DIFLUORINATED COMPOUNDS AS DEPIGMENTING OR LIGHTENING AGENTS

Abstract

The present invention relates to a compound having the following formula (I) as well as a method for preparing such a compound, a cosmetic or pharmaceutical composition containing such a compound, and the use thereof as a depigmenting, lightening, bleaching or whitening agent and for treating pigmentation disorders, notably by topical application on the skin.

##STR00001##

Claims

1. A compound having the following formula I: ##STR00044## or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any proportion, wherein: R.sub.1 represents a hydrogen atom, OH, OSiR.sub.3R.sub.4R.sub.5, OR.sub.6, OC(O)R.sub.7, OCO.sub.2R.sub.8, OC(O)NR.sub.9R.sub.10, OP(O)(OR.sub.11).sub.2, or OSO.sub.3R.sub.12, R.sub.2 represents OH, OSiR.sub.13R.sub.14R.sub.15, OR.sub.16, OC(O)R.sub.17, OCO.sub.2R.sub.18, OC(O)NR.sub.19R.sub.20, OP(O)(OR.sub.21).sub.2, OSO.sub.3R.sub.22, NH.sub.2, NHR.sub.33, or NR.sub.33R.sub.34, X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 represent, independently from one another, a hydrogen atom, OH, OSiR.sub.23R.sub.24R.sub.25, OR.sub.26, OC(O)R.sub.27, OCO.sub.2R.sub.28, OC(O)NR.sub.29R.sub.30, OP(O)(OR.sub.31).sub.2, or OSO.sub.3R.sub.32, with: R.sub.3, R.sub.4, R.sub.5, R.sub.13, R.sub.14, R.sub.15, R.sub.23, R.sub.24 and R.sub.25 representing, independently from one another, a (C.sub.1-C.sub.6)alkyl, aryl, aryl-(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkyl-aryl group, R.sub.6, R.sub.16 and R.sub.26 representing, independently from one another, a O-protecting group; or a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (5- to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or heteroaryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or several groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group and a (C.sub.1-C.sub.6)alkoxy group, R.sub.7, R.sub.8, R.sub.17, R.sub.18, R.sub.27 and R.sub.28 representing, independently from one another, a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (5- to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or heteroaryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or several groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group and a (C.sub.1-C.sub.6)alkoxy group, R.sub.9, R.sub.10, R.sub.19, R.sub.20, R.sub.29 and R.sub.30 representing, independently from one another, a hydrogen atom; a N-protecting group; or a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (5- to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or heteroaryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or several groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group and a (C.sub.1-C.sub.6)alkoxy group, R.sub.11, R.sub.12, R.sub.21, R.sub.22, R.sub.31 and R.sub.32 representing, independently from one another, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, and R.sub.33 and R.sub.34 representing, independently from one another, a N-protecting group; or a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)-alkyl-aryl or (C.sub.1-C.sub.6)-alkyl-heteroaryl group, said group being optionally substituted by one or several groups selected from a halogen atom, OH, COOH and CHO.

2. The compound according to claim 1, wherein it is a compound having the following formula Ia: ##STR00045## or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any proportion, wherein R1, X1, X2, X3, X4 and X5 are as defined in claim 1 and R2a represents OH, OSiR13R14R15, OR16, OC(O)R17, OCO2R18, OC(O)NR19R20, OP(O)(OR21)2, or OSO3R22, with R13 to R22 as defined in claim 1.

3. The compound according to claim 1, wherein it is a compound having the following formula Ib: ##STR00046## or a cosmetically or pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any proportion, wherein R.sub.1, X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 are as defined in claim 1 and R.sub.2b represents NH.sub.2, NHR.sub.33, or NR.sub.33R.sub.34, with R.sub.33 and R.sub.34 as defined in claim 1.

4. The compound according to claim 1, wherein R.sub.1 represents a hydrogen atom, OH, OR6, OC(O)R7, OCO2R8 or OC(O)NR9R10.

5. The compound according to claim 1, wherein R.sub.2 represents NH.sub.2, NHR.sub.33, NR.sub.33R.sub.34, OH, OR.sub.16, OC(O)R.sub.17, OCO.sub.2R.sub.18 or OC(O)NR.sub.19R.sub.20.

6. The compound according to claim 1, wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 represent, independently from one another, a hydrogen atom, OH, OR.sub.26, OC(O)R.sub.27, OCO.sub.2R.sub.28, Or OC(O)NR.sub.29R.sub.30.

7. The compound according to claim 1, wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 represents a group other than a hydrogen atom.

8. The compound according to claim 7, wherein X.sub.3 represents a group other than a hydrogen atom.

9. The compound according to claim 8, wherein X.sub.1, X.sub.2, X.sub.4 and X.sub.5 each represent a hydrogen atom and X.sub.3 represents a group other than a hydrogen atom.

10. The compound according to claim 9, wherein: X.sub.1, X.sub.2, X.sub.4 and X.sub.5 each represent a hydrogen atom, X.sub.3 represents OH or OR.sub.26, R.sub.1 represents H, OH or OR.sub.6, and R.sub.2 represents NH.sub.2, NHR.sub.33, NR.sub.33R.sub.34, OH or OR.sub.16.

11. The compound according to claim 1, wherein: R.sub.6, R.sub.7, R.sub.8, R.sub.16, R.sub.17, R.sub.18, R.sub.26, R.sub.27, R.sub.28, R.sub.33 and R.sub.34 represent, independently from one another, a (C.sub.1-C.sub.6)alkyl, aryl or aryl-(C.sub.1-C.sub.6)alkyl group, and R.sub.9, R.sub.10, R.sub.19, R.sub.20, R.sub.29 and R.sub.30 represent, independently from one another, a hydrogen atom, or a (C.sub.1-C.sub.6)alkyl, aryl or aryl-(C.sub.1-C.sub.6)alkyl group.

12. The compound according to claim 1, wherein it is chosen among: ##STR00047## and cosmetically or pharmaceutically acceptable salts thereof.

13. The compound according to claim 12, wherein it is chosen among: ##STR00048## and cosmetically or pharmaceutically acceptable salts thereof.

14. A cosmetic or pharmaceutical composition comprising at least one compound according to claim 1 and at least one cosmetically or pharmaceutically acceptable excipient.

15-18. (canceled)

19. A method for the preparation of a compound according to claim 1 comprising: reacting a compound of following formula II: ##STR00049## with a compound of following formula III: ##STR00050## wherein X.sub.1X, X.sub.2X, X.sub.3X, X.sub.4X, X.sub.5X, R.sub.1X and R.sub.2X represent respectively X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, R.sub.1 and R.sub.2 as defined in claim 1, optionally in a protected form, and R represents a leaving group, deprotecting the R.sub.1, R.sub.2, X.sub.1, X.sub.2, X.sub.3, X.sub.4 and/or X.sub.5 groups when they are in a protected form, and optionally salifying the compound of formula I obtained in the previous step to give a cosmetically or pharmaceutically acceptable salt of the compound of formula I.

20. A method for the preparation of a compound according to claim 1 comprising: fluorinating the ketone function of a compound of following formula XI: ##STR00051## wherein X.sub.1X, X.sub.2X, X.sub.3X, X.sub.4X, X.sub.5X, R.sub.1X and R.sub.2X represent respectively X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, R.sub.1 and R.sub.2 as defined in claim 1, optionally in a protected form, deprotecting the R.sub.1, R.sub.2, X.sub.1, X.sub.2, X.sub.3, X.sub.4 and/or X.sub.5 groups when they are in a protected form, and optionally salifying the compound of formula I obtained in the previous step to give a cosmetically or pharmaceutically acceptable salt of the compound of formula I.

21. A method for the preparation of a compound according to claim 1 with X.sub.3OH comprising: oxidizing the aldehyde function of a compound of following formula XV: ##STR00052## wherein X.sub.1X, X.sub.2X, X.sub.4X, X.sub.5X, R.sub.1X and R.sub.2X represent respectively X.sub.1, X.sub.2, X.sub.4, X.sub.5, R.sub.1 and R.sub.2 as defined in claim 1, optionally in a protected form, deprotecting the R.sub.1, R.sub.2, X.sub.1, X.sub.2, X.sub.4 and/or X.sub.5 groups when they are in a protected form, and optionally salifying the compound of formula I obtained in the previous step to give a cosmetically or pharmaceutically acceptable salt of the compound of formula I.

22. The method according to claim 21, wherein the compound of formula XV is prepared by reacting a compound of following formula XVI: ##STR00053## wherein X.sub.1X, X.sub.2X, X.sub.4X and X.sub.5X are as defined in claim 21, with a compound of following formula XIV: ##STR00054## wherein R.sub.1X and R.sub.2X are as defined in claim 21.

23. A method for depigmenting, lightening, bleaching or whitening a skin by applying on said skin an efficient amount of a compound according to claim 1 to a person in need thereof.

24. A method for treating a pigmentation disorder of a skin by applying on said skin an efficient amount of a compound according to claim 1 to a person in need thereof.

25. The method according to claim 24, wherein the pigmentation disorder is a hyperpigmentation.

26. The method according to claim 25, wherein the hyperpigmentation results from overexposure to the sun, inflammation, injuries, burns, medicines or hormonal alteration.

Description

FIGURE

[0114] FIG. 1 represents the inhibition of human tyrosinase kinetics of compound 8 at 1.12 mM.

EXAMPLES

[0115] The following abbreviates have been used in the examples. [0116] DAST: Diethylaminosulfur trifluoride [0117] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene [0118] DCM: Dichloromethane [0119] DMF: Dimethylformamide [0120] eq.: equivalent [0121] ESI: Electrospray ionisation [0122] mCPBA: meta-Chloroperoxybenzoic acid [0123] NMR: Nuclear Magnetic Resonance [0124] rt: room temperature [0125] sat. aq.: saturated aqueous [0126] THF: Tetrahydrofuran

1. Preparation of the Compounds According to the Invention

Synthesis of Intermediate Compound 2

[0127] ##STR00016##

[0128] Under inert atmosphere, zinc (32.8 g, 501.9 mmol, 5 eq.) was added to a solution of compound 1 (prepared as described in J. Org. Chem. 2005, 70, 10139-10142) (45.6 g, 100.4 mmol, 1 eq.) in a mixture of ethanol (1.4 L)/water (70.2 mL)/AcOH (35.1 mL). The mixture was stirred at reflux for 1 h. Then the mixture was filtered over cotton to remove Zinc. The cotton was washed with ethyl acetate and the filtrate was concentrated, dissolved in ethyl acetate, washed with sat. aq. NaHCO.sub.3, water, dried over sodium sulfate, filtered and concentrated to give intermediate compound 2 (29.6 g, 99%) as a yellowish oil.

[0129] .sup.1H NMR (CDCl.sub.3, 300 MHz): 3.8 (dd, J=1.5 Hz, J=3.9 Hz, 1H); 4.2 (dd, J=3.9 Hz, J=7.5 Hz, 1H); 4.4 (d, J=12 Hz, 1H); 4.6-4.7 (m, 2H); 4.8 (d, J=12 Hz, 1H); 5.3-5.4 (m, 2H); 6 (ddd, J=7.8 Hz, J=10.5 Hz, J=17.4 Hz, 1H); 7.3-7.4 (m, 10H); 9.7 (d, J=1.5 Hz, 1H).

Synthesis of Intermediate Compound 3

[0130] ##STR00017##

[0131] Under inert atmosphere, 3-bromo-3,3-difluoropropene (12.3 mL, 119 mmol, 1.2 eq.) was added to a cooled heterogeneous solution (10 C.) of intermediate compound 2 (29.6 g, 99.7 mmol, 1 eq.) in THF (55.4 mL)/H.sub.2O (203 mL) and indium (13.7 g, 119 mmol, 1.2 eq.). The mixture was stirred at 10 C. for 1 hour. Then, HC12N was added and the mixture was extracted with Et.sub.2O. The organic layers were combined, dried over sodium sulfate and concentrated. The crude oil was purified by silica gel chromatography (Biotage SNAP 750 g, cyclohexane/ethyl acetate 100:0 to 73:17) to afford intermediate compound 3 (15.9 g, 43%) as a colorless oil.

[0132] Mass (ESI.sup.+): 375.2[M+H].sup.+, 392.2[M+NH.sub.4].sup.+, 397.2[M+Na].sup.+.

[0133] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 108.2 (d, J=251 Hz, 1F); 113.4 (d, J=251 Hz, 1F).

Synthesis of Intermediate Compound 4

[0134] ##STR00018##

[0135] Under inert atmosphere, Grubbs'II catalyst (2.09 g, 2.46 mmol, 8%) was added to a degazed solution of intermediate compound 3 (11.5 g, 30.8 mmol, 1 eq.) in toluene (164 mL). The mixture was stirred under reflux for 1 hour, filtered over a pad of SiO.sub.2 which was washed with ethyl acetate. The filtrate was concentrated and the crude compound was purified by silica gel chromatography (Biotage SNAP 340 g, cyclohexane/ethyl acetate 100:0 to 80:20) to afford intermediate compound 4 (5.9 g, 58%) as a brown solid.

[0136] Mass (ESI.sup.+): 364.2 [M+NH.sub.4].sup.+.

[0137] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 102.4 (d, J=274 Hz, 1F); 105.2 (d, J=274 Hz, 1F).

Synthesis of Intermediate Compound 5

[0138] ##STR00019##

[0139] Et.sub.3N (0.6 mL, 4.33 mmol, 1.5 eq.) followed by 10% Pd/C (0.184 g, 0.173 mmol, 6%) were added to a solution of intermediate compound 4 (1.00 g, 2.89 mmol, 1 eq.) in ethyl acetate (72 mL). The mixture was stirred 2 hours under hydrogen atmosphere at room temperature, filtered on millipore 0.45 m and concentrated. The crude compound was purified on silica gel chromatography (Biotage ZIP 45 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford intermediate compound 5 (838 mg, 83%) as a white solid.

[0140] Mass (ESI.sup.+): 366.2[M+NH.sub.4].sup.+, 371.1 [M+Na].sup.+, 387.1 [M+K].sup.+.

[0141] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 106.4 (d, J=242 Hz, 1F); 116.3 (brd, 1F).

Synthesis of Intermediate Compound 6

[0142] ##STR00020##

[0143] Pyridine (0.63 mL, 7.69 mmol, 4 eq) followed by trifluoromethanesulfonic anhydride (1.29 mL, 7.69 mmol, 4 eq) were added to a cooled solution (0 C.) of intermediate compound 5 (670 mg, 1.92 mmol, 1 eq.) in dichloromethane (17.9 mL) under inert atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with dichloromethane and washed twice with 2N HCl. The organic layer was dried over sodium sulfate and concentrated to give crude intermediate compound 6 (889 mg) as a dark residue. Intermediate compound 6 was engaged in the next step without further purification.

[0144] .sup.19F NMR (CDCl.sub.3, 282.5 MHz): 104.5 (dt, J=246 Hz, J=11 Hz, 1F); 115.5 (d, J=246 Hz, 1F).

Synthesis of Compound 7

[0145] ##STR00021##

[0146] K.sub.2CO.sub.3 (0.673 g, 4.87 mmol, 3 eq.) and benzyloxyphenol (1.14 g, 5.68 mmol, 3.5 eq.) were dissolved in DMF (3.9 mL) under an inert atmosphere, and this suspension was stirred at room temperature for 1 h. A solution of intermediate compound 6 (0.78 g, 1.62 mmol, 1 eq.) in DMF (1.56 mL) was added, and the mixture was heated to 110 C. overnight. Water was then added and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give a dark oil. This crude material was purified by a flash chromatography (Biotage ZIP 10 g, cyclohexane/ethyl acetate 100:0 to 87:13) to afford intermediate compound 7 (575 mg, 67%) as a yellowish oil.

[0147] Mass (ESI.sup.+): 548.3[M+NH.sub.4].sup.+, 553.2[M+Na].sup.+, 569.2[M+K].sup.+.

Synthesis of Compound 8

[0148] ##STR00022##

[0149] Pd/C 10% (128 mg, 0.12 mmol, 10%,) was added to a solution of compound 7 (637 mg, 1.2 mmol, 1 eq.) in THF (35 mL). Then, iN HCl (4.8 mL, 4.8 mmol, 4 eq.) was added. The mixture was stirred for 2 hours under hydrogen atmosphere at room temperature. The reaction mixture was filtered (H-PTFE 0.45 m) and concentrated. The crude residue was purified by a flash chromatography (Biotage SNAP 25 g, dichloromethane/methanol 100:0 to 90:10) to afford compound 8 (222 mg, 71%).

[0150] Mass(ESI.sup.): 259.1[MH].sup.+.

[0151] .sup.19Fdec (MeOD, 282.5 MHz): 104.7 (brd, J=257 Hz, 1F); 106.8 (brd, J=257 Hz, 1F).

Synthesis of Intermediate Compound 9

[0152] ##STR00023##

[0153] To a solution of cyclohex-2-enol in its racemic form (1.0 g, 9.68 mmol, 1 eq.) in DCM (70 mL) at 0 C. was added mCPBA (77%, 3.80 g, 16.9 mmol, 1.75 eq.). After stirring at room temperature for 16 h, the reaction mixture was washed with aqueous Na.sub.2S.sub.2O.sub.3. The organic layer was then dried over sodium sulfate, filtered and concentrated to afford intermediate compound 9 (360 mg, 33%) as a crude residue.

[0154] .sup.1H NMR (CDCl.sub.3, 300 MHz): 1.00-2.00 (m, 6H); 3.32 (s, 1H); 3.35 (s, 1H); 4.01 (s, 1H).

Synthesis of Intermediate Compound 10

[0155] ##STR00024##

[0156] A solution of intermediate compound 9 (360 mg, 3.15 mmol, 1 eq.) in THF (4 mL) was added to a suspension of NaH (204 mg, 8.52 mmol, 2.7 eq.) and BnBr (0.377 mL, 3.15 mmol, 1 eq.) in THF at 55 C. After heating at 55 C. for 4 h, ice was slowly added to the mixture which was then extracted twice with Et.sub.2O. The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was then purified by silica gel chromatography (Biotage ZIP 5 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford 10 (413 mg, 64%) as a yellow liquid.

[0157] Mass (IC.sup.+): 205.2.

Synthesis of Intermediate Compound 11

[0158] ##STR00025##

[0159] A solution of intermediate compound 10 (410 mg, 2.00 mmol, 1 eq.) in toluene (12.6 mL) under inert atmosphere was treated with trimethylsilyltrifluoromethanesulfonate (TMSOTf) (0.38 mL, 2.11 mmol, 1.05 eq.) followed by 2,6-lutidine (1.17 mL, 10.0 mmol, 5 eq.). After stirring for 30 min at room temperature, DBU (1.50 mL, 10.0 mmol, 5 eq.) was added. The reaction mixture was then diluted with 2N HCl, extracted twice with Et.sub.2O and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography over silica gel (Biotage ZIP 30 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford intermediate compound 11 (335 mg, 82%) as a yellow liquid.

[0160] .sup.1H NMR (CDCl.sub.3, 300 MHz): 1.54-2.60 (m, 4H); 2.39 (brs, 1H, OH); 3.65 (m, 1H); 4.22 (brs, 1H); 4.59 (d, 1H, J=11.7 Hz, OCHHPh); 4.63 (m, 1H); 4.68 (d, J=11.7 Hz, 1H, OCHHPh); 3.46 (m, 1H, CH); 5.82 (m, 1H, CH); 7.26-7.37 (m, 5H, HAr).

Synthesis of Intermediate Compound 12

[0161] ##STR00026##

[0162] p-Benzyloxyphenol (348 mg, 1.70 mmol, 1.2 eq.) and 1,1-(azodicarbonyl)dipiperidine (ADDP) (430 mg, 1.70 mmol, 1.2 eq.) were added to a solution of intermediate compound 11 (290 mg, 1.42 mmol, 1 eq.) in toluene (4.53 mL) under inert atmosphere. The mixture was cooled to 0 C. and P(nBu).sub.3 (0.45 mL, 1.70 mmol, 1.2 eq.) was added. The reaction mixture was then stirred at room temperature for 2 h before being diluted with DCM. The mixture was then concentrated and the crude residue was purified by flash chromatography over silica gel (Biotage SNAP 50 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford intermediate compound 12 (382 mg, 70%) as a yellow oil.

[0163] Mass (ESI.sup.+): 404.2 [M+NH.sub.4].sup.+; 409.1 [M+Na].sup.+; 425.1 [M+K].sup.+.

Synthesis of Intermediate Compound 13

[0164] ##STR00027##

[0165] BH.sub.3.Me.sub.2S (2M in THF, 0.37 mL, 0.74 mmol, 5 eq.) was slowly added to a solution of intermediate compound 12 (57.0 mg, 0.15 mmol, 1 eq.) in THF (0.75 mL) cooled to 0 C. The mixture was then stirred at room temperature for 20 hours. The reaction mixture was then cooled to 0 C. and H.sub.2O.sub.2 (30% w/v, 0.45 mL, 4.42 mmol, 30 eq.), water (0.19 mL, 10.32 mmol, 70 eq.) and NaOH (2M in water, 0.59 mL, 1.18 mmol, 8 eq.) were successively added. The mixture was then stirred for an additionnal 3 h at room temperature. Water was added to the mixture which was then extracted 3 times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography over silica gel (Biotage ZIP 10 g, cyclohexane/ethyl acetate 95:5 to 60:40) to afford intermediate compound 13 (22 mg, 37%) as a colourless oil.

[0166] Mass (ESI.sup.+): 422.3[M+NH.sub.4].sup.+.

Synthesis of Intermediate Compound 14

[0167] ##STR00028##

[0168] Dess Martin periodinane (34.6 mg, 0.08 mmol, 1.5 eq.) was added to a solution of intermediate compound 13 (22.0 mg, 0.05 mmol, 1 eq.) in DCM (0.16 mL). The reaction mixture was stirred at room temperature for 2 hours. NaOH (1M in water) was then added to the mixture which was then extracted 3 times with DCM. The combined organic layers were then dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography over silica gel (AIT 4 g, cyclohexane/ethyl acetate 93:7 to 40:60) to afford intermediate compound 14 (12 mg, 55%) as a colourless oil.

[0169] Mass (ESI.sup.+): 420.2[M+NH.sub.4].sup.+.

Synthesis of Compound 15

[0170] ##STR00029##

[0171] DAST (0.42 mL, 3.47 mmol, 10 eq.) was added to a solution of intermediate compound 14 (140 mg, 0.35 mmol, 1 eq.) in DCM (0.94 mL) under inert atmosphere. The mixture was stirred at room temperature for 2 hours before DCM was added. The diluted solution was then poured onto a cold aqueous solution of NaHCO.sub.3. The mixture was stirred 5 min before being extracted 3 times with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography over silica gel (Biotage SNAP KP-Sil 10 g, cyclohexane/ethyl acetate 99:1 to 90:10) to afford compound 15 (77 mg, 52%) as a yellow oil.

[0172] Mass (ESI.sup.+): 447.1 [M+Na].sup.+.

Synthesis of Compound 16

[0173] ##STR00030##

[0174] Pd/C (10%, 15.0 mg, 0.01 mmol, 0.3 eq.) was added to a solution of compound 15 (20 mg, 0.05 mmol, 1 eq) in ethyl acetate (1 mL) under inert atmosphere. The mixture was then stirred under hydrogen atmosphere (10 bars) overnight. The mixture was filtered (over Millipore 0.45 m) and the filter was washed with ethyl acetate. The filtrate was finally concentrated to afford compound 16 as a white solid in a quantitative yield.

[0175] Mass (ESI.sup.): 243.1[MH].sup.+.

[0176] .sup.19Fdec (MeOD, 282.5 MHz): 100.0 (d, J=246 Hz, 1F); 113.9 (d, J=246 Hz, 1F).

[0177] The compound 16 was obtained as a racemate mixture of the two following enantiomers 16a and 16b.

##STR00031##

Synthesis of Compound 18

[0178] ##STR00032##

[0179] DAST (5 eq., 13.5 g, 10.3 mL, 83.9 mmol) was added to a solution of 7-oxabicyclo[4.1.0]heptan-2-one (1 eq., 1.92 g, 1.7 mL, 16.8 mmol) in dry DCM (17 mL) under inert atmosphere, at room temperature. The reaction mixture was stirred for 2 h before being poured onto a mixture of ice and water. The organic layer was then filtered through a plug of silica gel. DCM was slowly removed by distillation from 45 C. under atmospheric pressure to 85 C. under reduced pressure. Compound 18 (1.94 g, 86%) was obtained as a yellowish liquid.

[0180] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 96.5 (d, J=263 Hz, 1F); 100.2 (d, J=263 Hz, 1F).

Synthesis of Compound 19

[0181] ##STR00033##

[0182] Tris(trifluoromethanesulfonic acid) erbium (10%, 0.47 g, 0.746 mmol) was added to a solution of compound 18 (1 eq., 1 g, 7.46 mmol) in benzyl alcohol (935 L, 8.95 mmol, 1.2 eq) and the mixture was stirred at room temperature for 4 h. A saturated solution of NaHCO.sub.3 followed by DCM were added to the mixture which was extracted twice with DCM. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by a flash chromatography (Biotage; AIT 120 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford compound 19 (935 mg, 3.86 mmol, 52%) as a yellowish solid.

[0183] Mass (ESI.sup.+): 260.1 [M+NH.sub.4].sup.+

[0184] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 104.1 (d, J=241 Hz, 1F); 118.0 (brd, J=241 Hz, 1F).

Synthesis of Compound 20

[0185] ##STR00034##

[0186] K.sub.2CO.sub.3 (6 eq., 222 mg, 1.61 mmol) was added to a solution of compound 19 (1 eq., 65 mg, 0.268 mmol) and 4-fluorobenzaldehyde (3 eq., 101 mg, 0.0881 mL, 0.805 mmol) in dry DMF (2.83 mL). The mixture was heated to 130 C. for 3 days. Water and brine were added to dissolve K.sub.2CO.sub.3, and the mixture was extracted twice with AcOEt. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellowish liquid. The analysis of the crude material showed some remaining compound 19 so the compound was re-engaged in the reaction under the same conditions. The mixture was stirred overnight and the same work-up than previously described was applied. The crude material was purified by flash chromatography (Biotage ZIP 10 g, cyclohexane/ethyl acetate 100:0 to 70:30) to afford compound 20 (73 mg, 0.211 mmol, 79%).

[0187] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 101.8 (d, J=247 Hz, 1F); 114.2 (brd, J=247 Hz, 1F).

Synthesis of Compound 21

[0188] ##STR00035##

[0189] Compound 20 (1 eq., 72 mg, 0.208 mmol) was added to a solution of m-CPBA (3.5 eq., 163 mg, 0.291 mL, 0.728 mmol) in dry DCM (3.47 mL) under an inert atmosphere. The reaction mixture was stirred at 45 C. for 16 hours. The mixture was then washed with sat. NaHCO.sub.3 and extracted twice with DCM. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellowish residue which was dissolved in methanol (0.866 mL). NaOH IM (5 eq., 1.04 mL, 1.04 mmol) was added and the mixture was stirred at room temperature for 1 h. The pH was adjusted to 2 with 2N HCl, and the mixture was filtered. The filtrate was extracted twice with DCM and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford crude compound 21 (64 mg, 92%, contains mCPBA residues).

[0190] Mass (ESI.sup.): 333.1 [MH].sup.; 379.1 [M.sub.+HCOO].sup.; 393.1 [M+CH.sub.3COO].sup..

[0191] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 104.2 (brd, J=242 Hz, 1F); 118.2 (brd, J=242 Hz, 1F).

Synthesis of Compound 16

[0192] ##STR00036##

[0193] Palladium on carbon (10% w %, 0.3 eq., 60.2 mg, 0.0565 mmol) was added to a solution of compound 21 (1 eq., 63 mg, 0.188 mmol) in ethyl acetate (4 mL). The reaction mixture was stirred overnight under hydrogen pressure (10 bars). The mixture was filtered over Millipore 0.45 m, and the black solid was washed with AcOEt. The filtrate was concentrate and purified over a flash chromatography (Biotage ZIP 10 g, cyclohexane/ethyl acetate 85:15 to 35:65) to afford compound 16 (20 mg, 0.0819 mmol, 43%).

[0194] .sup.19F NMR (MeOD, 282.5 MHz): 100.0 (d, J=246 Hz, 1F); 113.9 (d, J=246 Hz, 1F).

[0195] The compound 16 was obtained as a racemate mixture of the two following enantiomers 16a and 16b.

##STR00037##

Synthesis of Compounds 22a and 22b

[0196] ##STR00038##

[0197] DAST (5 eq., 3.02 mL, 24.7 mmol) was added to a solution of 7-oxabicyclo[4.1.0]heptan-2-one (1 eq., 0.5 mL, 4.94 mmol) in dry DCM (5 mL) under an inert atmosphere. The reaction was stirred at room temperature for 2 h. The mixture was then slowly poured into icy water, and the layers were separated. The organic layer was filtered through a plug of silica gel (eluted with a minimum volume of DCM). The filtrate containing the difluoro epoxide 18 was cooled to 0 C. and trimethylaluminium (1.05 eq., 2 M, 2.59 mL, 5.18 mmol) was added dropwise. After stirring for 1 h, (R)-(+)-1-phenylethylamine (1.15 eq., 0.74 mL, 5.68 mmol) was slowly added, and the mixture was stirred at 0 C. for 15 min, and refluxed overnight. A saturated aqueous solution of ammonium chloride was then added to the mixture and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by a flash chromatography (Biotage; AIT 25 g, cyclohexane/ethyl acetate 20:80 to 7:93) to afford compound 22a (420 mg, 1.65 mmol, 33%) as a yellowish solid and compound 22b (244 mg, 0.96 mmol, 19%).

[0198] Mass (ESI.sup.+): 256.1 [M+H].sup.+

[0199] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): [0200] 22a: 103.8 (d, J=239 Hz, 1F, CF.sub.2); 120.0 (d, J=240 Hz, 1F, CF.sub.2). [0201] 22b: 103.8 (d, J=238 Hz, 1F, CF.sub.2); 119.8 (d, J=238 Hz, 1F, CF.sub.2).

Synthesis of Compounds 23a and 23b

[0202] ##STR00039##

[0203] Palladium on activated carbon (0.25 eq, 20% on carbon 50% water wet 2.66 g, 4.99 mmol) and HCl 1N (1.4 eq., 1 M, 28 mL, 28 mmol) were added to a solution of 22a (1 eq., 5.1 g, 20 mmol) in THF (102 mL). The mixture was stirred overnight under hydrogen atmosphere and was then filtered over Millipore 0.45 m. The filtrate was concentrated and co-evaporated with toluene to afford crude 23a (4.03 g, 108%) as white solid. Crude 23b (2.78 g, 104%) was obtained under the same conditions from 22b (1 eq., 3.63 g, 14.2 mmol).

[0204] Mass (ESI.sup.+): 152.1 [MHCl+H].sup.+

[0205] .sup.19Fdec NMR (CDCl.sub.3, 282.5 MHz): 106.1 (d, J=242 Hz, 1F, CF.sub.2); 121.8 (d, J=242 Hz, IF, CF.sub.2).

Synthesis of Compounds 24a and 24b

[0206] ##STR00040##

[0207] Benzyl chloroformate (1.46 eq., 4.46 mL, 31.4 mmol) and NaHCO.sub.3 (3 eq., 5.41 g, 64.4 mmol) were successively added to a solution of 23a (1 eq., 4.03 g, 21.5 mmol) in ethanol (97.4 mL) under an inert atmosphere. The mixture was stirred at room temperature for 16 hours. Water was then added to the mixture, and ethanol was removed by evaporation. The aqueous solution was extracted twice with ethyl acetate, and the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford crude 24a (6.65 g, 109%) as a yellowish oil.

[0208] Crude 24b (4.74 g, 112%) was obtained under the same conditions from 23b (1 eq., 2.78 g, 14.82 mmol).

[0209] Mass (ESI.sup.+): 286.1 [M+H].sup.+; 303.2 [M+NH.sub.4].sup.+; 588.3 [2M+NH.sub.4].sup.+.

[0210] .sup.19Fdec NMR (CDCl.sub.3, 285.5 MHz): 105.1 (d, J=243 Hz, 1F, CF.sub.2); 118.2 (brd, J=243 Hz, 1F, CF.sub.2).

Synthesis of Compounds 25a and 25b

[0211] ##STR00041##

[0212] Pyridine (21.9 eq., 41.3 mL, 511 mmol) and triflic anhydride (3.27 eq., 12.7 mL, 76.3 mmol) were successively added to a solution of 24a (1 eq., 6.65 g, 23.3 mmol) in dry DCM (172 mL) cooled to 0 C., under inert atmosphere. The mixture was stirred at 0 C. for 1 hour before HCl (1.5M in water) was added. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified over a flash chromatography (Biotage; Macherey 200 g, cyclohexane/ethyl acetate from 98:2 to 63:37) to afford 25a (4.63 g, 57% over 3 steps) in the form of a yellowish solid. 25b (4.21 g, 71% over 3 steps) was obtained under the same conditions from 24b (1 eq., 4.74 g, 16.61 mmol).

[0213] Mass (ESI.sup.+): 435.1 [M+NH.sub.4].sup.+

[0214] .sup.19Fdec NMR (CDCl.sub.3, 285.5 MHz): 74.5 (d, J=9 Hz, CF.sub.3); 102.3 (d, J1=246 Hz, 1F, CF.sub.2); 115.5 (d, J=246 Hz, 1F, CF.sub.2).

Synthesis of Compounds 26a and 26b

[0215] ##STR00042##

[0216] K.sub.2CO.sub.3 (3 eq., 4.6 g, 33.3 mmol) and benzyloxyphenol (3.5 eq., 7.77 g, 38.8 mmol) were dissolved in DMF (26.6 mL) under an inert atmosphere, and this suspension was stirred at room temperature for 1 h. A solution of 25a (1 eq., 4.63 g, 11.1 mmol) in dry DMF (10.7 mL) was then added, and the mixture was heated to 130 C. for 3 hours. Water was then added to the mixture which was extracted 3 times with ethyl acetate. The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude material was purified by a flash chromatography (Biotage; SNAP 340 g, cyclohexane/ethyl acetate 97:3 to 55:45). Two purifications were required to get rid of remaining p-benzyloxyphenol. 26a (746 mg, 20%) was obtained in the form of a brown oil.

[0217] 26b (1.63 g, 48%) was obtained under the same conditions from 25b (4.21 g, 10.1 mmol). Only one purification by flash chromatography was necessary.

[0218] Mass (ESI.sup.+): 334.2 [M+H].sup.+

[0219] .sup.19Fdec NMR (CDCl.sub.3, 285.5 MHz): 101.1 (d, J=242 Hz, 1F, CF.sub.2); 117.0 (d, J=242 Hz, IF, CF.sub.2).

Synthesis of Compounds 28a and 28b

[0220] ##STR00043##

[0221] Palladium on activated carbon (0.1 eq, 20% on carbon 50% water wet, 118 mg, 0.22 mmol) and HCl 1N (1.4 eq., 1 M, 3.13 mL, 3.13 mmol) were added to a solution of 26a (1 eq., 745 mg, 2.23 mmol) in THF (65.7 mL). The mixture was stirred overnight under hydrogen atmosphere and was then filtered over Millipore 0.45 m. The solid residue was washed with methanol and the filtrate was concentrated to afford crude 27a (743 mg, 119%) as white solid. This solid was then dissolved in methanol and Amberlite IRA-67 was added until pH>7. The suspension was filtered and the filtrate was concentrated to afford 28a (289 mg, 54% over 2 steps) as a white solid.

[0222] 28b (140 mg, 58% over 2 steps) was obtained under the same conditions from 26b (333 mg, 1 mmol).

[0223] Mass (ESI.sup.+): 244.1 [M+H].sup.+.

[0224] .sup.19Fdec NMR (MeOD, 285.5 MHz): 101.4 (d, J=243 Hz, 1F, CF.sub.2); 117.4 (brd, J=243 Hz, 1F, CF.sub.2).

2. Biological Activity

[0225] In Vitro Efficacy of Compound 8 as Human Tyrosinase Inhibitor

[0226] The efficacy of compound 8 was evaluated by the inhibition of human tyrosinase in-tubo and compared to the prior art compound deoxyarbutin.

[0227] Methods

[0228] The assay was performed with a ready-to-use kit from Feldan Inc (Canada): the HumanLike Tyrosinase Assay kit (ref A021-a-001Kit).

[0229] The protocol was performed as described in the instructions for use of the manufacturer. Briefly, this kit is intended for the determination of human tyrosinase activity in presence of different inhibitors. The kit measures the conversion of L-Tyrosine into a dopachrome complex absorbing at 490 nm. The time course of the assay is 20 minutes, after which the results are analyzed and compared.

[0230] Results

[0231] The compound 8 and deoxyarbutin have been tested at a final concentration of 1.12 mM. The measured absorbances at 490 nm are reported in the table 1 and plotted in function of time in the FIG. 1.

TABLE-US-00001 TABLE 1 measured OD at 490 nm for 20 minutes with compound 8 and deoxyarbutin OD at 490 nm Deoxyarbutin Compound 8 Negative control Positive control 1.12 mM 1.12 mM (no enzyme) (no inhibitor) time 0 0.0000 0.0000 0.0000 0.0000 (min) 1 0.0100 0.0080 0.0030 0.0100 2 0.0195 0.0170 0.0060 0.0210 3 0.0290 0.0245 0.0080 0.0320 4 0.0385 0.0345 0.0110 0.0430 5 0.0480 0.0415 0.0140 0.0550 6 0.0585 0.0505 0.0180 0.0670 7 0.0695 0.0610 0.0210 0.0820 8 0.0800 0.0675 0.0230 0.0940 9 0.0935 0.0755 0.0270 0.1080 10 0.1035 0.0845 0.0310 0.1210 11 0.1155 0.0935 0.0350 0.1340 12 0.1265 0.1015 0.0390 0.1470 13 0.1385 0.1090 0.0430 0.1590 14 0.1500 0.1165 0.0460 0.1720 15 0.1615 0.1255 0.0500 0.1850 16 0.1735 0.1355 0.0550 0.1960 17 0.1846 0.1405 0.0580 0.2080 18 0.1975 0.1495 0.0630 0.2200 19 0.2095 0.1575 0.0660 0.2320 20 0.2220 0.1665 0.0700 0.2450

[0232] Moreover for each compound the efficacy as tyrosinase inhibitor was calculated using the following formula:

[00001]$\mathrm{Inhibitor}.Math..Math.\mathrm{efficacy}=100-\left(\frac{{\mathrm{OD}}_{490.Math..Math.n.Math..Math.m}.Math.\mathrm{assay}}{{\mathrm{OD}}_{490.Math..Math.n.Math..Math.m}.Math.\mathrm{positive}.Math..Math.\mathrm{control}.Math..Math.\left(\mathrm{no}.Math..Math.\mathrm{inhibitor}\right)}100\right)$

[0233] The results are reported in the table 2.

TABLE-US-00002 TABLE 2 Inhibitor efficacy of compound 8 and deoxyarbutin at T = 20 min Inhibitor efficacy (%) Compound 8 (1.12 mM) 32.0 Deoxyarbutin (1.12 mM) 9.4

[0234] In these tested conditions, the compound 8 has shown a 3.4 times better efficacy than deoxyarbutin, on human tyrosinase inhibition in vitro.

[0235] In Vitro Effect of Compounds 8, 16 and 28a on the Inhibition of Melanin Synthesis in Human Epidermal Melanocytes

[0236] Method

[0237] Human melanocytes are stimulated by L-tyrosine to induce an increase of the melanin synthesis and be able to measure an inhibition of this synthesis when a whitening agent is added.

[0238] Biological model: normal human epidermal melanocytes (NHEM), lightly pigmented, were cultured in medium M254 supplemented with PMA free HMGS-2; Insulin 5 ag/ml; Penicillin 50 U/ml; Streptomycin 50 ag/ml; Gentamycin 25 g/ml (incubator: 37 C. and 5% CO2).

[0239] Culture and treatment: melanocytes were seeded in 24-well plates and cultured in culture medium for 24 hours. The medium was then replaced by culture medium containing the test compounds or not (stimulated control) in presence of the inducer (L-tyrosine at 1 mM). The cells were then incubated for 240 hours with 2 treatment renewals after 72 and 168 hours of incubation. A non-stimulated control was performed in parallel. All experimental conditions were performed in n=3.

[0240] Melanin assay: at the end of incubation, the culture supernatants were removed and the melanin was extracted by cell lysis using a 0.5 N NaOH solution. The optical density (OD) of each experimental point was measured at 405 nm and melanin quantity was calculated using melanin standards (standard curve 0.39 to 100 g/ml melanin). Results were expressed in g/ml of melanin.

[0241] Results

[0242] Tested Concentrations:

[0243] The compounds have been tested beforehand at different concentrations on the NHEM culture to determine the higher non-cytotoxic concentration to be used to evaluate the potential inhibition of melanin synthesis. The determined concentration was 300 M for all compounds: 8, 16, 28a.

[0244] The results are reports in table 3.

TABLE-US-00003 TABLE 3 Effect of compounds 8, 16, 28a on melanin synthesis: Tested Melanin synthesis Sem concentration (g/ml) Mean (g/ml) (g/ml) P.sup.(1) Non-stimulated control 7.8 7.6 0.1 *** 7.3 7.7 Stimulation by Stimulated 23.3 22.9 0.2 L-tyrosine (1 mM) Control 22.8 22.6 8 300 M 9.2 9.3 0.1 *** 9.4 9.2 16 300 M 7.9 8.1 0.1 *** 8.2 8.2 28a 300 M 9.9 10.2 0.2 *** 10.5 10.2 .sup.(1)Threshold for statistical significance ns: >0.05, Not significant *: 0.01 to 0.05, Significant **: 0.001 to 0.01, Very significant ***: <0.001, Extremely significant

[0245] In the tested conditions the L-tyrosine stimulation increased the synthesis of melanin up to 22.9 g/ml (compared to 7.6 g/ml in unstimulated control).

[0246] The tested compounds 28a, 8 and 16 have shown a high inhibition effect by decreasing the melanin synthesis to 10.2 g/ml, 9.3 g/ml and 8.1 g/ml respectively.