Thiazole derivatives

Abstract

A compound of the formula (I): R 1 —NH—X—Y-Z (I) wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor, a pharmaceutical composition, a method for preventing or treating a VAP-1 associated disease, especially macular edema, which method includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a mammal, and the like.

1 . A compound of the formula (I):  
       R 1 —NH—X—Y-Z  (I)  
     wherein 
 R 1  is acyl;  
 X is a 1,3-thiazole ring;  
 wherein the 1,3-thiazole ring is optionally substituted at the 4 or 5-position, —Y-Z is a substituent at the 2, 4 or 5-position of the 1,3-thiazole ring and R 1 —NH— is a substituent at the 2, 4 or 5-position of the 1,3-thiazole ring, provided that when R 1 —NH— is a substituent at the 2-position of the 1,3-thiazole ring, R 1  should not be an acetyl group;  
 Y is a bond, lower alkylene, lower alkenylene or —CONH—; and  
 Z is a group of the formula:  
                     wherein R 2  is a group of the formula: -A-B-D-E 
 wherein 
 A is a bond, lower alkylene, —NH— or —SO 2 —;  
 B is a bond, lower alkylene, —CO— or —O—;  
 D is a bond, lower alkylene, —NH— or —CH 2 NH—; and  
 E is optionally protected amino, —N═CH 2 ,  
                     
 wherein  
 Q is —S— or —NH—; and  
 R 3  is hydrogen, lower alkyl, lower alkylthio or  
 —NH—R 4  wherein R 4  is hydrogen, —NH 2  or lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
 
   
   
       2 . The compound of  claim 1 , wherein Z is a group of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 2  is a group of the formula:  
     
       
         
         
             
             
         
       
     
     (wherein G is a bond, —NHCOCH 2 — or lower alkylene and R 4  is hydrogen, —NH 2  or lower alkyl); —NH 2 ; —CH 2 NH 2 ; —CH 2 ONH 2 ; 
 —CH 2 ON═CH 2 ;  
                     
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       3 . The compound of  claim 2 , wherein R 2  is a group of the formula:  
     
       
         
         
             
             
         
       
     
     (wherein G is a bond, —NHCOCH 2 — or lower alkylene and R 4  is hydrogen or lower alkyl); 
 —CH 2 NH 2 ; —CH 2 ONH 2 ; —CH 2 ON═CH 2 ;  
                     
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       4 . The compound of  claim 1 , wherein R 1  is alkylcarbonyl and X is a 1,3-thiazole ring optionally substituted by methylsulfonylbenzyl, or a pharmaceutically acceptable salt thereof.  
   
   
       5 - 6 . (canceled)  
   
   
       7 . A pharmaceutical composition, which comprises, as an active ingredient, the compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       8 . A method for producing a compound of the formula (I):  
       R 1 —NH—X—Y-Z  (I)  
     wherein 
 R 1  is acyl;  
 X is a 1,3-thiazole ring;  
 wherein the 1,3-thiazole ring is optionally substituted at the 4 or 5-position, —Y-Z is a substituent at the 2, 4 or 5-position of the 1,3-thiazole ring and R 1 —NH— is a substituent at the 2, 4 or 5-position of the 1,3-thiazole ring, provided that when R 1 —NH— is a substituent at the 2-position of the 1,3-thiazole ring, R 1  should not be an acetyl group;  
 Y is a bond, lower alkylene, lower alkenylene or —CONH—; and  
 Z is a group of the formula:  
                     wherein R 2  is a group of the formula: -A-B-D-E 
 wherein 
 A is a bond, lower alkylene, —NH— or —SO 2 —;  
 B is a bond, lower alkylene, —CO— or —O—;  
 D is a bond, lower alkylene, —NH— or —CH 2 NH—; and  
 E is optionally protected amino, —N═CH 2 ,  
                     
 wherein  
 
   
 Q is —S— or —NH—; and  
 R 3  is hydrogen, lower alkyl, lower alkylthio or —NH—R 4  wherein R 4  is hydrogen, —NH 2  or lower alkyl;  
 or a pharmaceutically acceptable salt thereof, which method comprises at least one step selected from the group consisting of (i) to (v):  
 (i) reacting Compound (1):  
                     
 with Compound (2):  
                     
 wherein L 1  is a leaving group and Z is as defined above, or a salt thereof;  
 (ii) reacting Compound (3): H 2 N—X-Z  
 wherein X and Z are as defined above, or a salt thereof with Compound (4): R-L 2  wherein R 1  is as defined above and L 2  is a leaving group;  
 (iii) reacting Compound (6): R 1 —NH—X—CHO  
 wherein R 1  and X are as defined above, or a salt thereof with Compound (7): L 3 -CH 2 -Z wherein L 3  is a leaving group and Z is as defined above, or a salt thereof;  
 (iv) reduction of Compound (10): R 1 —NH—X-(lower alkenylene)-Z  
 wherein R 1 , X and Z are as defined above, or a salt thereof to Compound (11): R 1 —NH—X-(lower alkylene)-Z  
 wherein R 1 , X and Z are as defined above, or a salt thereof; and  
 (v) reacting Compound (12): R 1 —NH—X—COOH or a reactive derivative thereof, wherein  
 R 1  and X are as defined above, or a salt thereof with Compound (13): L 4 -NH-Z wherein L 4  is a hydrogen atom or a protecting group and Z is as defined above, or a salt thereof.  
 
   
   
       9 - 16 . (canceled)  
   
   
       17 . A method for treating macular edema, which method comprises administering to a subject in need thereof a VAP-1 inhibitor in an amount sufficient to treat said subject for macular edema.  
   
   
       18 . (canceled)  
   
   
       19 . A method for treating a VAP-1 associated disease, which method comprises administering an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof to a mammal.  
   
   
       20 . The method of  claim 19 , wherein said VAP-1 associated disease is selected from the group consisting of cirrhosis, essential stabilized hypertension, diabetes, arthrosis, endothelium damage (in diabetes, atherosclerosis and hypertension), a cardiovascular disorder associated with diabetes and uraemia, pain associated with gout and arthritis, retinopathy (in diabetes patients), an (connective tissue) inflammatory disease or condition (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter's syndrome, Sjögren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis), a gastrointestinal inflammatory disease or condition [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], a central nervous system inflammatory disease or condition (multiple sclerosis, Alzheimer's disease, and ischaemia-reperfusion injury associated with ischemic stroke), a pulmonary inflammatory disease or condition (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), a (chronic) skin inflammatory disease or condition (psoriasis, allegic lesions, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris), a disease related to carbohydrate metabolism (diabetes and complications from diabetes) including microvascular and macrovascular disease (atherosclerosis, vascular retinopathies, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathies and autonomic neuropathy), foot ulcers, joint problems, and increased risk of infection), a disease related to aberrations in adipocyte differentiation or function or smooth muscle cell function (atherosclerosis and obesity), a vascular disease [atheromatous ateriosclerosis, nonatheromatous ateriosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Raynaud's disease and phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic arthritis, inflammatory bowel diseases, skin dermatoses, diabetes mellitus, SSAO-mediated complication [diabetes (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complication (heart attack, angina, strokes, amputations, blindness and renal failure)] and macular edema (diabetic and non-diabetic macular edema).  
   
   
       21 . The method of  claim 20 , wherein said VAP-1 associated disease is macular edema.  
   
   
       22 . The method of  claim 21 , wherein said macular edema is diabetic macular edema.  
   
   
       23 . The method of  claim 21 , wherein said macular edema is non-diabetic macular edema.  
   
   
       24 . A method of inhibiting VAP-1 in a subject in need thereof, comprising administering to the subject the compound as claimed in  claim 1  in an amount sufficient to inhibit VAP-1 in the subject.