US 20090176792A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0176792 A1 Gant et al. (43) Pub. Date: Jul. 9, 2009 (54) SUBSTITUTED Publication Classification DBENZHYDRYLPPERAZINES (51) Int. Cl. A63/4985 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA C07D 24I/04 (2006.01) (US); Sepehr Sarshar, Cardiff by A63/495 (2006.01) the Sea, CA (US) (52) U.S. Cl. ..................... 514/251544/396; 514/255.04 (57) ABSTRACT Correspondence Address: The present invention relates to new dibenzhydrylpiperazine GLOBAL PATENT GROUP - APX modulators of histamine receptors, pharmaceutical composi Ms. LaVern Hall tions thereof, and methods of use thereof. 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) Formula I (73) Assignee: AUSPEX PHARMACEUTICALS, INC., Vista, CA (US) (21) Appl. No.: 12/350,032 (22) Filed: Jan. 7, 2009 Related U.S. Application Data (60) Provisional application No. 61/019.520, filed on Jan. 7, 2008. US 2009/0176792 A1 Jul. 9, 2009 SUBSTITUTED 0005 Disclosed herein is a compound having structural DBENZHYDRYLPPERAZINES Formula I: (I) 0001. This application claims the benefit of priority of U.S. provisional application No. 61/019,520, filed Jan. 7, 2008, the disclosure of which is hereby incorporated by ref erence as if written herein in its entirety. 0002 The present invention is directed to dibenzhy drylpiperazine-based histamine receptor modulators and pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and medical use of Such com pounds for the treatment and/or management of nausea, kine tosis, emesis, Vertigo, dermatitis, migraines, labyrinthitis, Méniere's disease and/or any disorder ameliorated by modu lation of histamine receptors. 0003 Cyclizine (Marezine(R), Marzine(R), Emoquil.R., Valoid R, Echinatol(R), Fortravel(R), Medazine(R), Nauzine(R), Norizine(R), and Triazine(R), 1-benzhydryl-4-methyl-pipera or a pharmaceutically acceptable salt, Solvate, or prodrug Zine, is an orally or parenterally administered histamine thereof, wherein: receptor antagonist. Cyclizine is commonly prescribed to 0006 R-R are independently selected from the group prevent or ameliorate kinetosis (Schmid et al., J Travel Med consisting of hydrogen and deuterium; and 1994, 1(4), 203-206). In addition, it has shown promise in 0007 at least one of R-R is deuterium. preventing postoperative nausea, Vertigo, and emesis (Johns 0008 Also disclosed herein are pharmaceutical composi tions comprising at least one of the compounds disclosed etal, Anaesthesia 2006, 61 (11), 1053-7: Laffey etal, IrJ Med herein or a pharmaceutically acceptable salt, Solvate, or pro Sci 2002, 171 (3), 141-4). Further, cyclizine has been used to drug thereof; in combination with one or more pharmaceuti treat the following: dermatitis (Herman et al. J Cutan Med cally acceptable excipients or carriers. Surg 2003, 7(6), 467-73), migraines (Pradalier et al. Ceph 0009. Also disclosed herein are articles of manufacture alalgia 1985, 5(2), 107-13), labyrinthitis (Chirkova et al., Zh and kits containing compounds as disclosed herein. By way Ushn Nos Gorl Bolezn 1977, 2, 56-60), Méniere's disease of example only a kit or article of manufacture can include a (Nikolskaia M I, Vestn Otorinolaringol 1973, 34(4), 107-8) container (Such as a bottle) with a desired amount of at least and urticaria (Merk HF, JInvestig Dermatol Symp Proc 2001, one compound (or pharmaceutical composition of a com 6(2), 153-6). Cyclizine, as compared to other antihistamines, pound) as disclosed herein. Further, such a kit or article of manufacture can further include instructions for using said causes less drowsiness and affects the stomach directly. compound (or pharmaceutical composition of a compound) as disclosed herein. The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container. 0010. In another aspectare processes for preparing a com pound as disclosed herein as a histamine receptor modulator, or other pharmaceutically acceptable derivatives such as salts, Solvates, or prodrugs. 0011. In certain embodiments of the present invention, a method for the treatment, prevention, or amelioration of one or more symptoms of a histamine receptor-mediated disorder in a Subject by administering a therapeutically effective Cyclizine amount of a compound as disclosed herein. 0012. In other embodiments said histamine receptor-me 0004 Cyclizine is extensively metabolized in the liver to diated disorder is selected from the group consisting of nau form the N-demethylated derivative, norcyclizine. (Kuntz sea, kinetosis, emesis, Vertigo, dermatitis, migraines, labyrin man et al., Jof Pharmacology and Experimental Therapeutics thitis, and Méniere's disease. 0013. In certain embodiments said histamine receptor-me 1965, 40(1), 29-35; Kuntzman et al., of Pharmacology and diated disorder can be ameliorated by modulating histamine Experimental Therapeutics 1967, 158(2), 332-339). Norcy receptors. clizine localizes predominantly in the lung, spleen, liver and 0014. In further embodiments, said method comprises a kidney, and has little antihistamine activity. The most com compound disclosed herein and one or more pharmaceuti mon side effect associated with cyclizine administration is cally acceptable carriers. drowsiness. More troubling side effects include, but are not 0015. In yet further embodiments said method further limited to, restlessness, excitation, nervousness, insomnia, comprises administering another therapeutic agent. blurred vision, dry mouth, decreased appetite, difficulty uri 0016. In other embodiments said therapeutic agent is nating, and an irregular or fast heartbeat. Cyclizine has also selected from the group consisting of anti-migraine treat been found to inhibit cytochrome Paso CYP2D6, an important ments, anti-tussives, mucolytics, decongestants, anti-allergic liver enzyme. non-steroidals, expectorants, anti-histamine treatments, anti US 2009/0176792 A1 Jul. 9, 2009 retroviral agents, CYP3A inhibitors, CYP3A inducers, pro 0025. In further embodiments, said anti-migraine treate tease inhibitors, adrenergic agonists, anti-cholinergics, mast ment is selected from the group consisting of caffeine, cell stabilizers, Xanthines, leukotriene antagonists, glucocor erogotamine, dihydroergotamine, methysergide, lisuride, ticoids treatments, antibacterial agents, antifungal agents, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetor sepsis treatments, steroidals, local or general anesthetics, one, almotriptan, eletriptan, froVatriptan, naratriptan, riza NSAIDs, NRIs, DARIs, SNRIs, sedatives, NDRIs, SNDRIs, triptan, Sumatriptan, Zolmitriptan, caffeine, flumedroxone, monoamine oxidase inhibitors, hypothalamic phospholipids, butalbital, chlorpromazine, prednisone, codeine, morphine, ECE inhibitors, opioids, thromboxane receptor antagonists, diphenhydramine hydrochloride, acetaminophen, ibuprofen, potassium channel openers, thrombin inhibitors, hypotha acetylsalicylic acid, dichloralphenaZone, isometheptene and lamic phospholipids, growth factor inhibitors, anti-platelet naproxen. agents, P2Y (AC) antagonists, anticoagulants, low molecular 0026. In certain embodiments, said anti-migraine treat weight heparins, Factor VIIa Inhibitors and Factor Xa Inhibi ment is ergotamine. tors, renin inhibitors, NEP inhibitors, vasopepsidase inhibi 0027. In yet other embodiments, said anti-migraine treat tors, squalene synthetase inhibitors, anti-atherosclerotic ment is caffeine. agents, MTP Inhibitors, calcium channel blockers, potassium 0028. In other embodiments said method has at least one channel activators, alpha-muscarinic agents, beta-muscarinic effect selected from the group consisting of: agents, antiarrhythmic agents, diuretics, thrombolytic agents, 0029 a) decreased inter-individual variation in plasma anti-diabetic agents, mineralocorticoid receptor antagonists, levels of said compound or a metabolite thereofas com growth hormone secretagogues, aP2 inhibitors, phosphodi pared to the non-isotopically enriched compound; esterase inhibitors, protein tyrosine kinase inhibitors, antiin 0030 b) increased average plasma levels of said com flammatories, antiproliferatives, chemotherapeutic agents, pound per dosage unit thereofas compared to the non immunosuppressants, anticancer agents and cytotoxic isotopically enriched compound; agents, antimetabolites, antibiotics, farnesyl-protein trans 0.031 c) decreased average plasma levels of at least one ferase inhibitors, hormonal agents, microtubule-disruptor metabolite of said compound per dosage unit thereof as agents, microtubule-stablizing agents, plant-derived prod compared to the non-isotopically enriched compound; ucts, epipodophyllotoxins, taxanes, topoisomerase inhibi 0.032 d) increased average plasma levels of at least one tors, prenyl-protein transferase inhibitors, cyclosporins, cyto metabolite of said compound per dosage unit thereof as toxic drugs, TNF-alpha inhibitors, anti-TNF antibodies and compared to the non-isotopically enriched compound; soluble TNF receptors, cyclooxygenase-2 (COX-2) inhibi and tors, and miscellaneous agents. 0033 e) an improved clinical effect during the treat 0017. In yet further embodiments said therapeutic agent is ment in said Subject per dosage unit thereofas compared an anti-tussive. to the non-isotopically enriched compound. 0018. In other embodiments said therapeutic agent is a 0034. In yet further embodiments said method has at least mucolytic. two effects selected