COMPOUNDS, COMPOSITIONS, AND METHODS OF MAKING AND USING THE SAME

20180297966 · 2018-10-18

Inventors

Cpc classification

International classification

Abstract

Compounds are provided according to Formula (I), and hydrates thereof, and compositions thereof; and methods of using and making the same. Compounds of the present invention are contemplated useful for suppressing pain during cosmetic, medical, and dental procedures. In another aspect, provided herein is a composition comprising the compound of Formula (I) or hydrate thereof and a pharmaceutically acceptable carrier.

Claims

1. A compound of Formula (I): ##STR00074## or hydrate thereof, wherein: B is a sweetener; X is C(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, 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 R.sup.Z; R.sup.1 is hydrogen, 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 R.sup.Z; each of R.sup.3 and R.sup.4 is independently hydrogen, 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.sup.Z; A is: ##STR00075## wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, 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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl, C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NR.sup.Z1R.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1; 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.

2. The compound of claim 1 or hydrate thereof, wherein the compound is a compound of Formula (I-A): ##STR00076## provided that the compound is not lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, prilocaine saccharinate, prilocaine acesulfamate, procaine saccharinate, or cinchocaine saccharinate.

3. The compound of claim 1 or hydrate thereof, wherein the compound is a compound of Formula (I-B): ##STR00077## provided that the compound is not benzocaine saccharinate.

4. The compound of claim 1 or hydrate thereof, wherein B is saccharinate, acesulfamate, glycyrrherinate, mono-glycyrrhizinate, tri-glycyrrhizinate, vanillate, ferrulate, glycinate, cinnamate, enoxolone, cyclamate, steviol, aspartamate, di-glycyrrhinizinate, neotame

5. The hydrate of claim 1, wherein the hydrate is a monohydrate.

6. The compound of claim 1, wherein X is C(O)NR.sup.A or NR.sup.AC(O).

7. The compound of claim 1 or hydrate thereof, wherein B is saccharinate or acesulfamate and R.sup.2 and R.sup.3 are not CH.sub.2CH.sub.3.

8. The compound of claim 1 or hydrate thereof, wherein each of R.sup.2a and R.sup.2b is independently hydrogen.

9. The compound of claim 1 or hydrate thereof, wherein R.sup.2a and R.sup.2b are hydrogen.

10. The compound of claim 1 or hydrate thereof, wherein each of R.sup.2a and R.sup.2b is independently hydrogen or alkyl independently substituted with 0-5 occurrences of R.sup.Z and n is 1.

11. The compound of claim 1 or hydrate thereof, wherein each of R.sup.3 and R.sup.4 is independently hydrogen or alkyl independently substituted with 0-5 occurrences of R.sup.Z.

12. The compound of claim 1 or hydrate thereof, wherein each of R.sup.3 and R.sup.4 is independently hydrogen or CH.sub.3.

13. The compound of claim 1 or hydrate thereof, wherein if n is 1, R.sup.3 or R.sup.4 and R.sup.2a or R.sup.2b together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z.

14. The compound of claim 3 or hydrate thereof, wherein at least one of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is not hydrogen.

15. The compound of claim 3 or hydrate thereof, wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen.

16. The compound of claim 3 or hydrate thereof, wherein R.sup.3 and R.sup.4 are hydrogen and X is C(O)O.

17. The compound of claim 1 or hydrate thereof, wherein the compound is a compound of Formula (I-C), ##STR00078## wherein C is a 5-10 membered ring substituted with 0-5 occurrences of R.sup.Z; provided that the compound or hydrates thereof is not: lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, cinchocaine saccharinate, prilocaine saccharinate, or prilocaine acesulfamate.

18. The compound of claim 17 or hydrate thereof, wherein C is, ##STR00079## wherein each of R.sup.B, R.sup.C, R.sup.D, R.sup.E, or R.sup.F is independently hydrogen or C.sub.1-C.sub.6 alkyl.

19. The compound of claim 17 or hydrate thereof, wherein R.sup.3 is n-butyl and R.sup.2a and R.sup.4, together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z.

20. The compound of claim 17 or hydrate thereof, wherein R.sup.3 is methyl and R.sup.2a and R.sup.4, together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z.

21. The compound of claim 17 or hydrate thereof, wherein R.sup.2a is methyl and R.sup.4 is n-propyl.

22. The compound of claim 1 or hydrate thereof, wherein the salt is represented by Formula (I-D): ##STR00080## wherein R.sup.9 is hydrogen or C.sub.1-C.sub.6 alkyl and R.sup.10 is hydrogen or C.sub.1-C.sub.6 alkoxy; provided that the compound is not procaine saccharinate.

23. The compound of claim 22 or hydrate thereof, wherein R.sup.3 and R.sup.4 are CH.sub.2CH.sub.3.

24. The compound of claim 22 or hydrate thereof, wherein n is 2.

25. The compound of claim 22, wherein R.sup.3 and R.sup.4 are CH.sub.2CH.sub.3, R.sup.9 is hydrogen or C.sub.1-C.sub.6 alkyl, and R.sup.10 is hydrogen or C.sub.1-C.sub.6 alkoxy.

26. The compound of claim 1 or hydrate thereof, wherein the salt is represented by Formula (I-E): ##STR00081## wherein m is 1, 2, 3, or 4 and Y is NR.sup.AC(O) or C(O)NR.sup.A.

27. The compound of claim 26 or hydrate thereof, wherein X is C(O)NR.sup.A1 and Y is NR.sup.A1C(O).

28. The compound of claim 26 or hydrate thereof, wherein R.sup.1 is aralkyl.

29. The compound of claim 26 or hydrate thereof, wherein R.sup.2a and R.sup.2b are hydrogen.

30. The compound of claim 26 or hydrate thereof, wherein R.sup.2a and R.sup.2b are hydrogen and R is aralkyl.

31. The compound of claim 26 or hydrate thereof, wherein n is 1 and m is 1.

32. The compound of claim 1 or hydrate thereof, wherein the compound is lidocaine glycyrrherinate, lidocaine mono-glycyrrhizinate, lidocaine tri-glycyrrhizinate, lidocaine vanillate, lidocaine ferrulate, lidocaine glycinate, lidocaine cinnamate, lidocaine enoxolone, lidocaine cyclamate, lidocaine steviol, lidocaine aspartamate, lidocaine di-glycyrrhinizinate, lidocaine neotame, tetracaine saccharinate, tetracaine acesulfamate, tetracaine glycyrrherinate, tetracaine mono-glycyrrhizinate, tetracaine tri-glycyrrhizinate, tetracaine vanillate, tetracaine ferrulate, tetracaine glycinate, tetracaine cinnamate, tetracaine enoxolone, tetracaine cyclamate, tetracaine steviol, tetracaine aspartamate, tetracaine di-glycyrrhinizinate, tetracaine neotame, bupivacaine glycyrrherinate, bupivacaine mono-glycyrrhizinate, bupivacaine tri-glycyrrhizinate, bupivacaine vanillate, bupivacaine ferrulate, bupivacaine glycinate, bupivacaine cinnamate, bupivacaine enoxolone, bupivacaine cyclamate, bupivacaine steviol, bupivacaine aspartamate, bupivacaine di-glycyrrhinizinate, bupivacaine neotame, mepivacaine saccharinate, mepivacaine acesulfamate, mepivacaine glycyrrherinate, mepivacaine mono-glycyrrhizinate, mepivacaine tri-glycyrrhizinate, mepivacaine vanillate, mepivacaine ferrulate, mepivacaine glycinate, mepivacaine cinnamate, mepivacaine enoxolone, mepivacaine cyclamate, mepivacaine steviol, mepivacaine aspartamate, mepivacaine di-glycyrrhinizinate, mepivacaine neotame, articaine saccharinate, articaine acesulfamate, articaine glycyrrherinate, articaine mono-glycyrrhizinate, articaine tri-glycyrrhizinate, articaine vanillate, articaine ferrulate, articaine glycinate, articaine cinnamate, articaine enoxolone, articaine cyclamate, articaine steviol, articaine aspartamate, articaine di-glycyrrhinizinate, articaine neotame, prilocaine glycyrrherinate, prilocaine mono-glycyrrhizinate, prilocaine tri-glycyrrhizinate, prilocaine vanillate, prilocaine ferrulate, prilocaine glycinate, prilocaine cinnamate, prilocaine enoxolone, prilocaine cyclamate, prilocaine steviol, prilocaine aspartamate, prilocaine di-glycyrrhinizinate, prilocaine neotame, procaine acesulfamate, procaine glycyrrherinate, procaine mono-glycyrrhizinate, procaine tri-glycyrrhizinate, procaine vanillate, procaine ferrulate, procaine glycinate, procaine cinnamate, procaine enoxolone, procaine cyclamate, procaine steviol, procaine aspartamate, procaine di-glycyrrhinizinate, procaine neotame, oxybuprocaine saccharinate, oxybuprocaine acesulfamate, oxybuprocaine glycyrrherinate, oxybuprocaine mono-glycyrrhizinate, oxybuprocaine tri-glycyrrhizinate, oxybuprocaine vanillate, oxybuprocaine ferrulate, oxybuprocaine glycinate, oxybuprocaine cinnamate, oxybuprocaine enoxolone, oxybuprocaine cyclamate, oxybuprocaine steviol, oxybuprocaine aspartamate, oxybuprocaine di-glycyrrhinizinate, oxybuprocaine neotame, ropivacaine saccharinate, ropivacaine acesulfamate, ropivacaine glycyrrherinate, ropivacaine mono-glycyrrhizinate, ropivacaine tri-glycyrrhizinate, ropivacaine vanillate, ropivacaine ferrulate, ropivacaine glycinate, ropivacaine cinnamate, ropivacaine enoxolone, ropivacaine cyclamate, ropivacaine steviol, ropivacaine aspartamate, ropivacaine di-glycyrrhinizinate, ropivacaine neotame, cinchocaine acesulfamate, cinchocaine glycyrrherinate, cinchocaine mono-glycyrrhizinate, cinchocaine tri-glycyrrhizinate, cinchocaine vanillate, cinchocaine ferrulate, cinchocaine glycinate, cinchocaine cinnamate, cinchocaine enoxolone, cinchocaine cyclamate, cinchocaine steviol, cinchocaine aspartamate, cinchocaine di-glycyrrhinizinate, cinchocaine neotame, benzocaine acesulfamate, benzocaine glycyrrherinate, benzocaine mono-glycyrrhizinate, benzocaine tri-glycyrrhizinate, benzocaine vanillate, benzocaine ferrulate, benzocaine glycinate, benzocaine cinnamate, benzocaine enoxolone, benzocaine cyclamate, benzocaine steviol, benzocaine aspartamate, benzocaine di-glycyrrhinizinate, benzocaine neotame, oxetacaine saccharinate, oxetacaine acesulfamate, oxetacaine glycyrrherinate, oxetacaine mono-glycyrrhizinate, oxetacaine tri-glycyrrhizinate, oxetacaine vanillate, oxetacaine ferrulate, oxetacaine glycinate, oxetacaine cinnamate, oxetacaine enoxolone, oxetacaine cyclamate, oxetacaine steviol, oxetacaine aspartamate, oxetacaine di-glycyrrhinizinate, or oxetacaine neotame.

33. The compound of claim 1 or hydrate thereof, wherein the compound is epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, epinephrine neotame, levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame.

34. A composition comprising the compound of claim 1 or hydrate thereof and a pharmaceutically acceptable carrier.

35. The composition of claim 34, further comprising epinephrine, levonodefrin, a salt of epinephrine, a salt of levonordefrin, or hydrate thereof.

36. The composition of claim 34, wherein the composition is formulated for injection.

37. The composition of claim 34, wherein the composition is formulated for oral, intraoral, subcutaneous, transdermal, or transmucosal administration.

38. The composition of claim 35, wherein the salt is epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, epinephrine neotame, levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame.

39. The compound of claim 1 or hydrate thereof, wherein the pH of the compound is at least 3.0.

40. The composition of claim 34, wherein the pH of the composition ranges from about 3.6 to about 5.5.

41. The composition of claim 34, wherein the composition further comprises at least 0.000001% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

42. The composition of claim 34, wherein the further composition comprises from about 0.000001% by weight to about 10% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

43. The composition of claim 34, wherein the composition further comprises about 0.00001% by weight of epinephrine, levonordefrin, a salt of ephineprhine, a salt of levonordefrin, or hydrate thereof.

44. The composition of claim 34, wherein the composition comprises at least 0.0001% by weight of a compound of Formula (I) or hydrate thereof.

45. The composition of claim 34, wherein the composition comprises from about 0.1% by weight to about 10% by weight of a compound of Formula (I) or hydrate thereof.

46. The composition of claim 34, wherein the composition, when formulated for injection, comprises from about 1% by weight to about 3% by weight of a compound of Formula (I) or hydrate thereof.

47. The composition of claim 34, wherein the composition, when formulated for injection, comprises about 1% by weight of a compound of Formula (I) or hydrate thereof.

48. The composition of claim 34, wherein the composition, when formulated for topical or transdermal administration, comprises from about 1% by weight to about 10% by weight of a compound of Formula (I) or hydrate thereof.

49. The composition of claim 34, wherein the composition, when formulated for topical or transdermal administration, comprises about 5% by weight of a compound of Formula (I) or hydrate thereof.

50. A method for making the compound of Formula (I) or hydrate thereof, the method comprising dissolving the compound of Formula (II): ##STR00082## wherein: X.sup.1 is OH or a halide anion; X is C(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, 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 R.sup.Z; R.sup.1 is hydrogen, 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 R.sup.Z; each of R.sup.3 and R.sup.4 is independently hydrogen, 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.sup.Z; A is: ##STR00083## wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, 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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl, C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NR.sup.Z1R.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1; provided that the following compounds or hydrates thereof are excluded: ##STR00084## and an organic salt in a solvent, wherein a metal halide precipitates or is solubilized and the compound of Formula (I) or hydrate thereof remains solubilized.

51. The method of claim 50, wherein the organic salt is sodium saccharinate, sodium acesulfamate, sodium glycyrrherinate, sodium mono-glycyrrhizinate, sodium tri-glycyrrhizinate, sodium vanillate, sodium ferrulate, sodium glycinate, sodium cinnamate, sodium enoxolone, sodium cyclamate, sodium steviol, sodium aspartamate, sodium di-glycyrrhinizinate, sodium neotame, potassium saccharinate, potassium acesulfamate, potassium glycyrrherinate, potassium mono-glycyrrhizinate, potassium tri-glycyrrhizinate, potassium vanillate, potassium ferrulate, potassium glycinate, potassium cinnamate, potassium enoxolone, potassium cyclamate, potassium steviol, potassium aspartamate, potassium di-glycyrrhinizinate, or potassium neotame.

52. The method of claim 50, wherein X.sup.1 is chloride or OH.

53. The method of claim 50, wherein the solvent is acetonitrile.

54. A method of suppressing pain experienced by a subject during a cosmetic, medical, or dental procedure, comprising administering to the subject an effective amount of a composition comprising a compound of Formula (I) or hydrate thereof: ##STR00085## or hydrate thereof, wherein: B is a sweetener; X is C(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, 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 R.sup.Z; R.sup.1 is hydrogen, 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 R.sup.Z; each of R.sup.3 and R.sup.4 is independently hydrogen, 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.sup.Z; A is: ##STR00086## wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, 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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl, C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NR.sup.Z1R.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1.

55. The method of claim 54, wherein the composition comprises lidocaine saccharinate, lidocaine acesulfamate, lidocaine glycyrrherinate, lidocaine mono-glycyrrhizinate, lidocaine tri-glycyrrhizinate, lidocaine vanillate, lidocaine ferrulate, lidocaine glycinate, lidocaine cinnamate, lidocaine enoxolone, lidocaine cyclamate, lidocaine steviol, lidocaine aspartamate, lidocaine di-glycyrrhinizinate, lidocaine neotame, tetracaine saccharinate, tetracaine acesulfamate, tetracaine glycyrrherinate, tetracaine mono-glycyrrhizinate, tetracaine tri-glycyrrhizinate, tetracaine vanillate, tetracaine ferrulate, tetracaine glycinate, tetracaine cinnamate, tetracaine enoxolone, tetracaine cyclamate, tetracaine steviol, tetracaine aspartamate, tetracaine di-glycyrrhinizinate, tetracaine neotame, bupivacaine saccharinate, bupivacaine acesulfamate, bupivacaine glycyrrherinate, bupivacaine mono-glycyrrhizinate, bupivacaine tri-glycyrrhizinate, bupivacaine vanillate, bupivacaine ferrulate, bupivacaine glycinate, bupivacaine cinnamate, bupivacaine enoxolone, bupivacaine cyclamate, bupivacaine steviol, bupivacaine aspartamate, bupivacaine di-glycyrrhinizinate, bupivacaine neotame, mepivacaine saccharinate, mepivacaine acesulfamate, mepivacaine glycyrrherinate, mepivacaine mono-glycyrrhizinate, mepivacaine tri-glycyrrhizinate, mepivacaine vanillate, mepivacaine ferrulate, mepivacaine glycinate, mepivacaine cinnamate, mepivacaine enoxolone, mepivacaine cyclamate, mepivacaine steviol, mepivacaine aspartamate, mepivacaine di-glycyrrhinizinate, mepivacaine neotame, articaine saccharinate, articaine acesulfamate, articaine glycyrrherinate, articaine mono-glycyrrhizinate, articaine tri-glycyrrhizinate, articaine vanillate, articaine ferrulate, articaine glycinate, articaine cinnamate, articaine enoxolone, articaine cyclamate, articaine steviol, articaine aspartamate, articaine di-glycyrrhinizinate, articaine neotame, prilocaine saccharinate, prilocaine acesulfamate, prilocaine glycyrrherinate, prilocaine mono-glycyrrhizinate, prilocaine tri-glycyrrhizinate, prilocaine vanillate, prilocaine ferrulate, prilocaine glycinate, prilocaine cinnamate, prilocaine enoxolone, prilocaine cyclamate, prilocaine steviol, prilocaine aspartamate, prilocaine di-glycyrrhinizinate, prilocaine neotame, procaine saccharinate, procaine acesulfamate, procaine glycyrrherinate, procaine mono-glycyrrhizinate, procaine tri-glycyrrhizinate, procaine vanillate, procaine ferrulate, procaine glycinate, procaine cinnamate, procaine enoxolone, procaine cyclamate, procaine steviol, procaine aspartamate, procaine di-glycyrrhinizinate, procaine neotame, oxybuprocaine saccharinate, oxybuprocaine acesulfamate, oxybuprocaine glycyrrherinate, oxybuprocaine mono-glycyrrhizinate, oxybuprocaine tri-glycyrrhizinate, oxybuprocaine vanillate, oxybuprocaine ferrulate, oxybuprocaine glycinate, oxybuprocaine cinnamate, oxybuprocaine enoxolone, oxybuprocaine cyclamate, oxybuprocaine steviol, oxybuprocaine aspartamate, oxybuprocaine di-glycyrrhinizinate, oxybuprocaine neotame, ropivacaine saccharinate, ropivacaine acesulfamate, ropivacaine glycyrrherinate, ropivacaine mono-glycyrrhizinate, ropivacaine tri-glycyrrhizinate, ropivacaine vanillate, ropivacaine ferrulate, ropivacaine glycinate, ropivacaine cinnamate, ropivacaine enoxolone, ropivacaine cyclamate, ropivacaine steviol, ropivacaine aspartamate, ropivacaine di-glycyrrhinizinate, ropivacaine neotame, cinchocaine saccharinate, cinchocaine acesulfamate, cinchocaine glycyrrherinate, cinchocaine mono-glycyrrhizinate, cinchocaine tri-glycyrrhizinate, cinchocaine vanillate, cinchocaine ferrulate, cinchocaine glycinate, cinchocaine cinnamate, cinchocaine enoxolone, cinchocaine cyclamate, cinchocaine steviol, cinchocaine aspartamate, cinchocaine di-glycyrrhinizinate, cinchocaine neotame, benzocaine saccharinate, benzocaine acesulfamate, benzocaine glycyrrherinate, benzocaine mono-glycyrrhizinate, benzocaine tri-glycyrrhizinate, benzocaine vanillate, benzocaine ferrulate, benzocaine glycinate, benzocaine cinnamate, benzocaine enoxolone, benzocaine cyclamate, benzocaine steviol, benzocaine aspartamate, benzocaine di-glycyrrhinizinate, benzocaine neotame, oxetacaine saccharinate, oxetacaine acesulfamate, oxetacaine glycyrrherinate, oxetacaine mono-glycyrrhizinate, oxetacaine tri-glycyrrhizinate, oxetacaine vanillate, oxetacaine ferrulate, oxetacaine glycinate, oxetacaine cinnamate, oxetacaine enoxolone, oxetacaine cyclamate, oxetacaine steviol, oxetacaine aspartamate, oxetacaine di-glycyrrhinizinate, or oxetacaine neotame.

56. The method of claim 54, wherein the composition further comprises epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof and a pharmaceutically acceptable carrier.

57. The method of claim 56, wherein the salt of epinephrine is epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, or epinephrine neotame.

58. The method of claim 56, wherein the salt of levonordefrin is levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame.

59. The method of claim 54, wherein the composition is administered intraorally, epidurally, ocularly, intranasally, transdermally, subcutaneously, intramuscularly, or transmucosally.

60. The method of claim 54, wherein the composition is formulated for injection.

61. The method of claim 54, wherein the pH of the compound of Formula (I) or hydrate thereof is at least 3.0.

62. The method of claim 54, wherein the pH of the compound of Formula (I) or hydrate thereof ranges from about 3.5 to about 5.5.

63. The method of claim 54, wherein the pH of a composition comprising a compound of Formula (I) or hydrate thereof is at least 3.0.

64. The method of claim 54, wherein the pH of a composition comprising a compound of Formula (I) or hydrate thereof ranges from about 3.6 to about 5.5.

65. The method of claim 54, wherein the composition further comprises at least 0.000001% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

66. The method of claim 54, wherein the composition further comprises from about 0.000001% by weight to about 10% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

67. The method of claim 54, wherein the composition further comprises about 0.00001% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

68. The method of claim 54, wherein the composition further comprises at least 0.0001% by weight of a compound of Formula (I) or hydrate thereof.

69. The method of claim 54, wherein the composition further comprises from about 0.01% by weight to about 10% by weight of a compound of Formula (I) or hydrate thereof.

70. The method of claim 54, wherein the composition, when formulated for injection, comprises from about 1% by weight to about 3% by weight of a compound of Formula (I) or hydrate thereof.

71. The method of claim 54, wherein the composition, when formulated for injection, comprises about 1% by weight of a compound of Formula (I) or hydrate thereof.

72. The method of claim 54, wherein the composition, when formulated for topical or transdermal administration, comprises from about 1% by weight to about 10% by weight of a compound of Formula (I) or hydrate thereof.

73. The method of claim 54, wherein the composition, when formulated for topical or transdermal administration, comprises about 5% by weight of a compound of Formula (I) or hydrate thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] FIG. 1 is an exemplary chart that depicts withdrawal latency of animals' hindpaws in response to a thermal stimulus following injection of a composition comprising a compound of Formula (I).

[0070] FIG. 2 is an exemplary chart that depicts the relative palatability of a compound of Formula (I) exhibited by animals.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0071] As generally described herein, the present invention includes compounds and compositions thereof wherein the compounds are salts, wherein the anions of the salts are sweeteners, e.g., saccharinate, acesulfamate, glycyrrherinate, mono-glycyrrhizinate, tri-glycyrrhizinate, vanillate, ferrulate, glycinate, cinnamate, enoxolone, cyclamate, steviol, aspartamate, di-glycyrrhinizinate, neotame, and the cations are protonated organic amines. The chemical structures of the salts described herein are represented in such a way known to one skilled in the art. Saccharinate and acesulfamate anions may exist as their keto forms or enol forms as described below. In some embodiments, the compounds described herein can be formulated into compositions useful as local anesthetics for, e.g., surgery, e.g., oral surgery. In some embodiments, the compounds described herein are expected to be sweet-tasting and highly soluble in aqueous media, e.g., water or saline solution.

Compounds

[0072] In one aspect, the present invention provides a compound of Formula (I) or hydrate thereof:

##STR00014##

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(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z; R.sup.1 is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z; each of R.sup.3 and R.sup.4 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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.sup.Z;

[0073] A is:

##STR00015##

wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NRR.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1; 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.

[0074] In some embodiments, the compound is a compound of Formula (I-A):

##STR00016##

[0075] provided that the compound is not lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, prilocaine saccharinate, prilocaine acesulfamate, procaine saccharinate, or cinchocaine saccharinate.

[0076] In some embodiments, the compound is a compound of Formula (I-B):

##STR00017##

provided that the compound is not benzocaine saccharinate.

[0077] In some embodiments, B is saccharinate, acesulfamate, glycyrrherinate, mono-glycyrrhizinate, tri-glycyrrhizinate, vanillate, ferrulate, glycinate, cinnamate, enoxolone, cyclamate, steviol, aspartamate, di-glycyrrhinizinate, neotame

[0078] In some embodiments, the hydrate is a monohydrate. In some embodiments, X is C(O)NR.sup.A or NR.sup.AC(O). In some embodiments, B is saccharinate or acesulfamate and R.sup.2 and R.sup.3 are not CH.sub.2CH.sub.3. In some embodiments, each of R.sup.2a and R.sup.2b is independently hydrogen. In some embodiments, R.sup.2a and R.sup.2b are hydrogen. In some embodiments, each of R.sup.2a and R.sup.2b is independently hydrogen or alkyl (e.g., C.sub.1-C.sub.6 alkyl) independently substituted with 0-5 occurrences of R.sup.Z and n is 1. In some embodiments, each of R.sup.3 and R.sup.4 is independently hydrogen or alkyl (e.g., C.sub.1-C.sub.6 alkyl) independently substituted with 0-5 occurrences of R.sup.Z. In some embodiments, each of R.sup.3 and R.sup.4 is independently hydrogen or CH.sub.3.

[0079] In some embodiments, if n is 1, R.sup.3 or R.sup.4 and R.sup.2a or R.sup.2b, together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z. In some embodiments, at least one of R.sup.5, R.sup.6, R.sup.7, and R is not hydrogen. In some embodiments, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen. In some embodiments, R.sup.3 and R.sup.4 are hydrogen and X is C(O)O.

[0080] In some embodiments, the compound is a compound of Formula (I-C),

##STR00018##

wherein C is a 5-10 membered ring substituted with 0-5 occurrences of R.sup.Z;

[0081] provided that the compound or hydrates thereof is not: lidocaine saccharinate, lidocaine acesulfamate, bupivacaine saccharinate, bupivacaine acesulfamate, cinchocaine saccharinate, prilocaine saccharinate, or prilocaine acesulfamate.

[0082] In some embodiments, C is,

##STR00019##

wherein each of R.sup.B, R.sup.C, R.sup.D, R.sup.E, or R.sup.F is independently hydrogen or C.sub.1-C.sub.6 alkyl.

[0083] In some embodiments, R.sup.3 is n-butyl and R.sup.2a and R.sup.4, together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z. In some embodiments, R.sup.3 is methyl and R.sup.2a and R.sup.4, together with the atoms to which they are attached form a 6-membered ring substituted with 0-5 occurrences of R.sup.Z. In some embodiments, R.sup.2a is methyl and R.sup.4 is n-propyl.

[0084] In some embodiments, the salt is represented by Formula (I-D):

##STR00020##

wherein R.sup.9 is hydrogen or C.sub.1-C.sub.6 alkyl and R.sup.10 is hydrogen or C.sub.1-C.sub.6 alkoxy;

[0085] provided that the compound is not procaine saccharinate.

[0086] In some embodiments, R.sup.3 and R.sup.4 are CH.sub.2CH.sub.3. In some embodiments, n is 2. In some embodiments, R.sup.3 and R.sup.4 are CH.sub.2CH.sub.3, R.sup.9 is hydrogen or C.sub.1-C.sub.6 alkyl, and R.sup.10 is hydrogen or C.sub.1-C.sub.6 alkoxy.

[0087] In some embodiments, the salt is represented by Formula (I-E):

##STR00021##

wherein m is 1, 2, 3, or 4 and Y is NR.sup.AC(O) or C(O)NR.sup.A.

[0088] In some embodiments, X is C(O)NR.sup.A1 and Y is NR.sup.A1C(O). In some embodiments, R.sup.1 is aralkyl. In some embodiments, R.sup.2a and R.sup.2b are hydrogen. In some embodiments, R.sup.2a and R.sup.2b are hydrogen and R.sup.1 is aralkyl. In some embodiments, n is 1 and m is 1.

[0089] In some embodiments, the compound is lidocaine glycyrrherinate, lidocaine mono-glycyrrhizinate, lidocaine tri-glycyrrhizinate, lidocaine vanillate, lidocaine ferrulate, lidocaine glycinate, lidocaine cinnamate, lidocaine enoxolone, lidocaine cyclamate, lidocaine steviol, lidocaine aspartamate, lidocaine di-glycyrrhinizinate, lidocaine neotame, tetracaine saccharinate, tetracaine acesulfamate, tetracaine glycyrrherinate, tetracaine mono-glycyrrhizinate, tetracaine tri-glycyrrhizinate, tetracaine vanillate, tetracaine ferrulate, tetracaine glycinate, tetracaine cinnamate, tetracaine enoxolone, tetracaine cyclamate, tetracaine steviol, tetracaine aspartamate, tetracaine di-glycyrrhinizinate, tetracaine neotame, bupivacaine glycyrrherinate, bupivacaine mono-glycyrrhizinate, bupivacaine tri-glycyrrhizinate, bupivacaine vanillate, bupivacaine ferrulate, bupivacaine glycinate, bupivacaine cinnamate, bupivacaine enoxolone, bupivacaine cyclamate, bupivacaine steviol, bupivacaine aspartamate, bupivacaine di-glycyrrhinizinate, bupivacaine neotame, mepivacaine saccharinate, mepivacaine acesulfamate, mepivacaine glycyrrherinate, mepivacaine mono-glycyrrhizinate, mepivacaine tri-glycyrrhizinate, mepivacaine vanillate, mepivacaine ferrulate, mepivacaine glycinate, mepivacaine cinnamate, mepivacaine enoxolone, mepivacaine cyclamate, mepivacaine steviol, mepivacaine aspartamate, mepivacaine di-glycyrrhinizinate, mepivacaine neotame, articaine saccharinate, articaine acesulfamate, articaine glycyrrherinate, articaine mono-glycyrrhizinate, articaine tri-glycyrrhizinate, articaine vanillate, articaine ferrulate, articaine glycinate, articaine cinnamate, articaine enoxolone, articaine cyclamate, articaine steviol, articaine aspartamate, articaine di-glycyrrhinizinate, articaine neotame, prilocaine glycyrrherinate, prilocaine mono-glycyrrhizinate, prilocaine tri-glycyrrhizinate, prilocaine vanillate, prilocaine ferrulate, prilocaine glycinate, prilocaine cinnamate, prilocaine enoxolone, prilocaine cyclamate, prilocaine steviol, prilocaine aspartamate, prilocaine di-glycyrrhinizinate, prilocaine neotame, procaine acesulfamate, procaine glycyrrherinate, procaine mono-glycyrrhizinate, procaine tri-glycyrrhizinate, procaine vanillate, procaine ferrulate, procaine glycinate, procaine cinnamate, procaine enoxolone, procaine cyclamate, procaine steviol, procaine aspartamate, procaine di-glycyrrhinizinate, procaine neotame, oxybuprocaine saccharinate, oxybuprocaine acesulfamate, oxybuprocaine glycyrrherinate, oxybuprocaine mono-glycyrrhizinate, oxybuprocaine tri-glycyrrhizinate, oxybuprocaine vanillate, oxybuprocaine ferrulate, oxybuprocaine glycinate, oxybuprocaine cinnamate, oxybuprocaine enoxolone, oxybuprocaine cyclamate, oxybuprocaine steviol, oxybuprocaine aspartamate, oxybuprocaine di-glycyrrhinizinate, oxybuprocaine neotame, ropivacaine saccharinate, ropivacaine acesulfamate, ropivacaine glycyrrherinate, ropivacaine mono-glycyrrhizinate, ropivacaine tri-glycyrrhizinate, ropivacaine vanillate, ropivacaine ferrulate, ropivacaine glycinate, ropivacaine cinnamate, ropivacaine enoxolone, ropivacaine cyclamate, ropivacaine steviol, ropivacaine aspartamate, ropivacaine di-glycyrrhinizinate, ropivacaine neotame, cinchocaine acesulfamate, cinchocaine glycyrrherinate, cinchocaine mono-glycyrrhizinate, cinchocaine tri-glycyrrhizinate, cinchocaine vanillate, cinchocaine ferrulate, cinchocaine glycinate, cinchocaine cinnamate, cinchocaine enoxolone, cinchocaine cyclamate, cinchocaine steviol, cinchocaine aspartamate, cinchocaine di-glycyrrhinizinate, cinchocaine neotame, benzocaine acesulfamate, benzocaine glycyrrherinate, benzocaine mono-glycyrrhizinate, benzocaine tri-glycyrrhizinate, benzocaine vanillate, benzocaine ferrulate, benzocaine glycinate, benzocaine cinnamate, benzocaine enoxolone, benzocaine cyclamate, benzocaine steviol, benzocaine aspartamate, benzocaine di-glycyrrhinizinate, benzocaine neotame, oxetacaine saccharinate, oxetacaine acesulfamate, oxetacaine glycyrrherinate, oxetacaine mono-glycyrrhizinate, oxetacaine tri-glycyrrhizinate, oxetacaine vanillate, oxetacaine ferrulate, oxetacaine glycinate, oxetacaine cinnamate, oxetacaine enoxolone, oxetacaine cyclamate, oxetacaine steviol, oxetacaine aspartamate, oxetacaine di-glycyrrhinizinate, or oxetacaine neotame. In some embodiments, the compound is epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, epinephrine neotame, levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame.

[0090] Compounds of the present invention, e.g., a compound of Formula (I) or hydrate thereof, can be organic salts in which the cation is a protonated member of the caine family. A general structure of a caine salt provided by the present invention can be generally represented as a compound of Formula (A-1):

CaineH.sup.+B.sup.(A-1)

wherein anion B is a sweetener. Exemplary caines of Formula (A-1) are depicted in Table 1a and examples of B are shown in Table 1b below. The caines shown below are depicted in their neutral form, but are expected to be protonated as the component of a salt described herein, e.g., a compound of Formula (I).

TABLE-US-00001 TABLE 1a Caine [00022] embedded image Lidocaine [00023] Tetracaine [00024] Bupivacaine [00025] Mepivacaine [00026] Articaine [00027] Prilocaine [00028] Procaine [00029] Oxybuprocaine [00030] Ropivacaine [00031] Cinchocaine [00032] Benzocaine [00033] Oxetacaine

TABLE-US-00002 TABLE 1b Sweetener (B) [00034] embedded image Saccharinate [00035] Acesulfamate [00036] Enoxolone anion [00037] Mono-glycyrrhizinate [00038] Di-glycyrrhizinate [00039] Tri-glycyrrhizinate [00040] Vanillate [00041] Ferrulate [00042] Glycinate [00043] Cinnamate [00044] Cyclamate [00045] Steviol [00046] Neotame [00047] Aspartamate

[0091] Compounds of the present invention can also be other organic salts as depicted by Formula (A-2):

EH.sup.+B.sup.(A-2)

wherein cationic component E can be an organic amine, e.g., epinephrine or levonordefrin as shown in Table 2a and anion B is a sweetener as shown in Table 2b. As with the caines of Table 1a, the species shown in Table 2a are depicted in their neutral form, but are expected to be protonated as the component of a salt described herein, e.g., a compound of Formula (I).

TABLE-US-00003 TABLE 2a Component E [00048] embedded image Epinephrine [00049] Levonordefrin

TABLE-US-00004 TABLE 2b Sweetener (B) [00050] embedded image Saccharinate [00051] Acesulfamate [00052] Enoxolone [00053] Mono-glycyrrhizinate [00054] Di-glycyrrhizinate [00055] Tri-glycyrrhizinate [00056] Vanillate [00057] Ferrulate [00058] Glycinate [00059] Cinnamate [00060] Cyclamate [00061] Steviol [00062] Neotame [00063] Aspartamate

[0092] Salts in which the cation is a protonated caine species and the anion is a sweetener can be named as the combination of the name of the caine species followed by the name of the anionic sweetener. For example, a salt in which the cation is protonated oxybuprocaine and the anion is saccharinate can be named as oxybuprocaine saccharinate. Similarly, compounds of Formula (A-2), e.g., a salt in which the cation is protonated epinephrine and the anion is acesulfamate, can be identified as epinephrine acesulfamate and a salt in which the cation is protonated levonodefrin and the anion is vanillate can be named as levonodefrin vanillate.

Compositions, Formulations, and Routes of Administration

[0093] In another aspect, provided herein are compositions comprising a compound described herein, e.g., a compound of Formula (I), and a pharmaceutically acceptable carrier. In some embodiments, with respect to the composition, the pharmaceutically acceptable carrier is an injectable carrier, an oral carrier, or a topical carrier. In some embodiments, a composition can comprise at least 0.0001%, e.g., from about 0.01% by weight to about 10% by weight, of a compound of Formula (I) or hydrate thereof. In some embodiments, a composition can comprise about 1% by weight of a compound of Formula (I) or hydrate thereof.

Formulations and Routes of Administration

[0094] The present invention describes herein pharmaceutically acceptable formulations of compounds described herein, e.g., compounds of Formula (I) or hydrates thereof. The compositions provided herein can be administered by a variety of routes including oral, intraoral, transdermal, subcutaneous, intravenous, intramuscular, intranasal, and transmucosal administrations. Depending on the intended route of delivery, the compounds provided herein, e.g., compounds of Formula (I) or hydrates thereof, can be formulated as, e.g., injectable compositions, oral compositions, sprayable compositions, tablets, capsules, foams, or gels, or ointments, lotions, or patches that can be topically administered.

[0095] Generally, the compounds provided herein, e.g., a compound of Formula (I) are administered in an effective amount generally ranging from about 0.0001% by weight to about 10% by weight, e.g., from about 0.3% by weight to about 5% by weight, of the total composition. In some embodiments, a compound provided herein, e.g., a compound of Formula (I) or hydrate thereof, is administered in an amount of about 1% by weight of the total composition.

[0096] Compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. The compositions can be presented in unit dosage forms to facilitate accurate dosing. The term unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound, e.g., a compound of Formula (I) or hydrate thereof, is usually a minor component (e.g., from about 0.0001% by weight to about 10% by weight, e.g., from about 0.3% by weight to about 5% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. In some embodiments, compositions can be formulated for use in eye drops or for spraying into, e.g., nostrils or the mouth using pharmaceutically acceptable carriers and excipients known in the art.

[0097] Other liquid forms suitable for administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide.

[0098] The compositions and components described herein can be provided in the form of an oral rinse. Ingredients of such an oral rinse typically include one or more of an active ingredient (e.g., a compound of Formula (I) or hydrate thereof, e.g., from at least 0.0008%, from at least 0.001%, at least 0.003%, at least 0.004%, from about 0.001% to about 0.8%, from about 0.001% to about 0.005%, from about 0.003% to about 0.8%, from about 0.003% to about 0.02%, from about 0.003% to about 0.01%, from about 0.004% to about 0.8%, from about 0.004% to about 0.02%, from about 0.004% to about 0.01%), a non-fermentable sugar (e.g., from about 1% to about 70%, about 5% to about 70%, about 10% to about 70%, about 17% to about 70%, about 1% to about 65%, about 5% to about 70%, about 10% to about 70%, about 17% to about 65%, about 22% to about 33%), a thickener (e.g., from about 1% to about 20%, about 5% to about 15%, about 10% to about 15%, about 12.5%), a surfactant (e.g., from about 0.1% to about 2%, about 0.5% to about 2.5%, about 1% to about 2%, about 1%), and a preservative (e.g., from about 0.01% to about 4%, from about 0.01 to about 0.4%, from about 0.01 to about 0.2%, from about 0.2% to about 0.4%, about 0.1%). Such oral rinses may optionally include one or more of an anti-caries agent (from about 0% to about 0.1% as fluoride ion), an anti-calculus agent (from about 0.1% to about 3%), an antiseptic agent (e.g., thymol), an anesthetic agent (e.g., a local anesthetic agent (e.g., menthol)), a cleaning agent (e.g., methyl salicylate), a whitening agent (e.g., hydrogen peroxide), a base (e.g., sodium hydroxide), and a desensitizing agent (e.g., potassium nitrate).

[0099] In some embodiments, injectable formulations can be administered intraorally, instramuscularly, subcutaneously, or transmucosally. In some embodiments, injections are administered in the nose. Injectable compositions are typically based upon aqueous-based carriers, e.g., injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The active compound, e.g., a compound of Formula (I) or hydrate thereof, in such compositions is typically a minor component, often being from about 0.3% by weight to about 5% by weight and preferably from about 1% by weight to about 3% by weight, with the remainder being the injectable carrier and the like. In some embodiments, the active compound in such compositions is about 1% by weight with the remainder being the injectable carrier and the like.

[0100] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), e.g., a compound of Formula (I) or hydrate thereof, generally in an amount ranging from about 0.1% by weight to about 10% by weight, e.g., from about 0.5% by weight to about 10% by weight, of the total composition. In some embodiments, the transdermal composition comprises about 5% by weight of the total composition. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0101] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0102] The above-described components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0103] In some embodiments, compositions provided herein, e.g., compositions comprising a compound of Formula (I) or hydrate thereof, can further comprise epinephrine, levonordefrin, a salt of epinephrine, a salt of levonordefrin, or hydrate thereof. In some embodiments, the salt of epinephrine is epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, or epinephrine neotame. In some embodiments, the salt of levonordefrin is levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame. In some embodiments, epinephrine, levonordefrin, a salt of epinephrine, a salt of levonordefrin, or hydrate thereof comprises at least 0.000001% by weight of the total composition. In some embodiments, epinephrine, levonordefrin, a salt of epinephrine, a salt of levonordefrin, or hydrate thereof is administered in an effective amount ranging from about 0.000001% by weight to about 5% by weight, e.g., from about 0.000001% by weight to about 0.001% by weight of the total composition. In some embodiments, the salt of epinephrine, salt of levonordefrin, or hydrate thereof is generally administered in an effective amount of about 0.00001% by weight of the total composition.

[0104] In some embodiments, pharmaceutically acceptable excipients present in the compositions described herein, e.g., a composition comprising a compound of Formula (I) or hydrate thereof, can be, e.g., osmolality adjusting agents or pH adjusting agents. In some embodiments, the compositions described herein can comprise both osmolality adjusting agents and pH adjusting agents.

[0105] In some embodiments, the pH of a compound described herein can be at least 3.0, e.g., from about 3.5 to about 5.4. In other embodiments, the pH of a composition described herein, e.g., an aqueous compound formulated for injection, can be at least from about 3.0, e.g., from about 3.6 to about 4.4. In some embodiments, the pH of a compound described herein has a pH higher than a hydrochloride salt of the caine family, e.g., lidocaine hydrochloride.

Methods of Use

Local Anesthesia

[0106] Compounds described herein, e.g., a compound of Formula (I) or hydrate thereof, are formulated for use as local anesthetics. Thus, in an aspect, the present invention provides herein a method of suppressing pain experienced by a subject during a cosmetic, medical or dental procedure, comprising administering to the subject an effective amount of a composition comprising a compound of Formula (I) or hydrate thereof:

##STR00064##

or hydrate thereof, wherein:

[0107] 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(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z;

[0108] R.sup.1 is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z;

[0109] each of R.sup.3 and R.sup.4 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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.sup.Z;

[0110] A is:

##STR00065##

wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NR.sup.Z1R.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1.

[0111] In some embodiments, the composition is formulated for injection as described herein. In some embodiments, the composition is formulated as a lotion, ointment, or patch for transdermal administration as described herein. In some embodiments, the composition is administered intraorally, epidurally, intranasally, ocularly, transdermally, intramuscularly, subcutaneously, intramuscularly, or transmucosally. In some embodiments, administration of a composition described herein, e.g, a composition comprising a compound of Formula (I) by, e.g., intraoral administration, does not elicit an objectionable bitter taste experienced by a patient during, e.g., oral surgery. In some embodiments, the compounds described herein, e.g., a compound of Formula (I) or hydrate thereof, do not elicit pain or tissue damage associated with the lower pH of their corresponding hydrochloride salts and can therefore be more widely applied in medical procedures, e.g., epidural procedures, skin surgery, eye surgery, or biopsies, and cosmetic procedures, e.g., facial injections, hair transplants, or liposuction. In some embodiments, the pH of the compound of Formula (I) or hydrate thereof is at least 3.0, e.g. from about 3.5 to about 5.5. In some embodiments, the pH of a composition comprising a compound of Formula (I) or hydrate thereof is at least 3.0, e.g., from about 3.6 to about 5.5.

[0112] Compounds contemplated for use in local anesthesia as described herein can be salts comprising cations that function as the active local anesthetic, e.g., protonated caines, and anions capable of masking bitter tastes. In some embodiments, the compound for use as the local anesthetic can be, but is not limited to, lidocaine saccharinate, lidocaine acesulfamate, lidocaine glycyrrherinate, lidocaine mono-glycyrrhizinate, lidocaine tri-glycyrrhizinate, lidocaine vanillate, lidocaine ferrulate, lidocaine glycinate, lidocaine cinnamate, lidocaine enoxolone, lidocaine cyclamate, lidocaine steviol, lidocaine aspartamate, lidocaine di-glycyrrhinizinate, lidocaine neotame, tetracaine saccharinate, tetracaine acesulfamate, tetracaine glycyrrherinate, tetracaine mono-glycyrrhizinate, tetracaine tri-glycyrrhizinate, tetracaine vanillate, tetracaine ferrulate, tetracaine glycinate, tetracaine cinnamate, tetracaine enoxolone, tetracaine cyclamate, tetracaine steviol, tetracaine aspartamate, tetracaine di-glycyrrhinizinate, tetracaine neotame, bupivacaine saccharinate, bupivacaine acesulfamate, bupivacaine glycyrrherinate, bupivacaine mono-glycyrrhizinate, bupivacaine tri-glycyrrhizinate, bupivacaine vanillate, bupivacaine ferrulate, bupivacaine glycinate, bupivacaine cinnamate, bupivacaine enoxolone, bupivacaine cyclamate, bupivacaine steviol, bupivacaine aspartamate, bupivacaine di-glycyrrhinizinate, bupivacaine neotame, mepivacaine saccharinate, mepivacaine acesulfamate, mepivacaine glycyrrherinate, mepivacaine mono-glycyrrhizinate, mepivacaine tri-glycyrrhizinate, mepivacaine vanillate, mepivacaine ferrulate, mepivacaine glycinate, mepivacaine cinnamate, mepivacaine enoxolone, mepivacaine cyclamate, mepivacaine steviol, mepivacaine aspartamate, mepivacaine di-glycyrrhinizinate, mepivacaine neotame, articaine saccharinate, articaine acesulfamate, articaine glycyrrherinate, articaine mono-glycyrrhizinate, articaine tri-glycyrrhizinate, articaine vanillate, articaine ferrulate, articaine glycinate, articaine cinnamate, articaine enoxolone, articaine cyclamate, articaine steviol, articaine aspartamate, articaine di-glycyrrhinizinate, articaine neotame, prilocaine saccharinate, prilocaine acesulfamate, prilocaine glycyrrherinate, prilocaine mono-glycyrrhizinate, prilocaine tri-glycyrrhizinate, prilocaine vanillate, prilocaine ferrulate, prilocaine glycinate, prilocaine cinnamate, prilocaine enoxolone, prilocaine cyclamate, prilocaine steviol, prilocaine aspartamate, prilocaine di-glycyrrhinizinate, prilocaine neotame, procaine saccharinate, procaine acesulfamate, procaine glycyrrherinate, procaine mono-glycyrrhizinate, procaine tri-glycyrrhizinate, procaine vanillate, procaine ferrulate, procaine glycinate, procaine cinnamate, procaine enoxolone, procaine cyclamate, procaine steviol, procaine aspartamate, procaine di-glycyrrhinizinate, procaine neotame, oxybuprocaine saccharinate, oxybuprocaine acesulfamate, oxybuprocaine glycyrrherinate, oxybuprocaine mono-glycyrrhizinate, oxybuprocaine tri-glycyrrhizinate, oxybuprocaine vanillate, oxybuprocaine ferrulate, oxybuprocaine glycinate, oxybuprocaine cinnamate, oxybuprocaine enoxolone, oxybuprocaine cyclamate, oxybuprocaine steviol, oxybuprocaine aspartamate, oxybuprocaine di-glycyrrhinizinate, oxybuprocaine neotame, ropivacaine saccharinate, ropivacaine acesulfamate, ropivacaine glycyrrherinate, ropivacaine mono-glycyrrhizinate, ropivacaine tri-glycyrrhizinate, ropivacaine vanillate, ropivacaine ferrulate, ropivacaine glycinate, ropivacaine cinnamate, ropivacaine enoxolone, ropivacaine cyclamate, ropivacaine steviol, ropivacaine aspartamate, ropivacaine di-glycyrrhinizinate, ropivacaine neotame, cinchocaine saccharinate, cinchocaine acesulfamate, cinchocaine glycyrrherinate, cinchocaine mono-glycyrrhizinate, cinchocaine tri-glycyrrhizinate, cinchocaine vanillate, cinchocaine ferrulate, cinchocaine glycinate, cinchocaine cinnamate, cinchocaine enoxolone, cinchocaine cyclamate, cinchocaine steviol, cinchocaine aspartamate, cinchocaine di-glycyrrhinizinate, cinchocaine neotame, benzocaine saccharinate, benzocaine acesulfamate, benzocaine glycyrrherinate, benzocaine mono-glycyrrhizinate, benzocaine tri-glycyrrhizinate, benzocaine vanillate, benzocaine ferrulate, benzocaine glycinate, benzocaine cinnamate, benzocaine enoxolone, benzocaine cyclamate, benzocaine steviol, benzocaine aspartamate, benzocaine di-glycyrrhinizinate, benzocaine neotame, oxetacaine saccharinate, oxetacaine acesulfamate, oxetacaine glycyrrherinate, oxetacaine mono-glycyrrhizinate, oxetacaine tri-glycyrrhizinate, oxetacaine vanillate, oxetacaine ferrulate, oxetacaine glycinate, oxetacaine cinnamate, oxetacaine enoxolone, oxetacaine cyclamate, oxetacaine steviol, oxetacaine aspartamate, oxetacaine di-glycyrrhinizinate, or oxetacaine neotame. In some embodiments, the administered composition can comprise at least 0.0001% by weight of a compound of Formula (I) or hydrate thereof. In some embodiments, the administered composition, when formulated for injection, can comprise from about 1% by weight to about 3% by weight, e.g., 1% by weight, of a compound of Formula (I) or hydrate thereof. In some embodiments, the administered composition, when formulated for topical or transdermal administration, can comprise from about 1% by weight to about 10% by weight, e.g., about 5% by weight, of a compound of Formula (I) or hydrate thereof.

[0113] In some embodiments, the composition can further comprise epinephrine, levonordefrin, or a salt thereof and a pharmaceutically acceptable carrier. The epinephrine salt can be, but is not limited to, epinephrine saccharinate, epinephrine acesulfamate, epinephrine glycyrrherinate, epinephrine mono-glycyrrhizinate, epinephrine tri-glycyrrhizinate, epinephrine vanillate, epinephrine ferrulate, epinephrine glycinate, epinephrine cinnamate, epinephrine enoxolone, epinephrine cyclamate, epinephrine steviol, epinephrine aspartamate, epinephrine di-glycyrrhinizinate, epinephrine neotame. The levonordefrin salt can be, but is not limited to, levonordefrin saccharinate, levonordefrin acesulfamate, levonordefrin glycyrrherinate, levonordefrin mono-glycyrrhizinate, levonordefrin tri-glycyrrhizinate, levonordefrin vanillate, levonordefrin ferrulate, levonordefrin glycinate, levonordefrin cinnamate, levonordefrin enoxolone, levonordefrin cyclamate, levonordefrin steviol, levonordefrin aspartamate, levonordefrin di-glycyrrhinizinate, or levonordefrin neotame. In some embodiments, the administered composition comprises at least 0.000001% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof. In some embodiments, the administered composition comprises from about 0.000001% by weight to about 10% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof. In some embodiments, the administered composition comprises about 0.00001% by weight of epinephrine, levonordefrin, a salt of epinephrine, a salt of levonodefrin, or hydrate thereof.

Methods of Making

[0114] In another aspect, also provided herein is a method for making the compound of Formula (I) or hydrate thereof, the method comprising dissolving the compound of Formula (II):

##STR00066##

wherein: X.sup.1 is OH or a halide anion (e.g., chloride, bromide, or iodide); X is C(O)O, OC(O), C(O)NR.sup.A, or NR.sup.AC(O), or CH(OR.sup.A), wherein R.sup.A is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z; R.sup.1 is hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z; each of R.sup.3 and R.sup.4 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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.sup.Z;

[0115] A is:

##STR00067##

wherein: n is 1-5; each of R.sup.2a and R.sup.2b is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.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 R.sup.Z, or if n is 1, R.sup.2a or R.sup.2b and R.sup.3 or R.sup.4, together with the atoms to which they are attached form a 3-8 membered ring independently substituted with 0-5 occurrences of R.sup.Z; and each of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is independently hydrogen, alkyl (e.g., C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.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.sup.Z; and R.sup.Z is halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, NHR.sup.Z1, NR.sup.Z1R.sup.Z2, C(O)R.sup.Z1, C(O)R.sup.Z2, C(O)NR.sup.Z1R.sup.Z2, NR.sup.Z1C(O)R.sup.Z2, OR.sup.Z1, OR.sup.Z2, cyano, or nitro, wherein R.sup.Z1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 heteroalkyl, hydroxyl, cyano, or nitro and R.sup.Z2 is carbocyclylalkyl, heterocycylalkyl, aralkyl or heteroaralkyl substituted with 0-5 occurrences of R.sup.Z1;

[0116] provided that the following compounds or hydrates thereof are excluded:

##STR00068##

and an organic salt in a solvent, wherein a metal halide precipitates or is solubilized and the compound of Formula (I) or hydrate thereof remains solubilized.

[0117] In some embodiments, the organic salt can be, but is not limited to, sodium saccharinate, sodium acesulfamate, sodium glycyrrherinate, sodium mono-glycyrrhizinate, sodium tri-glycyrrhizinate, sodium vanillate, sodium ferrulate, sodium glycinate, sodium cinnamate, sodium enoxolone, sodium cyclamate, sodium steviol, sodium aspartamate, sodium di-glycyrrhinizinate, sodium neotame, potassium saccharinate, potassium acesulfamate, potassium glycyrrherinate, potassium mono-glycyrrhizinate, potassium tri-glycyrrhizinate, potassium vanillate, potassium ferrulate, potassium glycinate, potassium cinnamate, potassium enoxolone, potassium cyclamate, potassium steviol, potassium aspartamate, potassium di-glycyrrhinizinate, or potassium neotame. In some embodiments, X.sup.1 is chloride. In some embodiments, X.sup.1 is OH. In some embodiments, the solvent is acetonitrile. Other examples of solvents include, but are not limited to, water, 1,4-dioxane, ethyl acetate, acetone, methanol, ethanol, isopropanol, butanol, acetone, 2-butanone, ethylene glycol, ethylene glycol monomethyl ether, 1,2-dimethoxyethane, and 2-methoxyethanol. In another embodiment, the method produces a compound of Formula (I) or hydrate thereof in high yield, e.g., from about 90% yield to about 100% yield.

Abbreviations

[0118] MeCN: acetonitrile; MeOH: methanol; TLC: thin-layer chromatography; DMSO: dimethyl sulfoxide.

EXAMPLES

[0119] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Materials and Methods

[0120] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0121] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0122] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, or high-performance liquid chromatography (HPLC). The following schemes are presented with details as to the preparation of representative compounds that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

Animal Studies

[0123] Male Sprague Dawley rats (200-300 g, Charles River) were housed in groups of two and were maintained in a standard 12-h light/dark cycle and testing was completed in the light portion of the cycle between 09:00-12:00. Animals were placed into the behavioural procedure room 30 min prior to testing to acclimate. When not in testing sessions, food and water were made available ad libitum. Animal testing procedures complied with the ethical guidelines and standards established by the University of Florida's Institutional Animal Care & Use Committee and with the Guide for Care and Use of Laboratory Animals (National Research Council Guide for the Care and Use of Laboratory Animals. Washington, D.C., National Academy Press; 1996.).

[0124] .sup.1H-NMR reported herein (e.g., for the region between 6 (ppm) of about 0.5 ppm to about 8 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integratations) of a compound.

Example 1. Syntheses of Caine Salts 3a-3h

[0125] ##STR00069##

[0126] To the solution of a hydrochloride salt of a corresponding caines 1a-d (1.0 mmol) in MeCN (15 mL) equimolar quantity of the sweetener salt: (potassium 6-methyl-1,2,3-oxathiazin-4-olate 2,2-dioxide 0.185 g for 2a or sodium benzo[d]isothiazol-3-olate 1,1-dioxide 0.205 g for 2b) was added and the mixture was then stirred for 4h at the ultrasonic bath at 50 C. After the reaction was completed (followed by TLC), reaction mixture was filtered through the 22 micron membrane filter and the filtrate was taken to dryness. After that diethyl ether (325 mL) was added to product and it was evaporated to give products 3a-h in quantitative yields. Final products 3a-h are all water-soluble ionic conjugates that consist of the anion of a sweetener (acesulfamate or saccahine) and a representative of a caine family (mepivacaine, bupivacaine, prilocaine, articaine) as a cation.

Mepivacaine acesulfamate (3a)

[0127] White semisolid (97%, 0.396 g, 0.97 mmol). m.p. 84.0-86.0 C.; .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.21-7.09 (m, 3H), 5.53 (s, 1H), 4.17 (dd, J=11.9, 3.2 Hz, 1H), 3.54 (d, J=12.5 Hz, 1H), 3.18 (td, J=12.4, 3.1 Hz, 1H), 2.93 (d, J=1.1 Hz, 3H), 2.46-2.33 (m, 1H), 2.22 (d, J=0.9 Hz, 6H), 2.02 (t, J=1.0 Hz, 3H), 1.93 (s, 3H), 1.89-1.67 (m, 2H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 173.2, 168.8, 164.4, 137.2, 134.7, 129.9, 129.5, 102.8, 68.8, 56.7, 43.6, 31.0, 24.6, 22.9, 20.4, 19.1. HRMS (ESI) calcd for C.sub.15H.sub.22N.sub.2O [M+H].sup.+ 246.3535, found 247.1800; HRMS (ESI) calcd for C.sub.4H.sub.4NO.sub.4S [MH].sup. 161.9867, found 161.9873.

Bupivacaine Acesulfamate (3b)

[0128] Colorless oil (96%, 0.432 g, 0.96 mmol)). .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.18-7.11 (m, 3H), 5.55 (s, 1H), 4.32 (d, J=11.6 Hz, 1H), 3.69 (d, J=12.2 Hz, 1H), 3.19 (dq, J=16.5, 11.0, 8.5 Hz, 3H), 2.42 (d, J=12.2 Hz, 1H), 2.24 (s, 6H), 2.04 (s, 3H), 1.99-1.70 (m, 7H), 1.41 (q, J=7.4 Hz, 2H), 0.99 (t, J=7.3 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 173.2, 169.0, 164.4, 137.2, 134.7, 129.9, 129.9, 129.5, 102.9, 57.8, 53.7, 31.0, 27.3, 24.4, 21.5, 21.5, 20.4, 19.1, 14.4. HRMS (ESI) calcd for C.sub.18H.sub.28N.sub.2O [M+H].sup.+ 288.2196, found 289.2262; HRMS (ESI) calcd for C.sub.4H.sub.4NO.sub.4S [MH].sup. 161.9867, found 161.9872.

Prilocaine Acesulfamate (3c)

[0129] White solid (98%, 0.375 g, 0.98 mmol)). m.p. 145.2-145.8 C.; .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.38-7.34 (m, 1H), 7.25-7.15 (m, 3H), 5.52 (s, 1H), 4.20 (q, J=0.6 Hz, 1H), 3.12-2.92 (m, 2H), 2.26 (s, 3H), 2.02 (s, 3H), 1.71 (dd, J=23.5, 7.3 Hz, 2H), 1.66 (d, J=0.6 Hz, 3H), 1.02 (t, J=7.4 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 173.0, 169.6, 164.2, 136.1, 134.6, 132.0, 132.0, 128.3, 127.7, 127.1, 102.5, 57.9, 49.39, 21.1, 18.4, 17.2, 11.5. HRMS (ESI) calcd for C.sub.13H.sub.20N.sub.2O [M+H].sup.+ 220.1576, found 221.1645; HRMS (ESI) calcd for C.sub.4H.sub.4NO.sub.4S [MH].sup. 161.9867, found 161.9875.

Articaine Acesulfamate (3d)

[0130] White solid (98%, 0.438 g, 0.98 mmol). m.p. 166.2-169.8 C.; .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.41-7.40 (m, 1H), 3.83-3.82 (m 4H), 3.08-3.04 (m, 2H), 2.13 (t, J=1.4 Hz, 3H), 2.04-2.03 (m, 4H), 1.78-1.70 (m, 5H), 1.06-1.01 (m, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 173.3, 169.8, 164.5, 163.6, 140.2, 138.5, 128.75, 125.4, 102.8, 58.1, 53.0, 49.78, 21.3, 20.4, 17.4, 14.6, 11.8. HRMS (ESI) calcd for C.sub.13H.sub.20N.sub.2O.sub.3S [M+H].sup.+ 284.1195, found 285.1261; HRMS (ESI) calcd for C.sub.4H.sub.4NO.sub.4S [MH].sup. 161.9867, found 161.9875.

Mepivacaine Saccharinate (3e)

[0131] Colorless oil (95%, 0.407 g, 0.95 mmol); .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.82-7.76 (m, 2H), 7.75-7.65 (m, 2H), 7.18-7.09 (m, 3H), 4.20 (dd, J=11.8, 3.3 Hz, 1H), 3.53 (d, J=12.4 Hz, 1H), 3.18 (td, J=12.5, 3.1 Hz, 1H), 2.94 (s, 3H), 2.39 (dd, J=14.0, 3.5 Hz, 1H), 2.39 (d, J=3.4 Hz, 1H), 2.27 (s, 6H), 1.95 (d, J=12.6 Hz, 2H), 1.90-1.60 (m, 2H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 172.2, 168.5, 145.7, 136.9, 135.1, 134.4, 134.1, 133.7, 129.5, 129.2, 124.66, 121.2, 68.4, 56.4, 43.3, 30.6, 24.2, 22.5, 18.8. HRMS (ESI) calcd for C.sub.15H.sub.22N.sub.2O [M+H].sup.+ 246.1727, found 247.1799; HRMS (ESI) calcd for C.sub.7H.sub.4NO.sub.3S [MH].sup. 181.9917, found 181.9924.

Bupivacaine Saccharinate (3f)

[0132] White solid (97%, 0.456 g, 0.97 mmol). m.p. 162.4-164.8 C. .sup.1H NMR (300 MHz, DMSO-d.sub.6, ) 10.17 (s, 1H), 9.70 (s, 1H), 7.64-7.57 (m, 1H), 7.58 (s, 1H), 7.13 (m, 3H), 4.07 (s, 1H), 3.52 (d, J=12.4 Hz, 1H), 3.11-3.01 (m, 4H), 2.15 (s, 6H), 1.92-1.52 (m, 7H), 1.31 (q, J=7.4 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 172.4, 168.7, 145.8, 136.8, 136.8, 135.2, 134.4, 134.07, 133.7, 129.6, 129.2, 124.7, 121.2, 57.4, 53.3, 30.7, 27.0, 24.0, 21.2, 18.7, 14.1. HRMS (ESI) calcd for C.sub.18H.sub.28N.sub.2O [M+H].sup.+ 288.2196, found 289.2266; HRMS (ESI) calcd for C.sub.7H.sub.4NO.sub.3S [MH].sup. 181.9917, found 181.9924.

Prilocaine Saccharinate (3g)

[0133] White solid (96%, 0.386 g, 0.96 mmol). m.p. 122.0-123.4 C.; .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.81-7.69 (m, 3H), 7.41-7.38 (dd, J=7.3, 2.0 Hz, 1H), 7.30-7.20 (m, 4H), 4.22 (q, J=7.0 Hz, 1H), 3.11-3.05 (m, 2H), 2.29 (s, 3H), 1.78 (m, 5H), 1.06 (t, J=7.4 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 172.7, 169.9, 146.1, 136.4, 135.5, 134.9, 134.4, 134.0, 132.4, 128.6, 128.1, 127.4, 125.0, 121.6, 58.3, 49.7, 21.5, 18.7, 17.6, 11.9. HRMS (ESI) calcd for C.sub.13H.sub.20N.sub.2O [M+H].sup.+220.1576, found 221.1646; HRMS (ESI) calcd for C.sub.7H.sub.4NO.sub.3S [MH].sup. 181.9917, found 181.9923.

Articaine Saccharinate (3h)

[0134] Yellow oil (99%, 0.462 g, 0.99 mmol). .sup.1H NMR (300 MHz, CD.sub.3OD, ) 8.79-8.76 (m, 2H), 8.69-8.66 (m, 2H), 8.39 (t, J=1.1 Hz, 1H), 5.31 (d, J=6.0 Hz, 1H), 4.81-4.80 (m, 3H), 4.10-4.05 (m, 2H), 3.11 (dt, J=2.1, 1.0 Hz, 3H), 2.73 (d, J=7.0 Hz, 5H), 2.01 (t, J=7.4 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 172.7, 169.8, 163.5, 145.9, 140.1, 138.4, 138.4, 134.3, 133.9, 128.8, 124.9, 124.9, 121.5, 58.1, 53.0, 49.8, 21.3, 17.5, 14.6, 11.8. HRMS (ESI) calcd for C.sub.13H.sub.20N.sub.2O.sub.3S [M+H].sup.+ 284.1195, found 285.1261; HRMS (ESI) calcd for C.sub.7H.sub.4NO.sub.3S [MH].sup. 181.9917, found 181.9925.

Example 2. Syntheses of Salts of Epinephrine Acesulfamate (4a) and Epinephrine Saccharinate (4b)

[0135] ##STR00070##

[0136] Syntheses of 5a and 5b: To the solution of epinephrine hydrochloride (1.0 mmol, 220 mg) in MeCN (15 mL) equimolar quantity of sweetener potassium salt (sodium 6-methyl-1,2,3-oxathiazin-4-olate 2,2-dioxide 0.185 g for 2a and sodium benzo[d]isothiazol-3-olate 1,1-dioxide 0.205 g for 2b) was added and the mixture was then stirred for 4h at the ultrasonic bath at 50 C. After the reaction was completed (followed by TLC), reaction mixture was filtered through the 22 micron membrane filter and the filtrate was taken to dryness. After that diethyl ether (325 mL) was added to product and it was evaporated to give products 5a and 5b in quantitative yields.

Epinephrine Acesulfamate (4a)

[0137] Colorless oil (99%, 0.343 g, 0.99 mmol). .sup.1H NMR (300 MHz, CD.sub.3OD, ) 6.88 (s, 1H), 6.79-6.72 (m, 2H), 5.53 (s, 1H), 4.83-4.79 (m, 1H), 3.18-3.04 (m, 2H), 2.74 (s, 3H), 2.05-2.04 (m 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 172.0, 163.2, 145.7, 145.6, 132.8, 117.7, 115.6, 113.4, 100.4, 69.0, 55.9, 33.0, 19.0. HRMS (ESI) calcd for C.sub.9H.sub.14NO.sub.3 [M+H].sup.+ 184.0968, found 184.0964; HRMS (ESI) calcd for C.sub.4H.sub.4NO.sub.4S [MH].sup. 161.9867, found 161.9866.

Epinephrine Saccharinate (4b)

[0138] Yellow solid (96%, 0.352 g, 0.96 mmol). m.p. 82.0-83.2 C. .sup.1H NMR (300 MHz, CD.sub.3OD, ) 7.72-7.63 (m, 2H), 6.93 (d, J=2.0 Hz, 1H), 6.82-6.72 (m, 2H), 4.88 (dd, J=9.4, 3.9 Hz, 3H), 2.77 (s, 3H), 2.02 (d, J=0.6 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD, ) 171.3, 145.4, 145.3, 144.2, 133.7, 132.9, 132.6, 132.5, 123.5, 120.0, 117.7, 115.5, 113.3, 68.8, 55.7, 32.9. HRMS (ESI) calcd for C.sub.9H.sub.14NO.sub.3 [M+H].sup.+ 184.0968, found 184.0966; HRMS (ESI) calcd for C.sub.7H.sub.4NO.sub.3S [MH].sup. 181.9917, found 181.9918.

Example 3. Syntheses of Lidocaine Vanillate (5a) and Lidocaine Mono-Glycyrrhizinate (5b)

[0139] ##STR00071##

[0140] Sodium vanillate (6a) or sodium mono-glycyrrhizinate (6b) was mixed with equimolar amounts of lidocaine hydrochloride for four hours 50 C. in 1:1 MeOH/H.sub.2O. After the solvent mixture was evaporated, the crude reaction mixture was dissolved in MeCN and sodium chloride was filtered off. Evaporation of MeCN yielded lidocaine vannilate (5a) as a light yellow solid (97% yield) or lidocaine mono-glycyrrhizinate (5b) as an off-white semisolid. (96% yield).

Lidocaine Vanillate (5a)

[0141] .sup.1H NMR (400 MHz, CD.sub.3OD, ) 7.42-7.37 (m, 3H), 6.95 (d, J=1.2 Hz, 2H), 6.65 (d, J=10.8 Hz, 2H), 3.72 (d, J=2.0 Hz, 2H), 2.75 (q, J=9.6 Hz, 4H), 2.07 (s, 6H), 1.10-1.04 (m, 6H). .sup.13C NMR (75 MHz, CD.sub.3OD, ) 169.9, 150.4, 147.1, 135.4, 133.7, 127.8, 127.2, 123.6, 114.3, 114.2, 112.5, 55.6, 55.0, 46.9, 17.3, 10.5.

Lidocaine Mono-Glycyrrhizinate (5b)

[0142] .sup.1H NMR (400 MHz, CD.sub.3OD, ) 7.10 (d, J=3.6 Hz, 2H), 5.98 (br s, 1H), 3.81-3.73 (m, 2H), 3.21 (s, 1H), 3.11-3.06 (m, 2H), 2.84-2.76 (m, 4H), 2.45 (s, 1H), 2.21 (s, 6H), 2.04-1.83 (m, 3H), 1.74-1.69 (m, 4H), 1.41 (d, J=7.6 Hz, 4H), 1.28-1.17 (m, 16H), 0.99 (s, 3H), 0.83 (s, 3H), 0.8 (s, 3H). .sup.13C NMR (75 MHz, CD.sub.3OD, ) 202.7, 181.1, 173.1, 136.8, 129.3, 129.1, 128.6, 79.5, 71.1, 63.3, 57.7, 56.3, 50.1, 45.3, 44.8, 42.8, 40.5, 39.3, 38.5, 36.5, 34.0, 33.1, 32.3, 29.4, 29.0, 28.8, 27.9, 27.8, 27.6, 26.9, 25.5, 24.0, 19.4, 18.7, 17.1, 16.5, 12.5.

Example 4. Syntheses of Oxybuprocaine Saccharinate (7a) and Oxybuprocaine Acesulfamate (7b)

Oxybuprocaine Saccharinate

[0143] ##STR00072##

[0144] To a solution of oxybuprocaine hydrochloride (73 mg, 0.21 mmol) in 2 mL of ethanol was added the suspension of sodium saccharinate (43 mg, 0.21 mmol, 1 eq) in 2 mL of ethanol and reaction mixture was stirred at room temperature overnight.

[0145] The reaction mixture was then filtered and evaporated, the residue was dissolved in 3 mL of acetonitrile and after filtration and evaporation the product 7a was obtained as an off-white semisolid (103 mg, quantitative yield).

[0146] .sup.1H NMR (500 MHz, CD.sub.3CN, ) 7.75 (m, 1H); 7.65 (m, 3H); 7.5 (d, 1H); 7.4 (s, 1H); 6.65 (d, 1H); 4.8 (br. s, 2H); 4.65 (t, 2H); 4.05 (t, 2H); 3.55 (t, 2H); 3.35 (q, 4H); 2.0 (m, 4H); 1.8 (m, 2H); 1.55 (m, 2H); 1.4 (t, 6H); 1.0 (t, 3H).

Oxybuprocaine Acesulfamate

[0147] ##STR00073##

[0148] To a solution of oxybuprocaine hydrochloride (48 mg, 0.139 mmol) in 2 mL of ethanol was added a suspension of potassium acesulfame (28 mg, 0.139 mmol, 1 equivalent) in 2 mL of ethanol, and the reaction mixture was stirred at room temperature overnight.

[0149] The reaction mixture was then filtered and the solvent evaporated; the residue was dissolved in 3 mL of acetonitrile and after filtration and evaporation the product 7b was obtained as a yellow oil (67 mg, quantitative yield).

[0150] .sup.1H NMR (500 MHz, CD.sub.3CN, ) 7.55 (d, 1H); 7.45 (s, 1H); 6.75 (d, 1H); 5.4 (s, 1H); 4.8 (broad s, 2H); 4.6 (t, 2H); 4.1 (t, 2H); 3.45 (t, 2H); 3.25 (q, 4H); 2.0 (m, 10H); 1.8 (m, 2H); 1.6 (m, 2H); 1.4 (t, 6H); 1.0 (t, 3H)

Example 5. pH of Exemplary Salts

[0151] The pH values of saccharinate and acesulfamate caine salts 3a-3h with respect to concentration (conc.) as a weight-by volume percentage (% w/v) are shown in Table 1 below.

TABLE-US-00005 TABLE 1 Conc. (% w/v) pH Sodium saccharinate 10% 5.63 5% 6.09 2% 6.19 Potassium acesulfamate 10% 5.78 5% 6.33 2% 5.98 Mepivacaine hydrochloride 10% 3.73 5% 3.77 2% 4.53 Mepivacaine saccharinate 10% 3.95 5% 4.06 2% 4.23 Mepivacaine acesulfamate 10% 4.00 5% 4.87 2% 4.91 Bupivacaine hydrochloride 10% 4.23 5% 4.81 2% 5.22 Bupivacaine saccharinate 10% 3.84 5% 3.66 2% 5.19 Bupivacaine acesulfamate 10% 4.25 5% 5.13 2% 5.38 Lidocaine hydrochloride 10% 3.94 5% 4.53 2% 4.65 Lidocaine acesulfamate 10% 4.84 5% 5.08 2% 5.26 Lidocaine saccharinate 10% 4.31 5% 4.41 2% 4.51 Prilocaine hydrochloride 10% 2.10 5% 3.42 2% 4.60 Prilocaine saccharinate 10% 4.47 5% 4.96 2% 5.04 Prilocaine acesulfamate 10% 4.71 5% 5.00 2% 5.16 Epinephrine hydrochloride 10% 2.72 5% 3.91 2% 4.84 Epinephrine saccharinate 10% 3.57 5% 4.03 2% 4.41 Epinephrine acesulfamate 10% 4.01 5% 4.14 2% 4.34 Articaine hydrochloride 10% 4.22 5% 4.62 2% 4.78 Articaine saccharinate 10% 3.83 5% 3.95 2% 4.15 Articaine acesulfamate 10% 3.50 5% 3.79 2% 3.95

Example 6. Responses of Rats to Pain after Administration of a Caine Salt

[0152] 1% by weight solutions of 3a-3h were injected into the hindpaw of rats and withdrawal latency to a thermal stimulus was recorded 10 minutes post-injection. Response to hindpaw heat pain was determined by placing unrestrained rats on a clear glass platform under a small plastic cage and rats habituated for 5 min. A radiant heat source was aimed directly under the ventral hindpaw surface and the time to paw withdrawal was recorded. Baseline responses were obtained under nave conditions (e.g., no injection), while post-treatment effects of caine salts 3a-3h in the respective vehicle (water) were assessed for 10 minutes following injection (100 l). A cutoff of 32 seconds was used to prevent tissue damage. FIG. 2 shows that caine salts 3a, 3b, 3c, 3d, 3e, 3f, and 3h (N=10 animals/group) produced a significant increase in latency time as compared to the nave animals, indicating that the indicated caine salts were effective in inhibiting pain.

Example 7. Palatability Assessments of Caine Salts 3a-3h

[0153] Rats were food-fasted (12-15 hours) prior to testing. Rats were then placed in an Orofacial Pain Assessment Device (OPAD, Stoelting Company, Wood Dale, Ill.) which consisted of a holding chamber and a bottle that contained the various test solutions. Animals (N=5/solution) were placed in the holding chamber and allowed access to the solution for 7 minutes and the number of solution licking events were automatically recorded. FIG. 2 shows that rats successfully consumed the different caine salt solutions.

OTHER EMBODIMENTS

[0154] In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0155] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0156] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0157] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

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