WO 2017/066787 Al 20 April 2017 (20.04.2017) P O P C T

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WO 2017/066787 Al 20 April 2017 (20.04.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/066787 Al 20 April 2017 (20.04.2017) P O P C T (51) International Patent Classification: A. [US/US]; 46262 SW 97th Terrace, Gainesville, FL A61P 23/02 (2006.01) A61M 5/14 (2006.01) 32608 (US). OSTROV, David [US/US]; 401 SW 43rd A61K 47/26 (2006.01) Terrace, Gainesville, FL 32607 (US). CASTLEMAN, William, L. [US/US]; 4330 SW 77th St., Gainesville, FL (21) International Application Number: 32608 (US). PCT/US2016/057393 (74) Agent: MCCARTY, Catherine, M.; Lando & Anastasi, (22) International Filing Date: LLP, Riverfront Office Park, One Main Street, Suite 1100, 17 October 2016 (17.10.201 6) Cambridge, MA 02142 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (30) Priority Data: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, 62/243,012 17 October 2015 (17. 10.2015) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (72) Inventors; and HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (71) Applicants : LEBEDYEVA, Iryna, O. [UA/US]; 1602 KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, Winter St, Augusta, GA 30904 (US). OLIFERENKO, Al¬ MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, exander, A. [US/US]; 2251 NW 41st Street, Suite F, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, Gainesville, FL 32606 (US). NEUBERT, John, K. SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, [US/US]; 8426 SW 14th Lane, Gainesville, FL 32607 TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (US). ALTSCHULER, Gary, I. [US/US]; 4146 SW 96th ZW. Drive, Gainesville, FL 32608 (US). HROMAS, Robert, [Continued on nextpage] (54) Title: COMPOUNDS, COMPOSITIONS, AND METHODS OF MAKING AND USING THE SAME (57) Abstract: Compounds are provided according to Formula (I), and hydrates thereof, and compositions thereof; and methods of using and making the same. 2 Compounds of the present invention are contemplated useful for suppressing pain 20 during cosmetic, medical, and dental pro cedures. In another aspect, provided herein S is a composition comprising the compound of Formula (I) or hydrate thereof and a 0 pharmaceutically acceptable carrier. 0 Baseline A S % AA 1° BA BS 1% PA PS Ί % MA ' (naive) Treatment Thermal hindpaw latency following local anaesthetic Injection, One percent solutions were injected into the hindpaw of animals and withdrawal latency to a thermal stimulus was recorded 0 minutes post-injection. All caine salts (N=10 animals/group) except priiocaine saccharinate produced a significant increase in latency time as compared to non-injected naive animals, indicating that the caine salts were effective in inhibiting pain, F G. 1 H+ B (I) w o 2017/066787 A i III II II 11 III 11 1II III Hill lllll 111 I Illlll 1 llll 11llll (84) Designated States (unless otherwise indicated, for every Published: Mnd of regional protection available): ARIPO (BW, GH, — with international search report (Art. 21(3)) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, — before the expiration of the time limit for amending the TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, claims and to be republished in the event of receipt of DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, amendments (Rule 48.2(h)) LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). COMPOUNDS, COMPOSITIONS, AND METHODS OF MAKING AND USING THE SAME Claim of Priority This application claims priority from U.S.S.N. 62/243,012 filed October 17, 2015, which is incorporated herein by reference in its entirety. Background of the Invention Local anesthesia is essential for suppressing pain during cosmetic, medical, or dental procedures such as, e.g., surgery, e.g., oral surgery. However, patients often perceive the receipt of intraoral local anesthesia as the most painful and sometimes the only objectionable part of these procedures and may therefore avoid obtaining necessary medical or dental care. For example, a significant number of patients detect an unpleasant bitter and metallic taste following intraoral injections of compositions comprising commonly used local anesthetics, e.g., lidocaine hydrochloride, which causes them to experience great anxiety during the medical or dental procedure. Further, hydrochloride salts that are commonly used in compositions formulated for local anesthesia, e.g., compositions comprising lidocaine hydrochloride and epinephrine hydrochloride, are acidic and can consequently cause additional pain and tissue damage. As a result, there exists a need for compositions comprising local anesthetics that possess a higher pH and/or do not possess objectionable tastes. Compounds, compositions, and methods of making and using the same are directed toward this end. Summary of the Invention The present invention includes compounds and compositions thereof and also contemplates their methods of making and use as local anesthetics in cosmetic, medical, and dental procedures. In one aspect, the present invention provides a compound of Formula (I) or hydrate thereof: or hydrate thereof, wherein: B is a sweetener (e.g., saccharinate, acesulfamate, glycyrrherinate, mono-glycyrrhizinate, tri-glycyrrhizinate, vanillate, ferrulate, glycinate, cinnamate, enoxolone, cyclamate, steviol, aspartamate, di-glycyrrhinizinate, neotame); X is -C(0)0-, -OC(O)-, - A A A A C(0)NR -, or -NR C(0)-, or -CH(OR )-, wherein R is hydrogen, alkyl (e.g., Ci-C 6 alkyl), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl is independently substituted with 0-5 occurrences of Z 1 R ; R is hydrogen, alkyl (e.g., Ci-C 6 alkyl), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl is independently substituted with 0-5 occurrences of RZ; each of R3 and R4 is independently hydrogen, alkyl (e.g., Ci-C 6 alkyl), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, and heteroaryl is independently substituted with 0-5 occurrences of R ; A is: a wherein: n is 1-5; each of R and R is independently hydrogen, alkyl (e.g., Ci-C6 alkyl), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl is independently substituted with 0-5 occurrences of , or if n is 1, R or R and R or R , together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of Rz ; and each of R5, R6, R7, and R is independently hydrogen, alkyl (e.g., Ci-C 6 alkyl), Ci-C 6 alkoxy, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocycylalkyl, aryl, aralkyl, heteroaralkyl, and heteroaryl is independently substituted with 0-5 occurrences of R ; z Z 1 Z 1 Z2 and R is halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, -NHR , -NR R , - C(0)R , -C(0)R , -C(0)NR^R , -NR^C(0)R , -OR , -OR , cyano, or nitro, wherein R Z2 is hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, hydroxyl, cyano, or nitro and R is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R ; provided that the compound or hydrate thereof is not lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, prilocaine saccharinate, prilocaine acesulfamate, procaine saccharinate, cinchocaine saccharinate, or benzocaine saccharinate. In some embodiments, the compound is a compound of Formula (I-A): provided that the compound is not lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, prilocaine saccharinate, prilocaine acesulfamate, procaine saccharinate, or cinchocaine saccharinate. In some embodiments, the compound is a compound of Formula (I-B): provided that the compound is not benzocaine saccharinate. In some embodiments, B is saccharinate, acesulfamate, glycyrrherinate, mono- glycyrrhizinate, tri-glycyrrhizinate, vanillate, ferrulate, glycinate, cinnamate, enoxolone, cyclamate, steviol, aspartamate, di-glycyrrhinizinate, neotame In some embodiments, the hydrate is a monohydrate. In some embodiments, X is - C(0)NR A- or -NRAC(0)-. In some embodiments, B is saccharinate or acesulfamate and R2 and 3 2a 2 R are not -CH 2CH3. In some embodiments, each of R and R is independently hydrogen. In some embodiments, R and R2b are hydrogen. In some embodiments, each of R2 and R2b is independently hydrogen or alkyl (e.g., Ci-C 6 alkyl) independently substituted with 0-5 Z 3 4 occurrences of and n is 1. In some embodiments, each of R and R is independently hydrogen or alkyl (e.g., Ci-C6 alkyl) independently substituted with 0-5 occurrences of R . some embodiments, each of R and R4 is independently hydrogen or -C¾. In some embodiments, if n is 1, R or R4 and R2a or R2 , together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R".Z In some embodiments, at least one of R5, R6, R7, and R8 is not hydrogen.
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