# US 10,245,248 B2 · FAP-activated therapeutic agents, and uses related thereto

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- Number: US 10,245,248 B2
- Document ID: US10245248B2
- Status: Granted
- Kind: B2
- Application number: 15/318,627
- Filed: 2015-06-15
- Published: 2017-05-04
- Granted: 2019-04-02
- Earliest claimed: 2014-06-13
- Assignees: Bach Biosciences, LLC
- Applicants: Trustees of Tufts College
- Inventors: William W. Bachovchin; Hung-sen Lai; David G. Sanford; Sarah E. Poplawski; Wengen Wu
- Web page: https://patentgrep.com/patent/US10245248B2

## CPC

- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/69: Boron compounds
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are prodrugs of therapeutic or imaging agents, which prodrugs are selectively cleaved by fibroblast activating protein (FAP) to release the agents. Upon cleavage by FAP of the FAP substrate, the prodrug releases the agent in its active form or in a form that is readily metabolized to its active form. Pharmaceutical compositions comprising the prodrugs, as well as methods of using the prodrugs to treat a disorder characterized by FAP upregulation are also disclosed.

## Claims

### Claim 1

A prodrug represented by the general formula
or a pharmaceutically acceptable salt thereof, wherein:
R1 represents (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkyl-C(O)—(C1-C10)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, or heteroaryl(C1-C10)alkyl, wherein any R1 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and thio (—SH); or —C(═X)R1 represents an N-terminally blocked alpha amino acid residue and X is O;
R2 represents H or a (C1-C6)alkyl;
R3 represents a (C1-C6)alkyl;
R4 is absent or represents one, two or three substituents, each independently selected from a (C1-C6)alkyl, —OH, —NH2, or halogen;
X represents O or S;
Cyt′, or Cyt′L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom; and
L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue; or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.

### Claim 2

A prodrug represented by the general formula
or a pharmaceutically acceptable salt thereof, wherein:
R1 represents a heteroaryl polycyclic moiety;
R2 represents H or a (C1-C6)alkyl;
Cyt′ or Cyt′L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom; and
L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue; or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.

### Claim 3

A prodrug represented by the general formula
or a pharmaceutically acceptable salt thereof, wherein:
R1 represents a heteroaryl moiety;
R2 represents H or a (C1-C6)alkyl;
Cyt′ or Cyt′-L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom; and
L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue; or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.

### Claim 4 (depends on 1)

The prodrug of claim 1, wherein Lisa self-immolative linker comprising a heterocycle.

### Claim 5 (depends on 4)

The prodrug of claim 4, wherein the self-immolative linker is selected from the group consisting of His-Ala, p-aminobenzyloxycarbonyl (PABC), and 2,4-bis(hydroxymethyl)aniline.

### Claim 6 (depends on 1)

A pharmaceutical composition, comprising a prodrug of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A method of treating a disorder characterized by fibroblast activation protein (FAP) upregulation, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 8

A prodrug represented by the general formula
or a pharmaceutically acceptable salt thereof, wherein:
R1 represents (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkyl-C(O)—(C1-C10)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, or heteroaryl(C1-C10)alkyl, wherein any R1 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and thio (—SH); or —C(═X)R1 represents an N-terminally blocked alpha amino acid residue and X is O;
R2 represents H or a (C1-C6)alkyl;
R3 represents H or a (C1-C6)alkyl;
R4 is absent or represents one, two or three substituents, each independently selected from a (C1-C6)alkyl, —OH, —NH2, or halogen;
X represents O or S;
Cyt′ represents a cytotoxic compound or cytostatic compound, less a hydrogen atom; and
L is a self-immolative linker comprising a heterocycle,
wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.

### Claim 9 (depends on 8)

The prodrug of claim 8, wherein the self-immolative linker is selected from the group consisting of His-Ala, p-aminobenzyloxycarbonyl (PABC), and 2,4-bis(hydroxymethyl)aniline.

### Claim 10 (depends on 8)

A pharmaceutical composition, comprising a prodrug of claim 8, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 8)

A method of treating a disorder characterized by fibroblast activation protein (FAP) upregulation, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of claim 8, or a pharmaceutically acceptable salt thereof.