Prodrugs of hydroxyl-comprising drugs
AssigneeAscendis Pharma A/S
InventorsUlrich Hersel, Torben Lebmann, Harald Rau
Life of this patent
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Abstract
The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising a biologically active moiety-linker conjugate D-L, wherein D is a hydroxyl-comprising biologically active moiety; and L is a promoiety comprising a moiety L1 represented by formula (I) and wherein L1 is substituted with one to four groups L2-Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein L2 is a single chemical bond or a spacer and Z is a carrier group. The invention also relates to pharmaceutical compositions comprising said prodrugs and their use as medicaments.
Claims16
A prodrug or a pharmaceutically acceptable salt thereof comprising a biologically active moiety-linker conjugate D-L, wherein
- D is a hydroxyl-comprising biologically active moiety;
- and
- L is a promoiety comprising
- i) a moiety L1 represented by formula (I),
- wherein the dashed line indicates attachment to a hydroxyl group of D by forming an ester or carbamate bond;
- Y is —C(R1)(R1a)—;
- or —N(R1)—;
- X is —C(R4)(R4a)—;
- —N(R4)—;
- —O—;
- —C(R4)(R4a)—C(R5)(R5a)—;
- —C(R4)(R4a)—N(R6)—;
- —N(R6)—C(R4)(R4a)—;
- —C(R4)(R4a)—O—;
- —O—C(R4)(R4a)—;
- —C(O)—N(R6)—;
- or —N(R6)—C(O)—;
- X1 is
- X2 is —C(R7)(R7a)—;
- or —C(R7)(R7a)—C(R8)(R8a)—;
- X3 is ═O;
- ═S;
- or ═N—CN;
- R1, R1a, R2, R2a, R3, R3a, R4, R4a, R5, R5, R6, R7, R7a, R8, R8a are independently selected from the group consisting of H;
- C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-20 heteroalkyl and Y1-T;
- and independently none, one or more of the pairs R1a/R4a, R1a/R5a, R4a/R5a, R7a/R8a are absent and the corresponding carbon atoms to which they are attached form a cis double bond;
- Y1 is a chemical bond or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl;
- T is selected from the group consisting of phenyl;
- naphthyl;
- indenyl;
- indanyl;
- tetralinyl;
- C3-10 cycloalkyl;
- 4- to 7-membered heterocyclyl;
- or 9- to 11-membered heterobicyclyl, wherein T is optionally substituted with one or more R9, which are the same or different;
- R9 is halogen;
- —CN;
- oxo (═O);
- —C(O)OH;
- —OH;
- —S(O)2NH2;
- —S(O)NH2;
- —S(O)2OH;
- —S(O)OH;
- —SH;
- —NH2;
- —NO2;
- C1-6 alkyl, or C1-10 heteroalkyl;
- optionally, one or more of the pairs R1/R1a, R1/R4, R1/R6, R1/R5, R2/R2a, R2/R3, R4/R4a, R4/R5, R5/R5a, R7/R7a, R7/R8, R8/R8a are joined together with the atom to which they are attached to form a a ring T;
- optionally, R3/R3a are joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle;
- and
- ii) a moiety L2, which is a chemical bond or a spacer, and L2 is bound to a polymeric carrier group Z,
- wherein L1 is substituted with one to four L2 moieties, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by L2;
- optionally, L1 is further substituted.
(canceled)
Dependencies are inferred from the claim text.