US 20080234237A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0234237 A1 MADDAFORD et al. (43) Pub. Date: Sep. 25, 2008 (54) QUINOLONE AND Related U.S. Application Data TETRAHYDROQUINOLONE AND RELATED COMPOUNDS HAVING NOS INHIBITORY (60) Provisional application No. 60/896,829, filed on Mar. ACTIVITY 23, 2007. (76) Inventors: Shawn MADDAFORD, Publication Classification Mississauga (CA); Jailall (51) Int. Cl. RAMNAUTH, Brampton (CA); A613/60 (2006.01) Suman RAKHIT, Mississauga C07D 409/4 (2006.01) (CA); Joanne PATMAN, A 6LX 3L/24709 (2006.01) Mississauga (CA); Subhash C. A6IP 25/06 (2006.01) ANNEDI, Mississauga (CA); John C07D 409/2 (2006.01) ANDREWS, Mississauga (CA): A6II 3/55 (2006.01) Peter DOVE, Toronto (CA); Sarah (52) U.S. Cl. ... 514/165; 54.6/158: 514/312: 514/212.07; SILVERMAN, Toronto (CA); Paul 540,523 Renton, Toronto (CA) (57) ABSTRACT Correspondence Address: CLARK & ELBNG LLP The present invention features quinolones, tetrahydroquino 101 FEDERAL STREET lines, and related compounds that inhibit nitric oxide synthase BOSTON, MA 02110 (US) (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS (21) Appl. No.: 12/054,083 isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can (22) Filed: Mar. 24, 2008 be used for treating or preventing various medical conditions. Standard Test Method for the Chung SNL Model of Thermal Hyperalgesia t = -7~-14 days to -30 II.in to 0 t 30, 60,90 & 120 min. - Baseline therinal paw Re-baseline Compound testing of therinal paw withdrawal, then L5/L6 thermal paw administration withdrawal using IR box as nerve ligation operation withdrawal by the i.p. (or radiant heat source p.o.)route Patent Application Publication Sep. 25, 2008 Sheet 1 of 16 US 2008/0234237 A1 Figure 1. Standard Test Method for the Chung SNL Model of Thermal Hyperalgesia t = -7- -14 days tri -30 min time O t =30, 60,90 & 120 min. Baseline thermal paw Re-baseline Compound testing of therinal paw withdrawal, then L5/L6 the Inal paw administration withdrawal using IR box as nerve ligation operation withdrawal by the i.p. (or radiant heat source p.o.)route Figure 2. Dose response relationship for i.p. injection of Compound 11 of the invention after 30 and 60 minutes of dosing in the Chung Model of neuropathic pain. 100 80 3. 60 s O. Ch C E 40 s -O-30 minutes SS As = 4.81 (2.79 to 8.31) mg/kg, i.p. 20 -- 60 minutes As = 10.9 (8.07 to 14.8) mg/kg, i.p. 3. O 30 Dose (mg/kg, i.p.) Patent Application Publication Sep. 25, 2008 Sheet 2 of 16 US 2008/0234237 A1 Figure 3. Response of Compound of Example 3 in Chung Model Compound 3 (30 mg/kg, i.p.) Does Not Attenuate Thermal Hyperalgesia of the Hindpaw in Rats with SNL 25 -8- Distilled water -- Compound 3 1 o 5 Baseline SNL 3. 6C 2 Time (minutes) after injection Patent Application Publication Sep. 25, 2008 Sheet 3 of 16 US 2008/0234237 A1 Figure 4. Antihyperalgesia Response of Compound from Example 23 in Chung Model after i.p. dosing at 30 mg/kg. Antihyperalgesia Effects of Example 23 in the L5L6 SNL SD Rats H ; 2O 15 - g 10 5 s i o f BL post-SNL 30 60 90 120 Time (min) Patent Application Publication Sep. 25, 2008 Sheet 4 of 16 US 2008/0234237 A1 Figure 5. Standard Test Method for the Chung (SNL) Model of Tactile Hypersensitivity = -7- -14 days t = -30 min ta 0 min t = 30, 60,90 & 120 min Baseline tactile Re-baseline Compound testing of tactile allodynia using allodynia, then tactile allodynia L5/L6 nerve ligation administration by the calibrated von Frey filaments operation i.p. (or p.o.) route Patent Application Publication Sep. 25, 2008 Sheet 5 of 16 US 2008/0234237 A1 Figure 6. Antiallodynic Response of Compound from Example 23 in Chung Model after i.p. dosing at 30 mg/kg. Antiallodynic Effects of Example 23 in the L5L6 SNL SD RafS 1 5 -- 30 mg kg, i.p. 1 2 9 6 3 O BL post SNL 3. 6 9 12 Time (min) Patent Application Publication Sep. 25, 2008 Sheet 6 of 16 US 2008/0234237 A1 Figure 7. Method for the Porreca Model of Tactile Hypersensitivity t = -30 mins t = -15 mins t = 0 Hr t = 1,2,3,4,5,6 Hrs Baseline paw Compound (30 mg/kg) or vehicle p.o. Inflammatory Repeat paw withdrawal withdrawal. injection Inediator onto the theasurementS. dura (1X in 10 mL) Patent Application Publication Sep. 25, 2008 Sheet 7 of 16 US 2008/0234237 A1 Figure 8. Antiallodynic Response of Compound from Example 23 in a Migraine Model after i.p. dosing at 30 mg/kg Administered 15 Minutes Prior to Inflammatory Soup (Dural Stimulation). Example 23 (30mg/kg, p.o.) Produces Attenuation of Tactile Hyperesthesia of the Hindpaw in Rats with Inflammation of the Dura. -- Example 2330 mg/kg, p.o. (&-15 min --Wehicle, p.o. &-15 min BL h 2h 3. 4h 5 6h Time after dural stimulation Patent Application Publication Sep. 25, 2008 Sheet 8 of 16 US 2008/0234237 A1 Figure 9. Antiahyperalgesic Response of Compound from Example 37 in Chung Model after i.p. dosing at 30 mg/kg. Antihyperalgesia Effects of Example 37 in the L5L6 SNL SD Rats -i-30 mg/kg, i.p. 1 O 5 O BL post-SNL 30 60 90 120 Time (min) Patent Application Publication Sep. 25, 2008 Sheet 9 of 16 US 2008/0234237 A1 Figure 10. Antiallodynic Response of Compound from Example 47 in Chung Model after i.p. dosing at 30 mg/kg. Antihyperalgesia Effects of Example 47 in the L56 SNL S Rats 3 O - -30 mg/kg, i.p. 2 5 2 O s O 5 BL post-SNL 30 SO 90 12 Time (min) Patent Application Publication Sep. 25, 2008 Sheet 10 of 16 US 2008/0234237 A1 Figure 11. Antiallodynic Response of Compound from Example 54 in Chung Model after i.p. dosing at 30 mg/kg. Antihyperalgesia Effects of Example 54 in the 56 SN SD Rats 3 O -- 30 mgkg, i.p. O5O5 5 O B L post-SNL 30 SO 90 120 150 18O Time (min) Patent Application Publication Sep. 25, 2008 Sheet 11 of 16 US 2008/0234237 A1 Figure 12. Antihyperalgesic Response of Compound from Example 28 in the Chung (SNL) Model of Neuropathic Pain after i.p. dosing at 30 mg/kg. Antihyperalgesia Effects of Example 28 in the L5L6 SNSD Rats 3 O -di-30 mg/kg, i.p. 2 5 2 O 1 5 1 O 5 O BL post-SNL 30 SO 90 120 Time (min) Patent Application Publication Sep. 25, 2008 Sheet 12 of 16 US 2008/0234237 A1 Figure 13. Antiallodynic Response of Compound from Example 28 in a Migraine Model after p.o. Dosing at 30 mg/kg Administered 15 Minutes Prior to Inflammatory Soup (Dural Stimulation). Example 28 (30mg/kg, p.o.) Produces Attenuation of Tactile Hyperesthesia of the Hindpaw in Rats with Inflammation of the Dura (p value = 0.01; 2 Factor ANOVA). S 15 O 12 3 s 9 s s - 6 S s 3 -H Example 28 30 mg/kg, p.o. (Q-15 min -- Vehicle, p.o. (Q-15 min BL 1h 2h 3h 4h 5h 6h Time after dural stimulation Patent Application Publication Sep. 25, 2008 Sheet 13 of 16 US 2008/0234237 A1 Figure 14. Antiallodynic Response of Compound from Example 11 in the Sciatic Nerve Cuff Model of Neuropathic Pain after a single dose at 30 mg/kg (i.p.). Effect of Single Dose Example 11 on Mechanical Threshold in Rats with Sciatic Nerve cuff (n=6) 1 O. -2 pre C s 7 8 se 2rs 24, rs 11 Days After Cuff limplantation Figure 15. Antiallodynic Response of Compound from Example 11 in the Sciatic Nerve Cuff Model of Neuropathic Pain after i.p. dosing at 30 mg/kg. Effect of Four Doses of Example 11 on Mechanical Threshold in Rats with Sciatic Nerve Cuff (n=4) sy . as reusasau awaa wa was a raw was a rewr as www.eas a law awe-a- - - - - - - - - - - - - - - - - - - - - - - - - - - - - -a- 7 5 A 2.5 A ours Hots s ots -2 Baseline 2s 27 Pre28 2. 4 Pre29 2 4h Pre3O 2 4 Pre31 2 4 32 Days After Cuff Implantation Patent Application Publication Sep. 25, 2008 Sheet 14 of 16 US 2008/0234237 A1 Figure 16. Effect of Administration of Example 11 on the frequency of paw lifts on a cold platform in the rat sciatic cuff model of neuropathic pain. Frequency of Paw Lifts on Cold Platform After 4 doses of Example 11 25 112O5O 5 O NPB NPB2 Post 4 doses Naive Neuropathic Pre & Post Figure 17. Effect of Administration of Example 11 (i.p. 30 mg/kg) hind leg weight distribution in the rat sciatic cuff model of neuropathic pain. Effect of Example 11 on Hindleg Weight Bearing in Rats with Sciatic Nerve Cuff (n=6) 2 5 1 5 Patent Application Publication Sep. 25, 2008 Sheet 15 of 16 US 2008/0234237 A1 Figure 18. Standard Test Method for the Visceral Pain Model of Tactile Hypersensitivity to -30 tie 0 to day 6 to-0 two 1.2.3, 4 Hrs Baseline Sodium butyrate twice daily for Baseline lower Compound Repeat Tactile lower back 3 days in to the colon back threshold injection Allodynia threshold Measurements Patent Application Publication Sep.