US 2012O172429A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0172429 A1 Woolf et al. (43) Pub. Date: Jul. 5, 2012 (54) PERMANENTLY CHARGED SODUMAND Publication Classification CALCUMI CHANNEL BLOCKERS AS ANT (51) Int. Cl. NFLAMMLATORY AGENTS A 6LX 3L/277 (2006.01) C07C 237/14 (2006.01) (76) Inventors: Clifford J. Woolf, Newton, MA C07C 255/33 (2006.01) (US); Bruce P. Bean, Waban, MA A6IP 25/00 (2006.01) (US) A6IP 29/00 (2006.01) A6IP II/06 (2006.01) A6IP II/IO (2006.01) (21) Appl. No.: 13/382,834 A6IP 9/02 (2006.01) A6IP 700 (2006.01) (22) PCT Fled: Jul. 9, 2010 A6IPI/00 (2006.01) A6IPI3/02 (2006.01) (86) PCT NO.: PCT/US 10/41537 A6IP 25/06 (2006.01) A6IP 7/06 (2006.01) S371 (c)(1), A6IP II/02 (2006.01) (2), (4) Date: Mar. 26, 2012 A6II 3/16 (2006.01) (52) U.S. Cl. .......... 514/523: 514/626:564/194; 558/408 Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/224,512, filed on Jul. The invention provides compounds, compositions, methods, 10, 2009. and kits for the treatment of neurogenic inflammation. Patent Application Publication US 2012/0172429 A1 7Z089||Z0897ZZOZ7Z euu||(SunO?) 3.Infi!--| Patent Application Publication Jul. 5, 2012 Sheet 2 of 2 US 2012/0172429 A1 Figure 2 1 uM Capsaicin - Before - After (3 min Wash) 1 uM Capsaicin +300 uMN-methyl-verapamil After (3 min Wash) US 2012/0172429 A1 Jul. 5, 2012 PERMANENTLY CHARGED SODUMAND of a compound that is capable of entering a nociceptor CALCUMI CHANNEL BLOCKERS AS ANT through a channel-forming receptor present in the nociceptor NFLAMMLATORY AGENTS when the receptor is activated and inhibiting a Voltage-gated ion channel present in the nociceptor, wherein the compound CROSS-REFERENCE TO RELATED does not substantially inhibit said channel when applied to the APPLICATIONS extracellular face of the channel and when the receptor is not 0001. This application claims benefit of U.S. Provisional activated. In certain embodiments, the compound is an inhibi Application No. 61/224,512, filed Jul. 10, 2009, which is tor of Voltage-gated sodium channels. Exemplary inhibitors hereby incorporated by reference. of this class are QX-314, N-methyl-procaine, QX-222, N-oc tyl-guanidine, 9-aminoacridine and pancuronium. In other FIELD OF THE INVENTION embodiments, the compound is a quarternary amine deriva 0002 The invention provides compounds, methods and tive or other charged derivative of a compound selected from kits for the treatment of neurogenic inflammation. riluzole, mexilitine, phenyloin, carbamazepine, procaine, articaine, bupivicaine, mepivicaine, tocainide, prilocaine, BACKGROUND OF THE INVENTION diisopyramide, bencyclane, quinidine, bretylium, lifarizine, 0003. The invention features methods and kits for the lamotrigine, flunarizine, and fluspirilene. In other embodi treatment of neurogenic inflammation by targeting nocicep ments, the compound is an inhibitor of calcium channels. tors with drugs of low molecular weight, while minimizing Inhibitors of this class include D-890, CERM 11888, N-me effects on non-pain-sensing neurons or other types of cells. thyl-verapamil, N-methylgallopamil, N-methyl-devapamil, According to the method of the invention, Small, hydrophilic dodecyltrimethylammonium, and terpene compounds (e.g., drug molecules gain access to the intracellular compartment sesquiterpenes), as well as charged derivatives (e.g., a quar of pain-sensing neurons via entry through receptor/channels ternary amine derivative or a guanylated derivative) of Vera that are present in pain-sensing neurons but to a lesser extent pamil, gallopamil, devapamil, diltiazem, fendiline, milbe or not at all in other types of neurons or in other types of fradil, or farnesyl amine. Still other exemplary inhibitors of tissue. Neurogenic inflammation is a mode of inflammation calcium channels can be described by Formulas XI-XIV) and mediated by the efferent (motor) functions of sensory neu in Tables 1, 2, and 3. In further embodiments, the ion channel rons, in which pro-inflammatory mediator molecules inhibitor is a charged derivative (e.g., a quarternary amine released in the periphery by pain-sensing neurons (nocicep derivative or a guanylated derivative) of any of compounds tors) both activate a variety of inflammatory pathways and (1)–(563). Exemplary derivatives are described herein. also act on the vascular system to alter blood flow and capil 0008. The channel-forming receptor can be activated prior lary permeability. to administering the compound by administration of a second 0004 Neurogenic inflammation contributes to the periph compound that opens the channel. Alternatively, the channel eral inflammation elicited by tissue injury, autoimmune dis forming receptor can be activated by endogenous compounds ease, infection, exposure to irritants in a variety of tissues, and present in the patient. is thought to play an important role in the pathogenesis of 0009. The invention also features a kit that includes a numerous disorders (e.g. migraine, arthritis, rhinitis, gastritis, composition for treating neurogenic inflammation inapatient colitis, cystitis, and Sunburn). and instructions for the administration of the composition to 0005 One way to reduce neurogenic inflammation is to a patient to treat neurogenic inflammation. The composition block excitability in nociceptors, thereby preventing the acti includes a compound that is capable of entering a nociceptor Vation of nociceptor peripheral terminals and the release of through a channel-forming receptor present in the nociceptor pro-inflammatory chemicals. Local anesthetics such as when the receptor is activated and inhibiting a Voltage-gated lidocaine and articaine act by inhibiting Voltage gated ion ion channel present in the nociceptor, wherein the compound channels in neurons. Local anesthetics are relatively hydro does not substantially inhibit said channel when applied to the phobic molecules that gain access to their blocking site on the extracellular face of the channel and when the receptor is not Sodium channel by diffusing into or through the cell mem activated. In certain embodiments, the compound is an inhibi brane. However, these anesthetics block sodium or calcium tor of Voltage-gated Sodium channels or calcium channels, channels and thereby the excitability of all neurons, not just Such as those described herein. In some embodiments, the pain-sensing neurons. Thus, administration of local anesthet compound is QX-314, N-methyl-procaine, QX-222, N-octyl ics produces unwanted or deleterious effects such as general guanidine, 9-aminoacridine, pancuronium, or another low numbness from block of low threshold pressure and touch molecular weight, charged molecule that inhibits Voltage receptors, motor deficits from block of motor axons and other gated Sodium channels when present inside of said nocicep complications from block of autonomic fibers. Local anes tor. In other embodiments, the compound is D-890, CERM thetics also act on Sodium channels on Smooth muscle in the 11888, N-methyl-verapamil, N-methylgallopamil, N-me cardiovascular and respiratory systems producing deleterious thyl-devapamil, and dodecyltrimethylammonium; a quarter effects. nary amine derivative, of Verapamil, gallopamil, devapamil, 0006. Accordingly, there is a need for an approach to diltiazem, fendiline, mibefradil, or farnesyl amine; a com reducing neurogenic inflammation that selectively targets pound according to any of Formulas (XI), (XII), (XIII-A), nociceptors. (XIII-B), (XIII-C), and (XIV); or a quarternary amine deriva tive or other charged derivative of any of compounds (1)- SUMMARY OF THE INVENTION (563). 0007. In a first aspect, the invention features a method for 0010. Any of the compositions, methods, and kits of the treating neurogenic inflammation in a patient, Such as a invention may optionally feature a second compound that human, by administering a therapeutically effective amount activates the channel-forming receptor. In one embodiment, US 2012/0172429 A1 Jul. 5, 2012 the second compound activates a channel-forming receptor (URB597), amylocaine, articaine, benzocaine, bupivacaine, selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. carbocaine, carticaine, chloroprocaine, cyclomethycaine, 0011 Activators of TRPV1 receptors include but are not dibucaine (cinchocaine), dimethocaine (larocaine), eti limited to capsaicin, eugenol, camphor, clotrimazole, arvanil docaine, hexylcaine, levobupivacaine, lidocaine, mepiv (N-arachidonoylvanillamine), anandamide, 2-aminoethoxy acaine, meprylcaine (oracaine), metabutoxycaine, piper diphenyl borate (2APB), AM404, resiniferatoxin, phorbol ocaine, prilocaine, procaine (novacaine), proparacaine, 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), propoxycaine, risocaine, ropivacaine, tetracaine (ame olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachi donyldopamine (NADA), 6'-iodoresiniferatoxin (6'-IRTX), thocaine), and trimecaine. Other activators of TRPA1 recep C18 N-acylethanolamines, lipoxygenase derivatives such as tors are described in Taylor-Clark et al., Mol Pharmacol 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (2007) PMID: 18000030; Macpherson et al., Nature (2007) (ICK) peptides (vanillotoxins), piperine, MSK195 (N-2-(3. 445:541-545; and Hillet al., J. Biol. Chem. (2007)282:7145 4-dimethylbenzyl)-3-(pivaloyloxy)propyl-2-4-(2-aminoet 7153. Still other TRPA1 activators include: femamate hoxy)-3-methoxyphenyl)acetamide), JYL79 (N-2-(3,4- NSAIDS (Hu et al., Pflugers Arch. 459(4):579-92 (2010)), dimethylbenzyl)-3-(pivaloyloxy)propyl-N'-(4-hydroxy-3-