Permanently charged sodium and calcium channel blockers as anti-inflammatory agents

Abstract

The invention provides compounds, compositions, methods, and kits for the treatment or neurogenic inflammation.

What is claimed is: 
     
         1 . A method for treating neurogenic inflammation in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound that is capable of (i) entering a nociceptor through a channel-forming receptor present in said nociceptor when said receptor is activated and (ii) inhibiting a voltage-gated ion channel present in said nociceptor, wherein said compound does not substantially inhibit said channel when applied to the extracellular face of said channel and when said receptor is not activated. 
     
     
         2 . The method of  claim 1 , wherein said compound inhibits voltage-gated sodium channels. 
     
     
         3 . The method of  claim 2 , wherein said compound is QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another low molecular weight, charged molecule that inhibits voltage-gated sodium channels when present inside of said nociceptor. 
     
     
         4 . The method of  claim 1 , wherein said compound is a quarternary amine derivative or other charged derivative of a compound selected from the group consisting of riluzole, mexilitine, phenytoin, carbamazepine, procaine, tocainide, prilocaine, articaine, bupivicaine, mepivicine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene. 
     
     
         5 . The method of  claim 1 , wherein said compound inhibits calcium channels. 
     
     
         6 . The method of  claim 5 , wherein said compound is selected from
 D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium;   a quaternary amine derivative of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesyl amine;   a compound according to any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); and   a quarternary amine derivative or other charged derivative of any of compounds (45)-(563).   
     
     
         7 . The method of  claim 1 , wherein said compound is a quarternary amine derivative or other charged derivative of any of compounds (1)-(563). 
     
     
         8 . The method of any of  claims 1 - 7 , wherein said channel-forming receptor has been activated prior to said administering of said compound. 
     
     
         9 . The method of any of  claims 1 - 8 , further comprising administering a second compound that activates said channel-forming receptor. 
     
     
         10 . The method of  claim 9 , wherein said second compound activates a channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. 
     
     
         11 . The method of  claim 10 , wherein said second compound is an activator of TRPV1 receptors, said activator selected from capsaicin, a capsaicinoid, eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea), articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine. 
     
     
         12 . The method of  claim 10 , wherein said second compound is an activator of TRPA1 receptors, said activator selected from cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine. 
     
     
         13 . The method of  claim 10 , wherein said second compound is an activator of P2X receptors, said activator selected from ATP, 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and A1′P5′-O-(3-thiotriphosphate). 
     
     
         14 . The method of  claim 10 , wherein said second compound is an activator of TRPM8 receptors, said activator selected from menthol, iciclin, eucalyptol, linalool, geraniol, and hydroxycitronellal. 
     
     
         15 . The method of any of  claims 1 - 14 , further comprising administering one or more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, or immune modulators. 
     
     
         16 . The method of any of  claims 1 - 14 , wherein said method is used to treat asthma, conjunctivitis, sepsis, sinusisitis, cough, arthritis, colitis, contact dermatitis, eczema, gastritis, cystitis, urethritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn, traumatic brain injury, acute lung injury, chemical warfare agents, inhaled tear gases, or inhaled pollutants. 
     
     
         17 . The method of any of  claims 1 - 14 , wherein said administering comprises intraarticular, surgical, intravenous, intramuscular, oral, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intraurethral, intravesicular, intrathecal, epidural, mucosal, aural, or ocular administration by injection, inhalation, or direct contact. 
     
     
         18 . The method any of  claims 1 - 14 , wherein said composition is formulated for controlled or sustained release over time. 
     
     
         19 . A kit comprising:
 a) a compound that is capable of (i) entering a nociceptor through a channel-forming receptor present in said nociceptor when said receptor is activated and (ii) inhibiting a voltage-gated ion channel present in said nociceptor, wherein said compound does not substantially inhibit said channel when applied to the extracellular face of said channel and when said receptor is not activated; and   b) instructions for administering said compound to a patient to treat neurogenic inflammation.   
     
     
         20 . The kit of  claim 19 , wherein said compound inhibits voltage-gated sodium channels. 
     
     
         21 . The kit of  claim 20 , wherein said compound is QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another low molecular weight, charged molecule that inhibits voltage-gated sodium channels when present inside of said nociceptor. 
     
     
         22 . The kit of  claim 19 , wherein said compound is a quarternary amine derivative or other charged derivative of a compound selected from the group consisting of riluzole, mexilitine, phenytoin, carbamazepine, procaine, tocainide, prilocaine, articaine, bupivicaine, mepivicine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene. 
     
     
         23 . The kit of  claim 19 , wherein said compound inhibits calcium channels. 
     
     
         24 . The kit of  claim 19 , wherein said compound is selected from
 D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium;   a quarternary amine derivative, of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesyl amine;   a compound according to any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); and   a quarternary amine derivative or other charged derivative of any of compounds (1)-(563).   
     
     
         25 . The kit of any of  claims 19 - 24 , further comprising:
 c) a second compound that activates said channel-forming receptor.   
     
     
         26 . The kit of  claim 25 , wherein said second compound activates a channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8. 
     
     
         27 . The kit of  claim 26 , wherein said second compound is an activator of TRPV1 receptors, said activator selected from capsaicin, a capsaicinoid, eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, and SU200 (N-(4-tert-butylbenzyl)-M-(4-hydroxy-3-methoxybenzyl)thiourea), articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine. 
     
     
         28 . The kit of  claim 26 , wherein said second compound is an activator of TRPA1 receptors, said activator selected from cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine. 
     
     
         29 . The kit of  claim 26 , wherein said second compound is an activator of P2X receptors, said activator selected from ATP, 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate). 
     
     
         30 . The kit of  claim 26 , wherein said second compound is an activator of TRPM8 receptors, said activator selected from menthol, iciclin, eucalyptol, linalool, geraniol, and hydroxycitronellal. 
     
     
         31 . The kit of any one of  claims 19 - 30 , further comprising one or more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, or immune modulators. 
     
     
         32 . A compound according to Formula (XI): 
       
         
           
           
               
               
           
         
       
       wherein
 each R 11A , R 11B , and R 11C  is selected, independently, from H or C 1-4  alkyl, and X′ is any pharmaceutically acceptable anion. 
 
     
     
         33 . The compound of  claim 32 , wherein said compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         34 . A compound according to Formula (XII), 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 12A , R 12B , R 12C , and R 12D  is, independently, selected from C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, and C 3-10  alkheterocyclyl; or R 12A  and R 12B  together complete a heterocyclic ring having at least one nitrogen atom; 
 n is an integer between 1-5; 
 each of R 12E  and R 12F  is, independently, selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, or C 3-10  alkheterocyclyl; and 
 X is any pharmaceutically acceptable anion. 
 
     
     
         35 . The compound of  claim 34 , wherein said compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         36 . A compound having a structure according to: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         each R 13A -R 13J  and R 13O -R 13T  is selected, independently, from H, halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, and C 3-10  alkheterocyclyl, OR 13AA , NR 13AB R 13AC , NR 13AD C(O)R 13AE , S(O)R 13AF , SO 2 R 13AG R 13AH , SO 2 NR 13AI R 13AJ , SO 3 R 13AK , CO 2 R 13AL , C(O)R 13AM , and C(O)NR 13AN R 13AO ; 
         each of R 13AA -R 13AO  is, independently, selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl; 
         each R 13K , R 13L , R 13M , and R 13N  is, independently, H or C 1-4  alkyl, or R 13K  and R 13L , or R 13M  and R 13N , combine to form C═O, or R 13K  and R 13M  combine to form C═C; 
         R 13Y  is H or C 1-4  alkyl; 
         R 13Z  and R 13Z′  are, independently, selected from H, halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, and C 3-10  alkheterocyclyl; and 
         X′ is any pharmaceutically acceptable anion. 
       
     
     
         37 . The compound of  claim 36 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         38 . A compound having a structure according to 
       
         
           
           
               
               
           
         
       
       wherein
 n is an integer between 0-5; 
 R 14A  is heterocyclyl, 
 each of R 14B , R 14C , R 14D ), and R 14E  is, independently, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, and C 3-10  alkheterocyclyl; and 
 R 14F  is selected from H, halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 2-4  heteroalkyl, C 7-14  alkaryl, C 3-10  alkcycloalkyl, and C 3-10  alkheterocyclyl, OR 14G , NR 14H R 14I , N R14J C(O)R 14K , S(O)R 14L , SO 2 R 14M R 14N , SO 2 N R14O R 14P , SO 3 R 14Q , CO 2 R 14R , C(O)R 14S , and C(O)NR 14T R 14V ; and each of R 14G -R 13AO  is, independently, selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl. 
 
     
     
         39 . The compound of  claim 37 , wherein said compound is 
       
         
           
           
               
               
           
         
       
       where X is a pharmaceutically acceptable anion. 
     
     
         40 . A pharmaceutical composition, comprising the compound of any of  claims 32 - 39  and a pharmaceutically acceptable excipient. 
     
     
         41 . A pharmaceutical composition, comprising a quarternary amine derivative or other charged derivative of any of compounds (1)-(563). 
     
     
         42 . The pharmaceutical composition of  claim 40  or  41 , wherein said composition is formulated for oral administration. 
     
     
         43 . The pharmaceutical composition of  claim 40  or  41 , wherein said composition is formulation for nasal administration. 
     
     
         44 . The pharmaceutical composition of  claim 40  or  41 , wherein said composition is formulation for inhalation administration.