US 20110245287A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday et al. (43) Pub. Date: Oct. 6, 2011 (54) HYBRD OPOD COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. A6II 3/4748 (2006.01) C07D 489/02 (2006.01) (76) Inventors: John W. Holaday, Bethesda, MD A6IP 25/04 (2006.01) (US); Philip Magistro, Randolph, (52) U.S. Cl. ........................................... 514/282:546/45 NJ (US) (57) ABSTRACT Disclosed are hybrid opioid compounds, mixed opioid salts, (21) Appl. No.: 13/024,298 compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof. More particu larly, in one aspect the hybrid opioid compound includes at (22) Filed: Feb. 9, 2011 least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different Related U.S. Application Data opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical composi (60) Provisional application No. 61/302,657, filed on Feb. tions, as well as to methods of treating pain in humans using 9, 2010. the hybrid compounds and mixed opioid salts. Patent Application Publication Oct. 6, 2011 Sheet 1 of 3 US 2011/0245287 A1 Oral antinociception of morphine, oxycodone and prodrug combinations in CD1 mice s Tigkg -- Morphine (2.80 mg/kg (1.95 - 4.02, 30' peak time -- (Oxycodone (1.93 mg/kg (1.33 - 2,65)) 30 peak time -- Oxy. Mor (1:1) (4.84 mg/kg (3.60 - 8.50) 60 peak tire --MLN 2-3 peak, effect at a hors 24% with closes at 2.5 art to rigg - D - MLN 2-45 (6.60 mg/kg (5.12 - 8.51)} 60 peak time Figure 1. In vivo evaluation of morphine and oxycodone either alone or in combination or as prodrugs MLN 2-31 and MLN 2-45 in CD1 mice. Patent Application Publication Oct. 6, 2011 Sheet 2 of 3 US 2011/0245287 A1 I.C.W. antinociception of morphine and the bivalent ligands in CD lice --Morphine ('pt - i.c. v.) -- MLN II - 83 (20 pt- i.c...) s s () 1000 10000 prolimouse Figure 2. In vivo evaluation of morphine or hybrid opioid compounds MLN 2-83, MLN 2 120 and MLN 2-121 in CD1 mice. Patent Application Publication Oct. 6, 2011 Sheet 3 of 3 US 2011/0245287 A1 L (1) Figure 3. US 2011/0245287 A1 Oct. 6, 2011 HYBRD OPOD COMPOUNDS AND ids and potentially toxic opioid metabolites (Smith, Clin. Exp. COMPOSITIONS Pharmacol. Physiol. 2000, 27, 524-528: Ross et al., Pain, 1997, 73, 151-157). 0010. The opioid receptor is thought to have four receptor 0001. This application claims priority to provisional appli Subtypes named mu (morphine receptor), sigma (the phen cation Ser. No. 61/302,657, filed Feb. 9, 2010, the entirety of cyclidine receptor), kappa (the ketocyclazocine receptor) and which is incorporated herein by reference. delta (the endorphin?enkephalin receptor). The biochemical and cellular effects of morphine, including analgesia, are BACKGROUND transduced through the mu opioid receptor (MOR), found in 0002 1. Technical Field high concentrations within the central nervous system (CNS). 0003. This invention is directed to hybrid opioid com The World Health Organization's guidelines for the manage pounds, mixed opioid salts, and compositions comprising the ment of chronic cancer pain recommend that clinicians hybrid opioid compounds and mixed opioid salts. Methods of reserve strong opioids Such as oxycodone and morphine for use comprising administering an effective amount of the the relief of moderate to severe cancer pain (World Health hybrid opioid compounds or mixed opioid salts to treat Organization, 1986) and that two strong opioids should not be humans Suffering from pain are also provided. co-administered, presumably because it is generally thought 0004 2. Description of Related Art that all opioids exert their analgesic effects through the same 0005 Opioid compounds remain key agents for the treat receptor mechanisms in the central nervous system. However, ment of a wide variety of acute and chronic pain. The World recent studies by Maree Smith and co-workers have shown Health Organization has recommended morphine as the anal that the antinociceptive effects of structurally related oxyc gesic of choice for the treatment of severe cancer pain. Addi odone and morphine are differentially antagonized by nor tionally, morphine and related opioids are widely used to BNI (a K-selective opioid antagonist) and naloxonazine (se alleviate moderate to severe pain after Surgery or trauma, or lective -opioid receptor antagonist), indicating that they associated with medical illness Such as heart attack. Patients produce antinociception through different opioid receptor with apparently similar pain states have large differences in mechanisms (see Ross et al., Pain 1997, 73, 151-157). Fur opioid dosing requirements. Factors that contribute to this thermore, it has been found that co-administration of Sub variability include psychosocial status, type of pain (nocice antinociceptive doses of oxycodone with morphine to rats ptive, inflammatory, neuropathic or mixed) and its severity, resulted in Synergistic levels of antinociception (Ross et al., concurrent medications, gender and other genetic aspects, Pain 2000, 84, 421-428). Importantly, it was found that ani and whether patients are opioid-naive or tolerant. mals that received the Sub-antinociceptive doses of oxyc 0006 Unfortunately, the effects produced by morphine odone and morphine were similar to control animals with and similar opioid compounds make them amenable to abuse respect to CNS side effects. Administration of equipotent and are associated with many undesirable side effects, all doses of either opioid alone resulted in sedation of the rats. mediated through activation of the mu (MOR) and other This may suggest that co-administration of Sub-analgesic opioid receptors. They include physical and psychological doses of oxycodone and morphine to patients may provide dependence leading to addiction and other diverse patho synergistic antinociceptive relief with a reduction of CNS physiological states. Other undesirable side effects associ related side effects. ated with the use of opioids include postoperative nausea and 0011. One of the most challenging aspects of the treatment Vomiting, drowsiness, respiratory depression and gastrointes of infectious disease is the development of drug-resistant tinal and bladder dysfunction. strains of the infectious agent. Disease-causing microbes that 0007. In addition to the adverse physiological effects have become resistant to drug therapy are an increasing pub listed above, a major associated risk is that repeated daily lic health problem. Tuberculosis, gonorrhea, malaria, and administrations of morphine or morphine-like opioids will childhood ear infections are just a few of the diseases that eventually induce significant tolerance to the therapeutic have become hard to treat with antibiotic drugs. The wide effects of the drug as well as initiating some degree of physi spread development of multi-drug resistant forms of malaria cal dependence. Opioid tolerance is a phenomenon whereby in Africa and South East Asia is one such troubling phenom chronic exposure to a drug diminishes its antinociceptive or enon. The protozoal parasite responsible, plasmodium falci analgesic effect, or creates the need for a higher dose to parum, has gained resistance to most forms of monotherapy, maintain its effect. including chloroquine, a cheap and effective antimalarial 0008. The degree of tolerance and physical dependence drug that has been used for more than 40 years. vary with the particular opioid employed, the correlation with 0012. The scientific community has been actively devel morphine opioid receptor-selective opioids such as morphine oping new drugs to combat the increasingly drug-resistant being high, the frequency of administration, and the quantity strains of these and other infectious agents. One interesting of opioid administered. approach to fight drug-resistant strains is the development of 0009. In a wide variety of clinical indications requiring hybrid drugs that combine active agents with independent prolonged use of opioids, tolerance induction and addiction modes of action. Using this strategy, new active agents have are closely linked, with the development of physical and been prepared that show much promise for the treatment of psychological dependence always a major concern. Addic resistant microbes. For example, Walsh and co-workers pre tion with physical dependence can be difficult to treat due to pared novel hybrid molecules comprising active components the effects of withdrawal associated with dependence. of the drugs artemisinin and quinine. Walsh et al., Bioorg. Another undesirable effect of opioid tolerance is that the Med. Chem. Lett., 2007, 17(13),3599. The hybrid drugs were higher opioid requirements of highly tolerant patients treated reported to have potent activity against 3D7 (drug resistant) for pain increase the likelihood of unpleasant non-analgesic and FcB1 strains of Plasmodium falciparum in culture. The side effects due to greater circulating concentrations of opio activity was found to be Superior to artemisinin and quinine US 2011/0245287 A1 Oct. 6, 2011 alone. Dechy-Cabaret et al., (Chembiochem, 2000, No. 4, morphine, alvimopan, benzomorphans, buprenorphine, 281-283) reported the preparation of a novel trioxaquine mol codeine, 6-desomorphine, dihydromorphine, dihydromor ecules that contain that combine the peroxide entity