IP Library › Granted Patent US 7,375,219

Granted Patent B2

US 7,375,219 · App. 11/404,267 · Granted May 20, 2008

Substituted indole compounds having NOS inhibitory activity

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,375,219
App. No.: 11/404,267
Granted: May 20, 2008
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, morphine/opioid induced tolerance and hyperalgesia.

Claims (163)

1. A compound having the formula:

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein,

R 1 is H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl;

R 2 is (CH 2 ) m2 X 2 , wherein X 2 is selected from the group consisting of:

wherein

each of R 2A and R 2B is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 2C and R 1D is, independently, H, OH, CO 2 R 2E , or NR 2F R 2G , wherein each of R 2E , R 2F , and R 2G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 2C and R 2D together with the carbon they are bonded to are C═O;

Z 2 is NR 2H , NC(O)R 2H , NC(O)OR 2H , NC(O)NHR 2H , NC(S)R 2H , NC(S)NHR 2H , NS(O) 2 R 2H , O, S, S(O), or S(O) 2 , wherein R 2H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

m2 is an integer of 0 to 6;

n2 is an integer of 1 to 4;

p2 is an integer of 0 to 2; and

q2 is an integer of 0 to 5;

R 3 is H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

R 5 is H, R 5A C(NH)NH(CH 2 ) r5 or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4 thioalkheterocyclyl; and

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4 thioalkheterocyclyl;

wherein one, but not both, of R 5 and R 6 is H.

2. A compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof,

wherein,

R 1 is (CH 2 ) m3 X 1 , wherein X 1 is selected from the group consisting of:

wherein

each of R 3C and R 3D is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-20 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 3C and R 3D together with the carbon they are bonded to are C═O;

Z 3 is NC(NH)R 3H , wherein R 3H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

m 3 is an integer of 0 to 6;

n 3 is an integer of 1 to 4;

p 3 is an integer of 0 to 2; and

q 3 is an integer of 0 to 5;

each of R 2 and R 3 is, independently, H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

wherein one, but not both, of R 5 and R 6 is H.

3. A compound having the formula:

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein,

R 1 is H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl;

R 2 is (CH 2 ) m3 X 2 , wherein X 2 is selected from the group consisting of:

wherein

each of R 3C and R 3D is, independently, H, OH, CO 2 R 3E or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 3C and R 3D together with the carbon they are bonded to are C═O;

m 3 is an integer of 0 to 6;

n 3 is an integer of 1 to 4;

p 3 is an integer of 0 to 2; and

q 3 is an integer of 0 to5;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

wherein one, but not both, of R 5 and R 6 is H.

4. A compound having the formula:

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein,

R 1 is H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl;

R 2 is H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

R 3 is (CH 2 ) m3 X 3 , wherein X 3 is selected from the group consisting of:

wherein

each of R 3C and R 3D is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F and R 3G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 3c and R 3D together with the carbon they are bonded to are C═O;

m 3 is an integer of 0 to 6;

n 3 is an integer of 1 to 4;

p 3 is an integer of 0 to 2; and

q 3 is an integer of 0 to 5;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

wherein one, but not both, of R 5 and R 6 is H.

5. A compound having the formula:

(I), or a pharmaceutically acceptable salt or prodrug thereof,

wherein,

R 1 is (CH 2 ) m1 X 1 , wherein X 1 is selected from the group consisting of:

wherein

each of R 1A and R 1B is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 1C and R 1D is, independently, H, OH, COR 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 1C and R 1D together with the carbon they are bonded to are C═O;

Z 1 is NR 1H , NC(O)R 1H , NC(O)OR 1H , NC(O)NHR 1H , NC(S)R 1H , NC(S)NHR 1H , NS(O) 2 R 1H , O, S, S(O), or S(O) 2 , wherein R 1H is H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

m1 is an integer of 2 to 6;

n1 is an integer of 1 to 4;

p1 is an integer of 0 to 2; and

q1 is an integer of 0 to 5;

R 2 is

wherein each of R 2J2 , R 2J3 , R 2J4 , R 2J5 , and R 26J is, independently, C 1-6 alkyl; OH; C 1-6 alkoxy; SH; C 1-6 thioalkoxy; Halo; NO 2 ; CN; CF 3 ; OCF 3 ; NR 2Ja R 2Jb , where each of R 2Ja and R 2Jb is, independently, H or C 1-6 alkyl; C(O)R 2Jc , where R 2Jc is H or C 1-6 alkyl; CO 2 R 2Jd , where R 2Jd is H or C 1-6 alkyl; tetrazolyl; C(O)NR 2Je R 2Jf , where each of R 2Je and R 2Jf is, independently, H or C 1-6 alkyl; OC(O)R 2Jg , where R 2Jg is C 1-6 alkyl; NHC(O)R 2Jh , where R 2Jh is H or C 1-6 alkyl; SO 3 H; S(O) 2 NR 2Ji R 2Ji , where each of R 2Ji and R 2Ji is, independently, H or C 1-6 alkyl; S(O)R 2Jk , where R 2Jk is C 1-6 alkyl; and S(O) 2 R 2Jl , where R 2Jl is C 1-6 alkyl;

R 3 is H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 1-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 or R 6H NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4 thioalkheterocyclyl;

wherein one, but not both, of R 5 and R 6 is H.

6. A compound having the formula:

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein,

R 1 is (CH 2 ) m1 X 1 , wherein X 1 is selected from the group consisting of:

wherein

each of R 1C and R 1D is, independently, H, OH, CO 2 R 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl, or R 1G and R 1D together with the carbon they are bonded to are C═O;

m1 is an integer of 2 to 6;

n1 is an integer of 1 to 4;

p1 is an integer of 0 to 2; and

q1 is an integer of 0 to 5;

R 3 is

wherein each of R 3J2 , R 3J3 , R 3J4 , R 3J5 , and R 3J6 is, independently, C 1-6 alkyl; OH; C 1-6 alkoxy; SH; C 1-6 thioalkoxy; Halo; NO 2 ; CN; CF 3 ; OCF 3 ; NR 3Ja R 3Jb , where each Of R 3Ja and R 3Jb is, independently, H or C 1-6 alkyl; C(O)R 3Jc , where R 3Jc is H or C 1-6 alkyl; CO 2 R 3Jd , where R 3Jd is H or C 1-6 alkyl; tetrazolyl; C(O)NR 3Je R 3Jf , where each of R 3Je and R 3Jf is, independently, H or C 1-6 alkyl; OC(O)R 3Jg , where R 3Jg is C 1-6 alkyl; NHC(O)R 3Jh , where R 3Jh is H or C 1-6 alkyl; SO 3 H; S(O) 2 NR 3Ji R 3Jj , where each of R 3Ji and R 3Jj is, independently, H or C 1-6 alkyl; S(O)R 3Jk , where R 3Jk is C 1-6 alkyl; and S(O) 2 R 3Jl , where R 3Jl is C 1-6 alkyl;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

wherein one, but not both, of R 5 and R 6 is H.

7. A compound selected from the group consisting of: 2-ethyl-1-(1H-indol-5-yl)-isothiourea; N-(1H-indol-5-yl)-thiophene-2-carboxamidine; N-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine; N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl }-thiophene-2-carboxamidine; 1-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-2-ethyl-isothiourea; N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine; N-(1-phenethyl-1H-indol-6-yl)-thiophene-2-carboxamidine; N-[3-(2-dimethylamino-ethyl)-1H-indol-5-yl]-thiophene-2-carboxamidine; N-(1-{2-[2-(4-bromo-phenyl)-ethylamino]-ethyl}-1H-indol-6-yl)-thiophene-2-carboxamidine; (+)-N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl}-thiophene-2-carboxamidine; (−)-N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl}-thiophene-2-carboxamidine; N-[1-(1-methyl-azepan-4-yl)-1H-indol-6-yl]-thiophene-2-carboxamidine; and N-[1-(2-piperidin-1-yl-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine.

8. A compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof,

wherein,

R 1 or R 3 is

wherein Z is NR X , R X is H or C 1-6 alkyl, o is an integer from 0-3, p is an integer from 1 to 2, q is an integer from 0 to 2, r is an integer from 0 to 1, s is an integer from 1 to 3, u is an integer from 0 to 1, and t is an integer from 5 to 7, and wherein said R 1 or R 3 substituent includes 0 to 6 carbon-carbon double bonds or 0 or 1 carbon-nitrogen double bonds;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy;

wherein one, but not both, of R 5 and R 6 is H; and

when R 1 or R 3 is not

R 1 is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl; and

R 3 is selected from H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl.

9. The compound of claim 8 , wherein said compound selectively inhibits nNOS over both eNOS and iNOS.

10. A compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein,

X is O or S;

R 1 is H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1 -4 alkheterocyclyl;

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy.

11. A compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein,

X is O or S;

R 1 is H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, or optionally substituted C 1-4 alkheterocyclyl;

each of R 2 and R 3 is, independently, H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 bridged heterocyclyl, optionally substituted C C 1-4 bridged alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl; and

each of R 4 and R 7 is, independently, H, F, C 1-6 alkyl, or C 1-6 alkoxy.

12. A compound selected from the group consisting of:

13. The compound of claim 11 , selected from the group consisting of:

14. The compound of claim 10 , wherein X is S.

15. The compound of claim 11 , wherein X is S.

16. The compound of claim 14 , having the formula:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein

R 3 is, independently, H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

R 5 is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl; and

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

18. The compound of claim 2 , wherein

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

19. The compound of claim 3 , wherein

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

20. The compound of claim 4 , wherein

R 2 is, independently, H, Hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl;

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

21. The compound of claim 5 , wherein

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

22. The compound of claim 6 , wherein

R 6 is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

23. The compound of claim 10 , wherein

24. The compound of claim 11 , wherein

Assignments (4)

RELEASE OF SECURITY AGREEMENTS AT 019035/0148 AND 019035/0222 Recorded Aug 17, 2007

From: VENTURES WEST 8 LIMITED PARTNERSHIP; NEW GENERATION BIOTECH (EQUITY) FUND INC.; H.I.G. VENTURE PARTNERS II, L.P.; H.I.G. VENTURES - NEURAXON, INC.; NEUROVENTURES FUND, L.P.; BDC CAPITAL INC.

To: NEURAXON INC.; NEURAXON (USA), INC.

Reel/Frame 019704/0978 →

SECURITY AGREEMENT Recorded Mar 20, 2007

From: NEURAXON INC.; NEURAXON (USA), INC.

To: VENTURES WEST 8 LIMITED PARTNERSHIP; NEW GENERATION BIOTECH (EQUITY) FUND INC.; H.I.G. VENTURE PARTNERS II, L.P.; H.I.G. VENTURES - NEURAXON, INC.; NEUROVENTURES FUND, L.P.

Reel/Frame 019035/0148 →

SECURITY AGREEMENT Recorded Mar 20, 2007

From: NEURAXON INC.; NEURAXON (USA), INC.

To: VENTURES WEST 8 LIMITED PARTNERSHIP; H.I.G. VENTURE PARTNERS II, L.P.; H.I.G. VENTURES - NEURAXON, INC.; NEW GENERATION BIOTECH (EQUITY) FUND INC.; NEUROVENTURES FUND, L.P.; BDC CAPITAL INC.

Reel/Frame 019035/0222 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2006

From: MADDAFORD, SHAWN; RAMNAUTH, JAILALL; RAKHIT, SUMAN; PATMAN, JOANNE; RENTON, PAUL; ANNEDI, SUBHASH

To: NEURAXON, INC.

Reel/Frame 017816/0212 →