Hydrazone derivatives and uses thereof

• US 20070207093A1
• Filed: 11/03/2006
• Published: 09/06/2007
• Est. Priority Date: 11/03/2005
• Status: Abandoned Application

• Current Assignee: Redpoint Bio Corporation
• Original Assignee: Linquagen Corporation
• Inventors: Bryant, Robert, Cerne, Rok, Lee, Seunghun, Atwal, Anita, Palmer, Roy, Atwal, Karnail
• Application Number:
  US11/592,228
• Publication Number:
  US 20070207093A1
• Time in Patent Office: Days
• US Class Current: 424/49
• CPC Class Codes: A23L 27/84 Flavour masking or reducing agents
• CPC Class Codes: A23L 27/86 Addition of bitterness inhibitors
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 8/40 containing nitrogen quinones containing nitrogen A61K8/355
• CPC Class Codes: A61K 8/415 Aminophenols
• CPC Class Codes: A61K 8/42 Amides
• CPC Class Codes: A61K 8/46 containing sulfur A61K8/44 takes precedence
• CPC Class Codes: A61K 8/49 containing heterocyclic compounds
• CPC Class Codes: A61K 8/4913 having five membered rings, e.g. pyrrolidone carboxylic acid
• CPC Class Codes: A61K 8/492 having condensed rings, e.g. indol
• CPC Class Codes: A61K 8/4926 having six membered rings
• CPC Class Codes: A61K 8/4946 Imidazoles or their condensed derivatives, e.g. benzimidazoles
• CPC Class Codes: A61K 8/4973 with oxygen as the only hetero atom
• CPC Class Codes: A61K 8/498 having 6-membered rings or their condensed derivatives, e.g. coumarin
• CPC Class Codes: A61K 8/69 containing fluorine
• CPC Class Codes: A61K 8/70 containing perfluoro groups, e.g. perfluoroethers
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin

Abstract

The present invention is directed to the use of a compound having the formula
wherein R¹, R², R³, R⁴, L¹, and L² are defined herein. The compounds of the present invention are useful as inhibitors of certain taste perceptions and functions. The invention is also directed to compositions comprising a compound according to the above formula.

Claims

1. A method of inhibiting a taste, comprising administering to a subject in need of said taste inhibiting one or more compounds of Formula I:

or a physiologically acceptable salt thereof, wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C-_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L²and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted;

wherein said compound is administered in an amount sufficient to inhibit said taste.

2. The method according to claim 1, wherein R¹ is optionally substituted C_6-10 aryl.

3. The method according to claim 1, wherein R¹ is optionally substituted 5-14 membered heteroaryl.

4. The method according to claim 1, wherein R¹ is optionally substituted C_3-10 cycloalkyl or optionally substituted C_3-10 cycloalkenyl.

5. The method according to claim 1, wherein R¹ is optionally substituted 3-10 membered cycloheteroalkyl or optionally substituted 3-10 membered cycloheteroalkenyl.

6. The method according to claim 1, wherein R¹ is optionally substituted C_1-6 alkyl.

7. The method according to claim 1, wherein R² is H.

8. The method according to claim 1, wherein R² is C-_1-6 alkyl.

9. The method according to claim 1, wherein R² is C_6-10 aryl or C_6-10 aryl(C_1-6)alkyl.

10. The method according to claim 1, wherein R³ is H.

11. The method according to claim 1, wherein R³ is C_1-6 alkyl.

12. The method according to claim 1, wherein R³ is C_6-10 aryl.

13. The method according to claim 1, wherein R³ is cyano.

14. The method according to claim 1, wherein R⁴ is optionally substituted C_1-6 alkyl.

15. The method according to claim 1, wherein R⁴ is optionally substituted C_6-10 .

16. The method according to claim 1, wherein R⁴ is optionally substituted 5-10 membered heteroaryl.

17. The method according to claim 1, wherein R⁴ is optionally substituted C_3-10 cycloalkyl or optionally substituted C_3-10 cycloalkenyl.

18. The method according to claim 1, wherein R⁴ is optionally substituted 3-10 membered cycloheteroalkyl or optionally substituted 3-10 membered cycloheteroalkenyl.

19. The method according to claim 1, wherein L¹ is absent.

20. The method according to claim 1, wherein L¹ is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted.

21. The method according to claim 1, wherein L¹ contains a cyclopropyl group.

22. The method according to claim 1, wherein L² is absent.

23. The method according to claim 1, wherein L² is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted.

24. The method according to claim 1, wherein R¹ is unsubstituted phenyl.

25. The method according to claim 1, wherein R¹ is phenyl or naphthyl, each of which is substituted 1, 2, or 3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_3-6 alkenyloxy, C_1-6 alkylenedioxy, C_1-6 alkoxy(C_1-6)alkyl, C_1-6 aminoalkyl, C_1-6 aminoalkoxy, C_1-6 hydroxyalkyl, C_2-6 hydroxyalkoxy, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_2-6 alkoxycarbonyl, carboxy, (C_1-6)alkoxy(C_2-6)alkoxy, C_2-6 carboxyalkoxy, and C_2-6 carboxyalkyl.

26. The method according to claim 1, wherein R¹ is a nitrogen-containing heteroaryl.

27. The method according to claim 1, R¹ is selected from the group consisting of pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl, and benzothiazolyl, each of which is optionally substituted.

28. The method according to claim 1, wherein R⁴ is unsubstituted phenyl.

29. The method according to claim 1, wherein R⁴ is phenyl or naphthyl, each of which is substituted 1, 2, or 3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_3-6 alkenyloxy, C_1-6 alkylenedioxy, C_1-6 alkoxy(C_1-6)alkyl, C_1-6 aminoalkyl, C_1-6 aminoalkoxy, C_1-6 hydroxyalkyl, C_2-6 hydroxyalkoxy, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_2-6 alkoxycarbonyl, carboxy, (C_1-6)alkoxy(C_2-6)alkoxy, C_2-6 carboxyalkoxy, and C_2-6 carboxyalkyl.

30. The method according to claim 1, wherein R⁴ is a nitrogen-containing heteroaryl.

31. The method according to claim 1, wherein R⁴ is selected from the group consisting of pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl, and benzothiazolyl, each of which is optionally substituted.

32. The method according to claim 1, wherein R¹ is optionally substituted C_6-10 aryl;

R²is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ is optionally substituted C_6-10 aryl.

33. The method according to claim 1, wherein R¹is optionally substituted C_6-10 aryl;

R² is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ is optionally substituted 5-10 membered heteroaryl.

34. The method according to claim 1, wherein R¹ is optionally substituted C_6-10 aryl;

R² is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ is optionally substituted 5-10 membered heteroaryl.

35. The method according to claim 1, wherein R¹ is optionally substituted 5-10 membered heteroaryl;

R² is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ is optionally substituted 5-10 membered heteroaryl.

36. The method according to claim 1, wherein R¹ is optionally substituted C_6-10 aryl;

R² is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ is optionally substituted C_3-10 cycloalkyl.

37. The method according to claim 1, wherein R¹ is optionally substituted 5-10 membered heteroaryl;

R² is H or C_1-6 alkyl;

R³ is H or C_1-6 alkyl; and

R⁴ and L² together form —

N═

N-aryl.

38. The method according to claim 1, wherein R¹ is optionally substituted 5-10 membered heteroaryl;

R⁴ is optionally substituted C_6-10 aryl, such as phenyl and naphthyl; and

L¹ and L² are absent.

39. The method according to claim 1, wherein R² is H, C_1-6 alkyl, or C_6-10 aryl(C_1-6)alkyl;

L¹ is absent, or is a linker containing 1-6 carbon and/or heteroatoms and which is optionally substituted;

R³, R⁴, and L² together with the carbon atom form a group selected from C_6-10 aryl, 5-10 membered heteroaryl, C_3-10 cycloalkyl, C_3-10 cycloalkenyl, 3-10 membered cycloheteroalkyl, 3-10 membered cycloheteroalkenyl, each of which is optionally substituted.

40. The method according to claim 1, wherein R¹ is heteroaryl;

R² is H;

R⁴ is heteroaryl;

L¹ is absent; and

L² is N═

N.

41. The method according to claim 1, wherein R¹ is a bicycloalkyl;

R² is H;

R³ is H;

R⁴ is aryl or heteroaryl;

L¹ is absent; and

L² is absent.

42. The method according to claim 1, wherein R¹ is aryl;

R² is H;

R³ is H;

R⁴ is aryl or heteroaryl;

L¹ is an optionally substituted a linker containing 2-4 carbon or hetero atoms; and

L² is absent.

43. The method according to claim 1, wherein R¹ is cycloalkenyl;

R² is H;

R³ is H;

R⁴ is aryl or heteroaryl;

L¹ is an optionally substituted a linker containing 2-4 carbon or hetero atoms; and

L² is absent.

44. The method according to claim 1, wherein the compound of Formula I selected from the group consisting of

methyl 4-((E)-((Z)-1-(2-(benzo[d]thiazol-2-1)hydrazono)-2-methyl-propyl)diazenyl)benzoate;

(E)-2-(4-bromo-2-((2-(quinolin-8-yl)hydrazono)methyl)phenoxy)acetic acid;

(E)-N′

-(3,4-dimethoxybenzylidene)-2-(naphthalene-1-yl)acetohydrazide;

(E)-N′

-(3,4-dimethoxybenzylidene)-2-phenylcyclopropane-carbohydrazide;

(E)-3-cyclohexenyl-4-hydroxy-N′

-(4-methoxybenzylidene)-butanehydrazide;

(E)-N′

-(3,4-dimethoxybenzylidene)-4-hydroxyhexanehydrazide;

2-((Z)-2-(phenyl-((E)-phenyldiazenyl)methylene)hydrazinyl)benzoic acid;

(E)-N′

-(3,4-dimethoxybenzylidene)-2-(m-tolyloxy)acetohydrazide;

(E)-N′

-(4-(allyloxy)-3-methoxybenzylidene)-2-(3-bromobenzylthio)-acetohydrazide;

(E)-N′

-(4-isopropylbenzylidene)bicyclo[4.1.0]heptane-7-carbohydrazide;

(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrophenyl)hydrazono)-ethylidene)indoline;

(E)-N′

-(4-(diethylamino)-2-hydroxybenzylidene)-2-phenylcyclo-propanecarbohydrazide;

(4-(trifluoromethylthio)phenyl)carbonohydrazonoyldicyanide;

N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindolin-3-ylidene)hydrazinyl)-3-oxo-1-phenylprop-1-en-2-yl)benzamide;

(Z)-2-(2-((1-butyl-1H-indol-3-yl)methylene)hydrazinyl)benzoic acid;

(E)-4-((2-benzyl-2-phenylhydrazono)methyl)pyridine;

(Z)-N′

-((1H-Pyrrol-2-yl)methylene)tricyclo[3.3.1.1^3,7]decane-3-carbohydrazide;

(Z)-1-(2-(4-(ethyl(2-hydroxyethyl)amino)phenyl)hydrazono)-naphthalen-2-(1H)-one;

(E)-4-((2-(5-chloro-3-(trifluoromethyl)pyridini-2-yl)-2-2-methyl-hydrazono)methyl)benzene-1,3-diol;

(E)-2-(3,4-dimethylphenylamino)-N′

-(4-morpholino-3-nitro-benzylidene)acetohydrazide;

(Z)-3-(2-nitro-5-(pyrrolidin-1-yl)phenyl)hydrazono)quinuclidine; and

(E)-2-((2-(1H-benzo[d]imidazol-2-yl)hydrazono)methyl)-5-(diethylamino)phenol.

45. The method according to claim 1, wherein the compound of Formula I is selected from the group consisting of

N-(3-(2-((6-Bromobenzo[d][1,3]dioxol-5-yl)methylene)hydrazinyl)-1-(4-(dimethylamino)phenyl)-3-oxoprop-1-en-2-yl)benzamide;

N-(1-(4-(Diethylamino)phenyl)-3-(2-(4-hydroxy-3-iodo-5-methoxybenzylidene)hydrazinyl)-3-oxoprop-1-en-2-yl)benzamide;

N′

-(4-Hydroxy-3-methoxybenzylidene)-3-(1-hydroxycyclopentyl)-propanehydrazide;

4-Nitro-N′

-(3,4,5-trimethoxybenzylidene)benzohydrazide;

N′

-(4-(diethylamino)-2-hydroxybenylidine)phenylcyclopropane-carboxhydrazide;

N′

-(5-Bromo-2-oxoindolin-3-ylidene)-2-(2-bromo-4-methoxyphenoxy)acetohydrazide;

3-(1H-indol-3-yl)-N′

-(3,4,5-trimethoxybenzylidene)propanehydrazide;

N′

-(2-oxoindolin-3-ylidene)-2-(2-methyl-4-(1,1-dimethylethyl)-phenoxy)acetohydrazide;

2-(4-Chlorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(3,4-dimethoxybenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-chlorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(3-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(4-chlorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(3-methoxybenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(4-chlorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(3-methylthiobenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-chlorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(2-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(2-chlorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-chlorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-chlorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(2-fluorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(3-fluorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

2-(4-fluorophenyl)-N′

-(4-trifluoromethylbenylidine)cyclopropane-carboxhydrazide;

N′

-(3,4-dimethoxybenzylidene)-2-(4,8-dimethylquinolin-2-ylthio)-acetohydrazide;

3-(9H-carbazol-9-yl)-N′

-(3,4-dimethoxybenzylidene)propane-hydrazide;

and physiologically acceptable salts thereof.

46. The method according to claim 1, wherein said subject is human.

47. The method according to claim 1, wherein the compound is administered in an amount from about 0.01 mg to about 100 mg.

48. The method according to claim 1, wherein the compound is administered as component of a pharmaceutical product.

49. The method according to claim 48, wherein the compound is present in the pharmaceutical product in an amount from about 0.01% to 50% by weight.

50. The method according to claim 1, wherein the compound is administered as component of a food product.

51. The method according to claim 50, wherein the compound is present in the food product in an amount from about 0.01% to 10% by weight.

52. The method according to claim 1, wherein the compound is administered as component of a dental hygienic product.

53. The method according to claim 52, wherein the compound is present in the dental hygienic product in an amount from about 0.01% to 20% by weight.

54. The method according to claim 1, wherein the taste is produced by a biologically active agent.

55. The method according to claim 1, wherein the taste is produced by one or more agents selected from the group consisting of antipyretics, analgesics, laxatives, appetite depressants, antacidics, antiasthmatics, antidiuretics, agents active against flatulence, antimigraine agents, psychopharmacological agents, spasmolytics, sedatives, antihyperkinetics, tranquilizers, antihistaminics, decongestants, beta-receptor blockers, agents for alcohol withdrawal, antitussives, fluorine supplements, local antibiotics, corticosteroid supplements, agents against goiter formation, antiepileptics, agents against dehydration, antiseptics, NSAIDs, gastrointestinal active agents, alkaloids, supplements for trace elements, ion-exchange resins, cholesterol-depressant agents, lipid-lowering agents, antiarrhythmics, and expectorants.

56. The method according to claim 1, wherein the taste is a bitter taste.

57. A method of inhibiting the depolarization of a taste receptor cell, comprising contacting said taste receptor cell with one or more compounds of Formula I:

or a physiologically acceptable salt thereof, wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted;

wherein said compound is administered in an amount sufficient to inhibit the depolarization of a taste receptor cell.

58. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and one or more compounds according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.

59. A method of preparing an improved pharmaceutical composition, wherein the improvement comprises adding to a pharmaceutical composition one or more compounds according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.

60. A food product comprising one or more food ingredients and one or more compounds according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.

61. A cosmetic product comprising one or more cosmetic ingredients and a compound according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C-_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.

62. A method of preparing an improved cosmetic product, wherein the improvement comprises adding to a cosmetic product a compound according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.

63. A dental hygienic product comprising one or more dental hygienic ingredients and a compound according to Formula I:

or physiologically acceptable salt thereof wherein

R¹ is C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, and C_1-6 alkyl, each of which is optionally substituted;

R² is H, C_1-6 alkyl, C_6-10 aryl, or C_6-10 aryl(C_1-6)alkyl;

R³ is H, C_1-6 alkyl, C_6-10 aryl, or cyano;

R⁴ is C_1-6 alkyl, C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano;

L¹ is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

L² is absent, or is a linker containing 1-10 carbon and/or heteroatoms and which is optionally substituted;

or

R³, R⁴, and L², together with the carbon atom to which L² and R³ are attached, form a group selected from C_6-14 aryl, 5-14 membered heteroaryl, C_3-14 cycloalkyl, C_3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl, 3-14 membered cycloheteroalkenyl, each of which is optionally substituted.