US 20120202860A2 (19) United States (10) Pub. No.: US 2012/0202860 A2 (12) Patent Application Publication (43) Pub. Date: Aug. 9, 2012 Mannion et al. REPUBLICATION (54) ANALGESIC COMPOUNDS, COMPOSITIONS tion of application No. 61/312,482, filed on Mar. 10, AND USES THEREOF 2010, now abandoned. (75) Inventors: James Mannion, Plainsboro, NJ (US); Publication Classification Scott Dax, Landenberg, PA (US) (51) Int. C. (73) Assignee: Galleon Pharmaceuticals, Inc., Hor A6II 3/426 (2006.01) sham, PA (US) A6IP 25/04 (2006.01) A6IP 39/06 (2006.01) (21) Appl. No.: 13/043,159 C07D 277/18 (2006.01) (22) Filed: Mar. 8, 2011 (52) U.S. Cl. ............................................ 514/370; 548/194 Prior Publication Data (57) ABSTRACT (65) US 2011/0224269 A1 Sep. 15, 2011 Related U.S. Application Data The invention relates to compounds, compositions, and meth ods for diminishing pain in a Subject in need thereof compris (63) Continuation of application No. 61/378,781, filed on ing administering the compounds and compositions herein Aug. 31, 2010, now abandoned, which is a continua described. Patent Application Publication Aug. 9, 2012 Sheet 1 of 31 US 2012/0202860 A2 AM - Vehicle PM 5- Cmpd. 2 (3 mg/kg) -A- Cmpd. 2 (10 mg/kg) ck -y- Cmpd. 2 (25 mg/kg) () N=5-6 R A. s 5) s s 50 -To-T-T- S s S 18 S S is & Time (anin) post-fentany Time (min) post-fentary Cmpd. 2 or Vehicle Fentanyl Fentanyl h 25 g/kg AM 25 g/kg PM se First latency recording First latency recording t Y. sy 15 min30 min 30 min 30 mint --|--|-- 60 120 180 210 30 6090 120 150 Time in min post fentany Time in min post fentany Figure 1 Patent Application Publication Aug. 9, 2012 Sheet 2 of 31 US 2012/0202860 A2 Vehicle Cmpd. 2 (3 mg/kg) N 6 Cmpd. 2 (10 mg/kg) 1st Fentany dose -- Cmpd, 225 mg/kg) 2nd Fentany dose - 5 50 S. w g 4. 30 E s s 's 20 s to s ---T-I-T- S S S Time (rrin} post-fertiary Time (min) post-fentary Cmpd, 2 or vehicle Fentany Fentanyl 25 g/kg 25ug/kg Baselin\' | runs recording N First latency recording 5m in 30min w '' 20 40 60 90 120 20 40 60 90 120 Time in min post fentany Time in min post fentany Figure 2 Patent Application Publication Aug. 9, 2012 Sheet 3 of 31 US 2012/0202860 A2 Cmpd. 2 or Vehicle Fentanyl Fentanyl (25ug/kg) E.) Fentanyl Fentanyl (25ug/kg) (25ug/kg) (25ug/kg) sk -- Cmnd. 2 1. sk xk sk -e- Vehicle I k n:6 k k 9 8 esseg Time (min) post-fentanyl Figure 3 Patent Application Publication Aug. 9, 2012 Sheet 4 of 31 US 2012/0202860 A2 First dose of Fantany -e- Vehicle -- Cmpd. 2 Cmpd. 2 pretreatment 15-min before 1 dose offentanyl Second dose offentanyl2.5h later Third dose offentany 2.5h later p P line (min) post-festiny Figure 4 Patent Application Publication Aug. 9, 2012 Sheet 5 of 31 US 2012/0202860 A2 Vehicle or Compound 2 given 15 min only before the 1 fentanyl administration Feintany Feintainyl Feitainyl Feintainy (25 g/kg, IV) (25 g/kg, V) (25 g/kg, IV) (25 g/kg, IV) re. Vehicle t-- Cmpd. 2 (25 mg/Kg) ' ' ', N-6 Time (min) post-fentany Figure 5 Patent Application Publication Aug. 9, 2012 Sheet 6 of 31 US 2012/0202860 A2 AM Day 1 PM Day 1 -er Vehicle - Cmpd, 2 (25 mg/Kg) O No.6 O s S S s S s line (nir post-?entary Time (nir post-fentary AMDay2 PM Day2 e an. to 5 5 810 10 s s o o mem--are m---a-a-a- & 8 & 9 Time (nir post-fetary Time (in post-?entary Figure 6 Patent Application Publication Aug. 9, 2012 Sheet 7 of 31 US 2012/0202860 A2 Fentanyl Fentanyi Fentanyl Fentanyl Fentanyl Fentanyl Fentanyl 25 uglkg 25 uglkg 25 glkg 25 uglkg 25 uglkg 25 g/kg 25 uglkg son 4,0h 4.0 h. 4.0 h 4,0h Pre 20 40 60 90 120 Baseline Day 1 Day 2 Day 3 Hamama -- Day 3 40 k -8- Vehicle -- Cmpd. 2 30 ***pz0.001 "pz0.05 20- a a a? A anae - - - www. 10 O Pre 20 40 60 90 120 Time (min) post-fentanyl Figure 7 Patent Application Publication Aug. 9, 2012 Sheet 8 of 31 US 2012/0202860 A2 Vehicle or Compound 2 (25 mg/kg, IV) given 15 min before intra-plantar administration of capsaicin (30 g) -O- Veh-Caps -a- Cmpd. 2 - Caps. N-6 Time (min) post-capsaicin Figure 8 Patent Application Publication Aug. 9, 2012 Sheet 9 of 31 US 2012/0202860 A2 C2 = Compound 2 arey it a a a saw a a we w w w s as we wo SO Vehicle C2 MC Figure 9 A Patent Application Publication Aug. 9, 2012 Sheet 10 of 31 US 2012/0202860 A2 Veh Veh Veh Veh Cmpd.2 Cmpd. 2 Cmpd, 2 Cmpd. 2 IMC IMC IMC IMC Baseline Stargery el H. H. H Compound 2 = 25 mg/kg, IV, Indomethacin = 15 mg/kg, IV, n=6/group *pC0.05, **pg0.01, ***p<0.001, compared to the vehicle time-point on the same day Figure 9 B Patent Application Publication Aug. 9, 2012 Sheet 11 of 31 US 2012/0202860 A2 C2 = Compound 2 24 post-surgery s x w w y w w y w w was a wy y or w w y w w w wr w O a a a a a is a w w is w a Figure 10 A Patent Application Publication Aug. 9, 2012 Sheet 12 of 31 US 2012/0202860 A2 Veh. Veh. Veh, C2 C2 C2 IMC IMC MC Surgery ! 6) O ) O 2 th 24 h. Compound 2 = 25 mg/kg, IV, Indomethacin = 15 mg/kg, IV, n=6/group p<0.05 Compared to vehicle time-point on the same day Figure 10 B Patent Application Publication Aug. 9, 2012 Sheet 13 of 31 US 2012/0202860 A2 Vehicle or Compound 2 (25 mg/kg, IV) given 15 min before the administration of SIN-1 (1 mg/kg, IV) Sin. Sin- Sir 30min 2 h 30min 2h 30min 2h Baseline Test. 1 Test 2 Test 3 25 o - Vehicle g 20 - - Cmpd. 2 s 15 s **p<0.01 5 to Ch 2 5 - Figure 11 Patent Application Publication Aug. 9, 2012 Sheet 14 of 31 US 2012/0202860 A2 Figure 12 Patent Application Publication Aug. 9, 2012 Sheet 15 of 31 US 2012/0202860 A2 Figure 13 Patent Application Publication Aug. 9, 2012 Sheet 16 of 31 US 2012/0202860 A2 Figure 14 Patent Application Publication Aug. 9, 2012 Sheet 17 of 31 US 2012/0202860 A2 Patent Application Publication Aug. 9, 2012 Sheet 18 of 31 US 2012/0202860 A2 -- wehicle (n=6) Compound 2 (25 mg/kg, i.W., n-6) O 5 Time (hours) Figure 16 Patent Application Publication Aug. 9, 2012 Sheet 19 of 31 US 2012/0202860 A2 fentanyl fentanyl fentanyl fentanyl fentanyl fentanyl 25/kg 25 g/kg 25ul/kg 25 J/kg 25ul/kg 25ul/kg -e- vehicle (n=6) -- Compound 2 (25 mg/kg, i.v., n =6) s o w°o AoW.S.3°S,888°N: so So So So So So so o So c? Time (min) Figure 17 Patent Application Publication Aug. 9, 2012 Sheet 20 of 31 US 2012/0202860 A2 A. Thermal hyperalgesia 2 5 15 1 O 5 Time post-FCA B. Tactile allodynia vehicle (n=6) Compound 2 (25 mg/kg, i.V., n-6) 3 s: O h r t K Time post-FCA Figure 18 Patent Application Publication Aug. 9, 2012 Sheet 21 of 31 US 2012/0202860 A2 A. 24 hours post-FCA vehicle (n=6) compound 2 (3 mg/kg.p.o. n=6) compound 2 (10 mg/kg, p.o. n=6) G compound 2 (30 mg/kg, p.o., n=6) NC 40 compound 2 (100 mg/kg, p.o. n=6) 9. celecoxib (30 mg/kg, p.o., n-6) O C 8e 30 as 20 has "cs 10 3. ?h.Vs O &S {&S 2 QY Figure 19 A Patent Application Publication Aug. 9, 2012 Sheet 22 of 31 US 2012/0202860 A2 B. 24-72 hours post-FCA vehicle (n=6) compound 2 (10 mg/kg, p.o. n=6) compound 2 (100 mg/kg, p.o., n-6) E celecoxib (30 mg/kg, p.o., n-6) 40 3O 20 1 O S. NN S S N rS S SY S. (S s's{es {&Sis & s' Figure 19 B Patent Application Publication Aug. 9, 2012 Sheet 23 of 31 US 2012/0202860 A2 A. Preemptive vehicle (n=6) compound 2 (10 mg/kg, p.o. n=6) 4. compound 2 (30 mg/kg, p.o., n=6) celecoxib (30 mg/kg, p.o. n=6) Figure 20 A Patent Application Publication Aug. 9, 2012 Sheet 24 of 31 US 2012/0202860 A2 B. 24 hours post-FCA 3.0 E 2.5 E 2.0 FCAIvehicle (nE-8) s - FC Alcompound 2 (10 mg/kg, p.o., n.8) 1.5 FC Alcompound 2 (30 mg/kg, p.o. n=8) ? were FC Alcelecoxib (30 mg/kg, p.o., n=8) Figure 20 B Patent Application Publication Aug. 9, 2012 Sheet 25 of 31 US 2012/0202860 A2 A.