Inhibitors of copper-containing amine oxidases

Abstract

The present invention is directed to hydrazono compounds that function as inhibitors of copper-containg amine oxidases commonly known as semicarbazide-sensitive amine oxidases (SSAO), including the human SSAO known as Vascular Adhesion Protein-1 (VAP-1). These SSAO inhibitors have therapeutic utility as drugs to treat conditions and diseases including, but not limited to, a number of inflammatory conditions and diseases (in particular chronic inflammatory conditions such as chronic arthritis, inflammatory bowel diseases, and chronic skin dermatoses), diseases related to carbohydrate metabolism and to aberrations in adipocyte differentiation or function and smooth muscle cell function, and vascular diseases. The compounds have the general formula: or a pharmaceutically acceptable solvate, hydrate, or salt thereof, wherein R 1 to R 8 and X are as defined herein.

What is claimed is:  
     
         1 . A method of inhibiting a copper-containing amine oxidase, comprising contacting said amine oxidase with an inhibitory amount of a hydrazino compound of Formula I or Formula II:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable solvate, hydrate, or salt thereof; wherein: 
 R 1  is hydrogen, (C 1 -C 4 )alkyl, aralkyl, (C 2 -C 5 )alkanoyl, aroyl or heteroaroyl;  
 R 2  is hydrogen, or optionally substituted (C 1 -C 4 )alkyl, optionally substituted cycloalkyl or optionally substituted aralkyl;  
 R 3 -R 6 , which can be the same or different, are hydrogen, optionally substituted (C 1 -C 4 )alkyl, optionally substituted aralkyl, optionally substituted phenyl or optionally substituted heteroaryl;  
 or R 1  and R 2 , together with the atoms to which they are attached, represent an optionally substituted heterocycle,  
 or R 2  and R 3 , together with the atoms to which they are attached, represent an optionally substituted heterocycle,  
 or R 3  and R 5 , together with the atoms to which they are attached, represent a saturated, optionally substituted carbocycle;  
 R 7  is hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 5 )alkanoyl or aralkyl;  
 R 8  is (C 1 -C 4 )alkyl or aralkyl;  
 n is 1, 2or 3; and  
 X is chloride, bromide, iodide or R 2 -sulfate, where R 2  is as defined herein.  
 
     
     
         2 . The method of  claim 1 , wherein said contacting occurs in vitro.  
     
     
         3 . The method of  claim 1 , wherein said contacting occurs in vivo.  
     
     
         4 . The method of  claim 1 , wherein n is 1.  
     
     
         5 . The method of  claim 1 , wherein R 1  is hydrogen.  
     
     
         6 . The method of  claim 1 , wherein R 2  is benzyl optionally substituted with alkyl, nitro, methoxy, or halogen.  
     
     
         7 . The method of  claim 1 , wherein R 6  is phenyl optionally substituted with alkyl, nitro, methoxy, or halogen, and R 5  is hydrogen.  
     
     
         8 . The method  claim 1 , wherein n is 1, and R 3  and R 5  together form a cyclohexane ring.  
     
     
         9 . The method of  claim 1 , wherein n is 1, R 4  is hydrogen, and R 2  and R 3  are taken together with the atoms to which they are attached to form an optionally substituted heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, tetrahydroisoquinoline, and pyrazolidine, wherein said heterocyclic ring is optionally substituted with alkyl, nitro, methoxy, or halogen.  
     
     
         10 . The method of  claim 1 , wherein n is 1, and R 3  and R 4 , which can be the same or different, are (C 1 -C 4 )alkyl.  
     
     
         11 . A method of treating an inflammatory disease or condition, a disease related to carbohydrate metabolism, a disease related to aberrations in adipocyte differentiation or function or smooth muscle cell function, or a vascular disease, comprising administering to an animal in need of such treatment an effective amount of a compound of Formula I or Formula II:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable solvate, hydrate, or salt thereof; wherein: 
 R 1  is hydrogen, (C 1 -C 4 )alkyl, aralkyl, (C 2 -C 5 )alkanoyl, aroyl or heteroaroyl;  
 R 2  is hydrogen, or optionally substituted (C 1 -C 4 )alkyl, optionally substituted cycloalkyl or optionally substituted aralkyl;  
 R 3 -R 6 , which can be the same or different, are hydrogen, optionally substituted (C 1 -C 4 )alkyl, optionally substituted aralkyl, optionally substituted phenyl or optionally substituted heteroaryl;  
 or R 1  and R 2 , together with the atoms to which they are attached, represent an optionally substituted heterocycle,  
 or R 2  and R 3 , together with the atoms to which they are attached, represent an optionally substituted heterocycle,  
 or R 3  and R 5 , together with the atoms to which they are attached, represent a saturated, optionally substituted carbocycle;  
 R 7  is hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 5 )alkanoyl or aralkyl;  
 R 8  is (C 1 -C 4 )alkyl or aralkyl;  
 n is 1, 2 or 3; and  
 X is chloride, bromide, iodide or R 2 -sulfate, where R 2  is as defined herein.  
 
     
     
         12 . The method of  claim 11 , wherein n is 1.  
     
     
         13 . The method of  claim 11 , wherein R 1  is hydrogen.  
     
     
         14 . The method of  claim 11 , wherein R 2  is benzyl optionally substituted with alkyl, nitro, methoxy, or halogen.  
     
     
         15 . The method of  claim 14 , wherein R 2  is benzyl substituted at the para position with methyl, nitro, methoxy, or chlorine.  
     
     
         16 . The method of  claim 11 , wherein R 6  is phenyl optionally substituted with alkyl, nitro, methoxy, or halogen, and R 5  is hydrogen.  
     
     
         17 . The method of  claim 16 , wherein the phenyl is substituted at the para position with methyl, nitro, methoxy, or chlorine.  
     
     
         18 . The method  claim 11 , wherein n is 1 and R 3  and R 5  together form a cyclohexane ring.  
     
     
         19 . The method of  claim 11 , wherein n is 1, R 4  is hydrogen, and R 2  and R 3  are taken together with the atoms to which they are attached to form an optionally substituted heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, tetrahydroisoquinoline, and pyrazolidine, wherein said heterocyclic ring is optionally substituted with alkyl, nitro, methoxy, or halogen.  
     
     
         20 . The method of  claim 19 , wherein said optionally substituted heterocyclic ring is selected from the group consisting of 1,2,3,4-tetrahydroisoquinoline, piperidine, and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.  
     
     
         21 . The method of  claim 11 , wherein n is 1, and R 3  and R 4 , which can be the same or different, are (C 1 -C 4 )alkyl.  
     
     
         22 . The method of  claim 21 , wherein R 3  and R 4  are both methyl.  
     
     
         23 . The method of  claim 11 , wherein said inflammatory disease or condition is a connective tissue inflammatory disease or condition.  
     
     
         24 . The method of  claim 23 , wherein said connective tissue inflammatory disease or condition is selected from the group consisting of ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, osteoarthritis or degenerative joint disease, rheumatoid arthritis, Sjögren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis and dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis.  
     
     
         25 . The method of  claim 11 , wherein said inflammatory disease or condition is a gastrointestinal inflammatory disease or condition.  
     
     
         26 . The method of  claim 25 , wherein said gastrointestinal inflammatory disease or condition is selected from the group consisting of Crohn's disease, ulcerative colitis, irritable bowel syndrome (spastic colon), fibrotic conditions of the liver, inflammation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis.  
     
     
         27 . The method of  claim 11 , wherein said inflammatory disease or condition is a central nervous system inflammatory disease or condition.  
     
     
         28 . The method of  claim 27 , wherein said central nervous system inflammatory disease or condition is selected from the group consisting of multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury associated with ischemic stroke.  
     
     
         29 . The method of  claim 11 , wherein said inflammatory disease or condition is a pulmonary inflammatory disease or condition.  
     
     
         30 . The method of  claim 29 , wherein said pulmonary inflammatory disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome.  
     
     
         31 . The method of  claim 11 , wherein said inflammatory disease or condition is a skin inflammatory disease or condition.  
     
     
         32 . The method of  claim 31 , wherein said skin inflammatory disease or condition is selected from the group consisting of contact dermatitis, atopic dermatitis, psoriasis, pityriasis rosea, lichen planus, and pityriasis rubra pilaris.  
     
     
         33 . The method of  claim 11 , wherein said disease related to carbohydrate metabolism is selected from the group consisting of diabetes, atherosclerosis, vascular retinopathies, retinopathy, nephropathy, nephrotic syndrome, polyneuropathy, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and increased risk of infection.  
     
     
         34 . The method of  claim 11 , wherein said disease related to aberrations in adipocyte differentiation or function or smooth muscle cell function is selected from the group consisting of atherosclerosis and obesity.  
     
     
         35 . The method of  claim 11 , wherein said vascular disease is selected from the group consisting of atheromatous ateriosclerosis, nonatheromatous ateriosclerosis, ischemic heart disease, peripheral aterial occlusion, thromboangiitis obliterans, and Raynaud's disease and phenomenon.  
     
     
         36 . The method of  claim 11 , wherein said compound of Formula I is selected from the group consisting of: 
 (1R,2S)-2-(1-methylhydrazino)-1-phenyl-1-propanol;    (1R*,2S*)-2-(1-methylhydrazino)-1-phenyl-1-propanol;    (1R*,2S*)-1-(2-hydroxy-1-methyl-2-phenylethyl)-1,1-dimethylhydrazinium iodide;    (1R*,2S*)-2-(1-methylhydrazino)-1,2-diphenylethanol;    2-(1-methylhydrazino)-1-phenylethanol;    2-(1-methylhydrazino)-2-phenylethanol;    1-[2-methoxy-2-(m-methoxyphenyl)ethyl]-1-methylhydrazine;    2-amino-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-methanol; and    2-(1-methylhydrazino)-1-(p-methoxyphenyl)ethanol;    or a pharmaceutically acceptable salt thereof.    
     
     
         37 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 11  and a pharmaceutically acceptable carrier or diluent.