Polyfunctional compounds, methods for preparing same and uses thereof

Abstract

Disclosed are polyfunctional compounds of formula: ##STR00001##
as well as methods for preparing same and the uses thereof, in particular in orthogonal or bioorthogonal processes.

Claims

1. Compound of general formula (I) ##STR00032## in which: Y is a reactive functional group selected from the group consisting of: (i) an N.sub.3 group, (ii) a (C.sub.2-C.sub.10) alkenyl group, (iii) a (C.sub.2-C.sub.10) alkynyl group, (iv) a (C.sub.3-C.sub.10) cycloalkenyl group, (v) a (C.sub.7-C.sub.10) cycloalkynyl group, (vi) an anthracenyl group, (vii) a furanyl group, (viii) a maleimidyl group, and (ix) a tetrazinyl group, A is a group selected from: (a) a linear or branched (CH.sub.2).sub.m alkylene chain, m being an integer from 0 to 20, (b) an aromatic group of 6 to 14 carbon atoms, (c) a (C.sub.3-C.sub.18) cycloalkyl group, and (d) a heterocyclic group comprising from 3 to 18 members, R.sub.1 is a (C.sub.2-C.sub.10) alkenyl group or a (C.sub.2-C.sub.10) alkynyl group n is an integer from 0 to 3.

2. Compound according to claim 1, in which R.sub.1 represents the CHCH.sub.2 group; n is equal to 1, said compound corresponding to general formula (Ia) ##STR00033## in which A and Y are as defined in claim 1.

3. Compound according to claim 2, said compound being selected from the group consisting of: ##STR00034## ##STR00035##

4. Compound according to claim 1, in which: R.sub.1 represents the CCH group; n is equal to 1, said compound corresponding to general formula (Ib) ##STR00036## in which A and Y are as defined in claim 1.

5. Method for the preparation of a compound of formula (Ia) according to claim 1, comprising: (i) reaction between a compound of formula (II) ##STR00037## in which Y and A are as defined in claim 1, and a compound of formula (IIIb) ##STR00038## in which R.sub.1 and n are as defined in claim 1, in order to obtain a compound of formula (IVb) ##STR00039## in which Y, A, R.sub.1 and n are as defined in claim 1; (ii) oxidation of the compound of formula (IVb) in order to obtain a compound of formula (Vb) ##STR00040## in which Y, A, R.sub.1 and n are as defined in claim 1; (iii) cyclization of a compound of formula (Vb) in order to obtain a compound of formula (I).

6. Method for the preparation of a compound of formula (Ia) ##STR00041## in which Y and A are as defined in claim 1, said method comprising the following steps: (i) reaction between a compound of formula (II) ##STR00042## in which Y and A are as defined in claim 1, and a compound of formula (IIIa) ##STR00043## X being selected from F, Cl, Br and I, in order to obtain a compound of formula (IVa) ##STR00044## in which Y and A are as defined in claim 1; (ii) oxidation of the compound of formula (IVa) in order to obtain a compound of formula (Va) ##STR00045## in which Y and A are as defined in claim 1; (iii) cyclization of a compound of formula (Va) in order to obtain a compound of formula (Ia).

7. Method according to claim 6, wherein step (ii) of said method successively comprises step (iia) and step (iib) step (iia) consisting of the oxidation of the compound of formula (IVa) in order to obtain a compound of formula (Va) ##STR00046## in which Y and A are as defined in claim 1; step (iib) consisting of the oxidation of the compound of formula (Va) in order to obtain a compound of formula (Va).

8. Method for coupling between, at most, four different molecules of interest selected from the group comprising a biological molecule of interest, a natural or synthetic polymer, said molecules of interest being either molecules bearing a primary amine, or molecules bearing a sulphhydryl group, or molecules bearing a reactive function in order to implement a cycloaddition or a polymerization, said method comprising the following steps: (i) bringing a compound of formula (I), (Ia) or (Ib) according to claim 1 into contact with a first molecule of interest, (ii) bringing said compound obtained at the end of step (i) into contact with a second molecule of interest, (iii) bringing the compound obtained at the end of step (ii) into contact with a third molecule of interest, (iv) bringing the compound obtained at the end of step (iii) into contact with a fourth molecule of interest.

9. Method according to claim 8, wherein the molecules of interest are selected from the group comprising proteins, antibodies, peptides, DNA, RNA, siRNAs, miRNAs, biological markers, hormones, vitamins, lipids, monosaccharides, oligosaccharides, polysaccharides, glycans and synthetic chemical molecules.

10. Method according to claim 8, wherein said method is a (bio)orthogonal method.

11. Coupling kit comprising at least one compound of formula (I), (Ia), or (Ib) according to claim 1, as coupling reagent.

12. Composition comprising a compound of formula (I), (Ia) or (Ib) according to claim 1 in combination with an aqueous or organic medium.

13. In vitro diagnostic method utilizing a compound of formula (I), (Ia) or (Ib) according to claim 1.

14. The compound of claim 1, wherein the (C.sub.2-C.sub.10) alkenyl group is substituted with an aryl group or an arylalkyl group.

15. The compound of claim 1, wherein the anthracenyl group, is substituted with a halogen or a linear or branched (C.sub.1-C.sub.4) alkyl.

16. The compound of claim 1, wherein the furanyl group is substituted with a halogen or a linear or branched (C.sub.1-C.sub.4) alkyl.

17. The compound of claim 1, wherein the maleimidyl group substituted with a halogen or a linear or branched (C.sub.1-C.sub.4) alkyl.

18. The compound of claim 1, wherein the tetrazinyl group substituted with a halogen or a linear or branched (C.sub.1-C.sub.4) alkyl.

19. The compound of claim 1, wherein the aromatic group of 6 to 14 carbon atoms is substituted with at least one substituent selected from the group comprising the halogen atoms and the linear or branched (C.sub.1-C.sub.4) alkyl groups.

20. The compound of claim 1, wherein the heterocyclic group comprising from 3 to 18 members is substituted with at least one substituent selected from the group comprising the halogen atoms and the linear or branched (C.sub.1-C.sub.4) alkyl groups.

21. The compound of claim 1, wherein the substituent Y is a (C.sub.3-C.sub.7) cycloalkenyl group.

22. The compound of claim 1, wherein the substituent Y is a cyclooctynyl group or a cyclooctyne derivative.

Description

(1) The invention is illustrated in more detail below, by means of the examples and figures.

(2) FIG. 1 shows the diagram of the method for the preparation of a compound of formula (Ia) of the invention.

(3) FIG. 2 shows different methods of coupling between a compound of the present invention and molecules of interest. The different types of molecules of interest are represented by round, oval or rectangular symbols. The function Z borne by a molecule of interest is a reactive function for implementing a cycloaddition, a hydrothiolation, or a polymerization.

(4) FIGS. 3A and 3B show the nuclear magnetic resonance (NMR) analysis (RMN) of the compound N-(4-(benzylcarbamoyl)hepta-1,6-dien-4-yl)-4-ethynylbenzamide (FIG. 3A) and of the compound N-(4-(benzylcarbamoyl)hepta-1,6-dien-4-yl)-4-(1-polyethyleneglycolmonomethylether-1H-1,2,3-triazol-4-yl)benzamide (FIG. 3B).

EXAMPLE 1

Protocol For The Preparation Of A Compound Of Formula (Ia).

(5) This is illustrated in the diagram shown in FIG. 1.

(6) 1.1 Synthesis of the Compound of Formula IVa

(7) Allyl bromide (3 mmol, 0.26 mL) is added dropwise to a two-necked flask provided with a refrigerant under argon, containing zinc (3.2 mmol, 209 mg) in suspension in 20 mL in THF and taken to reflux. The mixture is stirred at reflux for 90 minutes, then a solution of acylcyanhydrine of formula (II) (1 mmol) in 3 mL of THF is added dropwise. The mixture is stirred at reflux for 90 minutes, then is hydrolyzed by adding 10 mL of HCl (1M) at ambient temperature. The aqueous phase is extracted with ethyl acetate (220 mL). The organic phases are combined, basified with 2M NaOH, and washed with NaCl.sub.sat. After drying over MgSO.sub.4, filtration, and concentration under reduced pressure, the product of formula (IVa) is obtained pure.

(8) 1.2 Synthesis of the Compound of Formula (Va).

(9) TPAP (0.05 mmol; 12 mg) and NMO (3 mmol, 351 mg) are added to a flask containing 4 molecular sieve (760 mg) and alcohol of formula (IVa) (1 mmol) obtained in step 1, in suspension in 10 mL in CH.sub.2Cl.sub.2. The mixture is stirred for 30 minutes under argon and filtered on silica gel, then the silica is washed with CH.sub.2Cl.sub.2. After concentration of the filtrate under reduced pressure, the aldehyde of formula (Va) is obtained pure.

(10) 1.3 Synthesis of the Compound of Formula (Va)

(11) NaH.sub.2PO.sub.4, 2H.sub.2O (0.5 mmol; 78 mg), H.sub.2O.sub.2 38% (2 mmol; 0.2 mL) and 80% NaClO.sub.2 (1.5 mmol; 170 mg) are added to a flask containing the aldehyde of formula (Va) (1 mmol) obtained in step 2, dissolved in 10 mL of acetonitrile cooled in an ice bath. The solution is stirred at ambient temperature for 2 hours, then Na.sub.2SO.sub.3 (0.8 mmol; 101 mg) is added. The reaction is left under stirring for 1 hour and 2 mL of aqueous solution of KHSO.sub.4 (1M) is introduced. The aqueous phase is basified by adding a solution of NaOH (2M) then extracted with ethyl acetate (320 mL). The organic phases are combined, then washed with NaHCO.sub.3sat (320 mL). The aqueous phases are combined, acidified with concentrated HCl to pH=3, then extracted with ethyl acetate (320 mL). After drying over MgSO.sub.4, filtration, and concentration under reduced pressure, the acid of formula (Va) is obtained pure.

(12) 1.4 Synthesis of the Compound of Formula (Ia)

(13) The acid of formula (Va) (1 mmol) is dissolved in triethylamine (1.5 mmol; 0.21 mL) and 5 mL of acetone in a flask, under an argon atmosphere. The mixture is cooled by means of an ice bath, then ethyl chloroformate (1 mmol; 0.1 mL) is added dropwise and the solution is stirred at 0 C. for 3 hours. The mixture is filtered on silica gel, then the silica is washed with Et.sub.2O. After concentration of the filtrate under reduced pressure, the azlactone of formula (Ia) is obtained pure.

EXAMPLE 2

Synthesis of 4,4-Diallyl-2-(4-vinylphenyl)Oxazol-5(4H)-one (Compound (Ia1))

(14) The compound is synthesized according to the method described in example 1.

2.1/Synthesis of N-(4-(Hydroxymethyl)hepta-1,6-dien-4-yl)-4-vinylbenzamide

(15) This compound, corresponding to the formula below, is obtained by the protocol of step 1.1 of example 1 in the form of an oil having a brown colour (Yield=quantitative).

(16) ##STR00018##

(17) NMR .sup.1H (CDCl.sub.3, 400 MHz): =7.67 (m, 2 H, Ar); 7.44 (m, 2 H, Ar); 6.73 (dd, 1 H, J=17.6 Hz, J=11.0 Hz, H.sup.2); 6.41 (s, 1 H, NH); 5.9 (m, 2 H, H5, H5); 5.83 (dd, 1 H, J=0.7 Hz, J=17.6 Hz, H1); 5.35(dd, 1 H, J=0.7 Hz, J=11.0 Hz, H1), 5.22 (m, 4 H, H6, H6); 3.76 (s, 2 H, H.sup.3; 2.64 (m, 2 H, H4a, H4a), 2.4 (m, 2 H, H4b, H4b) ppm.

(18) NMR .sup.13C (CDCl.sub.3, 100 MHz): =167.9; 141.1; 135.9; 133.7; 133.1; 127.3; 126.5; 119.9; 116.3; 67.9; 60.2; 38.9 ppm.

(19) IR (film): =3395, 2928, 1737. 1638, 1499, 914, 856, 780 cm.sup.1.

(20) HRMS (ESI.sup.+): m/z [M+Na].sup.+ calculated for C.sub.17H.sub.21NNaO.sub.2: 294.1470; found: 294.1464.

2.2/Synthesis of N-(4-Formylhepta-1,6-dien-4-yl)-4-vinylbenzamide

(21) This compound, corresponding to the formula below, is obtained by the protocol of step 1.2 of example 1 in the form of a brown-coloured solid (Yield=68%).

(22) ##STR00019##

(23) NMR .sup.1H (CDCl.sub.3, 400 MHz): =9.46 (s, 1 H, H3), 7.73 (m, 2 H, Ar); 7.44 (m, 2 H, Ar); 6.91 (s, 1 H, NH); 6.73 (dd, 1 H, J=17.6 Hz, J=10.7 Hz, H1); 5; 82 (d, 1 H, J=17.7 Hz, H.sup.2); 5.66 (m, 2 H, H.sup.5); 5.35 (d, 1 H, J=11; 0 Hz, H1), 5.13 (m, 4 H, H6); 3.01 (dd, 2 H, J=14.3 Hz, J=7.3 Hz, H4a, H4a); 2.66 (dd, 2 H, J=14.3 Hz, J=7.3 Hz, H4b, H4b) ppm.

(24) NMR .sup.13C (CDCl.sub.3, 100 MHz): =200.0; 166.6; 141.1; 135.9; 133.1; 131.5; 127.3; 126.5; 120.1; 116.6; 65.7; 37.0 ppm.

(25) IR (film): =3293, 2920, 2160, 1635, 1547, 1251, 925, 842, 763 cm.sup.1.

2.3/Synthesis of 2-allyl-2-(4-vinyl benzamido)pent-4-enoic Acid

(26) This compound, corresponding to the formula below, is obtained by the protocol of step 1.3 of example 1 in the form of a white solid (Yield 58%).

(27) ##STR00020##

(28) RMN .sup.1H (DMSO, 400 MHz): =12.6 (bs, 1H, COOH); 8.11 (s, 1 H, NH); 7.80 (m, 2 H, Ar); 7.57 (m, 2 H, Ar); 6.80 (m, 1 H, H2); 5.95 (dd, 1 H, J=17.7 Hz, J=0.8 Hz, H1); 5.71 (m, 2 H, H4); 5.37 (dd, 1 H, J=10.8 Hz, J=0.8 Hz, H1); 5.08 (m, 4 H, H5); 2.75 (dd, 2 H, J=14.0 Hz, J=7.4 Hz, H3a, H3a), 2.64 (dd, 1 H, J=14.0 Hz, J=7.4 Hz, H3b, H3b) ppm.

(29) NMR .sup.13C (DMSO, 100 MHz): =173.4; 165.3; 139.9; 135.9; 133.5; 132.8; 127.6; 125.9; 118.6; 116.2; 61.4; 37.5 ppm.

(30) IR (film): =3365, 2924, 1713, 1600, 1525, 1333, 1220, 991, 916, 855 cm.sup.1.

(31) HRMS (ESI.sup.+): m/z [M+Na].sup.+ calculated for C.sub.17H.sub.20NO.sub.3: 286.1443; found: 286.1429.

2.4/Synthesis of 4,4-Diallyl-2-(4-vinylphenyl)oxazol-5(4H)-one

(32) The final compound (compound (Ia1)), corresponding to the formula below, is obtained by the protocol of step 1.4 of example 1 in the form of a clear yellow oil with a yield of 95%.

(33) ##STR00021##

(34) RMN .sup.1H (CDCl.sub.3, 400 MHz): =7.95 (m, 2H, Ar); 7.48 (3, 2H, Ar); 6.74 (dd, 1H, J=17.6 Hz, J=10.8 Hz, H2); 5.87 (d, 1H, J=17.6 Hz, H1); 5.66 (m, 2H, H4); 5.39 (d, 1H, J=17; 6 Hz, H1); 5.13 (m, 4H, H5); 2.7 (dd, 2H, J=13.6 Hz, J=6.9 Hz, H3a, H3a); 2.59 (dd, 2H, J=13.6 Hz, J=7.8 Hz, H3b, H3b) ppm.

(35) RMN .sup.13C (CDCl.sub.3, 100 MHz): =179.1; 159.9; 141.9; 135.9; 130.9; 128.3; 126.5; 124.9; 120.5; 116.7; 73.7; 41.1 ppm.

(36) IR (film): =3082, 2983, 1816, 1650, 1408, 1317, 1292, 1041, 972, 922, 890, 853, 709 cm.sup.1.

EXAMPLE 3

Synthesis of 4,4-Diallyl-2-(4-(Ethynyl)Phenyl)Oxazol-5(4H)-one (Compound (Ia2))

(37) The compound is synthesized according to the method described in example 1.

3.1/Synthesis of N-(4-(Hydroxymethyl)hepta-1,6-dien-4-yl)-4-((trimethylsilyl)ethynyl)benzamide

(38) This compound, corresponding to the formula below, is obtained by the protocol of step 1.1 of example 1 in the form of a yellow-coloured solid (Yield=quantitative).

(39) ##STR00022##

(40) RMN .sup.1H (CDCl.sub.3, 400 MHz): =7.63 (m, 2 H, Ar); 7.51 (m, 2 H, Ar); 6.37 (s, 1 H, NH); 5.90 (m, 2 H, H2); 5.23 (m, 2 H, H4); 3.76 (s, 2 H, H4); 2.65 (dd, 2 H, J=13.8 Hz, J=6.5 Hz, H3a, H3a); 2.38 (dd, 2 H, J=13.8 Hz, J=8.5 Hz, H3b, H3b) 0.25 (m, 9 H, H5) ppm.

(41) RMN .sup.13C (CDCl.sub.3, 100 MHz): =167.6; 134.3; 133.0; 132.3; 126.9; 126.8; 120.1; 104.0; 97.5; 68.1; 60.5; 39.1; 0.3 ppm.

(42) HRMS (ESI.sup.+): m/z [M+H].sup.+ calculated for C.sub.20H.sub.28NO.sub.2Si: 342.1889; found: 342.889.

3.2/Synthesis of N-(4-Formylhepta-1,6-dien-4-yl)-4-((trimethylsilyl)ethynyl)benzamide

(43) This compound, corresponding to the formula below, is obtained by the protocol of step 1.2 of example 1 in the form of a brown oil (Yield 61%).

(44) ##STR00023##

(45) RMN .sup.1H (CDCl.sub.3, 400 MHz): =9.30 (s, 1 H, CHO); 7.73 (m, 2 H, Ar); 7.53 (m, 2 H, Ar); 5.64 (m, 2 H, H4); 5.14 (m, 4 H, H5); 3.07 (dd, 2 H, J=14.2 Hz, J=7.5 Hz, H3a, H3a); 2.66 (dd, 2 H, J=14.2 Hz, J=7.5 Hz, H3b, H3b) 0.3 (s, 9H, CH.sub.3) ppm.

(46) RMN .sup.13C (CDCl.sub.3, 100 MHz): =166.6; 133.2; 132.6; 131.2; 131.9; 128.0; 127.2; 120.5; 104.0; 66.3; 41.2; 35.9; 0.6 ppm.

(47) HRMS (ESI.sup.+): m/z [M+H].sup.+ calculated for C.sub.20H.sub.26NO.sub.2: 340.1733; found: 340.1707.

(48) IR (film): =3293, 2158, 1741, 1629, 1525, 1251, 922, 842, 760 cm.sup.1.

3.3/Synthesis of 2-allyl-2-(4-ethynyl benzamido)pent-4-enoic Acid

(49) This compound, corresponding to the formula below, is obtained by the protocol of step 1.3 of example 1 in the form of a yellow solid (Yield 50%).

(50) ##STR00024##

(51) RMN .sup.1H (DMSO, 400 MHz): =12.6 (bs, 1 H, COOH); 8.23 (s, 1 H, NH); 7.82 (m, 2 H, Ar); 7.58 (m, 2 H, Ar); 5.71 (m, 2 H, H3); 5.07 (m, 4 H, H4); 4.37 (s, 1 H, H1); 2.74 (dd, 2 H, J=14.0 Hz, J=7.3 Hz, H3a, H3a); 2.61 (dd, 2H, J=14.0 Hz, J=7.3 Hz, H3b, H3b) ppm.

(52) RMN .sup.13C (DMSO, 100 MHz): =173.3; 165.0; 134.3; 132.7; 131.6; 124.9; 118.7; 82.8; 81.5; 61.4; 37.4 ppm.

3.4/Synthesis of 4,4-Diallyl-2-(4-(ethynyl)phenyl)oxazol-5(4H)-one (Compound (Ia2))

(53) The final compound (compound (Ia2)), corresponding to the formula below, is obtained by the protocol of step 1.4 of example 1 in the form of a brown oil with a yield of 98%.

(54) ##STR00025##

(55) RMN .sup.1H (CDCl.sub.3, 400 MHz): =7.73 (m, 2H, Ar); 7.55 (m, 2H, Ar); 5.64 (m, 2H, H3); 5.13 (m, 4H, H4); 3.27 (dd, 2H, J=14.1 Hz, J=7.7 Hz, H2a, H2a), 3.22 (s, 1H, H1); 2.70 (dd, 2H, J=14.1 Hz, J=7.0 Hz, H2b, H2b) ppm.

(56) NMR .sup.13C (CDCl.sub.3, 100 MHz): =176.6; 168.4; 133.7; 135.5; 131.5; 127.1; 126.3; 120.1; 82.6; 80.0; 66.0; 38.9 ppm.

(57) IR (film): =3283, 2980, 1721, 1609, 1531, 1499, 1235, 1097, 927, 855, 769 cm.sup.1.

EXAMPLE 4

Synthesis of 4,4-Diallyl-2-(Anthracen-9-yl)Oxazol-5(4H)-one (Compound (Ia3))

(58) The compound is synthesized according to the method described in example 1.

4.1/Synthesis of N-(4-(Hydroxymethyl)hepta-1,6-dien-4-yl)anthracene-9-carboxamide

(59) This compound, corresponding to the formula below, is obtained by the protocol of step 1.1 of example 1 in the form of a yellow-coloured solid (Yield=96%).

(60) ##STR00026##

(61) RMN .sup.1H (CDCl.sub.3, 400 MHz): =8.47 (s, 1 H, Ar); 8.10 (dd, 2 H, Ar); 8.00 (dd, 2 H, Ar); 7.5 (m, 4 H, Ar); 6.23 (s, 1 H, NH); 5.9 (m, 2 H, H3, H3); 5.15 (m, 4 H, H4, H4); 5.97 (s, 2 H, H.sup.1); 2.72 (dd, 2 H, J=13.7 Hz, J=6.9 Hz, H2a, H2a); 2.50 (dd, 2 H, J=13.7 Hz, J=8.2 Hz, H2b, H2b) ppm.

(62) RMN .sup.13C (CDCl.sub.3, 100 MHz): =170.7; 132.3; 131.4; 131.1; 128.7; 128.6; 127.9; 127.0; 125.6; 124.8; 120.3; 67.8; 61.8; 39.5 ppm.

(63) HRMS (ESI.sup.+): m/z [M+H].sup.+ calculated for C.sub.23H.sub.24NO.sub.2: 346.1807; found: 346.1798.

(64) IR (film): =2961. 2162, 1734, 1601, 1251, 1093, 842, 700 cm.sup.1.

4.2/Synthesis of N-(4-Formylhepta-1,6-dien-4-yl)anthracene-9-carboxamide

(65) This compound, corresponding to the formula below, is obtained by the protocol of step 1.2 of example 1 in the form of a yellow solid (Yield 64%).

(66) ##STR00027##

(67) RMN .sup.1H (CDCl.sub.3, 400 MHz): =9.67 (s, 1 H, CHO); 8.45 (s, 1 H, Ar); 8.14 (m, 2 H, Ar); 7.98 (m, 2 H, Ar); 7.47 (m, 4 H, Ar); 6.66 (s, 1 H, NH); 5.77 (m, 2 H, H2); 5.22 (m, 4 H, H1); 3.1 (dd, 2 H, J=14.5 Hz, J=7.6 Hz, H3a, H3a); 2.79 (dd, 2 H, J=14.6 Hz, J=7.0 Hz, H3b, H3b) ppm.

(68) RMN .sup.13C (CDCl.sub.3, 100 MHz): =199.5; 169.1; 131.2; 131.1; 130.7; 128.7; 128.6; 128.2; 126.8; 125.6; 124.8; 120.6; 66.0; 39.5 ppm.

(69) HRMS (ESI.sup.+): m/z [M+H].sup.+ calculated for C.sub.23H.sub.22NO.sub.2: 344.1651; found: 344.1654.

(70) IR (film): =3200, 3034, 2922, 1737, 1616, 1525, 1439, 994, 924, 735 Cm.sup.1.

4.3/Synthesis of 2-allyl-2-(anthracene-9-carboxamido)pent-4-enoic Acid

(71) This compound, corresponding to the formula below, is obtained by the protocol of step 1.3 of example 1 in the form of a yellow solid (Yield=35%).

(72) ##STR00028##

(73) RMN .sup.1H (DMSO, 400 MHz): =13.0 (bs, 1H, COOH); 9.03 (s, 1 H, Ar); 8.24 (m, 2 H, Ar); 8.10 (m, 2 H, Ar); 7.56 (m, 4 H, Ar); 5.88 (m, 2 H, H2); 5.20 (m, 4 H, H1); 2.91 (dd, 2 H, J=14.4 Hz, J=7.0 Hz, H3a, H3a); 2.60 (dd, 2 H, J=14.4 Hz, J=7.3 Hz, H3b, H3b) ppm.

(74) RMN .sup.13C (DMSO, 100 MHz): =173.4; 167.8; 132.7; 132.5; 130.6; 128.2; 127.7; 127.2; 126.1; 125.5; 125.4; 119.0; 61.3; 37.7 ppm.

(75) IR (film): =3380, 2918, 1721, 1611, 1510, 1443, 1205, 1130, 909, 732 cm.sup.1.

(76) HRMS (ESI.sup.+): m/z [M+H].sup.+ calculated for C.sub.23H.sub.22NO.sub.3: 360.1600; found: 360.1598.

4.4/Synthesis of 4,4-Diallyl-2-(anthracen-9-yl)oxazol-5(4H)-one (Compound (Ia3))

(77) Compound (Ia3), corresponding to the formula below, is obtained by the protocol of step 1.4 of example 1 in the form of a yellow solid with a yield of 90%.

(78) ##STR00029##

(79) RMN .sup.1H (CDCl.sub.3, 400 MHz): =8.61 (s, 1H, Ar); 8.30 (m, 2H, Ar); 8.05 (m, 2H, Ar); 7.52 (m, 4H, Ar); 5.96 (m, 2H, H2); 5.37 (m, 4H, H3); 2.86 (m, 4H, H1) ppm.

(80) RMN .sup.13C (CDCl.sub.3, 100 MHz): =179.6; 160.3; 131.5; 131.2; 130.9; 130.4; 128.9; 127.5; 125.6; 125.2; 121.3; 121.1; 119.9; 41.5 ppm.

(81) IR (film): =2924, 2853, 1816, 1657, 1302, 1197, 1054, 994, 922, 734 cm.sup.1.

EXAMPLE 5

Coupling Process

(82) Three types of coupling can be implemented by a compound of formula I of the present invention (FIG. 2).

(83) 5.1 Azlactone Ring Opening

(84) 0.1 mmol of a compound of formula (Ia2) with 0.6 mL of DMSO is introduced into a flask. Benzylamine is then introduced into the flask (11 L, 0.1 mmol) and the mixture is heated at 40 C. for 24 hours. 3M HCl is added in a small quantity, then the mixture is extracted using diethyl ether (310 mL). The product corresponding to the formula below (N-(4-(benzylcarbamoyl)hepta-1,6-dien-4-yl)-4-ethynylbenzamide) is recovered after passing through a rotary evaporator.

(85) ##STR00030##

(86) RMN .sup.1H (CDCl.sub.3, 400 MHz): =7.68 (m, 2 H, Ar); 7.48 (m, 3 H, Ar); 7.29 (m, 4 H, Ar); 5.67 (m, 2 H, H4); 5.08 (m, 4 H, H5); 4.15 (s, 2 H, H1); 3.27 (dd, 2 H, J=13.7 Hz, J=7.7 Hz, H3a, H3a); 3.19 (s, 1 H, H7); 2.65 (dd; 2 H; J=13.7 Hz; J=6.9 Hz; H3b; H3b) ppm.

(87) RMN .sup.13C (CDCl.sub.3, 100 MHz): =176.4; 165.7; 135.3; 132.9; 132.2; 129.3; 129.0; 128.7; 127.9; 126.9; 125.1; 118.8; 82.8; 79.4; 64.6; 44.1; 39.3 ppm.

(88) IR: =3376; 3071; 2928; 2259; 1639; 1525; 1490; 1026 cm.sup.1

(89) 5.2 Cycloaddition Protocol

(90) CuBr (0.32 mmol) is added to a Schlenk flask under argon containing 1 mmol of compound A obtained in the preceding step 5.1, 1 mmol of an azide B and pentamethyldiethylenetriamine (PMDETA, 1.2 mmol) in suspension in 10 mL of degassed DMF. The mixture is left under stirring at ambient temperature for 24 hours. The reaction is illustrated below.

(91) ##STR00031##

(92) After the reaction, the mixture is diluted in 50 mL of dichloromethane (DCM) and washed with an aqueous solution of ethylenediaminetetraacatate (0.03 mol/L). After drying over MgSO.sub.4, filtration, and concentration under reduced pressure, the product (N-(4-(benzylcarbamoyl)hepta-1,6-dien-4-yl)-4-(1-polyethyleneglycolmonomethylether-1H-1,2,3-triazol-4-yl)benzamide) is obtained in the form of a yellow solid.

(93) The cycloaddition product obtained is also characterized by proton nuclear magnetic resonance (FIGS. 3A and 3B) which shows that after reaction, the hydrogen peak of the alkyne corresponding to compound A (N-(4-(benzylcarbamoyl)hepta-1,6-dien-4-yl)-4-ethynylbenzamide) (FIG. 3A) has disappeared in favour of a new peak corresponding to the proton of the triazole ring of the cycloaddition product obtained (FIG. 3B).

(94) The cycloaddition product obtained can also be analyzed by time-of-flight mass spectrometry (MALDI-TOF-MS) which shows a distribution of the signals separated by the mass of an ethylene oxide unit, i.e. 44 Da.

(95) 5.3 Hydrothiolation Protocol

(96) Benzylmercaptan (2 mmol) and dimethoxyphenylacetophenone (0.1 mmol) are added to a flask under argon containing 1 mmol of a compound of formula I in suspension in 0.5 of dimethylformamide (DMF). The mixture is left under stirring at ambient temperature under UV for 1 hour, then concentrated under reduced pressure. Purification on silica gel is then carried out.