Aromatic sulfonyl alpha-cycloamino hydroxamic acid compounds

Abstract

An aromatic sulfonyl alpha-cycloamino hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated aromatic sulfonyl alpha-cycloamino hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

What is claimed is:  
     
         1 . A compound corresponding to Formula I:  
       
         
           
           
               
               
           
         
         wherein 
 m is zero 1, 2 or 3;  
 n is zero, 1, or 2, and the sum of m plus n is 1, 2 or 3;  
 R 2  is hydrido, C 1 -C 8  hydrocarbyl, C 1 -C 6  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl, aryl C 1 -C 4  hydrocarbyl, heteroaryl C 1 -C 4  hydrocarbyl, aryloxy C 1 -C 4  hydrocarbyl, or heteroaryloxy C 1 -C 4  hydrocarbyl; and  
 R 1  is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO 2 -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R 1  defining a three-dimensional volume, when rotated about an axis drawn through the SO 2 -bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO 2 -bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.  
 
       
     
     
         2 . The compound according to  claim 1  wherein said 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical of R 1  is substituted with a substituent, R 3 , that has a chain length of 3 to about 14 carbon atoms.  
     
     
         3 . The compound according to  claim 2  wherein said R 3  substituent is selected from the group consisting of a phenyl group, a phenoxy group, a thiophenoxy group, an anilino group, a phenylazo group, a phenylureido, a benzamido], a nicotinamido, an isonicotinamido, a picolinamido group, a heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and a heteroarylthio group.  
     
     
         4 . The compound according to  claim 3  wherein said R 3  substituent is itself substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group, wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.  
     
     
         5 . A compound corresponding to Formula I:  
       
         
           
           
               
               
           
         
         wherein 
 m is zero, 1, 2 or 3;  
 n is zero, 1, or 2, and the sum of m plus n is 1, 2 or 3;  
 R 2  is hydrido, C 1 -C 8  hydrocarbyl, C 1 -C 6  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl, aryl C 1 -C 4  hydrocarbyl, heteroaryl C 1 -C 4  hydrocarbyl, aryloxy C 1 -C 4  hydrocarbyl, or heteroaryloxy C 1 -C 4  hydrocarbyl; and  
 R 1  is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO 2 -group that is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent R 3  selected from the group consisting of one other single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group, a C 3 -C 14  hydrocarbyl group, a C 2 -C 14  hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group.  
 
       
     
     
         6 . The compound according to  claim 5  wherein said R 1  substituent is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and R 3  is a phenyl, phenoxy, thiophenoxy, phenylazo, benzamido, anilino, nicotinamido, isonicotinamido, picolinamido or phenylureido group  
     
     
         7 . The compound according to  claim 5  wherein said R 1  substituent is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and said R 3  is a phenyl, phenoxy, anilino or thiophenoxy group that is optionally substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C 1 -C 9  hydrocarbyloxy group, a C 1 -C 10  hydrocarbyl group, a di-C 1 -C 9  hydrocarbylamino group, a carboxyl C 1 -C 8  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxy carbonyl C 1 -C 4  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl group and a carboxamido C 1 -C 8  hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.  
     
     
         8 . The compound according to  claim 5  wherein m is 2 and n is zero.  
     
     
         9 . The compound according to  claim 5  wherein m is 1 and n is 2.  
     
     
         10 . A compound corresponding to Formula II:  
       
         
           
           
               
               
           
         
         wherein 
 R 2  is hydrido, C 1 -C 8  hydrocarbyl, C 1 -C 6  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl, aryl C 1 -C 4  hydrocarbyl, heteroaryl C 1 -C 4  hydrocarbyl, aryloxy C 1 -C 4  hydrocarbyl, or heteroaryloxy C 1 -C 4  hydrocarbyl; and  
 R 1  is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO 2 -group that is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent R 3  selected from the group consisting of one other single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group, a C 3 -C 14  hydrocarbyl group, a C 2 -C 14  hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group.  
 
       
     
     
         11 . The compound according to  claim 10  wherein R 1  is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C 6 -C 14  hydrocarbyl group, a C 6 -C 14  hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group a phenylureido group and a benzamido group.  
     
     
         12 . The compound according to  claim 10  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and R 3  is a phenyl, phenoxy, thiophenoxy, phenylazo, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group  
     
     
         13 . The compound according to  claim 10  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and said R 3  is a phenyl, phenoxy or thiophenoxy group that is optionally substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C 1 -C 9  hydrocarbyloxy group, a C 1 -C 10  hydrocarbyl group, a di-C 1 -C 9  hydrocarbylamino group, a carboxyl C 1 -C 8  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxy carbonyl C 1 -C 4  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl group and a carboxamido C 1 -C 8  hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.  
     
     
         14 . The compound according to  claim 10  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and said R 3  substituent is an benzamido, nicotinamido, an anilino, isonicotinamido, picolinamido or phenylureido group in which said R 3  substituent is optioinally substituted at its own meta- or para-position or both with a moiety selected from the group consisting of a halogen, a nitro, a C 1 -C 8  hydrocarbyl, a C 1 -C 7  hydrocarbyloxy, an amino and an amino-C 2 -C 4 -hydroxyalkyl group.  
     
     
         15 . A compound corresponding to Formula IV:  
       
         
           
           
               
               
           
         
         wherein: 
 R 2  is hydrido, C 1 -C 8  hydrocarbyl, C 1 -C 6  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl, aryl C 1 -C 4  hydrocarbyl, heteroaryl C 1 -C 4  hydrocarbyl, aryloxy C 1 -C 4  hydrocarbyl, or heteroaryloxy C 1 -C 4  hydrocarbyl; and  
 R 1  is a substituent containing a single aryl or heteroaryl radical bonded directly to the depicted SO 2 -group that is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C 3 -C 14  hydrocarbyl group, a C 2 -C 14  hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group.  
 
       
     
     
         16 . The compound according to  claim 15  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and R 3  is a phenyl, phenoxy, thiophenoxy, anilino, phenylazo, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group.  
     
     
         17 . The compound according to  claim 15  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and said R 3  is a phenyl, phenoxy, anilino, thiophenoxy, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group that is optionally substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C 1 -C 9  hydrocarbyloxy group, a C 1 -C 10  hydrocarbyl group, a di-C 1 -C 9  hydrocarbylamino group, a carboxyl C 1 -C 8  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxy carbonyl C 1 -C 4  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl group and a carboxamido C 1 -C 8  hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.  
     
     
         18 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         22 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         23 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         24 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         25 . A compound corresponding in structure to the formula  
       
         
           
           
               
               
           
         
       
     
     
         26 . A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a compound corresponding in structure to Formula I in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition:  
       
         
           
           
               
               
           
         
         wherein 
 m is zero, 1, 2 or 3;  
 n is zero, 1, or 2, and the sum of m plus n is 1, 2 or 3;  
 R 2  is hydrido, C 1 -C 8  hydrocarbyl, C 1 -C 6  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl, aryl C 1 -C 4  hydrocarbyl, heteroaryl C 1 -C 4  hydrocarbyl, aryloxy C 1 -C 4  hydrocarbyl, or heteroaryloxy C 1 -C 4  hydrocarbyl; and  
 R 1  is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO 2 -group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R 1  defining a three-dimensional volume, when rotated about an axis drawn through the SO 2 -bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO 2 -bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.  
 
       
     
     
         27 . The process according to  claim 26  wherein said compound corresponds in structure to either Formula II or Formula IV:  
       
         
           
           
               
               
           
         
       
     
     
         28 . The process according to  claim 27  wherein R 1  is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C 3 -C 14  hydrocarbyl group, a C 2 -C 14  hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, an anilino group, a 4-thiopyridyl group, a phenylazo group a phenylureido group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.  
     
     
         29 . The process according to  claim 27  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and R 3  is a phenyl, phenoxy, anilino, thiophenoxy, phenylazo, benzamido, nicotinamido, isonicotinamido, picolinamido or phenylureido group.  
     
     
         30 . The process according to  claim 29  wherein said R 1  radical is PhR 3  in which Ph is phenyl substituted with R 3  at the 4-position, and said R 3  is a phenyl, phenoxy, anilino or thiophenoxy group that is optionally substituted at the meta- or para-position or both with a moiety that is selected from the group consisting of a halogen, a C 1 -C 9  hydrocarbyloxy group, a C 1 -C 10  hydrocarbyl group, a di-C 1 -C 9  hydrocarbylamino group, a carboxyl C 1 -C 8  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxy carbonyl C 1 -C 4  hydrocarbyl group, a C 1 -C 4  hydrocarbyloxycarbonyl C 1 -C 4  hydrocarbyl group and a carboxamido C 1 -C 8  hydrocarbyl group, or is substituted at the meta- and para-positions by two methyl groups or by a methylenedioxy group.  
     
     
         31 . The process according to  claim 26  wherein said compound is administered a plurality of times.