Carbocyclic hydrazino inhibitors of copper-containing amine oxidases

Abstract

The present invention is directed to carbocyclic hydrazino compounds that function as inhibitors of copper-containing 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 novel compounds have the general formula: or a pharmaceutically acceptable solvate, hydrate, or salt thereof, wherein R 1 to R 11 are as defined herein.

What is claimed is:  
     
         1 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or an isomer or a pharmaceutically acceptable solvate, hydrate, or salt thereof:  
       wherein: 
 R 1  is hydrogen or (C 1 -C 4 )alkyl, aralkyl, (C 2 -C 5 )alkanoyl, aroyl or heteroaroyl;  
 R 2  is hydrogen, optionally substituted (C 1 -C 4 )alkyl, or optionally substituted aralkyl;  
 R 3 -R 5  and R 10 , 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;  
 R 3  and R 10  are cis or trans arranged;  
 R 11  is hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 5 )alkanoyl or aralkyl;  
 R 6 -R 9 , which can be the same or different, are hydrogen, optionally substituted (C 1 -C 4 )alkyl, halogen, hydroxy, optionally substituted (C 1 -C 4 )alkoxy, optionally substituted aralkyloxy, or (C 1 -C 4 )alkylamino;  
 n is 1, 2 or 3, provided that R 1  is not methyl when R 2  is methyl, n is 1 and R 3  to R 11  are hydrogen.  
 
     
     
         2 . The compound according to  claim 1 , wherein, in the compound of the Formula I, n has the meaning of 1.  
     
     
         3 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 1  has the meaning of hydrogen.  
     
     
         4 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 2  has the meaning of unsubstituted alkyl, preferably methyl.  
     
     
         5 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 11  is hydrogen.  
     
     
         6 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 3  is hydrogen.  
     
     
         7 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 4 , R 5  and R 10  are hydrogen.  
     
     
         8 . The compound according to  claim 1 , wherein, in the compound of the Formula I, R 6 , R 7 , R 8  and R 9  are hydrogen.  
     
     
         9 . A method of inhibiting a copper-containing amine oxidase comprising contacting said amine oxidase with an inhibitory effective amount of a compound of the Formula I′ 
       
         
           
           
               
               
           
         
       
       or an isomer or a pharmaceutically acceptable solvate, hydrate, or salt thereof;  
       wherein: 
 R 1  is hydrogen or (C 1 -C 4 )alkyl, aralkyl, (C 2 -C 5 )alkanoyl, aroyl or heteroaroyl;  
 R 2  is hydrogen, optionally substituted (C 1 -C 4 )alkyl, or optionally substituted aralkyl;  
 R 3 -R 5  and R 10 , 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;  
 R 3  and R 10  are cis or trans arranged;  
 R 11  is hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 5 )alkanoyl or aralkyl;  
 R 6 -R 9 , which can be the same or different, are hydrogen, optionally substituted (C 1 -C 4 )alkyl, halogen, hydroxy, optionally substituted (C 1 -C 4 )alkoxy, optionally substituted aralkyloxy, or (C 1 -C 4 )alkylamino;  
 n is 1, 2 or 3.  
 
     
     
         10 . The method according to  claim 9 , wherein said contacting occurs in vitro.  
     
     
         11 . The method according to  claim 9 , wherein said contacting occurs in vivo.  
     
     
         12 . 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 or such treatment or prevention an effective amount of a compound of Formula I′:  
       
         
           
           
               
               
           
         
       
       or an isomer or a pharmaceutically acceptable solvate, hydrate, or salt thereof;  
       wherein: 
 R 1  is hydrogen or (C 1 -C 4 )alkyl, aralkyl (C 2 -C 5 )alkanoyl, aroyl or heteroaroyl;  
 R 2  is hydrogen, optionally substituted (C 1 -C 4 )alkyl, or optionally substituted aralkyl;  
 R 3 -R 5  and R 10 , 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;  
 R 3  and R 10  are cis or trans arranged;  
 R 11  is hydrogen, (C 1 -C 4 )alkyl, (C 2 -C 5 )alkanoyl or aralkyl;  
 R 6 -R 9 , which can be the same or different, are hydrogen, optionally substituted (C 1 -C 4 )alkyl, halogen, hydroxy, optionally substituted (C 1 -C 4 )alkoxy, optionally substituted aralkyloxy, or (C 1 -C 4 )alkylamino;  
 n is 1, 2 or 3.  
 
     
     
         13 . The method according to  claim 12 , wherein, in the compound of the Formula I, n has the meaning of 1.  
     
     
         14 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 1 has the meaning of hydrogen.  
     
     
         15 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 2  has the meaning of unsubstituted alkyl, preferably methyl.  
     
     
         16 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 11  is hydrogen.  
     
     
         17 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 3  is hydrogen.  
     
     
         18 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 4 , R 5  and R 10  are hydrogen.  
     
     
         19 . The method according to  claim 12 , wherein, in the compound of the Formula I, R 6 , R 7 , R 8  and R 9  are hydrogen.  
     
     
         20 . The method of  claim 12 , wherein said inflammatory disease or condition is a connective tissue inflammatory disease or condition.  
     
     
         21 . The method of  claim 20 , 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, Behret'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.  
     
     
         22 . The method of  claim 12 , wherein said inflammatory disease or condition is a gastrointestinal inflammatory disease or condition.  
     
     
         23 . The method of  claim 22 , 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.  
     
     
         24 . The method of  claim 12 , wherein said inflammatory disease or condition is a central nervous system inflammatory disease or condition.  
     
     
         25 . The method of  claim 24 , wherein said central nervous system inflammatory disease or condition is selected from the group consisting of multiple sclerosis, Alzheimer's disease, and ischaemia-reperfusion injury associated with ischemic stroke.  
     
     
         26 . The method of  claim 12 , wherein said inflammatory disease or condition is a pulmonary inflammatory disease or condition.  
     
     
         27 . The method of  claim 26 , wherein said pulmonary inflammatory disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome.  
     
     
         28 . The method of  claim 12 , wherein said inflammatory disease or condition is a skin inflammatory disease or condition.  
     
     
         29 . The method of  claim 28 , 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.  
     
     
         30 . The method of  claim 12 , 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.  
     
     
         31 . The method of  claim 12 , 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.  
     
     
         32 . The method of  claim 12 , wherein said vascular disease is selected from the group consisting of atheromatous ateriosclerosis, nonatheromatous ateriosclerosis, ischemic heart disease, peripheral aterial occlusion, thromboangiitis obliterans (Buerger's disease), and Raynaud's disease and phenomenon.  
     
     
         33 . The method according to  claim 12 , wherein the compound is selected from 
 (1S,2S)-2-(1-Methylhydrazino)-1-indanol hydrogenmaleate    (1R*,2R*)-2-(1-Methylhydrazino)-1-indanol hydrogenmaleate    (1R*,2R*)-2-(1-Ethylhydrazino)-1-indanol hydrogenmaleate    (1R,2R)-2-(1-Methylhydrazino)-1-indanol hydrogenmaleate    (1S,2S)-2-(1-methylhydrazino)-1-indanol hydrogenmaleate    (1S,2S)-2-(1-methylhydrazino)-1-indanol fumarate    (1R,2R)-2-(1-methylhydrazino)-1-indanol fumarate    (1S,2S)-2-(1-methylhydrazino)-1-indanol succinate    (1R,2R)-2-(1-methylhydrazino)-1-indanol succinate    (1R,2R)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate    (1R,2R)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate    (1S,2S)-2-(1-methylhydrazino)-1-indanol (S,S)-tartrate    (1S,2S)-2-(1-methylhydrazino)-1-indanol (R,R)-tartrate    or an isomer, or a pharmaceutically acceptable solvate, hydrate or salt thereof.    
     
     
         34 . A pharmaceutical composition comprising a compound of any one of the  claims 1  to  8  and a pharmaceutically acceptable carrier and a diluent.  
     
     
         35 . A process for preparing a compound of  claim 1 , comprising:  
       subjecting an amino alcohol of the Formula II  
       
         
           
           
               
               
           
         
       
       to N-nitrosation, to form a compound of the Formula III  
       
         
           
           
               
               
           
         
       
       which compound of the formula III is thereafter reduced to give the desired compound of the formula I, in which the substituents R 1  to R 11  have the meanings given in  claim 1 , or an isomer, solvate, hydrate or salt thereof.  
     
     
         36 . A process for preparing a compound of the Formula I of  claim 1 , comprising reacting an amino alcohol of the Formula II  
       
         
           
           
               
               
           
         
       
       wherein R 11  is hydrogen, with an oxaziridine of the Formula V  
       
         
           
           
               
               
           
         
       
       wherein R 12  and R 13  have the meaning of C 1 -C 4  alkyl groups, or together represent a 5-7-member saturated carbocycle, to give an oxadiazine of the formula IV  
       
         
           
           
               
               
           
         
       
       which is hydrolysed to form the desired hydrazine alcohol of the formula I, wherein R 11  and R 1  are hydrogen, which compound obtained, if desired, is converted to a compound of the Formula I wherein R 11  and R 1  have a meaning other than hydrogen as defined in  claim 1 , whereby the substituents R 2  to R 10  have the meanings given in  claim 1 , or an isomer, solvate, hydrate or salt thereof.