Compounds reducing malodour perception and the use thereof

Abstract

The present invention relates to new malodour-counteracting agents of formula (I) or stereoisomers thereof, particularly useful in blocking the olfactory perception of androstenone, Formula (I), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and X have the same meaning as that defined in the claims. The present invention also relates to consumer products comprising said agents. The present invention also relates to the use of said agents to suppress or attenuate undesirable odour, as well as to methods to suppress or attenuate undesirable odour employing said compounds. ##STR00001##

Claims

1. An OR7D4 antagonist, wherein the antagonist comprising a compound of formula (I) or a stereoisomer thereof, ##STR00190## wherein the compound or stereoisomer thereof is an antagonist of the OR7D4 receptor, and wherein X is selected from the group consisting of —CN, —C(═O)OR.sup.8, —C(═O)—C.sub.1-6alkyl, —C(═O)—NR.sup.9R.sup.10, —CH.sub.2—OH, —CH.sub.2—CH.sub.2—OH, —C(═O)H, and C.sub.1-6alkoxyC.sub.1-6alkyl; R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.2 is a group selected from C.sub.5-6 alkyl, C.sub.5-6 alkenyl, 3-tert-butyl-1-methylpropyl, or C.sub.1alkyl substituted with a C.sub.5cycloalkyl; R.sup.3 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, and cyano; R.sup.4 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, and cyano; R.sup.5 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, and cyano; R.sup.6 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, and cyano; R.sup.7 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, and cyano; R.sup.8 is hydrogen or C.sub.1-6alkyl; R.sup.9 is hydrogen or C.sub.1-6alkyl; R.sup.10 is hydrogen or C.sub.1-6alkyl; with the following provisos: when X is —C(═O)—NR.sup.9R.sup.10 then R.sup.1 is —CH.sub.3; when X is —C(═O)H or —C(═O)OR.sup.8, then R.sup.4 is not C.sub.1-6alkoxy; and the compound of formula (I) is none of: methyl (2E,4E)-4-(4-fluorobenzylidene)-2-nonenoate; (2E,4Z)-4-benzylidene-2-methyldec-2-en-1-ol, methyl (2E,4E)-4[(4-methoxyphenyl)methylene]non-2-enoate; and (2E,4E)-4-benzylidenedec-2-enenitrile.

2. The OR7D4 antagonist according to claim 1, wherein X is selected from the group consisting of —CN, —C(═O)OC.sub.1-4alkyl, —C(═O)—OH, —C(═O)—C.sub.1-4alkyl, —C(═O)—NH.sub.2, —C(═O)—NHC.sub.1-4alkyl, —C(═O)—N(C.sub.1-4alkyl).sub.2, —CH.sub.2—OH, —CH.sub.2—CH.sub.2—OH, —C(═O)H, and C.sub.1-4alkoxyC.sub.1-4alkyl; R.sup.1 is hydrogen or C.sub.1-4alkyl; R.sup.2 is a group selected from C.sub.5-6alkyl, C.sub.5-6alkenyl, 3-tert-butyl-1-methylpropyl, or C.sub.1alkyl substituted with a C.sub.5cycloalkyl; R.sup.3 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl, and cyano; R.sup.4 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl, and cyano; R.sup.5 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl, and cyano; R.sup.6 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl, and cyano; and R.sup.7 is selected from the group consisting of hydrogen, halo, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl, and cyano.

3. The OR7D4 antagonist according to claim 1, wherein X is selected from the group consisting of —CN, —C(═O)OC.sub.1-2alkyl, —C(═O)OH, C(═O)—C.sub.1-2alkyl, —C(═O)—NH.sub.2, —C(═O)—NHC.sub.1-2alkyl, —C(═O)—N(CH.sub.3).sub.2), —CH.sub.2—OH, —CH.sub.2—CH.sub.2—OH, —C(═O)H, and C.sub.1-2alkoxyC.sub.1-2alkyl, R.sup.1 is hydrogen or C.sub.1-2alkyl; R.sup.2 is a group selected from C.sub.5-6alkyl, C.sub.5-6alkenyl, 3-tert-butyl-1-methylpropyl, or C.sub.1alkyl substituted with a C.sub.5cycloalkyl; R.sup.3 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.4 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.6 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; and R.sup.7 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano.

4. The OR7D4 antagonist according to claim 1, wherein X is selected from the group consisting of —CN, —C(═O)—O—CH.sub.3, —C(═O)—O—CH.sub.2—CH.sub.3, —C(═O)OH, —C(═O)—CH.sub.3, —C(═O)—CH.sub.2—CH.sub.3, —C(═O)—NH.sub.2, —C(═O)—NH—CH.sub.3, —C(═O)—N(CH.sub.3).sub.2, —CH.sub.2—OH, —CH.sub.2—CH.sub.2—OH, —C(═O)H, and —CH.sub.2—O—CH.sub.3, —CH.sub.2—O—CH.sub.2—CH.sub.3; R.sup.1 is hydrogen or —CH.sub.3; R.sup.2 is a group selected from C.sub.5-6alkyl, C.sub.5-6alkenyl, 3-tert-butyl-1-methylpropyl, or C.sub.1alkyl substituted with a C.sub.5cycloalkyl; R.sup.3 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.4 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.5 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; R.sup.6 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano; and R.sup.7 is selected from the group consisting of hydrogen, fluoro, chloro, C.sub.1-6alkyl, C.sub.1-2alkoxy, C.sub.1-2alkoxyC.sub.1-2alkyl, and cyano.

5. The OR7D4 antagonist according to claim 1, wherein X is selected from the group consisting of —CN, —C(═O)—O—CH.sub.3, —C(═O)—O—CH.sub.2—CH.sub.3, —C(═O)—CH.sub.3, —C(═O)—NH.sub.2, —C(═O)—NH—CH.sub.3, —C(═O)—N(CH.sub.3).sub.2; R.sup.1 is hydrogen or —CH.sub.3; R.sup.2 is a group selected from C.sub.5-6alkyl, C.sub.5-6alkenyl, 3-tert-butyl-1-methylpropyl, or C.sub.1alkyl substituted with a C.sub.5cycloalkyl; R.sup.3 is hydrogen; R.sup.4 is hydrogen; R.sup.5 is hydrogen; R.sup.6 is hydrogen; and R.sup.7 is hydrogen.

6. The OR7D4 antagonist according to claim 1, selected from the group consisting of: TABLE-US-00011 Compound Structure 1 5 7 8 9 10 11 12 13 14 17 18 19 21 22 23 24 26 28 29 30 33 34 38 39 40 42 43 44 45

7. A consumer product comprising a OR7D4 antagonist according to claim 1.

8. The consumer product according to claim 7, which is an antiperspirant or deodorant product, further comprising a cosmetically acceptable carrier.

9. The OR7D4 antagonist according to claim 1, selected from the group consisting of: TABLE-US-00012 Compound Structure 1 5 7 8 9 10 11 12 13 14 17 18 19 21 22 23 24 26 28 29 30 33 38 39 40 42 43 44 45

Description

BRIEF DESCRIPTION OF DRAWING

(1) FIG. 1 represents a graph plotting the luminescence as a function of compound 1 concentration showing the effect of compound 1 of the invention as antagonist of the OR7D4. This analysis has been performed according to the procedure given in example section.

EXAMPLES

(2) There now follows a series of non-limiting examples that serve to illustrate the invention.

CHEMICAL EXAMPLES

(3) The following abbreviations are used:

(4) NaH Sodium hydride

(5) THF Tetrahydrofuran

(6) n-Hex n-Hexyl

(7) h hour

(8) RT room temperature

(9) TLC Thin layer chromatography

(10) HCl Hydrochloric acid

(11) MTBE Methyl-TerButylEther

(12) NaHCO.sub.3 Sodium bicarbonate

(13) LC-MS Liquid Chromatography-Mass Spectrometry

(14) MS Mass Spectrometry

(15) HPLC High Performance Liquid Chromatography

(16) ESI Electrospray Ionisation

(17) NH.sub.4OAc Ammonium acetate

(18) min minute

(19) K.sub.2CO.sub.3 Potassium Carbonate

(20) MeI Methyl Iodide

(21) DCM Dichloromethane

(22) .sup.1H NMR Proton Nuclear Magnetic Resonance

(23) .sup.13C NMR Carbon Nuclear Magnetic Resonance

(24) EtOAc Ethyl Acetate

(25) AlCl.sub.3 Aluminium Chloride

(26) Et.sub.2O Diethyl ether

(27) Na.sub.2SO.sub.4 Sodium sulfate

(28) LAH Lithium Aluminium Hydride

(29) n-BuLi Butyl Lithium

(30) DMSO Dimethylsulfoxide

(31) DMSO-d6 Deuterated Dimethylsulfoxide

(32) TEA Triethylamine

(33) TFA trifluoroacetic acid

(34) ACN Acetonitrile

(35) aq aqueous

(36) CDCl.sub.3 Deuterated Chloroform

(37) EtOH Ethanol

(38) DIBAL-H Diisobutylaluminium hydride

(39) DME Dimethoxyethane

(40) MeOH Methanol

(41) H.sub.2O Water

(42) s singleton

(43) d doublet

(44) t triplet

(45) q quadruplet

(46) m multiplet

(47) EDCl.HCl N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride

(48) HOBt hydroxybenzotriazol

(49) DIPEA Diisopropylethylamine

(50) MeLi Methyl Lithium

(51) NH.sub.4Cl Ammonium Chloride

(52) MgSO.sub.4 Magnesium sulfate

(53) NaCl Sodium Chloride

(54) DMF Dimethylformamide

(55) KOH Potassium hydroxide

(56) mL Millilitres

Example 1: Synthesis of ethyl (E)-4-((E)-benzylidene)-2-methyldec-2-enoate (Compound 1) (Scheme 2)

(57) ##STR00114##

(58) To a stirred suspension of NaH (60% dispersion in mineral oil) (188 mg, 7.86 mmol) in THF (3 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (1.5 mL, 6.94 mmol) in THF (3 mL) drop wise at 20° C. under nitrogen atmosphere. After completion of the addition, the reaction mixture was stirred at 20° C. for 1 h. Again, the mixture was cooled to 5° C. and a solution of (E)-2-benzylideneoctanal in THF (4 mL) was added. After completion of the addition, the reaction mixture was stirred at 5° C. for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into 2N HCl solution (40 mL) and extracted with MTBE (2×30 mL). Separated organic layer was washed with saturated NaHCO.sub.3 solution (30 mL) and brine (30 mL). Organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10-20% EtOAc/hexanes to afford compound 1 (700 mg, 51%) as colourless liquid.

(59) Compound 1: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.42-7.35 (m, 2H), 7.34-7.20 (m, 3H), 7.15 (s, 1H), 6.56 (s, 1H), 4.21-4.12 (m, 2H), 2.40-2.34 (m, 2H), 2.00 (s, 3H), 1.44-1.35 (m, 2H), 1.28-1.20 (m, 9H), 0.85-0.79 (m, 3H); LC-MS (ESI): 89.60%; m/z 301.3 [M+H].sup.+ at RT 6.42 min and 10.39%; m/z 301.3[M+H].sup.+ at RT 6.08 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 90.37%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 18.73 min; ACN: 5 Mm NH.sub.4OAc; 1.0 mL/min).

Example 2: Synthesis of ethyl (2E,4E)-5-(3-methoxyphenyl)-2-methylpenta-2,4-dienoate (Compound 2) (Scheme 3)

(60) ##STR00115##

Step 1

(61) To a solution of 3-hydroxybenzaldehyde (5 g, 40.9 mmol) in acetone (50 mL) were added K.sub.2CO.sub.3 (11.3 g, 81.7 mmol) followed by MeI (2.5 mL, 40.9 mmol) at room temperature under nitrogen atmosphere. The resultant reaction mixture was heated to 60° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to RT and diluted with water (50 mL) and extracted with DCM (50 mL×2). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford 3-methoxybenzaldehyde (4.6 g, 82%) as light yellow syrup.

(62) 3-Methoxybenzaldehyde: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.98 (s, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.50 (d, J=7.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.28 (dt, J=7.0, 2.0 Hz, 1H), 3.83 (s, 3H); LC-MS (ESI): 99.20%; m/z 136.8 [M+H].sup.+; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 2

(63) To a stirred solution of 3-methoxybenzaldehyde from step 1 (4.9 g, 35.5 mmol) in THF (60 mL) was added ethyl (triphenylphosphoranylidene)acetate (18.5 g, 53.2 mmol) under nitrogen atmosphere. The resultant reaction mixture was stirred room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford ethyl (E)-3-(3-methoxyphenyl)acrylate (6.1 g, 83%) as light yellow syrup.

(64) Ethyl (E)-3-(3-methoxyphenyl)acrylate: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.61 (d, J=16.0 Hz, 1H), 7.33-7.26 (m, 3H), 6.98 (dd, J=8.5, 2.0 Hz, 1H), 6.65 (d, J=16.5 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); LC-MS (ESI): 95.15%; m/z 207.0 [M+H].sup.+ at RT 3.41 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc in water+5% ACN:ACN+5%2.5 mM NH.sub.4OAc in water; 0.8 mL/min).

Step 3

(65) To a stirred solution of LAH (189 mg, 4.85 mmol) in Et.sub.2O (15 mL) was added AlCl.sub.3 (647 mg, 4.85 mmol) at 0° C. under nitrogen atmosphere. After 15 minutes, ethyl (E)-3-(3-methoxyphenyl)acrylate from step 2 (1 g, 4.85 mmol) in Et.sub.2O (5 mL) was added drop wise and the stirring was continued at 0° C. for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.4 solution (5 mL), stirred for 30 minutes at room temperature and extracted with DCM (20 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 20% EtOAc/hexanes to afford Synthesis of (E)-3-(3-methoxyphenyl)prop-2-en-1-ol (520 mg, 72%) as light yellow syrup.

(66) (E)-3-(3-methoxyphenyl)prop-2-en-1-ol: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.22 (t, J=8.0 Hz, 1H), 6.99-6.96 (m, 2H), 6.80-6.78 (m, 1H), 6.51 (d, J=15.5 Hz, 1H), 6.40-6.35 (m, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.11 (t, J=5.5 Hz, 2H), 3.75 (s, 3H); LC-MS (ESI): 99.55%; m/z 165.2 [M+H].sup.+ at RT 3.17 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min).

Step 4

(67) To a stirred solution of (E)-3-(3-methoxyphenyl)prop-2-en-1-ol from step 3 (520 mg, 3.17 mmol) in DCM (20 mL) cooled to 0° C. was added Dess-Martin Periodinane (2.68 g, 6.34 mmol) under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (20 mL) and extracted with DCM (20 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexane to afford (E)-3-(3-methoxyphenyl)acrylaldehyde (540 mg, 95%) as yellow syrup.

(68) (E)-3-(3-methoxyphenyl)acrylaldehyde: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.67 (d, J=7.7 Hz, 1H), 7.71 (d, J=15.9 Hz, 1H), 7.42-7.29 (m, 3H), 7.08-7.03 (m, 1H), 6.90 (dd, J=15.9, 7.7 Hz, 1H), 3.81 (s, 3H); LC-MS: 99.74%; m/z 162.8 [M+H].sup.+ at RT 3.04 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OOCH in water+5% ACN:ACN+5%2.5 mM NH.sub.4OAc in water; 0.8 mL/min).

Step 5: Synthesis of ethyl (2E,4E)-5-(3-methoxyphenyl)-2-methylpenta-2,4-dienoate (Compound 2)

(69) To a stirred suspension of NaH (60% dispersion in mineral oil) (33 mg, 1.37 mmol) in THF (1 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (0.16 mL, 0.74 mmol) in THF (2 mL) at 20° C. under nitrogen atmosphere. After stirring for 1 h, (E)-3-(3-methoxyphenyl)acrylaldehyde (80 mg, 0.49 mmol) in THF (2 mL) was added drop wise and the stirring was continued at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with 2N HCl solution (10 mL) and extracted with Et.sub.2O (10 mL×2). Separated organic layer was washed with saturated NaHCO.sub.3, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford Compound 2 (95 mg, 78%) as colourless syrup.

(70) Compound 2: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.30-7.25 (m, 3H), 7.20-7.18 (m, 2H), 6.98 (d, J=3.5 Hz, 1H), 6.89 (dd, J=10.0, 3.0 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 2.02 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); LC-MS: 98.680%; m/z 246.9 [M+H].sup.+ at RT 2.97 min (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 88.08%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 11.70 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 3: Synthesis of ethyl (2E,4E)-5-(2-propylphenyl)penta-2,4-dienoate (Compound 3) and Compound 4 (Scheme 4)

(71) ##STR00116##

Step 1

(72) To a stirred solution of o-Tolyl methanol (2 g, 16.37 mmol) in dry Et.sub.2O (20 mL) was added n-BuLi (1.6M solution in hexane) (30.7 mL, 49.11 mmol) at room temperature under nitrogen atmosphere. The resultant reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to room temperature; ethyl iodine (1.3 mL, 16.37 mmol) was added and the stirring was continued at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×2). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford (2-propylphenyl)methanol (1.1 g, 46%) as syrup.

(73) (2-propylphenyl)methanol: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.35 (d, J=7.5 Hz, 1H), 7.16-7.11 (m, 3H), 5.02 (t, J=5.0 Hz, 1H), 4.50 (d, J=5.0 Hz, 2H), 2.58-2.53 (m, 2H), 1.56-1.50 (m, 2H), 0.92 (t, J=7.5 Hz, 3H); LC-MS (ESI): 64.65%; m/z 132.8 [M−H.sub.2O+H].sup.+; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 2

(74) To a solution of oxalyl chloride (0.5 mL, 5.33 mmol) in DCM (2 mL) was added DMSO (0.6 mL, 10.66 mmol) at −78° C. under nitrogen atmosphere and stirred for 1 h. After 1 h, (2-propylphenyl)methanol (200 mg, 1.33 mmol) in DCM (2 mL) was added drop wise and stirred for 3 h. The resultant reaction mixture was quenched with TEA (0.23 mL, 1.59 mmol) and stirred at room temperature for 1 h. The reaction was monitored by TLC; after completion of the reaction, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×2). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material 2-propylbenzaldehyde (180 mg, crude) was taken to next step without any further purification.

Step 3

(75) To a stirred solution of 2-propylbenzaldehyde (1 g, 6.75 mmol) in THF (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (3.5 g, 10.1 mmol) at RT under nitrogen atmosphere. The resultant reaction mixture was stirred room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were evaporated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 15% EtOAc/hexane to afford ethyl (E)-3-(2-propylphenyl)acrylate (900 mg, 61%) as light yellow syrup.

(76) Ethyl (E)-3-(2-propylphenyl)acrylate: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.90 (d, J=15.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.39-7.11 (m, 3H), 6.52 (d, J=15.9 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.76-2.63 (m, 2H), 1.51 (dt, J=14.9, 7.4 Hz, 2H), 1.36-1.20 (m, 3H), 0.95-0.80 (m, 3H).

Step 4

(77) To a stirred solution of LAH (161 mg, 4.12 mmol) in Et.sub.2O (40 mL) was added AlCl.sub.3 (550 mg, 4.12 mmol) at 0° C. under nitrogen atmosphere. After 15 minutes, ethyl (E)-3-(2-propylphenyl)acrylate (900 mg, 4.12 mmol) in Et.sub.2O (10 mL) was added drop wise and the reaction was stirred at 0° C. for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2N HCl solution (20 mL) and extracted with DCM (30 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexane to afford (E)-3-(2-propylphenyl)prop-2-en-1-ol (700 mg, 96%) as light yellow syrup.

(78) (E)-3-(2-propylphenyl)prop-2-en-1-ol: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.45 (d, J=7.5 Hz, 1H), 7.18-7.14 (m, 3H), 6.79 (d, J=16.0 Hz, 1H), 6.25-6.20 (m, 1H), 4.85 (t, J=5.5 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 2.63-2.59 (m, 2H), 1.54-1.46 (m, 2H), 0.90 (t, J=7.5 Hz, 3H).

Step 5: Synthesis of (E)-3-(2-propylphenyl)acrylaldehyde

(79) To a stirred solution of (E)-3-(2-propylphenyl)prop-2-en-1-ol (890 mg, 5.05 mmol) in DCM (50 mL) cooled to 0° C., was added Dess-Martin Periodinane (4.2 g, 10.1 mmol) portion wise under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (20 mL) and extracted with DCM (20 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material (compound A) (1.1 g, crude) was taken to next step without any further purification.

Step 6: Synthesis of ethyl (2E,4E)-5-(2-propylphenyl)penta-2,4-dienoate (Compound 3) and ethyl (2E,4E)-5-(2-pentylphenyl)penta-2,4-dienoate (Compound 4)

(80) To a stirred solution of compound A (1.1 g, 6.31 mmol) in THF (40 mL) was added C.sub.2-Wittig ylide (3.2 g, 9.47 mmol) at under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were evaporated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexane to afford mixture of products (1 g), which was separated by preparative HPLC to obtain Compound 3 (260 mg, 17%) and Compound 4 as a by-product (180 mg, 12%) as colourless syrup.

(81) Compound 3: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.64 (d, J=7.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.39 (d, J=15.0 Hz, 1H), 7.27-7.19 (m, 3H), 7.05-6.99 (m, 1H), 6.07 (d, J=15.5 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.70-2.67 (m, 2H), 1.52-1.48 (m, 2H), 1.24 (t, J=7.0 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H); LC-MS: 99.76%; m/z 244.9 [M+H].sup.+ at RT 3.24 min (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 99.74%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 12.83 min; ACN: 0.5% TFA; 1.0 mL/min).

(82) Compound 4: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.67-7.61 (m, 1H), 7.52 (dd, J=15.2, 11.0 Hz, 1H), 7.39 (d, J=15.4 Hz, 1H), 7.27-7.17 (m, 3H), 7.02 (dd, J=15.3, 11.0 Hz, 1H), 6.08 (d, J=15.3 Hz, 1H), 4.20-4.06 (m, 2H), 2.74-2.65 (m, 2H), 1.53-1.42 (m, 2H), 1.34-1.27 (m, 4H), 1.24 (t, J=7.1 Hz, 3H), 0.89-0.82 (m, 3H); LC-MS: 99.88%; m/z 273.0 [M+H].sup.+ at RT 3.50 min (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 99.53%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 14.32 min; ACN: 0.5% TFA; 1.0 mL/min).

Example 4: Synthesis of ethyl (E)-4-((E)-4-fluorobenzylidene)dec-2-enoate (Compound 5) (Scheme 5)

(83) ##STR00117##

Step 1: Synthesis of (E)-2-(4-fluorobenzylidene)octanal

(84) To a solution of octanal (3.5 mL, 23.4 mmol) in EtOH:H.sub.2O (40 mL, 1:1) were added KOH (1.31 g, 23.4 mmol) and 4-fluorobenzaldehyde (2 g, 15.1 mmol) at 0° C. and the mixture was stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, ethanol was removed. Crude material was diluted with water (30 mL) and extracted with DCM (2×30 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/hexanes to afford (E)-2-(4-fluorobenzylidene)octanal (550 mg, 15%) as light yellow syrup.

(85) .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.55 (s, 1H), 7.51 (dd, J=8.4, 5.5 Hz, 2H), 7.33-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.03-6.99 (m, 1H), 2.55-2.50 (m, 2H), 1.42-1.24 (m, 8H), 0.86 (t, J=6.7 Hz, 3H); LC-MS (ESI): 96.27%; m/z 235.0 [M+H].sup.+ at RT 3.25 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 2: Synthesis of ethyl (E)-4-((E)-4-fluorobenzylidene)dec-2-enoate

(86) To a stirred solution of (E)-2-(4-fluorobenzylidene)octanal from step 1 (850 mg, 3.63 mmol) in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (2.53 g, 7.26 mmol) in a sealed tube under nitrogen atmosphere. The reaction mixture was heated to 90° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were evaporated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes followed by preparative HPLC to afford ethyl (E)-4-((E)-4-fluorobenzylidene)dec-2-enoate (250 mg, 22%) light yellow syrup.

(87) Compound 5: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.38 (d, J=15.9 Hz, 1H), 7.29 (dd, J=8.5, 5.6 Hz, 2H), 7.07 (t, J=8.7 Hz, 2H), 6.75 (s, 1H), 5.98 (d, J=15.9 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 2.46-2.40 (m, 2H), 1.54-1.48 (m, 3H), 1.39-1.27 (m, 8H), 0.89 (t, J=6.8 Hz, 3H); LC-MS (ESI): 99.90%; m/z 305.1 [M+H].sup.+ at RT 3.59 min; (column; X-select CSH C-18 (50×3.0 mm, 2.7 μm); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 98.01%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 15.61 min; ACN+5 mM NH.sub.4OAc; 1.0 mL/min).

Example 5: Synthesis of ethyl (E)-4-((E)-2-ethoxybenzylidene)-2-methylhex-2-enoate (Compound 6) (Scheme 6)

(88) ##STR00118##

Step 1

(89) To a stirred suspension of NaH (60% dispersion in mineral oil) (226 mg, 5.66 mmol) in THF (7 mL) was added ethyl 2-(diethoxyphosphoryl)butanoate (1.18 mL, 4.95 mmol) in THF (3 mL) drop wise at 0° C. under nitrogen atmosphere. After completion of the addition, the reaction mixture was stirred at RT for 1 h. Again, the mixture was cooled to 0° C. and 2-ethoxybenzaldehyde (500 mg, 3.33 mmol) was added and the mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (3×20 mL). Separated organic layer was washed with saturated NaHCO.sub.3 solution (30 mL) and brine (30 mL). Organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 4% EtOAc/hexane to afford ethyl (E)-2-(2-ethoxybenzylidene)butanoate (500 mg, 60%) as colourless syrup.

(90) ethyl (E)-2-(2-ethoxybenzylidene)butanoate: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.28-7.26 (m, 1H), 7.23-7.14 (m, 1H), 6.97-6.78 (m, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.11-4.00 (m, 2H), 2.52-2.44 (m, 2H), 1.45-1.40 (m, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.18-1.13 (m, 3H); LC-MS (ESI): 70.79%; m/z 249.0 [M+H].sup.+ at RT 3.09 min; (column; column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 2

(91) To a stirred solution of (E)-2-(2-ethoxybenzylidene)butanoate from step 1 (300 mg, 1.21 mmol) in DCM (10 mL) was added DIBAL-H (1.6 mL, 1.81 mmol) drop wise at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium potassium tartrate solution (50 mL), stirred for 30 minutes at room temperature and extracted with DCM (20 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (E)-2-(2-ethoxybenzylidene)butan-1-ol (220 mg, 88%) as colourless syrup.

(92) (E)-2-(2-ethoxybenzylidene)butan-1-ol: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.25-7.15 (m, 2H), 6.96-6.87 (m, 2H), 6.59 (s, 1H), 6.43 (s, 1H), 4.29 (d, J=5.5 Hz, 2H), 4.10-4.03 (m, 2H), 2.32 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.7 Hz, 3H); HPLC (purity): 73.87%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 10.80 min; ACN+5 mM NH.sub.4OAc; 1.0 mL/min).

Step 3

(93) A solution of (E)-2-(2-ethoxybenzylidene)butan-1-ol from step 2 (300 mg, 1.45 mmol) in DCM (10 mL) was cooled to 0° C. and then added Dess-Martin Periodinane (1.1 g, 2.44 mmol) under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (10 mL) and extracted with DCM (10 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexane to afford (E)-2-(2-ethoxybenzylidene)butanal. (270 mg, 90%) as yellow syrup.

(94) (E)-2-(2-ethoxybenzylidene)butanal: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.58 (s, 1H), 7.64-7.55 (m, 1H), 7.48-7.45 (m, 1H), 7.38-7.31 (m, 1H), 7.18-7.15 (m, 1H), 7.02-6.97 (m, 1H), 4.14-4.05 (m, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H), 1.16-1.11 (m, 3H); LC-MS: 97.32%; m/z 204.9 [M+H].sup.+ at RT 2.90 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 95.55%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 11.42 min; ACN+5% 0.05% TFA: 0.05% TFA+5% ACN; 1.0 mL/min).

Step 4: Synthesis of ethyl (E)-4-((E)-2-ethoxybenzylidene)-2-methylhex-2-enoate (Compound 6)

(95) To a stirred suspension of NaH (60% dispersion in mineral oil) (105 mg, 1.70 mmol) in THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (0.49 mL, 2.30 mmol) at 0° C. under nitrogen atmosphere and the mixture was stirred at room temperature for 1 h. Again the reaction mixture was cooled 0° C. and (E)-2-(2-ethoxybenzylidene)butanal (270 mg, 1.55 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×20 mL). Separated organic layer was washed with saturated NaHCO.sub.3, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/hexanes followed by preparative HPLC to afford ethyl (E)-4-((E)-2-ethoxybenzylidene)-2-methylhex-2-enoate 6 (80 mg, 18%) as colourless syrup. The trans geometry is confirmed by NOE analysis.

(96) Compound 6: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.26-7.21 (m, 3H), 6.93 (t, J=7.5 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.57 (s, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.04 (q, J=6.9 Hz, 2H), 2.36 (q, J=7.5 Hz, 2H), 2.10 (d, J=1.2 Hz, 3H), 1.40 (t, J=6.9 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); LC-MS: 99.97%; m/z 289.0 [M+H].sup.+ at RT 3.44 min (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 91.34%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 14.13 min; ACN: 5 mM NH4OAc; 1.0 mL/min).

Example 6: Synthesis of ethyl (E)-4-((E)-4-cyanobenzylidene)-2-methyldec-2-enoate (Compound 7) (Scheme 7)

(97) ##STR00119##

Step 1

(98) To a solution of octanal (0.6 mL, 3.81 mmol) in DCM (20 mL) were added K.sub.2CO.sub.3 (2.6 g, 19.1 mmol), 4-isocyanobenzaldehyde (500 mg, 3.81 mmol) and benzyltriethyl ammonium chloride (434 mg, 1.91 mmol) at room temperature and the mixture was stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the mixture was diluted with water (20 mL) and extracted with DCM (2×20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford (E)-4-(2-formyloct-1-en-1-yl)benzonitrile (620 mg, 67%) as light yellow syrup.

(99) (E)-4-(2-formyloct-1-en-1-yl)benzonitrile: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.58 (s, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.21 (s, 1H), 2.52-2.42 (m, 2H), 1.40-1.21 (m, 8H), 0.88 (t, J=6.8 Hz, 3H); LC-MS (ESI): 97.44%; m/z 240.3 [M−H].sup.+ at RT 4.63 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM AqNH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 94.20%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 12.48 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

Step 2: Synthesis of ethyl (E)-4-((E)-4-cyanobenzylidene)-2-methyldec-2-enoate (Compound 7)

(100) To a stirred suspension of NaH (60% dispersion in mineral oil) (84 mg, 3.50 mmol) in THF (5 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (0.4 mL, 1.86 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. Again the reaction mixture was cooled to 0° C., and (E)-4-(2-formyloct-1-en-1-yl)benzonitrile (300 mg, 1.24 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2×20 mL). Separated organic layer was washed with saturated NaHCO.sub.3, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes followed by preparative HPLC to afford compound 7 (120 mg, 30%) as colourless syrup.

(101) Compound 7: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.64 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.21-7.17 (m, 1H), 6.45 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.38-2.31 (m, 2H), 2.05 (d, J=1.5 Hz, 3H), 1.49-1.40 (m, 4H), 1.34 (t, J=7.2 Hz, 3H), 1.31-1.27 (m, 4H), 0.87 (t, J=6.8 Hz, 3H); LC-MS (ESI): 13.18%; m/z 326.4 [M+H].sup.+ at RT 5.48 min and 86.81%; m/z 326.4 [M+H].sup.+ at RT 5.59 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM Aq. NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 10.29 & 86.63%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 14.42 & 14.75 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

(102) Compounds 8-15 have been prepared following the same chemical route and using the reagent described in the following table 2 (Scheme 8)

(103) ##STR00120##

(104) TABLE-US-00004 TABLE 2 Compound Aldehyde A Aldehyde B Phosphonate F 8 Benzaldehyde 7-Octenal Ethyl 2-(diethoxyphosphoryl)propanoate 9 Heptanal 10 Octanel Methyl (diethoxyphosphoryl) acetate 11 3,5,5-trimethylhexanal Ethyl 2-(diethoxyphosphoryl)propanoate 12 3-cyclopentyl pentanel 13 Octanel Ethyl (diethoxyphosphoryl)acetate 14 Heptanal 15 Pentanel

(105) Compound 8: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.38-7.33 (m, 2H), 7.29-7.23 (m, 3H), 7.21 (s, 1H), 6.51 (s, 1H), 5.83-5.73 (m, 1H), 5.03-4.91 (m, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.43-2.36 (m, 2H), 2.07 (d, J=1.2 Hz, 3H), 2.05-2.01 (m, 2H), 1.52-1.37 (m, 4H), 1.34 (t, J=7.0 Hz, 3H).

(106) Compound 9: .sup.1H NMR (300 MHz, CDCl3) δ 7.44-7.14 (m, 6H), 6.49 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.43-2.30 (m, 2H), 2.07 (d, J=1.5 Hz, 3H), 1.46 (dd, J=10.0, 5.4 Hz, 4H), 1.31 (ddd, J=14.4, 10.4, 7.1 Hz, 7H), 0.94-0.77 (m, 3H)

(107) Compound 10: .sup.1H NMR (300 MHz, CDCl3) δ 7.60-7.16 (m, 6H), 6.80 (s, 1H), 5.99 (d, J=15.8 Hz, 1H), 3.79 (s, 3H), 2.53-2.38 (m, 2H), 1.63-1.20 (m, 8H), 0.89 (t, J=6.7 Hz, 3H)

(108) Compound 11: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.40-7.33 (m, 3H), 7.28-7.25 (m, 3H), 6.36 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.10-3.14 (m, 1H), 2.07 (d, J=1.5 Hz, 3H), 1.50 (dd, J=7.3, 14.1 Hz, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.16 (d, J=4.5 Hz, 1H), 1.12 (d, J=7.0 Hz, 3H), 0.73 (s, 9H).

(109) Compound 12: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.39-7.34 (m, 2H), 7.31 (s, 2H), 7.29-7.24 (m, 2H), 6.52 (s, 1H), 4.26 (q, J=7.3 Hz, 2H), 2.45 (d, J=7.5 Hz, 2H), 2.10 (d, J=1.7 Hz, 3H), 2.01-1.92 (m, 1H), 1.76-1.68 (m, 2H), 1.54-1.46 (m, 4H), 1.35 (t, J=7.3 Hz, 3H), 1.14-1.05 (m, 2H).

(110) Compound 13: .sup.1H NMR (300 MHz, CDCl3) δ 7.84-7.67 (m, 6H), 7.47-7.16 (m, 2H), 6.79 (d, J=4.9 Hz, 1H), 6.02 (dd, J=22.7, 15.9 Hz, 1H), 4.22 (dq, J=14.2, 7.1 Hz, 2H), 2.52-2.32 (m, 2H), 1.62-1.49 (m, 2H), 1.31 (dt, J=8.9, 7.2 Hz, 7H), 0.89 (dd, J=8.2, 4.8 Hz, 3H)

(111) Compound 14: .sup.1H NMR (300 MHz, CDCl3) δ 7.47-7.21 (m, 6H), 6.80 (s, 1H), 5.98 (d, J=15.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.53-2.40 (m, 2H), 1.64-1.19 (m, 9H), 0.96-0.83 (m, 3H)

(112) Compound 15: .sup.1H NMR (300 MHz, CDCl3) δ 7.50-7.16 (m, 5H), 6.81 (s, 1H), 5.98 (d, J=15.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.42 (ddd, J=23.1, 11.8, 6.8 Hz, 2H), 1.70-1.47 (m, 2H), 1.33 (t, J=7.1 Hz, 3H), 0.99 (t, J=6.2 Hz, 3H).

Example 7: Synthesis of 4-benzylidenedec-2-enenitrile (Compound 16) (Scheme 9)

(113) ##STR00121##

(114) A suspension of sodium hydride (2.24 g, 55% dispersion in mineral oil, 51.3 mmol, 1.1 eq., washed twice with hexane) in 1,2-dimethoxyethane (DME, 100 ml) was treated dropwise with a solution of diethylcyanomethyl phosphonate (8.2 ml, 51.1 mmol, 1.1 eq.) in DME (10 ml). The resulting mixture was stirred for 1 h at 20° C., treated dropwise with a solution of alpha-hexyl-cinnamic aldehyde (10 g, 46.2 mmol) in DME (20 ml), stirred at 60° C. for 3 h, cooled to 20° C., poured into 2N aq. HCl/ice (200 ml), and extracted twice with MTBE (75 ml). The combined organic phases were washed three times with water (75 ml), four times with aqueous saturated NaCl solution (75 ml), dried (MgSO.sub.4), and concentrated. The crude yellow/orange oil (12.3 g) was distilled using a ball-to-ball distillation apparatus (Kugelrohr, 160-200° C. oven temperature, 0.06-0.07 mbar) and the fraction distilled at 180-200° C. (0.06-0.07 mbar, 7.31 g, 86:10:4 mixture of isomers, light yellow solid) was distilled again using the same apparatus (190-220° C. oven temperature, 0.06 mbar) giving pure 4-benzylidenedec-2-enenitrile (5.95 g, 54%, 83:13:4 mixture of isomers) as a white solid.

(115) Compound 16: .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.42-7.36 (m, 2H), 7.35-7.28 (m, 3H), 7.10 (dd, J=0.8, 16.4, 1H), 6.73 (br. s, 1H), 5.41 (br. d, J=16.4, 1H), 2.45-2.39 (m, 2H), 1.56-1.46 (m, 2H), 1.42-1.24 (m, 6H), 0.89 (t, J=6.8, Me). .sup.13C-NMR (CDCl.sub.3, 100 MHz): δ 154.79 (d), 139.42 (d), 138.50 (s), 135.91 (s), 129.11 (d, 2C), 128.58 (d, 2C), 128.28 (d), 118.70 (s), 94.94 (d), 31.44 (t), 29.47 (t), 28.55 (t), 26.63 (t), 22.57 (t), 14.01 (q). MS (EI): m/z 240 [M+H].sup.+

(116) Compounds 17 and 18 have been prepared following the same chemical route and using the reagent described in the following table 3 (Scheme 10).

(117) ##STR00122##

(118) TABLE-US-00005 TABLE 3 Compound Aldehyde C Phosphonate F 17 Hexyl cinnamaldehyde Diethyl (1-cyanoethyl)phosphonate 18 2-Benzylideneheptanal Diethylcyanomethyl phosphonate

(119) Compound 17 .sup.1H-NMR (300 MHz, CDCl3) δ 7.43-7.20 (m, 5H), 6.76 (s, 1H), 6.54 (dd, J=10.9, 9.7 Hz, 1H), 2.64-2.27 (m, 2H), 1.55 (s, 3H) 1.5-1.2 (m, 8H), 0.87 (t, J=6.0 Hz, 3H)

(120) Compound 18 .sup.1H-NMR (300 MHz, CDCl3) δ 7.52-7.26 (m, 5H), 7.11 (d, J=16.4 Hz, 1H), 6.75 (s, 1H), 5.41 (d, J=16.4 Hz, 1H), 2.51-2.35 (m, 2H), 1.66-1.44 (m, 2H), 1.36 (m, 4H), 1.02-0.81 (m, 3H)

Example 8: Synthesis of (E)-4-((E)-4-cyanobenzylidene)-2-methyldec-2-enoic Acid (Compound 19) (Scheme 11)

(121) ##STR00123##

(122) To a stirred solution of ethyl (E)-4-((E)-4-cyanobenzylidene)-2-methyldec-2-enoate (Compound 7) (30 mg, 0.09 mmol) in MeOH:H.sub.2O (4 mL, 1:1) was added NaOH (7 mg, 0.18 mmol) at room temperature. The reaction mixture was heated to reflux for 3 h. The reaction was monitored by TLC; after completion of the reaction, methanol solvent was removed under reduced pressure. The reaction mixture was diluted with water (5 mL) and acidified with 2N HCl solution (pH-2) and extracted with EtOAc (2×10 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified preparative TLC to afford Compound 19 (10 mg, 36%) as colourless syrup.

(123) Compound 19: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67-7.63 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.31-7.29 (m, 1H), 6.50 (s, 1H), 2.39-2.33 (m, 2H), 2.08 (d, J=1.4 Hz, 3H), 1.48-1.41 (m, 4H), 1.30-1.28 (m, 4H), 0.89-0.85 (m, 3H); LC-MS (ESI): 97.30%; m/z 296.1 [M−H].sup.+ at RT 3.77 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OOCH in water+5% ACN:ACN+5%2.5 mM NH.sub.4OOCH in water; 0.8 mL/min); HPLC (purity): 95.18%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 10.34 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

(124) Compound 20 from compound 6: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.38 (s, 1H), 7.26-7.22 (m, 2H), 6.97-6.92 (m, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.64 (s, 1H), 4.05 (q, J=6.9 Hz, 2H), 2.39 (q, J=7.4 Hz, 2H), 2.12 (s, 3H), 1.41 (br t, J=6.9 Hz, 3H), 1.07 (t, J=7.5 Hz, 3H); LC-MS (ESI): 99.76%; m/z 259.1 [M−H].sup.+ at RT 3.48 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OOCH in water+5% ACN:ACN+5%2.5 mM NH.sub.4OOCH in water; 0.8 mL/min); HPLC (purity): 99.75%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 11.04 min; ACN+0.05% TFA: 0.05% TFA+ACN; 1.0 mL/min).

Example 9: Synthesis of 4-benzylidene-2-methyldec-2-enoic Acid (Compound 21) from Compound 1 (Scheme 12)

(125) ##STR00124##

(126) Ethyl 4-benzylidene-2-methyldec-2-enoate 1 (2.7 g, 8.99 mmol) was treated at 0° C., with a solution of KOH (0.84 g, 13.5 mmol) in a mixture of EtOH (19 ml) and water (8 ml). The resulting suspension was stirred at 20° C. for 24 h, washed with hexane (50 ml) and the aqueous phase acidified with 2N HCl/ice (50 ml) and extracted three times with MTBE (50 ml). The combined organic phases were washed once with aq. saturated NaCl solution, dried (MgSO.sub.4), and concentrated giving crude 4-benzylidene-2-methyldec-2-enoic acid 21 (2.38 g, 97%, 81:13:6 mixture of isomers) as a brown oil.

(127) Compound 21 (major isomer); .sup.1H-NMR (CDCl.sub.3, 400 MHz): d 8.90-8.50 (br. s, 1H), 7.40-7.32 (m, 3H), 7.31-7.22 (m, 3H), 6.55 (br. s, 1H), 2.44-2.37 (m, 2H), 2.09 (d, J=1.3, Me), 1.52-1.41 (m, 2H), 1.36-1.21 (m, 6H), 0.87 (t, J=6.9, Me). .sup.13C-NMR (CDCl.sub.3, 100 MHz): δ 174.12 (s), 144.61 (d), 138.98 (s), 136.97 (s), 132.57 (d), 128.84 (d, 2C), 128.30 (d, 2C), 127.15 (d and s), 31.58 (t), 31.33 (t), 29.22 (t), 28.88 (t), 22.58 (t), 14.02 (q), 13.91 (q). MS (EI): 273 (MH.sup.+).

(128) Compound 22 from Compound 13:

(129) .sup.1H NMR (300 MHz, CDCl3) δ 7.41-7.21 (m, 6H), 6.84 (s, 1H), 6.02 (dd, J=21.9, 15.8 Hz, 1H), 2.53-2.30 (m, 2H), 1.56 (s, 2H), 1.45-1.17 (m, 6H), 0.89 (t, J=5.2 Hz, 3H)

Example 10: Synthesis of (E)-4-((E)-benzylidene)-2-methyldec-2-enamide (Compound 23) (Scheme 13)

(130) ##STR00125##

(131) To a stirred solution of (E)-4-((E)-benzylidene)-2-methyldec-2-enoic acid 21 (150 mg, 0.53 mmol) in DCM (5 mL) were added EDCl.HCl (111 mg, 0.71 mmol), HOBt (74 mg, 0.55 mmol), NH.sub.4Cl (44 mg, 0.82 mmol) and N-methylmorpholine (0.12 mL, 1.11 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was triturated with n-Hexane to afford Compound 23 (35 mg, 25%) as white solid.

(132) Compound 23: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.42-7.35 (m, 3H), 7.32-7.24 (m, 3H), 6.98 (br s, 1H), 6.80 (s, 1H), 6.44 (s, 1H), 2.35-2.29 (m, 2H), 1.96 (d, J=1.3 Hz, 3H), 1.45-1.36 (m, 2H), 1.31-1.17 (m, 6H), 0.83 (t, J=6.8 Hz, 3H); LC-MS (ESI): 99.83%; m/z 272.3 [M+H].sup.+; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); RT 4.56 min. 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 99.24%; (column: ZORBAX SB C-18 (150×4.6 mm, 5 μm); RT 10.81 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 11: Synthesis of (E)-4-((E)-benzylidene)-N,2-dimethyldec-2-enamide (Compound 24) (Scheme 14)

(133) ##STR00126##

(134) To a stirred solution of (E)-4-((Z)-benzylidene)-2-methyl-5-oxodec-2-enoic acid 21 (200 mg, 0.74 mmol) in DCM (6 mL) were added EDCl.HCl (148 mg, 0.96 mmol), HOBt (99 mg, 0.74 mmol), methylamine solution (2M in THF) (0.6 mL, 1.11 mmol) and DIPEA (0.24 mL, 1.47 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with DCM (30 mL) and washed with water (30 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 20-30% EtOAc/hexanes to afford the title compound 24 (80 mg, 38%) as white solid.

(135) Compound 24: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.84-7.81 (m, 1H), 7.39-7.33 (m, 2H), 7.29-7.22 (m, 3H), 6.72 (s, 1H), 6.41 (s, 1H), 2.65 (d, J=4.3 Hz, 3H), 2.32-2.28 (m, 2H), 1.95 (d, J=0.9 Hz, 3H), 1.42-1.34 (m, 2H), 1.28-1.15 (m, 6H), 0.81 (t, J=6.8 Hz, 3H); LC-MS (ESI): 91.80%; m/z 286.0 [M+H].sup.+; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); RT 3.77 min. 2.5 mM NH.sub.4OAc in water+5% ACN:ACN+5% 2.5 mM NH.sub.4OOCH in water; 0.8 mL/min); HPLC (purity): 99.26%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 11.26 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 12: Synthesis of (2E,4E)-5-(3-ethylphenyl)-N,N,4-trimethylpenta-2,4-dienamide (Compound 25) (Scheme 15)

(136) ##STR00127##

Step 1

(137) To a stirred suspension of NaH (60% dispersion in mineral oil) (101 mg, 4.20 mmol) in THF (3 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (0.47 mL, 2.23 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Again the reaction mixture was cooled 0° C. and 3-ethylbenzaldehyde (0.19 mL, 1.49 mmol) in THF (2 mL) was added and the stirring was continued at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). Separated organic layer was washed with saturated NaHCO.sub.3, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/hexanes to afford ethyl (E)-3-(3-ethylphenyl)-2-methylacrylate (250 mg, 77%) as white colour syrup.

(138) Ethyl (E)-3-(3-ethylphenyl)-2-methylacrylate: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.69 (s, 1H), 7.35-7.30 (m, 1H), 7.26-7.23 (m, 2H), 7.18 (d, J=7.5 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 2.69 (q, J=7.7 Hz, 2H), 2.14 (d, J=1.2 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.7 Hz, 3H); LC-MS (ESI): 82.65%; m/z 218.9 [M+H].sup.+ at RT 3.15 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 2

(139) To a stirred solution of ethyl (2E,4E)-5-(3-ethylphenyl)-4-methylpenta-2,4-dienoate (300 mg, 1.22 mmol) in MeOH:H.sub.2O (10 mL, 1:1) was added NaOH (98 mg, 2.45 mmol) at room temperature. The reaction mixture was heated to reflux for 3 h. The reaction was monitored by TLC; after completion of the reaction, methanol solvent was removed under reduced pressure. The reaction mixture was diluted with water (10 mL) and acidified with 2N HCl solution (pH-2) and extracted with EtOAc (2×20 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford (2E,4E)-5-(3-ethylphenyl)-4-methylpenta-2,4-dienoic acid (255 mg, 96%) as light yellow syrup.

(140) (2E,4E)-5-(3-ethylphenyl)-4-methylpenta-2,4-dienoic acid: .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 7.58 (d, J=15.6 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.21-7.18 (m, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.89 (s, 1H), 5.98 (d, J=15.6 Hz, 1H), 2.67 (q, J=7.5 Hz, 2H), 2.08 (s, 3H), 1.26 (t, J=7.7 Hz, 3H); LC-MS (ESI): 99.61%; m/z 215.6 [M−H].sup.+ at RT 3.24 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 98.22%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 10.35 min; ACN+5% 0.05% TFA: 0.05% TFA+5% ACN; 1.0 mL/min).

Step 3: Synthesis of (2E,4E)-5-(3-ethylphenyl)-N,N,4-trimethylpenta-2,4-dienamide (Compound 25)

(141) To a stirred solution of (2E,4E)-5-(3-ethylphenyl)-4-methylpenta-2,4-dienoic acid (250 mg, 1.15 mmol) in DCM (10 mL) were added EDCl.HCl (233 mg, 1.51 mmol), HOBt (156 mg, 1.15 mmol), DIPEA (0.4 mL, 2.31 mmol) and dimethyl amine.HCl (140 mg, 1.73 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3×20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 30% EtOAc/hexanes to afford compound 25 (130 mg, 46%) as yellow syrup.

(142) Compound 25: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.48 (dd, J=15.2, 1.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.19-7.15 (m, 2H), 7.11 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.39 (d, J=14.9 Hz, 1H), 3.14 (s, 3H), 3.06 (s, 3H), 2.66 (q, J=7.6 Hz, 2H), 2.07 (d, J=1.3 Hz, 3H), 1.25 (t, J=7.6 Hz, 3H); LC-MS (ESI): 98.90%; m/z 244.0 [M+H].sup.+ at RT 2.64 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 86.42%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 11.08 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

(143) Compound 26 has been prepared from compound 9 in two steps (steps 2 and 3 of example 12)

(144) Compound 26 .sup.1H NMR (300 MHz, CDCl3) δ 7.45-7.17 (m, 5H), 6.98 (s, 1H), 6.45 (s, 1H), 5.74 (s, 2H), 2.43-2.27 (m, 2H), 2.09 (d, J=1.3 Hz, 3H), 1.53-1.37 (m, 2H), 1.28 (dd, J=9.0, 5.3 Hz, 4H), 0.87 (t, J=6.8 Hz, 3H). Compound 27 has been prepared from compound 22 following the same chemical route, by performing step 3 of example 12, using NH.sub.3 instead of NH—(CH.sub.3).sub.2.

(145) Compound 27 has been prepared from compound 22 in one single step (step 3 of example 12) following the same chemical route:

(146) Compound 27 .sup.1H NMR (300 MHz, CDCl3) δ 7.46-7.17 (m, 6H), 6.78 (s, 1H), 6.03 (dd, J=23.1, 15.6 Hz, 1H), 5.52 (s, 2H), 2.53-2.31 (m, 2H), 1.55 (dd, J=10.2, 5.7 Hz, 2H), 1.44-1.20 (m, 6H), 0.89 (dd, J=8.7, 4.7 Hz, 3H)

Example 13: Synthesis of (E)-4-((E)-benzylidene)-N,N,2-trimethyldec-2-enamide (Compound 28) (Scheme 16)

(147) ##STR00128##

(148) To a stirred solution of (E)-4-((E)-benzylidene)-2-methyldec-2-enoic acid (200 mg, 0.74 mmol) in DCM (6 mL) were added EDCl.HCl (148 mg, 0.96 mmol), HOBt (99 mg, 0.74 mmol), DIPEA (0.24 mL, 1.47 mmol) and dimethylamine hydrochloride (89 mg, 1.11 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 20-30% EtOAc/hexanes to afford Compound 28 (55 mg, 25%) as colourless liquid.

(149) Compound 28: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.38-7.34 (m, 2H), 7.30-7.22 (m, 3H), 6.44 (s, 1H), 5.95 (s, 1H), 3.03-2.82 (m, 6H), 2.32-2.27 (m, 2H), 1.94 (d, J=1.4 Hz, 3H), 1.45-1.36 (m, 2H), 1.29-1.15 (m, 6H), 0.82 (t, J=6.8 Hz, 3H); LC-MS (ESI): 96.96%; m/z 300.3 [M+H].sup.+; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); RT 4.97 min. 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 94.69%; (column: ZORBAX SB C-18 (150×4.6 mm, 5 μm); RT 11.74 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 14: Synthesis of 5-benzylidene-3-methylundec-3-en-2-one (Compound 29) (Scheme 17)

(150) ##STR00129##

(151) At −78° C., a solution of crude 4-benzylidene-2-methyldec-2-enoic acid (2.38 g, 8.74 mmol, co-evaporated twice with toluene) in diethyl ether (130 ml) was treated dropwise within 40 min. with a 1.6M solution of MeLi in Et.sub.2O (12 ml, 19.2 mmol, 2.2 eq.) and the resulting solution was warmed to 0° C. within 30 min., stirred at that temperature for 2.5 h, cooled to −78° C., treated within 5 min. with acetone (0.83 ml), allowed to reached 0° C., poured into an aqueous saturated NH.sub.4Cl solution (100 ml), and extracted twice with MTBE (60 ml). The combined organic phases were washed once with aq. saturated NaCl solution, dried (MgSO.sub.4), and concentrated. The crude product (2.33 g, light yellow oil) was distilled (180° C. oven temperature, 0.06 mbar) using a ball-to-ball (Kugelrohr) distillation apparatus giving pure 5-benzylidene-3-methylundec-3-en-2-one 29 (2 g, 85%, 86:8:5 mixture of isomers) as a light yellow oil.

(152) Compound 29: (3E,5E)-5-benzylidene-3-methylundec-3-en-2-one (major isomer): .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.40-7.33 (m, 2H), 7.31-7.23 (m, 3H), 7.06 (br. s, 1H), 6.54 (br. s, 1H), 2.45-2.38 (m, 2H), 2.40 (s, Me), 2.01 (d, J=1.5, Me), 1.51-1.40 (m, 2H), 1.37-1.21 (m, 6H), 0.87 (t, J=6.9, Me). .sup.13C-NMR (CDCl.sub.3, 100 MHz): δ 200.32 (s), 143.24 (d), 139.08 (s), 137.37 (s), 136.95 (s), 132.27 (d), 128.79 (d, 2C), 128.31 (d, 2C), 127.13 (d), 31.57 (t), 31.46 (t), 29.21 (t), 28.90 (t), 25.84 (q), 22.56 (t), 14.01 (q), 13.22 (q). MS (EI): m/z 271 [M+H].sup.+

Example 15: Synthesis of (E)-5-((E)-benzylidene)undec-3-en-2-one (Compound 30) (Scheme 18)

(153) ##STR00130##

(154) A solution of (E)-2-benzylideneoctanal (500 mg, 2.31 mmol) and 1-(triphenyl-λ.sup.5-phosphanylidene)propan-2-one (736 mg, 2.31 mmol) in toluene (10 mL) in a sealed tube under argon atmosphere was heated to 110° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was purified through silica gel column chromatography using 10-15% EtOAc/hexanes to afford Compound 30 (200 mg, 33%) as pale yellow syrup.

(155) Compound 30: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.42-7.28 (m, 5H), 7.22 (s, 1H), 6.84 (s, 1H), 6.26 (d, J=16.1 Hz, 1H), 2.51-2.44 (m, 2H), 2.35 (s, 3H), 1.55-1.49 (m, 2H), 1.42-1.26 (m, 6H), 0.92-0.86 (m, 3H); LC-MS (ESI): 98.15%; m/z 257.1 [M+H].sup.+; (Column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 3.34 min. 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 95.26%; (column: X SELECT CSH C.sub.18 (150×4.6 mm, 3.5μ); RT 13.91 min; 5 Mm NH.sub.4OAc:ACN; 1.0 mL/min).

Example 16: Synthesis of (2E,4E)-5-(3-methoxyphenyl)-2-methylpenta-2,4-dien-1-ol (Compound 31) (Scheme 19)

(156) ##STR00131##

(157) A solution of (2E,4E)-5-(3-methoxyphenyl)-2-methylpenta-2,4-dienoate 2 (compound 2) (100 mg, 0.41 mmol) in DCM (5 mL) was cooled to −78° C. and then DIBAL-H (0.6 mL, 0.61 mmol) was added drop wise under nitrogen atmosphere. The resultant reaction mixture was stirred at −78° C. for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2N HCl solution (10 mL) and extracted with DCM (10 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 15% EtOAc/hexanes to afford compound 31 (42 mg, 51%) as white thick syrup.

(158) Compound 31: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.25-7.18 (m, 1H), 7.16-7.01 (m, 3H), 6.79-6.75 (m, 1H), 6.48 (d, J=15.5 Hz, 1H), 6.18 (br d, J=11.1 Hz, 1H), 4.85 (t, J=5.7 Hz, 1H), 3.90 (d, J=5.5 Hz, 2H), 3.76 (s, 3H), 1.80 (s, 3H); LC-MS (ESI): 99.19%; m/z 187.0 [M−OH+H].sup.+ at RT 2.37 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 88.12%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 9.22 min; ACN:0.5% TFA); 1.0 mL/min).

Example 17: Synthesis of (2E,4E)-5-(2-propylphenyl)penta-2,4-dien-1-ol (Compound 32) (Scheme 20)

(159) ##STR00132##

(160) A solution of ethyl (2E,4E)-5-(2-propylphenyl)penta-2,4-dienoate (Compound 3) (100 mg, 0.41 mmol) in DCM (20 mL) was cooled to −78° C. and then DIBAL-H (0.6 mL, 0.61 mmol) was added under nitrogen atmosphere. The resultant reaction mixture was stirred at −78° C. for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with sodium potassium tartrate solution (10 mL) and extracted with DCM (10 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 15% EtOAc/hexanes to afford compound 32 (21 mg, 25%) as colourless syrup.

(161) Compound 32: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57-7.51 (m, 1H), 7.21-7.13 (m, 3H), 6.79 (d, J=5.4 Hz, 2H), 6.48-6.39 (m, 1H), 5.95 (dt, J=15.2, 5.3 Hz, 1H), 4.78 (t, J=5.5 Hz, 1H), 4.05 (td, J=1.6, 5.4 Hz, 2H), 2.66-2.60 (m, 2H), 1.54-1.46 (m, 2H), 0.91 (t, J=7.4 Hz, 3H); LC-MS (ESI): 95.27%; m/z 184.9 [M−H.sub.2O+H].sup.+ at RT 2.71 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 87.46%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 10.58 min; ACN: 0.5% TFA); 1.0 mL/min).

Example 18: Synthesis of (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-en-1-ol (Compound 33) to Compound 35 (Scheme 21)

(162) ##STR00133##

(163) A solution of ethyl (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-enoate 5 (500 mg, 1.57 mmol) in DCM (10 mL) was cooled to −78° C. and then DIBAL-H (2.36 mL, 2.35 mmol) was added drop wise under nitrogen atmosphere. The resultant reaction mixture was stirred at −78° C. for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2N HCl solution (10 mL), stirred for 30 minutes and then extracted with DCM (3×10 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-en-1-ol 33 (230 mg, 53%) as colourless syrup.

(164) Compound 33: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.25-7.19 (m, 2H), 7.06-7.00 (m, 2H), 6.43 (s, 1H), 6.31 (dd, J=15.8, 0.7 Hz, 1H), 5.94 (dt, J=15.6, 6.0 Hz, 1H), 4.31-4.24 (m, 2H), 2.43-2.35 (m, 2H), 1.54-1.47 (m, 2H), 1.40-1.24 (m, 7H), 0.92-0.85 (m, 3H); LC-MS (ESI): 99.19%; m/z 244.9 [M−OH+H].sup.+ at RT 3.11 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 99.38%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 12.94 min; ACN+5% 0.5% TFA:0.5% TFA+5% ACN); 1.0 mL/min).

(165) Compound 34 has been prepared from compound 9 following the same chemical route as described in example 18.

(166) Compound 34: .sup.1H NMR (300 MHz, CDCl3) δ 7.51-7.07 (m, 5H), 6.35 (s, 1H), 6.00 (s, 1H), 4.13 (s, 2H), 2.35-2.21 (m, 2H), 1.88 (d, J=1.3 Hz, 3H), 1.66-1.15 (m, 6H), 0.87 (t, J=6.8 Hz, 3H).

(167) Compound 35 has been prepared using the same chemical route described in example 18 (Scheme 22):

(168) ##STR00134##

Step 1

(169) Pentanal (2 g, 23.2 mmol) was dissolved in EtOH (20 mL) and NaOH (1.4 g, 34.8 mmol) was added at 0° C. After stirring for 10 minutes, benzaldehyde (2.46 mL, 27.8 mmol) followed by BTEAC (2.6 g, 11.4 mmol) were added. The resultant reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion of the reaction, volatiles were removed under reduced pressure. Crude material was diluted with water (30 mL) and extracted with DCM (2×50 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford (E)-2-benzylidenepentanal (1.7 g, 42%) as syrup.

(170) LC-MS (ESI): 79.18%; m/z 175.3 [M+H].sup.+ at RT 4.58 min; (column; X Select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM Aq.NH.sub.4OAc:ACN; 0.8 mL/min).

Step 2: Synthesis of ethyl (E)-4-((E)-benzylidene)-2-methylhept-2-enoate

(171) NaH (60% dispersion in mineral oil) (664 mg, 27.6 mmol) was dissolved in THF (30 mL) and ethyl 2-(diethoxyphosphoryl)propanoate (3.14 mL, 14.6 mmol) was added to the mixture at 0° C. under nitrogen atmosphere. After stirring for 1 h at room temperature, (E)-2-benzylidenepentanal (1.7 g, 9.77 mmol) was added at 0° C. and stirring was continued for 16 h at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (2×30 mL). Separated organic layer was washed with saturated NaHCO.sub.3, dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford title compound (1.9 g, 76%) as colourless syrup.

(172) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.39-7.28 (s, 5H), 7.22 (s, 1H), 6.51 (s, 1H), 4.25 (d, J=7.2 Hz, 2H), 2.36 (d, J=8.0 Hz, 2H), 2.07 (d, J=1.5 Hz, 3H), 1.52-1.43 (m, 2H), 1.33 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).

(173) Further reduction of the so obtained ethyl ester using Example 18 protocol afforded compound 35

(174) Compound 35: .sup.1H NMR (300 MHz, CDCl3) δ 7.40-7.16 (m, 5H), 6.36 (s, 1H), 6.00 (s, 1H), 4.14 (s, 2H), 2.28 (dd, J=9.1, 6.7 Hz, 2H), 1.89 (d, J=1.2 Hz, 3H), 1.66-1.37 (m, 2H), 0.92 (dd, J=9.8, 4.9 Hz, 3H).

Example 19: Synthesis of (2E,4E)-5-(3-methoxyphenyl)-2-methylpenta-2,4-dienal (Compound 36) (Scheme 23)

(175) ##STR00135##

(176) A solution of compound 31 (50 mg, 0.24 mmol) in DCM (5 mL) was cooled to 0° C. and then Dess-Martin Periodinane (155 mg, 0.736 mmol) was added under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (10 mL) and extracted with DCM (10 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford compound 36 (38 mg, 77%) as light yellow syrup.

(177) Compound 36: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.49 (s, 1H), 7.50-7.41 (m, 1H), 7.35-7.19 (m, 4H), 7.13 (d, J=15.5 Hz, 1H), 6.96-6.91 (m, 1H), 3.81 (s, 3H), 1.89 (d, J=0.9 Hz, 3H); LC-MS: 93.69%; m/z 203.2[M+H].sup.+ at RT 4.01 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 93.90%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 10.18 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 20: Synthesis of (2E,4E)-5-(2-propylphenyl)penta-2,4-dienal (Compound 37) (Scheme 24)

(178) ##STR00136##

(179) A solution of compound 32 (60 mg, 0.29 mmol) in DCM (20 mL) was cooled to 0° C. and then Dess-Martin Periodinane (189 mg, 0.44 mmol) was added under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (10 mL) and extracted with DCM (20 mL×2). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford the compound (25 mg, 42%) as a thick syrup.

(180) Compound 37: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.63 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.33-7.27 (m, 3H), 7.24-7.18 (m, 2H), 6.97-6.91 (m, 1H), 6.27 (dd, J=15.0, 7.5 Hz, 1H), 2.70 (t, J=7.5 Hz, 2H), 1.63-1.57 (m, 2H), 0.98 (t, J=7.5 Hz, 3H); LC-MS: 99.90%; m/z 201.3[M+H].sup.+ at RT 4.45 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 97.07%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 11.44 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 21: Synthesis of (E)-4-((E)-4-fluorobenzylidene)dec-2-enal (Compound 38) (Scheme 25)

(181) ##STR00137##

(182) To a stirred solution of (E)-4-((E)-4-fluorobenzylidene)dec-2-en-1-ol (compound 33) (80 mg, 0.31 mmol) in DCM (5 mL) was added Dess-Martin Periodinane (194 mg, 0.45 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (10 mL) and extracted with DCM (20 mL×2). Separated organic layer was washed with saturated NaHCO.sub.3 solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford compound 38 (55 mg, 69%) as yellow syrup.

(183) Compound 38: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.64 (d, J=7.8 Hz, 1H), 7.34 (dd, J=8.7, 5.5 Hz, 2H), 7.19 (d, J=15.6 Hz, 1H), 7.10 (t, J=8.7 Hz, 2H), 6.85 (s, 1H), 6.29 (dd, J=15.6, 7.8 Hz, 1H), 2.51-2.44 (m, 2H), 1.53-1.49 (m, 2H), 1.42-1.35 (m, 2H), 1.33-1.25 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); LC-MS: 99.57%; m/z 261.3[M+H].sup.+ at RT 5.05 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM Aq NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 94.74%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 14.06 min; ACN+0.05% TFA: 0.05% TFA+ACN; 1.0 mL/min).

(184) Compounds 40 and 41 have been prepared from compound 34 and from compound 35, respectively, following the chemical route described in example 21.

(185) Compound 40: .sup.1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 7.45-7.27 (m, 5H), 6.86 (d, J=1.1 Hz, 1H), 6.73 (s, 1H), 2.50 (dd, J=9.2, 6.8 Hz, 2H), 2.00 (d, J=1.3 Hz, 3H), 1.61-1.23 (m, 6H), 0.88 (t, J=7.0 Hz, 3H)

(186) Compound 41: .sup.1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 7.45-7.20 (m, 5H), 6.88-6.82 (m, 1H), 6.74 (s, 1H), 2.54-2.42 (m, 2H), 2.00 (d, J=1.3 Hz, 3H), 1.66-1.41 (m, 2H), 0.95 (t, J=7.3 Hz, 3H)

Example 22: Synthesis of (E)-4-((E)-benzylidene)dec-2-en-1-ol (Compound 45) and (E)-4-((E)-benzylidene)dec-2-enal (Compound 39) (Scheme 26)

(187) ##STR00138##

Step 1

(188) A solution of (E)-2-benzylideneoctanal (1 g, 4.63 mmol) and ethyl 2-(triphenyl-λ.sup.5-phosphanylidene)acetate (3.22 g, 9.26 mmol) in toluene (10 mL) in a sealed tube under argon atmosphere was heated to 100° C. and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude. The crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford ethyl (E)-4-((E)-benzylidene)dec-2-enoate (1 g, 77%) as colourless syrup.

(189) Ethyl (E)-4-((E)-benzylidene)dec-2-enoate: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.44-7.25 (m, 6H), 6.80 (s, 1H), 5.98 (d, J=15.8 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.50-2.42 (m, 2H), 1.56-1.48 (m, 2H), 1.41-1.24 (m, 9H), 0.92-0.85 (m, 3H); LC-MS (ESI): 85.22%; m/z 287.1 [M+H].sup.+; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 μm); RT 4.73 min. 2.5 mM NH.sub.4OAC in water+5% ACN:ACN+5% 2.5 mM NH.sub.4OOCH in water; 0.8 mL/min).

Step 2: Synthesis of (E)-4-((E)-benzylidene)dec-2-en-1-ol

(190) To a stirred solution of lithium aluminium hydride (66 mg, 1.74 mmol) in diethylether (7 mL) was added aluminium chloride (233 mg, 1.74 mmol) at 0° C. under argon atmosphere. The mixture was stirred for 15 min. Ethyl (E)-4-((E)-benzylidene)dec-2-enoate (500 mg, 1.74 mmol) in diethylether (3 mL) was then added drop wise at 0° C. and the reaction mixture was stirred at the same temperature for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2 N HCl (10 mL), stirred for 30 min and extracted with CH.sub.2Cl.sub.2 (2×20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified through silica gel column chromatography using 20% EtOAc/hexanes to afford title compound (210 mg, 49%) as colourless syrup.

(191) (E)-4-((E)-benzylidene)dec-2-en-1-ol: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.37-7.32 (m, 2H), 7.29-7.27 (m, 2H), 7.25-7.20 (m, 1H), 6.48 (s, 1H), 6.33 (dd, J=15.7, 0.8 Hz, 1H), 5.98-5.915 (m, 1H), 4.28 (t, J=5.3 Hz, 2H), 2.46-2.40 (m, 2H), 1.60-1.55 (m, 1H), 1.54-1.50 (m, 1H), 1.41-1.32 (m, 3H), 1.32-1.24 (m, 4H), 0.91-0.86 (m, 3H); LC-MS (ESI): 97.08%; m/z 227.1 [M−H.sub.2O].sup.+; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 μm); RT 3.91 min. 2.5 mM NH.sub.4OOCH in water+5% ACN:ACN+5% 2.5 mM NH.sub.4OOCH in water; 0.8 mL/min); HPLC (purity): 92.14%; (column: X SELECT CSH C18 (150×4.6 mm, 3.5μ); RT 12.98 min; 5 Mm NH.sub.4OAc:ACN; 1.0 mL/min).

Step 3: Synthesis of (E)-4-((E)-benzylidene)dec-2-enal (Compound 39)

(192) To a stirred solution of Compound 45 (50 mg, 0.2 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added Dess-Martin periodinane (130 mg, 0.31 mmol) at 0° C. under argon atmosphere. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (5 mL) and extracted with CH.sub.2Cl.sub.2 (2×10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford the compound (35 mg, 71%) as pale yellow syrup.

(193) Compound 39: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.64 (d, J=7.8 Hz, 1H), 7.43-7.31 (m, 5H), 7.21 (d, J=15.6 Hz, 1H), 6.90 (s, 1H), 6.29 (dd, J=7.8, 15.6 Hz, 1H), 2.53-2.48 (m, 2H), 1.59-1.51 (m, 4H), 1.42-1.35 (m, 2H), 1.33-1.27 (m, 4H), 0.89 (br t, J=6.8 Hz, 3H); LC-MS (ESI): 87.11%; m/z 243.1 [M+H].sup.+; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 μm); RT 4.23 min. 2.5 mM NH.sub.4OOCH in water+5% ACN:ACN+5% 2.5 mM NH.sub.4OOCH in water; 0.8 mL/min).

Example 23: Synthesis of ((E)-2-((E)-3-methoxy-2-methylprop-1-en-1-yl)oct-1-en-1-yl)benzene (Compound 42) (Scheme 27)

(194) ##STR00139##

Step 1

(195) To a stirred solution of ethyl (E)-4-((E)-benzylidene)-2-methyldec-2-enoate (compound 1) (100 mg, 0.33 mmol) in Et.sub.2O (3 mL) was added LAH (24 mg, 0.66 mmol) at 0° C. under nitrogen atmosphere. The resultant reaction mixture was stirred at RT for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), stirred for 30 minutes at RT and then washed with water (20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford (E)-4-((E)-benzylidene)-2-methyldec-2-en-1-ol (40 mg, 47%) as colourless liquid.

(196) (E)-4-((E)-benzylidene)-2-methyldec-2-en-1-ol: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.38-7.32 (m, 2H), 7.28-7.19 (m, 3H), 6.30 (s, 1H), 5.95 (s, 1H), 4.84-4.78 (m, 1H), 3.91 (d, J=5.4 Hz, 2H), 2.30-2.22 (m, 2H), 1.77 (s, 3H), 1.45-1.37 (m, 2H), 1.32-1.16 (m, 6H), 0.83 (t, J=6.9 Hz, 3H); LC-MS (ESI): 94.50%; m/z 241.3[M-18+H].sup.+ at RT 5.14 min and 5.49%; m/z 241.3[M-18+H].sup.+ at RT 5.30 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); 2.5 mM NH.sub.4OAc:ACN; 0.8 mL/min); HPLC (purity): 87.17%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 11.99 min; ACN: 0.05% TFA; 1.0 mL/min).

Step 2: Synthesis of ((E)-2-((E)-3-methoxy-2-methylprop-1-en-1-yl)oct-1-en-1-yl)benzene (Compound 42)

(197) To a suspension of NaH (60% dispersion in mineral oil) (34 mg, 1.41 mmol) in DMF (5 mL) was added (E)-4-((E)-benzylidene)-2-methyldec-2-en-1-ol from step 1 (150 mg, 0.58 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h. Methyl iodide (0.07 mL, 1.16 mmol) was then added and the stirring was continued for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) and extracted with ether (2×20 mL). Separated organic layer was washed with water (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford compound 42 (125 mg, 79%) as colourless syrup.

(198) Compound 42: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.37-7.32 (m, 2H), 7.26-7.19 (m, 3H), 6.32 (s, 1H), 5.94 (s, 1H), 3.84 (s, 2H), 3.22 (s, 3H), 2.25 (t, J=8.1 Hz, 2H), 2.87 (s, 2H), 1.43-1.35 (m, 2H), 1.27-1.16 (m, 7H), 0.81 (t, J=6.9 Hz, 3H); LC-MS (ESI): 93.79%; m/z 241.1 [M−OCH.sub.3].sup.+ at RT 4.10 min and 4.13%; m/z 241.1[M−OCH.sub.3].sup.+ at RT 4.21 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 84.26%+10.13%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 20.95 & 22.14 min; ACN: 0.05% TFA; 1.0 mL/min).

Example 24: Synthesis of ((E)-2-((E)-3-ethoxy-2-methyl prop-1-en-1-yl)oct-1-en-1-yl)benzene (Compound 43) (Scheme 28)

(199) ##STR00140##

(200) To a suspension of NaH (60% dispersion in mineral oil) (34 mg, 1.41 mmol) in DMF (5 mL) was added (E)-4-((E)-benzylidene)-2-methyldec-2-en-1-ol (CC-014) (150 mg, 0.58 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1 h, and ethyl iodide (0.09 mL, 1.16 mmol) was then added and the stirring was continued for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) and extracted with ether (2×20 mL). Separated organic layer was washed with water (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford Compound 43 (125 mg, 75%) as colourless syrup.

(201) Compound 43: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.38-7.32 (m, 2H), 7.28-7.20 (m, 3H), 6.32 (s, 1H), 5.95 (s, 1H), 3.89 (s, 2H), 3.41 (q, J=7.1 Hz, 2H), 2.26 (t, J=7.5 Hz, 2H), 1.79 (s, 3H), 1.44-1.36 (m, 2H), 1.28-1.18 (m, 6H), 1.14 (t, J=6.9 Hz, 3H), 0.82 (t, J=6.9 Hz, 3H); LC-MS (ESI): 92.58%; m/z 240.9 [M-OEt].sup.+ at RT 4.34 min and 4.38%; m/z 240.0[M-OEt].sup.+ at RT 4.43 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min); HPLC (purity): 82.70%+9.94%; (column: ZORBAX SB C-18 (150×4.6 mm, 3.5 μm); RT 24.78 & 26.41 min; ACN+5% 0.05% TFA: 0.05% TFA+5% ACN; 1.0 mL/min).

Example 25: Synthesis of 1-((E)-2-((E)-3-ethoxy-2-methylprop-1-en-1-yl)oct-1-en-1-yl)-4-fluorobenzene (Compound 44) (Scheme 29)

(202) ##STR00141##

Step 1

(203) To a solution of octanal (3.5 mL, 23.4 mmol) in EtOH:H.sub.2O (40 mL, 1:1) were added KOH (1.31 g, 23.4 mmol) and 4-fluorobenzaldehyde (2 g, 15.6 mmol) at 0° C. The reaction mixture was stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, ethanol was removed. Crude material was diluted with water (30 mL) and extracted with DCM (3×30 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/hexanes to afford crude (E)-2-(4-fluorobenzylidene)octanal (1.3 g) as yellow syrup, which was taken to next step without any further purification.

Step 2

(204) Ethyl 2-(diethoxyphosphoryl)propanoate (1.8 mL, 8.33 mmol) was added drop wise at 0° C. under nitrogen atmosphere to a stirred suspension of NaH (60% dispersion in mineral oil) (377 mg, 15.7 mmol) in THF (10 mL). After completion of the addition, the reaction mixture was stirred at RT for 1 h. Again, the mixture was cooled to 0° C. and (E)-2-(4-fluorobenzylidene)octanal (1.3 g, 5.55 mmol) in THF (10 mL) was slowly added and the stirring was continued at RT for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched water (20 mL) and extracted with EtOAc (3×20 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 3% EtOAc/hexane to afford ethyl (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-enoate (1.1 g, 62%) as light yellow syrup.

(205) Ethyl (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-enoate: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.26-7.19 (m, 3H), 7.12-7.00 (m, 2H), 6.45 (s, 1H), 4.25 (q, J=6.9 Hz, 2H), 2.38-2.32 (m, 2H), 2.06 (s, 3H), 1.38-1.31 (m, 3H), 1.30-1.18 (m, 8H), 0.93-0.83 (m, 3H); LC-MS (ESI): 79.24%; m/z 318.9 [M+H].sup.+ at RT 3.70 min; (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); 0.025% Aq TFA+5% ACN:ACN+5% 0.025% Aq TFA; 1.2 mL/min).

Step 3

(206) A solution of ethyl (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-enoate (500 mg, 1.57 mmol) in DCM (10 mL) was cooled to −78° C. and then DIBAL-H (2.36 mL, 2.35 mmol) was added drop wise under nitrogen atmosphere. The resultant reaction mixture was stirred at −78° C. for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2N HCl solution (10 mL), stirred for 30 minutes and then extracted with DCM (3×10 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 10% EtOAc/hexanes to afford (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-en-1-ol (230 mg, 53%) as colourless syrup.

(207) (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-en-1-ol: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.20 (dd, J=8.4, 5.8 Hz, 2H), 7.06-6.99 (m, 2H), 6.30 (s, 1H), 5.98 (s, 1H), 4.13 (s, 2H), 2.28-2.23 (m, 2H), 1.87 (s, 3H), 1.47-1.38 (m, 3H), 1.33-1.21 (m, 5H), 0.87 (t, J=6.9 Hz, 3H); HPLC (purity): 86.31%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 13.38 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

Step 4: Synthesis of 1-((E)-2-((E)-3-ethoxy-2-methylprop-1-en-1-yl)oct-1-en-1-yl)-4-fluorobenzene (Compound 44)

(208) (E)-4-((E)-4-fluorobenzylidene)-2-methyldec-2-en-1-ol from step 3 (180 mg, 0.65 mmol) in THF (5 mL) was added to a stirred suspension of NaH (60% dispersion in mineral oil) (50 mg, 2.10 mmol) in THF (5 mL), at 0° C. under nitrogen atmosphere. After stirring for 15 minutes, ethyl iodide (0.11 mL, 1.30 mmol) was added and the stirring was continued at room temperature for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×15 mL). Separated organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford compound 44 (100 mg, 50%) as light yellow syrup.

(209) Compound 44: .sup.1H NMR (500 MHz, CDCl.sub.3): δ=7.20 (dd, J=8.4, 5.8 Hz, 2H), 7.01 (t, J=8.7 Hz, 2H), 6.30 (s, 1H), 5.95 (s, 1H), 3.95 (s, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.27-2.22 (m, 2H), 1.85 (d, J=0.9 Hz, 3H), 1.47-1.38 (m, 2H), 1.28-1.23 (m, 9H), 0.86 (t, J=6.9 Hz, 3H); LC-MS: 10.00%; m/z 259.3 [M-(OEt-1)].sup.+ at RT 4.47 min; (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); ACN: 2.5 mM NH.sub.4OAc; 0.8 mL/min); HPLC (purity): 99.78%; (column: XSELECT CSH C-18 (150×4.6 mm, 3.5 μm); RT 17.84 min; ACN: 5 mM NH.sub.4OAc; 1.0 mL/min).

Example 26: Synthesis of ethyl (E)-4-((E)-4-fluorobenzylidene)non-2-enoate Compound 45 (Scheme 30)

(210) ##STR00142##

Step 1

(211) Heptan-1-ol (6.2 mL, 43.02 mmol) was dissolved in DCM (50 mL) and Dess-Martin Periodinane (21.9 g, 51.63 mmol) was added portion wise at 0° C., under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water (50 mL) and filtered through a pad of celite. Obtained filtrate was washed with saturated NaHCO.sub.3 solution, dried over sodium sulfate and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes to afford heptanal (3.8 g, 77%) as syrup.

(212) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.86 (s, 1H), 2.47-2.39 (m, 2H), 1.68-1.54 (m, 2H), 1.36-1.24 (m, 6H), 0.90 (t, J=7.4 Hz, 3H).

Step 2

(213) Heptanal (3.8 g, 33.2 mmol) was dissolved in EtOH:H.sub.2O (60 mL, 2:1). KOH (279 mg, 48.2 mmol) followed by the addition of 4-fluorobenzaldehyde (4.9 g, 39.5 mmol) at 0° C. The resultant reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion of the reaction, volatiles were removed under reduced pressure. Crude material was diluted with water (30 mL) and extracted with DCM (2×50 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5-7% EtOAc/hexanes to afford 2-(4-fluorobenzylidene)heptanal (4 g) as yellow syrup. This material was used in the next step without any further purification.

Step 3: Synthesis of ethyl (E)-4-((E)-4-fluorobenzylidene)non-2-enoate (Compound 45)

(214) Crude 2-(4-fluorobenzylidene)heptanal (1.5 g, 6.81 mmol) was dissolved in PhCH.sub.3 (15 mL) and ethyl 2-(triphenyl-λ5-phosphanylidene)acetate (4.7 g, 13.5 mmol) was added in a sealed tube under nitrogen atmosphere. The resultant reaction mixture was heated to 100° C. and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and volatiles were evaporated under reduced pressure. Obtained crude material was purified through silica gel column chromatography using 5% EtOAc/hexanes followed by preparative HPLC to afford title compound 45 (1.05 g, 76%) as light yellow syrup.

(215) Compound 45: .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.40 (d, J=15.6 Hz, 1H), 7.31 (dd, J=5.5, 8.4 Hz, 2H), 7.08 (t, J=8.7 Hz, 2H), 6.76 (s, 1H), 5.99 (d, J=15.6 Hz, 1H), 4.26 (q, J=7.0 Hz, 2H), 2.47-2.41 (m, 2H), 1.59-1.53 (m, 2H), 1.39-1.32 (m, 7H), 0.92 (t, J=7.0 Hz, 3H). LC-MS (ESI): 98.74%; m/z 291.2 [M+H].sup.+ at RT 5.54 min; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 μm); 2.5 mM aq. NH.sub.4OAc:ACN; 0.8 mL/min). HPLC (purity): 93.55%; (column: X SELECT CSH C-18 (150×4.6 mm, 3.5μ); RT 16.27 min; 5 mM NH.sub.4OAc:ACN; 1.0 mL/min).

(216) ##STR00143##

(217) Compound 46 can be prepared as described in Horie Hiroaki, et al., “Nickel-catalyzed intermolecular codimerization of acrylates and alkynes”, Chemical Communications (Cambridge, United Kingdom), Volume: 47, Issue: 9, Pages: 2658-2660, Journal, 2011.

(218) In general the reaction can be performed in a 5 mL sealed vessel equipped with a teflon-coated magnetic stirrer tip. An acrylate (0.60 or 1.0 mmol) and an alkyne (0.50 mmol) are added to a solution of bis(1,5-dicyclooctadiene)nickel (14 mg, 0.050 mmol), tricyclohexylphosphine (14 mg, 0.050 mmol) and N-aryl-2-aminopyridine (0.10 mmol) in toluene (5 mL) in a dry box. The VIAL is taken outside the dry box and heated at 100° C. for 24 h. The reaction mixture is poured into 0.5N HCL aq. (30 mL) and the mixture is extracted with ethyl acetate (3×10 mL). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash silica gel column chromatography (hexane/AcOEt=40/1) to give the corresponding conjugated diene as a colourless oil.

(219) Compound 46: .sup.1H NMR (500 MHz, CDCl.sub.3): δ=7.39 (d, J=16.0 Hz, 1H), 7.29 (dd, J.sub.HH=9.0, J.sub.HF=5.0 Hz, 2H), 7.07 (dd, J.sub.HH=9.0, J.sub.HF=9.0 Hz, 2H), 6.75 (s, 1H), 5.98 (d, J=16.0 Hz, 1H, 3.79 (s, 3H), 2.43 (t, J=8.0 Hz, 2H), 1.53 (m, 2H), 1.34 (m, 4H), 0.90 (j, J=7.0 Hz, 3H). MS (EI): m/z (%) 276 ([M].sup.+, 56), 219 ([M-Bu].sup.+, 85), 159 (100), 109 ([F—C.sub.6H.sub.4—CH.sub.2].sup.+, 60).

BIOLOGICAL EXAMPLES

(220) Cell Culture and Cell Line Generation

(221) Cells were maintained in minimal essential medium (EMEM, Lonza) containing 10% fetal bovine serum (M10). HEK293T stably expressing olfactory chaperone proteins from the RTP family as described in WO 2006/002161 (introduced here as a reference) were generated by transfecting HEK293T cells with expression vector containing the chaperone gene sequences and a resistance gene to puromycin, using Lipofectamine 2000. A recombinant cell population was selected by adding 10 μg/ml of puromycin into the culture medium. Monoclonal populations were further obtained by limit dilution procedure. Briefly, a cell suspension was diluted to contain 1 cell per ml and this dilution was dispatched in poly-D-lysine-coated 96 well plates (200 μl of dilution per well). After 5 days of culture, the presence and number of cell colonies per well was checked under a phase contrast microscope. After 5 additional days of culture, wells containing a single colony were harvested and each collected population was amplified independently.

(222) Agonist and Tested Molecule Dilution

(223) The 5-alpha-androst-16-ene-3-one, used as an agonist of the human olfactory receptor OR7D4 and the tested molecules were diluted at a concentration of 1 mole/litre (M) into dimethyl sulfoxide (DMSO) to generate stock solutions.

(224) For concentration-response analysis, serial dilutions of the tested molecules were prepared from stock solutions in EMEM plated into 96-well plates.

(225) OR7D4 Expression and Luciferase Assay.

(226) To demonstrate the activation of OR7D4 by its agonist androstenone and the inhibition of this activation by antagonist compounds, a Luciferase-based gene reporter assay (Promega, Leiden, The Netherlands) was used as described in Saito et al. (Saito et al., 2004 Cell Vol. 119, 679-691). Briefly, cells were plated on poly-D-lysine-coated 96-well plates (BD Bioscience, Erembodegem-Dorp, Belgium) and transfected with a plasmid containing CRE-luciferase and a plasmid containing OR7D4. Sixteen hours after transfection, the culture medium was replaced by serum-free EMEM containing the tested ligands at a determined concentration. After four hours of incubation at 37° C. degree, cells were lysed and processed for luminescence measurement according to the manufacturer's protocols. Luminescence emission was recorded on a Spectra Max M5 reader (Molecular Devices, Sunnyvale, Calif.). Results were expressed as percentage of the response induced by 10 μM of the adenylate cyclase activator Forskolin.

(227) Identification of Antagonists for OR7D4

(228) The ability of the compounds of the invention to inhibit the activity of androstenone on OR7D4 receptor was assessed by the luciferase assay described above.

(229) To determine whether a molecule antagonizes OR7D4, this compound was introduced in the incubation medium of the Luciferase assay described above at a concentration of either 316 μM, 100 μM or 31.6 μM, along with the known activator of the receptor 5α-androst-16-en-3-one at a concentration of 31.6 μM. Molecules were considered as “hits” i.e., as having an antagonist effect on the receptor, if they induced a decrease of at least 50% of the luciferase production elicited upon activation of OR7D4 by 5α-androst-16-en-3-one.

(230) Putative antagonist molecule libraries containing compound 1 and other types of molecules were used to identify antagonist of the receptor OR7D4. The screening campaign was performed on the OR7D4 with a series of 112 putative antagonist molecules. In this screening campaign, compound 1 was identified as a hit.

(231) The compound 1 was further confirmed as antagonist of OR7D4 by performing dose-response analysis using the luciferase assay. Different concentrations of compound 1, ranging from 31.6 nM to 1 mM were tested on HEK293 cell expressing OR7D4 and stimulated with 31.6 μM of 5α-androst-16-en-3-one. The results presented on FIG. 1 show a decrease of Luciferase activity elicited 5α-androst-16-en-3-one proportional to the concentration of compound 1.

(232) As a control, cell that did not expressed the receptor were stimulated by forskolin, a pharmacological agent that induces a receptor-independent production of cAMP and induces therefore a production of Luciferase. This production is not affected by compound 1, indicating that its action as antagonist depends well on the OR7D4 receptor.

(233) The antagonistic property of compound 1 on OR7D4 was further confirmed by measuring the response of the OR7D4 to 5α-androsta-4,16-dien-3-one in presence of compound 1, using the luciferase assay as describe hereinabove. The observed inhibition was in the same range as the one observed when stimulating the receptor with 5α-androst-16-en-3-one. Typically, the IC50 recorded reached a value of 2.5 micromolar.

(234) Structure-Activity Relationship Study on OR7D4 Antagonist

(235) To further explore the antagonism on OR7D4, a series of compounds structurally related to compound 1 were synthesized and assessed as antagonists of OR7D4 by dose-response analysis using the luciferase assay. Table 4 summarizes the results of the structure-activity study by giving the IC50 (inhibitory concentration 50, i.e. the concentration of antagonist that induces a half decrease of the luciferase production obtained without antagonist) of the different tested analogues.

(236) TABLE-US-00006 TABLE 4 IC50 Com- (micro- pound Name or Structure molar) 1 2 2 25 3 50 4 16 5 14 6 25 7 0 13 8 1 9 1 10 2 11 8 12 8 13 7 14 14 15 85 16 8 17 0 12 18 13 19 45 20 32 21 62 22 75 23 1 24 2 25 126 26 11 27 0 14 28 2 29 1 30 6 31 63 32 126 33 18 34 19 35 53 36 79 37 0 126 38 25 39 6 40 29 41 187 42 25 43 126 44 22 45 4 46 25

(237) When tested in the above described assay, preferred compounds of the invention showed an IC.sub.50 comprised between 0.5 μM and 200 μM, indicating that such compounds are able to antagonize the activity of androstenone on OR7D4 receptor.

(238) Sensory Evaluation of Compounds of the Invention Versus Androstenone

(239) This example demonstrates the effect of the compound 1 in reducing 16-(5-alpha)-androstenone (“Androstenone”) odour in a sensory evaluation test, as predicted by the antagonistic effects observed in the bioassay described above. Androstenone is a key element of body malodour, particularly underarm, and generally has a strong unpleasant odour to those who can perceive it.

(240) Since it is not possible to assess androstenone in isolation in vivo, as other body malodour components will always be present, we have utilised an in vitro sensory tests, using the isolated material in jars. The sensory test consists of a standard “Triangle Test” where assessors have to identify the “odd jar out”, the one which contains just androstenone. They are also requested to identify whether the odd jar has a weaker or stronger androstenone smell than the other two.

(241) Each set also contains two blank jars to avoid potential ‘carry over’ effect of either the androstenone and/or compound 1.

(242) A set of five jars is prepared for each assessor to smell. Each set includes three test jars and the two blank jars, prepared as follows:

(243) Five 120 ml “Beatson” jars are used with a 4.5 cm diameter de-sized 100% cotton cloth placed into each jar. Five small round pieces of the same cotton are placed on top of a small vial lid in the jar on top of larger cotton cloth.

(244) One test jar contains just 50 μl of androstenone (1% in diethyl phthalate) at 6.2% in ethanol, dropped onto the 4.5 cm cloth and allowed to dry for 12 minutes to remove the ethanol. Two test jars contain androstenone (same level and procedure as above) and compound 1 (200 μl neat pipetted onto the small cloth piece resting on the vial lid, with no drying step). The two ingredients are kept separate to avoid direct contact and reduce other possible chemical effects which may affect the sensory perception of the ingredients when combined. The two blank jars contain cotton cloths only, without androstenone or compound 1. The jars are sealed and left at room temperature for 5 days prior to assessment to allow full equilibration of the poorly volatile materials.

(245) The jars are then coded and randomised for each assessor following the Williams Latin Square method which minimises the sample order effect and ensures sufficient assessments per sample in each test. The blank jars are always placed at positions two and four, for example:

(246) TABLE-US-00007 Position 1 Test jar Androstenone (A) Position 2 Blank jar Position 3 Test Jar Androstenone + Compound 1 (A + C1) Position 4 Blank jar Position 5 Test Jar Androstenone + Compound 1 (A + C1)

(247) Each respondent is asked to smell each jar following the order as set out by the test coordinator. Each jar is be opened and resealed before moving onto the next jar. An interval of twenty seconds is required between smelling each sample. The assessors record the presence of androstenone in each jar and add any comments on an assessment sheet as supplied for the test. Due to the possibility of adaptation, respondents are not allowed to repeatedly smell the samples within each test assessment.

(248) However, the test can be repeated after a suitable time interval (e.g. two hours) to confirm the results.

(249) The following results illustrate the utility of the invention. In the following table 5, the results for six assessors are shown. For all six assessors, the jar containing the androstenone alone was correctly identified as the “odd jar out” and had a significantly higher androstenone odour than the other two jars containing androstenone and compound 1. This clearly demonstrates the effectiveness of compound 1 in reducing androstenone odour (Table 5).

(250) TABLE-US-00008 TABLE 5 Jar Position Assessor 1 2 3 4 5 Odd one Out and Comment 1 A + C1 Blank A + C1 Blank A Jar 5 strong androstenone No androstenone in jars 1 and 3 2 A Blank A + C1 Blank A + C1 Jar 1 strong androstenone No androstenone in jars 3 and 5 3 A Blank A + C1 Blank A + C1 Jar 1 strong androstenone Weak androstenone in jars 3 and 5 4 A + C1 Blank A Blank A + C1 Jar 3 strong androstenone Weak androstenone in jars 1 and 5 5 A + C1 Blank A + C1 Blank A Jar 5 strong androstenone Weak androstenone in jars 1 and 3 6 A + C1 Blank A + C1 Blank A Jar 5 strong androstenone Weak androstenone in jars 1 and 3

(251) The test was repeated with a second compound of the invention—compound 16 (C16), referred to hereinabove (Table 6)—and similar results were achieved, again illustrating the utility of the invention. The testing protocol was identical; however, as compound 16 is a solid ingredient, 400 μl of a 50% dilution in diethyl phthalate was added to the test jars.

(252) TABLE-US-00009 TABLE 6 Jar Position Assessor 1 2 3 4 5 Odd one Out and Comment 1 A + C16 Blank A + C16 Blank A Jar 5 strong androstenone No androstenone in jars 1 and 3 2 A + C16 Blank A Blank A + C16 Jar 3 strong androstenone No androstenone in jars 1 and 5 3 A Blank A + C16 Blank A + C16 Jar 1 strong androstenone No androstenone in jars 3 and 5 4 A + C16 Blank A Blank A + C16 Jar 3 strong androstenone Weak androstenone in jars 1 and 5

(253) An alternative sensory test was also used to demonstrate the effect of compound 1 on the perception of androstenone. The test consists, in a first step, in microinjecting androstenone (at 0.6% in ethanol), compound 1 (pure) or androstenone+compound 1 in 10 L Tedlar™ bags specially conceived for gas sampling, previously loaded with a known volume of pure air (from oil free compressor with additional charcoal filters). Than the compound of interest (EtOH solution) is injected with a high accuracy micro-syringe through a septum placed on the tap-valve.

(254) The odour presentation device consists of a cylinder to be filled with clean air. The bag is inserted in the cylinder and connected to a sampling installation in the cylinder by means of a valve. By controlled injection of clean air into the cylinder, the interior pressure is raised and the sampling air is pressed in a controlled manner out of the sample container through the opened valve. This sampling air is transferred to the nose of the corresponding sensory odour panel member by means of a funnel. By this means, each sensory odour panel member receives an identical sample with a standardized volume flow and a constant provision time. The outlet flow rate is between 10-20 L/min (in order to avoid any mixing with ambient air before reaching the nose).

(255) The expert panel is entering the room 15 minutes before starting the test. The basic standard test is a rating in intensity and the use of the closest chemical descriptors according to the following order of presentation:

(256) Androstenone

(257) Compound 1

(258) Mix: androstenone+compound 1 (at same concentrations as for 1 and 2).

(259) Each assessor can smell for few seconds. A pause of min. 1 minute is considered between presentations.

(260) The individual rating is done with a resolution of 0.5 on a scale ranging from 0 (no odour) to 5 (saturating odour).

(261) The following results (Table 7) show that the typical odour of sweat of Androstenone completely disappears when androstenone is smelled in the presence of the compound 1 of the invention. The remaining odour of mushroom corresponds to the intrinsic smell of compound 1. Since the odour intensity of the compound 1 is lower than the one of androstenone alone, it cannot overpower the odour androstenone. Therefore, the suppression of androstenone perception cannot be accounted to a masking or covering effect of compound 1 but well to a true suppression of the perception of androstenone by antagonizing its cognate olfactory receptor namely OR7D4.

(262) TABLE-US-00010 TABLE 7 Androstenone Androstenone + compound 1 Assessor Intensity Odour description Intensity Odour description 1 4.5 Sweat 2.5 mushroom 2 4 Sweat 2 mushroom 3 3 Sweat 2 mushroom 4 3.5 Sweat 2 mushroom