ESTERS OF A RETINOID AND A TOCOPHEROL OR TERT-BUTYLHYDROQUINONE AND PREPARATIONS THEREOF

Abstract

The present disclosure provides esters of a retinoid and an alcohol selected from the group consisting of tocopherols and tert-butylhydroquinone, such as esters of Formula (I). The present disclosure also provides compositions and kits comprising the esters, methods of producing the esters, and methods of using the esters (e.g., for treating or preventing a skin disease, slowing the ageing of the skin, improving the appearance of the skin, or modulating a retinoid receptor).

##STR00001##

Claims

1. An ester of Formula (I): ##STR00059## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein X is of the formula: ##STR00060##

2. The ester of claim 1, wherein X is of the formula: ##STR00061##

3. The ester of claim 1, wherein the ester is of the formula: ##STR00062## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

4. The ester of claim 1, wherein the ester is of the formula: ##STR00063## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

5. The ester of claim 1, wherein the ester is of the formula: ##STR00064## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

6. The ester of claim 1, wherein the ester is of the formula: ##STR00065## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

7. The ester of claim 1, or a tautomer or isotopically labeled compound thereof.

8. A method of producing the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, the method comprising incubating a second reaction mixture for a second time duration sufficient to produce the ester, tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal, wherein the second reaction mixture comprises: (a) an anhydride of Formula (B): ##STR00066## or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein R is substituted or unsubstituted alkyl; (b) an alcohol of Formula (C):
HO—X   (C), or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof; (c) a second solvent; (d) optionally a second base; and (e) optionally an esterification catalyst.

9. The method of claim 8, wherein Formula (B) is of the formula: ##STR00067##

10-23. (canceled)

24. The method of claim 8, wherein the method further comprises incubating a third reaction mixture comprising the second reaction mixture and ethanolamine, or a salt thereof, for a third time duration.

25-29. (canceled)

30. The method of claim 8, wherein the method further comprises purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

31. (canceled)

32. The method of claim 8, wherein the method further comprises incubating a first reaction mixture for a first time duration sufficient to produce (a) of the second reaction mixture, wherein: the first reaction mixture comprises: (a) an acid of Formula (A1): ##STR00068## or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof; (b) a chloroformate of Formula (A2):
Cl—C(═O)—O—R   (A2), or an isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein R is substituted or unsubstituted alkyl; (c) a first solvent; and (d) optionally a first base; and the step of incubating a first reaction mixture is prior to the step of incubating the second reaction mixture.

33-48. (canceled)

49. The method of claim 32, wherein the method further comprises purifying (a) of the second reaction mixture, wherein the step of purifying (a) of the second reaction mixture is prior to the step of incubating the second reaction mixture.

50-52. (canceled)

53. A composition comprising: the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof; and optionally an excipient.

54-57. (canceled)

58. A composition comprising the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, produced by the method of claim 8.

59. A kit comprising: the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof; and optionally instructions for using the ester, tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal.

60. A method of treating a skin disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount of the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

61. A method of preventing a skin disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount of the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

62-68. (canceled)

69. A method of slowing the ageing of the skin or improving the appearance of the skin of a subject comprising administering to the subject an effective amount of the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

70. (canceled)

71. A method of modulating a retinoid receptor in a subject, biological sample, tissue, or cell comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of the ester of claim 1, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

72-75. (canceled)

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE

Esters and Method of Producing the Esters

[0106] In one aspect, the present disclosure provides an ester of Formula (I):

##STR00009##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein X is of the formula:

##STR00010##

[0107] In certain embodiments, X is of the formula:

##STR00011##

[0108] In certain embodiments, is:

##STR00012##

[0109] In certain embodiments, is:

##STR00013##

[0110] In certain embodiments, is:

##STR00014##

[0111] In certain embodiments, is:

##STR00015##

[0112] In certain embodiments, is:

##STR00016##

[0113] In certain embodiments, is:

##STR00017##

[0114] In certain embodiments, is:

##STR00018##

[0115] In certain embodiments, is:

##STR00019##

[0116] In certain embodiments, is:

##STR00020##

[0117] In certain embodiments, is:

##STR00021##

[0118] In certain embodiments, is:

##STR00022##

[0119] In certain embodiments, is:

##STR00023##

[0120] In certain embodiments, is:

##STR00024##

[0121] In certain embodiments, is:

##STR00025##

[0122] In certain embodiments, is:

##STR00026##

[0123] In certain embodiments, is:

##STR00027##

[0124] In certain embodiments, the ester is of Formula (1):

##STR00028##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the ester is of Formula (1), or a tautomer or isotopically labeled compound thereof. In certain embodiments, the ester is of Formula (1), or a tautomer thereof. In certain embodiments, Formula (1) is:

##STR00029##

[0125] In certain embodiments, the ester is of Formula (2):

##STR00030##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the ester is of Formula (2), or a tautomer or isotopically labeled compound thereof. In certain embodiments, the ester is of Formula (2), or a tautomer thereof. In certain embodiments, Formula (2) is:

##STR00031##

[0126] In certain embodiments, the ester is of Formula (3):

##STR00032##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the ester is of Formula (3), or a tautomer or isotopically labeled compound thereof. In certain embodiments, the ester is of Formula (3), or a tautomer thereof.

[0127] In certain embodiments, the ester is of Formula (4):

##STR00033##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the ester is of Formula (4), or a tautomer or isotopically labeled compound thereof. In certain embodiments, the ester is of Formula (4), or a tautomer thereof. In certain embodiments, Formula (4) is:

##STR00034##

[0128] In certain embodiments, the ester is of Formula (5):

##STR00035##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the ester is of Formula (5), or a tautomer or isotopically labeled compound thereof. In certain embodiments, the ester is of Formula (5), or a tautomer thereof. In certain embodiments, Formula (5) is:

##STR00036##

[0129] In certain embodiments, the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is a substantially racemic mixture of isomers (e.g., E/Z and/or stereoisomers). In certain embodiments, the molar concentration of most prevalent isomer in the mixture of isomers is between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or between 99% and 99.9%, inclusive.

[0130] In another aspect, the present disclosure provides a method of producing the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, the method comprising incubating a second reaction mixture for a second time duration sufficient to produce the ester, tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal, wherein the second reaction mixture comprises:

[0131] (a) an anhydride of Formula (B):

##STR00037##

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein R is substituted or unsubstituted alkyl;

[0132] (b) an alcohol of Formula (C):

HO—X   (C),

or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof;

[0133] (c) a second solvent;

[0134] (d) optionally a second base; and

[0135] (e) optionally an esterification catalyst.

[0136] In certain embodiments, Formula (B) is of the formula:

##STR00038##

[0137] In certain embodiments, Formula (C) is Formula (C1):

##STR00039##

and

[0138] Formula (I) is Formula (I1):

##STR00040##

[0139] In certain embodiments, Formula (C) or (C1) is of the formula:

##STR00041##

[0140] In certain embodiments, Formula (C) is Formula (C2):

##STR00042##

and

[0141] Formula (I) is Formula (I2):

##STR00043##

[0142] In certain embodiments, Formula (C) or (C2) is of the formula:

##STR00044##

[0143] In certain embodiments, Formula (C) is Formula (C3):

##STR00045##

[0144] Formula (I) is Formula (I3):

[0145] In certain embodiments, Formula (C) is Formula (C4):

##STR00046##

and

[0146] Formula (I) is Formula (I4):

##STR00047##

[0147] In certain embodiments, Formula (C) or (C4) is of the formula:

##STR00048##

[0148] In certain embodiments, Formula (C) is Formula (C5):

##STR00049##

and

[0149] Formula (I) is Formula (15):

##STR00050##

[0150] In certain embodiments, Formula (C) or (C5) is of the formula:

##STR00051##

[0151] In certain embodiments, the anhydride of Formula (B), or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is substantially a single isomer (e.g., E/Z and stereoisomer). In certain embodiments, the anhydride of Formula (B), or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is a mixture of isomers (e.g., E/Z isomers and/or stereoisomers), and the molar concentration of the most prevalent isomer (e.g., the isomer with fully retained isomerism with respect to the acid of Formula (A1), or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof) in the mixture of isomers is between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or between 99% and 99.9%, inclusive.

[0152] In certain embodiments, the molar ratio of the amount of (a) of the second reaction mixture to the amount of (b) of the second reaction mixture is between 1:0.1 and 1:0.3, between 1:0.3 and 1:0.75, between 1:0.75 and 1:1, between 1:1 and 1:1.25, between 1:1.25 and 1:3, or between 1:3 and 1:10, inclusive. In certain embodiments, the molar ratio of the amount of (a) of the second reaction mixture to the amount of (b) of the second reaction mixture is between 1:0.3 to 1:3, inclusive. In certain embodiments, the molar ratio of the amount of (a) of the second reaction mixture to the amount of (b) of the second reaction mixture is between 1:0.75 to 1:2, inclusive. In certain embodiments, the molar ratio of the amount of (a) of the second reaction mixture to the amount of (b) of the second reaction mixture is between 1:0.75 to 1:1.25, inclusive.

[0153] In certain embodiments, the second solvent is substantially one single solvent. In certain embodiments, the second solvent is a mixture of two or more (e.g., three) solvents (e.g., solvents described in this paragraph). In certain embodiments, the second solvent is an organic solvent. In certain embodiments, the second solvent is an aprotic solvent. In certain embodiments, the second solvent is an ether solvent. In certain embodiments, the second solvent is a ketone solvent. In certain embodiments, the second solvent is an alkane solvent. In certain embodiments, the second solvent is an alcohol solvent. In certain embodiments, the second solvent is an aromatic organic solvent. In certain embodiments, the second solvent is benzene, toluene, o-xylene, m-xylene, or p-xylene, or a mixture thereof. In certain embodiments, the second solvent is a non-aromatic organic solvent. In certain embodiments, the second solvent is acetonitrile, dioxane, or tetrahydrofuran, or a mixture thereof. In certain embodiments, the second solvent is acetonitrile. In certain embodiments, the first solvent is acetone, chloroform, dichloromethane, diethyl ether, ethyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran, or a mixture thereof. In certain embodiments, the second solvent is an inorganic solvent. In certain embodiments, the boiling point of the second solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, between 100 and 130, between 130 and 160, or between 160 and 200° C., inclusive.

[0154] In certain embodiments, the second base, if present, is an organic base. In certain embodiments, the second base, if present, is a mono-, di-, or tri-(unsubstituted C.sub.1-6 alkyl) amine. In certain embodiments, the second base, if present, is a tri-(unsubstituted C.sub.1-6 alkyl) amine. In certain embodiments, the second base, if present, is trimethylamine, triethylamine, or N,N-diisopropylethylamine, or a mixture thereof. In certain embodiments, the second base, if present, is a cyclic non-aromatic amine. In certain embodiments, the second base, if present, is an aromatic amine (e.g., pyridine). In certain embodiments, the second base, if present, is an inorganic base. In certain embodiments, the second base, if present, is Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, or K.sub.2CO.sub.3, or a mixture thereof. In certain embodiments, the second base, if present, is LiHCO.sub.3, NaHCO.sub.3, or KHCO.sub.3, or a mixture thereof. In certain embodiments, the second base, if present, is ammonia, ammonium carbonate, or ammonium hydroxide.

[0155] In certain embodiments, the molar ratio of the amount of the second base, if present, to the amount of (b) of the second reaction mixture is between 1:1 and 2:1, between 2:1 and 3:1, between 3:1 and 5:1, or between 5:1 and 10:1, inclusive. In certain embodiments, the molar ratio of the amount of the second base, if present, to the amount of (b) of the second reaction mixture is between 1:1 and 5:1, inclusive.

[0156] In certain embodiments, the esterification catalyst, if present, is a Yamaguchi esterification catalyst. In certain embodiments, the esterification catalyst, if present, is 4-dimethylaminopyridine, or a salt or solvate thereof. In certain embodiments, the esterification catalyst, if present, is 4-(pyrrolidin-1-yl)pyridine, or a salt or solvate thereof. In certain embodiments, the esterification catalyst, if present, is pyridine, or a salt thereof.

[0157] In certain embodiments, the molar ratio of the amount of the esterification catalyst, if present, to the amount of (b) of the second reaction mixture is between 0.01:1 and 0.03:1, between 0.03:1 and 0.1:1, between 0.1:1 and 0.3:1, between 0.3:1 and 1:1, between 1:1 and 2:1, or between 2:1 and 5:1, inclusive. In certain embodiments, the molar ratio of the amount of the esterification catalyst, if present, to the amount of (b) of the second reaction mixture is between 0.1:1 to 2:1, inclusive. In certain embodiments, the molar ratio of the amount of the esterification catalyst, if present, to the amount of (b) of the second reaction mixture is between 0.03:1 to 1:1, inclusive.

[0158] In certain embodiments, the second reaction mixture is substantially free of water (e.g., H.sub.2O, HDO, or D.sub.2O, or a mixture thereof). In certain embodiments, the second reaction mixture is between 95% and 97%, between 97% and 99%, between 99% and 99.9%, or between 99.9% and 99.99%, by weight, free of water.

[0159] In certain embodiments, the temperature of the second reaction mixture is between −20 and 0, between 0 and 20, between 20 and 40, between 40 and 60, between 60 and 80, or between 80 and 100° C., inclusive. In certain embodiments, the temperature of the second reaction mixture is between 0 and 60° C., inclusive. In certain embodiments, the temperature of the second reaction mixture is between 20 and 60° C., inclusive. In certain embodiments, the temperature of the second reaction mixture is between 30 and 60° C., inclusive. In certain embodiments, the temperature of the second reaction mixture is substantially constant over the second time duration.

[0160] In certain embodiments, the second time duration is between 1 and 10 minutes, between 10 and 60 minutes, between 1 and 3 hours, between 3 and 6 hours, between 6 and 12 hours, between 12 and 24 hours, or between 1 and 3 days, inclusive. In certain embodiments, the second time duration is between 10 minutes and 1 day, inclusive. In certain embodiments, the second time duration is between 20 minutes and 3 hours, inclusive.

[0161] In certain embodiments, the rate of conversion of (b) of the second reaction mixture to the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is between 10% and 20%, between 20% and 40%, between 40% and 60%, between 60% and 80%, or between 80% and 99%, inclusive. In certain embodiments, the rate of conversion of (b) of the second reaction mixture to the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is between 10% and 99%, inclusive. In certain embodiments, the rate of conversion of (b) of the second reaction mixture to the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is between 40% and 70%, inclusive.

[0162] In certain embodiments, the method further comprises incubating a third reaction mixture comprising the second reaction mixture and ethanolamine, or a salt thereof, for a third time duration.

[0163] In certain embodiments, the molar ratio of the amount of ethanolamine, or a salt thereof, to the amount of (b) of the second reaction mixture is between 0.1:1 and 1:1, between 1:1 and 10:1, between 10:1 and 100:1, or between 100:1 and 1,000:1, inclusive. In certain embodiments, the molar ratio of the amount of ethanolamine, or a salt thereof, to the amount of (b) of the second reaction mixture is between 1:1 and 100:1, inclusive.

[0164] In certain embodiments, the temperature of the third reaction mixture is between −20 and 0, between 0 and 20, between 20 and 40, between 40 and 60, between 60 and 80, or between 80 and 100° C., inclusive. In certain embodiments, the temperature of the third reaction mixture is between 0 and 60° C., inclusive. In certain embodiments, the temperature of the third reaction mixture is between 20 and 60° C., inclusive. In certain embodiments, the temperature of the third reaction mixture is between 30 and 60° C., inclusive. In certain embodiments, the temperature of the third reaction mixture is substantially constant over the third time duration.

[0165] In certain embodiments, the third time duration is between 1 and 10 minutes, between 10 and 60 minutes, between 1 and 3 hours, between 3 and 6 hours, between 6 and 12 hours, between 12 and hours, or between 1 and 3 days, inclusive. In certain embodiments, the third time duration is between 10 minutes and 1 day, inclusive. In certain embodiments, the third time duration is between 10 minutes and 1.5 hours, inclusive.

[0166] In certain embodiments, the third reaction mixture is substantially free of water (e.g., H.sub.2O, HDO, or D.sub.2O, or a mixture thereof). In certain embodiments, the third reaction mixture is between 95% and 97%, between 97% and 99%, between 99% and 99.9%, or between 99.9% and 99.99%, by weight, free of water.

[0167] In certain embodiments, the step of incubating the third reaction mixture is immediately after the step of incubating the second reaction mixture.

[0168] In certain embodiments, the method further comprises purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof. In certain embodiments, the step of purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, comprises liquid-liquid phase separation, drying, filtration, concentration, chromatography, decolorization, or recrystallization, or a combination thereof. In certain embodiments, the liquid-liquid phase separation is a separation of an organic liquid phase and an aqueous phase. In certain embodiments, the drying is drying an organic liquid phase over a solid drying agent (e.g., anhydrous Na.sub.2SO.sub.4, anhydrous MgSO.sub.4, anhydrous CaSO.sub.4, anhydrous CaCl.sub.2), or activated molecular sieves). In certain embodiments, the filtration is a filtration of a mixture of a liquid phase (e.g., organic liquid phase) and a solid drying agent, or hydrates thereof, to remove the solid drying agent, or the hydrates thereof. In certain embodiments, the concentration is concentration of a liquid phase (e.g., organic liquid phase) to remove part or substantially all of the volatiles (e.g., organic solvents). In certain embodiments, the concentration is performed under a pressure lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive). In certain embodiments, the concentration is performed under a temperature of between 0 and 10, between 10 and 20, between 20 and 25, between 25 and 35, between 35 and 50, or between 50 and 80° C., inclusive. In certain embodiments, the chromatography is flash chromatography (e.g., normal-phase flash chromatography (e.g., over silica gel)). In certain embodiments, the chromatography is high-performance liquid chromatography (HPLC) (e.g., reverse-phase HPLC or normal-phase HPLC). In certain embodiments, the decolorization comprises redissolving in an organic solvent, decolorization, and concentration. In certain embodiments, the decolorization comprises contacting with a solid decolorization agent (e.g., activated charcoal). In certain embodiments, the recrystallization is a single-solvent recrystallization. In certain embodiments, the recrystallization is a multi-solvent (e.g., bi-solvent or tri-solvent) recrystallization.

[0169] In certain embodiments, the recrystallization is a hot filtration-recrystallization. In certain embodiments, the step of purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, further comprises removing part or substantially all of the volatiles (e.g., organic solvents) by decreasing the pressure (e.g., to a pressure of lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive) and/or increasing the temperature (e.g., to a temperature between 25 and 35, between 35 and 50, or between and 80° C., inclusive).

[0170] In certain embodiments, in the reaction mixture (e.g., the second or third rection mixture) immediately before the step of purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, the molar concentration of the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, in all compounds that are present in the reaction mixture and comprise a moiety of the formula:

##STR00052##

is between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or between 99% and 99.9%, inclusive.

[0171] In certain embodiments, in the reaction mixture (e.g., the second or third reaction mixture) immediately before the step of purifying the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, is a mixture of isomers (e.g., E/Z isomers and/or stereoisomers), and the molar concentration of the most prevalent isomer (e.g., the isomer with fully retained isomerism with respect to the anhydride of Formula (B), or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, and the alcohol of Formula (C), or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof) in the mixture of isomers is between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 99%, or between 99% and 99.9%, inclusive.

[0172] In certain embodiments, the method further comprises incubating a first reaction mixture for a first time duration sufficient to produce (a) of the second reaction mixture, wherein:

[0173] the first reaction mixture comprises: [0174] (a) an acid of Formula (A1):

##STR00053##

[0175] or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof; (b) a chloroformate of Formula (A2):

Cl—C(═O)—O—R   (A2),

[0176] or an isotopically labeled compound, solvate, polymorph, or co-crystal thereof, wherein R is substituted or unsubstituted alkyl; [0177] (c) a first solvent; and [0178] (d) optionally a first base; and

[0179] the step of incubating a first reaction mixture is prior to the step of incubating the second reaction mixture.

[0180] In certain embodiments, (a) of the first reaction mixture is of the formula:

##STR00054##

or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof (e.g., a tautomer, isotopically labeled compound, or salt thereof).

[0181] In certain embodiments, (a) of the first reaction mixture is of the formula:

##STR00055##

or a tautomer, isotopically labeled compound, salt, solvate, polymorph, or co-crystal thereof (e.g., a tautomer, isotopically labeled compound, or salt thereof).

[0182] In certain embodiments, R is unsubstituted alkyl. In certain embodiments, R is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R is unsubstituted methyl. In certain embodiments, R is unsubstituted ethyl. In certain embodiments, R is unsubstituted propyl (e.g., n-Pr or i-Pr). In certain embodiments, R is unsubstituted butyl (e.g., n-Bu, sec-Bu, i-Bu, or t-Bu). In certain embodiments, R is unsubstituted ethyl. In certain embodiments, R is unsubstituted methyl, unsubstituted n-propyl, unsubstituted n-butyl, or unsubstituted isobutyl. In certain embodiments, R is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R is substituted C.sub.1-6 alkyl. In certain embodiments, R is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, R is —CF.sub.3. In certain embodiments, R is substituted ethyl, substituted propyl, or substituted butyl.

[0183] In certain embodiments, the molar ratio of the amount of (a) of the first reaction mixture to the amount of (b) of the first reaction mixture is between 1:0.3 and 1:0.5, between 1:0.5 and 1:0.67, between 1:0.67 and 1:1, between 1:1 and 1:1.2, between 1:1.2 and 1:2, between 1:2 and 1:3, inclusive. In certain embodiments, the molar ratio of the amount of (a) of the first reaction mixture to the amount of (b) of the first reaction mixture is between 1:1 to 1:1.2, inclusive. In certain embodiments, the molar ratio of the amount of (a) of the first reaction mixture to the amount of (b) of the first reaction mixture is between 1:0.67 to 1:1, inclusive.

[0184] In certain embodiments, the first solvent is substantially one single solvent. In certain embodiments, the first solvent is a mixture of two or more (e.g., three) solvents (e.g., solvents described in this paragraph). In certain embodiments, the first solvent is an organic solvent. In certain embodiments, the first solvent is an aprotic solvent. In certain embodiments, the first solvent is an ether solvent. In certain embodiments, the first solvent is a ketone solvent. In certain embodiments, the first solvent is an alkane solvent. In certain embodiments, the first solvent is an alcohol solvent. In certain embodiments, the first solvent is an aromatic organic solvent. In certain embodiments, the first solvent is benzene, toluene, o-xylene, m-xylene, or p-xylene, or a mixture thereof. In certain embodiments, the first solvent is a non-aromatic organic solvent. In certain embodiments, the first solvent is tetrahydrofuran, dichloromethane, or dioxane, or a mixture thereof. In certain embodiments, the first solvent is tetrahydrofuran. In certain embodiments, the first solvent is methyl tert-butyl ether or 2-methyltetrahydrofuran, or a mixture thereof. In certain embodiments, the first solvent is acetone, acetonitrile, chloroform, diethyl ether, or ethyl acetate, or a mixture thereof. In certain embodiments, the first solvent is an inorganic solvent. In certain embodiments, the boiling point of the first solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, between 100 and 130, between 130 and 160, or between 160 and 200° C., inclusive.

[0185] In certain embodiments, the first base, if present, is an organic base. In certain embodiments, the first base, if present, is a mono-, di-, or tri-(unsubstituted C.sub.1-6 alkyl) amine. In certain embodiments, the first base, if present, is a tri-(unsubstituted C.sub.1-6 alkyl) amine. In certain embodiments, the first base, if present, is trimethylamine, triethylamine, or N,N-diisopropylethylamine, or a mixture thereof. In certain embodiments, the first base, if present, is a cyclic non-aromatic amine. In certain embodiments, the first base, if present, is an aromatic amine (e.g., pyridine). In certain embodiments, the first base, if present, is trimethylamine, triethylamine, N,N-diisopropylethylamine, or pyridine. In certain embodiments, the first base, if present, is an inorganic base. In certain embodiments, the first base, if present, is Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, or K.sub.2CO.sub.3, or a mixture thereof. In certain embodiments, the first base, if present, is LiHCO.sub.3, NaHCO.sub.3, or KHCO.sub.3, or a mixture thereof. In certain embodiments, the first base, if present, is ammonia, ammonium carbonate, or ammonium hydroxide.

[0186] In certain embodiments, the molar ratio of the amount of the first base, if present, to the amount of (a) of the first reaction mixture is between 1:1 and 2:1, between 2:1 and 3:1, between 3:1 and 5:1, or between 5:1 and 10:1, inclusive. In certain embodiments, the molar ratio of the amount of the first base, if present, to the amount of (a) of the first reaction mixture is between 1:1 and 5:1, inclusive.

[0187] In certain embodiments, the temperature of the first reaction mixture is between −40 and −20, between −20 and 0, between 0 and 20, between 20 and 40, or between 40 and 60, inclusive. In certain embodiments, the temperature of the first reaction mixture is between −20 and 40° C., inclusive. In certain embodiments, the temperature of the first reaction mixture is between −20 and 20° C., inclusive. In certain embodiments, the temperature of the first reaction mixture is between 0 and 5° C., inclusive. In certain embodiments, the temperature of the first reaction mixture is substantially constant over the first time duration.

[0188] In certain embodiments, the first time duration is between 1 and 10 minutes, between 10 and 60 minutes, between 1 and 3 hours, between 3 and 6 hours, between 6 and 12 hours, between 12 and hours, or between 1 and 3 days, inclusive. In certain embodiments, the first time duration is between 10 minutes and 1 day, inclusive. In certain embodiments, the first time duration is between 20 minutes and 3 hours, inclusive.

[0189] In certain embodiments, the first reaction mixture is substantially free of water (e.g., H.sub.2O, HDO, or D.sub.2O, or a mixture thereof). In certain embodiments, the first reaction mixture is between 95% and 97%, between 97% and 99%, between 99% and 99.9%, or between 99.9% and 99.99%, by weight, free of water.

[0190] In certain embodiments, the pressure of the first, second, and third reaction mixtures is about 1 atm.

[0191] In certain embodiments, the rate of conversion of (a) of the first reaction mixture to (a) of the second reaction mixture is between 10% and 20%, between 20% and 40%, between 40% and 60%, between 60% and 80%, or between 80% and 99.9%, inclusive. In certain embodiments, rate of conversion of (a) of the first reaction mixture to (a) of the second reaction mixture is between 10% and 99.9%, inclusive. In certain embodiments, rate of conversion of (a) of the first reaction mixture to (a) of the second reaction mixture is between 50% and 99.9%, inclusive. In certain embodiments, rate of conversion of (a) of the first reaction mixture to (a) of the second reaction mixture is between 90% and 99.9%, inclusive.

[0192] In certain embodiments, the method further comprises purifying (a) of the second reaction mixture, wherein the step of purifying (a) of the second reaction mixture is prior to the step of incubating the second reaction mixture. In certain embodiments, the step of purifying (a) of the second reaction mixture comprises:

[0193] mixing the first reaction mixture with a non-polar organic solvent;

[0194] subsequently, filtration; and

[0195] subsequently and optionally, concentration.

[0196] In certain embodiments, the non-polar organic solvent is substantially one single solvent. In certain embodiments, the non-polar organic solvent is a mixture of two or more (e.g., three) solvents (e.g., solvents described in this paragraph). In certain embodiments, the non-polar organic solvent is an alkane solvent. In certain embodiments, the non-polar organic solvent is a pentane, a hexane, a heptane, or a petroleum ether, or a combination thereof. In certain embodiments, the non-polar organic solvent is an aromatic non-polar organic solvent. In certain embodiments, the non-polar organic solvent is benzene, toluene, o-xylene, m-xylene, or p-xylene, or a mixture thereof. In certain embodiments, the boiling point of the non-polar organic solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, between 100 and 130, between 130 and 160, or between and 200° C., inclusive. In certain embodiments, the filtration is a filtration of a mixture of a liquid phase and a solid phase to remove the solid phase (e.g., a salt of the first base, e.g., a HCl salt of the first base). In certain embodiments, the concentration is concentration of a liquid phase (e.g., organic liquid phase) to remove part or substantially all of the volatiles (e.g., organic solvents). In certain embodiments, the concentration is performed under a pressure lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive). In certain embodiments, the concentration is performed under a temperature of between 0 and 10, between 10 and 20, between 20 and 25, between 25 and 35, between 35 and 50, or between 50 and 80° C., inclusive. In certain embodiments, the method does not further comprise purifying (a) of the second reaction mixture prior to the step of incubating the second reaction mixture.

Compositions and Kits

[0197] In another aspect, the present disclosure provides a composition comprising:

[0198] the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof; and

[0199] optionally an excipient.

[0200] In certain embodiments, the excipient, if present, is a cosmetically acceptable excipient. In certain embodiments, the composition is a cosmetic composition. In certain embodiments, the excipient, if present, is a pharmaceutically acceptable excipient. In certain embodiments, the composition is a pharmaceutical composition.

[0201] In certain embodiments, the composition further comprises an additional agent (e.g., additional cosmetic agent or additional pharmaceutical agent, or a combination thereof). The additional agent is different from the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof.

[0202] In certain embodiments, the composition is suitable for topical (e.g., by powders, ointments, creams, and/or drops) administration to a subject. In certain embodiments, the composition is suitable for oral administration to a subject. In certain embodiments, the composition is suitable for: enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, mucosal, nasal, buccal, or sublingual administration to a subject; administration to a subject by intratracheal instillation, bronchial instillation, and/or inhalation; and/or administration to a subject as an oral spray, nasal spray, and/or aerosol.

[0203] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human two-years and older. In certain embodiments, the subject is a human eighteen-years and older.

[0204] In another aspect, the present disclosure provides a composition comprising the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, produced by the method.

[0205] The compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0206] The compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0207] Relative amounts of the active ingredient, the excipient, and/or any additional ingredients in a composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0208] Pharmaceutically acceptable excipients used in the manufacture of provided compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0209] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0210] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0211] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj© 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0212] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum©), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0213] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0214] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.

[0215] Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0216] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0217] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0218] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0219] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0220] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0221] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0222] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0223] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0224] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0225] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0226] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0227] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0228] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0229] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0230] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0231] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0232] Suitable devices for use in delivering intradermal compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0233] Formulations suitable for topical administration include liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0234] A composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0235] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0236] The compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0237] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0238] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0239] A composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0240] Although the descriptions of compositions provided herein are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0241] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0242] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or composition described herein is suitable for topical administration to the eye of a subject.

[0243] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0244] Dose ranges as described herein provide guidance for the administration of provided compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0245] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a composition including one of the compound and the additional pharmaceutical agent, but not both.

[0246] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or composition and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0247] The additional pharmaceutical agents include anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0248] In another aspect, the present disclosure provides a kit comprising:

[0249] the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition; and

[0250] optionally instructions for using the ester, tautomer, isotopically labeled compound, solvate, polymorph, co-crystal, or composition.

[0251] In certain embodiments, the kit comprises a first container, wherein the first container comprises the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container comprises the instructions. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). In certain embodiments, the instructions comprise prescribing information. In certain embodiments, the second container comprises the first container. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container comprises the excipient. In certain embodiments, the third container comprises the additional agent. In certain embodiments, the second container comprises the third container. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or box.

Methods of Use

[0252] In another aspect, the present disclosure provides a method of treating a skin disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount of the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition. In certain embodiments, the effective amount is a therapeutically effective amount.

[0253] In another aspect, the present disclosure provides a method of preventing a skin disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount of the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition. In certain embodiments, the effective amount is a prophylactically effective amount.

[0254] In certain embodiments, the skin disease is acantholysis, acne, acute febrile neutrophilic dermatosis, alopecia, anhidrosis, atrophic skin disease, autoimmune skin disease, Beare-Stevenson cutis gyrata syndrome, Behcet syndrome, blister, body odor, CEDNIK syndrome, cafe au lait spot, chilblain, congenital sensory neuropathy with anhidrosis, cutaneous edema, cutaneous fibrosis, cutaneous fistula, cutaneous leishmaniasis, cutaneous mastocytosis, dandruff, decubitus ulcer, dermal elastosis, dermatitis, dermatomyositis, dry skin, ectodermal dysplasia, Ehlers-Danlos syndrome, erythema, fish lymphocystis disease, genodermatosis, Graves dermopathy, Harada syndrome, Hoof disease, hyperhidrosis, ichthyosis, incontinentia pigmenti, jaundice, keloid, keratosis, lentigo, lichenoid dermatosis, lupus erythematosus, lupus verrucosus, MEDNIK syndrome, mammary gland disease, microphthalmia with linear skin defects syndrome, miliaria, mucinosis, nail disease, necrobiosis lipoidica, nephrogenic systemic fibrosis, neurocutaneous syndrome, neurotic excoriation, neutrophilic dermatosis, nevus, occupational skin disease, PAPA syndrome, pachydermoperiostosis, panniculitis, parapsoriasis, passive cutaneous anaphylaxis, photosensitivity disorders, pityriasis, pruritus, psitticine beak and feather disease, pustular skin disease, rhagades, rosacea, scale drop disease, scalp disease, scar, scleredema adultorum, scleredema neonatorum, scleroderma, seborrhea, severe dermatitis, multiple allergies and metabolic wasting syndrome, skin aging, skin appendage disease, skin depigmentation, skin desquamation, skin hyperpigmentation, skin hyperplasia, skin hyperproliferative disorders, skin hypopigmentation, skin infection, skin injury, skin irritation, skin lesion, skin necrosis, skin neoplasm, skin rash, skin striae, skin ulcer, steroid-induced atrophy, sweat gland disease, toxic epidermal necrolysis, Uasin Gishu disease, ulcer, urticaria, xanthomatosis, or xeroderma pigmentosum. In certain embodiments, the skin disease is acne. In certain embodiments, the skin disease is an autoimmune skin disease. In certain embodiments, the autoimmune skin disease is psoriasis. In certain embodiments, the skin disease is keratosis. In certain embodiments, the keratosis is wart. In certain embodiments, the skin disease is dermal elastosis, dry skin, seborrhea, rosacea, or lentigo.

[0255] In another aspect, the present disclosure provides a method of slowing the ageing of the skin or improving the appearance of the skin of a subject comprising administering to the subject an effective amount of the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition. In certain embodiments, the effective amount is a cosmetically effective amount. In certain embodiments, the effective amount is effective in reducing wrinkles, lentigo, or warts in the skin or skin tags.

[0256] In another aspect, the present disclosure provides a method of modulating a retinoid receptor in a subject, biological sample, tissue, or cell comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of the ester, or a tautomer, isotopically labeled compound, solvate, polymorph, or co-crystal thereof, or the composition. In certain embodiments, the retinoid receptor is a retinoic acid receptor (e.g., retinoic acid receptor alpha, retinoic acid receptor beta, retinoic acid receptor gamma). In certain embodiments, the retinoid receptor is a retinoic acid receptor-related orphan receptor. In certain embodiments, the retinoid receptor is a retinoid X receptor. In certain embodiments, the effective amount is effective in activating the retinoid receptor in the subject, biological sample, tissue, or cell. In certain embodiments, the effective amount is effective in inhibiting the retinoid receptor in the subject, biological sample, tissue, or cell.

[0257] In certain embodiments, the administration is topical administration. In certain embodiments, the administration is oral administration. In certain embodiments, the administration is enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, mucosal, nasal, buccal, or sublingual administration; administration by intratracheal instillation, bronchial instillation, and/or inhalation; and/or administration as an oral spray, nasal spray, and/or aerosol.

[0258] In certain embodiments, the biological sample, tissue, or cell is in vitro. In certain embodiments, the biological sample, tissue, or cell is in vivo. the biological sample, tissue, or cell is ex vivo.

EXAMPLES

[0259] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples are offered to illustrate the methods and uses described herein and are not to be construed in any way as limiting their scope.

Example 1. Synthesis of (±)α-tocopheryl retinoate

[0260] ##STR00056##

[0261] Retinoic acid (5.00 g, 16.64 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 100 ml). Triethylamine (TEA, 5.0 ml) was added, and the mixture was stirred for five minutes. The solution of ethyl chloroformate (1.81 g, 16.64 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for two hours.

[0262] Most of solvent was evaporated under reduced pressure. Hexane (50 ml) was added, and the mixture was stirred for five minutes. The triethylamine hydrochloride was collected by filtration. The filtrate was evaporated under reduced pressure.

[0263] The yellow residue was dissolved in anhydrous acetonitrile (ACN, 100 ml), and (±)α-tocopherol (7.16 g, 16.64 mmol) was added. After the mixture was stirred for five minutes, triethylamine (12.5 ml) and 4-dimethylaminopyridine (DMAP, 1.25 g) were added. The mixture was warmed to 50° C. and stirred for five hours.

[0264] Ethanolamine (5.0 ml) was added, and the mixture was stirred at 50° C. for 30 minutes.

[0265] Most of solvent was evaporated under reduced pressure, and the residue was mixed with ethyl acetate (200 ml). The ethyl acetate layer was washed with 1.0 N hydrochloride solution (200 ml), brine (200 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product, which was purified by silica gel column with hexane/ethyl acetate as eluent to give 11.38 g of pale-yellow oil product. Molecular Formular: C.sub.49H.sub.76O.sub.3. .sup.1H NMR: (400 MHz, DMSO-d.sub.6): 0.75-0.87 (m, 12H), 0.93 (d, 6H), 0.97-1.05 (m, 2H), 1.01 (s, 3H), 1.06-1.13 (m, 2H), 1.15-1.30 (m, 12H), 1.48 (m, 3H), 1.57 (m, 2H), 1.69 (m, 2H), 1.93 (m, 3H), 1.97 (s, 3H), 1.99 (t, 3H), 2.00 (s, 3H), 2.01 (s, 6H), 2.02 (s, 3H), 2.33 (s, 3H), 2.56 (t, 2H), 6.21 (m, 2H), 6.29 (d, 1H), 6.53 (d, 1H), 7.15 (dd, 1H), 7.34 (s, 1H).

Example 2. Synthesis of (+)δ-tocopheroyl retinoate

[0266] ##STR00057##

[0267] Retinoic acid (1.00 g, 3.33 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). Triethylamine (1.0 ml) was added, and the mixture was stirred for five minutes. The solution of ethyl chloroformate (0.36 g, 3.33 mmol) in tetrahydrofuran (1 ml) was added dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for two hours.

[0268] Hexane (50 ml) was added, and the triethylamine hydrochloride was collected by filtration. The filtrate was evaporated under reduced pressure.

[0269] The yellow residue was dissolved in anhydrous acetonitrile (50 ml), and (+)δ-tocopherol (1.49 g, 90%, 3.33 mmol) was added. After the mixture was stirred for five minutes, triethylamine (2.5 ml) and 4-dimethylaminopyridine (0.25 g) were added. The mixture was warmed to 50° C. and stirred for three hours.

[0270] Ethanolamine (1.0 ml) was added, and the mixture was stirred at 50° C. for 30 minutes. Most of solvent was evaporated under reduced pressure, and the residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with 1.0 N hydrochloride solution (100 ml), brine (100 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product, which was purified by silica gel column with hexane/ethyl acetate as eluent to give 2.14 g of pale-yellow oil product. Molecular Formular: C.sub.47H.sub.72O.sub.3; Exact Mass: 684.55; m/z: 685.55 (M+1).sup.+, 707.54 (M+Na).sup.+. .sup.1H NMR: (400 MHz, DMSO-d.sub.6): 0.75-0.87 (m, 12H), 0.93 (d, 6H), 0.98-1.08 (m, 2H), 1.01 (s, 3H), 1.15-1.30 (m, 14H), 1.30-1.40 (m, 2H), 1.42-1.52 (m, 5H), 1.53-1.59 (m, 2H), 1.60 (m, 2H), 1.67 (s, 3H), 1.85 (m, 2H), 2.00 (s, 3H), 2.06 (s, 3H), 2.30 (s, 3H), 2.69 (m, 2H), 6.03 (s, 1H), 6.17 (m, 1H), 6.28 (m, 1H), 6.48 (d, 1H), 6.69 (d, 1H), 6.73 (d, 1H), 6.77 (d, 1H), 7.14 (dd, 1H).

Example 3. Synthesis of 3-tert-butyl-4-hydroxyphenyl retinoate

[0271] ##STR00058##

[0272] Retinoic acid (2.00 g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). Triethylamine (2.0 ml) was added, and the mixture was stirred for five minutes. The solution of ethyl chloroformate (0.72 g, 6.66 mmol) in tetrahydrofuran (1 ml) was added dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for two hours.

[0273] Hexane (50 ml) was added and the triethylamine hydrochloride was collected by filtration. The filtrate was evaporated under reduced pressure.

[0274] The yellow residue was dissolved in anhydrous acetonitrile (50 ml), and tert-butylhydroquinone (TBHQ, 1.64 g, 9.99 mmol) was added. After the mixture was stirred for five minutes, triethylamine (5 ml) and 4-dimethylaminopyridine (1.00 g) were added. The mixture was warmed to 50° C. and stirred for four hours.

[0275] Most of solvent was evaporated under reduced pressure, and the residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with 1.0 N hydrochloride solution (100 ml), brine (100 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product, which was purified by silica gel column with hexane/ethyl acetate as eluent to give 1.89 g yellow crystal powder. Molecular Formular: C.sub.30H.sub.40O.sub.3; Exact Mass: 448.30; m/z: 449.30 (M+1).sup.+, 471.28 (M+Na).sup.+. .sup.1H NMR: (400 MHz, DMSO-d.sub.6): 1.01 (s, 6H), 1.32 (s, 9H), 1.43 (m, 2H), 1.57 (m, 2H), 1.69 (s, 3H), 1.99 (m, 2H), 2.00 (s, 3H), 2.33 (s, 3H), 6.03 (s, 1H), 6.20 (t, 1H), 6.28 (t, 2H), 6.49 (d, 1H), 6.75 (d, 2H), 6.80 (m, 1H), 7.13 (dd, 1H), 9.37 (s, 1H).

Example 4. Analysis of Agonist Activity for RAR (Retinoic Acid Receptor)

Methods

[0276] Reporter Cells (Indigo Biosciences, catalog #IB02201, IB02101, IB00821) were used in the assays. The reporter cells expressed a receptor hybrid in which the native N-terminal DNA binding domain (DBD) had been replaced with that of the yeast Gal4 DBD. The reporter gene, firefly luciferase, is functionally linked to the Gal4 upstream activation sequence (UAS). Receptor assays were performed as follows, Steps 1 to 3.

[0277] Step 1: A suspension of Reporter Cells was prepared in Cell Recovery Medium (CRM: containing charcoal-stripped FBS) and 100 μL of the Reporter Cell suspension was dispensed into each of the wells of a white 96-well assay plate. Step 2: Test and reference compound master stocks were prepared as solutions at 1,000× concentration in DMSO relative to the final treatment concentration. This intermediate stock was subsequently diluted directly into INDIGO Biosciences's Compound Screening Medium (CSM; containing charcoal-stripped FBS) to generate ‘2×-concentration’ treatment media. 100 μL of each prepared treatment medium was dispensed into duplicate assay wells pre-dispensed with a 100 μL suspension of Reporter Cells, thereby achieving the desired final treatment concentrations. The concentration of residual DMSO in all assay wells was 0.1% for the test and reference compounds. Assay plates were incubated at 37° C., 5% CO2 and ˜70% humidity for 23 hours. DMSO control was used to determine background activity. Retinoic acid was used with its EC100 concentration to show 100% activity of each receptor. Retinol served as positive control.

[0278] Step 3: Following the incubation period, treatment media were discarded and 100 μL/well of Luciferase Detection Reagent was added per well to determine receptor activity in terms of relative luminescence units (RLUs). Data processing: Fold activation: [Ave RLU Test Cmpd/Ave RLU DMSO].

Results

[0279]

TABLE-US-00001 TABLE 1 Agonist activities of (±)α-tocopheryl retinoate, (+)δ-tocopheroyl retinoate, and 3-tert-butyl-4-hydroxyphenyl retinoate to RAR alpha, beta and gamma receptor RAR alpha RAR beta RAR gamma Concen- Fold Concen- Fold Concen- Fold tration Activation tration Activation tration Activation Control 0.1% 1 0.1% 1 0.1% 1 DMSO Retinoic acid  2.5 μM 4526  0.2 μM 318  0.1 μM 706 Retinol 0.01 μM 1.77 0.01 μM 1.63 0.01 μM 2.28  0.1 μM 6.35  0.1 μM 4.91  0.1 μM 18.5    1 μM 518    1 μM 127    1 μM 368 (±)α-tocopheryl 0.01 μM 1.27 0.01 μM 0.882 0.01 μM 1.79 retinoate  0.1 μM 9.14  0.1 μM 6.33  0.1 μM 23.8    1 μM 552    1 μM 149    1 μM 365 (+)δ- 0.01 μM 0.620 0.01 μM 1.57 0.01 μM 1.10 Tocopheroyl  0.1 μM 5.25  0.1 μM 3.96  0.1 μM 8.45 retinoate    1 μM 251    1 μM 53.4    1 μM 315 3-tert-Butyl-4- 0.01 μM 1,573 0.01 μM 232 0.01 μM 541 hydroxyphenyl  0.1 μM 2,768  0.1 μM 287  0.1 μM 1,010 retinoate    1 μM 3,414    1 μM 331    1 μM 701

[0280] As shown in Table 1, (±)α-tocopheryl retinoate, (+)δ-tocopheroyl retinoate, and 3-tert-butyl-4-hydroxyphenyl retinoate exhibited agonist activity towards RAR alpha, beta, and gamma receptors. In particular, 3-tert-butyl-4-hydroxyphenyl retinoate showed higher activity than retinol at all tested concentrations and exhibited a comparable activity to retinoic acid.

EQUIVALENTS AND SCOPE

[0281] 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 present disclosure 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 present disclosure 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.

[0282] Furthermore, the present disclosure 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 present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure 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 present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0283] 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 present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0284] 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.