IP Library › Granted Patent US 7,951,940
Granted Patent B2
US 7,951,940 · App. 12/047,963 · Granted May 31, 2011

Substituted indole compounds having NOS inhibitory activity

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Quick Facts
Patent No.
US 7,951,940
App. No.
12/047,963
Granted
May 31, 2011
Kind
B2
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 (41)

1. A compound having the formula:

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, optionally substituted C 2-9 heterocyclyl, 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 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 5B NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A is 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; R 5B is 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 or R 6B 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; R 6B is optionally substituted C 6-10 aryl, 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. The compound of claim 1 , wherein,

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 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 or R 5A C(NH)NH(CH 2 ), r5 , wherein r5 is an integer from 0 to 2, R 5A is 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 C 1-4 thioalkaryl, or optionally substituted C 1-4 thioalkheterocyclyl.

3. The compound of claims 1 or 2 , wherein R 5 is R 5A C(NH)NH(CH 2 ) r5 , and R 5A is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2 -isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, and 4-isothiazole.

4. The compound of claim 1 or 2 , wherein R 6 is R 6A C(NH)NH(CH 2 ) r6 , and R 6A is methyl, fluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, and 4-isothiazole.

5. The compound of claims 1 or 2 , wherein one or more of R 1 , R 2 , and R 3 is not H.

6. The compound of claims 1 or 2 , 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, 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 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.

7. The compound of claims 1 or 2 , wherein R 3 is (CH 2 ) m3 X 3 , wherein X 3 is selected from the group consisting of:

wherein

each of R 3A and R 3B 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 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;

Z 3 is NR 3H , NC(O)R 3H , NC(O)OR 3H , NC(O)NHR 3H , NC(S)R 3H , NC(S)NHR 3H , NS(O) 2 R 3H , O, S, S(O), or S(O) 2 , 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;

m3 is an integer of 2 to 6;

n3 is an integer of 1 to 4;

p3 is an integer of 0 to 2; and

q3 is an integer of 0 to 5.

8. The compound of claim 1 , wherein said compound selectively inhibits neuronal nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS).

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

10. The compound of claim 1 , wherein R 5 is R 5B NHC(S)NH(CH 2 ) r5 , and R 5B is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, or thio-t-butyloxy.

11. The compound of claim 1 , wherein R 6 is R 6B NHC(S)NH(CH 2 ) r6 , and R 6B is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole.

12. The compound of claim 1 , wherein R 1 or R 3 is optionally substituted C 2-9 heterocyclyl or optionally substituted C 1-4 alkheterocyclyl, wherein the heterocyclyl moiety is a bicyclic, nitrogen containing heterocyclyl.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2008
From: MADDAFORD, SHAWN; RAMNAUTH, JAILALL; RAKHIT, SUMAN; PATMAN, JOANNE; RENTON, PAUL; ANNEDI, SUBHASH
To: NEURAXON, INC.
Reel/Frame 021689/0742 →