US2014213620A1PendingUtilityA1
Histone deacetylase inhibitors
Est. expiryFeb 14, 2026(expired)· nominal 20-yr term from priority
A61P 43/00A61P 35/00A61P 29/00A61P 17/14A61P 17/06A61P 17/00A61K 9/0014A61K 31/231C07C 235/78C07D 413/12C07C 259/06C07D 319/06A61K 31/337A61K 31/165
60
PatentIndex Score
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Cited by
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Claims
Abstract
In recognition of the need to develop novel therapeutic agents, the present invention provides novel histone deacetylase inhibitors. These compounds include an ester bond making them sensitive to deactivation by esterases. Therefore, these compounds are particularly useful in the treatment of skin disorders. When the compounds reaches the bloodstream, an esterase or an enzyme with esterase activity cleaves the compound into biologically inactive fragments or fragments with greatly reduced activity Ideally these degradation products exhibit a short serum and/or systemic half-life and are eliminated rapidly. These compounds and pharmaceutical compositions thereof are particularly useful in treating cutaneous T-cell lymphoma, neurofibromatosis, psoriasis, hair loss, skin pigmentation, and dermatitis, for example. The present invention also provides methods for preparing compounds of the invention and intermediates thereto.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I),
wherein
A comprises a functional group that inhibits histone deacetylase;
L is a linker moiety; and
Ar is a substituted or unsubstituted aryl or heteroaryl moiety; substituted or unsustituted, branched or unbranched arylaliphatic or heteroarylaliphatic moiety; a substituted or unsubstituted cyclic or heterocyclic moiety; substituted or unsustituted, branched or unbranched cyclicaliphatic or heterocyclicaliphatic moiety; and pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 , wherein A is a functional group that chelates Zn 2+ .
3 . The compound of claim 1 , wherein A is selected from the group consisting of:
4 . The compound of claim 1 , wherein A comprises
5 . The compound of claim 1 , wherein A comprises
6 . The compound of claim 1 , wherein A comprises
7 . The compound of any one of claims 1 - 6 , wherein Ar is arylaliphatic.
8 . The compound of any one of claims 1 - 6 , wherein Ar is heteroarylaliphatic.
9 . The compound of any one of claims 1 - 6 , wherein Ar is substituted or unsubstituted aryl.
10 . The compound of any one of claims 1 - 6 , wherein Ar is a substituted phenyl moiety.
11 . The compound of any one of claims 1 - 6 , wherein Ar is chosen from one of the following:
12 . The compound of any one of claims 1 - 6 , wherein Ar is a substituted or unsubstituted heteroaryl moiety.
13 . The compound of any one of claims 1 - 6 , wherein Ar is chosen from one of the following:
14 . The compound of any one of claims 1 - 13 , wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic moiety; a substituted or unsubstituted, cyclic or acyclic, branched or unbranched heteroaliphatic moiety; a substituted or unsubstituted aryl moiety; a substituted or unsubstituted heteroaryl moiety.
15 . The compound of any one of claims 1 - 13 , wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic moiety.
16 . The compound of any one of claims 1 - 13 , wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched heteroaliphatic moiety.
17 . The compound of any one of claims 1 - 13 , wherein L is C 1 -C 15 alkylidene.
18 . The compound of any one of claims 1 - 13 , wherein L is C 1 -C 10 alkylidene.
19 . The compound of any one of claims 1 - 13 , wherein L is C 2 -C 6 alkylidene.
20 . The compound of any one of claims 1 - 13 , wherein L is an unbranched, unsubstituted, acyclic alkyl chain.
21 . The compound of any one of claims 1 - 13 , wherein L is selected from one of the following:
22 . The compound of any one of claims 1 - 13 , wherein L is selected from one of the following:
23 . The compound of any one of claims 1 - 13 , wherein L is
24 . The compound of any one of claims 1 - 13 of the formula (Ia):
wherein
n is an integer between 0 and 15.
25 . The compound of any one of claims 1 - 13 of the formula (Ib):
wherein
n is an integer between 0 and 15, inclusive;
m is an integer between 1 and 5, inclusive; and
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
26 . The compound of claim 25 , wherein n is an integer between 1 and 8, inclusive.
27 . The compound of claim 25 , wherein n is 5, 6 or 7.
28 . The compound of claim 25 , wherein n is 6.
29 . The compound of any one of claims 25 - 28 , wherein m is 1.
30 . The compound of any one of claims 25 - 28 , wherein m is 2.
31 . The compound of any one of claims 25 - 28 , wherein m is 3.
32 . The compound of any one of claims 25 - 31 , wherein R 1 comprises a substituted or unsubstituted 1,3-dioxane ring.
33 . The compound of any one of claims 25 - 31 , wherein R 1 is halogen.
34 . The compound of any one of claim 25 - 31 , wherein R 1 is —OR A .
35 . The compound of any one of claims 25 - 31 , wherein R 1 is —N(R A ) 2 .
36 . The compound of any one of claims 25 - 31 , wherein R 1 is —NHR A .
37 . The compound of any one of claims 25 - 31 , wherein R 1 is C 1 -C 6 alkyl.
38 . The compound of any one of claim 25 - 31 , wherein R 1 is substituted or unsubstituted acyl.
39 . The compound of any one of claims 25 - 31 , wherein R 1 is —C(═O)OR A , wherein R A is hydrogen or C 1 -C 6 alkyl.
40 . The compound of any one of claims 25 - 31 , wherein R 1 is —C(═O)N(R A ) 2 , wherein R A is hydrogen or C 1 -C 6 alkyl.
41 . The compound of any one of claims 25 - 31 , wherein R 1 is —C(═O)NH 2 .
42 . The compound of any one of claims 25 - 31 , wherein R 1 is —CHO.
43 . The compound of any one of claims 25 - 31 , wherein R 1 is —NHC(═O)R A , wherein R A is C 1 -C 6 alkyl.
44 . The compound of claim 1 of formula (Ic):
wherein
n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive; more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
45 . The compound of claim 1 of formula:
wherein
n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive; more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
46 . The compound of claim 1 of formula:
wherein
n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive; more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
47 . The compound of claim 1 of formula:
wherein
n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive; more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
48 . The compound of claim 44 , 45 , 46 , or 47 , wherein n is an integer between 1 and 8, inclusive.
49 . The compound of claim 44 , 45 , 46 , or 47 , wherein n is 5, 6 or 7.
50 . The compound of claim 44 , 45 , 46 , or 47 , wherein n is 6.
51 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 comprises a substituted or unsubstituted 1,3-dioxane ring.
52 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is halogen.
53 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —OR A .
54 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —N(R A ) 2 .
55 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —NHR A .
56 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is C 1 -C 6 alkyl.
57 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is substituted or unsubstituted acyl.
58 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —C(═O)OR A , wherein R A is hydrogen or C 1 -C 6 alkyl.
59 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —C(═O)N(R A ) 2 , wherein R A is hydrogen or C 1 -C 6 alkyl.
60 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —C(═O)NH 2 .
61 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —CHO.
62 . The compound of claim 44 , 45 , 46 , or 47 , wherein R 1 is —NHC(═O)R A , wherein R A is C 1 -C 6 alkyl.
63 . The compound of claim 1 of formula (If):
wherein n is an integer between 1 and 6, inclusive.
64 . The compound of claim 63 , wherein Ar is substituted or unsubstituted phenyl.
65 . The compound of claim 1 of formula (Ig):
wherein
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
66 . The compound of claim 65 , wherein R 2 is —CH 2 —X(R B ) n ; wherein X is O, S, or N; and n is 1 or 2
67 . The compound of claim 1 of formula (Ih):
wherein
n is an integer between 1 and 6, inclusive;
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
68 . The compound of claim 1 of formula (Ii):
wherein
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
69 . The compound of claim 1 of formula (Ij):
wherein
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
70 . The compound of any one of claim 65 , 66 , 67 , 68 , or 69 , wherein R 2 is
71 . The compound of claim 68 of formula (Il):
wherein
n is an integer between 0 and 5, inclusive; and
Z is hydrogen, —(CH 2 ) q OR Z , —(CH 2 ) q SR Z , —(CH 2 ) q N(R Z ) 2 , —C(═O)R Z , —C(═O)N(R Z ) 2 , or an alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R Z is independently hydrogen, a protecting group, a solid support unit, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety.
72 . The compound of claim 71 of formula:
73 . A compound of claim 1 of formula:
74 . A pharmaceutical composition comprising a compound of one of the claims 1 - 73 and a pharmaceutically acceptable excipient.
75 . A method of inhibiting histone deacetylase, the method comprising steps of:
contacting a histone deacetylase with a compound of one of the claims 1 - 34 .
76 . The method of claim 75 , wherein the histone deacetylase is purified.
77 . The method of claim 75 , wherein the histone deacetylase is in a cell.
78 . The method of claim 75 , 76 , or 77 , wherein the histone deacetylase is HDAC6.
79 . A method of treating a subject with a proliferative disorder, the method comprising steps of:
administering a therapeutically effective amount of a compound of one of claims 1 - 34 to a subject.
80 . The method of claim 79 , wherein the subject is a mammal.
81 . The method of claim 79 , wherein the subject is human.
82 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is cancer.
83 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is an inflammatory disease.
84 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is a proliferative disorder associated with the skin.
85 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is cutaneous T-cell lymphoma.
86 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is a skin cancer.
87 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is a benign skin growth.
88 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is psoriasis.
89 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is a dermatitis.
90 . The method of claim 79 , 80 , or 81 , wherein the proliferative disorder is neurofibromatosis.
91 . The method of any one of claims 79 - 90 , wherein the step of administering comprises administering the compound topically.
92 . The method of any one of claims 79 - 90 , wherein the compound is cleaved by an esterase in vivo.
93 . The method of claim 92 , wherein the compound is cleaved by an esterase found in the bloodstream.
94 . The method of any one of claims 79 - 90 , wherein the compound is inactivated by an esterase in vivo.
95 . The method of claim 94 , wherein the compound is inactivated by an esterase found in the bloodstream.
96 . A method of treating a subject with hair loss, the method comprising steps of:
administering a therapeutically effective amount of a compound of any one of claims 1 - 73 to a subject.
97 . A method of treating a subject suffering from skin hyperpigmentation, the method comprising steps of:
administering a therapeutically effective amount of a compound of any one of claims 1 - 73 to a subject.
98 . A method of administering a compound of any one of claims 1 - 73 , the method comprising:
administering topically a compound of any one of claims 1 - 72 to a subject.
99 . The method of claim 98 , wherein the step of administering comprises administering the compound to the subject's skin.
100 . The method of claim 98 , wherein the step of administering comprises administering the compound to the subject's hair.
101 . A method for synthesizing a compound of formula (III A ), the method comprising steps of:
providing an epoxy alcohol having the structure:
reacting the epoxy alcohol with a reagent having the structure R 2 XH under suitable conditions to generate a diol having the core structure:
reacting the diol with a reagent having the structure R 3 CH(OMe) 2 under suitable conditions to generate a compound of formula (III A ):
wherein R 1 is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
R 2 is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
X is —O—, —C(R 2A ) 2 —, —S—, or —NR 2A —, wherein R 2A is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
or wherein two or more occurrences of R 2 and R 2A , taken together, form an alicyclic or heterocyclic moiety, or an aryl or heteroaryl moiety;
R 3 is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and
R Z is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety and is optionally attached to a solid support.
102 . A method of synthesizing a compound of formula:
the method comprising steps of:
providing an epoxy alcohol having the structure:
reacting the epoxy alcohol with a reagent having the structure R 2 XH under suitable conditions to generate a diol having the core structure:
subjecting the diol to a reagent having the structure:
wherein R 4C is a nitrogen protecting group, under suitable conditions to generate an amine having the structure:
reacting the amine with a reagent having the structure:
under suitable conditions to generate a scaffold having the core structure:
wherein R 1 is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
R 2 is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
X is —O—, —C(R 2A ) 2 —, —S—, or —NR 2A —, wherein R 2A is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
or wherein two or more occurrences of R 2 and R 2A , taken together, form an alicyclic or heterocyclic moiety, or an aryl or heteroaryl moiety;
r is 0 or 1;
s is an integer from 2-5;
w is an integer from 0-4;
R 4A comprises a metal chelator;
each occurrence of R 4D is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, halogen, CN, NO 2 , or WR W1 wherein W is O, S, NR W2 , —C(═O), —S(═O), —SO 2 , —C(═O)O—, —OC(═O), —C(═O)NR W2 , —NR W2 C(═O); wherein each occurrence of R W1 and R W2 is independently hydrogen, a protecting group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NR W2 , R W1 and R W2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or any two adjacent occurrences of R 2B , taken together with the atoms to which they are attached, form a substituted or unsubstituted, saturated or unsaturated alicyclic or heterocyclic moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; and
R Z is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety and is optionally attached to a solid support.Cited by (0)
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