Neuroprotective polyphenol analogs

Patent metadata

Field	Value
Publication number	US-9744164-B2
Application number	US-201615054906-A
Country	US
Kind code	B2
Filing date	Feb 26, 2016
Priority date	Aug 12, 2011
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

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

The invention claimed is:

1. A compound having a formula I

or a structure selected from

or a pharmaceutically acceptable salt thereof, wherein:
Z is N and

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 is C 1-6 alkyl;
each R 5 is, independently for each occurrence, 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 —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, or partially 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, 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 —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 6 , together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, or partially 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 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 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 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

wherein:
each R 5 is, independently for each occurrence, C 1-6 alkyl, 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, C 1-6 alkyl, 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; or
(b) the compound is of Formula IIA; R 2 is H; and R 3 is H or optionally substituted C 1-6 alkyl.

4. The compound of claim 1 , wherein R 2 is H or OH.

5. The compound of claim 2 , wherein the compound is of Formula IIA, R 2 is —OR a , and R 3 is H.

6. The compound of claim 5 , wherein R 2 is —OH.

7. The compound according to claim 1 , wherein the compound is:
4-ethoxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-023);
4-cyclopentyloxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-121);
4-methoxy-2-(4-dimethylaminophenyl)quinoline (CMS-109);
4-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-110);
4-isopropoxy-2-(4-dimethylaminophenyl)quinoline (CMS-112); or
4-isopropoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-113).

8. The compound of claim 1 , wherein the compound is

9. A pharmaceutical composition comprising one or more compounds of claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle.

10. A method of promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons, comprising administering an effective amount of one or more compounds of claim 1 to the neurons.

11. The method of claim 10 wherein the method promotes, increases, and/or enhances the protection, grow

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

• A61P25/28

  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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

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