Neuroprotective polyphenol analogs

Patent metadata

Field	Value
Publication number	US-2016206609-A1
Application number	US-201615054906-A
Country	US
Kind code	A1
Filing date	Feb 26, 2016
Priority date	Aug 12, 2011
Publication date	Jul 21, 2016
Grant date	—

Abstract

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.

First claim

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

R 1 is —N(R c ) 2 ;
R 2 is H, optionally substituted C 1-6 alkyl, —OR a , —NO 2 or —N(R c ) 2 ;
R 3 is H, optionally substituted C 1-6 alkyl or —OR a ;
R 4 , when present, is R a ;
each R 5 is, independently for each occurrence, H, R e , R b , R e substituted with one or more of the same or different R a and/or R b , —OR e substituted with one or more of the same or different R a and/or R b , —SR e substituted with one or more of the same or different R a and/or R b , —C(O)R e substituted with one or more of the same or different R a and/or R b , —N(R a )R c where R c is substituted with one or more of the same or different R a and/or R b , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2 or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b , or, alternatively, two of R 5 , 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 R a and/or R b ;
each R 6 is, independently for each occurrence, H, R e , R b , R e substituted with one or more of the same or different R a and/or R b , —OR e substituted with one or more of the same or different R a and/or R b , —SR e substituted with one or more of the same or different R a and/or R b , —C(O)R e substituted with one or more of the same or different R a and/or R b , —N(R a )R e where R e is substituted with one or more of the same or different R a and/or R b , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2 or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b , or, alternatively, two of R 6 , 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 R a and/or R b ;
each R a is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R b is independently for each occurrence ═O, ═S, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo, —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O) 2 N(R c ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —┌N(R a )C(O)┐ n R a , —[N(R a )C(O)] n OR a or —[N(R a )C(O)] n N(R c ) 2 ;
each R c is independently for each occurrence R a , or, alternatively, two R c 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 R a and/or R d groups;
each R d is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , —N(R a ) 2 , halo, —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O) 2 N(R a ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —C(O)—C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )—(C(R a ) 2 ) m —OR a , —┌N(R a )C(O)┐ n OR a , —[N(R a )C(O)] n N(R a ) 2 or —N(R a )C(O)C 1-6 haloalkyl, or, alternatively, two R d , 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 R a ;
each R e is independently for each occurrence C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 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.

2 . The compound of claim 1 , according to Formula IIA or IIIA,

wherein:
R 4 , when present, is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl;
each R 5 is, independently for each occurrence, H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 , or two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, the 6-membered aryl ring optionally substituted with one or more R a and/or R b ; and
each R 6 is, independently for each occurrence, H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 .

3 . The compound of claim 2 , wherein:
(a) the compound is of Formula IIA; R 2 is —OR a ; and R 3 is H or optionally substituted C 1-6 alkyl; (b) the compound is of Formula IIIA; R 2 is —OR a ; and R 3 is H, C 1-6 alkyl or —OR a ; (c) the compound is of Formula IIIA; R 2 is optionally substituted C 1-6 alkyl; and R 3 is H, C 1-6 alkyl or —OR a ; (d) The compound is of Formula IIA; R 2 is H; and R 3 is H or optionally substituted C 1-6 alkyl; or (e) the compound is of Formula IIIA; R 2 is H; and R 3 is H, C 1-6 alkyl or —OR a .

4 . The compound of claim 1 , according to Formula IIIF,

wherein R 2 is H or —OR a ; R 3 is H, C 1-6 alkyl or —OR a ; and each of R 5 and R 6 is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 ; and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a and/or R.

Assignees

• Salk Inst For Biological Studi

Inventors

• Schubert David R
• Maher Pamela A
• Chiruta Chandramouli

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title