Treatment of inflammatory disorders in non-human mammals

Abstract

The present invention relates to the prevention, reduction, inhibition and reversal of pain and inflammation in a non-human mammal by administration of an inhibitor of soluble epoxide hydrolase, as sole active agent or co-administered with other active agents.

What is claimed is: 
     
         1 . A method of preventing, ameliorating, delaying the progression and/or reversing the progression of an inflammatory condition in a non-human mammal, comprising administering to the mammal an inhibitor of soluble epoxide hydrolase (sEH). 
     
     
         2 . A method of enhancing or maintaining the anti-inflammatory efficacy and/or anti-nociceptive efficacy and reducing undesirable side effects of a non-steroidal anti-inflammatory drug (“NSAID”) in a non-human mammal, comprising co-administering to the non-human mammal in need thereof an inhibitor of soluble epoxide hydrolase and the anti-inflammatory agent. 
     
     
         3 . A method of preventing, ameliorating, delaying the progression and/or reversing the progression of chronic pain in a non-human mammal, comprising administering to the mammal an inhibitor of soluble epoxide hydrolase (sEH). 
     
     
         4 . A method of enhancing or maintaining the anti-nociceptive efficacy on chronic or neuropathic pain and reducing undesirable side effects of an active agent selected from the group consisting of NSAIDs, Gamma-aminobutyric Acid (GABA) analogs, phosphodiesterase inhibitors, N-methyl-D-aspartate receptor antagonists, opioids and sodium channel blockers, or analogs or pro-drugs thereof, in a non-human mammal, comprising co-administering to the non-human mammal in need thereof an inhibitor of soluble epoxide hydrolase and the active agent, or an analog or pro-drug thereof. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the non-human mammal is canine, feline, equine, bovine, ovine or porcine. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the non-human mammal is an ungulate. 
     
     
         7 . The method of  claim 6 , wherein the inflammatory condition is laminitis. 
     
     
         8 . The method of any one of  claims 1  to  6 , wherein the inflammatory condition is selected from the group consisting of traumatic injury, surgery, hip dysplasia, osteoarthritis and tendonitis. 
     
     
         9 . The method of any one of  claims 1  to  8 , wherein the inflammatory condition is acute. 
     
     
         10 . The method of any one of  claims 1  to  8 , wherein the inflammatory condition is chronic. 
     
     
         11 . The method of any one of  claims 1  to  10 , wherein the non-human mammal is further experiencing neuropathic and/or post-surgical pain. 
     
     
         12 . The method of any one of  claims 1  to  11 , wherein the inhibitor of sEH comprises a primary pharmacophore selected from the group consisting of a urea, a carbamate, and an amide. 
     
     
         13 . The method of  claim 12 , wherein the inhibitor of sEH comprises a cyclohexyl moiety, aromatic moiety, substituted aromatic moiety or alkyl moiety attached to the pharmacophore. 
     
     
         14 . The method of  claim 12 , wherein the inhibitor of sEH comprises a cyclohexyl ether moiety attached to the pharmacophore. 
     
     
         15 . The method of  claim 12 , wherein the inhibitor of sEH comprises a phenyl ether or piperidine moiety attached to the pharmacophore. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the inhibitor of sEH comprises a polyether secondary pharmacophore. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein the inhibitor of sEH has an IC50 of less than about 100 μM. 
     
     
         18 . The method of any one of  claims 1  to  17 , wherein the inhibitor of sEH is selected from the group consisting of:
 a) 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea or 3,4,4′-trichlorocarbanilide (TCC; compound 295); 
 b) 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; compound 700); 
 c) 1-adamantanyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl]}urea (AEPU; compound 950); 
 d) 1-(1-acetylpiperidin-4-yl)-3-adamantanylurea (APAU; compound 1153); 
 e) trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; compound 1471); 
 f) cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (cAUCB; compound 1686); 
 g) 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS; compound 1709); 
 h) trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (tTUCB; compound 1728); 
 i) 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; compound 1770); 
 j) 1-(1-ethylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPSE; compound 2213) 
 k) 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (CPTU; compound 2214); 
 l) trans-N-methyl-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzamide (tMAUCB; compound 2225) 
 m) trans-N-methyl-4-[4-((3-trifluoromethyl-4-chlorophenyl)-ureido)-cyclohexyloxy]-benzamide (tMTCUCB; compound 2226); 
 n) cis-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (cMTUCB; compound 2228); and 
 o) 1-cycloheptyl-3-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)urea (HDP3U; compound 2247). 
 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the inhibitor of sEH is selected from the group consisting of:
 a) 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea or 3,4,4′-trichlorocarbanilide (TCC; compound 295); 
 b) 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; compound 700); 
 c) 1-adamantanyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl]}urea (AEPU; compound 950); 
 d) 1-(1-acetylpiperidin-4-yl)-3-adamantanylurea (APAU; compound 1153); 
 e) trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; compound 1471); 
 f) cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (cAUCB; compound 1686); 
 g) trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (tTUCB; compound 1728); 
 h) trans-N-methyl-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzamide (tMAUCB; compound 2225) 
 i) trans-N-methyl-4-[4-((3-trifluoromethyl-4-chlorophenyl)-ureido)-cyclohexyloxy]-benzamide (tMTCUCB; compound 2226); 
 j) cis-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (cMTUCB; compound 2228); and 
 k) 1-cycloheptyl-3-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)urea (HDP3U; compound 2247). 
 
     
     
         20 . The method of any one of  claims 1  to  17 , wherein the inhibitor of sEH is selected from the group consisting of:
 a) trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; compound 1471); 
 b) 4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (tTUCB; compound 1728); 
 c) 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; compound 1770); 
 d) trans-2-(4-(4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamido)-acetic acid (compound 2283); 
 e) N-(methylsulfonyl)-4-(trans-4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2728); 
 f) 1-(trans-4-(4-(1H-tetrazol-5-yl)-phenoxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2806); 
 g) 4-(trans-4-(3-(2-fluorophenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2736); 
 h) 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2803); 
 i) 4-(3-fluoro-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2807); 
 j) N-hydroxy-4-(trans-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2761); 
 k) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-((1r,4r)-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoate (compound 2796); 
 l) 1-(4-oxocyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2809); 
 m) methyl 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexylamino)-benzoate (compound 2804); 
 n) 1-(4-(pyrimidin-2-yloxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2810); and 
 o) 4-(trans-4-(3-(4-(difluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2805). 
 
     
     
         21 . The method of any one of  claims 1  to  20 , wherein a non-steroidal anti-inflammatory drug (NSAID) was previously administered and wherein the NSAID did not prevent, ameliorate, delay or reverse progression of the inflammatory and/or neuropathic pain condition. 
     
     
         22 . The method of any one of  claims 1  to  21 , where the inhibitor of sEH is co-administered with one or more NSAIDs. 
     
     
         23 . The method of  claim 22 , wherein one or both of the inhibitor of sEH and the NSAID is administered in a sub-therapeutic amount. 
     
     
         24 . The method of any one of  claims 1  to  23 , wherein the NSAID inhibits one or more enzymes selected from the group consisting of cyclo-oxygenase (“COX”)-1, COX-2, and 5-lipoxygenase (“5-LOX”). 
     
     
         25 . The method of any one of  claims 1  to  24 , wherein the NSAID is selected from the group consisting of flunixin meglumine, phenylbutazone, aspirin, acetaminophen, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, dipyrone, ketorolac, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, vedaprofen, meclofenamate sodium, mefenamic acid, meloxicam, carprofen, nabumetone, naproxen sodium, piroxicam, tolmetin sodium, magnesium salicylate, choline salicylate, salsalate, sodium salicylate, alkyl salicylate and disalicylate. 
     
     
         26 . The method of any one of  claims 1  to  24 , wherein the NSAID is a selective inhibitor of COX-2. 
     
     
         27 . The method of  claim 26 , wherein the selective inhibitor of COX-2 is selected from the group consisting of celecoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, deracoxib and firocoxib. 
     
     
         28 . The method of any one of  claims 22  to  27 , wherein one or both of the inhibitor of sEH and the NSAID are administered in a sub-therapeutic amount. 
     
     
         29 . The method of any one of  claims 21  to  28 , wherein a dual inhibitor of sEH and COX-2 is administered. 
     
     
         30 . The method of any one of  claims 4  to  29 , wherein an active agent selected from the group consisting of Gamma-aminobutyric Acid (GABA) analogs, N-methyl-D-aspartate receptor antagonists, phosphodiesterase inhibitors, opioids and sodium channel blockers, or analogs or pro-drugs thereof, was previously administered and wherein the active agent did not prevent, ameliorate, delay or reverse the inflammatory and/or neuropathic pain condition. 
     
     
         31 . The method of any one of  claims 1  to  30 , wherein the inhibitor of sEH is co-administered with an active agent selected from the group consisting of Gamma-aminobutyric Acid (GABA) analogs, N-methyl-D-aspartate receptor antagonists, phosphodiesterase inhibitors, opioids and sodium channel blockers, or analogs or pro-drugs thereof. 
     
     
         32 . The method of  claim 31 , wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, and analogs or pro-drugs thereof. 
     
     
         33 . The method of any one of  claims 1  to  31 , wherein the inhibitor of sEH is co-administered with an N-methyl-D-aspartate receptor antagonist, or an analog or pro-drug thereof. 
     
     
         34 . The method of  claim 33 , wherein the N-methyl-D-aspartate receptor antagonist is selected from the group consisting of: AP5 (APV, R-2-amino-5-phosphonopentanoate); AP7 (2-amino-7-phosphonoheptanoic acid); CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid); Selfotel; Amantadine; Dextrallorphan; Dextromethorphan; Dextrorphan; Dizocilpine (MK-801); Eticyclidine; Gacyclidine; Ibogaine; Memantine; Methoxetamine; Nitrous oxide; Phencyclidine; Rolicyclidine; Tenocyclidine; Methoxydine; Tiletamine; Xenon; Neramexane; Eliprodil; Etoxadrol; Dexoxadrol; NEFA ((4aR,9aS)—N-Ethyl-4,4a,9,9a-tetrahydro-1H-fluoren-4a-amine); Remacemide; Delucemine; 8a-Phenyldecahydroquinoline (8A-PDHQ); Aptiganel (Cerestat, CNS-1102); Dexanabinol (HU-211); Rhynchophylline; and Ketamine. 
     
     
         35 . The method of any one of  claims 1  to  31 , wherein the inhibitor of sEH is co-administered with an opioid, or an analog or pro-drug thereof. 
     
     
         36 . The method of  claim 30 , wherein the opioid is selected from the group consisting of morphine, codeine, thebaine, heroin, hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, buprenorphine, fentanyl, pethidine, methadone, tramadol and dextropropoxyphene. 
     
     
         37 . The method of any one of  claims 1  to  31 , wherein the inhibitor of sEH is co-administered with a sodium channel blockers, or an analog or pro-drug thereof. 
     
     
         38 . The method of  claim 37 , wherein the sodium channel blocker is selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine, Dimethocaine/Larocaine, Piperocaine, Propoxycaine, Procaine/Novocaine, Proparacaine, Tetracaine/Amethocaine, Articaine, Bupivacaine, Cinchocaine/Dibucaine, Etidocaine, Levobupivacaine, Lidocaine/Lignocaine, Mepivacaine, Prilocaine, Ropivacaine, Trimecaine, and Lidocaine/prilocaine (EMLA), quinidine, procainamide, disopryamide, tocainide, mexiletine, flecainide, propafenone, moricizine, Carbamazepine, Phenytoin, Fosphenytoin, Oxcarbazepine, Lamotrigine, and Zonisamide. 
     
     
         39 . The method of any one of  claims 1  to  31 , wherein the inhibitor of sEH is co-administered with a phosphodiesterase inhibitor, or an analog or pro-drug thereof. 
     
     
         40 . The method of  claim 39 , wherein the phosphodiesterase inhibitor is selected from the group consisting of rolipram, roflumilast, cilomilast, ariflo, HT0712, ibudilast, mesembrine, cilostamide, enoxamone, milrinone, siguazodan, BRL-50481, sildenafil, zaprinast, tadalafil, udenafil, avanafil and vardenafil. 
     
     
         41 . The method of any one of  claims 31  to  40 , wherein one or more of the inhibitor of sEH and the active agent selected from the group consisting of Gamma-aminobutyric Acid (GABA) analogs, N-methyl-D-aspartate receptor antagonists, phosphodiesterase inhibitors, opioids and sodium channel blockers, or analogs or pro-drugs thereof, are administered in a sub-therapeutic amount.