# US 11,298,341 B2 · PSMA binding ligand-linker conjugates and methods for using

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- Number: US 11,298,341 B2
- Document ID: US11298341B2
- Status: Granted
- Kind: B2
- Application number: 16/507,713
- Filed: 2019-07-10
- Published: 2020-05-21
- Granted: 2022-04-12
- Earliest claimed: 2007-08-17
- Assignees: Purdue Research Foundation
- Applicants: Purdue Research Foundation
- Inventors: Philip S. Low; Sumith A. Kularatne
- Web page: https://patentgrep.com/patent/US11298341B2

## CPC

- A61K 31/426: 1,3-Thiazoles
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/547: {Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent}
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- 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)
- A61K 49/0041: {Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N)}
- A61K 49/0043: {Fluorescein, used in vivo}
- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61K 51/04: Organic compounds
- A61K 51/0402: {carboxylic acid carriers, fatty acids (amino acids A61K51/0406)}
- A61K 51/0489: {Phosphates or phosphonates, e.g. bone-seeking phosphonates; (phospholipids: A61K51/0408; nucleotides or nucleic acids: A61K51/0491)}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61P 13/08: of the prostate
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 323/52: the carbon skeleton being acyclic and saturated
- C07D 207/416: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07K 5/08: Tripeptides
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical composition containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.

## Claims

### Claim 1

A compound of the formula:
B-L-IA
or a pharmaceutically acceptable salt thereof, wherein:
B is of the formula
wherein * represents the point of attachment to L;
L is a divalent linker of at least 14 atoms in length, the divalent linker comprising one or more of a divalent cycloalkyl, cycloalkane diradical, cycloalkylene, alkylenecycloalkyl, cycloalkylenecarbonyl, heterocyclyl, aryl, arylalkylene, heteroaryl, a divalent amino alkylene carbonyl group, arylene, or cyclo-imide group and at least one group:
—N(H)—(CR′R″)q—C(O)—
wherein q is 1, R′ is hydrogen, and R″ is the side chain of glutamic acid;
and L does not comprise an arylalkyl side chain; and
IA is an optical imaging agent selected from the group consisting of fluorescein, BODIPY F1, BODIPY 505, tetramethylrhodamine, ALEXA FLUOR™ 488, ALEXA FLUOR™ 647, DYLIGHT™ 680, DYLIGHT™ 800, IR800CW, indocyanine green, OREGON GREEN™ 488, OREGON GREEN™ 514, Texas Red, and phycoerythrin.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a divalent cycloalkylenecarbonyl group, a divalent amino alkylene carbonyl group, and at least one group —N(H)—(CR′R″)qC(O)—.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is between about 14 and about 31 atoms in length.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a cycloalkyl group selected from the group consisting of cyclopropyl, cyclohexyl, 3-ethylcyclopent-1-yl, cyclopropylethyl, and cyclohexylmethyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a cycloalkylene group selected from the group consisting of cycloprop-1,1-diyl, cycloprop-1,2-diyl, cyclohex-1,4-diyl, 3-ethylcyclopent-1,2-diyl, and 1-methylenecyclohex-4-yl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a heterocyclyl group selected from the group consisting alkylheterocyclyl, heteroalkylheterocyclyl, heterocyclylalkyl, and heterocyclylheteroalkyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a heterocyclyl group selected from the group consisting of aziridine, pyrrolidine, oxazolidine, 3-methoxypyrrolidine, and 3-methylpiperazine.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a heterocyclyl group selected from the group consisting of tetrahydrofuran-2-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, morpholin-1-yl, tetrahydrofuran-2-ylmethyl, piperidin-1-ylethyl, piperidin-4-ylmethyl, piperazin-1-ylpropyl, and morpholin-1-ylethyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises an aryl group selected from the group consisting of phenyl and naphthyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L comprises a heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, indolyl, and benzoxazolyl.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.