# US 11,298,427 B2 · Prodrugs comprising a pyroglutamate linker

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- Number: US 11,298,427 B2
- Document ID: US11298427B2
- Status: Granted
- Kind: B2
- Application number: 15/577,606
- Filed: 2016-05-25
- Published: 2019-07-18
- Granted: 2022-04-12
- Earliest claimed: 2015-05-29
- Assignees: Ascendis Pharma A/S; Ascendis Pharma AS
- Applicants: Ascendis Pharma A/S; Ascendis Pharma Inc.
- Inventors: Harald Rau; Nicola Bisek; Samuel Weisbrod
- Web page: https://patentgrep.com/patent/US11298427B2

## CPC

- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to novel prodrugs of primary or secondary amine-comprising biologically active moieties and pharmaceutically acceptable salts thereof, prodrug reagents, pharmaceutical compositions comprising said prodrugs and the use of prodrugs.

## Claims

### Claim 1

A conjugate D-L1 or a pharmaceutically acceptable salt thereof,
wherein
-D is a primary or secondary amine-comprising biologically active moiety; and
-L1 is represented by formula (I):
wherein:
the dashed line indicates attachment to the primary or secondary amine of the biologically active moiety;
—X1 is selected from the group consisting of —C(R5R5a)—, —O—, —N(R5)—, and —S—;
—R4 is methyl;
—R1, R1a, R2, R3, R4a, R5, and —R5a are independently of each other selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein:
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R6, which are the same or different; and
C1-6 alkyl, C2-6 alkenyl, and C2-6 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(R7)—, —S(O)2N(R7)—, —S(O)N(R7)—, —S(O)2—, —S(O)—, —N(R7)S(O)2N(R7a)—, —S—, —N(R7)—, —OC(OR7)(R7a)—, —N(R7)C(O)N(R7a)—, and —OC(O)N(R7)—, provided that the nitrogen marked with the asterisk is connected to —R2 through an SP3-hybridized carbon atom of —R2;
each T is independently of each other selected from the group consisting of phenyl, naphthyl, indenyl, indenyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, wherein:
each T is independently optionally substituted with one or more R6, which are the same or different;
each —R6, —R7, and —R7a 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;
═Y1 is selected from ═O and ═NR5;
optionally, one or more of the pairs —R1/—R1a, —R2/—R3, —R5/—R5a, and —R4/—R4a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl, 3- to 10-membered heterocyclyl or a 8- to 11-membered heterobicyclyl;
optionally, one or more of the pairs —R1/—R2, —R1/—R5a, —R1a/—R2, —R1a/—R3, —R1a/—R5, —R1a/—R5a, —R2/—R5, —R2/—R5a, —R3/—R5, —R3/—R5a are joined together with the atoms to which they are attached to form a ring —A—, where:
—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;
wherein -L1 is substituted with one to five moieties -L2-Z, wherein the one to five hydrogens for substitutions are given by —R1, —R1a, —R2, —R3, —R4a, —R5, —R5a, —R6 or —R7 of -L1, wherein:
-L2- is a single chemical bond or a spacer moiety; and
-Z is a carrier moiety.

### Claim 2 (depends on 1)

The conjugate or a pharmaceutically acceptable salt thereof of claim 1;
wherein D is a small molecule biologically active moiety, oligonucleotide moiety, peptide nucleic acid moiety, peptide moiety, or protein moiety.

### Claim 3 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is a C8-18 alkyl group or a polymer with a molecular weight of at least 0.5 kDa.

### Claim 4 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, 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(hydroxyethyl-oxazolines), 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, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.

### Claim 5 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is a protein.

### Claim 6 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is a PEG-based polymer comprising at least 10% PEG.

### Claim 7 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is a water-soluble polymer.

### Claim 8 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein -Z is a PEG-based hydrogel comprising at least 10% PEG.

### Claim 9 (depends on 1)

The conjugate or 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)S(O)2N(Ry1a)—, —S—, N(Ry1)—, —OC(ORy1)(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
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)—;
Ry4 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
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(Ry5Ry5a), —S(O)2N(Ry5Ry5a), —S(O)N(Ry5Ry5a), —S(O)2Ry5, —S(O)Ry5, —N(Ry5)S(O)2N(Ry5aRy5b), —SRy5, —N(Ry5Ry5a), —NO2, —OC(O)Ry5, —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; and
each —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.

### Claim 10 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein one hydrogen atom given by —R1, —R1a, —R2, —R3, —R4a, —R5, —R5a, —R6 or —R7 is replaced by one moiety -L2-Z.

### Claim 11 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein —R4a is —H which is substituted with -L2-Z.

### Claim 12 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein —R1, —R1a, —R2, —R3, —R4a, —R5 and —R5a are independently of each other selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

### Claim 13 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein —X1— of is —C(R5R5a)—.

### Claim 14 (depends on 1)

The conjugate or pharmaceutically acceptable salt thereof of claim 1;
wherein ═Y1 is ═O.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising:
the conjugate or pharmaceutically acceptable salt thereof of claim 1; and
one or more excipients.

### Claim 16 (depends on 1)

A method comprising:
administering the conjugate or pharmaceutically acceptable salt thereof of claim 1 as a medicament.