# US 2024/0197604 A1 · Compounds with cooling sensation properties

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- Number: US 2024/0197604 A1
- Document ID: US20240197604A1
- Status: Published application
- Kind: A1
- Application number: 18/286,525
- Filed: 2022-04-21
- Published: 2024-06-20
- Earliest claimed: 2021-04-21
- Assignees: Givaudan SA
- Applicants: Givaudan SA
- Inventors: Corinne BAUMGARTNER; Nicolas COCITO ARMANINO; Thierry GRANIER
- Web page: https://patentgrep.com/patent/US20240197604A1

## CPC

- A61K 8/4946: {Imidazoles or their condensed derivatives, e.g. benzimidazoles}
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61P 27/00: Drugs for disorders of the senses
- A61Q 11/00: Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 2800/244: Endothermic; Cooling; Cooling sensation
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are TRPM8 modulators for achieving a cooling effect on skin and mucousa.

## Claims

### Claim 1

A method of modulating of transient receptor potential channel melastatin member 8 (TRPM8) comprising bringing the receptor into contact with an oxalate of a compound of formula (I)
wherein
R1 is selected from methyl, —CH2OH, and —C(O)OH,
R2 is selected from methyl, ethyl, and —CH2—OH,
R3 is selected from hydrogen and —OH, and
X is selected from CH2, S,>S═O, and >SO2.

### Claim 2 (depends on 1)

A non-medical method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with an oxalate of a compound of formula (I) as defined in claim 1.

### Claim 3 (depends on 1)

A consumer product comprising an oxalate as defined in claim 1.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising an oxalate as defined in claim 1.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

A medicament comprising the oxalate as defined in claim 1.

### Claim 7

A composition for inducing a cooling sensation wherein the composition comprises an oxalate of a compound of formula (I)
wherein
R1 is selected from methyl, —CH2OH, and —C(O)OH,
R2 is selected from methyl, ethyl, and —CH2—OH,
R3 is selected from hydrogen and —OH, and
X is selected from CH2, S, >S═O, and >SO2.

### Claim 8 (depends on 7)

The composition according to claim 7 comprising a further cooling compound.

### Claim 9 (depends on 8)

The composition according to claim 8, wherein the further cooling compound is selected from the group consisting of menthol, menthone, p-menthanecarboxamides, N-2,3-trimethyl-2-isopropyl-butanamide, menthyl lactate, menthone glycerol acetal, 3-(1-menthoxy)-propane-1,2-diol, p-menthane-3,8-diol, isopulegol, monomenthyl succinate, monomenthyl glutarate, o-menthylglycerol, menthyl N,N-dimethylsuccinamate, 2-(sec-butyl)cyclohexan-1-one, N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, 2-(4-ethylphenoxy)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 3-(benzo[d][1,3]dioxol-5-yl)-N,N- diphenylacrylamide, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-ethoxypropyl)-2-methoxyphenol, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol, N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and mixtures thereof.

### Claim 10

A method of purification by crystallization of a compound of formula (I), comprising the steps:
a) admixing a compound of formula (I) with oxalic acid in the presence of an alcoholic solvent,
b) followed by the addition of an anti-solvent, and
c) separation of the oxalate of the compound of formula (I)

### Claim 11

An oxalate of a compound of formula (I)
wherein
R1 is selected from methyl, —CH2OH, and —C(O)OH,
R2 is selected from methyl, ethyl, and —CH2—OH,
R3 is selected from hydrogen and —OH, and
X is selected from CH2, S, >S═O, and >SO2.

### Claim 12 (depends on 11)

The oxalate according to claim 11 selected from an oxalate of at least one of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one;
1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid;
2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one;
1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one; 4-(2-(1-(2- (methylsulfinyl)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid; 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one; 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one; or 4-(2-(1-(2-(methylsulfonyl)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid.