3-phenyl-furan-(5H)-2-one and dihydrofuran-2-one derivatives as antibacterial agents

Abstract

The invention concerns a compound of formula (I), wherein, for example: R 1 is of the formula —NHC(═O)(1-4C)alkyl; R 2 and R 3 are hydrogen or fluoro; R 4 and R 5 are hydrogen or methyl; >A-B- is of the formula >C═CH—, >CHCH 2 , or >C(OH)CH 2 —(> represents two single bonds); D is O, S, SO, SO 2 or —NR 7 ; wherein R 7 is hydrogen, R 10 CO—, R 10 SO 2 —, R a OC(R b )═CH(C═O)—, R c C(═O)C(═O)—, R d N═C(R e )C(═O)—, R f NHC(R g )═CHC(═O)— or R 14 CH(R 13 )(CH 2 ) m —; wherein R 10 is (1-6C)alkyl [optionally substituted by, for example, hydroxy or (1-6C)alkanoyl], R 11 C(O)O(1-6C)alkyl or R 12 O—; wherein R 11 is optionally substituted (1-6C)alkyl; R 12 is optionally substituted (1-6C)alkyl; R a , R b , R c , R d , R e , R f , R g are (1-6)alkyl; m is 0 or 1; R 13 is cyano; R 14 is hydrogen or (1-4C)alkyl; >X—Y— is of the formula >C═CH— or >CHCH 2 —; and pharmaceutically acceptable salts thereof; processes for the preparation; pharmaceutical compositions containing them and their use as antibacterial agents.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydroxy or of the formula —NHC(═O)(1-4C)alkyl or —NHS(O) n (1-4C)alkyl wherein n is 0, 1 or 2;  
 R 2  and R 3  are independently hydrogen or fluoro;  
 R 4  and R 5  are independently hydrogen or methyl  
 >A-B- is of the formula >C═CH—, >CHCH 2 — or >C(OH)CH 2 — (>represents two single bonds);  
 D is O, S, SO, SO 2  or NR 7 ;  
 R 7  is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR (as defined hereinbelow) or a tetrazole ring system (optionally mono-substituted in the 1- or 2-position of the tetrazole ring) wherein the tetrazole ring system is joined to the nitrogen in NR 7  by a ring carbon atom;  
 or R 7  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), (1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, 2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 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), 3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy-4-oxopyran-2-yl, N-acetylpyrrolidin-2-yl, 5-oxo-tetrahydrofuran-2-yl, benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, cyano, halo, (1-10C)alkoxy, benzyloxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-6C)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)NH—, fluoro(i 4C)alkylS(O) p NH—, fluoro(1-4C)alkylS(O) p ((1-4C)alkyl)NH—, 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 20  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 7  is of the formula R a OC(R b )═CH(C═O)—, R c C(═O)C(═O)—, R d N═C(R e )C(═O)— or R f NHC(R g )═CHC(═O)— wherein R a  is (1-6C)alkyl, R b  is hydrogen or (1-6C)alkyl, or R a  and R b  together form a (3-4C)alkylene chain, R c  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 d  is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, R e  is hydrogen or (1-6C)alkyl, R f  is hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl and R g  is hydrogen or (1-6C)alkyl;  
 or R 7  is of the formula R 14 CH(R 13 )(CH 2 ) m — wherein m is O 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; wherein AR is optionally substituted phenyl, 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, a 5- or 6-membered cycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl, pyrimidin-2-ylthio, 1,4-benzodioxan-6-yl, sulfolan-3-yl, pyridin-2-yl; 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;  
 >X—Y— is of the formula >C═CH— or >CHCH 2 —;  
 and pharmaceutically-acceptable salts thereof.  
 
     
     
         2 . A compound of the formula (I) as claimed in  claim 1  wherein: 
 R 1  is hydroxy or of the formula —NHC(═O)(1-4C)alkyl or —NHS(O),(1-4C)alkyl wherein n is 0, 1 or 2;  
 R 2  and R 3  are independently hydrogen or fluoro;  
 R 4  and R 5  are independently hydrogen or methyl;  
 >A-B- is of the formula >C═CH—, >CHCH 2 , or >C(OH)CH 2 — (>represents two single bonds);  
 D is O, S, SO, SO 2  or —NR 7 ;  
 wherein R 7  is hydrogen, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl or optionally substituted: phenyl, phenyl(1-4C)alkyl, 5- or 6-membered heteroaryl, naphthyl or 5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ring systems are joined to the nitrogen in NR 7  by a ring carbon atom;  
 or R 7  is of the formula R 10 CO— or R 10 SO 2 — 
 wherein R 10  is amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, or (1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy, cyano, (1-6C)alkoxy, benzyloxy, (1-6C) alkanoyl, amino, (1-4C)alkylamino, di-(1-4C) alkylamino, (1-6C)alkanoylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O) p  NH—, (1-4C)alkylS(O) p ((1-4C)alkyl)NH—, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, or (1-4C)alkylS(O) p  wherein p is 1 or 2];  
 or R 10  is of the formula R 11 C(O)O(1-6C)alkyl wherein R 11  is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (1-6C)alkyl;  
 or R 10  is of the formula R 12 O— wherein R 12  is optionally substituted (1-6C)alkyl; or R 7  is of the formula R a OC(R b )═CH(C═O)—, R c C(═O)C(═O)—, R d N═C(R e )C(═O) or RNHC(R g )═CHC(═O)— wherein R a  is (1-6C)alkyl, R b  is hydrogen or (1-6C)alkyl or R a  and R b  together form a (3-4C)alkylene chain, R c  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, Rd is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, R e  is hydrogen or (1-6C)alkyl, R f  is (1-6C)alkyl, phenyl or a 5- or 6-membered heteroaryl and R g  is hydrogen or (1-6C)alkyl;  
 or R 7  is of the formula R 14 CH(R 13 )(CH 2 ) m — wherein m is 0 or, 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;  
 >X—Y— is of the formula >C═CH— or >CHCH 2 —;  
 and pharmaceutically-acceptable salts thereof.  
 
     
     
         3 . A compound of the formula (1) as claimed in claims  1  and  2  wherein: 
 R 1  of the formula —NHC(═O)(1-4C)alkyl;  
 R 2  and R 3  are independently hydrogen or fluoro;  
 R 4  and R 5  are independently hydrogen or methyl;  
 >A-B- is of the formula >C═CH— or >CHCH 2  (>represents two single bonds);  
 D is O, S or —NR 7 ;  
 wherein R 7  is hydrogen, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl or optionally substituted: phenyl, phenyl(1-4C)alkyl, 5- or 6-membered heteroaryl, naphthyl or 5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ring systems are joined to the nitrogen in NR 7  by a ring carbon atom;  
 or R 7  is of the formula R 10 CO— or R 10 SO 2 —;  
 wherein R 10  is amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, or (1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy, cyano, (1-6C)alkoxy, benzyloxy, (1-6C) alkanoyl, amino, (1-4C)alkylamino, di-(1-4C) alkylamino, (1-6C)alkanoylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O) p  NH—, (1-4C)alkylS(O) p ((1-4C)alkyl)NH—, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, or (1-4C)alkylS(O) p  wherein p is 1 or 2];  
 or R 10  is of the formula R 11 C(O)O(1-6C)alkyl wherein R 11  is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (1-6C)alkyl;  
 or R 10  is of the formula R 12 O— wherein R 12  is optionally substituted (1-6C)alkyl;  
 or R 7  is of the formula R a OC(R b )═CH(C═O)—, R c C(═O)C(═O)—, R d N═C(R e )C(═O)— or R f NHC(R g )═CHC(═O)— wherein R a is ( 1-6C)alkyl, R b  is hydrogen or (1-6C)alkyl or R a  and R b  together form a (3-4C)alkylene chain, R c  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)alkloxy, di-(1-4C)alkylamino(2-6C)alkoxy, R d  is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, R e  is hydrogen or (1-6C)alkyl, R f is ( 1-6C)alkyl, phenyl or a 5- or 6-membered heteroaryl and R g  is hydrogen or (1-6C)alkyl;  
 or R 7  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;  
 >X—Y— is of the formula >C═CH— or >CHCH 2 —;  
 and pharmaceutically-acceptable salts thereof.  
 
     
     
         4 . A compound of the formula (I) as claimed in  claims 1  to  3  wherein R 1  is acetamido; >X—Y— is of the formula >C═CH—; both R 2  and R 3  are hydrogen; >A-B- is of the formula >C═CH—; R 4  and R 5  are hydrogen; D is O, S or of the formula —NR 7 ; R 7  is hydrogen or of the formula R 10 CO—; R 10  is hydroxy(1-4C)alkyl, (1-4C)alkanoyloxy(1-4C)alkyl or (1-5C)alkoxy; and pharmaceutically-acceptable salts thereof.  
     
     
         5 . A compound of the formula (I) as claimed in  claims 1  to  3  wherein R 1  is acetamido; >X—Y— is of the formula >C═CH—; one of R 2  and R 3  is hydrogen and the other is fluoro; >A-B- is of the formula >C═CH—; R 4  and R 5  are hydrogen; D is O, S or of the formula —NR 7 ; R 7  is hydrogen or of the formula R 10 CO—; R 10  is hydroxy(1-4C)alkyl, (1-4C)alkanoyloxy(1-4C)alkyl or (1-5C)alkoxy; and pharmaceutically-acceptable salts thereof.  
     
     
         6 . A compound of the formula (I), or a pharmaceutically-acceptable salt thereof, as claimed in  claims 1  to  4  selected from: 
 5R-acetamidomethyl-3-(4-[1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl]phenyl)-furan-2(5H)-one and  
 5R-acetamidomethyl-3-(4-[2,3-dihydropyran-4-yl]phenyl)furan-2(5H)-one.  
 
     
     
         7 . A process for the preparation of a compound of the formula (I) as claimed in  claims 1  to  6  which comprises: 
 (a) the deprotection of a compound of formula (II):  
                     
 (b) the modification of a substituent in or the introduction of a substituent into another compound of the formula (I) or (II);  
 (c) when R 20  is of the formula —NHS(O) n (1-4C)alkyl, wherein n is 1 or 2, the oxidation of a compound of the formula (I) or (II) wherein n is 0 or, when n is 2 the oxidation of a compound of the formula (I) or (II) wherein n is 1;  
 (d) when R 20  is of the formula —NHC(═O)(1-4C)alkyl or —NHS(O) n (1-4C)alkyl, and >A 1 -B 1 — is >C═C—, >CHCH 2 —, or protected >C(OH)CH 2 — the reaction of a compound of the formula (III) with a compound of formula (IV):  
                     
 (e) when R 20  is hydroxy and >X—Y— is >CHCH 2 —:  
 the reaction of a compound of the formula (V) wherein >A 1 -B 1 - is >C═CH—, >CHCH 2 — or protected >C(OH)CH 2 with a compound of formula (VI):  
                     
 or the reaction of a compound of the formula (V) with a compound of the formula (VII):  
                     
 (f) when >A 1 -B 1 - is >C═CH—, the reaction of a compound of the formula (VIII) with a compound of the formula (IX):  
                     
 (g) when >A 1 -B 1 - is >CHCH 2 — and >X—Y— is >CHCH 2 —, the catalytic hydrogenation of a compound of the formula (I) or (II) wherein >A 1 -B 1 — is >C═CH— and >X-Y is >CHCH 2 —;  
 (h) when >A 1 -B 1 - is >C═CH— and >X—Y— is >CHCH 2 —, the elimination of the elements of water, or HOCOR 23 ′, or HOSO 2 R 24  from a compound of the formula (X):  
                     
 (i) when >A 1 -B 1 - is >C═CH— and >X—Y— is >CH═CH—, the elimination of the elements of water, HOCOR 23  or HOSO 2 R 24  from a compound of the formula (X) wherein >X—Y— is >C(OR 25 )—CH 2 —;  
 (j) when >A 1 -B 1 — is >C═CH— and >X—Y— is >C═CH— the elimination of PhSOH from a compound of the formula (XI);  
                     
 (k) when D is NR 7  and R 7  is R 10 CO—, R 10 S(O) n — or R 10 CS—, the reaction of a compound of the formula (XII) wherein >A 1 -B 1 — is >C═CH—, >CHCH 2  or protected >C(OH)CH 2 —, with a compound of the formula (XIII), (XIV) or (XV) respectively wherein n is 2:  
                     
 (l) when R 20  is of the formula —N(CO 2 R 26 )CO(1-4C)alkyl; from a compound of the formula (I) and (II) wherein R 1  or R 20  is hydroxy;  
 wherein R 2 —R 5  and >X—Y— are as hereinabove defined; >A 1 -B 1 - is >A-B- or protected >C(OH)CH 2 — and D 1  is D in which functional groups are optionally protected; R 19  is —C(═O)(1-4C)alkyl or —S(O) n (1-4C)alkyl; R 20  is R 1  or protected R 1 ; R 21  is hydrogen or (1-6C)alkyl; R 22  is a protecting group; R 23  is (1-4C)alkyl; R 24  is an optionally substituted phenyl group; R 25  is hydrogen, (1-5C)alkanoyl or arylsulfonyl; R 26  is (1-4C)alkyl or benzyl; n is 0, 1 or 2 unless otherwise stated; L 1 , L 2  and L 4a  are leaving groups, L 4b  is a leaving group (for example (1-4C)alkoxy), L 3  is an iodo or triflate leaving group, L 4  is hydroxy or a leaving group and Z is a trialkyltin residue, a boronate acid or ester residue or a zinc monohalide and thereafter if necessary any protecting groups are removed and a pharmaceutically-acceptable salt formed; and when an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material, or by resolution of a racemic form of the compound or intermediate using a standard procedure; and when a pure regioisomer of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.  
 
     
     
         8 . A pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in  claims 1  to  6  and a pharmaceutically-acceptable diluent or carrier.  
     
     
         9 . The use of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in  claims 1  to  6  in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.