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(12) Patent Application Publication (10) Pub. No.: US 2017/0096418 A1 Patron Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0096418 A1 Patron Et Al US 201700 96418A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0096418 A1 Patron et al. (43) Pub. Date: Apr. 6, 2017 (54) COMPOUNDS USEFUL AS MODULATORS Related U.S. Application Data OF TRPM8 (60) Provisional application No. 62/236,080, filed on Oct. (71) Applicant: Senomyx, Inc., San Diego, CA (US) 1, 2015. (72) Inventors: Andrew P. Patron, San Marcos, CA Publication Classification (US); Alain Noncovich, San Diego, CA (51) Int. Cl. (US); Jane Ung, San Diego, CA (US); C07D 409/2 (2006.01) Timothy Davis, Santee, CA (US); A6IR 9/00 (2006.01) Joseph R. Fotsing, San Diego, CA A63L/455 (2006.01) (US); Chad Priest, Leucadia, CA (US); (52) U.S. Cl. Catherine Tachdjian, San Diego, CA CPC ........ C07D 409/12 (2013.01); A61K 31/4155 (US) (2013.01); A61K 9/0014 (2013.01) (21) Appl. No.: 15/282,432 (57) ABSTRACT The present disclosure relates to compounds which are (22) Filed: Sep. 30, 2016 useful as cooling sensation compounds. US 2017/0096418 A1 Apr. 6, 2017 COMPOUNDS USEFUL AS MODULATORS -continued OF TRPM8 RELATED APPLICATIONS 0001. This application claims the benefit of U.S. Provi sional Application No. 62/236,080, filed Oct. 1, 2015, which is incorporated herein by reference in its entirety. BACKGROUND 0002 Field 0003. The present invention relates to compounds useful as cooling agents. 0004 Background Description 0005 Modulators of the Melastatin Transient Receptor or a salt or solvate thereof. Potential Channel 8 (TRPM8) are known to have a cooling effect. TRPM8 is a channel involved in the chemesthetic O008) In some embodiments the compound can have the sensation, such as cool to cold temperatures as well as the Structure sensation of known cooling agents. Such as Menthol and Icilin. However, many of the currently known TRPM8 modulators have deficiencies with regard to strength and/or duration of effect, skin and/or mucosa irritation, odor, taste, solubility, and/or toxicity. SUMMARY 0006. The present disclosure relates to compounds useful as cooling agents. In some embodiments, the compounds are modulators of TRPM8. Some embodiments include com pounds, ingestible compositions, personal care products, and or a salt thereof. pharmaceutical compositions, and the use and preparation 0009 In some embodiments the compound has the struc thereof. In particular, Some embodiments, relate to specific ture pyrazolyl and thiophenyl Substituted acetamide compounds as disclosed herein. 0007 Some embodiments include a compound selected from F Orrls -/ or a salt thereof. 0010. In some embodiments the compound can have the Structure O Nulls N S MeO % f V HN or a salt thereof. O011 In some embodiments the compound can have the Structure US 2017/0096418 A1 Apr. 6, 2017 TABLE 1. O Compound S-ty Number Structure 1,N / 101 O ouls N S or a salt thereof. 2 / 0012. In some embodiments the compound can have the N Structure HN\, f O 102 O oul S ouls N e CO) / F N 2 f 1, / \ A / HN or a salt thereof. 103 O 0013. In some embodiments, a composition is provided, comprising any one of the above compounds and at least one carrier. sus N S 0014. In some embodiments, the composition can be an ingestible composition or personal care product. MeO N% f 0015. In some embodiments, the composition can be a V food or beverage. HN 0016. In some embodiments, the composition can be a topical personal care product. 104 O 0017. In some embodiments, the composition can be in form of a Solid, semi-solid, plaster, Solution, Suspension, N S lotion, cream, foam, gel, paste, or emulsion. 0018. In some embodiments, a compound disclosed 2 7 herein in the composition can be in a concentration ranging N from about 0.0001 ppm to 100,000 ppm. HN\, f 0019. In some embodiments, the compound disclosed herein in the composition can be in a concentration ranging from about 1 ppm to 500 ppm. 105 O 0020. In some embodiments, the composition can be a textile product or a packaging material. Nulls N S 0021. Some embodiments include a method of modulat ing transient receptor potential channel melastatin member 8 2 / (TRPM8) comprising contacting the receptor with a com N pound of the present disclosure, or a salt or solvate thereof. HN\, f In some embodiments, the compound can be a TRPM8 receptor agonist. 0022. Some embodiments include a method of modulat ing the cooling sensation of a composition comprising 0025. In some embodiments, the compound can have the combining the composition with a compound of the present structure of Compound 101, or a salt thereof: disclosure, or a salt or solvate thereof, to form a modified composition. 0023. Some embodiments include a method of inducing a cooling sensation in a human or animal comprising con tacting the human or animal with a compound of the present disclosure, or a salt or solvate thereof. DETAILED DESCRIPTION 0024. Some embodiments provide a compound selected from the compounds listed in Table 1, or a salt thereof. US 2017/0096418 A1 Apr. 6, 2017 0026. In some embodiments, the compound can have the 0034. In some embodiments, the composition comprising structure of Compound 102, or a salt thereof: a compound selected from Compounds 101-105 can be a topical personal care product. 0035. In some embodiments, the composition comprising a compound selected from Compounds 101-105 can be in form of a Solid, semi-solid, plaster, Solution, Suspension, lotion, cream, foam, gel, paste, emulsion, or a combination thereof. 0036. In some embodiments, the composition can com prise a compound selected from Compounds 101-105 in a N concentration ranging from about 0.0001 ppm to 100,000 ppm. 0037. In some embodiments, the composition can com 0027. In some embodiments, the compound can have the prise a compound selected from Compounds 101-105 in a structure of Compound 103, or a salt thereof: concentration ranging from about 1 ppm to 500 ppm. 0038. In some embodiments, the composition comprising a compound selected from Compounds 101-105 can be a textile product or a packaging material. 0039. In some embodiments, a method of modulating transient receptor potential channel melastatin member 8 (TRPM8) is provided, comprising contacting the receptor with a compound comprising a compound selected from MeO Compounds 101-105, or a salt or solvate thereof. In some A / embodiments, the method can be in vitro or in vivo. In some embodiments of the method of modulating TRPM8, the compound comprising a compound selected from Com 0028. In some embodiments, the compound can have the pounds 101-105 can be a TRPM8 receptor agonist. structure of Compound 104, or a salt thereof: 0040. In some embodiments, a method of modulating the cooling sensation of a composition is provided, comprising combining the composition with a compound selected from Compounds 101-105, or a salt or solvate thereof, to form a modified composition. 0041. In some embodiments, a method of inducing a cooling sensation in a human or animal is provided, com prising contacting the human or animal with a compound selected from Compounds 101-105, or a salt or solvate A / thereof. DEFINITIONS 0029. In some embodiments, the compound can have the structure of Compound 105, or a salt thereof: 0042 Unless defined otherwise, all technical and scien tific terms used herein have the same meaning as is com monly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. 0043 Compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise A / indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic 0030. In some embodiments, a composition is provided, forms. In addition, Some of the compounds disclosed herein comprising any one Compounds 101-105 and at least one may form Solvates with water (i.e., hydrates) or common carrier. organic solvents. Unless otherwise indicated, such Solvates 0031. In some embodiments, a personal product is pro are included in the scope of the compounds disclosed herein. vided comprising a compound selected from Compounds 0044) Isotopes may be present in the compounds 101-105, or a salt thereof. described. Each chemical element as represented in a com pound structure may include any isotope of said element. 0032. In some embodiments, the composition comprising For example, in a compound structure a hydrogenatom may a compound selected from Compounds 101-105 can be an be explicitly disclosed or understood to be present in the ingestible composition or a personal care composition. compound. At any position of the compound that a hydrogen 0033. In some embodiments, the composition comprising atom may be present, the hydrogen atom can be any isotope a compound selected from Compounds 101-105 can be an of hydrogen, including but not limited to hydrogen-1 (pro ingestible composition that is a food or beverage. tium) and hydrogen-2 (deuterium). Thus, reference herein to US 2017/0096418 A1 Apr. 6, 2017 a compound encompasses all potential isotopic forms unless fruit or vegetable juices, vinegar, marinades, beer, wine, the context clearly dictates otherwise. natural water/fat emulsions such as milk or condensed milk, 0045. The skilled artisan will recognize that some struc edible oils and shortenings, fatty acids and their alkyl esters, tures described herein may be resonance forms or tautomers low molecular weight oligomers of propylene glycol, glyc of compounds that may be fairly represented by other eryl esters of fatty acids, and dispersions or emulsions of chemical structures, even when kinetically; the artisan rec Such hydrophobic Substances in aqueous media, salts such as ognizes that Such structures may only represent a very Small Sodium chloride, wheat flours, solvents such as ethanol, portion of a sample of Such compound(s).
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