CNP prodrugs with carrier attachment at the ring moiety

1. A C-type natriuretic peptide (CNP) prodrug or a pharmaceutically acceptable salt thereof comprising

a CNP moiety —D comprising a ring moiety, wherein the ring moiety has the amino acid sequence of SEQ ID NO:96, provided the methionine at position 11 of SEQ ID NO:96 can be substituted with asparagine, the ring moiety being between two cysteine residues forming a disulfide bridge; and

a non-toxic carrier moiety —Z that is conjugated through a moiety —L 2 — to a reversible prodrug linker moiety —L 1 —, which reversible prodrug linker moiety —L 1 — is covalently and reversibly conjugated to a side chain of an amino acid residue of said ring moiety of —D or to the backbone of said ring moiety of —D; and wherein —L 2 — is a chemical bond or a spacer.

2. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 1 — is covalently and reversibly conjugated to the side chain of an amino acid residue of the ring moiety of —D.

3. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 1 — is conjugated to the ring moiety of —D through a functional group of a corresponding CNP drug D-H selected from the group consisting of carboxylic acid, primary amine, hydroxyl, disulfide and guanidine.

4. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 1 — is connected to the ring moiety of —D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine.

5. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the amino acid residue of the ring moiety of —D to which —L 1 — is conjugated is selected from the group consisting of lysine, serine, aspartic acid and arginine.

6. The CNP prodrug or pharmaceutically acceptable salt thereof of claim 1 , wherein the amino acid residue of the ring moiety of —D to which —L 1 — is conjugated is lysine.

7. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —D has the sequence of SEQ ID NO:24.

8. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —D has the sequence of SEQ ID NO:24 and —L 1 — is conjugated to the lysine at position 26.

9. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 1 — is of formula (II):

wherein the dashed line indicates attachment to a nitrogen of an amino acid side chain of the ring moiety of the CNP moiety by forming an amide bond;

—X— is —C(R 4 R 4a )—; —N(R 4 )—; —O—; —C(R 4 R 4a )—C(R 5 R 5a )—; —C(R 5 R 5a )—C(R 4 R 4a )—; —C(R 4 R 4a )—N(R 6 )—; —N(R 6 )—C(R 4 R 4a )—; —C(R 4 R 4a )—O—; —O—C(R 4 R 4a )—; or —C(R 7 R 7a )—;

X 1 is C; or S(O);

—X 2 — is —C(R 8 R 8a )—; or —C(R 8 R 8a )—C(R 9 R 9a )—;

═X 3 is ═O; ═S; or ═N—CN;

—R 1 , —R 1a , —R 2 , —R 2a , —R 4 , —R 4a , —R 5 , —R 5a , —R 6 , —R 8 , —R 8a , —R 9 , —R 9a are independently selected from the group consisting of —H; and C 1-6 alkyl;

—R 3 , —R 3a are independently selected from the group consisting of —H; and C 1-6 alkyl, provided that in case one of —R 3 , —R 3a or both are other than —H they are connected to N to which they are attached through an sp 3 -hybridized carbon atom;

—R 7 is —N(R 10 R 10a ); or —NR 10 —(C═O)—R 11 ;

—R 7a , —R 10 , —R 10a , —R 11 are independently of each other —H; or C 1-6 alkyl;

optionally, one or more of the

pairs —R 1a /—R 4a , —R 1a /—R 5a , —R 1a /—R 7a , —R 4a /—R 5a , —R 8a /—R 9a form a chemical bond;

optionally, one or more of the

pairs —R 1 /—R 1a , —R 2 /—R 2a , —R 4 /—R 4a , —R 5 /—R 5a , —R 8 /—R 8a ,

—R 9 /—R 9a are joined together with the atom to which they are attached to form a C 3-10 cycloalkyl; or 3- to 10-membered heterocyclyl;

optionally, one or more of the

pairs —R 1 /—R 4 , —R 1 /—R 5 , —R 1 /—R 6 , —R 1 /—R 7a , —R 4 /—R 5 , —R 4 /—R 6 , —R 8 /—R 9 , —R 2 /—R 3 are joined together with the atoms to which they are attached to form a ring A;

optionally, R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;

A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and

wherein —L 1 — is substituted with —L 2 —Z and wherein —L 1 — is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by —L 2 —Z or a substituent.

10. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 2 — is selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 2 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y3 )—, —S(O) 2 N(R y3 )—, —S(O)N(R y3 )—, —S(O) 2 —, —S(O)—, —N(R y3 )S(O) 2 N(R y3a )—, —S—, —N(R y3 )—, —OC(OR y3 )(R y3a )—, —N(R y3 )C(O)N(R y3a )—, and —OC(O)N(R y3 )—;

—R y1 and —R y1a are independently of each other selected from the group consisting of —H, -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R y2 , which are the same or different, and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y4 )—, —S(O) 2 N(R y4 )—, —S(O)N(R y4 )—, —S(O) 2 —, —S(O)—, —N(R y4 )S(O) 2 N(R y4a )—, —S—, —N(R y4 )—, —OC(OR y4 )(R y4a )—, —N(R y4 )C(O)N(R y4a )—, and —OC(O)N(R y4a )—;

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more —R y2 , which are the same or different;

each —R y2 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR y5 , —OR y5 , —C(O)R y5 , —C(O)N(R y5 R y5a ), —S(O) 2 N(R y5 R y5a ), —S(O)N(R y5 R y5a ), —S(O) 2 R y5 , —S(O)R y5 , —N(R y5 )S(O) 2 N(R y5a R y5b ), —SR y5 , —N(R y5 R y5a ), —NO 2 , —OC(O)R y5 , —N(R y5 )C(O)R y5a , —N(R y5 )S(O) 2 R y5a , —N(R y5 )S(O)R y5a , —N(R y5 )C(O)OR y5a , —N(R y5 )C(O)N(R y5a R y5b ), —OC(O)N(R y5 R y5a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

each —R y3 , —R y3a , —R y4 , R y4a , —R y5 , —R y5a and —R y5b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

11. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z comprises a branched polymer.

12. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein the branched moiety —Z has a molecular weight of 10 kDa to 80 kDa.

13. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z comprises a moiety of formula (a)

wherein

the dashed line indicates attachment to —L 2 — or to the remainder of —Z;

BP a is a branching point selected from the group consisting of —N<, —CR< and >C<;

—R is selected from the group consisting of —H and C 1-6 alkyl;

a is 0 if BP a is —N< or —CR< and a is 1 if BP a is >C<;

—S a —, —S a′ —, —S a″ — and —S a′″ — are independently of each other a chemical bond or are selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 1 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 )S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—;

each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently optionally substituted with one or more —R 1 , which are the same or different;

each —R 1 is independently selected from the group consisting of halogen, —CN, oxo(═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

each —R 2 , —R 2a , —R 3 , —R 3a and —R 3b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

—P a′ , —P a″ and —P a′″ are independently a polymeric moiety.

14. A pharmaceutical composition comprising at least one CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 and at least one excipient.

15. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z comprises a fatty acid derivative.

16. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is a fatty acid derivative.

17. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —L 1 — is of formula (V):

wherein the dashed line indicates attachment to an amine functional group of a side chain of an amino acid residue of the ring moiety of the CNP moiety;

—R 1 is selected from the group consisting of optionally substituted C 1 —C 6 linear, branched, or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and —NR 5 2 ;

—R 2 is selected from the group consisting of —H; optionally substituted C 1 —C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

—R 3 is selected from the group consisting of —H; optionally substituted C 1 —C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;

—R 4 is selected from the group consisting of —H; optionally substituted C 1 —C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; and

each —R 5 is independently of each other selected from the group consisting of —H; optionally substituted C 1 —C 6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when taken together two —R 5 can be cycloalkyl or cycloheteroalkyl.