Substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments

Abstract

The present invention relates to substituted Azetidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.

1 . A substituted azetidine compound of general formula I,  
     
       
         
         
             
             
         
       
     
     wherein 
 A represents a —C═O-moiety, a —CH 2 -moiety, a —CH 2 —C═O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a —O—C(═O)-moiety bonded to the azetidine ring via its carbonyl carbon atom,  
 R 1 , R 3 , identical or different, represent a hydrogen atom or a linear or branched, saturated or unsaturated C 1-4 -aliphatic group,  
 R 2  represents a hydrogen atom, a hydroxyl group or a C 1-3 -alkoxy group,  
 or R 1  and R 2  or R 2  and R 3  together form an —O—CH 2 —CH 2 -chain, which is optionally substituted with one or more methyl groups  
 with the proviso that R 1 , R 2  and R 3  do not identically represent a hydrogen atom, and if A represents a —CH 2 -moiety, then at least two of the residues R 1 , R 2  and R 3  do not identically represent a hydrogen atom,  
 R 4  represents a hydrogen atom, an optionally at least mono-substituted aryl group, or a linear or branched, saturated or unsaturated aliphatic group, which may be substituted by one or more substituents independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy and branched or unbranched C 1-4 -perfluoroalkyl,  
 R 5  represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, an —OR 7 -moiety, -an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—R 3 -moiety, an —N(OH)—CO—NH 2 -moiety, an —O(CH 2 ) 1-4 —ONO 2 -moiety, an optionally at least mono-substituted aryl group, or a carboxy-group,  
 R 6  represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, an —OR 9 -moiety, -an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—R 10 -moiety, an —N(OH)—CO—NH 2 -moiety, an optionally at least mono-substituted aryl group, or a carboxy-group, and  
 R 7 , R 8 , R 9 , R 10 , independent from one another, represent a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group,  
 with the provisos that  
 if A represents a —(C═O)-moiety, R 4  represents a hydrogen atom and one of the residues R 5  and R 6  represents a hydrogen atom, then the other one of these residues R 5  and R 6  does not represent an —NH 2 -moiety, a —CONH 2 -moiety, or a methyl group, which is substituted by an —NH 2 -moiety or an azaheterocycle, and  
 if A represents a —C═O-moiety, a —CH 2 —C═O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a —O—C(═O)-moiety bonded to the azetidine ring via its carbonyl carbon atom and one of the residues R 5  and R 6  represents a hydrogen atom or an optionally at least mono-substituted, linear or branched, saturated or unsaturated aliphatic group, then the other one of these residues R 5  and R 6  does not represent an —NH 2 — or a COOH-moiety,  
 optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.  
 
   
   
       2 . The compound according to  claim 1 , wherein R 1  and R 3 , identical or different, represent a hydrogen atom or a linear or branched C 1-4 -alkyl group.  
   
   
       3 . The compound according to  claim 1  wherein R 1  and R 3  are identical and represent a C 1-4 -alkyl group, preferably a C 3-4  alkyl group, more preferably an iso-propyl group or a tert.-Butyl group.  
   
   
       4 . The compound according to  claim 1 , wherein R 2  represents a hydrogen atom, a hydroxyl group or a methoxy group.  
   
   
       5 . The compound according to  claim 1 , wherein R 4  represents a hydrogen atom, an optionally at least mono-substituted phenyl group, or a linear or branched, saturated or unsaturated C 1-6  aliphatic group, whereby said aliphatic group may be substituted by one or more substituents independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy and branched or unbranched C 1-4 -perfluoroalkyl, preferably a hydrogen atom, a methyl group or an unsubstituted phenyl group.  
   
   
       6 . The compound according to  claim 1 , wherein R 5  represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6  aliphatic group, an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—R 8 -moiety, an —N(OH)—CO—NH 2 -moiety, an —O(CH 2 )4-ONO 2 -moiety, an optionally at least mono-substituted phenyl group, or a carboxy-group, preferably a hydrogen atom, a bromine atom, a hydroxyl group, an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—R 3 -moiety, an —N(OH)—CO—NH 2  H 2 -moiety, an —O(CH 2 ) 4 —ONO 2 -moiety, an unsubstituted phenyl group, or a carboxy-group.  
   
   
       7 . The compound according to  claim 1 , wherein R 6  represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6  aliphatic group, an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—R 8 —moiety, an —N(OH)—CO—NH 2 -moiety, an optionally at least mono-substituted phenyl group, or a carboxy-group, preferably a hydrogen atom, a hydroxyl group or a methyl group.  
   
   
       8 . The compound according to  claim 1 , wherein R 7 , R 8 , R 9 , R 10 , independent from one another, represent a linear or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6  aliphatic group, preferably a linear or branched, optionally at least mono-substituted C 1-6  alkyl group, more preferably a methyl group or an ethyl group, which is optionally perfluorinated.  
   
   
       9 . The compound according to  claim 1  of general formula I,  
     
       
         
         
             
             
         
       
     
     wherein 
 A represents a —C═O-moiety, a —CH 2 -moiety, a —CH 2 —C═O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a —O—C(═O)-moiety bonded to the azetidine ring via its carbonyl carbon atom,  
 R 1 , R 3  both identically represent a linear or branched C 1-4 -alkyl group, preferably an iso-propyl group or a tert.-butyl group,  
 R 2  represents a hydrogen atom, a hydroxyl group or a linear or branched C 1-4 -alkoxy group,  
 or R 1  and R 2  or R 2  and R 3  together form an —O—CH 2 —C(CH 3 ) 2 -chain, whereby the oxygen atom of said chain is bonded to the 4-position of the phenyl ring,  
 R 4  represents a hydrogen atom, a linear or branched C 1-4  alkyl group or an unsubstituted phenyl group,  
 R 5  represents a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an —NH—CO—CF 3 -moiety, an —N(OH)—CO—NH 2 H 2 -moiety, an —O(CH 2 ) 4 ONO 2  moiety, or an unsubstituted phenyl group, and  
 R 6  represents a hydrogen atom, a linear or branched C 1-4 -alkyl group, or a hydroxyl group,  
 optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.  
 
   
   
       10 . The compound according to  claim 1  of general formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 A represents a —C═O-moiety, a —CH 2 -moiety, a —CH 2 —C═O-moiety bonded to the azetidine ring via its carbonyl carbon atom, or a —O—C(═O)-moiety bonded to the azetidine ring via its carbonyl carbon atom,  
 R 1 , R 3  both identically represent an iso-propyl group or a tert.-butyl group,  
 R 2  represents a hydrogen atom, a hydroxyl group or a methoxy group,  
 or R 1  and R 2  or R 2  and R 3  together form an —O—CH 2 H 2 —C(CH 3 ) 2 -chain, whereby the oxygen atom of said chain is bonded to the 4-position of the phenyl ring,  
 R 4  represents a hydrogen atom, a methyl group or an unsubstituted phenyl group,  
 R 5  represents a bromine atom, a hydroxyl group, an —NH 2 -moiety, a —CO—NH 2 -moiety, an —NH—CO—CF 3 -moiety, an —N(OH)—CO—NH 2 -moiety, an —O(CH 2 ) 4 ONO 2 -moiety, an unsubstituted phenyl group, or a carboxy-group, and  
 R 6  represent a hydrogen atom, a methyl group or a hydroxyl group,  
 optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.  
 
   
   
       11 . The compounds according to  claim 1  selected from the group consisting of 
 (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;    (3,5-di-tert-butyl-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;    (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-methanone;    (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-methyl-azetidin-1-yl)-methanone;    (3-Bromo-azetidin-1-yl)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-methanone;    (3,5-di-tert-butyl-4-methoxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;    (3-hydroxy-azetidin-1-yl)-(4-hydroxy-3,5-diisopropyl-phenyl)-methanone;    (3,5-di-tert-butyl-phenyl)-[3-(4-nitrooxy-butoxy)-azetidin-1-yl]-methanone;    (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-phenyl-azetidin-1-yl)-methanone;    (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-phenyl-azetidin-1-yl)-methanone;    (7-tert-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-(3-hydroxy-azetidin-1-yl)-methanone;    [1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea;    N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-(2S,3R)-2-methyl-azetidin-3-yl]-2,2,2-trifluoro-acetamide;    (3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol;    (3,5-di-tert-butyl-4-hydroxy-phenyl)-1-(3-hydroxy-azetidin-1-yl)-ethanone; and    (3-hydroxy-azetidine-1-carboxylic acid)-3,5-di-tert-butyl-phenyl ester.    optionally in form of a corresponding salt or a corresponding solvate.    
   
   
       12 . A process for the preparation of a substituted azetidine compound of general formula I according to  claim 1 , comprising reacting at least one compound of general formula II,  
     
       
         
         
             
             
         
       
       wherein R 1 -R 3  have the meaning according to  claim 1 , X represents a bond or an —(CH 2 )-moiety and R represents a carboxy group or an activated carbonyl group, with at least one compound of general formula III,  
       
         
           
           
               
               
           
         
       
       optionally in the form of a corresponding salt, wherein R 4 -R6 have the meaning according to  claim 1 , to yield a compound of general formula I according to  claim 1 , wherein A represents a —(C═O)-moiety or an —(CH 2 )—CO-moiety, which is optionally purified and/or optionally isolated,  
       and optionally at least one compound of general formula I according to  claim 1 , wherein A represents a —(C═O)-moiety is reduced to yield at least one compound of general formula I according to  claim 1 , wherein A represents a —(CH2)-moiety, which is optionally purified and/or isolated,  
       or at least one compound of general formula IV,  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 3  have the meaning according to  claim 1 , is reacted with at least one compound of general formula III given above, to yield at least one compound of general formula I according to  claim 1 , wherein A represents an O—(C═O)-moiety, and said compound is optionally purified and/or optionally isolated.  
     
   
   
       13 . A medicament comprising at least one substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.  
   
   
       14 . The medicament according to  claim 13  containing an amount of the compound effective for the inhibition of Cyclooxygenase-1, for the prophylaxis and/or treatment of Cyclooxygenase-1 related disorders, for the inhibition of Cyclooxgenase-2 and/or for the prophylaxis and/or treatment of Cyclooxygenase-2 related disorders.  
   
   
       15 . The medicament according to  claim 13  containing an amount of the compound effective for the prophylaxis and/or treatment of pain, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lower back pain, neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis, gout, ankylosing spondylitis, bursitis, edema, inflammations following dental procedures, inflammations following dental procedures, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's disease, sclerodoma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcefs syndrome, polymyositis, gingivitis, hypersensivity, conjunctivitis, swelling occurring after injury and myocardia ischemia, for the prophylaxis and/or treatment of asthma, for the prophylaxis and/or treatment of bronchitis, for the prophylaxis and/or treatment of tendinitis, for the prophylaxis and/or treatment of bursitis, for the prophylaxis and/or treatment of skin related conditions, whereby said skin related conditions may preferably be selected from the group consisting of psoriasis, eczema, bums and dermatitis, for the prophylaxis and/or treatment of gastrointestinal disorders, whereby said gastrointestinal disorders may preferably be selected from the group consisting of inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, or for treatment of fever, or for the prophylaxis and/or treatment of cancer or a cancer-related disorders, whereby said cancer or related disorder may preferably be selected from the group consisting of brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell cancer, prostate cancer, renal cell carcinoma and other known cancers that effect epithelial cells throughout the body, for the prophylaxis and/or treatment of polyps, for the prophylaxis and/or treatment of angiogenesis mediated disorders, preferably selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinalneovascularisation, diabethic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, vascular necrosis of the bone and endometriosis.  
   
   
       16 . The medicament according to  claim 13  containing an amount of the compound effective for the prophylaxis and/or treatment of pain.  
   
   
       17 . The medicament according to  claim 13  containing an amount of the compound effective for the prophylaxis and/or treatment of inflammation.  
   
   
       18 . The medicament according to  claim 13  containing an amount of the compound effective for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lower back pain, neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis, gout, ankylosing spondylitis, bursitis, edema, inflammations following dental procedures, inflammations following dental procedures, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's disease, sclerodoma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensivity, conjunctivitis, swelling setting occurring after injury and myocardia ischemia.  
   
   
       19 . A method for the preparation of a medicament for the inhibition of Cyclooxygenase-1, for the prophylaxis and/or treatment of Cyclooxygenase-1 related disorders, for the inhibition of Cyclooxgenase-2 and/or for the prophylaxis and/or treatment of Cyclooxygenase-2 related disorders, comprising providing an effective amount of at least one substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.  
   
   
       20 . A method for the prophylaxis and/or treatment of pain, for the prophylaxis and/or treatment of inflammation and/or for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lower back pain, neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis, gout, ankylosing spondylitis, bursitis, edema, inflammations following dental procedures, inflammations following dental procedures, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's disease, sclerodoma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensivity, conjunctivitis, swelling occurring after injury and myocardia ischemia, for the prophylaxis and/or treatment of asthma, for the prophylaxis and/or treatment of bronchitis, for the prophylaxis and/or treatment of tendinitis, for the prophylaxis and/or treatment of bursitis, for the prophylaxis and/or treatment of skin related conditions, whereby said skin related conditions may preferably be selected from the group consisting of psoriasis, eczema, burns and dermatitis, for the prophylaxis and/or treatment of gastrointestinal disorders, whereby said gastrointestinal disorders may preferably be selected from the group consisting of inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, or for treatment of fever, or for the prophylaxis and/or treatment of cancer or a cancer-related disorders, whereby said cancer or related disorder may preferably be selected from the group consisting of brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell cancer, prostate cancer, renal cell carcinoma and other known cancers that effect epithelial cells throughout the body, for the prophylaxis and/or treatment of polyps, for the prophylaxis and/or treatment of angiogenesis mediated disorders, preferably selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinalneovascularisation, diabethic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, vascular necrosis of the bone and endometriosis, comprising applying to a patient in need thereof an effective amount of a substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.  
   
   
       21 . A method for the prophylaxis and/or treatment of pain, comprising applying to a patient in need thereof an effective amount of a substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.  
   
   
       22 . A method for the prophylaxis and/or treatment of inflammation, comprising applying to a patient in need thereof an effective amount of a substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.  
   
   
       23 . A method for the prophylaxis and/or treatment of inflammation related disorders, whereby said inflammation-related disorders may preferably be selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lower back pain, neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis, gout, ankylosing spondylitis, bursitis, edema, inflammations following dental procedures, inflammations following dental procedures, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's disease, sclerodoma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensivity, conjunctivitis, swelling occurring after injury and myocardia ischemia, comprising applying to a patient in need thereof an effective amount of a substituted azetidine compound according to  claim 1  and optionally one or more pharmaceutically acceptable excipients.