preferably having from 6 to 12 carbon atoms, comprising at least one aromatic group, for example a phenyl, cinnamyl or resaphylyl group. Phenyl is the most preferred aryl group.

 By "metabolite" is meant a compound derived from metabolism, in the body of an animal! or a human, or at the cellular level, unsaturated fatty acid corresponding to an unsaturated fatty acyl as described in the context of the invention, or a derivative thereof.

In particular, the compound of formula (I) used in the context of ^the invention is FAceDoPC or l-acetyl-2-docosahexaénoyÎ ~ glycérophosphocboline, corresponding to formula (I) wherein X ^™ 0, R is the acyl of docosahexaenoic acid.

 The compounds of formula (I) may be prepared according to the method described in application WO 94/12170, or according to the method described in application WO 2008/068413 or methods derived therefrom

 The subject of the present invention is the compounds of formula (I) as defined in the context of the invention, as well as their salts, pharmaceutically acceptable solvates and hydrates, for their use as a medicament for the treatment of intestinal inflammation. or an intestinal cancer. In particular, such drugs or compositions are intended for the treatment of humans.

 "Treatment" means any therapeutic, prophylactic, curative or suppressive measure of a disease, condition or disorder leading to a desirable clinical effect or any beneficial effect, including in particular the suppression or reduction of one or more symptoms, the regression, slowing down or cessation of the progression of the disease or the disorder associated with it,

By their activity, the compounds of formula (I) as defined within the scope of the invention, as well as their salts, pharmaceutically acceptable solvates and hydrates, may be used for the manufacture of a medicament, intended to treat inflammation Intestinal or intestinal cancer The invention also relates to methods of treating an intestinal inflammation or an intestinal cancer in which an effective amount, and in particular a therapeutically effective amount, of a compound of formula (I) as defined in the context of the invention, or a pharmaceutically acceptable salts _"solvates or hydrates, is administered to a human patient or animai tei requiring treatment.

 The compounds of formula (I) are not cytotoxic. By their activity, the compounds of formula (I) as defined within the scope of the invention, as well as their salts, pharmaceutically acceptable solvates and hydrates, can be used for the manufacture of a medicament for treating inflammation. intestinal or intestinal cancer.

Pharmaceutical compositions and medicaments, for their use in the treatment of intestinal inflammation or intestinal cancer, comprising a compound of formula (1) as defined in the context of the invention, or a salt thereof, solvates or pharmaceutically acceptable hydrate _"in combination with at least one pharmaceutically acceptable excipient, are: also part of the invention in such compositions, the compound of formula (I) as defined within the framework of the invention, or of its solvates or pharmaceutically acceptable salts or hydrates is present in a therapeutically effective amount.

In particular, the compound of formula (I) or its solvates or pharmaceutically acceptable salts or hydrates is the active substance of the pharmaceutical composition or the drug, that is to say the substance used to obtain the therapeutic activity or prophylactic on ^intestinal inflammation or intestinal cancer concerned.

By "effective amount" means any amount of a composition which prevents the occurrence of one or more signs of ^ ^affection that one wishes to prevent (in the case of prophylactic treatment ^f) denotes or improves one or more of the characteristic parameters of the condition being treated (in the case of curative treatment) By "therapeutically effective amount" is meant any amount of a composition that improves one or more of the characteristic parameters of the condition being treated.

 In order to obtain the desired effect, the compound seion the invention will be present in the composition or the drug at an effective dose, and in particular therapeutically effective, The dose of active ingredient varies, for example, between a nanogram and a tenth of gram per kg of body weight of the patient to whom it is administered, and per day.

Such pharmaceutical compositions administered to animals and, in particular to humans, contain an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. above, and one or more suitable excipients such as the European Pharmacopoeia edition 7 ^ee. The excipients present in the pharmaceutical compositions according to ^the invention are chosen according to the pharmaceutical form and the desired mode of administration. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, intraperitoneal, intracartilage, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active ingredients of formula (I), or their pharmaceutically acceptable salts or seis or hydrates, may be administered in unit dosage form, in admixture with conventional pharmaceutical carriers, to animals and humans for the treatment of intestinal cancer or targeted intestinal inflammation. Suitable unit dosage forms include oral forms, such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intranasal, subcutaneous, intramuscular, intra-cartilage or intravenous administration forms and rectal administration forms, For topical application, the compounds according to the invention can be used in creams, ointments, patches or lotions. The composition or the medicament may comprise, in addition to the compound of formula (I), 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 excipients which make it possible to obtain the formulation in the desired form, for example of capsule, granule, tablet, gel, suppository, solution, suspension, emulsion, cream ...

 In particular, the composition, medicament, use or method according to the invention may involve parenteral administration, in particular intravenous or intraperitoneal administration, oral administration and thus pharmaceutical compositions and medicaments adapted for such a mode of administration. are preferred.

 When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier, such as geiatine, starch, lactose, magnesium stearate, talc, gum arabic or the like, The tablets can be coated with sucrose, a cellulose derivative, or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient,

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

 The pharmaceutical compositions containing a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates or hydrates, may also be in liquid form, for example, solutions, emulsions, suspensions or syrups, liquid carriers Suitable examples are water, organic solvents such as glycerol or glycols, and mixtures thereof in various proportions in water.

A preparation in syrup or elixir form or for administration in the form of drops may contain the active ingredient together with a sweetener acalohque, an antiseptic, as well as an agent giving taste and appropriate co. The water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinyl pyrrolidone, as well as with sweeteners or preservatives. taste correctors,

 According to another of its aspects, the subject of the invention is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition or a drug, comprising a compound of formula (I) or a of its pharmaceutically acceptable salts or solvates or hydrates as defined in the context of the invention, in combination with at least one pharmaceutically acceptable excipient, for its use in the treatment of an intestinal disease or condition:

 ~ where a decrease in the expression and / or activity of cyciooxygenase II (COX II) is desired, and / or

 - where a decrease in the expression of BCL-2 and / or HSP-2? is desired, and / or

 ~ in which the expression and / or activity of cyciooxygenase II (COX II), and in particular a strong expression and / or activity of COX II, contributes to the pathological state and / or symptoms of illness or affection;

as well as compounds of formula (I) as defined within the framework of the invention, and salts and pharmaceutically acceptable solvates and hydrates, for use in his manufacturing ^a medicament for the treatment, especially in being human, of such a patt ology or affection;

and its methods of treating such a pathology or condition in which an effective, and in particular therapeutically effective, amount of a compound of formula (I) as defined in the scope of the invention, or one of its solvates or pharmaceutically acceptable salts or hydrates, is administered to a human or animal patient in need of such treatment. In general, all the variants indicated above for the compounds (I) are applicable mutatis mutandis to the drugs, compositions, methods and uses employing these compounds.

 According to particular embodiments of the compositions, medicaments, methods and uses according to the invention, said composition, said medicament, said method or said use will exclude the use of said composition or said medicament for an anti-pitting negation activity. and in particular for its effect against cardiovascular diseases, including atherosclerosis and against deficiencies or deficiencies in essential fatty acids, particularly in the brain, especially described in WO 94/12170, and an activity modulating or inhibiting the activity of PAF, in particular described in application WO 3013/037862.

The following examples illustrate ^the invention but have no limiting character.

AceDoPC is prepared according to the process described in WO 3/068413, by trans-esterification of the sn-1 position of palmitoyl _. 2 ~ docosahexaénoyl-giycéropriosphocholine (PC-DHA), by iipase in the presence of vinyl acetate and in the absence of water, allowing the direct obtention of AceDoPC AceDoPC was subjected to the following tests:

The parental HT29 cell line (HT29p), derived from a colonic adenocarcinoma, was cultured in monolayer up to 80% confluence in DME medium (Dutbecco's Modlfied Eagle Medium) containing 10% Decomplemented Fetal Calf Serum (FBS). i% Penicillin-

The molecule was tested in solution in 0.2% ethanol, compared to cellular controls incubated with the same ethanol concentration. Cell proliferation

Elf was tested by If rate of incorporation of BrdU (5-bromo-2 ^f - deoxyuridine) ,. synthetic nucleoside of thymidine, in ΑΟΝ newly synthesized by the cells being replicated,

4 _* Expression proteicies.

 The expression of the anti-apoptotic proteins Bd-2 and HSP-27 were measured by immunoblotting (western biotting) with a specific commercial antibody provided by Sigma-Aldnch according to the methodology recommended by this supplier.

 The anti-apoptotic activity of these proteins has been established in the literature:

for Bcl-2:

Expression of celi surviva / death genes: Bcl-2 and Bax at the rate of colon cancer prognos. Biochimica et Biophysica Acta 1741 (2005) 25-29 Monika Pau! ~ _F Samojedny Daouta Kokoci ska ArkadiusΣ Samojedny, Urszula Mazurek,

Robert Partyka, Zbigniew Lorenz, Tadeusz Wilczok,

 The Bel 2 famíly; regulators of the life-or-deat celiuiar switch Hat Rev

Cancer, 2 (9) (2002), pp 647-656, S. Corv, XM <Adams _f

 Bcl-2 constitutively suppresses pS3-dependent apoptosis in colorectal cancer ceiis. Genes Dev. 2003 »17: 832-837, Jiang and Jo Milner,

 For HSP27:

 Heat shock protein 27 enhances the tumorlgenicity of Immunogenic rat colon carcinoma cell clones. Cancer Res. 1998 Dec 1; 58 (23): 5495-9. Garrido Cl, Fromentin A, Bonnette B, Favre N, Moutet M, Ârrigo AP, Mehien P, Soiary E,

Apoptosis Versus Cell Differentiation: Role of Heat Shock Proteins HSP90, HSP70 and H5P27, Prion 2007, 1 (1), p53-60. David Lanneau, Aurelie de Thonel, Sebastien Maurel, Ceiine Dideiot & Carmen Garrido. The expression of inducible ilso-form cydo ~ oxygenase-2 (COX H) was measured in the same way with an antibody provided by Abcam, Prostagiandins D ₂ e E ₂ (also called PGE2 and PGD2) representative of the general prostaglandin biosynthetic pathway in situ, and pro-inflammatory prostaglandins derived from (COX II), were measured by high performance liquid chromatography coupled with CLC-MS / MS tandem mass spectrometry), methodology used by the IBiSA functional lipidomic platform (XMBL-INSA Lyon).

 These prostagiandins were measured on cultured cells and in the presence of constitutive and inducible cyclooxygenase iso-forms pure,

Resistates obtained

Figure 1 shows the evolution of COX II protease expression at different concentrations of AceDoPC (1, 2 and 20 μΜ).

 The Igra 2 presents a revolution in the secretion of PGE2 in the absence of AceDoPC and at a concentration of 20 μΜ in AceDoPC

 Figure 3 shows the evolution of proliferation of HT29P cells at different concentrations of AceDoPC (1, 2, 20 and 100 μM).

 Figure 4 shows the evolution of Bel -2 protic expression at different concentrations of AceDoPC {1, 2 and 20 μΗ)>

 Figura 5 shows the protic expression of HSP-27 at different concentrations of AceDoPC (1, 2 and 20 μΜ).

In these figures, p: probability or risk; CI: control that was made without AceDoPC, ^that is to say in the presence of a solvent.

 The results presented in these figures show; that on the cells

Intestinal tumors:

 the protelque expression of the COX H inductive cyclooxygenase is reduced by approximately 1/3 by 20 μl of AceDoPC (FIG 1),

this decrease by the same concentration of AceDoP increases to approximately 30% by measuring the PGE2 resulting from COX Π (FIG, 2), This result suggests an additional inhibition of the COX II activity, which is in agreement with those presented later on the purified COX II.

 The results presented Fyg, 3 to 5 show;

 - the proliferation of cancer cells is inhibited by approximately

50% at a concentration of 100 μΜ of AeeDoPC (Fig. 3),

the protein expression of the two anti-apoptotic proteins 8cl-2 and HSP-27 is significant at low concentrations of AeeDoPC (1 μM in FIGS _. 4 and 5, respectively),

 AceDoPC therefore has an anti-proliferative activity on cancer cells, certainly related to the under expression of the two anti-apoptotic proteins and to a decrease in the expression of COX IL.

The tests carried out on purified hydroxydrogenase were carried out in order to compare the effect of AeeDoPC with its acetyl-free equivalent (1-fyso, 2-DHA-PC) and with its acetylated analogue without DHA (1-acetyl, 2-yloyl). PC}, since DHA is known to inhibit COX purified (GH Rao Radhe _f e _{f t} White 3G 1983 117 (2): 549-555) the results are presented in Tables 1 and 2 below. The results are presented in ng and represent the sum of PGD2 - PGE2, then the average of the three measurements made more or less SD (deviation or standard error) is given,

Talblea 1;

 Effect of compounds: 1-iyso, 2-DHA-PC, i-acetyl, 2-oleoyl-PC and AceDoPC on human recombinant COX II protein (40 units of COX II / sample)

Tableau 2 :

Table 2:

 Effect of compounds; l-lyso-2-DHA-PC, 1-acetyl-2-oleoyi-PC and AceDoPC on sheep COX I protein (40 COX I units / sample)

Numbers bearing the same letter in expon are not significantly different from each other; a and b therefore indicate two different values. Asterisks allow to specify the level of meaning,

* p <0.05, ** p <0.01 versus control. ANOVA (varian analysis) followed by the Fischer test. It appears:

 - a stronger inhibition of CGX II with AceDoPC compared to 1-iyso-2-DHA-PQ which suggests a clean effect of acetyl. In the case where the DHA is replaced by an oieoyie radical, a lower inhibition is observed compared to the other two compounds tested,

 - The results are close on COX I (constitutive cyclooxygenase) ,, with however a lesser effect of the presence of the acetyl radical in 1-acetyl-oiéoyl-PC, Note however that the inhibition is stronger against COX II than COX I, which is an advantage for the intestine.

 These results suggest that AceDoPC would be able to acetylate protein targets because of a possibie acttvation of the acetyl group, present in the external position on the AceDoPC, or more generally of the acetyl group on the compounds of formula (I).

Claims

1 - Compound of formula (I)

Formula (I) in which :  X represents O, S or NH, and  represents unsaturated fatty acyl comprising at least one carbon-carbon double bond, or even at least two carbon-carbon double bonds; or one of its pharmaceutically acceptable hydrates, seis or soivates, in the form of a pure isomer or a mixture of isomers in all proportions, or medicament or pharmaceutical composition comprising such a compound of formula (I) or a hydrate thereof ,, seis soivats or pharmaceutically _acceptable, in the form of a pure isomer or a dlsomères mixture in all proportions, for use in the treatment of intestinal cancer or intestinal inflammation. 2 - Compound of formula (I):

Formula (I) in which :  X represents O, S or MH, and R represents an unsaturated fatty acyl comprising at least one carbon-carbon double bond, or even at least two carbon-carbon double bonds; or one of its pharmaceutically acceptable hydrates, salts or solvates, in the form of a pure isomer or a mixture of isomers in all proportions ,. or a drug or a pharmaceutical composition comprising such a compound of formula (I) or one of its pharmaceutically acceptable hydrates, salts or solvates, in the form of a pure isomer or a mixture of isomers in all proportions, for its use in the treatment of an intestinal disease or condition:  where a decrease in the expression and / or activity of cyclooxygenase II (COX II) is desired, and / or  - where a decrease in the expression of Bd-2 and / or HSP-2? is desired, and / or  in which the expression and / or activity of cyclooxygenase (COX II), and in particular a strong expression and / or activity of COX II, contributes to the pathological state and / or symptoms of the disease or condition. 3 - Compound, drug or pharmaceutical composition for its use, according to claim 1 or 2, characterized in that R is chosen from: * Dienes or trienes, chosen in particular from dienes EE, ZZ, EZ and ZE, your ZZ dienes being preferred, and trienes EZE, ΕΕΣ ZEE, ZZE _f ZEZ, EZZ, EEE and ZZZ, the EZE and ZZZ trienes being preferred,  polyunsaturated fatty acyies comprising 2, 3, 4, 5 or 6 carbon-carbon double bonds separated by a carbon atom, in particular in which the carbon-carbon double bonds are all of Z configuration, and more particularly fatty acid corresponding to an n-3 or n-6 fatty acid,  their derivatives, and their meiaboiites.  4 - A compound, a medicament or a pharmaceutical composition for its use, according to one of Claims 1 to 3, characterized in that R represents a trisene fatty acid EZE conjugated or corresponds to the acyl part of DHA, EPA, DPA, ARA, LNA. or LA,  5 - Compound, drug or pharmaceutical composition for its use, according to one of claims 1 to 4 characterized in that the compound of formula (I) used is 1-acetyl-2-docosahexaénoyi-glycerophosphoehoilne. 6 - compound, drug or pharmaceutical composition for use according to ^one of claims 1 to 5 _f in the treatment of chronic intestinal disease inflammatoir, especially for the treatment of ulcerative colitis or Crohn's disease, or in the treatment of colonic diverticuioses.