Title of Invention

A COMPOUND OF FORMULA I

Abstract Compounds of the formula (I) give a cooling sensation to the mouth and skin. In Formula I, m is 0 or 1, Y and Z are selected independently from the group consisting of H, OH, C1-C4 straight or branched alkyl, or, a C1-C4 straight or branched alkoxy, X is (CH2)n-R, where n is 0 or 1 and R is a group with non-bonding electrons, with the provisos that: (a) when Y and Z are H, X is not F, OH, MeO or NO2 in the 4-position and is not OH in the 2 or 6-position; (b) when Y or Z is H then X, Y and Z are such that (i) the groups in the 3- and 4-positions are not both OMe, (ii) the groups in the 4- and 5-positions are not both OMe, (iii) the groups in 3- and 5-positions are not OMe if the group in the 4-position is OH, and (iv) the groups in the 3- and 5-positions are not OH if the group in the 4-position is methyl. The compounds give a cooling sensation up to ten times more powerful than the best current commercial materials.
Full Text

COMPOUNDS
This invention relates to cooling compounds.
Cooling compounds, that is, chemical compounds that impart a cooling sensation to the skin or the mucous membranes of the body, are well known to the art and are widely used in a variety of products such as foodstuffs, tobacco products, beverages, dentifrices, mouthwashes and toiletries.
One class of cooling compounds that have enjoyed substantial success consists of N-substituted p-menthane carboxamides. Examples of these compounds are described in, for example, British Patents GB 1,351,761-2 and United States Patent US 4,150,052.
It has now been found that a particular selection of such compounds exhibits a cooling effect that is both surprisingly strong and long-lasting. The invention therefore provides a compound of the formula I

in which m is 0 or 1, Y and Z are selected independently from the group consisting of H, OH, C1-C4 straight or branched alkyl, or, a C1-C4 straight or branched alkoxy, X is (CH)n-R, where n is 0 or 1 and R is a group with non-bonding electrons, with the provisos that:
(a) when Y and Z are H, X is not F, OH, MeO or NO2 in the 4-position and is not OH in the 2 or 6-position
(b) when Y or Z is H then X, Y and Z are such that
(i) the groups in the 3- and 4-positions are not both OMe, (ii) the groups in the 4- and 5-positions are not both OMe,

(iii) the groups in 3- and 5-positions are not OMe if the group in the 4-position is OH,
and
(iv) the groups in the 3- and 5-positions are not OH if the group in the 4-position is
methyl.
The preferred compounds are those in which X is in the 4-position. The most preferred compounds are when X is in the 4-position and Y and Z are H, OH, Me or OMe.
Preferred groups with non-bonding electrons are halogens, OH, OMe, N02, CN, Ac, SO2NH2, CHO, C02H and C1-C4 alkyl carboxylates such as C02Et.
The compounds may be easily prepared and isolated by art-recognized methods
They are distinguished from similar compounds of the prior art by their surprisingly high cooling effect (up to 10 times higher than that of similar known compounds) and by the longevity of the cooling effect, which adds to their attractiveness in a large variety of products.
For example, a small group of panelists was asked to taste various solutions of cooling compounds and indicate which solutions had a cooling intensity similar or slightly higher than that of a solution of menthol at 2ppm. In a second experiment, the same panel was asked to taste the solutions at the chosen concentrations and to record the cooling intensity at regular time intervals until no cooling could be sensed in the mouth. Results are shown in table 1.

last up to 3 times longer than menthol, the reference cooling compound. Compounds of Formula I are also much stronger and last longer than WS-3, the best cooling compound of the prior art.

The compounds of the invention may be used in products that are applied to the mouth or the skin to give a cooling sensation. By "applying" is meant any form of bringing into contact, for example, oral ingestion or, in the case of tobacco products, inhalation. In the case of application to the skin, it may be, for example, by including the compound in a cream or salve, or in a sprayable composition. The invention therefore also provides a method of providing a cooling effect to the mouth or skin by applying thereto a product comprising a compound as hereinabove described.
The invention is now further described by means of the following non-limiting examples, which describe preferred embodiments.
Example 1
Preparation of N-(4-cyanomethylphenyl) p-menthanecarboxamide
To a flask, were added 6.6 g (50 mmol) of 4-aminobenzyl cyanide, 4.04 mL of pyridine and 100 mL MtBE. To this mixture, 10 g of p-menthanecarboxyl chloride were added dropwise over 5 minutes. The reaction mixture was stirred for 24 h. To the reaction mixture, 50mL of water were added. The mixture was separated. The organic layer was washed with 50 mL of water and 50 mL of brine. The organic layer was dried over MgSCU . The solvent was evaporated in vacuo to afford the crude product, which was recrystallized from hexanes to afford 10.1 g of the desired product with the following spectroscopic properties:
MS: 299 ([M+l]),298 ([M+]), 132, 83
]H NMR (300 MHz; CDC13) 8: 7.58 (d, 2H), 7.49 (s, 1H), 7.27 (d, 2H), 3.73 (s, 2H), 2.2 (t, 1H),
1.96 -1.57 (m, 5H), 1.48 -1.21 (m, 2H), 1.172- 0.99 (m, 2H), 0.94 (d, 3H), 0.93 (d, 3H), 0.85 (d,
3H)
13 C NMR (75 MHz; CDC13)8: 174.4, 137.8, 128.3, 125.1, 120.3, 118.2 , 50.5, 44.3, 39.25, 34.3,
32.1, 28.7, 23.8, 22.9, 22.1,, 21.2, 16.1

Example2
Preparation of N-(4-sulfamoylphenyl) p-menthanecarboxamide:
A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties: MS: 339([M+1]), 338([M+]), 172, 83
]H NMR (300 MHz; DMSO) 5: 10.21 (s, IH), 7.76 (d, IH) 7.73 (d, 2H), 7.23 (s, 2H), 2.26-2.42 (m, IH), 1.45-1.85 (m, 5H), 1.29-1.44 (m, 2H), 0.89 (d, 3H), 0.86 (d,3H), 0.78 (d, 3H)
13C NMR (75 MHz; DMSO) 5: 174.6, 142.3, 138.3, 126.7, 118.8, 48.9, 43.7, 34.3, 31.9, 28.6, 23.7,22.35,21.3,16.25
Example 3
Preparation of N-(4-cyanophenyl) p-menthanecarboxamide:
A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties: MS: 285([M+1]), 284 ([M+]), 139, 83
JH NMR (300 MHz; CDC13) 5: 7.69 (d, 2H), 7.6 (d,2 H), 7.5 (s, IH), 1.85-1.97 (m, IH), 1.69-1.84 (m, 3H), 1.55-1.69 (m, 2H), 1.21-1.47 (m, 2H), 0.979-1.16 (m, 2H), 0.95 (d, 3H), 0.93 (d,3H), 0.82 (d, 3H)
13CNMR(300MHz;CDCl3)8: 174.6, 133.1, 119.4, 118.7, 100.35,50.7,44.4,39.25,34.2, 32.1, 28.8, 23.7, 22.0, 21.2, 16.1, 14.0
Example 4
Preparation of N-(4-acetylphenyl) p-menthanecarboxamide:
A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties:
MS: 302([M+1]), 301([M+]), 135, 83

H NMR (300 MHz; CDC13) 5: 7.93 (d, 2H), 7.66 (d, 2H), 7.63 (s, IH), 2.57 (s, 3H), 2.09-2.31 (m, IH), 1.84-1.98 (m, IH), 1.68-1.85 (m, 5H), 1.56-1.68 (m, IH), 1.17-1.48 (m, 2H),), 0.93 (d, 3H), 0.91 (d, 3H), 0.83 (d, 3H)
13C NMR (75 MHz; CDC13) 8: 197.1, 174.9, 142.7, 129.9, 119.2,51.2,44.9,39.8,34.8,32.6,
29.2,26.6,24.3,22.4,21.5,16.6
Example 5
Preparation of N-(4-hydroxymethylphenyl) p-menthanecarboxamide:
A preparation similar to that described in example 1 gives the desired product with the following spectroscopic properties:
MS: 290 (M+l), 289 (M+), 123, 83
'HNMR (300 MHz, DMSO) 5:9.9 (s, IH), 7.54 (d, 2H), 7.21 (d, 2H), 4.2(s, 2H), 2.36-2.1 (m,
IH), 1.8-1.59 (m, 6H), 1.57-1.44 (m,lH), 1.21-0.9 (m, 4H), 0.87(dd, 3H), 0.85 (dd, 3H), 0.79 (d,
2H)
13C NMR (75 MHz; DMSO) 8: 173.7, 137.7, 137.1, 126.7, 118.9,62.6,48.6,43.6,34,2,31.7,
28.3,23.6,22.2,21.1,16.1
Example 6
Preparation of N-(3-hydroxy-4-methoxyphenyl) p-menthanecarboxamide:
A preparation similar to that described in example 1 gives the desired product with the
following spectroscopic properties:
MS: 306([M+1]), 305([M+]), 139, 83
'H NMR (300 MHz; CDCI3) 8: 7.14 (s, IH), 7.08 (d, IH), 6.78 (d, IH), 5.7 (s, IH), 3.8 (s, 3H),
2.02-2.21 (m, 2H), 1.53-1.94 (m, 5H), 1.17-1.48 (m, 2H), 0.97-1.17 (m, 2H), 0.92 (dd, 3H),
0.91(dd,3H),0.82(d, 3H)
13C NMR (75 MHz; CDCI3) 5: 173.9, 145.6, 143.3, 131.7, 111.65, 110.8, 107.4,56.1,50.5,
44.4, 39.2, 32.15, 34.4, 28.6, 23.8,22.1,21.2,16.1

Example 7
Application in mouthwash
Alcohol 95% 177mL
Sorbitol 70% 250 g Compound of example 1 as
a 1% solution in alcohol 50mL Peppermint oil, Terpeneless 0.300 g
Methyl salicylate 0.640 g
Eucalyptol 0.922 g
Thymol 0.639 g
Benzoic acid 1.500 g
Pluronic™F127 5.000 g
Sodium Saccharin 0.600 g
Sodium Citrate 0.300 g
Citric Acid 0.100 g
Water q.s. 1 liter
The ingredients are mixed. 30 mL of obtained solution is put in the mouth, swished around, gargled and spit out. An intense cooling is felt in every area of the mouth as well as the lips. The cooling perception lasts for several hours.
Example 8
Application in toothpaste
Opaque toothgel 97.000 g Compound of example 2
as a 2% solution in PG 2.500g
Peppermint oil, Terpeneless 0.500g
The materials are mixed in the toothgel, and a panelist's teeth are brushed using this toothgel. The mouth is rinsed with water and the water spit out. An intense cooling sensation is felt by the panelist in all areas of the mouth. The cooling perception lasts for several hours.


Claims:
1. A compound of the formula I

in which m is 0 or 1, Y and Z are selected independently from the group consisting of H, OH, C1-C4 straight or branched alkyl, or, a C1-C4 straight or branched alkoxy, X is (CH2)n-R, where n is 0 or 1 and R is a group with non-bonding electrons, with the provisos that:
(a) when Y and Z are H, X is not F, OH, MeO or NO2 in the 4-position and is not OH in the 2 or 6-position
(b) when Y or Z is H then X, Y and Z are such that
(i) the groups in the 3- and 4-positions are not both OMe,
(ii) the groups in the 4- and 5-positions are not both OMe,
(iii) the groups in 3- and 5-positions are not OMe if the group in the 4-position is
OH, and
(iv) the groups in the 3- and 5-positions are not OH if the group in the 4-position
is methyl.
A compound according to claim 1, in which X is in the 4-position.
A compound according to claim 2, in which Y and Z are selected from the group consisting of H, OH, Me and OMe.
A compound according to claim 1, in which R is selected from the group consisting of halogens, OH, OMe, N02, CN, Ac, S02NH2, CHO, C02H and C1-C4 alkyl carboxylates.

A method of providing a cooling effect to the mouth or skin by applying thereto a product comprising a compound according to claim 1.


Documents:

1756-CHENP-2006 AMENDED PAGES OF SPECIFICATION 11-07-2011.pdf

1756-CHENP-2006 AMENDED CLAIMS 11-07-2011.pdf

1756-CHENP-2006 CORREPONDENCE OTHERS 24-11-2011.pdf

1756-CHENP-2006 CORRESPONDENCE OTHERS 21-02-2011.pdf

1756-chenp-2006 form-1 11-07-2011.pdf

1756-chenp-2006 form-3 11-07-2011.pdf

1756-CHENP-2006 OTHER PATENT DOCUMENT 11-07-2011.pdf

1756-CHENP-2006 POWER OF ATTORNEY 11-07-2011.pdf

1756-CHENP-2006 AMENDED PAGES OF SPECIFICATION 12-12-2011.pdf

1756-CHENP-2006 AMENDED CLAIMS 12-12-2011.pdf

1756-CHENP-2006 CORRESPONDENCE OTHERS 12-12-2011.pdf

1756-CHENP-2006 EXAMINATION REPORT REPLY RECEIVED 11-07-2011.pdf

1756-CHENP-2006 CORRESPONDENCE OTHERS.pdf

1756-CHENP-2006 CORRESPONDENCE PO.pdf

1756-CHENP-2006 FORM-18.pdf

1756-chenp-2006-abstract.image.jpg

1756-chenp-2006-abstract.pdf

1756-chenp-2006-claims.pdf

1756-chenp-2006-correspondnece-others.pdf

1756-chenp-2006-description(complete).pdf

1756-chenp-2006-form 1.pdf

1756-chenp-2006-form 26.pdf

1756-chenp-2006-form 3.pdf

1756-chenp-2006-form 5.pdf

1756-chenp-2006-pct.pdf


Patent Number 250921
Indian Patent Application Number 1756/CHENP/2006
PG Journal Number 06/2012
Publication Date 10-Feb-2012
Grant Date 07-Feb-2012
Date of Filing 19-May-2006
Name of Patentee GIVAUDAN SA
Applicant Address Chemin de la Parfumerie 5, CH-1214 Vernier
Inventors:
# Inventor's Name Inventor's Address
1 GALOPIN, Christophe 7232 Rolling Meadows Drive, West Chester, Ohio 45069.
2 KRAWEC, Pablo, Victor 11311 Ironwood Court, Cincinnati, Ohio 45249
3 SLACK, Jay, Patrick 9925 Stonebridge Drive, Loveland, Ohio 45140
4 TIGANI, Lori 3633 Bellecrest Ave, Cincinnati, Ohio 45208
PCT International Classification Number C07C233/57,A61K7/16
PCT International Application Number PCT/CH2004/000646
PCT International Filing date 2004-10-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/523,977 2003-11-21 U.S.A.