SPIROKETALS AND USES THEREOF
20210069082 · 2021-03-11
Assignee
Inventors
Cpc classification
A61K8/498
HUMAN NECESSITIES
C07F7/2208
CHEMISTRY; METALLURGY
International classification
C07F7/18
CHEMISTRY; METALLURGY
Abstract
The invention relates to novel spiroketal antioxidants, including compounds of Formula (I) and (II). The compounds have antioxidant properties and are useful for the treatment and/or prevention of diseases and conditions associated with oxidative stress in the body (e.g., metabolic conditions, neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, renal diseases). The invention provides pharmaceutical compositions comprising the compounds, and kits comprising the same. Additionally, the invention provides uses of the compounds described herein (e.g., for inhibiting the concentration or production of reactive oxygen species (ROS), inhibiting the concentration or production of reactive nitrogen species (RNS), reducing oxidative stress, inhibiting NADPH oxidase activity, and for slowing or reducing the effects of aging).
##STR00001##
Claims
1. A compound of Formula (I): ##STR00128## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c; R.sup.2 is hydrogen, halogen, optionally substituted alkyl, OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c; R.sup.3 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; each instance of R.sup.4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, OR.sup.O, N(R.sup.N).sub.2; or SR.sup.S; each instance of R.sup.5 is independently hydrogen, halogen, CN, NO.sub.2, N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; each instance of R.sup.1a, R.sup.2a, and R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.1b, R.sup.2b, and R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; each instance of R.sup.1b, R.sup.2b, and R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acryl, or a nitrogen protecting group; or optionally two R.sup.1b, R.sup.2b, or R.sup.N on the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.1c, R.sup.2c, and R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; s is 0, 1, 2, or 3; p is 0, 1, 2, or 3; provided that the sum of s and p is 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, or 4.
2-3. (canceled)
4. The compound of claim 1, wherein the compound is of the formula: ##STR00129## or a pharmaceutically acceptable salt thereof.
5-6. (canceled)
7. The compound of claim 1, wherein the compound is of the formula: ##STR00130## or a pharmaceutically acceptable salt thereof.
8-9. (canceled)
10. The compound of claim 1, wherein the compound is of the formula: ##STR00131## or a pharmaceutically acceptable salt thereof.
11-12. (canceled)
13. The compound of claim 1, wherein the compound is of the formula: ##STR00132## or a pharmaceutically acceptable salt thereof.
14-15. (canceled)
16. The compound of claim 1, wherein the compound is of the formula: ##STR00133## or a pharmaceutically acceptable salt thereof.
17-18. (canceled)
19. The compound of claim 1, wherein the compound is of the formula: ##STR00134## or a pharmaceutically acceptable salt thereof.
20-21. (canceled)
22. The compound of claim 1, wherein the compound is of the formula: ##STR00135## or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1, wherein the compound is selected from the group consisting of: ##STR00136## and pharmaceutically acceptable salts thereof.
24-27. (canceled)
28. A compound of Formula (II): ##STR00137## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is halogen, optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c; R.sup.2 is hydrogen, halogen, optionally substituted alkyl, OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c; R.sup.3 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; R.sup.6 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; each instance of R.sup.4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; each instance of R.sup.5 is independently hydrogen, halogen, CN, NO.sub.2, N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S; each instance of R.sup.1a, R.sup.2a, and R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.1b, R.sup.2b, and R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.1b, R.sup.2b, or R.sup.N on the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.1c, R.sup.2c, and R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; s is 0, 1, 2, or 3; p is 0, 1, 2, or 3; provided that the sum of s and p is 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, or 4.
29-38. (canceled)
39. The compound of claim 28, wherein the compound is selected from the group consisting of: ##STR00138## and pharmaceutically acceptable salts thereof.
40. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein s is 1.
41. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein p is 1.
42. (canceled)
43. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R.sup.1 is OR.sup.1a.
44. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R.sup.2 is OR.sup.2a.
45-49. (canceled)
50. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein n is 0.
51. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R.sup.3 is OR.sup.O or hydrogen.
52-56. (canceled)
57. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
58. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein at least one instance of R.sup.5 is optionally substituted acyl.
59-62. (canceled)
63. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
64. A method for treating a disease in a subject, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof; wherein the disease is a metabolic disorder, renal disease, proliferative disease, inflammatory disease, autoimmune disease, neurodegenerative disease, or cardiovascular disease.
65-72. (canceled)
73. A method for inhibiting the production or concentration of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) in a cell, biological sample, or subject; for inhibiting the activity of NADPH oxidase in a cell, biological sample, or subject; or for reducing oxidative stress in a cell, biological sample, or subject, the method comprising administering to the subject, or contacting the biological sample or cell, with a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
74-93. (canceled)
94. A cosmetic composition comprising a compound of claim 1, or a salt thereof, and a cosmetically acceptable excipient.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0113] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
[0114]
[0115]
[0116]
[0117]
[0118]
[0119]
[0120]
[0121]
[0122]
[0123]
[0124]
[0125]
[0126]
[0127]
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0128] Provided herein are novel spiroketals, including compounds of Formulae (I) and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. The compounds provided herein have antioxidant properties, and therefore are useful in the treatment of diseases and/or conditions (e.g., metabolic conditions, neurodegenerative disorders, cardiovascular diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, renal diseases). In particular, the compounds are useful for treating and/or preventing diseases and conditions associated with oxidative stress in a subject. The compounds are also useful for reducing oxidative stress in a cell, biological sample, or subject, for inhibiting NADPH oxidase activity in a cell, biological sample, or subject, and for inhibiting the concentration or production of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) in a cell, biological sample, or subject.
Compounds
[0129] One aspect of the present invention relates to novel spiroketal compounds. In one aspect, the present invention provides compounds of Formula (I):
##STR00011##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:
[0130] R.sup.1 is optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c;
[0131] R.sup.2 is hydrogen, halogen, optionally substituted alkyl, OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c;
[0132] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0133] each instance of R.sup.4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0134] each instance of R.sup.5 is independently hydrogen, halogen, CN, NO.sub.2, N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0135] each instance of R.sup.1a, R.sup.2a, and R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
[0136] each instance of R.sup.1b, R.sup.2b, and R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.1b, R.sup.2b, and R.sup.N on the same nitrogen are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
[0137] each instance of R.sup.1c, R.sup.2c, and R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;
[0138] s is 0, 1, 2, or 3;
[0139] p is 0, 1, 2, or 3;
[0140] provided that the sum of s and p is 1, 2, or 3;
[0141] n is 0, 1, 2, 3, 4, 5, or 6; and
[0142] m is 0, 1, 2, 3, or 4.
[0143] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00012##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0144] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00013##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0145] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00014## ##STR00015##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0146] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00016##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0147] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00017##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0148] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00018##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0149] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00019##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0150] In certain embodiments, the sum of p and s is 1, 2, or 3. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00020##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0151] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00021##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0152] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00022##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0153] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00023##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0154] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00024##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0155] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00025##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0156] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00026##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0157] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00027##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0158] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00028##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0159] In certain embodiments, the sum of p and s is 1, 2, or 3. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00029##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0160] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00030##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0161] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00031##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0162] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00032##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0163] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00033##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0164] In certain embodiments, the compound of Formula (I) is of one of the following
##STR00034##
[0165] formulae:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0166] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00035##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0167] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00036##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0168] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00037##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0169] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00038##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0170] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00039##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0171] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00040##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0172] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00041##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0173] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00042##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0174] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00043##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0175] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00044##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0176] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00045##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0177] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00046##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0178] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00047##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0179] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00048##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0180] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00049##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0181] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00050##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0182] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00051##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0183] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00052##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0184] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00053##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0185] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00054##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0186] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00055##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0187] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00056##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0188] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00057##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0189] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00058##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0190] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00059##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0191] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00060##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0192] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00061##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0193] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00062##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0194] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00063##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0195] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00064##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0196] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00065##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0197] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00066##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0198] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00067##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0199] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00068##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0200] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00069##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0201] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00070##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0202] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00071##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0203] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00072##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0204] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00073##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0205] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00074##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0206] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00075##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0207] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00076##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0208] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00077##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0209] In certain embodiments, the compound of Formula (I) is of one of the following formulae:
##STR00078##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0210] In certain embodiments, the compound of Formula (I) is of the formula:
##STR00079##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0211] In certain embodiments, R.sup.1 is OR.sup.1a; R.sup.2 is OR.sup.2a; and R.sup.3 is hydrogen. In certain embodiments, R.sup.1 is OR.sup.1a; R.sup.2 is OR.sup.2a; and R.sup.3 is OR.sup.O. In certain embodiments, R.sup.1 is OH; R.sup.2 is OH; and R.sup.3 is hydrogen. In certain embodiments, R.sup.1 is OH; R.sup.2 is OH; and R.sup.3 is OH.
[0212] In another aspect, the present invention provides compounds of Formula (II):
##STR00080##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:
[0213] R.sup.1 is halogen, optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c;
[0214] R.sup.2 is hydrogen, halogen, optionally substituted alkyl, OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c;
[0215] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0216] R.sup.6 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0217] each instance of R.sup.4 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted acyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0218] each instance of R.sup.5 is independently hydrogen, halogen, CN, NO.sub.2, N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S;
[0219] each instance of R.sup.1a, R.sup.2a, and R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
[0220] each instance of R.sup.1b, R.sup.2b, and R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.1b, R.sup.2b, or R.sup.N on the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
[0221] each instance of R.sup.1c, R.sup.2c, and R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;
[0222] s is 0, 1, 2, or 3;
[0223] p is 0, 1, 2, or 3;
[0224] provided that the sum of s and p is 1, 2, or 3;
[0225] n is 0, 1, 2, 3, 4, 5, or 6; and
[0226] m is 0, 1, 2, 3, or 4.
[0227] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00081##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0228] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00082##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0229] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00083##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0230] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00084##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0231] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00085##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0232] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00086## ##STR00087##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0233] In certain embodiments, the sum of p and s is 1, 2, or 3. In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00088##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0234] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00089##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0235] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00090##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0236] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00091##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0237] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00092##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0238] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00093##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0239] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00094##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0240] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00095##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0241] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00096##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0242] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00097##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0243] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00098##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0244] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00099##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0245] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00100##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0246] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00101##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0247] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00102##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0248] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00103##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0249] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00104##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0250] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00105##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0251] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00106##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0252] In certain embodiments, the compound of Formula (II) is of one of the following formulae:
##STR00107##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0253] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00108##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0254] In certain embodiments, the compound of Formula (II) is of the formula:
##STR00109##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0255] In certain embodiments, the compound of Formula (II) is selected from the group consisting of:
##STR00110##
[0256] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
[0257] In certain embodiments, the compound of Formula (II) is selected from the group consisting of:
##STR00111##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
[0258] In certain embodiments, R.sup.6 is hydrogen; R.sup.1 is OR.sup.1a; R.sup.2 is OR.sup.2a; and R.sup.3 is hydrogen. In certain embodiments, R.sup.6 is hydrogen; R.sup.1 is OR.sup.1a; R.sup.2 is OR.sup.2a; and R.sup.3 is OR.sup.O. In certain embodiments, R.sup.6 is hydrogen; R.sup.1 is OH; R.sup.2 is OH; and R.sup.3 is hydrogen. In certain embodiments, R.sup.6 is hydrogen; R.sup.1 is OH; R.sup.2 is OH; and R.sup.3 is OH.
Group R.SUP.1
[0259] As generally defined herein, R.sup.1 is halogen, optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c. In certain embodiments, R.sup.1 is optionally substituted alkyl, OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c. In certain embodiments, R.sup.1 is OR.sup.1a, N(R.sup.1b).sub.2, or SR.sup.1c. In certain embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1 is OR.sup.1a. In certain embodiments, R.sup.1 is N(R.sup.1b).sub.2. In certain embodiments, R.sup.1 is SR.sup.1c. In certain embodiments, R.sup.1 is OH. In certain embodiments, R.sup.1 is NH.sub.2. In certain embodiments, R.sup.1 is SH.
[0260] As generally defined herein, R.sup.1a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.1a is hydrogen. In certain embodiments, R.sup.1a is optionally substituted alkyl. In certain embodiments, R.sup.1a is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1a is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1a is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1a is optionally substituted alkenyl. In certain embodiments, R.sup.1a is optionally substituted alkynyl. In certain embodiments, R.sup.1a is optionally substituted carbocyclyl. In certain embodiments, R.sup.1a is optionally substituted heterocyclyl. In certain embodiments, R.sup.1a is optionally substituted aryl. In certain embodiments, R.sup.1a is optionally substituted heteroaryl. In certain embodiments, R.sup.1a is optionally substituted acyl. In certain embodiments, R.sup.1a is an oxygen protecting group.
[0261] As generally defined herein, each instance of R.sup.1b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.1b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.1b is hydrogen. In certain embodiments, R.sup.1b is optionally substituted alkyl. In certain embodiments, R.sup.1b is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1b is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1b is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1b is optionally substituted alkenyl. In certain embodiments, R.sup.1b is optionally substituted alkynyl. In certain embodiments, R.sup.1b is optionally substituted carbocyclyl. In certain embodiments, R.sup.1b is optionally substituted heterocyclyl. In certain embodiments, R.sup.1b is optionally substituted aryl. In certain embodiments, R.sup.1b is optionally substituted heteroaryl. In certain embodiments, R.sup.1b is optionally substituted acyl. In certain embodiments, R.sup.1b is a nitrogen protecting group. In certain embodiments, two R.sup.1b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl
[0262] As generally defined herein, R.sup.1c is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, R.sup.1c is hydrogen. In certain embodiments, R.sup.1c is optionally substituted alkyl. In certain embodiments, R.sup.1c is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1c is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1c is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1c is optionally substituted alkenyl. In certain embodiments, R.sup.1c is optionally substituted alkynyl. In certain embodiments, R.sup.1c is optionally substituted carbocyclyl. In certain embodiments, R.sup.1c is optionally substituted heterocyclyl. In certain embodiments, R.sup.1c is optionally substituted aryl. In certain embodiments, R.sup.1c is optionally substituted heteroaryl. In certain embodiments, R.sup.1c is optionally substituted acyl. In certain embodiments, R.sup.1c is a sulfur protecting group.
Group R.SUP.2
[0263] As generally defined herein, R.sup.2 is hydrogen, halogen, optionally substituted alkyl, OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c. In certain embodiments, R.sup.2 is OR.sup.2a, N(R.sup.2b).sub.2, or SR.sup.2c. In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is halogen (e.g., Cl, F, Br, I). In certain embodiments, R.sup.2 is optionally substituted alkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2 is OR.sup.1a. In certain embodiments, R.sup.2 is N(R.sup.2b).sub.2. In certain embodiments, R.sup.2 is SR.sup.2c. In certain embodiments, R.sup.2 is OH. In certain embodiments, R.sup.2 is NH.sub.2. In certain embodiments, R.sup.2 is SH.
[0264] As generally defined herein, R.sup.2a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.2a is hydrogen. In certain embodiments, R.sup.2a is optionally substituted alkyl. In certain embodiments, R.sup.2a is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2a is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2a is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2a is optionally substituted alkenyl. In certain embodiments. R.sup.2a is optionally substituted alkynyl. In certain embodiments, R.sup.2a is optionally substituted carbocyclyl. In certain embodiments, R.sup.2a is optionally substituted heterocyclyl. In certain embodiments, R.sup.2a is optionally substituted aryl. In certain embodiments, R.sup.2a is optionally substituted heteroaryl. In certain embodiments, R.sup.2a is optionally substituted acyl. In certain embodiments, R.sup.2a is an oxygen protecting group.
[0265] As generally defined herein, each instance of R.sup.2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.2b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.2b is hydrogen. In certain embodiments, R.sup.2b is optionally substituted alkyl. In certain embodiments, R.sup.2b is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2b is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2b is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2b is optionally substituted alkenyl. In certain embodiments, R.sup.2b is optionally substituted alkynyl. In certain embodiments, R.sup.2b is optionally substituted carbocyclyl. In certain embodiments, R.sup.2b is optionally substituted heterocyclyl. In certain embodiments, R.sup.2b is optionally substituted aryl. In certain embodiments, R.sup.2b is optionally substituted heteroaryl. In certain embodiments, R.sup.2b is optionally substituted acyl. In certain embodiments, R.sup.2b is a nitrogen protecting group. In certain embodiments, two R.sup.2b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl
[0266] As generally defined herein, R.sup.2c is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, R.sup.2c is hydrogen. In certain embodiments, R.sup.2c is optionally substituted alkyl. In certain embodiments, R.sup.2c is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2c is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2c is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2c is optionally substituted alkenyl. In certain embodiments, R.sup.2c is optionally substituted alkynyl. In certain embodiments, R.sup.2c is optionally substituted carbocyclyl. In certain embodiments, R.sup.2c is optionally substituted heterocyclyl. In certain embodiments, R.sup.2c is optionally substituted aryl. In certain embodiments. R.sup.2c is optionally substituted heteroaryl. In certain embodiments, R.sup.2c is optionally substituted acyl. In certain embodiments, R.sup.2c is a sulfur protecting group.
Group R.SUP.3
[0267] As generally defined herein, R.sup.3 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, R.sup.3 is OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is halogen (e.g., Cl, F, Br, I). In certain embodiments, R.sup.3 is optionally substituted alkyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.3 is OR.sup.O. In certain embodiments, R.sup.3 is N(R.sup.N).sub.2. In certain embodiments, R.sup.3 is SR.sup.S. In certain embodiments, R.sup.3 is OH. In certain embodiments, R.sup.3 is NH.sub.2. In certain embodiments, R.sup.3 is SH.
Group R.SUP.4
[0268] As generally defined herein, each instance of R.sup.4 is independently hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, at least one instance of R.sup.4 is hydrogen. In certain embodiments, each instance of R.sup.4 is hydrogen. In certain embodiments, at least one instance of R.sup.4 is halogen (e.g., Cl, F, Br, I). In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkyl. In certain embodiments, R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.4 is OR.sup.O. In certain embodiments, at least one instance of R.sup.4 is N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.4 is SR.sup.S. In certain embodiments, R.sup.4 is OH. In certain embodiments, R.sup.4 is NH.sub.2. In certain embodiments, R.sup.4 is SH.
Group R.SUP.5
[0269] As generally defined herein, each instance of R.sup.5 is independently hydrogen, halogen, CN, NO.sub.2, N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, at least one instance of R.sup.5 is hydrogen. In certain embodiments, each instance of R.sup.5 is hydrogen. In certain embodiments, at least one instance of R.sup.5 is halogen (e.g., Cl, F, Br, I). In certain embodiments, at least one instance of R.sup.5 is Cl. In certain embodiments, at least one instance of R.sup.5 is Br. In certain embodiments, at least one instance of R.sup.5 is I. In certain embodiments, at least one instance of R.sup.5 is F. In certain embodiments, at least one instance of R.sup.5 is CN. In certain embodiments, at least one instance of R.sup.5 is NO.sub.2. In certain embodiments, at least one instance of R.sup.5 is N.sub.3. In certain embodiments, at least one instance of R.sup.5 is optionally substituted alkyl. In certain embodiments, R.sup.5 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted C.sub.1-6 acyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted C.sub.1-3 acyl. In certain embodiments, at least one instance of R.sup.5 is unsubstituted C.sub.1-3 acyl. In certain embodiments, at least one instance of R.sup.5 is C(O)H. In certain embodiments, one instance of R.sup.5 is C(O)H. In certain embodiments, at least one instance of R.sup.5 is an aldehyde, ester, amide, or carboxylic acid moiety. In certain embodiments, at least one instance of R.sup.5 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.5 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.5 is OR.sup.O. In certain embodiments, at least one instance of R.sup.5 is N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.5 is or SR.sup.S.
[0270] In certain embodiments, the group represented by the formula:
##STR00112##
is of one of the following formulae:
##STR00113##
[0271] In certain embodiments, the group represented by the formula:
##STR00114##
is of the formula:
##STR00115##
[0272] In certain embodiments, the group represented by the formula:
##STR00116##
is of the formula:
##STR00117##
[0273] In certain embodiments, the group represented by the formula:
##STR00118##
is of the formula:
##STR00119##
Group R.SUP.6
[0274] As generally defined herein, R.sup.6 is hydrogen, halogen, optionally substituted alkyl, OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, R.sup.6 is OR.sup.O, N(R.sup.N).sub.2, or SR.sup.S. In certain embodiments, R.sup.6 is hydrogen. In certain embodiments, R.sup.6 is halogen (e.g., Cl, F, Br, I). In certain embodiments, R.sup.6 is optionally substituted alkyl. In certain embodiments, R.sup.6 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.6 is OR.sup.O. In certain embodiments, R.sup.6 is N(R.sup.N).sub.2. In certain embodiments, R.sup.6 is SR.sup.S. In certain embodiments, R.sup.6 is OH. In certain embodiments, R.sup.6 is NH.sub.2. In certain embodiments, R.sup.6 is SH.
Groups R.sup.O, R.sup.N, and R.sup.S
[0275] As generally defined herein, R.sup.O is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.O is hydrogen. In certain embodiments, R.sup.O is optionally substituted alkyl. In certain embodiments, R.sup.O is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.O is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.O is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.O is optionally substituted alkenyl. In certain embodiments, R.sup.O is optionally substituted alkynyl. In certain embodiments, R.sup.O is optionally substituted carbocyclyl. In certain embodiments, R.sup.O is optionally substituted heterocyclyl. In certain embodiments, R.sup.O is optionally substituted aryl. In certain embodiments, R.sup.O is optionally substituted heteroaryl. In certain embodiments, R.sup.O is optionally substituted acyl. In certain embodiments, R.sup.O is an oxygen protecting group.
[0276] As generally defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.N are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.N is hydrogen. In certain embodiments, R.sup.N is optionally substituted alkyl. In certain embodiments, R.sup.N is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.N is optionally substituted alkenyl. In certain embodiments, R.sup.N is optionally substituted alkynyl. In certain embodiments, R.sup.N is optionally substituted carbocyclyl. In certain embodiments, R.sup.N is optionally substituted heterocyclyl. In certain embodiments, R.sup.N is optionally substituted aryl. In certain embodiments, R.sup.N is optionally substituted heteroaryl. In certain embodiments, R.sup.N is optionally substituted acyl. In certain embodiments, R.sup.N is a nitrogen protecting group. In certain embodiments, two R.sup.N are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl
[0277] As generally defined herein, R.sup.S is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, R.sup.S is hydrogen. In certain embodiments, R.sup.S is optionally substituted alkyl. In certain embodiments, R.sup.S is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.S is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.S is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.S is optionally substituted alkenyl. In certain embodiments, R.sup.S is optionally substituted alkynyl. In certain embodiments, R.sup.S is optionally substituted carbocyclyl. In certain embodiments, R.sup.S is optionally substituted heterocyclyl. In certain embodiments, R.sup.S is optionally substituted aryl. In certain embodiments, R.sup.S is optionally substituted heteroaryl. In certain embodiments, R.sup.S is optionally substituted acyl. In certain embodiments, R.sup.S is a sulfur protecting group.
s, p, n, and m
[0278] As generally defined herein, s is 0, 1, 2, or 3. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3.
[0279] As generally defined herein, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
[0280] In certain embodiments, the sum of s and p is 1, 2, or 3. In certain embodiments, the sum of s and p is 1. In certain embodiments, s is 0 and p is 1. In certain embodiments, s is 1 and p is 0. In certain embodiments, the sum of s and p is 2. In certain embodiments, s is 2 and p is 0. In certain embodiments, s is 1 and p is 1. In certain embodiments, s is 0 and p is 2. In certain embodiments, the sum of s and p is 3. In certain embodiments, s is 3 and p is 0. In certain embodiments, s is 2 and p is 1. In certain embodiments, s is 1 and p is 2. In certain embodiments, s is 0 and p is 3.
[0281] As generally defined herein, n is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.
[0282] As generally defined herein, m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.
Compositions, Kits, and Administration
[0283] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.
[0284] In certain embodiments, the compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the amount is an amount effective for treating a disease associated with oxidative stress in a subject. In certain embodiments, the amount is an amount effective for reducing oxidative stress in a subject or cell. In certain embodiments, the amount is an amount effective for treating a metabolic condition (e.g., diabetes (e.g., type I, type II), pre-diabetes, diabetic nephropathy). In certain embodiments, the amount is an amount effective for treating a proliferative disease (e.g., cancer, benign neoplasm). In certain embodiments, the amount is an amount effective for treating an inflammatory disease. In certain embodiments, the amount is an amount effective for treating an autoimmune disease. In certain embodiments, the amount is an amount effective for treating a cardiovascular disease. In certain embodiments, the amount is an amount effective for treating a renal disease (e.g., kidney failure, chronic kidney disease). In certain embodiments, the amount is an amount effective for treating a neurodegenerative disease.
[0285] The present disclosure also provides cosmetic compositions comprising a compound of Formula (I) or (II), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a cosmetically acceptable excipient.
[0286] 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.
[0287] 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 pharmaceutical 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.
[0288] Relative amounts of the active ingredient, the excipient(s), 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.
[0289] Pharmaceutically and cosmetically 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.
[0290] 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.
[0291] 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.
[0292] 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 (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.
[0293] 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.
[0294] 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.
[0295] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
[0296] 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. 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.
[0297] 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.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0298] 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.
[0299] 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, German 115, Germaben II, Neolone, Kathon, and Euxyl.
[0300] 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.
[0301] 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.
[0302] 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, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
[0303] 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.
[0304] 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.
[0305] 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.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] 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.
[0310] 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.
[0311] 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.
[0312] Suitable devices for use in delivering intradermal pharmaceutical 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.
[0313] Formulations suitable for topical administration include, but are not limited to, 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.
[0314] 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. 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).
[0315] 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, but not limited to, 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.
[0316] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical 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.
[0317] 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 pharmaceutical 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.
[0318] 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.
[0319] 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.
[0320] 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.
[0321] 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 pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
[0322] 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 g and 1 g, 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 ma and 100 ma, between 100 ma 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.
[0323] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical 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.
[0324] 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), 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 pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
[0325] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which 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, mucomoteins, 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., metabolic condition, proliferative disease, cardiovascular disease, inflammatory disease, autoimmune disease, neurodegenerative disease, renal disease). 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.
[0326] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer 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.
[0327] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising an excipient for dilution or suspension of a composition or compound described herein. In some embodiments, the composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
[0328] Thus, in one aspect, provided are kits including a first container comprising a compound or composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., metabolic condition, proliferative disease, cardiovascular disease, inflammatory disease, autoimmune disease, neurodegenerative disease, renal disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting ROS and/or RNS, and/or reducing oxidative stress in subject or cell. In certain embodiments, the kits are useful in cosmetic applications.
[0329] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., metabolic condition, proliferative disease, cardiovascular disease, inflammatory disease, autoimmune disease, neurodegenerative disease, renal disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof.
Methods of Treatment and Uses
[0330] The present invention also provides methods of using compounds of Formulae (I) and (II), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical and cosmetic compositions thereof.
[0331] Provided herein is a method for the treating and/or preventing of disease in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.
[0332] Also provided herein is the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease in a subject.
[0333] In certain embodiments, the disease is a genetic disease, proliferative disease (e.g., cancer), disease associated with angiogenesis, neoplasm, inflammatory disease, autoimmune disease, liver disease, renal disease, spleen disease, pulmonary disease, hematological disease, neurological disease (e.g., neurodegenerative disease), painful condition, psychiatric disorder, or metabolic disorder (e.g., a diabetic condition). In certain embodiments, the disease is a metabolic disorder, renal disease, proliferative disease, inflammatory disease, autoimmune disease, neurodegenerative disease, or cardiovascular disease. In certain embodiments, the disease is a metabolic disorder. In certain embodiments, the disease is diabetes (e.g., type I diabetes, type II diabetes). In certain embodiments, the disease is diabetic nephropathy. In certain embodiments, the disease is a renal disease. In certain embodiments, the disease is kidney failure. In certain embodiments, the disease is chronic kidney disease. In certain embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is a cardiovascular disease.
[0334] In certain embodiments, the disease is a disease associated with (e.g., caused or exacerbated by) oxidative stress in a subject.
[0335] Provided herein is a method of inhibiting concentration of or production of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) in a cell, subject, or biological sample, the method comprising administering to the subject, or contacting the cell or biological sample with, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the reactive species are inhibited in a subject. In certain embodiments, the reactive species are inhibited in a biological sample. In certain embodiments, the reactive species are inhibited in a cell. In certain embodiments, the concentration or production of reactive oxygen species (ROS) is inhibited. In certain embodiments, the concentration or production of reactive nitrogen species (RNS) is inhibited. In certain embodiments, the concentration of the reactive species (e.g., ROS and/or RNS) is inhibited. In certain embodiments, the ROS and/or RNS are neutralized. In certain embodiments, the production of ROS and/or RNS is inhibited. In certain embodiments, the production of ROS is inhibited. Inhibition of reactive species such as ROS and/or RNS can lead to a reduction of oxidative stress in a cell, subject, or biological sample.
[0336] Also provided herein is the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for inhibiting the concentration or production of ROS and/or RNS in a subject or biological sample. In certain embodiments, the production of ROS and/or RNS is inhibited. In certain embodiments, the production of ROS is inhibited.
[0337] Provided herein is a method for inhibiting the activity of NADPH oxidase in a cell, subject, or biological sample, the method comprising administering to the subject, or contacting the biological sample or cell with, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the NADPH oxidase is inhibited in a subject. In certain embodiments, the NADPH oxidase is inhibited in a biological sample. In certain embodiments, the NADPH oxidase is inhibited in a cell.
[0338] Also provided herein is the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for inhibiting the activity of NADPH oxidase in a subject or biological sample.
[0339] Provided herein is a method of reducing oxidative stress in a cell, subject, or biological sample, the method comprising administering to the subject, or contacting the cell or biological sample, with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the oxidative stress is reduced in a subject. In certain embodiments, the oxidative stress is reduced in a cell. In certain embodiments, the oxidative stress is reduced in a biological sample.
[0340] Also provided herein is the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for reducing oxidative stress in a cell, subject, or biological sample.
[0341] Provided herein is a method of reducing or slowing the effects of aging in a subject, the method comprising administering to the subject a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical or cosmetic composition thereof.
[0342] Also provided herein is the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical or cosmetic composition thereof, for the manufacture of a medicament for reducing the effects of aging in a subject.
[0343] Also provided herein are uses of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a cosmetic composition thereof, in cosmetic applications.
[0344] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal, such as a transgenic mouse or transgenic pig.
[0345] In certain embodiments, the provided methods and uses comprise contacting a cell with an effective amount of a compound, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition, as described herein. The cell may be contacted in vitro or in vivo. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in vitro.
[0346] In certain embodiments, the provided methods and uses comprise contacting a biological sample with an effective amount of a compound, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition, as described herein. The biological sample may be contacted in vitro or ex vivo.
[0347] A compound or composition provided herein may be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized 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.
EXAMPLES
[0348] These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope, as defined by the claims.
Spiroketal Antioxidants
[0349] Biological evaluation of the entire family of pyrrolomorpholine spiroketal natural products 1-6 was recently reported. Antioxidant activity was assessed using a fluorescence-based assay to measure intracellular ROS levels in a rat mesangial cell model of hyperglycemia-induced oxidative stress. For measurement of antioxidant activity, see, e.g., Wang et al. Radical Biol. Med. 1999, 27, 612-616; Magalhes et al. Anal. Chim. Acta. 2008, 613, 1-19. These studies identified acortatarin A (1) as the most promising inhibitor in this model, with an IC.sub.50 of 4.9 M and achieving complete inhibition of ROS induction at higher concentrations. Described herein are analogues based on systematic modification of acortatarin A (See
[0350] It has been postulated that acortatarin A may exert its antioxidant effect is through direct quenching of ROS via the pyrrole moiety. To investigate this possibility, benzannulated spiroketal analogue 8 was deigned that retains the aromaticity of the pyrrole but is unlikely to undergo direct oxidation. Alternatively, the aldehyde moiety of acortatarin A may react covalently with putative protein targets. Thus, the corresponding proteo, methyl, hydroxymethyl and methyl ester analogues 9ad were envisioned, as well as the corresponding desformylbenzene analogue 7 in the benzannulated series. To investigate the necessity of specific structural motifs, the pyrrole motif was deleted in the morpholine spiroketals 10ac as well as the deaza spiroketal analogue 11. Conversely, the ribose motif in pyrrolomorpholine analogue 12 was also deleted. Finally, as acortatarin A may be hydrolyzed intracellularly, acyclic analogue 13 was designed to assess the necessity of the spiroketal motif for activity.
Synthesis of Compounds
[0351] Due to the prohibitively low isolation yields of pyrrolomorpholine natural products from the natural sources, efficient synthetic access is required for detailed biological investigation and mechanism-of-action studies. Accordingly, this family has attracted considerable attention from the synthetic community. For additional syntheses of pyrrolomorpholine spiroketal natural products, see, e.g., Sudhakar et al. Org. Lett. 2011, 13, 5452-5455; Geng et al. Synlett 2012, 23, 855-858; Borrero et al. J. Org. Chem. 2012, 77, 8410-8416; Teranishi et al. Biosci. Biotechnol. Biochem. 2013, 77, 676-678; Cao et al. Nat. Prod. Bioprospect. 2015, 5, 37-45; Cao et al. Synlett 2015, 26, 921-926; Wood et al. Org. Biomol. Chem. 2016, 14, 7659-7664. Concise, highly stereoselective syntheses of the complete family of pyrrolomorpholine spiroketal natural products and analogues, as well as early investigations of the bioactivity of the natural products and non-natural 2-hydroxypyranose analogues have been reported previously (see, e.g., Wurst et al. Org. Lett. 2012, 14, 4442-4445).
[0352] The stereoselective synthesis of acortatarin A via spirocyclization of a glycal precursor has been reported previously. Thus, it was envisioned that the desired acortatarin A analogues could be accessed through stereocontrolled cyclizations of the corresponding furanoglycal precursors. The synthesis of desformylbenzene analogue 7 was achieved from silyl-protected ribal 14, synthesized from d-thymidine as previously reported, which was Cl-stannylated to give 15 (See
[0353] En route to compound 8, an umpolung approach was utilized in which the benzyl side chain of 24 is installed via radical coupling (See
[0354] To access aldehyde-modified analogues 9ad, the oxidation state of the aldehyde was adjusted directly in silyl-protected acortatarin A 27 (See
[0355] Despyrrolo analogues 10 and 11 were next synthesized, which lack the potentially oxidizable pyrrole ring of acortatarin A. Morpholine spiroketals 10ac were accessed from C1-formylglycal 31, prepared from protected ribal 14, via reductive amination with ethanolamine to afford cyclization precursor 33 (See
Synthetic Procedures
triisopropyl(((2R,3S)-5-(tributylstannyl)-2-(((triisopropylsilyl)oxy)-methyl)-2,3-dihydrofuran-3-yl)oxy)silane (C1-tributylstannyl Glycal, 15)
[0356] ##STR00120##
[0357] In a 50 mL roundbottom flask, TIPS-protected ribal 14 (401 mg, 0.936 mmol), which was prepared as previously described (see, e.g., Wurst, J. M.; Verano, A. L.; Tan, D. S., Stereoselective synthesis of acortatarins A and B. Org. Lett. 2012, 14, 4442-4445), was dissolved in THF (15 mL) and cooled to 78 C. To the pre-cooled solution, tert-butyllithium (2.1 mL, 1.7 M in pentane, 3.0 equiv) was added slowly via syringe. The yellow solution was stirred at 78 C. for 15 min, then warmed to 42 C., stirred for 1 h, then re-cooled to 78 C. Tributyltin chloride (1.07 mL, 3.98 mmol, 3.0 equiv) was added dropwise via syringe. The reaction was stirred for 30 min at 78 C., then warmed to rt and quenched with satd aq NaHCO.sub.3. The reaction mixture was extracted with ether 3, and the combined organic extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography with pure hexanes first to remove excess tin, then 7:1 hexanes/CH.sub.2Cl.sub.2+0.5% Et.sub.3N afforded the desired glycal stannane 15 (756 mg, 90% yield) as a clear oil.
[0358] TLC: R.sub.f 0.44 (19:1 hexanes/EtOAc). IR (ATR): 2971, 2642, 1624, 1487, 1376, 1227, 1170, 1021, 915, 867, 811, 707. .sup.1H-NMR (600 MHz): 5.14-5.11 (m, 1H), 4.97 (t, 1H, J=2.5), 4.31 (ddd, 1H, J=7.3, 5.4, 2.4), 3.76 (dd, 1H, J=10.2, 5.3), 3.50 (dd, 1H, J=10.3, 6.8), 1.59-1.45 (m, 6H), 1.31 (h, 6H, J=7.3), 1.11-1.00 (m, 42H), 1.00-0.95 (m, 6H), 0.88 (t, 9H, J=7.3). .sup.13C-NMR (151 MHz): 167.4, 115.4, 90.0, 76.4, 63.2, 28.9, 27.2, 18.1, 18.0, 13.7, 12.4, 9.6. HRMS m/z calcd for C.sub.35H.sub.74O.sub.3Si.sub.2SnNa ([M+Na].sup.+) 741.4096; found 741.4118.
(2-(((4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)-4,5-dihydro-furan-2-yl)methyl)phenyl)methanol (TIPS-Protected Benzylglycal Alcohol, 18)
[0359] ##STR00121##
[0360] To a stirred solution of glycal stannane 15 (383 mg, 0.53 mmol) in anhyd toluene (0.1 M) was added benzyl bromide 16 (156 mg, 0.64 mmol, 1.2 equiv), copper(I) iodide (41 mg, 0.21 mmol, 0.4 equiv) and Pd(PPh.sub.3).sub.4 (123 mg, 0.11 mmol, 0.2 equiv). The yellow solution was shielded from light with aluminum foil and heated to 80 C. for 8 h, and then cooled to rt and concentrated to dryness. Purification by silica flash chromatography with 95:5 hexanes/EtOAc+0.5% Et.sub.3N yielded the partially purified 0-acetyl C1-benzylglycal 17 as a colorless oil. TLC: R.sub.f 0.32 (9:1 benzene/acetone).
[0361] O-Acetyl C1-benzylglycal 17 (315 mg, 0.53 mmol) was then dissolved in 1:1 THF/MeOH (0.1 M) and K.sub.2CO.sub.3 (148 mg, 1.1 mmol, 2.0 equiv) was added. After stirring for 4 h, the mixture was diluted with Et.sub.2O, washed with satd aq NaHCO.sub.3, dried with Na.sub.2SO.sub.4, and concentrated by rotary evaporation. Purification by silica flash chromatography (10:1 hexanes/EtOAc+1% Et.sub.3N) afforded the free alcohol 18 (279 mg, 56% over 2 steps) as a colorless oil.
[0362] TLC: R.sub.f 0.24 (9:1 benzene/acetone). IR (ATR): 3442 (OH st), 3066, 2931, 2865, 1687, 1461, 1422, 1379, 1091, 994, 878, 734, 711. .sup.1H-NMR (600 MHz): 7.20-7.13 (m, 2H), 7.13-7.10 (m, 1H), 7.01 (dd, 1H, J=6.6, 2.2), 4.95 (d, 1H, J=14.8), 4.70 (d, 1H, J=14.8), 4.38 (d, 1H, J=2.0), 4.16 (d, 1H, J=2.0), 3.88 (d, 1H, J=11.8), 3.81 (dd, 1H, J=10.9), 3.61 (d, 1H, J=11.8), 3.23 (d, 1H, J=16.9), 2.88 (d, 1H, J=16.9), 1.16-1.01 (m, 42H). .sup.13C-NMR (151 MHz): 154.3, 133.7, 132.0, 128.6, 126.5, 123.8, 87.6, 72.1, 63.4, 62.8, 47.1, 37.5, 18.1, 11.8. ESI-MS m/z (rel int): (pos) 571.4 ([M+Na].sup.+, 100); (neg) 583.4 ([M+Cl].sup., 80).
triisopropyl(((2S,4S,5R)-4-((triisopropylsilyl)oxy)-4,5-dihydro-3H-spiro-[furan-2,3-isochroman]-5-yl)methoxy)silane (TIPS-Protected Desformyl-Benzene Spiroketal, 19)
[0363] ##STR00122##
[0364] In a 10 mL roundbottom flask, benzylglycal alcohol 18 (21 mg, 0.039 mmol) was dissolved in THF (0.01 M) and cooled to 78 C. Sodium hexamethyldisilazane (0.2 M in THF, 1.0 equiv) was added slowly via syringe and stirred for 15 min. Mercuric acetate (14 mg, 0.043 mmol, 1.1 equiv) was added and warmed to 0 C. for 1 h, then rt for an additional 5 h. After a total of 6 h, NaBH.sub.4 (2.9 mg, 0.077 mmol, 2.0 equiv) was added and stirred for 5 min. The reaction was quenched with satd aq NaHCO.sub.3, washed with water, brine, dried over MgSO.sub.4, filtered, and concentrated by rotary evaporation. The crude product was filtered over a short plug of silica gel using EtOAc+0.5% Et.sub.3N to remove residual mercury, affording the desired benzannulated spiroketal 19 as a mixture of 80:20 /-spiroketals (19.3 mg, 91%) as a clear oil.
[0365] TLC: R.sub.f 0.20 (4:1 hexanes/EtOAc). IR (ATR): 3061, 2935, 2854, 1464, 1419, 1371, 1243, 1012, 882, 767, 751. .sup.1H-NMR (600 MHz): 7.16-7.14 (m, 2H), 7.04-7.02 (m, 1H), 6.99-6.97 (m, 1H), 4.99 (d, 1H, J=15.0), 4.71 (d, 1H, J=14.9), 4.59 (ddd, 1H, J=7.8, 4.8, 3.8), 4.08-4.06 (m, 1H), 3.84 (dd, 1H, J=11.2, 2.8), 3.80 (dd, 1H, J=11.2, 3.5), 3.07 (d, 1H, J=16.1), 2.81 (d, 1H, J=16.1), 2.24 (dd, 1H, J=13.4, 7.7), 2.18 (dd, 1H, J=13.4, 3.8) 1.12-0.97 (m, 42H). .sup.13C-NMR (151 MHz): 133.9, 132.1, 128.7, 126.2, 125.8, 123.8, 104.9, 87.3, 71.8, 62.9, 62.7, 47.3, 37.4, 18.0, 11.9. HRMS m/z calcd for C.sub.31H.sub.56O.sub.4Si.sub.2Na ([M+Na].sup.+) 571.3615; found 571.3631.
(2S,4S,5R)-5-(hydroxymethyl)-4,5-dihydro-3H-spiro[furan-2,3-isochroman]-4-ol (Desformylbenzene -Spiroketal, 9)
[0366] ##STR00123##
[0367] In a 4-mL vial, TIPS-protected benzannulated spiroketal 19 (12.3 mg, 0.022 mmol) was dissolved in THF (0.02 M, 1.1 mL) and cooled to 0 C. Tetrabutylammonium fluoride (1.0 M in THF, 49 L, 2.2 equiv) was added and the reaction was stirred for 2 h. Concentration by rotary evaporation afforded the crude product. Purification by silica flash chromatography (99:1 CHCl.sub.3/MeOH+1% Et.sub.3N) yielded benzannulated a-spiroketal 7 as a single diastereomer (4.5 mg, 75%) as white needles.
[0368] TLC: R.sub.f 0.17 (99:1 CH.sub.3C1/MeOH). IR (ATR): 3437 (OH st), 3058, 2931, 2851, 1463, 1417, 1368, 1241, 1009, 891, 763, 755. .sup.1H-NMR (600 MHz): 7.19 (dd, 2H, J=5.7, 3.2), 7.13-7.10 (m, 1H), 7.03-7.00 (m, 1H), 4.98 (d, 1H, J=14.9), 4.76 (d, 1H, J=11.1), 4.65 (td, 1H, J=6.6, 4.3), 4.14 (dd, 1H, J=8.0, 4.0), 3.79 (dd, 1H, J=11.9, 3.8), 3.75-3.71 (m, 1H), 3.21 (d, 1H, J=16.3), 3.02 (d, 1H, J=16.2), 2.22 (dd, 1H, J=13.8, 1.2), 2.17 (dd, 1H, J=13.8, 6.3). .sup.13C-NMR (151 MHz): 132.6, 131.2, 128.7, 126.8, 126.3, 123.9, 105.8, 87.9, 72.6, 63.9, 63.2, 46.3, 37.5. HRMS m/z calcd for C.sub.13H.sub.16O.sub.4Na ([M+Na].sup.+) 259.0946; found 259.0951.
2-(((4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)-4,5-di-hydrofuran-2-yl)methyl)isophthalonitrile (TIPS-Protected C1-dicyanobenzyl-glycal, 24)
[0369] ##STR00124##
[0370] In a 15 mL roundbottom flask, TIPS-protected C1-tributylstannyl glycal 15 (50 mg, 0.070 mmol) was dissolved in CH.sub.2Cl.sub.2 (0.01 M, 7 mL) and cooled to 0 C. A solution of iodine (27 mg, 0.104 mmol, 1.5 equiv) in CH.sub.2Cl.sub.2 (1 mL) was added dropwise via syringe to the glycal stannane solution until a pale purple color persisted. The reaction was immediately quenched by the addition of 1 mL 10% aq Na.sub.2S.sub.2O.sub.3 and extracted with CH.sub.2Cl.sub.2 (25 mL). The combined extracts were dried over MgSO.sub.4, filtered, and concentrated by rotary evaporation to provide the crude C1-iodoglycal 22 as a colorless oil, which was used immediately in the next reaction without further purification.
[0371] The crude C1-iodoglycal 22, prepared above, and dicyanotoluene 23 (40 mg, 0.28 mmol, 4.0 equiv) were dissolved in benzene. Azobisisobutyronitrile (11.5 mg, 0.070 mmol, 1.0 equiv) was added, and the reaction mixture was stirred at 80 C. for 3 h. Upon cooling to rt, the reaction mixture was extracted with EtOAc, washed with water, brine, dried over MgSO.sub.4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography with 19:1 hexanes/EtOAc+0.5% Et.sub.3N provided the desired dicyanobenzyl glycal 24 (23.3 mg, 59% from glycal stannane 17) as a white solid.
[0372] TLC: R.sub.f 0.31 (9:1 hexanes/EtOAc). IR (ATR): 2916, 2872, 2451, 2231 (CN st), 1671, 1469, 1361, 1143, 972, 919, 886, 846, 725. .sup.1H-NMR (500 MHz): 7.91 (d, 1H, J=1.6), 7.90 (d, 1H, J=1.6), 7.57 (t, 1H, J=1.7), 5.07 (d, 1H, J=7.9), 5.01 (d, 1H, J=2.5), 4.40 (td, 1H, J=5.1, 2.9), 4.19 (s, 2H), 3.81 (dd, 1H, J=10.7, 5.0), 3.72 (dd, 1H, J=10.7, 5.1), 1.13-1.00 (m, 42H). .sup.13C-NMR (151 MHz): 143.2, 138.1, 128.4, 116.8, 114.3, 89.3, 73.5, 64.1, 62.4, 46.8, 38.5, 18.1, 12.8. ESI-MS m/z (rel int): (pos) 591.4 ([M+Na].sup.+, 100); (neg) 603.1 ([M+Cl].sup., 35).
2-(((4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)-4,5-dihydrofuran-2-yl)methyl)isophthalaldehyde (TIPS-protected benzylglycal dialdehyde, SI)
[0373] ##STR00125##
[0374] In a 25 mL roundbottom flask, TIPS-protected dicyanobenzyl glycal 24 (64 mg, 0.11 mmol) was dissolved in CH.sub.2Cl.sub.2 (0.01 M) and cooled to 0 C. A solution of diisobutylaluminum hydride (DIBAL-H) in hexane (0.1 M, 0.24 mmol, 2.1 equiv) was added dropwise over 20 min. The reaction mixture was allowed to warm slowly to rt over 4 h. The reaction mixture was re-cooled to 0 C. and poured into a 50 mL beaker filled with ice and precooled aqueous 1 N HCl (25 mL). The mixture was vigorously stirred for 1.5 h, and then extracted with dichloromethane (310 mL). The combined organic extracts were washed with 1 N NaHCO.sub.3, water, brine, dried over MgSO.sub.4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography with 19:1 hexanes/EtOAc+0.5% Et.sub.3N to afford benzylglycal dialdehyde S1 (45 mg, 70%) as a white solid.
[0375] TLC: R.sub.f 0.22 (9:1 hexanes/EtOAc). IR (ATR): 2923, 2881, 2462, 1771 (C O st), 1462, 1365, 1140, 986, 912, 881, 858, 711. .sup.1H-NMR (500 MHz): 10.03 (s, 2H), 7.79 (dt, 1H, J=7.5, 1.5), 7.64 (dt, 1H, J=7.7, 1.5), 7.52 (t, 1H, J=7.6), 5.07 (t, 1H, J=2.6), 5.02 (t, 1H, J=2.7), 4.78 (dd, 2H, J=7.6, 5.6), 4.35 (td, 1H, J=5.5, 2.7), 3.79 (dd, 1H, J=10.6, 5.4), 3.66 (dd, 1H, J=10.6, 5.6), 1.14-1.00 (m, 42H). .sup.13C-NMR (151 MHz): 179.2, 158.8, 145.9, 137.3, 122.1, 119.0, 88.1, 71.2, 63.4, 61.4, 45.2, 18.0, 11.8. ESI-MS m/z (rel int): (pos) 574.6 ([M+Na].sup.+, 100); (neg) 586.4 ([M+Cl].sup., 80).
3-(hydroxymethyl)-2-(((4S,5R)-4-((triisopropylsilyl)oxy)-5-(((triisopropyl-silyl)oxy)methyl)-4,5-dihydrofuran-2-yl)methyl)benzaldehyde (TIPS-Protect-Ed Benzylglycal Monoalcohol, 25)
[0376] ##STR00126##
[0377] In a 15 mL roundbottom flask, TIPS-protected benzylglycal dialdehyde 51 (31.3 mg, 0.054 mmol) was dissolved in THF and cooled to 0 C. Sodium borohydride (1 mg, 0.016 mmol, 0.5 equiv) was added and stirred for 1.5 h at 0 C. Careful monitoring of the reaction by TLC allowed for minimal over-reduction and minimal remaining starting material. The reaction was quenched with NaHCO.sub.3. The reaction mixture was extracted with EtOAc, washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography with 9:1 hexanes/EtOAc+0.5% Et.sub.3N afforded benzylglycal monoalcohol 25 (23.9 mg, 76%) as a white solid.
[0378] TLC: R.sub.f 0.28 (4:1 hexanes/EtOAc). IR (ATR): 3438 (OH st), 3042, 2928, 2861, 1676, 1454, 1421, 1309, 1151, 982, 859, 761, 731, 689. .sup.1H-NMR (600 MHz): 9.93 (s, 1H), 8.04 (dd, 2H, J=7.7, 1.7), 7.47 (t, 1H, J=7.7), 6.16 (d, 2H), 4.99 (d, 1H, J=2.9), 4.96 (d, 1H, J=2.5), 4.51 (s, 2H), 4.30 (td, 1H, J=4.8, 2.9), 3.72 (dd, 1H, J=10.7, 4.8), 3.65 (1H, dd, J=10.9, 4.9), 0.96 (m, 42H). .sup.13C-NMR (151 MHz): 179.9, 160.5, 145.9, 137.3, 132.1, 129.0, 128.3, 127.5, 102.7, 90.5, 76.1, 63.3, 59.1, 38.5, 18.0, 11.9. ESI-MS m/z (rel int): (pos) 599.4 ([M+Na].sup.+, 100); (neg) 611.8 ([M+Cl].sup., 75).
(2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)-4,5-dihydro-3H-spiro[furan-2,3-isochromane]-5-carbaldehyde (formylbenzene -spiroketal, 8)
[0379] ##STR00127##
[0380] In a 10 mL roundbottom flask, TIPS-protected benzylglycal monoalcohol 25 (11.6 mg, 0.20 mmol) was dissolved in THF and cooled to 78 C. Sodium hexamethyldisilazane (0.1 M, 0.022 mmol, 1.1 equiv) was added dropwise and stirred for 15 min. Mercuric acetate (7.7 mg, 0.024 mmol, 1.2 equiv) was added and stirred at 0 C. for 1 h, then warmed to rt for 5 h. Sodium borohydride (1.6 mg, 0.040 mmol, 2.0 equiv) was added and stirred for 5 min, then the reaction was quenched with satd aq NaHCO.sub.3. The reaction mixture was extracted with EtOAc, washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated by rotary evaporation. The crude product was filtered over a plug of silica gel to remove residual mercury to provide an 80:20 / mixture of crude TIPS-protected formylbenzene spiroketal 26 (11 mg, 90%) as a colorless oil, which was taken forward directly to deprotection. TLC: R.sub.f 0.23 (19:1 hexanes/EtOAc).
[0381] In a 4-mL vial, crude TIPS-protected formylbenzene glycal 26 (11 mg, 0.019 mmol) was dissolved in THF and cooled to 0 C. Tetrabutylammonium fluoride (1.0 M in THF, 0.042 mmol, 2.2 equiv) was added and stirred for 2 h. Upon warming to rt, concentration by rotary evaporation provided formylbenzene a-spiroketal 8 (3.6 mg, 72%) as a white solid.
[0382] TLC: R.sub.f 0.24 (98:2 CH.sub.3C1/MeOH). IR (ATR): 3341 (OH st), 2951, 2761, 2213, 1774, 1653, 1361, 1259, 1142, 1092, 1012, 848, 816, 786, 721, 689. .sup.1H-NMR (600 MHz): 9.87 (s, 1H), 8.01 (dd, 2H, J=7.7, 1.7), 7.49 (t, 1H, J=7.7), 6.97 (d, 1H, J=14.6), 6.54 (d, 1H, J=14.5), 5.00 (d, 1H, J=2.9), 4.96 (d, 1H, J=2.9), 4.81 (d, 1H, J=14.9), 4.31 (td, 1H, J=4.8, 2.9), 3.74 (dd, 1H, J=10.7, 4.8), 3.67 (1H, dd, J=10.9, 4.9), 2.25 (dd, 1H, J=13.8, 1.2), 2.21 (dd, 1H, J=13.8, 6.3). .sup.13C-NMR (151 MHz): 178.2, 158.3, 145.9, 137.3, 132.1, 129.0, 128.3, 127.5, 101.4, 91.3, 77.1, 63.7, 60.2, 39.0. HRMS m/z calcd for C.sub.14H.sub.16O.sub.5Na ([M+Na].sup.+) 287.0895; found 287.0901.
Biological Activity
[0383] Inhibitory activity of the compounds against hyperglycemia-induced ROS production in rat mesangial cells was evaluated, with N-acetyl cysteine used as a positive control (Table 1, entry 1). Consistent with previous report, acortatarin A exhibited an IC.sub.50 of 4.9 M and achieved complete inhibition of ROS induction at higher concentrations (Table 1, entry 2). Strikingly, replacement of the pyrrole ring with a benzene ring was advantageous in both desformylbenzene analogue 7 and formylbenzene analogue 8 (Table 1, entries 3,4). This suggests that acortatarin A likely does not function through direct quenching of ROS by pyrrole oxidation. Along these lines, it was also demonstrated that acortatarin A is unreactive to equimolar concentrations of H.sub.2O.sub.2, OH radical, as well as the reactive nitrogen species peroxynitrite. Similarly, Aponick and coworkers have previously reported first and second oxidation potentials of +1.74 and 1.90 V for acortatarin A in cyclic voltametry studies, in contrast to the low oxidation potentials of less than +0.70 V for most direct ROS quenchers.
[0384] Desformylbenzene analogue 7 was the most effective antioxidant, reducing ROS production to normal levels at a concentration of 5 M; in contrast, 20 M of acortatarin A was required for complete inhibition. This suggests that the aldehyde may not be required for activity of the benzannulated scaffold, and thus, that the mechanism of action may not involve formation of covalent adducts. In contrast, the desformylpyrrole analogue 9a showed no antioxidant activity (Table 1, entry 5), indicating that the aldehyde is required for activity of the pyrrolomorpholine scaffold. We hypothesize that the electron-withdrawing aldehyde in acortatarin A is essential to protect the pyrrole from oxidation, and indeed, treatment of desformylpyrrole analogue 9a with H.sub.2O.sub.2 leads to decomposition. Accordingly, the more electron-rich methylpyrrole analogue 9b and hydroxymethylpyrrole analogue 9c were also inactive (Table 1, entry 6,7), while the carboxymethylpyrrole analogue 9d retained activity (Table 1, entry 8).
[0385] Furthermore, simplified analogues 10-12 showed no activity (Table 1, entries 9-13), indicating that the tricyclic ring system is required for activity. The acortatarin A hydrolysis product 13 also exhibited no effect on ROS production (Table 1, entry 14), suggesting that the spiroketal motif is required for activity. However, it should be noted that the hydrolysis product 13 is very polar (C log P=2.05 vs 0.99 for acortatarin A) and may not be able to enter cells, and thus it is still possible that 13 is the active pharmacophore if hydrolysis of acortatarin A occurs intracellularly.
TABLE-US-00001 TABLE 1 Inhibition of high glucose-induced ROS production in rat mesangial cells..sup.a IC.sub.50 (M) Maximum % ROS Entry Compound [s.d. log IC.sub.50].sup.b Inhibition.sup.c 1 N-acetyl-cysteine.sup.d n.a. 100%*** 2 acortatarin A (1) 4.9 [0.06] 100%*** 3 desformylbenzene 7 1.4 [0.17] 100%*** 4 formylbenzene 8 7.1 [0.06] 100%*** 5 desformylpyrrole 9a >200 n.a. 6 methylpyrrole 9b >200 n.a. 7 hydroxymethylpyrrole 9c >200 n.a. 8 carbomethoxypyrrole 9d 12 [0.06] 95%*** 9 morpholine 10a >200 n.a. 10 N-methyl morpholine 10b >200 n.a. 11 N-acetyl morpholine 10c >200 n.a. 12 despyrrole 11 >200 n.a. 13 pyrrolomorpholine 12 >200 n.a. 14 hydrolysis product 13 >200 n.a. 15 2-deoxy-D-ribose >200 n.a. For Table 1: .sup.aCells were treated with compound (0-200 M) under normal (5.6 mM) or high (30 mM) glucose conditions and overall ROS levels were measured using the fluorescent probe DCFH-DA (50 M). .sup.bData are expressed as mean IC.sub.50 of three independent experiments, each performed in triplicate, with the standard deviation of the log IC.sub.50 shown in brackets. .sup.cStatistical significance relative to untreated cells under high-glucose conditions was assessed using a two-tailed unpaired Student t-test with 95% confidence intervals; ***p 0.001. .sup.dN-acetyl-cysteine (1 mM) was used as a positive control.
Antioxidant Activity Assays
[0386] The inhibitory effects of the pyrrolomorpholine spiroketals on high glucose-induced oxidative stress were evaluated in rat mesangial cells (RMC). The rat mesangial cells, obtained from the American Type Culture Collection (CRL-2573), were cultured at 37 C. in Dulbecco's modified Eagle's medium (DMEM) containing 5.6 mM glucose (normal glucose), 10% fetal calf serum (FCS), nonessential amino acids, penicillin/streptomycin under a humidified atmosphere of 95% air and 5% CO.sub.2. Rat mesangial cells were seeded in 96-well plates approximately 24 hours before the start of all experiments. For more details on the antioxidant activity assays, see, e.g., Wang et al. Free Radical Biol. Med. 1999, 27, 612-616; Magalhes et al. Anal. Chim. Acta. 2008, 613, 1-19; Peng et al. Org. Lett. 2010, 12, 4932-4935; Hung et al. Am. J. Nephrol. 2009, 29, 192-202.
[0387] For each experiment, rat mesangial cells were incubated with pyrrolomorpholine spiroketal compound (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 200 M) or 1 mM N-acetyl cysteine (NAC, positive control) in the presence of either 5.6 mM (normal glucose, NG) or 30 mM (high glucose, HG) D-glucose for 3 h. RMC were then incubated with 50 M dichloro-dihydro-fluorescein diacetate (DCFH-DA) for 45 min, and intracellular production of ROS was detected by 2,7-dichlorofluorescein (DCF) fluorescence (485 nm excitation, 530 emission) as measured by a microplate reader (SpectraMax M5/M5, Molecular Devices). Values are expressed as percentage of ROS inhibition, where fluorescence from untreated cells under normal glucose conditions was set at 0% and untreated cells under high glucose conditions was set at 100%.
[0388] The MTT viability assay was performed in every experiment to assess the cellular toxicity of each compound. The results showed that all compounds were non-toxic up to 200 M over 72 h (data not shown). In addition, cell viability was evaluated by trypan blue exclusion test, which indicated that all compounds were non-toxic up to 200 M over 72 h.
EQUIVALENTS AND SCOPE
[0389] Text here. In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[0390] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0391] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[0392] 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.