The document discusses new and potential cooling compounds. It summarizes menthol production and uses. It then describes various compounds that activate cold-sensitive ion channels in the skin and mouth to produce cooling sensations, including synthetic compounds that are significantly more potent than menthol. Finally, it discusses additional novel compounds reported to have cooling properties with low or no bitterness.

1. New Cooling Related Compounds
John C. Leffingwell
Society of Flavor Chemist’s
November 20, 2008
Revised Jan. 20, 2009

2. World Production of Menthol
Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press

3. World Uses of Menthol
Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press

4. Thermo TRP Receptors & Agonists
Table 4 Thermoreceptor Agonists
Chemical agonist (botanical source) ThermoTRP
Capsaicin (hot chilli peppers, e.g., Tabasco) TRPV1
Piperine (black pepper corns) TRPV1
Allicin (fresh garlic) TRPV1, TRPA1
Camphor (Cinnamomum camphora) TRPV3, TRPV1
D-9-Tetrahydrocannabinol (Cannabis sativa) TRPV2, TRPA1
2-Aminoethoxydiphenyl borate (synthetic) TRPV1, TRPV2, TRPV3
4-a-phorbol 12,13-didecanoate (synthetic) TRPV4
(-)-Menthol (peppermint) TRMP8, TRPV3
1,8-Cineole, eucalyptol (eucalyptus) TRPM8
WS-3 (synthetic) TRPM8
Icilin (synthetic) TRPM8, TRPA1
Cinnamaldehyde (cinnamon, cassia) TRPA1, TRPV3
Allyl isothiocyanate (mustard, horseradish) TRPA1
Benzyl isothiocyanate (mustard, horseradish) TRPA1
Phenethyl isothiocyanate (mustard, horseradish) TRPA1
Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press

5. Menthoxy Cooling Agents Thru GRAS 23
O
O
OH O OH O
O OH
OH OH
(-)- Isopulegol Coolact-10 Frescolat ML Frescolat MGA
FEMA 2962 FEMA 3784 FEMA 3748 FEMA 3807
0.25 X Menthol 0.2-0.4 X Menthol 0.43 X Menthol 0.41 X Menthol
O OH
+
OH OH O O OH
HO HO HO
Coolact 38D MHB MMPD
FEMA 4053 FEMA 4308 FEMA 3849
0.11 X Menthol ~0.45 X Menthol
OH O
O O O
O
Coolact 5 Menthone lactic acid ketal Menthyl methyl ether
FEMA 4154 FEMA 4285 FEMA 4054

6. More Menthoxy Cooling Agents Thru GRAS 23
O O O
OH
O O OH
O
Monomenthyl succinate Monomenthyl glutarate
FEMA 3810 FEMA 4006
~0.2-0.3 X Menthol ~0.1-0.15 Menthol
O
H
N
O O
Questice
FEMA 4155
O R1 O
R2 OH
O O O O
Menthol propylene glycol carbonate Menthol ethylene glycol carbonate
FEMA 3806 Frescolat MGC
Isomer 1 – R1=OH, R2=CH3 FEMA 3805
Isomer 1 – R1=CH3, R2=OH

7. Amide GRAS Cooling Agents Thru GRAS 23
H
N
O O N
H
WS-3 WS-23
FEMA 3455 FEMA 3804
1.5 X Menthol 0.75 X Menthol
O
H
N CO2Et N
O
O O
WS-5
FEMA 4309 Menthyl N,N-dimethylsuccinamide
4 X Menthol FEMA 4230

8. Givaudan’s New Powerful GRAS Cooling Agents
Furrer et al., Chem. Percept. (June 2008) 1:119–126; Galopin et al., US Patent
7,414,152 (August 19, 2008); Bell et al., WO2007019719 (Feb. 22, 2007)
H H
N N
O CN O N
2j = FEMA 4496 2k = FEMA 4549
10 X Menthol 40-100 X Menthol

9. New GRAS 24 Related Cooling Agents
O
N
H O N
H
Menthyl N-Ethyl-2,2-diisopropyl-
cyclopropanecarboxamide butanamide
FEMA 4558 FEMA 4557
Not Cooling – Umami-like
U.S. Patent Application 20080292763
H H
N N
OH
O N O CN
N-(2-(Pyridin-2-yl)ethyl)-3-p- N-p-Benzeneacetonitrile- Cubebol
menthanecarboxamide menthanecarboxamide FEMA 4497
FEMA 4549 FEMA 4496
40-100 X Menthol 10 X Menthol

10. Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press

11. Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press

12. Relative Cooling & Bitterness in 5% sucrose
Johnson SS, Stawski BZ, Sheldon GT. Confections Containing a Blend of
Physiological Cooling Agents. U.S. Patent Application 20070248717,
2007, Oct. 25. (Wrigley)

13. Adapted from Johnson SS, Stawski BZ, Sheldon GT. Confections
Containing a Blend of Physiological Cooling Agents. U.S. Patent
Application 20070248717, 2007, Oct. 25. (Wrigley)

14. Other Potential Cooling Agents
Leffingwell, Handbook of Cosmetic Science and Technology, 3d edition (2009), In Press;
From WO 2006103401 (2006) & US20070155755 (2007)

15. Other Potential Cooling Agents
OH
H
O OH N O
OH
O O O
WS-30 WS-14 WS-4
0.2-0.25 X Menthol 0.75 X Menthol 0.16-0.33 X Menthol
O O
O NH
HN HN C2H5O
O NC O
~2.2 X Menthol ~10 X Menthol ~0.75 X Menthol
WO 2006/099762 (2006) WO 2006/099762 (2006) US Patent 7030273 (2007)

16. Other Potential Cooling Agents
O
H H
N N O
O O
O
Hase-1 N-benzo[1,3]dioxol-5-yl-
Cooling, No bitterness 3-p-menthanecarboxamide
JP2004059474 (2004) ~100 X Menthol
WO 2006/092074 (2006)