# US 11,992,536 B2 · Dual-targeting compound and preparation method and application thereof

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- Number: US 11,992,536 B2
- Document ID: US11992536B2
- Status: Granted
- Kind: B2
- Application number: 18/546,989
- Filed: 2022-12-09
- Published: 2024-04-25
- Granted: 2024-05-28
- Earliest claimed: 2022-09-29
- Assignees: Yantai Lannacheng Biotechnology Co., Ltd.
- Applicants: Yantai Lannacheng Biotechnology Co., Ltd.
- Inventors: Xiaoyuan Chen; Pengfei Xu; Xiaoming Wu; Zhide Guo; Qingbao Yang; Xuejun Wen
- Web page: https://patentgrep.com/patent/US11992536B2

## CPC

- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- C07K 7/64: Cyclic peptides containing only normal peptide links
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61K 51/082: {the peptide being a RGD-containing peptide}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61P 35/00: Antineoplastic agents
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present disclosure relates to the fields of nuclear medicine and molecular imaging, and specifically relates to a dual-targeting compound and a preparation method and application thereof. The dual-targeting compound has the following structure shown in Formula (I). The present disclosure also provides a dual-targeting compound capable of being labeled with a radionuclide, and the compound has the following structure shown in Formula (I-1) or Formula (1-2). The dual-targeting compound of the present disclosure has high affinity for an FAP target and an integrin αvβ3 target, can realize synergistic targeting of the FAP target and the integrin αvβ3 target in tumors, and has high uptake in tumors and long retention time in tumors. The present disclosure also provides a radionuclide labeled dual-targeting compound based on the dual-targeting compound, and a preparation method and application thereof in preparation of medicines for diagnosis or therapy of diseases characterized by overexpression of FAP and/or integrin αvβ3.

## Claims

### Claim 1

A dual-targeting compound, wherein the compound structurally contains ligand structures specifically binding to FAP and integrin αvβ3 at the same time, and the compound has the following structure shown in Formula (I):

### Claim 2

A dual-targeting compound capable of being labeled with a radionuclide, wherein the compound structurally contains ligands specifically binding to FAP and integrin αvβ3 at the same time and a nuclide chelating structure, and the compound has the following structure shown in Formula (I-1) or Formula (I-2):

### Claim 3 (depends on 2)

A method for preparing the dual-targeting compound capable of being labeled with a radionuclide according to claim 2, comprising the following steps: (i) reacting 6-hydroxyquinoline-4-carboxylic acid with amino of tert-butyl glycinate by amide condensation to obtain Compound 2; (ii) reacting Compound 2 and 1-bromo-3-chloropropane to obtain Compound 3: (iii) reacting Compound 3 and tert-butyl 1-piperazinecarboxylate to obtain Compound 4 (iv) removing a Boc protective group and a tert-butyl protective group from Compound 4 under acidic conditions to obtain Compound 5, and introducing a Boc protective group to piperazine ring of Compound 5, followed by an amide condensation reaction with (S)-pyrrolidene-2-carbonitrile hydrochloride; (v) removing the Boc protective group, carrying out a condensation reaction with N-Boc-3-[2-(2-aminoethoxy)ethoxy]propionic acid; (vi) removing the Boc protective group, and carrying out a reaction with Fmoc-O-tert-butyl-L-glutamic acid to obtain Compound 9; (vii) reacting Compound 9 with p-toluenesulfonic acid monohydrate, followed by a reaction with DCC and NHS to obtain Intermediate 10, c(RGDfK) with amino-dipolyethylene glycol to obtain Compound 11 and remove the Boc to obtain Compound 12, followed by reacting Intermediate 10 and Compound 12 to obtain a dual-targeting compound; (viii) removing an Fmoc protective group and then carrying out a reaction with a nuclide chelating agent, wherein the nuclide chelating agent is 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid or 1,4,7-triazacyclononane-1,4,7-triacetic acid; and (ix) removing a tert-butyl protective group on a chelating group to obtain a dual-targeting compound capable of being labeled with a radionuclide,
wherein Compound 2 has the following Formula (II):
wherein Compound 3 has the following Formula (III):
wherein Compound 4 has the following Formula (IV):
wherein Compound 5 has the following Formula (V):
wherein Compound 9 has the following Formula (IX):
wherein Intermediate 10 has the following Formula (X):
wherein Compound 12 has the following Formula (XII)

### Claim 4 (depends on 2)

A radionuclide labeled dual-targeting compound, comprising the dual-targeting compound capable of being labeled with a radionuclide according to claim 2 and a radionuclide; and the radionuclide is selected from an α-ray emitting isotope, a β-ray emitting isotope, a γ-ray emitting isotope, an auger electron emitting isotope, or an X-ray emitting isotope.

### Claim 5 (depends on 4)

The radionuclide labeled dual-targeting compound according to claim 4, wherein the radionuclide is selected from any one of 18F, 51Cr, 67Ga, 68Ga, 111In, 99mTc, 186Re, 188Re, 139La, 140La, 175Yb, 153Sm, 166Ho, 86Y, 90Y, 149Pm, 165Dy, 169Er, 177Lu, 47Sc, 142Pr, 159Gd, 212Bi, 213Bi, 72As, 72Se, 97Ru, 109Pd, 105Rh, 105Rh, 101mRh, 119Sb, 128Ba, 123I, 124I, 131I, 197Hg, 159Gd, 212Bi, 213Bi, 72As, 72Se, 97Ru, 109Pd, 105Rh, 101mRh, 119Sb, 128Ba, 123I, 124I, 131I, 197Hg, 211At, 151Eu, 153Eu, 169Eu, 201Tl, 203Pb, 212Pb, 64Cu, 67Cu, 198Au, 225Ac, 227Th, 89Zr, or 199Ag.

### Claim 6 (depends on 4)

The radionuclide labeled dual-targeting compound according to claim 4, wherein the radionuclide is selected from 18F, 64Cu, 68Ga, 89Zr, 90Y 111In, 99mTc, 177Lu, 188Re, or 225Ac.

### Claim 7 (depends on 2)

A method for preparing a radionuclide labeled dual-targeting compound, wherein the radionuclide labeled dual-targeting compound is obtained by labeling any one of the dual-targeting compounds capable of being labeled with a radionuclide according to claim 2 with a radionuclide; and the radionuclide is selected from an α-ray emitting isotope, a β-ray emitting isotope, a γ-ray emitting isotope, an auger electron emitting isotope, or an X-ray emitting isotope; the method comprising: reacting the dual-targeting compound capable of being labeled with a radionuclide according to claim 2 with a radionuclide by wet labeling or freeze-drying labeling to obtain the radionuclide labeled dual-targeting compound.

### Claim 8 (depends on 4)

A pharmaceutical composition, comprising the radionuclide labeled dual-targeting compound according to claim 4, or a pharmaceutically acceptable hydrate, solvate or salt thereof.

### Claim 9 (depends on 1)

A method of diagnosing or treating a disease characterized by overexpression of at least one selected from the group consisting of FAP and integrin αvβ3, comprising: administering, to a subject in need thereof, an effective amount of the dual-targeting compound according to claim 1, or a pharmaceutically acceptable hydrate, solvate or salt thereof, comprising a radionuclide.

### Claim 10 (depends on 2)

A method of diagnosing or treating a disease characterized by overexpression of at least one selected from the group consisting of FAP and integrin αvβ3, comprising: administering, to a subject in need thereof, an effective amount of the dual-targeting compound capable of being labeled with a radionuclide according to claim 2, or a pharmaceutically acceptable hydrate, solvate or salt thereof, comprising a radionuclide.

### Claim 11 (depends on 4)

A method of diagnosing or treating a disease characterized by overexpression of at least one selected from the group consisting of FAP and integrin αvβ3, comprising: administering, to a subject in need thereof, an effective amount of the radionuclide labeled dual-targeting compound according to claim 4, or a pharmaceutically acceptable hydrate, solvate or salt thereof.

### Claim 12 (depends on 8)

A method of diagnosing or treating a disease characterized by overexpression of at least one selected from the group consisting of FAP and integrin αvβ3, comprising: administering, to a subject in need thereof, an effective amount of the pharmaceutical composition according to claim 8.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the disease characterized by overexpression of at least one selected from the group consisting of FAP and integrin αvβ3 comprises cancer, chronic inflammation, atherosclerosis, or cicatricial diseases.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the cancer is selected from breast cancer, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal cell carcinoma, neuroendocrine carcinoma, carcinogenic osteomalacia, sarcoma, cancer of unknown primary, thymic carcinoma, glioma, neuroglioma, astrocytoma, cervical cancer, and prostate cancer.