NEUROPROTECTIVE POLYPHENOL ANALOGS

摘要

The present invention provides neuroprotective polyphenol compounds, which can be synthetic analogs of fisetin, baicalein or chlorogenic acid, that maintain neuroprotective, anti-inflammatory, glutathione promoting, and/or antioxidant properties. The neuroprotective polyphenol compounds are useful for promoting, enhancing and/or increasing neuron protection, growth and/or regeneration. The polyphenol compounds further find use for increasing and or maintaining intracellular glutathione (GSH) levels. The polyphenol compounds are also useful for treating, preventing, mitigating and/or delaying neurodegenerative conditions, including diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementias, multiple sclerosis, traumatic brain injury, spinal cord injury or ALS.

主权项

1. A compound having a formula I or a structure selected from or a pharmaceutically acceptable salt thereof, wherein: Z is N or O, when Z is N then and
when Z is O, then R1 is —N(Rc)2; R2 is H, optionally substituted C1-6alkyl, —ORa, —NO2 or —N(Rc)2; R3 is H, optionally substituted C1-6alkyl or —ORa; R4, when present, is Ra; each R5 is, independently for each occurrence, H, Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —ORe substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Rc where Rc is substituted with one or more of the same or different Ra and/or Rb, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—Rb, —S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)—(C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb, or, alternatively, two of R5, together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, partially saturated or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra and/or Rb; each R6 is, independently for each occurrence, H, Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —ORe substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Re where Re is substituted with one or more of the same or different Ra and/or Rb, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)—(C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb, or, alternatively, two of R6, together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, partially saturated or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra and/or Rb; each Ra is independently for each occurrence H, C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 3-10 membered heteroalicyclyl, 4-11membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; each Rb is independently for each occurrence ═O, ═S, —ORa, —O—(C(Ra)2)m—ORa, —SRa, ═NRa, ═NORa, —N(Rc)2, halo, —CF3, —CN, —NO2, —S(O)Ra, —S(O)2Ra, —SO3Ra, —S(O)2N(Rc)2, —C(O)Ra, —CO2Ra, —C(O)N(Rc)2, —OC(O)N(Rc)2, —┌N(Ra)C(O)┐nRa, —[N(Ra)C(O)]nORa or —[N(Ra)C(O)]nN(Rc)2; each Rc is independently for each occurrence Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra and/or Rd groups; each Rd is ═O, —ORa, haloC1-3alkyloxy, C1-6alkyl, ═S, —SRa, —N(Ra)2, halo, —CF3, —CN, —NO2, —S(O)Ra, —S(O2)Ra, —SO3Ra, —S(O)2N(Ra)2, —C(O)Ra, —CO2Ra, —C(O)N(Ra)2, —OC(O)N(Ra)2, —[N(Ra)C(O)]nRa, —(C(Ra)2)n—ORa, —C(O)—C1-6haloalkyl, —OC(O)Ra, —O(C(Ra)2)m—ORa, —S(C(Ra)2)m—ORa, —N(Ra)—(C(Ra)2)m—ORa, —┌N(Ra)C(O)┐nORa, —[N(Ra)C(O)]nN(Ra)2 or —N(Ra)C(O)C1-6haloalkyl, or, alternatively, two Rd, taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more Ra; each Re is independently for each occurrence C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; each m is 1, 2 or 3; each n is 0, 1, 2 or 3; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2 or 3.