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(12) Patent Application Publication (10) Pub. No.: US 2016/0002195 A1 Makriyannis Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0002195 A1 Makriyannis Et Al US 2016.0002195A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002195 A1 Makriyannis et al. (43) Pub. Date: Jan. 7, 2016 (54) CANNABINERGC NTRATEESTERS AND Publication Classification RELATED ANALOGS (51) Int. Cl. (71) Applicant: Northeastern University, Boston, MA C07D 3II/80 (2006.01) (US) C07D 23L/56 (2006.01) CD7C 203/00 (2006.01) (72) Inventors: Alexandros Makriyannis, Watertown, C07D 209/12 (2006.01) MA (US); Venkata Kiran Vemuri, C07D 405/04 (2006.01) Boston, MA (US) C07C309/68 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/770,331 CPC ............ C07D 31 1/80 (2013.01); C07D405/04 (2013.01); C07C309/68 (2013.01); C07C (22) PCT Fled: Feb. 26, 2014 203/00 (2013.01); C07D 209/12 (2013.01); C07D 231/56 (2013.01); C07C 2101/16 (86) PCT NO.: PCT/US2O14/O18582 (2013.01) S371 (c)(1), (57) ABSTRACT (2) Date: Aug. 25, 2015 The present technology relates to novel cannabinergic nitrate esters and related analogs, process of preparation, pharma ceutical compositions and their methods of use as medica Related U.S. Application Data ments, pharmacological tools and/or biomarkers. The novel (60) Provisional application No. 61/769,410, filed on Feb. cannabinergic nitrate ester compounds provide medicaments 26, 2013. useful in treating a variety of diseases and medical disorders. Patent Application Publication Jan. 7, 2016 Sheet 1 of 15 US 2016/0002195 A1 F.G. 1 1NHO C OH ONO 1NHO C ONO abn-cannabidiol compound 1 compound 78 O O N N ONO ONO2 compound 84 compound 117 Patent Application Publication Jan. 7, 2016 Sheet 2 of 15 US 2016/0002195 A1 FIG. 2 Control 8 O O O 7000 ACompd 1 covalent 6O OO labeling of CB receptors 5OOO 4OOO 3000 2O OO 1000 O 5 10 15 20 25 HCP-55,940 (nM) Patent Application Publication Jan. 7, 2016 Sheet 3 of 15 US 2016/0002195 A1 FG. 3 S Control S2 ACompd 84 covalent St labeling of CB receptors E . C E 5 O 15 O HCP-55,940 (n M) Patent Application Publication Jan. 7, 2016 Sheet 4 of 15 US 2016/0002195 A1 FIG. 4 3. SS K. 8. M 8 & is s: SSSS& s N &-axxxxxl s & 3 & $8 * & LogCompd 1 nM Patent Application Publication Jan. 7, 2016 Sheet 5 of 15 US 2016/0002195 A1 FIG.S 8. &SS SS K, 0.7 nM *xsa 7s & &S Y. SS 35 \ Š-os-My-Mgrxxx8-Y-8 3. & 8. 3. LogCompd 1 nM Patent Application Publication Jan. 7, 2016 Sheet 6 of 15 US 2016/0002195 A1 FIG. 6 R. 3388 w S. S Šws s: s& w & s & & Patent Application Publication Jan. 7, 2016 Sheet 7 of 15 US 2016/0002195 A1 FIG. 7 888.2 sR. & F3% MY sax giCorps its Patent Application Publication Jan. 7, 2016 Sheet 8 of 15 US 2016/0002195 A1 FG. 8 Ess3.888 &S33S - S -8 - 8 2 3 logicoax: iii. Patent Application Publication Jan. 7, 2016 Sheet 9 of 15 US 2016/0002195 A1 FIG. 9 So EDs 7.9 mM, A71% N. &.S 88: s &8. s s : xes & ^ 3 st ^:- was 8 $3 ~ reser ar r: & & s & Yr LogCompd 78 nM. Patent Application Publication Jan. 7, 2016 Sheet 10 of 15 US 2016/0002195 A1 FIG 10 8 ED2.1nM, A59% -4 -3 -2 2 3. 4. LogCompa 78 nM Patent Application Publication Jan. 7, 2016 Sheet 11 of 15 US 2016/0002195 A1 FIG 11 100 O Morphine A-THC 5075 - A COmpd 1 25 O -------- O. 1 0.3 1.0 3.0 1 0 30 100 dose (mg/kg) Patent Application Publication Jan. 7, 2016 Sheet 12 of 15 US 2016/0002195 A1 FIG. 12 100 75 50 O 0.1 mg/Kg Compd 1 Y 1 mg/Kg CompC 1 25 60 18O 300 42O 1440 Time (min) Patent Application Publication Jan. 7, 2016 Sheet 13 of 15 US 2016/0002195 A1 F.G. 13 100 -H Compd 84 -O-A-THC 75 s ? 50 x s e SS 25 O Time (min) Patent Application Publication Jan. 7, 2016 Sheet 14 of 15 US 2016/0002195 A1 FIG. 14 100 75 s -H Compa 117 : 50 -O- A- THC ? x s e SS 25 O s 2O 40 60 120 18O 360 Time (min) Patent Application Publication Jan. 7, 2016 Sheet 15 of 15 US 2016/0002195 A1 FG, is basis . its US 2016/0002195 A1 Jan. 7, 2016 CANNABINERGC NTRATE ESTERS AND exceedingly low levels in brain, CB2 receptors are expressed RELATED ANALOGS mainly by immune and hematopoietic cells, osteoclasts, and osteoblasts and mediate immune responses, inflammation, CROSS-REFERENCE TO RELATED inflammatory and neuropathic pain, and bone remodeling. APPLICATIONS Largely because of this psychoactivity as well as its preva 0001. This application claims the benefit of priority to lence and early availability in synthetic form as a research U.S. Provisional Patent Application No. 61/769,410, filed tool, A-THC attained the status of prototypic cannabinoid Feb. 26, 2013, which is incorporated herein by reference for and became the focus of many pharmacological and mecha any and all purposes. nistic studies. 0005 Much of this research in vivo was aimed at elucidat ing the effects of A-THC in experimental animals as well as FIELD human subjects with the aid of newly-synthesized A-THC 0002 The present technology generally relates to biologi analogs and related compounds such as nabilone, A-tetrahy cally active novel cannabinergic compounds. In particular, drocannabinol, 11-OH-A-tetrahydrocannabinol, canna the present technology is related to novel cannabinergic bidiol (ex., GWP42003), cannabinol, A-tetrahydrocannabi nitrate esters and related analogs. varin (ex., GWP42004), CP-47,497, dexanabinol, Ajulemic acid, HU-210, 8-B-OH-tetrahydrocannabinol, 8-C-OH-tet BACKGROUND rahydrocannabinol, SAB-378, nabitan, menabitan, A-40174, 0003 Human recreational use of the hemp plant Cannabis Org 28611, nonabine, BAY38-7271, GRC10693, S-777469, sativa ("marijuana') and anecdotal attempts to exploit it for AZD'940, GW-842,166X, GW-405,833, levonantradol, dim potential therapeutic benefit have been documented through ethylheptylpyran and the AM1703 analog PRS-211,375 out millennia. Some of marijuana's popularity as a recre (Cannabinor). Some of these compounds were radiolabeled ational substance and medicament reflects its ability to alter and used as molecular probes as well. Virtually all cannab sensory perception and relieve anxiety. Other medicinal inoid-related medications granted regulatory approvals thus effects of marijuana unrelated to its psychoactive properties, far are directly related to Cannabis, most of which act as Such as pain relief, have also been recorded in ancient texts. agonists at the CB1 and CB2 receptors. A-tetrahydrocannabinol (A-THC) and cannabidiol are the 0006. It has been suggested that tetrahydrocannabivarin two major phytocannabinoids that were identified along with acts as a CB1 neutral antagonist while A-THC is known to approximately 60 other phytocannabinoids present in Can act as a CB1 partial agonist. A-THC (dronabinol, MarinolR) nabis. A-THC, cannabidiol, and some other phytocannab and its synthetic analog, the CB1/CB2 agonist, nabilone (Ce inoids are bioactive with, for example, intriguing anti-inflam samet(R) are licensed as anti-nausea and anti-emetic medica matory, anticonvulsive, and anti-emetic effects of potential tions for chemotherapy patients. Nabilone is also approved as therapeutic value. However, A-THC is regarded as the sole an appetite stimulant to treat acquired immune deficiency psychotropic cannabinoid in Cannabis. Given A-THC's psy syndrome-related cachexia. SativeX(R), a standardized Can chotropic effects, many biological investigations employed nabis extract containing an approximately equal mixture of brain and brain plasma membranes as study-objects. Consen the two phytocannabinoids (A-THC and cannabidiol) for SuS data describing several key characteristics of cannabinoid mulated as a Sublingual spray, was first licensed for allevia action emerged: A-THC, its synthetic analogs and related tion of neuropathic pain in multiple Sclerosis patients and compounds elicit biological effects in a stereo- and structur subsequently approved for cancer pain relief. The low ally selective manner; their binding to brain plasma mem reported frequency of abuse and neurocongnitive side-effects branes is avid, Saturable, Stereospecific, concordant with in of Cannabis extracts/A-THC derivatives has invited their vitro and in vivo bioresponses (e.g., adenylyl cyclase inhibi continued clinical evaluation. Aside from nabilone, other Syn tion, analgesia), and nonrandom in select brain regions. thetic cannabinoid-receptor activators such as CP55,940 have 0004. These characteristics strongly implied that cannab been studied clinically for alleviation of emesis; motor-re inoid pharmacology is receptor-mediated, spurring the search lated symptoms in patients with multiple Sclerosis, Tourette's for discrete mammalian cannabinoid receptors whose activa syndrome, or Parkinson's disease; intraocular pressure in tion by A-THC wouldelicit psychotropic effects. The search glaucoma patients; neuropathic pain; or post-trauma brain led to the discovery and cloning of two G protein-coupled damage. receptors (GPCRs) for cannabinoids (CB), designated CB1 and CB2, which in humans share 44% sequence homology. SUMMARY The CB1 receptor subtype is localized primarily in the central 0007. In one aspect, a compound of formula (I), or a phar nervous system (CNS), reflecting its prevalence as the most maceutically acceptable salt thereof is provided: abundant GPCR in brain. CB1 receptors are distributed among the cortex, cerebellum, hippocampus, and basal gan glia, brain regions that control motor, cognitive, emotional, (I) and sensory functions. Hence, central CB1 receptor activa tion mediates most cannabinoid psychotropic and behavioral effects. The CB1 receptor is also present in high density in the brainstem, hypothalamus, and pituitary gland, loci influenc ing pain perception; hormonal activity; thermoregulation; and cardiovascular, gastrointestinal, and respiratory physiol ogy.
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