Oxazolidinone And/Or Isoxazoline As Antibacterial Agents

Abstract

Compounds of Formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, and compounds as shown in Formula (I) wherein C is for example (D), (E), (F); wherein A and B are independently selected from (i) and (ii); R 2 a to R 3 b are independently selected from hydrogen and fluorine; R 1 a and R 1 b are independently selected from, for example, hydroxy, —NHC(═W)R 4 , (a) and (b); wherein W is O or S; R 4 is, for example, hydrogen, amino, (1-4C)alkyl; HET-1 is, for example, a C-linked 5-membered heteroaryl ring; HET-2 is, for example, an N-linked 5-membered, fully or partially unsaturated heterocyclic ring; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

1 . A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, 
     
       
         
         
             
             
         
       
     
     wherein in (I) C is a biaryl moiety C′—C″ 
     
       
         
         
             
             
         
       
     
     where C′ and C″ are independently aryl or heteroaryl rings such that the central fragment C is represented by any one of the groups D to L below: 
     
       
         
         
             
             
         
       
       wherein the groups D to L may be attached to rings A and B in either orientation; 
       wherein A and B are independently selected from 
     
     
       
         
         
             
             
         
       
     
     wherein i) and/or ii) are linked as shown in (I) via the 3-position to group C and substituted in the 5-position as shown in (I) by —CH 2 —R 1 a and —CH 2 —R 1 b;
 R 1 a, R 2 b, R 1 a and R a b are independently hydrogen or fluorine; 
 R 1 a and R 1 b are independently selected from hydroxy, —OSi(tri-(1-6C)alkyl) (wherein the 3 (1-6C)alkyl groups are independently selected from all possible (1-6C)alkyl groups), —NHC(═W)R 4 , —OC(═O)R 4 , 
 
     
       
         
         
             
             
         
       
     
     wherein W is O or S;
 R 4  is hydrogen, amino, (1-8C)alkyl, —NHR 12 , —N(R 12 )(R 13 ), —OR 12  or —SR 12 , (2-4C)alkenyl, (1-8C)alkylaryl, mono-, di-, tri- and per-halo(1-8C)alkyl, —(CH 2 )p(3-6C)cycloalkyl or —(CH 2 )p(3-6C)cycloalkenyl wherein p is 0, 1 or 2; 
 wherein in a) HET-1 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen and cyano and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; or 
 HET-1 is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen and cyano and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; 
 wherein in b) 
 HET-2 is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen and cyano and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; or HET-2 is an N-linked 6-membered di-hydro-heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom by oxo or thioxo and/or which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen and cyano and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; 
 and wherein at each occurrence, alkyl, alkenyl, cycloalkyl cycloalkenyl in substituents on HET-1 and HET-2, or in R 4  is optionally substituted with one, two, three or more F, Cl or CN; wherein in c) 
 R 5  is hydrogen, (3-6C)cycloalkyl, phenyloxycarbonyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C)alkyl (optionally substituted by cyano or (1-4C)alkoxycarbonyl), —CO 2 R 8 , —C(═O)R 8 , —C(═O)SR 8 , —C(═S)R 8 , P(O)(OR 9 )(OR 10 ) and —SO 2 R 11 , wherein R 8 , R 9 , R 10  and R 11  are as defined hereinbelow; 
 R 6  is cyano, —COR 12 , —SO 2 NHR 12 , —CONHR 12 , —CON(R 12 )(R 13 ), —SO 2 R 12 , —SO 2 NBR 12 , —SO 2 N(R 12 )(R 13 ) or NO 2 , wherein R 12  and R 13  are as defined hereinbelow; 
 R 7  is hydrogen, amino, (1-8C)alkyl, —NHR 12 , —N(R 12 )(R 13 ), —OR 12  or —SR 12 , (2-4C)alkenyl, (1-8C)alkylaryl, mono-, di-, tri- and per-halo(1-8C)alkyl, —(CH 2 )p(3-6C)cycloalkyl or —(CH 2 )p(3-6C)cycloalkenyl wherein p is 0, 1 or 2; 
 R 8  is hydrogen, (3-6C)cycloalkyl, phenyl, benzyl, (1-5C)alkanoyl, (1-6C)alkyl (optionally substituted by substituents independently selected from (1-5C)alkoxycarbonyl, hydroxy, cyano, up to 3 halogen atoms and —NR 14 R 15  (wherein R 14  and R 15  are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (1-4C)alkyl and (1-4C)alkyl substituted with one, two, three or more halogen atoms) and (1-4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R 14 )(R 15 ) group, R 14  and R 15  may additionally be taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group); 
 R 9  and R 10  are independently selected from hydrogen and (1-4C)alkyl; 
 R 11  is (1-4C)alkyl or phenyl; 
 R 12  and R 13  are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (1-4C)alkyl and (1-4C)alkyl substituted with one, two, three or more halogen atoms) and (1-4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R 12 )(R 13 ) group, R 12  and R 13  may additionally be taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group; provided that, when group C is group I or group J and both groups A and B are oxazolidinones and the oxazolidinone (A or B) that is linked to the pyridyl group in C bears a substitutent (R 1 a-CH 2  or R 1 b—CH 2  respectively) that is either an hydroxymethyl group or an acetoxymethyl group then the oxazolidinone (B or A) linked to the phenyl group in C is not substituted by an acetamidomethyl group (R 1 b-CH 2  or R 1 a-CH 2  respectively). 
 
   
   
       2 . A compound as claimed in  claim 1  or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is group D; R 1 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from hydroxy, —NHCO(1-4C)alkyl, —NHCS(1-4C)alkyl, —NHCOO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 and HET-2 are as defined in  claim 1 . 
   
   
       3 . A compound as claimed in  claim 1  or  2 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is group D; R 1 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from hydroxy, —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 and HET-2 are as defined in  claim 1 . 
   
   
       4 . A compound as claimed in any one of  claims 1  to  3 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein one of A and B is an oxazolidinone ring and the other is an isoxazoline ring. 
   
   
       5 . A compound as claimed in any one of  claims 1  to  3 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is group D; A and B are both oxazolidinone rings; R 2 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       6 . A compound as claimed in any one of  claims 1  to  3 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is group D; one of A or B is an oxazolidinone ring and the other is an isoxazoline ring; R 2 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       7 . A compound as claimed in  claim 5  or  6 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein HET-2 is 1,2,3-triazol-1-yl substituted by methyl or trifluoromethyl. 
   
   
       8 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is selected from groups E, J and I; A and B are both oxazolidinone rings; R 2 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       9 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is selected from groups E, J and I; one of A and B is an oxazolidinone ring and the other is an isoxazoline ring; R 2 a and R 2 b are both hydrogen; either R 3 a and R 3 b are both hydrogen or both are fluorine; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       10 . A compound as claimed in  claim 8  or  9 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein HET-2 is 1,2,3-triazol-1-yl substituted by methyl or trifluoromethyl. 
   
   
       11 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is selected from groups E, J and I; A and B are both oxazolidinone rings; one of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the others are hydrogen; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       12 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein C is selected from groups E, J and I; one of A and B is an oxazolidinone ring and the other is an isoxazoline ring; one of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the others are hydrogen; R 1 a and R 1 b are independently selected from —NHCO(1-4C)alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl. 
   
   
       13 . A compound as claimed in  claim 11  or  12 , or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein HET-2 is 1,2,3-triazol-1-yl substituted with methyl or trifluoromethyl. 
   
   
       14 . A compound selected from:
 (5S,5S′)—N-(3-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,2′-difluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide;   N-[((5S,5′RS)-3-{4′-[5-(Hydroxymethyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;   (5R,5RS′)-3-{2-Fluoro-4′-[5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]-1,1′biphenyl-4-yl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;   N-[((5S)-3-{4′-[(5R)-5-(Hydroxymethyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;   N-[((5S)-3-{4′-[(5S)-5-(Hydroxymethyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide; and   (5R)-3-(3-Fluoro-4-{5-[5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]thien-2-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;   or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof.   
   
   
       15 . A pro-drug of a compound as claimed in any one of the previous claims. 
   
   
       16 . A method for producing an antibacterial effect in a warm blooded animal which comprises administering to said animal an effective amount of a compound of the invention as claimed in any one of  claims 1  to  14 , or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof. 
   
   
       17 . A compound of the invention as claimed in any one of  claims 1  to  14 , or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, for use as a medicament. 
   
   
       18 . The use of a compound of the invention as claimed in any one of  claims 1  to  14 , or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal. 
   
   
       19 . A pharmaceutical composition which comprises a compound of the invention as claimed in any one of  claims 1  to  14 , or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier. 
   
   
       20 . A process for the preparation of a compound of formula (I) as claimed in  claim 1  or pharmaceutically acceptable salts or in-vivo hydrolysable esters thereof, which process comprises one of processes (a) to (d):
 (a) by modifying a substituent in, or introducing a substituent into another compound of the invention by using standard chemistry;   (b) by reaction of two molecules of a compound of formula (II) (wherein X is a leaving group useful in palladium coupling) such that an aryl-aryl, heteroaryl-aryl, or heteroaryl-heteroaryl bond replaces the two aryl-X or heteroaryl-X bonds;   
     
       
         
         
             
             
         
       
       (c) by reaction of a (hetero)biaryl derivative MO carbamate with an appropriately substituted oxirane to form an oxazolidinone ring at the undeveloped aryl position; 
     
     
       
         
         
             
             
         
       
       or by variations on this process in which the carbamate is replaced by an isocyanate or by an amine or/and in which the oxirane is replaced by an equivalent reagent X—CH 2 CH(O-optionally protected)CH 2 R 1 a where X is a displaceable group; 
       (d) by reaction of a (hetero)biaryl derivative (IV) to form an isoxazoline ring at the undeveloped aryl position, 
     
     
       
         
         
             
             
         
       
     
     or by variations on this process in which the reactive intermediate (a nitrile oxide IV″) is obtained other than by oxidation of an oxime (IV′).