Carrier-linked carbamate prodrug linkers

Patent metadata

Field	Value
Publication number	US-9561285-B2
Application number	US-201113574120-A
Country	US
Kind code	B2
Filing date	Jan 21, 2011
Priority date	Jan 22, 2010
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof, comprising a drug linker conjugate D-L, wherein D being a biologically active moiety containing an aromatic hydroxyl group is conjugated to one or more polymeric carriers via secondary carbamate-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeutically useful half-lives. The invention also relates to pharmaceutical compositions comprising said prodrugs and their use as medicaments.

First claim

The invention claimed is:

1. A prodrug or a pharmaceutically acceptable salt thereof comprising:
a drug linker conjugate D-L;
wherein D is a biologically active moiety containing an aromatic hydroxyl group; and
wherein L is a non-biologically active linker having a first and a second amine group, wherein:
the first amine group is a primary, secondary, or tertiary amine, or a quaternary ammonium cation; and
L is connected to D through a carbamate bond connecting the second amine group and the aromatic hydroxyl group of D;

wherein L comprises:
i) a moiety L 1 of formula (I);

wherein the dashed line indicates the attachment of L 1 to the aromatic hydroxyl group of D by forming a carbamate group;
wherein R 1 is selected from the group consisting of:
C 1-4 alkyl;
heteroalkyl;
C 3-7 cycloalkyl; and

wherein R 2 , R 2a , R 3 , and R 3a are independently selected from hydrogen, substituted or non-substituted linear, branched or cyclic C 1-4 alkyl, and heteroalkyl; and
wherein m is independently 2, 3 or 4; and

ii) a moiety L 2 , which is a chemical bond or a spacer, wherein:
L 2 is bound to a carrier group Z; and
Z is a polymer with a molecular weight ≧500 g/mol selected from the group consisting of:
2-methacryloyl-oxyethyl phosphoyl cholins, hydrogels, PEG based hydrogels, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyloxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof;

wherein L 1 is substituted with one to four L 2 moieties, by replacing any one to four hydrogen(s) of L 1 with a moiety L 2 ; and

wherein optionally, L is further substituted.

2. The prodrug according to claim 1 ;
wherein L 2 is a chemical bond.

3. The prodrug according to claim 1 ;
wherein the carrier group Z is a hydrogel.

4. The prodrug of claim 3 ;
wherein the hydrogel is composed of backbone moieties interconnected by hydrolytically degradable bonds.

5. The prodrug of claim 4 ;
wherein the backbone moieties have a molecular weight in the range of from 1 kDa to 20 kDa.

6. The prodrug of claim 4 ;
wherein backbone moieties are linked together through crosslinker moieties, each crosslinker moiety being terminated by at least two of the hydrolytically degradable bonds.

7. The prodrug of claim 6 ;
wherein the crosslinker moieties have a molecular weight in the range of from 0.5 kDa to 5 kDa.

8. A pharmaceutical composition comprising:
a prodrug of claim 1 or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8 ;
wherein the pharmaceutical composition is dry.

10. A pharmaceutical composition according to claim 8 ;
wherein the prodrug is sufficiently dosed in the composition to provide a therapeutically effective amount of biologically active agent for at least 12 hours in one application.

11. A kit of parts comprising:
a needle; and
a container containing:
reconstitution solution; and
the dry composition according to claim 10 configured for use with the needle.

12. The kit of parts according to claim 11 ;
wherein the container is a dual-chamber syringe; and
wherein one of the two chambers of the dual-chamber syringe contains the dry pharmaceutical composition and the second chamber of said dual-chamber syringe contains the reconstitution solution.

13. The prodrug according to claim 1 ;
wherein the prodrug is configured for use as pharmaceutical.

14. A method for the synthesis of a prodrug or a pharmaceutically acceptable salt thereof according to claim 1 , comprising:
a step of reacting a prodrug precursor L-Y or L 1 -Y with a biologically active drug D-H, to obtain the drug linker conjugate D-L or a drug linker intermediate D-L 1 by forming a carbamate bond;
wherein Y is a leaving group.

15. The prodrug according to claim 1 ;
wherein the carrier group Z is a PEG based hydrogel.

16. The prodrug according to claim 1 ;
wherein the carrier group Z is a biodegradable poly(ethylene glycol) based water-insoluble hydrogel.

Assignees

• Rau Harald
• Lessmann Torben
• Ascendis Pharma As

Inventors

• Rau Harald
• Lessmann Torben

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K47/6903 Primary

  the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/48215 Primary

  Human Necessities · mapped topic

• A61K47/48338

  Human Necessities · mapped topic