OLEIC ACID DERIVATIVES, PHARMACEUTICAL COMPOSITION OR FOOD COMPOSITION COMPRISING SAID OLEIC ACID DERIVATIVES, AND THEIR USES

Abstract

Disclosed is an oleic acid derivative including a hydrophobic part C17H33 linked to a particular polar head part “A”, especially for use as a medicament, for instance, for the treatment of a disorder caused by the GPR120 receptor and/or the CD36 receptor, including administering to a subject in need thereof a therapeutically effective amount of the oleic acid derivative or of the pharmaceutical composition. Also disclosed is the use of the oleic acid derivative as a food composition.

Claims

1. Oleic acid derivative of Formula (I) (Z or E) below comprising a hydrophobic part C.sub.17H.sub.33 linked to a polar head part “A”: ##STR00067## wherein said polar head part A is selected from A.sup.1 to A.sup.4 below: ##STR00068## wherein R.sup.1 and R.sup.2 are independently selected from the group composed of: H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 8 carbon atoms, or R.sup.1 and R.sup.2 are linked together to form a divalent radical of formula —R.sup.1-R.sup.2—, wherein —R.sup.1-R.sup.2— is —CH.sub.2—CH.sub.2— or —(CH.sub.2).sub.3—; with the proviso that: when R.sup.1 or R.sup.2═H, respectively R.sup.2 or R.sup.1 is different from H or from a straight alkyl group containing 2 or 8 carbon atoms, or when R.sup.1 or R.sup.2=—CH.sub.2CH.sub.3 or —CH(CH.sub.3).sub.2 or —(CH.sub.2).sub.3CH.sub.3, R.sup.1 and R.sup.2 are not identical; R.sup.3 is independently selected from the group composed of: ##STR00069## wherein R.sup.4 is independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, n is an integer selected from 1 to 4, and n′ is an integer that is equal to 0 or 1 with the proviso that when R.sup.4═H, n′≠0; “*” is the carbon atom which is attached to the oxygen atom of the A.sup.2 polar head; R.sup.12 is independently selected from the group composed a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, or an aromatic group or —CO.sub.2R.sup.13 in which R.sup.13 is a saturated alkyl group containing 1 to 4 carbon atoms; R.sup.14, R.sup.15, R.sup.16 is independently selected from H or CH.sub.3; R.sup.5, R.sup.6 and R.sup.7 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, or —CO.sub.2R.sup.8 in which R.sup.8 is a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, with the proviso that when R.sup.7 is H or CH.sub.3, at least one of R.sup.5 and R.sup.6 are different from H or CH.sub.3; R.sup.11 is selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 10 carbon atoms, R.sup.9═H or CH.sub.3 and R.sup.10 is a straight or branched alkyl group containing 2 to 10 carbon atoms; or a pharmaceutically/food quality acceptable salts thereof.

2. The oleic acid derivatives according to claim 1, having a molecular weight ranging from about 300 to about 600 g/mol.

3. The oleic acid derivatives according to claim 1, wherein in A.sup.1, R.sup.1 and R.sup.2 are independently selected from the group composed of methyl, or a saturated or unsaturated, straight or branched alkyl group containing 4 to 6 carbon atoms.

4. The oleic acid derivatives according to claim 1, wherein in A1, R.sup.1 and R.sup.2 are linked together so that —R.sup.1-R.sup.2— is —(CH.sub.2).sub.3 or R.sup.1 and R.sup.2 are a saturated straight alkyl group containing 4 carbon atoms, or a pharmaceutically/food quality acceptable salts thereof.

5. The oleic acid derivatives according to claim 1, wherein in A.sup.2, R.sup.3 is ##STR00070## wherein R.sup.4 is H, n=1, n′=1; or R.sup.4 is CH.sub.3, n=1, n′=1; or R.sup.4 is H, n=2, n′=1; or a pharmaceutically/food quality acceptable salts thereof.

6. The oleic acid derivatives according to claim 1, wherein in A.sup.2, R.sup.3 is ##STR00071## or a pharmaceutically/food quality acceptable salts thereof.

7. The oleic acid derivatives according to claim 1, wherein in A.sup.3, R.sup.5 is H, R.sup.6 is —CO.sub.2CH.sub.3 and R.sup.7 is H or R.sup.5 is —CO.sub.2CH.sub.3, R.sup.6 is H and R.sup.7 is H, or a pharmaceutically/food quality acceptable salts thereof.

8. The oleic acid derivatives according to claim 1, wherein in A.sup.4, R.sup.9 is H, R.sup.10 is C.sub.2H.sub.5 and R.sup.11 is H, or a pharmaceutically/food quality acceptable salts thereof.

9. A medicament comprising the oleic acid derivatives of Formula (I) below comprising a hydrophobic part C.sub.17H.sub.33 (Z or E) linked to a polar head part “A” ##STR00072## wherein said polar head part A is selected from A.sup.1 to A.sup.4 below: ##STR00073## wherein R.sup.1 and R.sup.2 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 8 carbon atoms, or R.sup.1 and R.sup.2 are linked together to form a divalent radical of formula —R.sup.1-R.sup.2—, R.sup.3 is independently selected from the group composed of: ##STR00074## wherein R.sup.4 is independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, n is an integer selected from 1 to 4, and n′ is an integer that is equal to 0 or 1; “*” is the carbon atom which is attached to the oxygen atom of the A.sup.2 polar head; R.sup.12 is independently selected from the group composed from H or an alkyl group containing 1 to 4 carbon atoms, or an aromatic group (such as Ph, Tol, Xyl) or —CO.sub.2R.sup.13 in which R.sup.13 is a saturated alkyl group containing 1 to 4 carbon atoms, R.sup.14, R.sup.15, R.sup.16 is independently selected from H or CH.sub.3; or R.sup.14═H or CH.sub.3 and R.sup.15=R.sup.16═H; R.sup.5, R.sup.6 and R.sup.7 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, or —CO.sub.2R.sup.8 in which R.sup.8 is a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, with the proviso that when R.sup.7 is H or CH.sub.3, R.sup.5 and R.sup.6 are different from H or CH.sub.3; R.sup.11 is selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 10 carbon atoms, is H or CH.sub.3 and R.sup.10 is a straight or branched alkyl group containing 2 to 10 carbon atoms; or a pharmaceutically/food quality acceptable salts thereof.

10. A pharmaceutical composition or food composition comprising, respectively, at least one pharmaceutically acceptable carrier and at least one oleic acid derivative as defined in claim 9. at least one food ingredient and/or at least one food additive and at least one oleic acid derivative such as defined in claim 9.

11. A method for treatment of a disorder modulated by the GPR120 receptor and/or the CD36 receptor, comprising: administering to a subject in need thereof a therapeutically effective amount of an oleic acid derivatives of Formula (I) below comprising a hydrophobic part C.sub.17H.sub.33 (Z or E) linked to a polar head part “A” ##STR00075## wherein said polar head part A is selected from A.sup.1 to A.sup.4 below: ##STR00076## wherein R.sup.1 and R.sup.2 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 8 carbon atoms, or R.sup.1 and R.sup.2 are linked together to form a divalent radical of formula —R.sup.1-R.sup.2—, R.sup.3 is independently selected from the group composed of: ##STR00077## wherein R.sup.4 is independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, n is an integer selected from 1 to 4, and n′ is an integer that is equal to 0 or 1; “*” is the carbon atom which is attached to the oxygen atom of the A.sup.2 polar head; R.sup.12 is independently selected from the group composed from H or an alkyl group containing 1 to 4 carbon atoms, or an aromatic group (such as Ph, Tol, Xyl) or —CO.sub.2R.sup.13 in which R.sup.13 is a saturated alkyl group containing 1 to 4 carbon atoms, R.sup.14, R.sup.15, R.sup.16 is independently selected from H or CH.sub.3; or R.sup.14═H or CH.sub.3 and R.sup.15=R.sup.16═H; R.sup.5, R.sup.6 and R.sup.7 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms, or —CO.sub.2R.sup.8 in which R.sup.8 is a saturated or unsaturated, straight or branched alkyl group containing 1 to 4 carbon atoms; R.sup.9 to R.sup.11 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 10 carbon atoms; or administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically/food quality acceptable salts thereof or pharmaceutical composition according to claim 10.

12. The oleic acid derivatives according to claim 1, wherein the disorder modulated by the GPR120 receptor and/or the CD36 receptor is selected from the group consisting of: diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, body weight disorder, fatty liver disease, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), lipid disorders and liver diseases.

13. An appetite suppressant comprising the oleic acid derivative according to claim 1.

14. A food supplement or dietary supplement for animal or human food, or ready-cooked dish, or animal feedstuff, comprising the food composition according to claim 10.

15. A method of enhancing taste, modulating taste, suppressing appetite, or improving the physical appearance of individuals, comprising applying an effective amount of the oleic acid derivative according to claim 1.

16. The oleic acid derivative of claim 1, wherein: R.sup.4 is CH.sub.3; R.sup.14=R.sup.15=R.sup.16═CH.sub.3 or R.sup.14═H or CH.sub.3 and R.sup.15=R.sup.16═H; and R.sup.5 and R.sup.6 are different from H or CH.sub.3.

17. The oleic acid derivatives according to claim 1, having a molecular weight ranging from 330 to 460 g/mol.

18. The oleic acid derivatives according to claim 3, wherein when R.sup.1 or R.sup.2=—(CH.sub.2).sub.3CH.sub.3, respectively R.sup.2 or R.sup.1≠—(CH.sub.2).sub.3CH.sub.3.

19. The oleic acid derivatives according to claim 1, wherein in A.sup.1, R.sup.1 and R.sup.2 are independently selected from the group composed of methyl, or a saturated or unsaturated, straight or branched alkyl group containing 4 to 6 carbon atoms with the proviso that when R.sup.1 or R.sup.2=—(CH.sub.2).sub.3CH.sub.3, respectively R.sup.2 or R.sup.1≠—(CH.sub.2).sub.3CH.sub.3.

20. The oleic acid derivatives of claim 9, wherein: when R.sup.4═H, n′≠0 and n≠1; R.sup.14=R.sup.15=R.sup.16═CH.sub.3; and R.sup.11 is selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 2 to 10 carbon atoms.

Description

DESCRIPTION OF THE FIGURES

[0211] The present invention will be hereafter illustrated without being limited thereto by means of the following examples. It will be referred to the following figures in the examples:

[0212] FIG. 1A: Measurement of intracellular free calcium concentrations, [Ca.sup.2+]i (F.sub.340/F.sub.380) induced by the introduction of one oleic acid derivative according to the invention: compound 3a, in mouse taste bud cells loaded with Fura-2/AM probe—the arrow indicates the time when compound 3a, without any interruption in the recording, was added into the cuvette, containing the cells—the figure shows a single trace of several times reproduced experiments;

[0213] FIG. 1B: Action of the CD36 inhibitor (20 μM SSO, Sulfo-/V-succinimidyl Oleate) on the increase in intracellular free calcium concentrations, [Ca.sup.2+]l (F.sub.340/F.sub.380), by the oleic acid derivative described in FIG. 1A (compound 3a) in mouse taste bud cells loaded with Fura-2/AM probe—the arrow indicates the time when compound 3a, without any interruption in the recording, was added into the cuvette, containing the cells—the figure shows a single trace of several times reproduced experiments—the SSO completely blocked the responses triggered by OA and 3a;

[0214] FIG. 2A: Measurement of intracellular free calcium concentrations, [Ca.sup.2+]i (F.sub.340/F.sub.380) induced by the introduction of one oleic acid derivative according to the invention: compound 2a, in mouse taste bud cells loaded with Fura-2/AM probe—the arrow indicates the time when the agonist (2a), without any interruption in the recording, was added into the cuvette, containing the cells—the figure shows a single trace of several times reproduced experiments;

[0215] FIG. 2B: Action of the CD36 inhibitor (20 μM SSO, Sulfo-/V-succinimidyl Oleate) on the increase in intracellular free calcium concentration [Ca.sup.2+]l (F.sub.340/F.sub.380), by the oleic acid derivative described in FIG. 2A in mouse taste bud cells loaded with Fura-2/AM probe (the cells were pre-incubated for 15 minutes prior to the addition of 2a compound)—the arrow indicates the time when compound 2a, without any interruption in the recording, was added into the cuvette, containing the cells—the figure shows a single trace of several times reproduced experiments—the SSO partially blocked the responses triggered by OA and 2a;

[0216] FIG. 3: Effect of GPR120 inhibitor (AH7614 that is a commercially available known GPR120 antagonist) at 20 μM on the increase in [Ca.sup.2+]l (F.sub.340/F.sub.380) by the oleic acid derivative 2a according to the invention (at 50 μM) in mouse taste bud cells, the cells were pre-incubated for 15 minutes prior to the addition of 2a compound—the arrow indicates the time when the agonist (2a), without any interruption in the recording, was added into the cuvette, containing the cells—the figure shows a single trace of several times reproduced experiments;

[0217] FIG. 4: Gustatory preference for the oleic acid derivative 3a according to the invention in a two bottle-preference test; this figure shows the dose-dependent effect of 3a; n=18 per group; the asterisk shows the significant difference as compared to the control solution (p<***) as per statistical students t-test of significance: the mice are subjected to two bottles: one (CTRL=control) containing water plus xanthan gum) and other TEST contains the same mixture and compound 3a at increasing concentrations as mentioned in the Figure—the bottles were weighed before and after 12 hrs of interval and the solution consumed by the animals was deduced; and

[0218] FIG. 5: Gustatory preference for the oleic acid derivative 2a according to the invention in a two bottle-preference test; this figure shows the dose-dependent effect of 2a; n=18 per group; the asterisk shows the significant difference as compared to the control solution (p<***) as per statistical students t-test of significance: the mice are subjected to two bottles: one (CTRL=control) containing water plus xanthan gum) and other TEST contains the same mixture and compound 2a at increasing concentrations as mentioned in the Figure—the bottles were weighed before and after 12 hrs of interval and the solution consumed by the animals was deduced.

[0219] FIG. 6: Effect of oleic acid derivative 3a (FIG. 6A) and oleic acid derivative 2a (FIG. 6B) on diet-induced obesity. The animals were kept on a high-fat diet (HFD) for 28 weeks; however, from 10.sup.th week onwards, the baby-bottles/feeders contained either control solution (control group) or analogues (3a or 2a). The arrows indicate when the lipid analogues were added. The results are expressed as the means±SEM (n=10). p values represent the significant differences between the group of mice given either water and analogues in the feeder bottles.

[0220] FIG. 7: CRP concentrations in blood circulation. The results are expressed as the means±SEM (n=10). p values represent the significant differences between the group of mice given either water and analogues in the feeder bottles. Abbreviations: HFD=high-fat diet.

EXAMPLES

1. Synthesis of Different Oleic Acid Derivatives of the Invention

1.1 Synthesis of (Z)-(3-methyloxetan-3-yl)methyl octadec-9-enoate, with n=1 and n′=1 and R.SUP.4.═CH.SUB.3., Also Called, Compound 2a (17FM016)

[0221] ##STR00051##

[0222] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0223] A solution of 3-methyl-3-oxetane methanol (0.14 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70). m.sub.pure=231 mg. Aspect: colorless oil. Yield: 90%.

[0224] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.37-5.30 (m, 2H), 4.52 (d, 2H, J=6.0 Hz), 4.38 (d, 2H, J=6.0 Hz), 4.15 (s, 2H), 2.35 (t, 2H, J=7.6 Hz), 2.02-1.98 (m, 4H), 1.66-1.61 (m, 2H), 1.33-1.26 (m, 23H), 0.88 (t, 3H, J=7.0 Hz).

[0225] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.87, 129.99, 129.68, 79.56 (2×), 68.43, 39.06, 34.19, 31.87, 29.73, 29.65, 29.49, 29.28 (2×), 29.12, 29.09, 29.06, 27.18, 27.12, 24.94, 22.64, 21.17, 14.07.

[0226] IR (neat cm.sup.−1) ν=3003 (small), 2923 (broad), 2854 (broad), 1739 (strong), 1460, 1377 (small), 1351 (small), 1239, 1162 (broad), 1119 (small), 1090 (small), 983 (strong), 940 (small), 834 (small), 722 (broad).

[0227] HRMS calcd for C.sub.23H.sub.43O.sub.3 [M+H].sup.+=367.3207; found: 367.3207.

1.2 Synthesis of (E)-(3-methyloxetan-3-yl)methyl octadec-9-enoate, with n=1 and n′=1 and R.SUP.4.═CH.SUB.3., Also Called, Compound 2b (17FM020)

[0228] ##STR00052##

[0229] In a round bottom flask were introduced elaidic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0230] A solution of 3-methyl-3-oxetane methanol (0.14 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70). m.sub.pure=212.7 mg. Aspect: white solid. Yield: 83%.

[0231] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.43-5.32 (m, 2H), 4.52 (d, 2H, J=6.0 Hz), 4.38 (d, 2H, J=6.0 Hz), 4.16 (s, 2H), 2.35 (t, 2H, J=7.6 Hz), 1.98-1.94 (m, 4H), 1.70-1.56 (m, 3H), 1.37-1.22 (m, 22H), 0.88 (t, 3H, J=6.9 Hz).

[0232] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.89, 130.49, 130.18, 79.59 (2×), 68.45, 39.11, 34.22, 32.59, 32.53, 31.89, 29.65, 29.55, 29.48, 29.30, 29.17, 29.11, 29.09, 28.94, 24.98, 22.67, 21.20, 14.09.

[0233] IR (neat cm.sup.−1) ν=2963 (small), 2918 (strong), 2849 (strong), 1737 (strong), 1466, 1413, 1392, 1357 (small), 1314 (small), 1294 (small), 1253, 1209, 1162 (broad), 1095 (small), 1065 (small), 1041 (small), 999, 962 (strong), 932 (small), 908 (small), 836 (small), 776 (small), 757 (small), 720, 662 (small), 575 (small), 526 (small), 445 (small), 410 (small).

[0234] HRMS calcd for C.sub.23H.sub.43O.sub.3 [M+H].sup.+: 367.3207; found: 367.3208.

1.3 Synthesis of (Z)-(tetrahydrofuran-2-yl)methyl octadec-9-enoate with n=3 and n′=0 and R.SUP.4.═H, Called Hereafter Compound 2c (17FM060)

[0235] ##STR00053##

[0236] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0237] A solution of (±)-tetrahydrofurfuryl alcohol (0.14 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2 (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70). m.sub.pure=235 mg. Aspect: colorless oil. Yield: 92%.

[0238] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.41-5.26 (m, 2H), 4.16 (dd, 1H, J=3.6 Hz, J=11.2 Hz), 4.11 (qd, 1H, J=3.5 Hz, J=6.9 Hz), 3.99 (dd, 1H, J=6.6 Hz, J=11.3 Hz), 3.89 (dt, 1H, J=6.6 Hz, J=8.7 Hz), 3.83-3.76 (m, 1H), 2.34 (t, 2H, J=7.6 Hz), 2.00 (qd, 5H, J=2.2 Hz, J=6.3 Hz), 1.97-1.84 (m, 2H), 1.65-1.56 (m, 4H), 1.37-1.21 (m, 19H), 0.88 (t, 3H, J=6.8 Hz).

[0239] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.80, 129.98, 129.75, 76.56, 68.42, 66.31, 34.21, 31.89, 29.76, 29.68, 29.51, 29.31, 29.30, 29.15, 29.10, 29.09, 28.01, 27.21, 27.16, 25.65, 24.92, 22.66, 14.08.

[0240] IR (neat cm.sup.−1) ν: 3008 (small), 2924 (broad), 2854 (broad), 1737 (strong), 1458, 1362 (small), 1239, 1169 (broad), 1082 (broad), 1023, 991, 916, 722 (broad).

[0241] HRMS calcd for C.sub.23H.sub.43O.sub.3 [M+H].sup.+: 367.3207; found: 367.3204.

1.4 Synthesis of (Z)-(tetrahydrofuran-3-yl) methyl octadec-9-enoate with n=2, n′=1 and R.SUP.4.═H, Called Hereafter Compound 2d (18FM094)

[0242] ##STR00054##

[0243] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0244] A solution of tetrahydro-3-furanmethanol (0.14 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70), m=236.1 mg. Aspect: colorless oil. yield: 93%.

[0245] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.34 (qd, 2H, J=1.9 Hz, J=3.9 Hz), 4.09 (dd, 1H, J=6.5 Hz, J=10.9 Hz), 3.97 (dd, 1H, J=8.0 Hz, J=10.9 Hz), 3.90-3.82 (m, 2H), 3.79-3.71 (m, 1H), 3.56 (dd, 1H, J=5.6 Hz, J=8.8 Hz), 2.62-2.51 (m, 1H), 2.30 (t, 2H, J=7.5 Hz), 2.08-1.96 (m, 5H), 1.67-1.57 (m, 4H), 1.37-1.20 (m, 19H), 0.88 (t, 3H, J=6.9 Hz).

[0246] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.77, 130.00, 129.71, 70.54, 67.70, 65.66, 38.26, 34.25, 31.89, 29.75, 29.67, 29.50, 29.30 (2×), 29.14, 29.10, 29.08, 28.94, 27.20, 27.14, 24.95, 22.66, 14.09.

1.5 Synthesis of (Z)-(oxetan-3-yl)methyl octadec-9-enoate with n=1, n′=1 and R.SUP.4.═H, Called Hereafter Compound 2e (17FM057)

[0247] ##STR00055##

[0248] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0249] A solution of 3-oxatane alcohol (0.12 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70). m.sub.pure=233.5 mg. Aspect: colorless oil. Yield: 95%.

[0250] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.40-5.29 (m, 2H), 4.79 (dd, 2H, J=6.3 Hz, J=7.9 Hz), 4.47 (t, 2H, J=6.2 Hz), 4.30 (d, 2H, J=6.7 Hz), 3.34-3.21 (m, 1H), 2.32 (t, 2H, J=7.6 Hz), 2.01 (q, 5H, J=6.3 Hz), 1.67-1.54 (m, 3H), 1.36-1.22 (m, 18H), 0.94-0.82 (m, 3H).

[0251] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.79, 130.01, 129.69, 74.09 (2×), 64.98, 34.16, 34.11, 31.88, 29.74, 29.66, 29.50, 29.29 (2×), 29.12, 29.08 (2×), 27.20, 27.14, 24.92, 22.65, 14.08.

[0252] IR (neat cm.sup.−1) ν=3003 (small), 2923 (broad), 2853 (broad), 1738 (strong), 1461, 1362 (small), 1240, 1164 (broad), 1119 (small), 1092 (small), 984 (strong), 946 (small) 855 (small), 723 (broad).

[0253] HRMS calcd for C.sub.22H.sub.41O.sub.3 [M+H].sup.+: 353.3050; found: 353.3052.

1.6 Synthesis of (Z)-(oxiran-2-yl)methyl octadec-9-enoate with n=1, n′=0 and R.SUP.4.═H, Called Hereafter Compound 2f (17FM066)

[0254] ##STR00056##

[0255] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0256] A solution of glycidol (105.2 mg, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.70). m.sub.pure=235.5 mg. Aspect: colorless oil. Yield: 99%.

[0257] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.42-5.27 (m, 2H), 4.41 (dd, 1H, J=3.0 Hz, J=12.3 Hz), 3.91 (dd, 1H, J=6.3 Hz, J=12.3 Hz), 3.25-3.12 (m, 1H), 2.84 (td, 1H, J=1.5 Hz, J=4.4 Hz), 2.64 (dd, 1H, J=2.6 Hz, J=4.9 Hz), 2.38-2.28 (m, 2H), 2.07-1.92 (m, 4H), 1.63 (q, 2H, J=7.4 Hz), 1.36-1.27 (m, 20H), 0.88 (td, 3H, J=1.6 Hz, J=6.9 Hz).

[0258] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.52, 130.00, 130.72, 64.74, 49.38, 44.65, 34.13, 34.05, 31.89, 29.75, 29.67, 29.51, 29.31, 29.13, 29.08, 27.21, 27.15, 24.89, 24.85, 22.67, 14.09.

[0259] IR (neat cm.sup.−1) ν=3004 (small), 2923 (broad), 2853 (broad), 1739 (strong), 1458, 1374 (small), 1358 (small), 1243, 1172 (broad), 1118, 1092, 1052, 1017, 910 (small), 855 (small), 722 (small).

[0260] HRMS calcd for C.sub.21H.sub.38O.sub.3Na [M+Na].sup.+: 361.2713; found: 361.2714.

1.7 Synthesis of (Z)-oxopropyl octadec-9-enoate Called Hereafter Compound 2g (17FM064)

[0261] ##STR00057##

[0262] In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0263] A solution of hydroxyacetone (0.2 mL, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1.5), R.sub.f=0.60). m.sub.pure=234 mg. Aspect: colorless oil. Yield: 99%.

[0264] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.43-5.25 (m, 2H), 4.64 (s, 2H), 2.42 (t, 2H, J=7.6 Hz), 2.16 (s, 3H), 2.08-1.94 (m, 4H), 1.67 (p, 2H, J=7.5 Hz), 1.34-1.26 (m, 20H), 0.88 (t, 3H, J=6.9 Hz).

[0265] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 201.67, 173.02, 130.00, 129.74, 68.14, 33.81, 31.89, 29.76, 29.68, 29.51, 29.31, 29.30, 29.14, 29.08, 29.05, 27.21, 27.16, 26.05, 24.83, 22.67, 14.08

[0266] IR (neat cm.sup.−1) ν: 3004 (small), 2923 (broad), 2853, 1734 (strong), 1462 (broad), 1418 (broad), 1373 (broad), 1357 (broad), 1270 (small), 1239 (small), 1195 (small), 1153 (broad), 1120, 1094 (small), 1057 (small), 967 (small), 894 (small), 723 (broad).

[0267] HRMS calcd for C.sub.21H.sub.39O.sub.3 [M+H].sup.+: 339.2894; found: 339.2893.

1.8 Synthesis of (Z)-(2,5,5-trimethyl-1,3-dioxan-2-yl)methyl octadec-9-enoate, Called Hereafter Compound 2h (17FM058)

[0268] ##STR00058##

[0269] This compound was prepared by reaction of oleic acid and 2,2,5-trimethyl-1,3-dioxane-5-methanol (called hereafter 17FM025), known in literature and prepared as describe below.

##STR00059##

[0270] 17FM025: In a round bottom flask were introduced tris(hydroxymethyl)ethane (2 g, 16.7 mmol) and a catalytic quantity of PTSA (2 mg) in acetone under inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was neutralized with 50 mg of K.sub.2CO.sub.3, filtrated and evaporated to give the desired product with 96% of purity. m.sub.pure=2.64 g. Aspect: colorless oil. Yield: 98%.

[0271] .sup.1H NMR (500 MHz, DMSO) δ (ppm): 4.57 (t, 1H, J=5.4 Hz), 3.49 (AB system, 2H, J=11.7 Hz), 3.44 (AB system, 2H, J=11.7 Hz), 3.35 (d, 1H, J=5.3 Hz), 1.33 (s, 3H), 1.27 (s, 3H), 0.75 (s, 3H).

[0272] .sup.13C {.sup.1H} NMR (126 MHz, DMSO) δ (ppm): 96.92, 65.34 (2×), 63.61, 34.22, 25.80, 21.57, 17.61.

[0273] Compound 2h: In a round bottom flask were introduced oleic acid (200 mg, 0.7 mmol) and dichloromethane (2 mL) under inert atmosphere. The mixture was cooled to 0° C. and oxalyl chloride (0.07 mL, 0.78 mmol) was introduced dropwise. Then the catalytic quantity of DMF (5 μL) was added. The reaction mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step. Aspect: yellow oil with slight precipitate.

[0274] A solution of 2,5,5-trimethyl-1,3-dioxane-2-methanol (228 mg, 1.42 mmol), triethylamine (0.2 mL, 1.42 mmol) in THF (4 mL) was prepared in a round bottom flask under inert atmosphere. The mixture was cooled to 0° C. and freshly prepared oleoyl chloride (212 mg, 0.7 mmol) in THF (4 mL) was added via cannula. After stirring for overnight at RT, the mixture was worked up by addition of distilled water (6 mL). The product was extracted with ethyl acetate (3×15 mL), dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.73). m.sub.pure=262 mg. Aspect: colorless oil. Yield: 87%.

[0275] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.47-5.18 (m, 2H), 4.15 (s, 2H), 3.70-3.57 (m, 4H), 2.32 (t, 2H, J=7.6 Hz), 2.14-1.88 (m, 4H), 1.63 (t, 2H, J=7.2 Hz), 1.44 (s, 3H), 1.40 (s, 3H), 1.37-1.19 (m, 20H), 0.88 (t, 3H, J=6.8 Hz), 0.85 (s, 3H).

[0276] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 173.77, 130.00, 129.73, 98.04, 66.63, 66.31 (2×), 34.30, 33.54, 31.89, 29.76, 29.68, 29.51, 29.31, 29.30, 29.15, 29.09, 27.21 (2×), 27.16, 26.74, 24.96, 22.67, 20.58, 17.80, 14.09.

[0277] IR (neat cm.sup.−1) ν=2993 (small), 2923 (broad), 2854 (broad), 1737 (strong), 1456 (broad), 1395 (small), 1372, 1349 (small), 1265 (broad), 1246 (broad), 1227 (broad), 1206 (broad), 1186 (broad), 1155 (broad), 1090 (strong), 1043, 1025 (broad), 933 (small), 912 (small), 830 (strong), 729 (broad), 673 (small).

[0278] HRMS calcd for C.sub.26H.sub.48O.sub.4Na [M+Na].sup.+: 447.3448; found: 447.3431.

1.9 Synthesis of ethyl (S)-[(Z)-heptadec-8-en-yl-4,5-dihydrooxazole-4-carboxylate Called Hereafter Compound 2i (18FM100)

[0279] ##STR00060##

[0280] In a round bottom flask were introduced (S)-ethyl-3-hydroxy-2((Z)-octadeca-9-enamido)-propanoate (500 mg, 1.26 mmol), dry DCM (3 mL) and iPr.sub.2NEt (0.5 mL, 2.77 mmol) under inert atmosphere. After 30 min, the mixture was cooled to 0° C. and Deoxofluor (0.6 mL, 2.77 mmol) was added dropwise. After 16 h at room temperature, the crude mixture was directly engaged on SiO.sub.2 gel chromatography for purification, (petroleum ether/ethyl acetate (6:4), R.sub.f=0.71). m.sub.pure=268.3 mg. Aspect: yellow oil. Yield: 56%.

[0281] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.42-5.26 (m, 2H), 4.76-4.65 (m, 1H), 4.49-4.42 (m, 1H), 4.37 (dd, 1H, J=8.7 Hz, J=10.6 Hz), 4.30-4.17 (m, 2H), 2.38-2.27 (m, 2H), 2.08-1.94 (m, 4H), 1.70-1.59 (m, 3H), 1.38-1.21 (m, 22H), 0.88 (t, 3H, J=6.9 Hz).

[0282] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 171.38, 170.81, 129.97, 129.75, 69.26, 68.22, 61.57, 31.89, 29.75, 29.68, 29.50, 29.30, 29.09 (2×), 27.96, 27.20, 27.16, 25.91, 22.66, 14.13, 14.09. 2 C are missing.

[0283] HRMS calcd for C.sub.23H.sub.42NO.sub.3 [M+H].sup.+: 380.3159; found: 380.3156.

1.10 Synthesis of ethyl (S)-3-hydroxy-2-[(Z)-octadec-9-enamido]propanoate Called Hereafter Compound 2j (18FM099)

[0284] ##STR00061##

[0285] This compound was prepared by reaction of oleic acid and L-serine ethyl ester hydrochloride salt (called hereafter 18FM097), known in literature and prepared as describe below.

[0286] 18FM097:

##STR00062##

[0287] In a round bottom flask were introduced L-serine (2 g, 19.03 mmol) in ethanol (20 mL) under inert atmosphere. The mixture was cooled to 0° C. and SOCl.sub.2 was added dropwise. The reaction mixture was refluxed overnight before evaporation to dryness to give the L-serine ethyl ester as hydrochloride salt. m.sub.pure=2.5 g. Aspect: white solid. Yield: quant.

[0288] .sup.1H NMR (500 MHz, DMSO) δ (ppm) δ 8.52 (s, 3H), 5.60 (t, 1H, J=5.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 4.07 (t, 1H, J=3.6 Hz), 3.95-3.75 (m, 2H), 1.23 (t, 3H, J=7.1 Hz).

[0289] .sup.13C {.sup.1H} NMR (126 MHz, DMSO) δ (ppm): 168.42, 62.54, 59.85, 54.79, 14.36.

[0290] Compound 2j: In a round bottom flask were introduced oleic acid (1 g, 3.54 mmol), dry THF (50 mL), L-serine ethyl ester hydrochloride salt (600 mg, 3.54 mmol), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (2.03 g, 3.9 mmol) under inert atmosphere. The mixture was treated with iPr.sub.2NEt (1.36 mL, 7.8 mmol) and stirred for 4 h at room temperature. After removing solvent under vacuum, the residue was dissolved in EtOAc, successively treated by HCl 1N, water, saturated aqueous NaHCO.sub.3 and brine. The organic layer was dried over MgSO.sub.4 and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (1:3), R.sub.f=0.58). m.sub.pure=1.13 g. Aspect: white solid. Yield: 80%.

[0291] .sup.1H NMR (500 MHz, DMSO) δ (ppm): 8.01 (bd, 1H, J=7.6 Hz), 5.40-5.21 (m, 2H), 4.95 (t, 1H, J=5.7 Hz), 4.30 (dt, 1H, J=5.0 Hz, J=7.9 Hz), 4.07 (q, 2H, J=7.1 Hz), 3.63 (ddt, 2H, J=5.3 Hz, J=10.6 Hz, J=33.3 Hz), 2.17-2.08 (m, 2H), 2.06-1.91 (m, 4H), 1.56-1.44 (m, 2H), 1.30-1.12 (m, 23H), 0.85 (t, 3H, J=6.8 Hz).

[0292] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): δ 173.80, 170.55, 129.87, 129.59, 63.27, 63.13, 61.70, 54.59, 36.34, 31.78, 29.65, 29.61, 29.40, 29.20 (2×), 29.17, 29.12, 29.04, 27.10, 27.07, 25.48, 22.56, 13.99.

[0293] HRMS calcd for C.sub.23H.sub.44NO.sub.4 [M+H].sup.+: 398.3265; found: 398.3258.

1.11 Synthesis of diethyl (Z)-octadec-9-en-1-yl phosphonate, called Hereafter Compound 3a (17FM026)

[0294] ##STR00063##

[0295] This compound was prepared from oleic acid via the alcohol (17FM018) and the bromide (17FM023) described below. Both precursors are known in literature.

[0296] 17FM018:

##STR00064##

[0297] In a round bottom flask was suspended LiAlH.sub.4 (0.36 g, 9.4 mmol) in THF (50 mL). A solution of oleic acid (2.5 mL, 7.9 mmol) in THF (20 mL) was added dropwise at 0° C. The mixture was slowly warmed up to room temperature and stirred overnight. The mixture was quenched by addition of distilled water (17 mL) and 15% aqueous NaOH (12 mL). The mixture was diluted in EtOAc, transferred in a separating funnel then washed with brine. The organic phase was dried over MgSO.sub.4, filtered over celite and concentrated. The product was purified by a column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (5:1), R.sub.f=0.80). m.sub.pure=1.9 g. Aspect: colorless oil. Yield: 75%.

[0298] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.38-5.31 (m, 2H), 3.64 (t, 2H, J=6.7 Hz), 2.02-1.99 (m, 4H), 1.56 (quint, 2H, J=6.9 Hz), 1.36-1.27 (m, 22H), 0.88 (t, 3H, J=6.9 Hz).

[0299] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 129.93, 129.78, 63.06, 32.76, 31.87, 29.73, 29.71, 29.49, 29.47, 29.37, 29.29 (2×), 29.20, 27.18, 27.16, 25.71, 22.65, 14.07.

[0300] 17FM023:

##STR00065##

[0301] In a round bottom flask containing (Z)-octadeca-9-en-1-ol (1.55 g, 5.8 mmol) in DCM (30 mL), was added carbon tetrabromide (3.5 g, 10.6 mmol) at 0° C., the mixture is let stirred for 10 minutes, then triphenylphosphine (3.1 g, 11.6 mmol) was added. The solution was stirred for 10 min at 0° C., then let warmed up overnight and concentrated under reduced pressure. The product was purified by a column chromatography on SiO.sub.2. (petroleum ether, R.sub.f=0.90). m.sub.pure=1.9 g. Aspect: colorless oil. Yield: 99%.

[0302] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.36-5.29 (m, 2H), 3.38 (t, 2H, J=6.9 Hz), 2.01-1.97 (m, 4H), 1.83 (quint, 2H, J=7.2 Hz), 1.43-1.37 (m, 2H), 1.39-1.31 (m, 20H), 0.86 (t, 3H, J=7.1 Hz)

[0303] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 130.01, 129.76, 33.94, 32.84, 31.90, 29.76, 29.70, 29.52, 29.32 (2×), 29.16, 28.74, 28.17, 27.21, 27.16, 22.67, 14.08, one C is missing.

[0304] Compound 3a (17FM026)

[0305] In a Schlenk were introduced diethyl phosphite (1.3 mL, 10.3 mmol) and THF (8 mL). The mixture was cooled to 0° C. and NaHMDS 2M (6.0 mL, 12.0 mmol) was added. The mixture was stirred at room temperature for half an hour. Then the reaction was cooled to 0° C. and (Z)-octadec-9-en-1-yl-bromide (1.4 g, 4.3 mmol) in THF (8 mL) was transferred on the reaction mixture via cannula. After 30 minutes, the mixture was stirred overnight at 25° C. The reaction medium was concentrated under reduced pressure, and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (1:4), R.sub.f=0.50). m.sub.pure=1.34 g. Aspect: slightly yellow oil. Yield: 80%.

[0306] .sup.1H NMR (500 MHz, CD.sub.2Cl.sub.2) δ (ppm): 5.37-5.31 (m, 2H), 4.14-4.03 (m, 4H), 2.04-1.98 (m, 4H), 1.75-1.54 (m, 5H), 1.62-1.57 (m, 2H), 1.38-1.24 (m, 25H), 0.88 (t, 3H, J=7.0 Hz)

[0307] .sup.13C {.sup.1H} NMR (126 MHz, CD.sub.2Cl.sub.2) δ (ppm): 129.98, 129.78, 67.09, 61.38 (d, J=7.2 Hz), 53.42, 31.90, 30.69, 30.55, 29.76, 29.73, 29.52, 29.32, 29.31 (d, J=2.9 Hz), 29.23, 29.08, 27.20 (d, J=3.0 Hz), 26.26, 25.14, 22.68, 22.40 (d, J=5.0 Hz), 16.47 (d, J=6.7 Hz), 14.11

[0308] .sup.31P {.sup.1H} NMR (203 MHz, CDCl.sub.3) δ (ppm): +32.65.

[0309] IR (neat cm.sup.−1) ν=2922 (broad), 2853, 1462 (small), 1391 (small), 1368 (small), 1243 (broad), 1163 (small), 1096 (small), 1056 (broad), 1028 (strong), 955 (broad), 813 (small), 784 (small), 722 (small).

[0310] HRMS calcd for C.sub.22H.sub.45O.sub.3PNa [M+Na].sup.+: 411.2999; found 411.2998.

1.11 Synthesis of dibutyl (Z)-octadec-9-en-1-yl phosphonate, Called Hereafter compound 3c (18FM110)

[0311] ##STR00066##

[0312] This compound was prepared from oleic acid via the alcohol (17FM018) and the bromide (17FM023) described above. Both precursors are known in literature.

[0313] In a Schlenk were introduced dibutyl phosphite (0.74 mL, 3.79 mmol) and THF (4 mL). The mixture was cooled to 0° C. and NaHMDS 2M (2.12 mL, 4.24 mmol) was added. The mixture was stirred at room temperature for half an hour. Then the reaction was cooled to 0° C. and (Z)-octadec-9-en-1-yl-bromide (500 mg, 1.51 mmol) in THF (4 mL) was transferred on the reaction mixture via cannula. After 30 minutes, the mixture was stirred overnight at 25° C. The reaction medium was concentrated under reduced pressure, and purified by column chromatography on SiO.sub.2. (petroleum ether/ethyl acetate (1:1), R.sub.f=0.50). m.sub.pure=537.4 mg. Aspect: slightly yellow oil. Yield: 80%.

[0314] .sup.1H NMR (500 MHz, CDCl.sub.3) δ (ppm): 5.37-5.31 (m, 2H), 4.01 (qq, 4H, J=6.7 Hz, J=10.0 Hz), 2.02-1.99 (m, 4H), 1.74-1.54 (m, 8H), 1.44-1.26 (m, 32H), 0.93 (t, 6H, J=7.4 Hz), 0.88 (t, 3H, J=6.9 Hz).

[0315] .sup.13C {.sup.1H} NMR (126 MHz, CDCl.sub.3) δ (ppm): 129.96, 129.77, 65.16, 65.10, 32.64, 32.59, 31.89, 30.67, 30.53, 29.75, 29.72, 29.50, 29.30, 29.28, 29.22, 29.07, 27.20, 27.18, 26.09, 24.97, 22.67, 22.45, 22.40, 18.76, 14.09, 13.62

[0316] .sup.31P {.sup.1H} NMR (203 MHz, CDCl.sub.3) δ (ppm): +32.58.

[0317] HRMS calcd for C.sub.26H.sub.53O.sub.3PNa [M+Na].sup.+: 467.3617; found: 467.3625.

2. Biological Properties

2.1 Materials and Methods

[0318] a—Animals

[0319] Eight weeks old, male mice (C57Bl/6 black) were purchased from the Janvier Elevage (Le Mans) and used for the experiments.

b—Isolation of Taste Bud Cells

[0320] The experimental protocol for isolation/purification of taste cells from fungiform papillae was approved by the Regional Ethical Committee (protocol number: A0508).

[0321] The technique to isolate taste bud cells from mouse fungiform papillae has been described in the publication of El-Yassimi A, Hichami A, Besnard P, Khan NA. “Linoleic acid” induces calcium signaling, Src kinase phosphorylation, and neurotransmitter release in mouse CD36-positive gustatory cells”—J. Biol. Chem. 2008, May 9, 283(19), 12949-59.

[0322] Briefly, lingual epithelium was separated by enzymatic dissociation which contained the following: elastase and dispase mixture, 2 mg/ml each, in Tyrode's buffer (120 mM NaCl; 5 mM KCl; 10 mM HEPES ((4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); 1 mM CaCl.sub.2; 1 mM MgCl.sub.2; 10 mM glucose; 10 mM Na pyruvate, pH 7.4). The taste bud cells were isolated by incubating lingual epithelium in RPMI 1640 medium containing 2 mM EDTA, 1.2 mg/ml elastase, 0.6 mg/ml collagenase (type I), and 0.6 mg/ml trypsin inhibitor at 37° C. for 10 minutes, followed by centrifugation (600 g, 10 minutes). The cell populations, after separation, were suspended in fresh RPMI 1640 medium containing 10% fetal calf serum, 200 U/ml penicillin, and 0.2 mg/ml streptomycin, seeded onto a Poly-D-Lysine-coated dishes, and cultured for 24 hours. At the end of this period, the cells were used for the experiments or stained with trypan blue to assess their viability.

c—“Ca.sup.2+ Signaling” for Showing the Interaction with CD36 and/or GPR120 Fat Taste Receptors

[0323] Ca.sup.2+ is the key second messenger in mammalian cells. It regulates a variety of cellular functions. Phospholipase C (PLC) is responsible for the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP.sub.2), generating two second messengers, i.e., inositol-1,4,5-triphosphate (hereafter IP.sub.3) and diacylglycerol (DAG). The PLCβ subfamily is of particular interest, given its prominent role in neuronal and Taste Bud Cells (TBC) signaling, and its regulation by G Protein-Coupled Receptors (hereafter GPCR). IP.sub.3 is freely diffusible and binds to IP.sub.3-specific receptors, leading to the release of Ca.sup.2+ from the endoplasmic reticulum (ER) which represents the intracellular Ca.sup.2+ pool.

[0324] As regards taste perception, an increase in [Ca.sup.2+]i has been considered as one of the earliest mechanisms, involved in the transfer of taste message from the tongue to the brain. The publication of El-Yassimi et al. (2008) mentioned above shows that CD36 and GPR120 (Ozdener M. H. et al. “CD36- and GPR120-mediated Ca.sup.2+ signaling in human taste bud cells mediates differential responses to fatty acids and is altered in obese mice”—Gastroenterology 2014, April, 146(4), 995-1005) in human and mouse taste bud cells are coupled to an increase in free [Ca.sup.2+]i during their activation by fatty acids like linoleic acid. Oleic acid also triggered the same response (unpublished observations). In mouse taste bud cells, the fatty acids via CD36 induced the phosphorylation of src-kinases, (Fyn.sup.59 and Yes.sup.62) and regulated the increases in [Ca.sup.2+]i by opening of Ca.sup.2+ channels (El-Yassimi et al. 2008), whose opening was controlled by stromal interaction molecule-1, STIM-1 (publication Dramane G. et al. “STIM1 regulates calcium signaling in taste bud cells and preference for fat in mice”, J. Clin. Invest. 2012, June, 122(6), 2267-82).

[0325] Thus, it can be stated that Ca.sup.2+ signaling (under the control of STIM1), plays a key role in the signaling of fat taste transduction in mice.

[0326] Therefore, the mobilization of intracellular Ca.sup.2+ in response to the fatty acid derivatives of the invention was studied by the Applicant.

d—Method of Measurement of the Ca.sup.2+ Signaling in Mouse Bud Cells

[0327] The mouse taste bud cells were seeded in 24-well plates (with glass bottom), containing poly-D-lysine for better adhesion to the surface. After 24 h, taste cells were incubated for 45 minutes with a fluorescent probe, Fura-2/AM (1 μM) in calcium buffer (110 mM NaCl, 5.4 mM, KCl, 25 mM, NaHCO.sub.3, 0.8 mM, MgCl.sub.2, 0.4 mM, KH.sub.2PO.sub.4, 20 mM, Hepes-Na, 0.33 mM, NaHPO.sub.4, 1.2 mM, CaCl.sub.2, pH 7.4). Then, the cells are washed with phosphate buffer saline (PBS) and taken up in calcium buffer.

[0328] The changes in intracellular Ca.sup.2+ (F.sub.340/F.sub.380) were monitored under a Nikon microscope (TiU) by using an S Fluor 40× oil immersion objective.

[0329] Especially, the increases in [Ca.sup.2+]i were measured as follows: the mice taste bud cells were cultured on Willico-Dish wells with a glass bottom and loaded with a fluorescent probe, Fura-2/AM. The changes in intracellular Ca.sup.2+ (F.sub.340/F.sub.380) were monitored under the Nikon microscope (TiU) by using S-fluor 40× oil immersion objective. The planes were taken at Z intervals of 0.3 μm, and NIS-Elements software was used to deconvolve the images. The microscope was equipped with EM-CCD (Lucas) camera for real time recording of 16-bit digital images. The dual excitation fluorescence imaging system was used for studies of individual cells. The changes in intracellular Ca.sup.2+ were expressed as ΔRatio, which was calculated as the difference between the peak F.sub.340/F.sub.380 ratio. The data were summarized from the large number of individual cells (20-40 cells in a single run, with 3-9 identical experiments done in at least three cell preparations). The results were analyzed with the NIS-elements software, the variation in [Ca.sup.2+]i is expressed as A ratio (F.sub.340/F.sub.380) which was calculated with the difference of spectra at two wavelengths, i.e., 340 nm and 380 nm.

[0330] CD36: in order to assess if the oleic acid derivatives according to the invention exert their actions via CD36, the sulfo-N-succinimidyl oleate (SSO) was used. SSO is a CD36 inhibitor/blocker/antagonist.

[0331] Experiments were performed in the presence or absence of SSO with respect to calcium signaling to verify whether our analogs act well via this lipid receptor. Especially, for this assay with compounds 3a, 2a and oleic acid (control) were tested.

[0332] GPR120: in order to assess if the oleic acid derivatives according to the invention exert their actions via GPR120, AH7614 was used. This commercially available compound is a GPR120 antagonist.

[0333] Experiments were performed in the presence or absence of SSO or AH7614 with respect to calcium signaling to verify whether our analogs exert their action via this lipid receptor. Especially, for this assay compounds 3a, 2a and oleic acid (control) were tested.

2.1 Results

[0334] a—Action on CD36 Fat Taste Receptor (FIG. 1 and FIG. 2)

[0335] FIG. 1A shows that compound 3a, in mice taste bud cells, induces a huge increase in [Ca.sup.2+]i via CD36. This phenomenon is, however, abolished by the presence of SSO as it is shown in FIG. 1B. This figure proves that compound 3a is a complete CD36 agonist (i.e. binds to CD36) as its action was completely suppressed by SSO.

[0336] FIG. 2A also shows that compound 2a, in mice taste bud cells, induces a huge increase in [Ca.sup.2+]i via CD36. The compound 2a appears to be a partial agonist because its action on the increases in [Ca.sup.2+]i was curtailed, but not completely suppressed, by SSO (FIG. 2B).

b—Action on GPR120 Fat Taste Receptor (FIG. 3)

[0337] As it is shown by FIG. 3, compound 2a according to the invention also acts via GPR120 since AH7614 abolished, at least partially, its action on the increase in [Ca.sup.2+]i in mouse gustatory cells. Indeed, FIG. 3 shows that the response of compound 2a was significantly curtailed, but not suppressed, by AH7614.

[0338] Thus, these results show that compound 2a acts on both receptors CD36 and GPR120.

3. Fat-Like Taste Perception

3.1 Materials and Methods

[0339] a—Animals

[0340] Eight weeks old, male mice (C57Bl/6 black) were purchased from the “Janvier Elevage” (Le Mans) and used for these experiments.

b—Methods of Two-Bottle Preference Test

[0341] The mice are placed individually in cages in a controlled environment (humidity and constant temperature) and have free access to a standard diet. 6 hours before the tests, the mice are deprived of water.

[0342] During the behavioral experiments, the mice were offered two bottles simultaneously for 12 hours (night period).

[0343] The mice are subjected to a choice between the “control” solution and the experimental solution (FIG. 4 and FIG. 5). [0344] control solutions contain 0.3% xanthan gum, w/v, (Sigma Life Science, USA) in water to reproduce lipid texture and minimize bias due to differences in appearance between the two bottles; [0345] the experimental solution contains, either the “test compound” according to the invention at a concentration varying from 10 to 100 μM (compound 3a, FIG. 4 or compound 2a, FIG. 5) or only xanthan gum at 0.2% (v/v) (control test). To avoid the preference for one side, the position of each bottle is changed during each test.

[0346] To estimate the consumption of control and experimental solutions, the bottles are weighed before and after each experiment. The mice are allowed to take rest for 48 hours between each experiment.

3.2 Results (FIG. 4 to FIG. 5)

[0347] a—Compound 3a

[0348] As it is shown by FIG. 4, mice exhibit spontaneous preference for a solution containing the oleic acid derivative according to the invention, i.e. compound 3a as compared to the control (CTRL) solution containing xanthan gum. The preference is optimal at a concentration of 75 μM of compound 3a.

b—Compound 2a

[0349] Similarly, mice exhibit spontaneous preference for a solution containing compound 2a. It can be observed from FIG. 5 that mice prefer compound 2a at 75 μM. This is much lesser (102 times) than the concentration that is used for oleic acid in two-bottle preference tests.

4. Anti-Obesity Effects

4.1 Materials and Methods

[0350] a—Mice and Diet-Induced Obesity:

[0351] C57BL/6J male mice, aged between 6 to 10 weeks (16-20 g), were obtained from Janvier Labs (France). They were housed individually in a controlled environment with a 12 h light/dark cycle with food (SAFE, France) and water ad libitum. The palm oil (Huilerie Vigean, France) was the main fat component in high-fat diets. The high-fat diet was prepared weekly and stored at 4° C. until further use. The study was conducted as per Declaration of Helsinki and European ethical guidelines for the care and use of animals for experimentation. All the experimental protocols (protocol number: 16158) were approved by the Regional Ethical Committee of the University of Burgundy (Dijon, France).

[0352] The mice were grouped at random (n=10/group) and fed with either of the following diets: standard diet (STD) or high-fat diet (HFD). The body weight, food, and water intake were measured, weekly.

Composition of the Diets

[0353]

TABLE-US-00012 Content (%) STD HFD Proteins 66.8 40.07 starch 16.10 14.6 Fats 3.10 35.3 Cholesterol — 0.03 Cellulose 3.9 2.7 Vitamins 5 3.4 Minerals 5.1 3.9 Energy (Kcal/100 g) 359.5 536.65 Fat energy (% of total energy) 8 60 Standard diet (STD); high-fat diet (HFD)

Fatty Acid Composition of the Diets

[0354]

TABLE-US-00013 Fatty acids (%) STD HFD SFA 18.82 45.85 MUFA 26.38 40.02 PUFA 54.8 14.13 Standard diet (STD); high-fat diet (HFD) SFA: saturated fatty acids; MUFA: monounsaturated fatty acids; PUFA: polyunsaturated fatty acids.

[0355] After 10 weeks of feeding the diets, obese animals were divided into two groups: one groups continued to be fed on the same HFD; however, another group was fed on the same diet and received either NKS-3 or NKS-5) until 28.sup.th of weeks of experimentation. At the end, the animals were sacrificed, under a fasting condition, and used for different analysis in blood and different tissues.

b—Determination of the Inflammatory Marker:

[0356] The CRP concentration was determined in sera by an automatic analyzer (Gilford Model 2000 system, a Beckman System T.R).

c—Statistical Analysis:

[0357] Results are expressed as mean±SEM (standard error of mean). Data were analyzed by using Statistica (4.1, StatSoft, Paris, France). The significance of difference between groups was determined by one-way analysis of variance (ANOVA), followed by least-significant-difference (LSD) test. For all the tests, the significance level chosen was p<0.05.

4.2 Fat Taste Analogues Exert Anti-Obesity Effects in Mice;

[0358] In order to elucidate the beneficial effects and especially during obesity, experiments were conducted on obese C57BL/6J mice. The mice were maintained on a high-fat diet for 10 weeks and an increase in body weight in a progressive and linear manner was observed in these animals. In order to test the curative/interventional effects on obesity, the animals were divided into two groups: one group that consumed only the high-fat diet (HFD) and the other consuming the same diet and also receiving 3a or 2a in ad libitum baby bottles/feeders. From the 10th week of the diet, we introduced lipid analogues into the bottles at 75 μM that corresponded to their preference in the double choice test. From the first week of administration of analogues, there was a significant decrease in body weight in the obese mouse by these two lipid analogues (2a was more powerful than 3a). In addition, the decrease in obesity was maintained until the 28th week of feeding a HFD (FIGS. 6A and 6B). The study was stopped after the 28th week of the diet because the animals reached the age of 34 weeks and beyond that age, the aging factor may interfere with the growth.

4.3 Fat Taste Analogues Decrease Inflammatory Marker in the Blood in Mice:

[0359] The C-reactive protein (CRP), synthesized in the liver, is a protein that appears in the blood during inflammatory conditions such as obesity. It rises rapidly after the onset of inflammation. It is, therefore, a stable biological marker for detecting inflammation at an early stage. The CRP appears in all inflammatory processes and does not cross the placenta. FIG. 7 shows that the two oleic acid analogues (3a and 2a) significantly decreased the concentrations of circulating CRP, demonstrating that these agents also normalize the inflammatory status in obese mice.