Methods of treating inflammation or neuropathic pain

Abstract

Provided herein are methods of treating inflammation or neuropathic pain using an effective dose of a monoacylglycerol lipase inhibitor or a composition thereof.

What is claimed is: 
     
         1 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the effective dose is from about 1 mg to about 500 mg. 
     
     
         2 . A method of treating Epilepsy/Seizure Disorder, Multiple Sclerosis, Neuromyelitis Optica (NMO), Tourette Syndrome, Alzheimer Disease, or abdominal pain associated with Irritable Bowel Syndrome in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the effective dose is from about 1 mg to about 100 mg. 
     
     
         3 . A method of treating acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vasoocclussive painful crises in sickle cell disease, spasticity or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the effective dose is from about 1 mg to about 100 mg. 
     
     
         4 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein a fragment of Compound 1 is covalently attached to at least 30% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         5 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the plasma AUC 0-inf  of Compound 1 is at least 0.05 μM·hr after administration of the effective dose. 
     
     
         6 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.05 μM·hr after administration of the effective dose. 
     
     
         7 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 40% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         8 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 50% of MGLL in PBMCs from the patient after administration of the effective dose 
     
     
         9 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 60% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         10 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 70% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         11 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 80% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         12 . The method of  claim 4 , wherein a fragment of Compound 1 is covalently attached to at least 90% of MGLL in PBMCs from the patient after administration of the effective dose. 
     
     
         13 . The method of any one of  claims 4  and  7 - 12 , wherein measurement of fragments of Compound 1 covalently attached to MGLL in PBMCs from the patient is performed using an in vitro assay. 
     
     
         14 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.1 μM·hr after administration of the effective dose. 
     
     
         15 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.2 μM·hr after administration of the effective dose. 
     
     
         16 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.3 μM·hr after administration of the effective dose. 
     
     
         17 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.4 μM·hr after administration of the effective dose. 
     
     
         18 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.5 μM·hr after administration of the effective dose. 
     
     
         19 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.6 μM·hr after administration of the effective dose. 
     
     
         20 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.7 μM·hr after administration of the effective dose. 
     
     
         21 . The method of  claim 5 , wherein the plasma AUC 0-inf  of Compound 1 is at least 0.8 μM·hr after administration of the effective dose. 
     
     
         22 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.1 μM·hr after administration of the effective dose. 
     
     
         23 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.2 μM·hr after administration of the effective dose. 
     
     
         24 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.3 μM·hr after administration of the effective dose. 
     
     
         25 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.4 μM·hr after administration of the effective dose. 
     
     
         26 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.5 μM·hr after administration of the effective dose. 
     
     
         27 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.6 μM·hr after administration of the effective dose. 
     
     
         28 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.7 μM·hr after administration of the effective dose. 
     
     
         29 . The method of  claim 6 , wherein the steady state plasma AUC 0-inf  of Compound 1 is at least 0.8 μM·hr after administration of the effective dose. 
     
     
         30 . The method of any one of  claims 4 - 29 , wherein the effective dose is from about 1 mg to about 500 mg. 
     
     
         31 . The method of any one of  claims 1  and  4 - 29 , wherein the effective dose is from about 2 mg to about 400 mg. 
     
     
         32 . The method of any one of  claims 1  and  4 - 29 , wherein the effective dose is from about 10 mg to about 160 mg. 
     
     
         33 . The method of any one of  claims 1 - 29 , wherein the effective dose is from about 2 mg to about 100 mg. 
     
     
         34 . The method of any one of  claims 1 - 29 , wherein the effective dose is from about 2 mg to about 50 mg. 
     
     
         35 . The method of any one of  claims 1 - 29 , wherein the effective dose is from about 2 mg to about 20 mg. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein Compound 1 is administered orally. 
     
     
         37 . The method of  claim 36 , wherein the effective dose is taken with food. 
     
     
         38 . The method of  claim 36 , wherein the effective dose is taken without food. 
     
     
         39 . The method of any one of  claims 1 - 38 , wherein the effective dose is administered to the patient once per day. 
     
     
         40 . The method of any one of  claims 1 - 38 , wherein the effective dose is administered to the patient twice per day. 
     
     
         41 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.05 μM·hr. 
     
     
         42 . The method of  claim 41 , wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.1 μM·hr. 
     
     
         43 . The method of  claim 41 , wherein wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.2 μM·hr. 
     
     
         44 . A method of treating Epilepsy/Seizure Disorder, Multiple Sclerosis, Neuromyelitis Optica (NMO), Tourette Syndrome, Alzheimer Disease, or abdominal pain associated with Irritable Bowel Syndrome in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.05 μM·hr. 
     
     
         45 . The method of  claim 44 , wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.1 μM·hr. 
     
     
         46 . The method of  claim 44 , wherein wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.2 μM·hr. 
     
     
         47 . A method of treating acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vasoocclussive painful crises in sickle cell disease, spasticity or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides a plasma AUC 0-inf  of at least 0.05 μM·hr. 
     
     
         48 . A method of treating inflammation or neuropathic pain in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides at least 30% of MGLL in PBMCs from the patient to be covalently attached to a fragment of Compound 1. 
     
     
         49 . A method of treating Epilepsy/Seizure Disorder, Multiple Sclerosis, Neuromyelitis Optica (NMO), Tourette Syndrome, Alzheimer Disease, or abdominal pain associated with Irritable Bowel Syndrome in a patient in need thereof, comprising administering to the patient in need thereof a composition comprising 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, wherein administration of the composition provides at least 30% of MGLL in PBMCs from the patient to be covalently attached to a fragment of Compound 1. 
     
     
         50 . The method of any one of  claims 40 - 49 , wherein Compound 1 is administered orally. 
     
     
         51 . A method of binding MGLL with 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1) in PBMCs in a subject after administration of an effective dose of Compound 1, or a pharmaceutically acceptable salt thereof, to the subject, wherein a fragment of Compound 1 is covalently attached to at least 30% MGLL in PBMCs. 
     
     
         52 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 40% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         53 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 50% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         54 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 60% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         55 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 70% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         56 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 80% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         57 . The method of  claim 51 , wherein a fragment of Compound 1 is covalently attached to at least 90% of MGLL in PBMCs from the subject after administration of the effective dose. 
     
     
         58 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 1 mg to about 500 mg. 
     
     
         59 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 2 mg to about 400 mg. 
     
     
         60 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 10 mg to about 160 mg. 
     
     
         61 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 2 mg to about 100 mg. 
     
     
         62 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 2 mg to about 50 mg. 
     
     
         63 . The method of any one of  claims 51 - 57 , wherein the effective dose is from about 2 mg to about 20 mg. 
     
     
         64 . The method of any one of  claims 51 - 63 , wherein Compound 1 is administered orally. 
     
     
         65 . A pharmaceutical composition for the treatment of inflammation or neuropathic pain, wherein the pharmaceutical composition comprises an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the effective dose is from about 1 mg to about 500 mg. 
     
     
         66 . The pharmaceutical composition of  claim 65 , wherein the effective dose is from about 2 mg to about 400 mg. 
     
     
         67 . The pharmaceutical composition of  claim 65 , wherein the effective dose is from about 10 mg to about 160 mg. 
     
     
         68 . The pharmaceutical composition of  claim 65 , wherein the effective dose is from about 2 mg to about 100 mg. 
     
     
         69 . The pharmaceutical composition of  claim 65 , wherein the effective dose is from about 2 mg to about 50 mg. 
     
     
         70 . The pharmaceutical composition of  claim 65 , wherein the effective dose is from about 2 mg to about 20 mg. 
     
     
         71 . A pharmaceutical composition for the treatment of Epilepsy/Seizure Disorder, Multiple Sclerosis, Neuromyelitis Optica (NMO), Tourette Syndrome, Alzheimer Disease, or abdominal pain associated with Irritable Bowel Syndrome, wherein the pharmaceutical composition comprises an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the effective dose is from about 1 mg to about 100 mg. 
     
     
         72 . A pharmaceutical composition for the treatment of acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vasoocclussive painful crises in sickle cell disease, spasticity or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia, wherein the pharmaceutical composition comprises an effective dose of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the effective dose is from about 1 mg to about 100 mg. 
     
     
         73 . The pharmaceutical composition of  claim 71  or  claim 72 , wherein the effective dose is from about 2 mg to about 100 mg. 
     
     
         74 . The pharmaceutical composition of  claim 71  or  claim 72 , wherein the effective dose is from about 2 mg to about 50 mg. 
     
     
         75 . The pharmaceutical composition of  claim 71  or  claim 72 , wherein the effective dose is from about 2 mg to about 20 mg.