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US 20190177308A9 ( 19 ) United States ( 10 ) Pub . No. : US 2019 /0177308 A9 ( 12 ) Patent Application Publication ( 48 ) Pub . Date : Jun . 13 , 2019 Patron et al. CORRECTED PUBLICATION ( 54 ) COMPOUNDS USEFUL AS MODULATORS Prior Publication Data OF TRPM8 ( 15 ) Correction of US 2018 /0273517 A1 Sep . 27 , 2018 See Claims 2 - 9 , 11 , 14 , 15 , 17 , and 18 . (71 ) Applicant: Senomyx , Inc ., San Diego , CA (US ) ( 65 ) US 2018 /0273517 A1 Sep . 27 , 2018 ( 72 ) Inventors : Andrew P . Patron , San Diego , CA Related U . S . Application Data ( US ) ; Alain Noncovich , San Diego , CA (60 ) Provisional application No. 62 / 236 , 080 , filed on Oct . (US ) ; Timothy Davis , San Diego , CA 1 , 2015 . (US ) ; Chad Priest , San Diego , CA Publication Classification (US ) ; Joseph R . Fotsing, San Diego , (51 ) Int. Ci. C07D 409 / 12 ( 2006 .01 ) CA (US ) ; Jane Ung, San Diego , CA A23L 33/ 10 (2006 . 01 ) (US ) ; Catherine Tachdjian , San Diego , A23L 2 / 52 ( 2006 .01 ) CA (US ) B650 81/ 18 ( 2006 .01 ) B65D 65 / 38 (2006 .01 ) (52 ) U . S . CI. (21 ) Appl . No. : 15 / 764, 204 CPC .. .. C07D 409 / 12 ( 2013 . 01 ) ; A23L 33 / 10 ( 2016 . 08 ) ; A23V 2002/ 00 ( 2013 . 01) ; B65D ( 22 ) PCT Filed : Sep . 21, 2016 81/ 18 ( 2013 .01 ) ; B65D 65/ 38 ( 2013 .01 ) ; A23L PCT/ US2016 / 052777 2 /52 ( 2013 .01 ) ( 86 ) PCT No. : ( 57 ) ABSTRACT $ 371 ( c ) ( 1 ) , The present disclosure relates to compounds which are ( 2 ) Date : Mar. 28 , 2018 useful as cooling sensation compounds. US 2019 /0177308 A9 Jun . 13 , 2019 COMPOUNDS USEFUL AS MODULATORS -continued OF TRPM8 RELATED APPLICATIONS [0001 ] This application claims the benefit of U . S . Provi and sional Application No . 62 / 236 ,080 , filed Oct . 1 , 2015 , which is incorporated herein by reference in its entirety . HN BACKGROUND conto Field [0002 ] The present invention relates to compounds useful as cooling agents . Background Description [0003 ] Modulators of the Melastatin Transient Receptor Potential Channel 8 mums) are known to have a cooling or a salt or solvate thereof. effect . TRPM8 is a channel involved in the chemesthetic [0006 ] In some embodiments the compound can have the sensation , such as cool to cold temperatures as well as the sensation of known cooling agents , such as Menthol and structure 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 [ 0004 ] The present disclosure relates to compounds useful as cooling agents . In some embodiments , the compounds are HN modulators of TRPM8. Some embodiments include com pounds, ingestible compositions , personal care products , and pharmaceutical compositions, and the use and preparation or a salt thereof. thereof . In particular , some embodiments, relate to specific pyrazolyl and thiophenyl substituted acetamide compounds [0007 ] In some embodiments the compound has the struc as disclosed herein . ture [ 0005 ] Some embodiments include a compound selected from HN zg or a salt thereof. [0008 ] In some embodiments the compound can have the structure Meo Me01 ? ! or a salt thereof. US 2019 /0177308 A9 Jun . 13 , 2019 [0009 ] In some embodiments the compound can have the DETAILED DESCRIPTION structure [0022 ] Some embodiments provide a compound selected from the compounds listed in Table 1 , or a salt thereof. TABLE 1 Compound Number Structure 101 or a salt thereof. [0010 ] In some embodiments the compound can have the AT structure HN 102 N 103 or a salt thereof. [0011 ] In some embodiments , a composition is provided , comprising any one of the above compounds and at least one carrier . Meo [0012 ] In some embodiments , the composition can be an ingestible composition or personal care product . [ 0013] In some embodiments , the composition can be a food or beverage . 104104 [0014 ] In some embodiments , the composition can be a topical personal care product . [0015 ] In some embodiments , the composition can be in form of a solid , semi- solid , plaster, solution , suspension , lotion , cream , foam , gel , paste , or emulsion . [ 0016 ] In some embodiments , a compound disclosed HN herein in the composition can in a concentration ranging 105 from about 0 .0001 ppm to 100 ,000 ppm . 10017 ] In some embodiments , the compound disclosed herein in the position can in a concentration ranging from about 1 ppm to 500 ppm . [ 0018 ] In some embodiments , the composition can be a textile product or a packaging material. HN [0019 ] Some embodiments include a method of modulat ing transient receptor potential channelmelastatin member 8 ( TRPM8 ) comprising contacting the receptor with a com [0023 ]. In some embodiments , the compound can have the pound of the present disclosure , or a salt or solvate thereof. In some embodiments, the compound can be a TRPM8 structure of Compound 101, or a salt thereof: receptor agonist. [ 0020 ] Some embodiments include a method of modulat ing the cooling sensation of a composition comprising combining the composition with a compound of the present disclosure , or a salt or solvate thereof, to form a modified composition . [ 0021 ] Some embodiments include a method of inducing a cooling sensation in a human or animal comprising con HN tacting the human or animal with a compound of the present disclosure , or a salt or solvate thereof. US 2019 /0177308 A9 Jun . 13 , 2019 [0024 ] In some embodiments , the compound can have the [0032 ] 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 . [0033 ] 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. [0034 ]. In some embodiments , the composition can com prise a compound selected from Compounds 101 - 105 in a concentration ranging from about 0 .0001 ppm to 100 ,000 HN ppm . 0035 ] In some embodiments , the composition can com [0025 ] 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 . 10036 ] In some embodiments , the composition comprising a compound selected from Compounds 101 - 105 can be a textile product or a packaging material. 10037 ] 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 HN embodiments , the method can be in vitro or in vivo . In some oyo embodiments of the method of modulating TRPM8 , the compound comprising a compound selected from Com [0026 ] 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: [ 0038 ) 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 . 10039 ] 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 HN thereof. Definitions 00271 In some embodiments , the compound can have the [ 0040 ] Unless defined otherwise , all technical and scien structure of Compound 105 , or a salt thereof: 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 . [0041 ] Compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise HN indicated , all such forms are included in the scope of the compounds disclosed herein including any polymorphic [0028 ] 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 [0029 ] 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 0042 Isotopes may be present in the compounds described . Each chemical element as represented in a com 101 - 105 , or a salt thereof. pound structure may include any isotope of said element. [0030 ] In some embodiments , the composition comprising For example , in a compound structure a hydrogen atom 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 [ 0031 ] In some embodiments , the composition comprising atom may be present, the hydrogen atom can be any isotope a compound selected