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1. (WO2017093157) PIPERIDINE, PYRROLIDINE AND 2-OXO-1,3-OXAZINANE DERIVATIVES AS INHIBITORS OF BACTERIAL EFFLUX-PUMPS FOR THE TREATMENT OF MICROBIAL INFECTIONS
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Claims

1. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof


wherein

ASC is


Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom, wherein a -CH2-CH2- moiety adjacent to the nitrogen atom is optionally replaced by a -C(=0)-0- moiety to form a carbamate;

X represents a bond or -CH2-;

AR1 and AR2 represent phenyl;

Rl, R2 and R3 represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, CrC6alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl la, CHO,

C(0)N(R12)R13 or 0-R14;

R5, R6 and R7 represent independently hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge;

R9a and R9b represent independently hydrogen or methyl;

RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or CpCehaloalkoxy; RlOb represents C3-C8cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q; Rl la and Rl lb represent independently at each occurrence hydrogen or CpCealkyl;

R12 and R13 represent independently at each occurrence hydrogen, Ci-C4alkyl, Ci-C ihaloalkyl or d-C4alkoxy-C i -C4alkyl;

R14 represents Ci-Cealkyl, Ci-Cehaloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P, Cp C6alkylene-Cycle-Q;

Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R15, or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O;

Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;

R15 and R16 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy;

LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -CH2-S-, -(CH2)2-S-, -S-CH2-, -C(CH3)2-, -(CH2)2-or -CH=CH-CH2-;

L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-;

wherein

when LI represents -CH2-0-, L2 represents Ci-C7alkylene- as defined above,

Ring A is a 6-membered ring, then

at least one of Rl, R2 and R3 represents independently Br, C2-Cealkyl, Ci-Cehaloalkyl, C2 Cealkoxy or d-Cehaloalkoxy; or

R4 represents CI, F, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, CpCealkylene-RlOb, C2-C6alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14 and R14 represents C2-C6alkyl, Cr Cehaloalkyl, C2-Cealkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P or CpCealkylene- Cycle-Q;

and wherein the compound of formula I is not

3-Pyrrolidinemethanamine, l-[[2-methoxy-4-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinemethanamine, l-[[2-[(2-chloro-6-fluorophenyl)methoxy]phenyl]methyl]-;

3-Azetidinamine, 1 -[[4-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinamine, 1 -[[2-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinamine, l-[[5-bromo-2-[(4-chlorophenyl)methoxy]phenyl]methyl]-N-methyl-;

3-Pyrrolidinamine, l-[[5-bromo-2-[(4-chlorophenyl)methoxy]phenyl]methyl]-;

2- Pyrrolidinemethanamine, l-[[3-(phenylmethoxy)phenyl]methyl]-;

3- Pyrrolidinamine, l-[[2-[[(5-bromo-2-methoxyphenyl)methyl]thio]-3-chlorophenyl]methyl]-; 3-Pyrrolidinamine, l-[[2-[[(5-bromo-2-methoxyphenyl)methyl]thio]phenyl]methyl]-;

4-Piperidinamine, 1 -[[2-(2-phenylethoxy)phenyl]methyl]-;

4-Piperidinamine, 1 -[[3-(2-phenylethoxy)phenyl]methyl]-;

4-Piperidinamine, 1 -[[4-(2-phenylethoxy)phenyl]methyl]-.

2. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein when LI represents -CH2-0-, L2 is Ci-C7alkylene- as defined above and Ring A is a 6-membered ring, then

at least one of Rl , R2 and R3 represents Br or C2-Cealkyl; or

R4 is 0-C2-C4alkenyl; and

preferably at least R4 and L2 are at the meta positions on AR2 with respect to the position of LI .

3. The compound according to claim 1 or 2 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound of formula I is not


3-Azetidinamine, 1 -[[3-(phenylmethoxy)phenyl]methyl]-;

2- Pyrrolidinemethanamine, N-methyl-l-[[3-(phenylmethoxy)phenyl]methyl]-;

3- Pyrrolidinemethanamine, l-[[3-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinamine, l-[[4-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinamine, 1 -[2-[3-(phenylmethoxy)phenyl]ethyl]-;

3-Pyrrolidinamine, 1 -[[3-(phenylmethoxy)phenyl]methyl]-;

3 -Pyrrolidinemethanamine, 1 - [2- [3 -(phenylmethoxy)phenyl] ethyl] -;

3-Pyrrolidinemethanamine, N-methyl-l-[[3-(phenylmethoxy)phenyl]methyl]-; 3-Pyrrolidinemethanamine, N-methyl-l-[[2-(phenylmethoxy)phenyl]methyl]-;

2- Pyrrolidinemethanamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]-;

3- Pyrrolidinamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]-;

3 -Pyrrolidinamine, N-methyl- 1 - [ [3 -(phenylmethoxy)phenyl] methyl] - ; 2- Pyrrolidinemethanamine, l-[[4-(phenylmethoxy)phenyl]methyl]-;

3- Pyrrolidinamine, 1 -[2-[4-(phenylmethoxy)phenyl]ethyl]-;

3 -Pyrrolidinamine, N-methyl- 1 - [2- [4-(phenylmethoxy)phenyl] ethyl] -;

3-Pyrrolidinemethanamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]-;

3-Pyrrolidinemethanamine, 1 -[2-[4-(phenylmethoxy)phenyl]ethyl]-;

3-Pyrrolidinemethanamine, l-[[4-(phenylmethoxy)phenyl]methyl]-;

3 -Pyrrolidinamine, N-methyl- 1 - [ [2 -(phenylmethoxy)phenyl] methyl] - ;

3 -Pyrrolidinamine, N-methyl- 1 - [2- [3 -(phenylmethoxy)phenyl] ethyl] -;

3-Pyrrolidinemethanamine, l-[[2-(phenylmethoxy)phenyl]methyl]-.

4. The compound according to any one of claims 1 to 3 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein when LI represents -CH2-0- then at least one of Rl, R2, R3 and R4 is not hydrogen.

5. The compound according to any one of claims 1 to 4 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of Rl, R2, R3 and R4 is not hydrogen.

6. The compound according to any one of claims 1 to 5 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Rl represents halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp

Cehaloalkoxy.

7. The compound according to any one of claims 1 to 6 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

R4 represents hydrogen, halogen, CrC4alkyl, C2-C6alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or O-R14;

R5, R6 and R7 represent hydrogen;

R12 represents independently at each occurrence hydrogen, Ci-C2alkyl or Ci-C4alkoxy-Ci-C4alkyl;

R13 represents independently at each occurrence hydrogen or methyl; and

R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q representing a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.

8. The compound according to any one claims 1 to 7 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one.

9. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 is at the meta position on AR2 with respect to the position of LI and L2 is at the meta position on AR2 with respect to R4.

10. The compound according to any one of claims 1 to 9 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, and wherein preferably L2 represents -CH2- or -CH2-CH2-.

11. The compound according to any one of claims 1 to 10 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2-.

12. The compound according to any one of claims 1 to 11 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one; and

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, and wherein preferably L2 represents -CH2- or -CH2-CH2-.

13. The compound according to any one of claims 1 to 12, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula 1-20 to 1-24.



(1-22)


14. The compound according to any one of claims 1 to 7 and 13 or pharmaceutically acceptable salt, 5 solvate or hydrate thereof, wherein

Ring A represents a ring selected from pyrrolidine, piperidine or l,3-oxazinan-2-one;

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-;

X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring or at the 5-position on the l,3-oxazinan-2-one ring; and

10 R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

15. The compound according to any one of claims 1 to 14 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

ASC is ASC-a, ASC-b or ASC-c


and wherein preferably R9a and R9b represent hydrogen.

20 16. The compound according to any one of claims 1 to to 15 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

R4 represents 0-R14, wherein R14 represents CpCealkyl, C2-C6alkenyl, C2-C6alkylene-Cycle-Q, and wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

25 17. The compound according to any one of claims 1 and 13 to 16 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one;

Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl;

R3 is hydrogen;

R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenyl, Ci-C4alkylene-R10b, C2-C4alkenylene-R10b, C(0)ORl 1 a, CHO, C(0)N(R12)R13 or O-Rl 4;

R5, R6 and R7 represent hydrogen;

R9a and R9b represent hydrogen;

RlOb represents C(0)ORl l a;

Rl la represents hydrogen or Ci-C4alkyl;

R12 represents Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl;

R13 represents hydrogen;

R14 represents Ci-Cealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q;

Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl;

LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2; and

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-.

18. The compound according to any one of claims 1 to 17 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

R8 represents methyl.

19. The compound according to any one of claims 1 to 18 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein X represents -CH2-.

20. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent, and wherein the compound of formula I is


wherein

ASC is


Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom, wherein a -CH2-CH2- moiety adjacent to the nitrogen atom is optionally replaced by a -C(=0)-0- moiety to form a carbamate;

X represents a bond or -CH2-;

AR1 and AR2 represent phenyl;

Rl, R2 and R3 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, CrC6alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl la, CHO,

C(0)N(R12)R13 or 0-R14;

R5, R6 and R7 represent independently hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge;

R9a and R9b represent independently hydrogen or methyl;

RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or CpCehaloalkoxy; RlOb represents C3-C8cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q; Rl la and Rl lb represent independently at each occurrence hydrogen or CpCealkyl;

R12 and R13 represent independently at each occurrence hydrogen, Ci-C4alkyl, Ci-C4haloalkyl or d-C4alkoxy-C i -C4alkyl;

R14 represents CpCealkyl, CpCehaloalkyl, C2-Cealkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P, Cp C6alkylene-Cycle-Q;

Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 Rl 5 or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O;

Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;

R15 and R16 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy;

LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -CH2-S-, -(CH2)2-S-, -S-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-;

L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein 5 the terminal moiety of L2 is not -C(=0)- ;

and wherein preferably the compound of formula I is as defined in any one of claims 1 to 19.

21. The compound for use in a method according to claim 20 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

10 Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one; and

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, and wherein preferably L2 represents -CH2- or -CH2-CH2-.

22. The compound for use in a method according to claim 20 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

15 Ring A represents a ring selected from pyrrolidine, piperidine or l,3-oxazinan-2-one;

L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-;

X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring or at the 5-position on the l,3-oxazinan-2-one ring; and

R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

20

23. A pharmaceutical product comprising (i) a compound of formula I as defined in any one of claims 1 to 22 or pharmaceutically acceptable salt, solvate or hydrate thereof and an (ii) an antimicrobial agent.

24. A method of treating a subject with a microbial infection or susceptible to a microbial infection, said 25 method comprising administering the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof as defined in any one of claims 1 to 22, to said subject, and wherein said subject is receiving the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof in combination with an antimicrobial agent.

30 25. A compound for use in a method according to any one of claims 20 to 22 or pharmaceutically

acceptable salt, solvate or hydrate thereof, or a pharmaceutical product according to claim 23 or method according to claim 24, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the antimicrobial agent is a tetracycline antibiotic.

26. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof for use in a method as according to any one of claims 20 to 22, or a pharmaceutical product according to claim 23, or a method according to claim 24, wherein the antimicrobial agent is an oxazolidinone antibiotic, e.g. linezolid.