Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Abstract

Compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

1 . A compound capable of modifying ion channels, in vivo, having a formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: 
       wherein A is N, CR 4 , a carbon atom bound to L, or is not an atom; 
       one of W, Z, B, Y and X is a carbon atom bound to L if A is not an atom, another of W, Z, B, Y and X is a carbon atom bound to G, and each of the remaining W, Z, B, Y and X is independently N or CR 4 ; 
       L is substituted or unsubstituted —(C—C)—, —(CR 5 ═CR 6 )— or —(C≡C)—; 
       G is C═O, C═S or SO 2 ; 
       R 1  is substituted or unsubstituted aliphatic, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; 
       R 2  is hydrogen or substituted or unsubstituted alkyl; 
       R 3  is substituted or unsubstituted aliphatic, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; 
       each R 4  is independently hydrogen, alkyl, substituted or unsubstituted alkyl, acyl, acylamino, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, carboxyl, cyano, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio; and 
     
     each of R 5  and R 6  is independently H, halo, or substituted or unsubstituted aliphatic, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. 
   
   
       2 .- 40 . (canceled) 
   
   
       41 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 5, 13, 17, 35, 81, 87, 111, 117, 142, 143, 185, 196, 208, 211, 213, 238, 239, 275, or 305, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       42 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is II, 20, 24, 98, 116, 121, 194, 217, 286, or 304, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       43 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 2, 3, 15, 30, 31, 32, 33, 37, 39, 40, 41, 42, 43, 44, 45, 47, 61, 62, 66, 78, 130, 132, 136, 145, 148, 150, 151, 153, 156, 158, 169, 171, 172, 225, 226, 227, 228, 230, 233, 242, 244, 245, 246, 247, 248, 249, 252, 313, 330, 331, 332, 334, 336, 337, 338, or 358, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       44 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 48, 52, 53, 64, 67, 68, 70, 71, 72, 74, 75, 76, 77, 105, 106, 166, 168, 202, 203, 234, 256, 259, 260, 261, 324, 341, 344, 345, or 351, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       45 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 54, 55, 204, or 205, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       46 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 8, 12, 56, 65, 181, 207, 214, 237, or 287, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       47 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 6, 9, 14, 16, 26, 29, 49, 60, 80, 88, 93, 95, 109, 112, 120, 123, 125, 126, 127, 139, 164, 179, 183, 190, 191, 192, 193, 197, 198, 206, 209, 216, 218, 219, 223, 224, 236, 267, 281, 283, 308, 315, 316, 356, or 357, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       48 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, or 412, or a pharmaceutically acceptable salt or prodrug thereof. 
   
   
       49 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 411, 413-439, or 440, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       50 . A compound according to  claim 1  wherein the compound is of Table 1 and wherein the compound ID No. is 388, 389, 390, 391, 392, 470, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, or 405, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers thereof. 
   
   
       51 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 1 . 
   
   
       52 .- 54 . (canceled) 
   
   
       55 . A method for preventing, treating, ameliorating or managing a disease or condition which comprises administering to a patient in need of such prevention, treatment, amelioration or management, a prophylactically or therapeutically effective amount of a compound of  claim 1 , or the pharmaceutical composition of  claim 51 . 
   
   
       56 .- 59 . (canceled) 
   
   
       60 . A method for preventing, treating, ameliorating or managing a disease or condition, which comprises administering to a patient in need of such prevention, treatment, amelioration or management a prophylactically or therapeutically acceptable amount of a compound of  claim 1 , or the pharmaceutical composition of  claim 51 , wherein the disease or condition is: pain including acute, inflammatory and neuropathic pain; chronic pain; dental pain; headache including migraine, cluster headache and tension headache; Parkinson's disease; Alzheimer's disease; multiple sclerosis; diseases and disorders mediated by or result in neuroinflammation, traumatic brain injury, stroke, or encephalitis; centrally-mediated neuropsychiatric diseases and disorders including depression, mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders including allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or result in inflammation including arthritis, rheumatoid arthritis and osteoarthritis; myocardial infarction; autoimmune diseases and disorders; uveitis and atherosclerosis; itch/pruritus, psoriasis; alopecia (hair loss); obesity; lipid disorders; cancer; high blood pressure; spinal cord injury; or renal disorders. 
   
   
       61 .- 66 . (canceled) 
   
   
       67 . A method for preparing a compound of  claim 1  which comprises contacting a compound of the formula R 3 -L-Cy-COCl or R 3 -L-Cy-SO 2 Cl with a compound of the formula R 1 R 2 NH under conditions sufficient to form the compound of  claim 1 ; and wherein Cy is aryl or heteroaryl. 
   
   
       68 . A method of treating a mammal suffering from at least one symptom selected from the group consisting of symptoms of exposure to capsaicin, symptoms of burns or irritation due to exposure to heat, symptoms of burns or irritation due to exposure to light, symptoms of burns, bronchoconstriction or irritation due to exposure to tear gas, and symptoms of burns or exposure irritation due to exposure to acid which amount of a compound of  claim 1 , or the pharmaceutical composition of  claim 51 . 
   
   
       69 .- 72 . (canceled)