The present invention relates to prodrugs of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising such CNP prodrugs and their uses. In an embodiment, the CNP prodrugs are conjugates of CNP peptides to poly(ethylene glycol) through a reversible linker.
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1. A CNP prodrug or a pharmaceutically acceptable salt thereof, wherein the prodrug is of formula (Ia) or (Ib) ZL2-L1-D)x (Ia)D(L1-L2-Z)y (Ib),wherein-D is a CNP moiety;-L1- is a reversible prodrug linker moiety;-L2- is a single chemical bond or a spacer moiety;—Z is a water-soluble carrier moie
1. A CNP prodrug or a pharmaceutically acceptable salt thereof, wherein the prodrug is of formula (Ia) or (Ib) ZL2-L1-D)x (Ia)D(L1-L2-Z)y (Ib),wherein-D is a CNP moiety;-L1- is a reversible prodrug linker moiety;-L2- is a single chemical bond or a spacer moiety;—Z is a water-soluble carrier moiety;x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; andy is an integer selected from the group consisting of 1, 2, 3, 4 and 5. 2. (canceled) 3. (canceled) 4. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein the CNP prodrug is of formula (Ia). 5. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein x is 1. 6. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein CNP moiety has the sequence of SEQ ID NO:25 or SEQ ID NO:24. 7. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein the CNP moiety has the sequence of SEQ ID NO:24. 8. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein -L1- is conjugated to the side chain of an amino acid residue of the ring moiety of -D or to the backbone of the ring moiety of -D. 9. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein -L1- is conjugated to the side chain of an amino acid residue of the ring moiety of -D selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. 10. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein -D has the sequence of SEQ ID NO:24 and -L1- is conjugated to the lysine at position 26 of -D. 11. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein the moiety -L1- is of formula (II): wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond;—X— is —C(R4R4a)—; —N(R4)—; —O—; —C(R4R4a)—C(R5R5a)—; —C(R5R5a)—C(R4R4a)—;—C(R4R4a)—N(R6)—; —N(R6)—C(R4R4a)—; —C(R4R4a)—O—; —O—C(R4R4a)—; or —C(R7R7a)—;X1 is C; or S(O);—X2- is —C(R8R8a)—; or —C(R8R8a)—C(R9R9a)—;═X3 is ═O; ═S; or ═N—CN;—R1, —R1a, —R2, —R2a, —R4, —R4a, —R5, —R5a, —R6, —R8, —Ra, —R9, —R9a are independently selected from the group consisting of —H; and C1-6 alkyl;—R3, —R3a are independently selected from the group consisting of —H; and C1-6 alkyl, provided that in case one of —R3, —R3a or both are other than -H they are connected to N to which they are attached through an SP3-hybridized carbon atom;—R7 is —N(R10R10a); or —NR10—(C═O)—R11;—R7a, —R10, —R10a, —R11 are independently of each other —H; or C1-6 alkyl;optionally, one or more of the pairs —R1a/—R4a, —R1a/—R5a, —R1a/—R7a, —R4a/—R5a, —R8a/—R9a form a chemical bond;optionally, one or more of the pairs —R1/—R1a, —R2/—R2a, —R4/—R4a, —R5/—R5a, —RS/—Ra, —R9/—R9a are joined together with the atom to which they are attached to form a C3- to cycloalkyl; or 3- to 10-membered heterocyclyl;optionally, one or more of the pairs —R1/—R4, —R1/—R5, —R1/—R6, —R1/—R7a, —R4/—R5, —R4/—R6, —R/—R9, —R2/—R3 are joined together with the atoms to which they are attached to form a ring A;optionally, R3/R3a 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; C3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; andwherein -L1- is substituted with -L2-Z or -L2-Z′ and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2-Z or -L2-Z′ or a substituent;wherein-L2- is a single chemical bond or a spacer;—Z is a water-soluble carrier; and—Z′ is a water-insoluble carrier. 12. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —X— is —C(R4R4a)— or —N(R4)—. 13. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R4 is substituted with -L2-Z or -L2-Z′. 14. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein X1 is C. 15. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein ═X3 is ═O. 16. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —X2— is —C(R8R8a)—. 17. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R1 and —R1a are —H. 18. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R2 and —R2a are —H. 19. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R3 is —H and —R3a is methyl. 20. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R4 and —R4a are —H. 21. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11, wherein —R8 and —R8a are —H. 22. The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1, wherein -L2- is selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(Ry1)—, —S(O)2N(Ry1)—, —S(O)N(Ry1)—, —S(O)2—,—S(O)—; —N(Ry1)5(O)2N(Ry1a)—, —S—, —N(Ry1)—, —OC(ORy1a)(Ry1a)—,—N(Ry1)C(O)N(Ry1a)—, —OC(O)N(Ry1)—, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more —Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 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(Ry3)—, —S(O)2N(Ry3)—, —S(O)N(Ry3)—, —S(O)2—, —S(O)—, —N(Ry3)S(O)2N(Ry3a)—, —S—, —N(Ry3)—, —OC(ORy3)(Ry3a)—, —N(Ry3)C(O)N(Ry3a)—, and —OC(O)N(Ry3)—; —Ry1 and —Ry1a are independently of each other selected from the group consisting of —H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more —Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 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(Ry4)—, —S(O)2N(Ry4)—, —S(O)N(Ry4)—, —S(O)2—, —S(O)—, —N(Ry4)S(O)2N(Ry4a)—, —S—, —N(Ry4)—, —OC(ORy4)(Ry4a)—, —N(Ry4)C(O)N(Ry4a)—, and —OC(O)N(Ry4)—; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 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 —Ry2, which are the same or different;each —Ry2 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COORy5, —ORy5, —C(O)Ry5, —C(O)N(Ry5R5ya), —S(O)2N(Ry5R5ya), —S(O)N(Ry5R5ya), —S(O)2R5, —S(O)Ry5, —N(Ry5)S(O)2N(Ry5aRy5b), —SRy5, —N(Ry5Ry5a), —NO2, —OC(O)R5, —N(Ry5)C(O)Ry5a, —N(Ry5)S(O)2Ry5a, —N(Ry5)S(O)Ry5a, —N(Ry5)C(O)ORy5a, —N(Ry5)C(O)N(Ry5aRy5b), —OC(O)N(Ry5Ry5a), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach —Ry3, —Ry3a, —Ry4, —Ry4a, —Ry5, —Ry5a and —Ry5b is independently selected from the group consisting of —H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different. 23-59. (canceled)
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