Nanoscale neuromodulating platform for retina neuron activation apparatus and method

Patent metadata

Field	Value
Publication number	US-9399145-B2
Application number	US-201213662138-A
Country	US
Kind code	B2
Filing date	Oct 26, 2012
Priority date	Apr 28, 2005
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

The present invention relates to methods and compositions for modulating receptors in postsynaptic neurons of damaged or diseased retinas. The invention also related to methods for using the compositions set forth herein for treatment of diseases of hyperexcitability such as epilepsy.

First claim

We claim:

1. A compound of formula:

and pharmaceutically acceptable salts thereof, wherein
R 1 and R 2 are independently C 1 -C 12 alkyl, halo(C 1 -C 12 alkyl), C 2 -C 12 alkenyl, or C 2 -C 12 alkynyl, each optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, —CN, —NO 2 , —OR 6 , —NR 6 2 , —CO 2 R 6 , —CONR 6 2 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle is optionally substituted with 1, 2, 3 or 4 R 7 ;
R 3 is hydrogen, C 1 -C 6 alkyl, or halo(C 1 -C 6 alkyl);
R 4 and R 5 are independently halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 6 , —NR 6 2 , —CO 2 R 6 , or —CONR 6 2 ;
X is —N(R 8 )—, —N(R 8 )CH 2 —, —N(R 8 )CHR 8 —, —N(R 8 )(CHR 8 ) 2-5 —, or —O—;
Y═Z is —N═N— or —C(R 8 )═C(R 8 )—; and
R 9 is hydrogen, —CHR 6a , —OR 6a , —NR 6a 2 , —CO 2 R 6a , —CONR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —NR 6a 2 , —N(R 8 )CO—(CH 2 ) 1-6 —NR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 6a , —N(R 8 )CO—(CH 2 ) 1-6 —N(R 8 )COR 6a , —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 10 , or —N(R 8 )CO—(CH 2 ) 1-6 —N(R 8 )COR 10 , wherein R 10 is —CH 2 CH 2 (OCH 2 CH 2 ) 2-50 —N(R 8 )COR 6a ;
where each R 6 independently is hydrogen, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl(C 1 -C 6 alkyl)-, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, or heterocycle(C 1 -C 6 alkyl)-, wherein each alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle is optionally substituted with 1, 2, 3 or 4 R 7 , or two R 6 with the nitrogen to which they are attached form a heterocycle optionally substituted with 1, 2, 3 or 4 R 7 ;
where each R 6a independently is hydrogen, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl(C 1 -C 6 alkyl)-, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, or heterocycle(C 1 -C 6 alkyl)-, wherein each alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle is optionally substituted with 1, 2, 3 or 4 R 7 , or two R 6 with the nitrogen to which they are attached form a heterocycle optionally substituted with 1, 2, 3 or 4 R 7 ;
where each R 7 independently is halogen, —CN, —NO 2 , —N 3 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, —CO 2 H, —COH, —CO 2 R 8 , or —CON(R 8 ) 2 ; and
where each R 8 independently is hydrogen or C 1 -C 6 alkyl.

2. The compound according to claim 1 , wherein R 3 is hydrogen.

3. The compound according to claim 1 , wherein R 1 and R 2 are independently C 1 -C 12 alkyl, optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 6 , —NR 6 2 , —CO 2 R 6 , —CONR 6 2 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle.

4. The compound according to claim 3 , wherein R 1 and R 2 are independently unsubstituted C 1 -C 12 alkyl.

5. The compound according to claim 1 , wherein X is —NH— or —O—.

6. The compound according to claim 1 , wherein X is —N(R 8 )CH 2 —, —N(R 8 )CHR 8 —, or —N(R 8 )(CHR 8 ) 2-5 —.

7. The compound according to claim 6 , wherein X is —NHCH 2 —.

8. The compound according to claim 1 , wherein R 4 and R 5 are independently selected from the group consisting of halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 6 , and —NR 6 2 .

9. The compound according to claim 1 , wherein R 4 and R 5 are absent.

10. The compound according to claim 1 , wherein Y═Z are —N═N—.

11. The compound according to claim 1 , wherein Y═Z are —CH═CH—.

12. The compound according to claim 1 , wherein R 9 is hydrogen, —CO 2 R 6a , —CONR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —NR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 6a , or —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 10 , wherein R 10 is —CH 2 CH 2 (OCH 2 CH 2 ) 2-50 —N(R 8 )COR 6a .

13. The compound according to claim 12 , wherein R 9 is hydrogen, —CO 2 H, or —CONH—(CH 2 ) 2 —NH 2 .

14. The compound according to claim 13 , wherein R 9 is —CONH—(CH 2 ) 2 —NH 2 .

15. The compound according to claim 12 , wherein R 9 is —CONH—(CH 2 ) 2 —NHCOR 10 , wherein R 10 is —CH 2 CH 2 (OCH 2 CH 2 ) 2-50 —NHCOR 6a , and R 6a is heterocycle(C 1 -C 6 alkyl) or heteroaryl(C 1 -C 6 alkyl).

16. The compound according to claim 15 , wherein R 9 is

17. The compound according to claim 1 , wherein
R 1 and R 2 are independently C 1 -C 12 alkyl, halo(C 1 -C 12 alkyl), C 2 -C 12 alkenyl, or C 2 -C 12 alkynyl, each optionally substituted with 1, 2, 3 or 4 substituents selected from halogen, —CN, —NO 2 , —OR 6 , —NR 6 2 , —CO 2 R 6 and —CONR 6 2 ;
R 3 is hydrogen, C 1 -C 6 alkyl, or halo(C 1 -C 6 alkyl);
R 4 and R 5 are independently halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 6 , —NR 6 2 , —CO 2 R 6 , or —CONR 6 2 ;
X is —N(R 8 )—, —N(R 8 )CH 2 —, —N(R 8 )CHR 8 —, —N(R 8 )(CHR 8 ) 2-5 —, or —O—;
Y═Z is —N═N— or —C(R 8 )═C(R 8 )—; and
R 9 is hydrogen, —CHR 6a , —OR 6a , —NR 6a 2 , —CO 2 R 6a , —CONR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —NR 6a 2 , —N(R 8 )CO—(CH 2 ) 1-6 —NR 6a 2 , —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 6a , —N(R 8 )CO—(CH 2 ) 1-6 —N(R 8 )COR 6a , —CON(R 8 )—(CH 2 ) 1-6 —N(R 8 )COR 10 , or —N(R 8 )CO—(CH 2 ) 1-6 —N(R 8 )COR 10 , wherein R 10 is —CH 2 CH 2 (OCH 2 CH) 2-50 —N(R 8 )COR 6a ;
where each R 6 independently is hydrogen, C 1 -C 6 alkyl or halo(C 1 -C 6 alkyl), wherein each alkyl is optionally substituted with 1, 2, 3 or 4 R 7 , or two R 6 with the nitrogen to which they are attached form a heterocycle optionally substituted with 1, 2, 3 or 4 R 7 ;
where each R 6a independently is hydrogen, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6 alkyl)-, C 3 -C 8 cycloalkyl(C 1 -C 6 alkyl)-, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, or heterocycle(C 1 -C 6 alkyl)-, wherein each alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle is optionally substituted with 1, 2, 3 or 4 R 7 , or two R 6 with the nitrogen to which they are attached form a heterocycle optionally substituted with 1, 2, 3 or 4 R 7 ;
where each R 7 independently is halogen, —CN, —NO 2 , —N 3 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, —CO 2 H, —COH, —CO 2 R 8 , or —CON(R 8 ) 2 ; and
wherein each R 8 is independently hydrogen or C 1 -C 6 alkyl.

18. The compound according to claim 1 , which is:

19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 and an acceptable carrier, excipient and/or diluent.

20. A method of activating a GABA receptor comprising administering an effective amount of a compound or a pharmaceutically acceptable salt of claim 1 .

21. The method of claim 20 wherein said GABA receptor is a GABA A .

22. A method of treating a disease of hyperexcitability comprising administering

Assignees

• Pepperberg David R
• Bruzik Karol
• Yue Lan
• Pawlowski Michal
• Qian Haohua
• Univ Illinois

Inventors

• Pepperberg David R
• Bruzik Karol
• Yue Lan
• Pawlowski Michal
• Qian Haohua

Classifications

• C07C245/08

  with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene · CPC title

• A61N5/0622

  Optical stimulation for exciting neural tissue · CPC title

• A61K31/655

  Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds · CPC title

• A61N5/062 Primary

  Photodynamic therapy, i.e. excitation of an agent · CPC title

• C07D207/452

  with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom · CPC title