Antibiotic oxazolidinone derivatives

Abstract

The invention concerns a compound of formula (I): wherein, for example: T is of formula (IB) or (IC): R 1 is of the formula —NHC(═O)R b wherein R b is (1-4C)alkyl; R 2 and R 3 are hydrogen or fluoro; A—B— is C═CH— or CH—CH 2 —; wherein when T is of formula (IB); R 6 is, for example, (1-4C)alkyl; R 5 is hydrogen, R 10 CO—, R 10 SO 2 — or R 10 CS— wherein R 10 is, for example, optionally substituted phenyl, or (1-10C)alkyl; or when T is of formula (IB) or (IC); R 5 and R 6 are linked to give a 5- or 6-membered ring which is fused to the ring shown in (IB) or (IC) so as to give an optionally substituted bicyclic ring; and pharmaceutically-acceptable salts thereof, processes for their preparation; pharmaceutical compositions containing them and their use as antibacterial agents.

1 . A compound of the formula (I),  
       
         
           
           
               
               
           
         
       
       wherein: 
 T is of the formula (IA), (IB) or (IC);  
                     
 wherein the R 6  group in (IC) may be in the 2- or 6-position relative to the ring nitrogen atom);  
 R 1  is chloro, fluoro, (1-4C)alkanesulfonyloxy, azido, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, or of the formula —NHC(═O)R b  wherein R b  is hydrogen, (1-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (1-4C)alkyl, or of the formula —NHS(O) n (1-4C)alkyl wherein n is 0, 1 or 2;  
 R 2  and R 3  are independently hydrogen or fluoro;  
 >A—B— is >C═CH—, >C(R 4 )—CH 2 —, >CH—CH 2 —, >C═C(R 4a )—, >C(R 4 )—CH(R 4a )— or >CH—CH(R 4a )—(wherein, herein and hereinafter, > represents two single bonds), provided that >A—B— is not >C═CH—, >C═C(R 4a )—, >C(R 4 )—CH(R 4a )— or >CH—CH(R 4a )— when T is of the formula (IA); wherein R 4  is hydrogen, hydroxy, halo, (1-4C)alkyl or (1-4C)alkanoyloxy;  
 R 4a  is (1-4C)alkyl;  
 m is 0 or 1;  
 wherein when T is of the formula (IA) or (IB);  
 R 6  is (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for R 5  hereinbelow (excluding R 5  as hydrogen);  
 R 5  is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, trityl or AR (as defined hereinbelow);  
 or R 5  is of the formula R 10 CO—, R 10 SO 2 — or R 10 CS—  
 wherein R 10  is AR (as defined hereinbelow), cyclopentyl or cyclohexyl (wherein the last two-mentioned cycloalkyl rings are optionally mono- or disubstituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl), benzyloxy, (1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, 2-(2-furyl)ethenyl, 2-(2-thienyl)ethenyl, 2-phenylethenyl (wherein the phenyl substituent is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, benzyloxy, cyano, halo, (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,  N -(1-4C)alkyl- N -(2-6C)alkanoylamino, (1-4C)alkylS(O) p NH—, (1-4C)alkylS(O) p ((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O) p NH—, fluoro(1-4C)alkylS(O) p ((1-4C)alkyl)N—, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O) q —, phenylS(O) q — (wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2];  
 or R 10  is of the formula R 11 C(O)O(1-6C)alkyl wherein R 11  is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;  
 or R 10  is of the formula R 12 O— wherein R 12  is optionally substituted (1-6C)alkyl;  
 or R 5  is of the formula R d OC(R e )═CH(C═O)—, R f C(═O)C(═O)—, R g N═C(R h )C(O)— or R i NHC(R j )═CHC(═O)— wherein R d  is (1-6C)alkyl, R e  is hydrogen or (1-6C)alkyl, or R d  and R e  together form a (3-4C)alkylene chain, R f  is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy, R g  is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, R h  is hydrogen or (1-6C)alkyl, R i  is hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl and R j  is hydrogen or (1-6C)alkyl;  
 or R 5  is of the formula R 14 CH(R 13 )(CH 2 ) m — wherein m is 0 or 1, R 13  is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 13  is not fluoro or hydroxy) and R 14  is hydrogen or (1-4C)alkyl;  
 or when T is of the formula (IA), (IB) or (IC) R 5  is ethenyl, 2-(AR)ethenyl, 2-(1-4C)alkylethenyl or of the formula (ID)  
                     
 wherein X is —OR 15 , —SR 15 , —NHR 15  and —N(R 15 ) 2  wherein R 15  is hydrogen (when X is —NHR 15  and —N(R 15 ) 2 ), (1-4C)alkyl or AR (as defined hereinbelow, when X is —OR 15 , —SR 15  and —NHR 15 ); and R 16  is cyano, nitro, (1-4C)alkylsulfonyl, (4-10C)cycloalkylsulfonyl, phenylsulfonyl, (1-4C)alkanoyl and (1-4C)alkoxycarbonyl;  
 or when T is of the formula (IA), (IB) or (IC);  
 R 5  and R 6  are linked to give a group of the formula (IE) to (IT) [in which the N-atom shown is linked to R 5  in (IA) to (IC), and the adjacent carbon atom shown in (IE) to (IT) is linked to R 6  in (IA) to (IC)] so that a 5- or 6-membered ring is formed which is fused to the ring shown in (IA), (IB) or (IC) so as to give a bicyclic ring structure:  
                                       
 wherein  
 D is independently selected from >C(R 7 )(R 8 ) [or ═C(R 8 )— when D is connected to a carbon-carbon double bond, wherein═represents a carbon-carbon double bond], S(O) p  [wherein p is 0, 1 or 2] and —O— [when D is not connected to a carbon-carbon double bond] and —NR 9  [or N when D is connected to a carbon-carbon double bond];  
 is E independently selected from >C(R 7 )(R 8 ) [or ═C(R 8 )— when E is connected to a carbon-carbon double bond], S(O) p  [wherein p is 0, 1 or 2] and >C═O [when E is not connected to a carbon-carbon double bond];  
 wherein R 7  and R 8  are independently selected from hydrogen, (1-4C)alkyl, (optionally substituted by hydroxy, trifluoromethyl, (1-4C)alkyl S(O) q — (wherein q is 0, 1 or 2), (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,  N -(1-4C)alkylcarbamoyl, di( N -(1-4C)alkyl)carbamoyl, cyano, nitro, amino,  N -(1-4C)alkylamino, di( N -(1-4C)alkyl)amino or (1-4C)alkanoylamino), hydroxy [when D and E are not connected to a carbon-carbon double bond], (1-4C)alkoxy, halo, trifluoromethyl, thiol, (1-4C)alkyl S(O) q  (wherein q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl,  N -(1-4C)alkylcarbamoyl, di( N -(1-4C)alkyl)carbamoyl, (2-4C)alkenyl (optionally substituted by carboxy or (1-4C)alkoxycarbonyl), cyano, (1-4C)alkanoylamino, amino,  N -(1-4C)alkylamino, di( N -(1-4C)alkyl)amino or nitro;  
 wherein R 9  is hydrogen, AR, trifluoromethyl, hydroxy, cyano, ethenyl, 2-(AR)ethenyl, 2-(1-4C)alkyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, halo (provided that (1-10C)alkyl is not methyl when substituted by hydroxy or halo), cyano, (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,  N -(1-4C)alkyl- N -(2-6C)alkanoylamino, (1-4C)alkylS(O) p NH—, (1-4C)alkylS(O) p ((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O) p NH—, fluoro(1-4C)alkylS(O) p ((1-4C)alkyl)N—, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O) q —, phenylS(O) q — (wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), AR or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2];  
 or R 9  is of the formula R 11 C(O)O(1-6C)alkyl wherein R 11  is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;  
 or R 9  is of the formula R 12 O— wherein R 12  is optionally substituted (1-6C)alkyl;  
 wherein AR is optionally substituted phenyl, phenylcarbonyl (when in AR-oxymethyl), optionally substituted phenyl (1-4C)alkyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted naphthyl or an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom;  
 wherein CY is a 4-, 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered cycloalkenyl ring; wherein any of the afore-mentioned ring systems in CY may be optionally substituted by up to three substituents independently selected from halo, (1-4C)alkyl (including geminal disubstitution when CY is a cycloalkyl or cycloalkenyl ring), acyl, oxo and nitro-(1-4C)alkyl;  
 or a pharmaceutically-acceptable salt thereof.  
 
     
     
         2 . A compound of formula (I), as claimed in  claim 1 , wherein R 1  is acetamido; or a pharmaceutically-acceptable salt thereof.  
     
     
         3 . A compound of formula (IU), as claimed in claims  1  and  2 ,  
       
         
           
           
               
               
           
         
       
       wherein R 1  is acetamido, R 2  and R 3  are independently hydrogen or fluoro, and wherein T, as defined in  claim 1 , is of the formula (IB) (wherein m is 0), >A—B— is of the formula >C═CH—, R 6  is benzyloxycarbonyl, (1-4C)alkoxycarbonyl, hydroxy-(1-4C)alkyl, AR-oxymethyl (especially benzoyloxymethyl) and Ar-thiomethyl (especially pyrithidin-2-ylthiomethyl), R 5  is hydrogen, trityl, cyano, acetoxyacetyl, (1-6C)alkoxycarbonyl, AR (especially pyrimidin-2-yl), R 10 CO— or R 10 SO 2 — wherein R 10  is preferably hydrogen or (1-10C)alkyl (optionally substituted by benzyloxy or hydroxy); or a pharmaceutically-acceptable salt thereof.  
     
     
         4 . A compound of formula (IU), as defined in  claim 3 , and as claimed in claims  1  and  2 , wherein R 1  is acetamido, R 2  and R 3  are independently hydrogen or fluoro, and wherein T, as defined in  claim 1 , is of the formula (IB) (wherein m is 0), >A—B— is of the formula >C═CH—, and R 5  and R 6  are linked to give a group of the formula (IE) to (IK) so that a 5-membered ring is formed which is fused to the ring shown in (IB) to give a 5/5-bicyclic ring structure; or a pharmaceutically-acceptable salt thereof. 
 N-((5S)-3-(4-(1-methylsulphonyl-2S-benzyloxycarbonyl-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-(1-cyano-2S-benzyloxycarbonyl-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-(1-formyl-2S-benzyloxycarbonyl-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-(1-cyano-2S-(pyrimidin-2-yl)thiomethyl-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-(2S-benzoyloxymethyl-1-cyano-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-(2S-benzoyloxymethyl-1-formyl-2,5-dihydropyrrol-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-((7aS)[3H,5H]-3-oxo-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(3-fluoro-4-((7aS)[3H,5H]-3-oxo-1,7a-dihydropyrrolo[1,2c]oxazole-6-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(3,5-difluoro-4-((7aS)[3H,5H]-3-oxo-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-((7aS)[5H]-3-oxo-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;  
 N-((5S)-3-(4-((7aR)[3H,5H]-3-oxo-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide; or a pharmaceutically-acceptable salt thereof.  
 
     
     
         6 . A pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  5 , and a pharmaceutically acceptable diluent or carrier.  
     
     
         7 . The use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  5 , in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.  
     
     
         8 . A method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  5 .