US 20110086818A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0086818 A1 Bean et al. (43) Pub. Date: Apr. 14, 2011 (54) METHODS, COMPOSITIONS, AND KITS FOR A6II 3/085 (2006.01) TREATING PAN AND PRURITUS A63/37 (2006.01) A6II 3/17 (2006.01) (75) Inventors: Bruce P. Bean, Waban, MA (US); A6II 3L/24 (2006.01) Clifford J. Woolf, Newton, MA A6II 3/53 (2006.01) (US) A6II 3/55 (2006.01) A63L/352 (2006.01) (73) Assignees: Presidents and Fellows of A6II 3/428 (2006.01) Harvard College, Cambridge, MA A63/4965 (2006.01) (US). The General Hospital A6II 3/438 (2006.01) Corporation, Boston, MA (US) C07D 277/82 (2006.01) CD7C 2 II/26 (2006.01) (21) Appl. No.: 12/922,038 C07D 233/72 (2006.01) 1-1. C07D 22.3/8 (2006.01) (22) PCT Filed: Mar. 11, 2009 CD7C 229/60 (2006.01) C07D 333/36 (2006.01) (86). PCT No.: PCT/USO9/O1541 C07D 2II/32 (2006.01) C07C 237/20 (2006.01) S371 (c)(1), C07D 453/02 (2006.01) (2),2). (4) DateDate: Dec.ec. 8,5, 2010 C07D 25.3/075 (2006.01) Related U.S. Application Data C07D 24I/04 (2006.01) C07D 47L/It (2006.01) (60) Provisional application No. 61/069,018, filed on Mar. A6IP 25/04 (2006.01) 11, 2008. (52) U.S. Cl. ........... 514/64; 514/627: 514/626; 514/535: Publication Classification 514/330; 514/692; 514/396; 514/560; 514/568; 514/450; 514/321; 514/299; 514/.447: 514/720; (51) Int. C. 514/653: 514/580: 514/646; 514/331; 514/540: A6 IK3I/69 (2006.01) 514/242: 514/385; 514/217: 514/453: 514/367; A6 IK3I/35 (2006.01) 514/305:514/255.04: 514/278: 548/152; A6 IK3I/I67 (2006.01) 564/305; 548/321.1; 540/589; 560/43; 549/69; A6 IK 3L/245 (2006.01) 546/225; 564/194; 546/133: 564/289; 544/182: A6 IK 3/445 (2006.01) 544/403; 546/20 A6 IK 3L/25 (2006.01) A6 IK 3/4164 (2006.01) (57) ABSTRACT A6 IK 3L/20 (2006.01) A6 IK3I/I9 (2006.01) The invention features methods, compositions, and kits for A6 IK3I/335 (2006.01) selective inhibition of pain-and itch sensing neurons (nocice A6 IK 3/4453 (2006.01) ptors and pruriceptors) by drug molecules of Small molecule A6 IK 3/439 (2006.01) weight, while minimizing effects on non-pain-sensing neu A6 IK3I/38 (2006.01) rons or other types of cells. Capsaicin Capsaicin 1 nA 1S -5 mV -5 mV -70 mV. — -70 mV. - 0.35mA 5 mS - Control - QX-314,5mM — Capsaicin, 1 uM - Casaicin, 1 M+ QX-314,5mM Patent Application Publication Apr. 14, 2011 Sheet 1 of 9 US 2011/0086818 A1 - - - - Capsaicin Capsaicin - 1S 1 nA -5 mV -5 mV 70 mV- -70 mV 0.35nA 5 mS - Control — QX-314, 5mM — Capsaicin, 1 LM - Casaicin, 1 uM+ QX-314,5mM 8: 1.2 asa o:V. 5.8 5-04a 33 f$ 0.6 Capsaicinmem + QX-314 P V.1: : 0.4 -14 0.2 -16 O -80-60-40-20 O 20 40 60 80 E E E E E Vm (mV) to v led Co lo Co Ltd a v- v- N in -- COntrol S5 -o-QX-314 > 3. -A-Capsaicin c is -v- Capsaicin + QX-314 Patent Application Publication !!!)? Patent Application Publication Apr. 14, 2011 Sheet 3 of 9 US 2011/0086818 A1 5560 d - as3/6 "as S. 50 45 - A- OX - 314 O 40 -H Capsaicin is 35 E 30 -O- Capsaicin + QX-314 3 25 is 20 15 2 10 5 * O 2153060 90120 180 240 300 360 420 9. Time (min) 66 aum 463/6 3/63/6 -A- OX- 314 -H Capsaicin -O- Capsaicin + QX-314 2 1530 6090 120 180240 300 360 420 . Time (min) Patent Application Publication Apr. 14, 2011 Sheet 4 of 9 US 2011/0086818 A1 FIG. 4A 6/6 k k 3/6 60 - . 4/6 55 -A- OX- 314 -- Capsaicin 30 -O- Capsaicin + QX-314 2 15 30 60 90 120 180 240 300 360 . Time (min) FIG. 4B 2 - 36. 1616 14 10 - A - OX - 314 6 -H Capsaicin 4 -O- Capsaicin + QX-314 2 O 2 15 30 60 90 120 180 240 300 360 s Time (min) Patent Application Publication Apr. 14, 2011 Sheet 6 of 9 US 2011/0086818 A1 FIG. 5 nE 10 - Control — Eugenol, 100 uM3 min — Eugenol, 100 uM+ QX-314, 5mM, 1 min - Eugenol, 100 uM+ QX-314, 5mM, 3 min - Eugenol, 100 uM+ QX-314, 5mM, 5min --- Eugenol, 100 uM+ QX-314, 5mM, 7 min FIG. 6 250 pA 2.5 mS - Vehicle - 50 uMMO, 5 min — 50 uMMO + 5 mM QX-314, 1 min - 50 uMMO + 5 mMQX-314, 3min 50 uMMO+5 mM QX-314, 5 min US 2011/0086818 A1 (6) pouse.JuleOueupeW O CN re (S) Kouee eujeu. Patent Application Publication Apr. 14, 2011 Sheet 8 of 9 d ls Cd to O to O ?o O O O CO 09 O lo Y. N. cro cro CN CN r v (6) pouseu LeolueugeW 9/9 s St. go s CY) COLOSCOCNN-ooooon colorSrcycN-O CNNNNNNNvvrver-reviv-v - (S) Kouee eujeu. Patent Application Publication Apr. 14, 2011 Sheet 9 of 9 US 2011/0086818 A1 FIG. 8 25 Capsaicin Capsaicin + QX-314 US 2011/0086818 A1 Apr. 14, 2011 METHODS, COMPOSITIONS, AND KITS FOR example, due to trauma, Surgery, herniation of an interverte TREATING PAN AND PRURITUS bral disk, spinal cord injury, diabetes, infection with herpes Zoster (shingles), HIV/AIDS, late-stage cancer, amputation BACKGROUND OF THE INVENTION (including mastectomy), carpal tunnel syndrome, chronic 0001. The invention features methods, compositions, and alcohol use, exposure to radiation, and as an unintended side kits for selective inhibition of pain-and itch sensing neurons effect of neurotoxic treatment agents, such as certain anti (nociceptors and pruriceptors) by drug molecules of Small HIV and chemotherapeutic drugs. molecule weight, while minimizing effects on non-pain-sens 0006. In contrast to nociceptive pain, neuropathic pain is ing neurons or other types of cells. According to the method frequently described as “burning.” “electric.” “tingling,” or of the invention, Small, hydrophilic drug molecules gain “shooting in nature. It is often characterized by chronic access to the intracellular compartment of pain-sensing neu allodynia (defined as pain resulting from a stimulus that does rons via entry through receptors that are present in pain- and not ordinarily elicit a painful response, such as light touch) itch-sensing neurons but to a lesser extent or not at all in other and hyperalgesia (defined as an increased sensitivity to a types of neurons or in other types of tissue. normally painful stimulus), and may persist for months or 0002 Local anesthetics such as lidocaine and articaine act years beyond the apparent healing of any damaged tissues. by inhibiting Voltage-dependent sodium channels in neurons. 0007 Pain may occur in patients with cancer, which may These anesthetics block sodium channels and thereby the be due to multiple causes; inflammation, compression, inva excitability of all neurons, not just pain-sensing neurons (no Sion, metastatic spread into bone or other tissues. ciceptors). Thus, while the goal of topical or regional anes 0008. There are some conditions where pain occurs in the thesia is to block transmission of signals in nociceptors to absence of a noxious stimulus, tissue damage oralesion to the prevent pain, administration of local anesthetics also pro nervous system, called dysfunctional pain and these include duces unwanted or deleterious effects such as general numb but are not limited to fibromyalgia, tension type headache, ness from block of low threshold pressure and touch recep irritable bowel disorders and erythermalgia. tors, motor deficits from block of motor axons and other 0009 Migraine is a headache associated with the activa complications from block of autonomic fibers. Local anes tion of sensory fibers innervating the meninges of the brain. thetics are relatively hydrophobic molecules that gain access 0010 Itch (pruritus) is a dermatological condition that to their blocking site on the Sodium channel by diffusing into may be localized and generalized and can be associated with or through the cell membrane. Permanently-charged deriva skin lesions (rash, atopic eczema, wheals). Itch accompanies tives of these compounds (such as QX-314, a quaternary many conditions including but not limited to stress, anxiety, nitrogen derivative of lidocaine), which are not membrane UV radiation from the sun, metabolic and endocrine disorders permeant, have no effect on neuronal sodium channels when (e.g., liver or kidney disease, hyperthyroidism), cancers (e.g., applied to the external surface of the nerve membrane but can lymphoma), reactions to drugs or food, parasitic and fungal block sodium channels if somehow introduced inside the cell, infections, allergic reactions, diseases of the blood (e.g., poly for example by a micropipette used for whole-cell electro cythemia Vera), and dermatological conditions. Itch is medi physiological recording from isolated neurons. Pain-sensing ated by a Subset of Small diameter primary sensory neurons, neurons differ from other types of neurons in expressing (in the pruriceptor, that share many features of nociceptor neu most cases) the TRPV1 receptor/channel, activated by painful rons, including but not limited to expression of TRPV1 chan heat or by capsaicin, the pungent ingredient in chili pepper. nels. Certain itch mediators—such as eicosanoids, histamine, Other types of receptors selectively expressed in various bradykinin, ATP and various neurotrophins have endovanil types of pain-sensing and itch-sensing (pruriceptor) neurons loid functions.