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1. WO2020109792 - ANTIBACTERIAL ANTISENSE AGENTS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,


wherein,

ANTISENSE is an oligonucleotide having natural, artificial and/or modified nucleobases, the oligonucleotide selected from the group consisting of phosphodiester oligonucleotides (PDOs), phosphorothioate oligonucleotides (PSOs), phosphorodiamidate morpholino oligonucleotides (PMOs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs), 2’-0-Alkyl oligonucleotides (2’-0-Me, 2’-0-Et. 2’-0-methoxyethyl) and combinations thereof; wherein the oligonucleotide is bonded to the remainder of the molecule of formula I via a terminal amino group present within the ANTISENSE sequence; and

1.2 is a spacer that forms a chemical bond to a terminal amino group present within the ANTISENSE sequence and a second chemical bond to the terminal carbonyl of the remainder of the molecule of formula I and is chosen from the group consisting of:


SUGAR is any tautomeric form of the acyl fragment of an /V-acylmuramic acid or 1 ,6-anhydro- /V-acylmuramic acid having the structure:


Ri and R6 are each independently selected from the group consisting of:

H, C1-6 alkyl, Ci-e substituted alkyl, C3-8 cycloalkyl, C3-8 substituted cycloalkyl, phenyl and benzyl;

R2 and R3 are each independently selected from the group consisting of:

H, C1-6 alkyl, C1-6 substituted alkyl, C3-8 cycloalkyl, C3-8 substituted cycloalkyl, phenyl and benzyl, or both together with the carbon atom to which they are attached form a ring containing 3, 4, 5 or 6 carbon atoms; and

R4 and R5 are each independently selected from the group consisting of:

H, C1-6 alkyl, C1-6 substituted alkyl, C3-8 cycloalkyl, C3-8 substituted cycloalkyl, phenyl and benzyl, or both together with the carbon atom to which they are attached form a ring containing 3, 4, 5 or 6 carbon atoms;

or

R2 and R4 together with the adjacent carbon atoms to which they are attached form a ring containing 3, 4, 5 or 6 carbon atoms; and R3 and Rs are each independently selected from the group consisting of: H, C1-6 alkyl, C1-6 substituted alkyl, C3-8 cycloalkyl, C3-8 substituted cycloalkyl, phenyl and benzyl, or both together with the carbon atom to which they are attached form a ring containing 3, 4, 5 or 6 carbon atoms;

R7, Re and Rg are each independently selected from the group consisting of:

H, acetyl, benzoyl; and

R10 is selected from the group consisting of:

methyl, ethyl, propyl; and

m is 0 or 1 or 2; and

n is 0 or 1 or 2 or 3 or 4, wherein when n is 2, 3 or 4, each

residue is independently selected; and

p is 0 or 1 ; and

q is 0 or 1 .

2. The compound according to claim 1 wherein the ANTISENSE is a phosphorodiamidate morpholino oligonucleotide (PMO) or a peptide nucleic acid (PNA).

3. The compound according to any preceding claim wherein p is 1 .

4. The compound according to any preceding claim wherein Ri is selected from the group consisting of: H, Ci-e alkyl and Ci-e substituted alkyl.

5. The compound according to claim 3 wherein Ri is H.

6. The compound according to claim 3 wherein Ri is Me.

7. The compound according to claim 1 or claim 2 wherein p is 0.

8. The compound according to any preceding claim wherein n is 1 .

9. The compound according to any preceding claim wherein one of R2 and R3 is H and the other is C1-6 alkyl.

10. The compound according to any preceding claim wherein m is 0 and R4 and Rs are absent.

1 1 . The compound according to any of claims 1 to 7 wherein n is 2 and wherein one


, wherein R2a, R3a, R4a,

R5a, R6a and m’ have the same respective definition as the moieties R2, R3, R4, Rs, R6 and m as described in claim 1 .

12. The compound of claim 1 1 wherein one of R2 and R3 is H and the other is C1-6 alkyl and Råa and R3a are each H.

13. The compound of claim 1 1 or claim 12 wherein m is 0.

14. The compound of any of claims 1 1 to 13 wherein m’ is 2.

15. The compound of any of claims 1 1 to 14 wherein R4a and Rsa are H.

16. The compound of any of 1 1 to 15 wherein R6a is H.

17. The compound of any preceding claim wherein R6 is H.

18. The compound of any preceding claim wherein q is 1 .

19. The compound of any preceding claim wherein l_2 has the structure:

f any of claims 1 to 18 wherein l_2 has the structure:


21 . The compound of any of claims 1 to 17 wherein q is 0.

22. The compound according to claim 1 or claim 2 wherein n is 1 , m is 0, R6 is H, R2 is H, R3 is

Me, p is 1 , Ri is H or Me, q is 1 , and l_2 has the structure:

23. The compound according to claim 1 or claim 2 wherein n is 1 , m is 0, R6 is H, R2 is H, R3 is

Me, p is 1 , Ri is H or Me, q is 1 , and L2 has the structure:

24. The compound according to claim 1 or claim 2 wherein n is 1 , m is 0, F¾ is H, F¾ is H, R3 is

Me, p is 1 , Ri is H or Me, q is 1 , and L2 has the structure:

25. The compound according to claim 1 or claim 2 wherein p is 0, n is 2 and q is 0, wherein one


, wherein R2a, R3a, R4a, R5a, R6a and m’ have the same respective definition as the moieties R2, R3, R4, Rs, R6 and m as described in claim 1 .

26. The compound according to claim 25, wherein R2 and R3 are each independently selected from the group consisting of: H and C1-6 alkyl, R2a and R3a are each H, R4, Rs, R4a and Rsa are each H, m is 0, m’ is 2, R6 is H and R6a is H.

27. The compound according to any preceding claim wherein the SUGAR is


28. The compound according to any preceding claim wherein the ANTISENSE includes a

sequence that is selected from the group consisting of:





29. A compound according to any of the preceding claims for use as a medicament.

30. A pharmaceutical or veterinary composition comprising a compound according to any of claims 1 to 28 and a pharmaceutically acceptable or veterinarily acceptable diluent, excipient and/or carrier.

31 . A compound according to any of claims 1 to 28 for use in the treatment of bacterial infections. 32. A compound according to any of claims 1 to 28 for use in the treatment of multi-drug resistant

(MDR) infections.

33. A compound according to any of claims 1 to 28 for use in the treatment of gram-negative bacterial infections.

34. A compound according to any of claims 1 to 28 for use as a therapeutic in combination with an effective amount any other antibiotic.