Cystobactamides

Abstract

The present invention provides cystobactamides of formula (I) and the use thereof for the treatment or prophylaxis of bacterial infections:

1 . A compound of formula (V) 
       
         
           
           
               
               
           
         
         wherein 
         R 51  is a hydrogen atom, or a C 1-6  alkyl group; 
         R 52  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 53  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 54  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 55  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         D is N or CR 56 ; 
         E is N or CR 57 ; 
         G is N or CR 58 ; 
         M is N or CR 59 ; 
         R 56  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 57  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 58  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 59  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; and 
         Ar 6  is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         or a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof. 
       
     
     
         2 . A compound according to  claim 1  of formula (VI) 
       
         
           
           
               
               
           
         
         wherein 
         R 51  is a hydrogen atom, or a C 1-6  alkyl group; 
         R 53  is F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         D is N or CR 56 ; 
         R 56  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 57  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 58  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 59  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; and 
         Ar 6  is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         or a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof. 
       
     
     
         3 . A compound according to  claim 1  of formula (VII) 
       
         
           
           
               
               
           
         
         wherein 
         R 51  is a hydrogen atom, or a C 1-6  alkyl group; 
         R 53  is F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         D is N or CR 56 ; 
         R 56  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 57  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 58  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 59  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 60  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; 
         R 61  is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6  alkyl group or a group of formula —O—C 1-6  alkyl; and 
         R 8  is a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, an alkylcycloalkyl, a heteroalkylcycloalkyl, an aryl, a heteroaryl, an aralkyl or a heteroaralkyl group; 
         or a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof. 
       
     
     
         4 . A compound according to  claim 1  of formula (IV) 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is a group of formula —O—C 1-6  alkyl; 
         R 6  is a hydroxy group; 
         R 7  is a group of formula —O—C 1-6  alkyl; and 
         R 8  is a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, an alkylcycloalkyl, a heteroalkylcycloalkyl, an aryl, a heteroaryl, an aralkyl or a heteroaralkyl group; 
         or a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof. 
       
     
     
         5 . A compound according to  claim 3 , wherein R 8  is a hydrogen atom or a group of the following formula: 
       
         
           
           
               
               
           
         
         wherein R 9  is COOH or CONH 2  and R 10  is COOH or CONH 2 . 
       
     
     
         6 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Ar 1  is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         Ar 2  is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         Ar 3  is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         Ar 4  is absent or an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         Ar 5  is absent or an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen; 
         L 1  is a bond, an oxygen atom, a sulphur atom or a group of formula NH, CONH, NHCO, COO, OCO, CONR 3 , NR 3 CO, OCONH, NHCOO, NHCONH, OCONR 3 , NR 3 COO, NR 3 CONR 4 , NR 3 , —CNR 3 —, —CO—, —SO—, —SO 2 —, —SO 2 NH—, —NHSO 2 —, —SO 2 NR 3 —, —NR 3 SO 2 —, —COCH 2 —, —CH 2 CO—, —COCR 3 R 4 —, —CR 3 R 4 CO—, —NHCSNH—, —NR 3 CSNR 4 , —CH═CH—, —CR 3 ═CR 4 —, or a heteroarylene group having 5 or 6 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, or a heteroalkylene group; 
         L 2  is a bond, an oxygen atom, a sulphur atom or a group of formula NH, CONH, NHCO, COO, OCO, CONR 3 , NR 3 CO, OCONH, NHCOO, NHCONH, OCONR 3 , NR 3 COO, NR 3 CONR 4 , NR 3 , —CNR 3 —, —CO—, —SO—, —SO 2 —, —SO 2 NH—, —NHSO 2 —, —SO 2 NR 3 —, —NR 3 SO 2 —, —COCH 2 —, —CH 2 CO—, —COCR 3 R 4 —, —CR 3 R 4 CO—, —NHCSNH—, —NR 3 CSNR 4 , —CH═CH—, —CR 3 ═CR 4 —, or a heteroarylene group having 5 or 6 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, or a heteroalkylene group; 
         L 3  is absent or a bond, an oxygen atom, a sulphur atom or a group of formula NH, CONH, NHCO, COO, OCO, CONR 3 , NR 3 CO, OCONH, NHCOO, NHCONH, OCONR 3 , NR 3 COO, NR 3 CONR 4 , NR 3 , —CNR 3 —, —CO—, —SO—, —SO 2 —, —SO 2 NH—, —NHSO 2 —, —SO 2 NR 3 —, —NR 3 SO 2 —, —COCH 2 —, —CH 2 CO—, —COCR 3 R 4 —, —CR 3 R 4 CO—, —NHCSNH—, —NR 3 CSNR 4 , —CH═CH—, —CR 3 ═CR 4 —, or a heteroarylene group having 5 or 6 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, or a heteroalkylene group; 
         L 4  is absent or a bond, an oxygen atom, a sulphur atom or a group of formula NH, CONH, NHCO, COO, OCO, CONR 3 , NR 3 CO, OCONH, NHCOO, NHCONH, OCONR 3 , NR 3 COO, NR 3 CONR 4 , NR 3 , —CNR 3 —, —CO—, —SO—, —SO 2 —, —SO 2 NH—, —NHSO 2 —, —SO 2 NR 3 —, —NR 3 SO 2 —, —COCH 2 —, —CH 2 CO—, —COCR 3 R 4 —, —CR 3 R 4 CO—, —NHCSNH—, —NR 3 CSNR 4 , —CH═CH—, —CR 3 ═CR 4 —, or a heteroarylene group having 5 or 6 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, or a heteroalkylene group; 
         R 1  is a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a thiol group, a nitro group, a group of formula —COOH, —SO 2 NH 2 , —CONH 2 , —NO 2  or —CN, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, an alkylcycloalkyl, a heteroalkylcycloalkyl, an aryl, a heteroaryl, an aralkyl or a heteroaralkyl group; 
         R 2  is a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a thiol group, a nitro group, a group of formula —COOH, —SO 2 NH 2 , —CONH 2 , —NO 2  or —CN, an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a cycloalkyl, a heterocycloalkyl, an alkylcycloalkyl, a heteroalkylcycloalkyl, an aryl, a heteroaryl, an aralkyl or a heteroaralkyl group; 
         the groups R 3  are independently from each other a hydrogen atom or a C 1-6  alkyl group; and 
         the groups R 4  are independently from each other a hydrogen atom or a C 1-6  alkyl group; 
         or a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof. 
       
     
     
         8 . A compound according to  claim 7  of formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         Ar 1 , Ar 2 , Ar 3 , L 1 , L 2 , R 1  and R 2  are as defined in  claim 7 . 
       
     
     
         9 . A compound according to  claim 7 , wherein
 Ar 1  is an optionally substituted 1,4-phenylene group or an optionally substituted 1,3-heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen;   Ar 2  is an optionally substituted 1,4-phenylene group or an optionally substituted 1,3-heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen;   Ar 3  is an optionally substituted 1,4-phenylene group or an optionally substituted 1,3-heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen;   Ar 4  is absent or an optionally substituted 1,4-phenylene group or an optionally substituted 1,3-heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen; and   Ar 5  is absent or an optionally substituted 1,4-phenylene group or an optionally substituted 1,3-heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen.   
     
     
         10 . A compound according to  claim 7 , wherein
 L 1  is a group of formula —CONH—, —NHCO—, —SO 2 NH—, —NHSO 2 —, —CH═CH—, —CR 3 ═CR 4 — or an optionally substituted heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein R 3  and R 4  are independently from each other a C 1-6  alkyl group;   L 2  is a group of formula —CONH—, —NHCO—, —SO 2 NH—, —NHSO 2 —, —CH═CH—, —CR 3 ═CR 4 — or an optionally substituted heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein R 3  and R 4  are independently from each other a C 1-6  alkyl group;   L 3  is absent or a group of formula —CONH—, —NHCO—, —SO 2 NH—, —NHSO 2 —, —CH═CH—, —CR 3 ═CR 4 — or an optionally substituted heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein R 3  and R 4  are independently from each other a C 1-6  alkyl group; and   L 4  is absent or a group of formula —CONH—, —NHCO—, —SO 2 NH—, —NHSO 2 —, —CH═CH—, —CR 3 ═CR 4 — or an optionally substituted heteroarylene group having 5 ring atoms including 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein R 3  and R 4  are independently from each other a C 1-6  alkyl group.   
     
     
         11 . A compound according to  claim 7 , wherein R 1  is a hydrogen atom, a halogen atom or a group of formula —OH, —NH 2 , —COOH, —SO 2 NH 2 , —CONH 2 , —NO 2 , —CN, -alkyl (e.g. —CF 3 ), —O-alkyl, —O—CO-alkyl, —NH-alkyl, —NH—CO-alkyl, or an optionally substituted heteroaryl group having 5 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen, or an optionally substituted heterocycloalkyl group having 5 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen. 
     
     
         12 . A compound according to  claim 7 , wherein R 2  is a hydrogen atom, a halogen atom or a group of formula —OH, —NH 2 , —COOH, —SO 2 NH 2 , —CONH 2 , —NO 2 , —CN, -alkyl (e.g. —CF 3 ), —O-alkyl, —O—CO-alkyl, —NH-alkyl, —NH—CO-alkyl, or an optionally substituted heteroaryl group having 5 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen, or an optionally substituted heterocycloalkyl group having 5 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen. 
     
     
         13 . A compound according to  claim 7 , wherein L 1  is NHCO (wherein the nitrogen atom is bound to Ar 1 ) or a group of the following formula: 
       
         
           
           
               
               
           
         
         (wherein the NH group is bound to Ar 1 ), wherein R 30  is a hydrogen atom or a C 1-3  alkyl group; and/or 
         L 2  is NHCO (wherein the nitrogen atom is bound to Ar 2 ) or a group of the following formula: 
       
       
         
           
           
               
               
           
         
         (wherein the NH group is bound to Ar 2 ), wherein R 30  is a hydrogen atom or a C 1-3  alkyl group; and/or 
         wherein L 3  is absent or a group of the following formula: 
       
       
         
           
           
               
               
           
         
         (wherein the NH group is bound to Ar 3 ), wherein R 30  is a hydrogen atom or a C 1-3  alkyl group; and/or 
         wherein L 4  is absent or NHCO (wherein the nitrogen atom is bound to Ar 4 ). 
       
     
     
         14 . Pharmaceutical composition comprising a compound according to  claim 7 , and optionally one or more carrier substances and/or one or more adjuvants. 
     
     
         15 . Compound or pharmaceutical composition according to  claim 7 , for use in the treatment or prophylaxis of bacterial infections. 
     
     
         16 . A recombinant biosynthesis cluster capable of synthesizing a cystobactamide selected from the group consisting of cystobactamide A, B, C, D, E, F, G and H, wherein the cluster comprises all of the polypeptides, or a functional variant thereof, according to SEQ ID NOs. 40 to 73. 
     
     
         17 . An isolated, synthetic or recombinant nucleic acid comprising:
 (i) a sequence encoding a cystobactamide biosynthesis cluster, wherein the sequence has a sequence identity to the full-length sequence of SEQ ID NO. 1 from at least 85%, 90%, 95%, 96%, 97%, 98%, 98.5%, 99%, or 99.5% to 100%;   (ii) a sequence encoding a NRPS, wherein the sequence has a sequence identity to the full-length sequence of any of SEQ ID NOs. 8, 9, 12 or 13 from at least 85%, 90%, 95%, 96%, 97%, 98%, 98.5%, 99%, or 99.5% to 100%;   (iii) a sequence completely complementary to the full length sequence of any nucleic acid sequence of (i) or (ii); or   (iv) a sequence encoding a polypeptide according to any of SEQ ID NOs. 46, 47, 50 or 51.   
     
     
         18 . A vector comprising at least one nucleic acid according to  claim 17 . 
     
     
         19 . A recombinant host cell comprising at least one nucleic acid according to  claim 17 . 
     
     
         20 . A method for the preparation of a compound according to  claim 6 , the method comprising the steps of:
 (a) culturing  Cystobacter velatus  strain MCy8071 (DSM27004) or a recombinant host cell of  claim 19 ; and   (b) separating and retaining the compound from the culture broth.   
     
     
         21 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject an effective amount of a compound of  claim 7 . 
     
     
         22 . The method of  claim 21  wherein the subject is identified as suffering from a bacterial infection and the compound is administered to the identified subject. 
     
     
         23 . The method of  claim 21  wherein the subject is a human. 
     
     
         24 . A method for treating a subject suffering from or susceptible to a bacterial infection, comprising administering to the subject an effective amount of a compound of  claim 1 .