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(12) Patent Application Publication (10) Pub. No.: US 2010/0204220 A1 Attala Et Al US 20100204220A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0204220 A1 Attala et al. (43) Pub. Date: Aug. 12, 2010 (54) HETEROCYCLIC MODULATORS OF Related U.S. Application Data CANNABINOID RECEPTORS (60) Provisional application No. 60/949,536, filed on Jul. 13, 2007, provisional application No. 61/036,321, (75) Inventors: Mohamed Naquib Attala, filed on Mar. 13, 2008. Houston, TX (US); Philippe Diaz, Publication Classification Missoula, MT (US) (51) Int. Cl. A6II 3/343 (2006.01) Correspondence Address: C07D 307/79 (2006.01) Nielsen IP Law LLC C07D 405/ (2006.01) 1177 West Loop South, Suite 1600 C07D 405/2 (2006.01) Houston, TX 77027 (US) C07D 413/10 (2006.01) A63L/4525 (2006.01) A63L/35 (2006.01) (73) Assignee: Board of Regents, The University A 6LX 3/5.377 (2006.01) of Texas System A6IP 25/00 (2006.01) A6IP 25/30 (2006.01) (21) Appl. No.: 12/668,840 (52) U.S. Cl. ...................... 514/233.5; 549/469; 546/196: 549/414:544/153: 514/469; 514/320: 514/459 (22) PCT Fled: Jul. 14, 2008 (57) ABSTRACT Heterocyclic compounds which modulate cannabinoid (86) PCT NO.: PCT/US08/69977 receptors are presented. Pharmaceutical compositions con taining these compounds, methods of using these compounds S371 (c)(1), as modulators of cannabinoid receptors and processes for (2), (4) Date: Mar. 2, 2010 synthesizing these compounds are also described herein. Patent Application Publication Aug. 12, 2010 Sheet 1 of 20 US 2010/0204220 A1 10 O- - - - - - - - - - - - - - - - - - - - -------------------------------------------- 9-10 O 3-20 a. S$ -30 -40 ----- 1 O 100 OOO 10OOO 10OOOO Ligand (nM) Figure 1A 80 70 EC50 = 478.9 nM O 100 1000 OOOO 100000 Ligand (nM) Figure 1B Patent Application Publication Aug. 12, 2010 Sheet 2 of 20 US 2010/0204220 A1 30 2O 1 O 20 10 100 1000 10000 1OOOOO Ligand (nM) Figure 2A 100 90 ECE 160 nM H 1 10 100 1000 1OOOO 1OOOOO Ligand (nM) Figure 2B Patent Application Publication Aug. 12, 2010 Sheet 3 of 20 US 2010/0204220 A1 -3-2 OO -4 O 50 SO 1 10 100 1OOO OOOO OOOOO Ligand (nM) Figure 3A 8O EC = 408 nM 6 O 4 O 2O A. O Ham O 100 1000 0000 10000 Ligand (nM) Figure 3B Patent Application Publication Aug. 12, 2010 Sheet 4 of 20 US 2010/0204220 A1 1 6 IgEEE------------ --- 1 N 1 2 1 O -E Example3 (30 mg/kg, IP) (n=1) Hm O 10 20 30 40 50 60 7O 80 90 100 110 120 Time (min) Figure 4 Patent Application Publication Aug. 12, 2010 Sheet 5 of 20 US 2010/0204220 A1 bt be 1 V E. Example3 (100 ug, IT) (n=2) V -O- Dimethyl Sulfoxide (5ul, IT) (n=1) 9 12 VV 3 N 1 N H th 3 t O 3 3 s A. O 10 20 30 40 50 60 70 80 90 Time (min) Figure 5 Patent Application Publication Aug. 12, 2010 Sheet 6 of 20 US 2010/0204220 A1 * Example3 (5 mg/kg, IP) (n = 5) "A Morphine (5 mg/kg, IP) (n = 4) 7 1 Hmmm, O 10 20 30 40 50 60 70 80 90 100 110 120 Time (min) Figure 6 Patent Application Publication Aug. 12, 2010 Sheet 7 of 20 US 2010/0204220 A1 O ON ON O O O O NaOH, EtOH, HO O O 1. KCO, Pd(OAc), Piperidine, HATU n-BuNC,Ph-B(OH), DMF ( ) DEA, DMF, CHCI, ( ) Figure 7 Patent Application Publication Aug. 12, 2010 Sheet 8 of 20 US 2010/0204220 A1 100- B 4O 13 -12 1 0 9 8 7 6 Log CP55940 W g M Log Compound in Example 3M Figure 8A Figure 8B Patent Application Publication Aug. 12, 2010 Sheet 9 of 20 US 2010/0204220 A1 10A90 1000 B s 80 g 70 a 500 is 60 50 is 3 2 1 is -500 isA. 0 A.s & -10 -20 -1000 O 10 20 30 40 SO 60 7O 80 90 10010120 Time (min) g Compound of Example 3 (10 mg/kg) -E Compound of Example 3 (3 mg/kg) t Compound of Example 3 (1 mg/kg) se Vehicle Figure 9 Patent Application Publication Aug. 12, 2010 Sheet 10 of 20 US 2010/0204220 A1 Right (contralateral) paw - Right paw 8 e left (ipsilateral) paw 8 6 s 4. 4. 2 2 O O 0 1 2 3 4 5 6 7 8 O 1 2 3 4 5 7 8 9 10111213141516 Day Day Figure 10A Figure 10B Patent Application Publication Aug. 12, 2010 Sheet 11 of 20 US 2010/0204220 A1 E Compound of Example 3-5 mg/kg (contralateral paw) - Compound of Example 3- 10 mg/kg (contralateral paw) - Compound of Example 3- 15 mg/kg (contralateral paw) s 8 - Compound of Example 3-5 mg/kg (ipsilateral paw) -- Compound of Example 3-10 mg/kg (ipsilateral paw) -- Compound of Example 3- 15 mg/kg (ipsilateral paw) Vehicle (ipsilateral paw) is O 8. Tineni Figure 11A 's s O 8 s i 2 is . w. S. Compound of Example 3 (mg/kg) Figure 11C Figure 11B Patent Application Publication Aug. 12, 2010 Sheet 12 of 20 US 2010/0204220 A1 4000 3 O O O 2000 1000 Figure 12 Patent Application Publication Aug. 12, 2010 Sheet 13 of 20 US 2010/0204220 A1 4000 (Ony)plousºuq}|eMelp??^^Med 2000 | (6X/6uu01)ºeldueXE?opunoduuoo |||||||||||||||||||||||cºdulexaºpunoduco-ºdoxoen Figure 13 Patent Application Publication US 2010/0204220 A1 Figure 14A (aas)áðubre,qenwerp??yamedsaw% Patent Application Publication Aug. 12, 2010 Sheet 15 of 20 US 2010/0204220 A1 ****sae (6)||6uug)ÇeduexE.JopunoduuOO Figure 14C (6X/6uuGL)ºelduexH?opunoduloo (3)prousæuua?enaeapua?aawaedadw% Figure 14D Patent Application Publication Aug. 12, 2010 Sheet 16 of 20 US 2010/0204220 A1 2 1. 5 4. 2 O 1 2 3 4 5 6 7 8 9 O 1112 131415 1617 1819 2021222324252627 28 Day On Paclitaxel 4d -e Paclitaxel 4d + Vehicle Paclitaxel 4d + Compound of Example 3-4d Paclitaxel 4d + Compound of Example 3-14d Figure 15 C Paclitaxel 4d + Melatonin 4d O Paclitaxel 4d + Melatonin 14d Patent Application Publication Aug. 12, 2010 Sheet 17 of 20 US 2010/0204220 A1 Vehicle Compound of Example 3 (15/mg/kg) Win 55,212-2 (7 mg/kg) Haloperidol (1 mg/kg) 3. i Figure 16A Vehicle Compound of Example 3 (15/mg/kg) Win 55,212-2 (7 mg/kg) in Haloperidol (1 mg/kg) Figure 16B Patent Application Publication Aug. 12, 2010 Sheet 18 of 20 US 2010/0204220 A1 Vehicle Compound of Example 3 (15/mg/kg) Win 55,212-2 (7 mg/kg) Haloperidol (1 mg/kg) Figure 16C Vehicle Compound of Example 3 (15/mg/kg) Win 55,212-2 (7 mg/kg) Haloperidol (1 mg/kg) s Figure 16D Patent Application Publication Aug. 12, 2010 Sheet 19 of 20 US 2010/0204220 A1 10 the Paclitaxel 8 a Vehicle of Example 3 + Paclitaxel --he Compound of Example 3 10d + Paclitaxel 4d 0 1 2 3 4 5 6 7 8 9 101112131415 16171819202122232425262728 Day Figure 17 O 1 2 3 4 5 G 8 9112314156 Day Figure 18 Patent Application Publication Aug. 12, 2010 Sheet 20 of 20 US 2010/0204220 A1 in Paclitaxel - Vehicles + Paclitaxel nk Compound of Example 3 4d + Paclitaxel - Compound of Example 3 10d + Paclitaxel 8 2 3 4 S 6 8 1, 2 Day Figure 19A Paclitaxel SA - Vehicles + Paclitaxel * Compound of Example 3 4d + Paclitaxel 4d - Compound of Example 3 10d + Paclitaxel 4d t A. 2 3 8, 9 12 Day Figure 19B US 2010/0204220 A1 Aug. 12, 2010 HETEROCYCLIC MODULATORS OF 0008. A class of heterocyclic compounds, useful in treat CANNABINOID RECEPTORS ing cannobinoid receptor mediated disorders and conditions, is presented and defined by the structural Formula I: CROSS-REFERENCE TO RELATED APPLICATIONS 0001. This application claims priority to U.S. Pat. App. Ser. No. 60/949,536 filed Jul. 13, 2007 and to U.S. Pat. App. Ser. No. 61/036,321 filed Mar. 13, 2008. These applications are incorporated by reference herein it their entirety. FIELD OF THE INVENTION 0002 The present invention is directed to new heterocy clic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulating cannabinoid receptor activity in human or animal or a salt, ester or prodrug thereof, wherein: subject are provided for the treatment of diseases. 0009 R' is selected from the group consisting of NH, NHR'. NRR, any carbon atom of which may be STATEMENT REGARDING FEDERALLY optionally substituted; SPONSORED RESEARCH ORDEVELOPMENT I0010 R is selected from the group consisting of hydro 0003. None. gen, aryl, alkyl, cycloalkyl, aralkyl, alkenyl, and alky nyl, any carbon atom of which may be optionally Sub THE NAMES OF THE PARTIES TO AJOINT stituted; RESEARCH AGREEMENT I0011 R is selected from the group consisting of hydro 0004. None. gen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any carbon atom of which may be REFERENCE TO SEQUENCE LISTING optionally Substituted; and 0005. None. 0012 R and R vary independently and are selected from the group consisting of aryl, alkyl, cycloalkyl, BACKGROUND OF THE INVENTION aralkyl, alkenyl, and alkynyl, any carbonatom of which may be optionally substituted, 0006 CB1 and CB2 are two cannabinoid receptors that belong to the GPCR family and have very different functions and by the structural Formula III: and distribution. While no x-ray structure is available for these receptors, various models have been described on the basis of the X-ray structure of rhodopsin, a GPCR belonging protein responsible of the light sensitivity in vision.
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