# US 11,433,087 B2 · Anti-tumor compound with high CD169 affinity, method thereof, and use thereof

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- Number: US 11,433,087 B2
- Document ID: US11433087B2
- Status: Granted
- Kind: B2
- Application number: 16/847,770
- Filed: 2020-04-14
- Published: 2020-07-30
- Granted: 2022-09-06
- Earliest claimed: 2017-10-14
- Assignees: Xiamen Nuokangde Biological Technology Co., Ltd.
- Applicants: Xiamen Nuokangde Biological Technology Co., Ltd.
- Inventors: Xu Yan; Xuchun Han; Xianwu Wang
- Web page: https://patentgrep.com/patent/US11433087B2

## CPC

- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61P 35/00: Antineoplastic agents
- C07D 495/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The disclosure provides a CD169 high affinity anti-tumor compound (TCC-Neu5A) and its preparation and application. The CD169 high affinity anti-tumor compound is a small molecule compound, which has specific and broad-spectrum tumor killing characteristics. TCC-Neu5Ac could targets tumor cells in vivo and metabolize onto a surface of the tumor cells to form CD169 ligands. These tumor cells are recognized and phagocytized by CD169-positive macrophages, which then release tumor-related antigens and present them to other immune cells, triggering an anti-tumor immune response. The CD169 high affinity anti-tumor compound provided by the disclosure is effective for a variety of tumors and has an inhibitory effect on tumor metastasis. In addition, the CD169 high affinity anti-tumor compound provided by the disclosure can not only be injected but also be orally administered. Cytotoxicity and animal toxicity of the CD169 high affinity anti-tumor compound are very low.

## Claims

### Claim 1

An anti-tumor compound with high CD169 affinity, wherein the chemical structure of the anti-tumor compound is as follows:

### Claim 2

A method for preparing an anti-tumor compound with high CD169 affinity having the chemical structure of:
wherein the method for preparing the anti-tumor compound with high CD169 affinity comprises:
1) mixing Tccsia methyl ester, methanol, and NaOH solution, and stirring at room temperature to obtain a first mixture,
2) adding HCl aqueous solution into the first mixture, and adjusting a pH of the first mixture to 7 to obtain a second mixture, and
3) removing a solvent of the second mixture, and purifying a first residue of the second mixture having the solvent removed to obtain a first solid, wherein the first solid is the anti-tumor compound with high CD169 affinity.

### Claim 3 (depends on 2)

The method for preparing the anti-tumor compound with high CD169 affinity according to claim 2, wherein, in step 3, purifying the first residue of the second mixture having the solvent removed comprises:
purifying the first residue of the second mixture having the solvent removed by a column chromatography, and
using CH2Cl2:MeOH=2:1 in the column chromatography.

### Claim 4 (depends on 2)

The method for preparing the anti-tumor compound with high CD169 affinity according to claim 2, wherein a method for preparing the Tccsia methyl ester in step 1 comprises:
S110) mixing N3Sia methyl ester, palladium on carbon (Pd/C) catalyst, and anhydrous methanol to obtain a third mixture,
S120) adding acetyl chloride in the third mixture, and adjusting a pH of the third mixture to 1-2 to obtain a fourth mixture,
S130) stirring the fourth mixture in H2 atmosphere until, when monitoring through thin layer chromatography, the fourth mixture is fully reacted to obtain a fifth mixture,
S140) filtering the fifth mixture to remove the Pd/C catalyst, and evaporating to remove a solvent of the fifth mixture to obtain a residual mixture,
S150) mixing the residual mixture, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, terminal complement complex carboxyl group (TCC-COOH), and dimethylformamide (DMF), and stirring in a dark environment to obtain a sixth mixture,
S160) evaporating the sixth mixture to remove a solvent of the sixth mixture, and purifying a second residue of the sixth mixture having the solvent removed by a second column chromatography to obtain a second solid, wherein the second solid is the TCCSia methyl ester, and
S170) in Step S160, using CH2Cl2:MeOH=10:1 in the second column chromatography.

### Claim 5 (depends on 4)

The method for preparing the anti-tumor compound with high CD169 affinity according to claim 4, wherein a method for preparing the N3Sia methyl ester comprises:
S210) adding sodium azide and TOSSia methyl ester into DMF to obtain a seventh mixture,
S220) heating the seventh mixture to 80° C., and further heating to remove a solvent of the seventh mixture,
S230) purifying a third residue of the seventh mixture having the solvent removed by a third column chromatography to obtain a third solid, wherein the third solid is the N3Sia methyl ester, and
S240) in step S230, using EtOAc:MeOH=20:1 in the third column chromatography.

### Claim 6 (depends on 5)

The method for preparing the anti-tumor compound with high CD169 affinity according to claim 5, wherein a method for preparing the TOSSia methyl ester comprises:
S310) mixing sialic acid, trifluoroacetic acid, and anhydrous methanol at the room temperature, and stirring until being clarified to obtain an eighth mixture,
S320) evaporating the eighth mixture to remove a solvent of the eighth mixture to obtain sialic acid methyl ester solid,
S330) drying the sialic acid methyl ester solid with P2O5 in vacuum to obtain a ninth mixture,
S340) evaporating the ninth mixture together with anhydrous pyridine to further remove water to obtain a tenth mixture,
S350) dissolving the tenth mixture in anhydrous pyridine, cooling to 0° C., and adding p-toluenesulfonyl chloride to obtain an eleventh mixture,
S360) heating the eleventh mixture to the room temperature, stirring, and heating under a reduced pressure to remove a solvent of the eleventh mixture,
S370) purifying a fourth residue of the eleventh mixture having the solvent removed by a fourth column chromatography to obtain a white solid, wherein the white solid is the TOSsSia methyl ester, and
S380) in step S370, using EtOAc:MeOH=20:1 in the fourth column chromatography.

### Claim 7 (depends on 1)

A method, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 1 using a solution to obtain an anti-tumor drugs.

### Claim 8 (depends on 2)

A method further, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 2 using a solution to obtain an anti-tumor drugs.

### Claim 9 (depends on 3)

A method further, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 3 using a solution to obtain an anti-tumor drugs.

### Claim 10 (depends on 4)

A method further, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 4 using a solution to obtain an anti-tumor drugs.

### Claim 11 (depends on 5)

A method further, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 5 using a solution to obtain an anti-tumor drugs.

### Claim 12 (depends on 6)

A method further, comprising:
diluting the anti-tumor compound with high CD169 affinity according to claim 6 using a solution to obtain an anti-tumor drugs.

### Claim 13 (depends on 1)

A method, comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 1 for treating a tumor.

### Claim 14 (depends on 2)

A method, further comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 2 for treating a tumor.

### Claim 15 (depends on 3)

A method, further comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 3 for treating a tumor.

### Claim 16 (depends on 4)

A method, further comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 4 for treating a tumor.

### Claim 17 (depends on 5)

A method, further comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 5 for treating a tumor.

### Claim 18 (depends on 6)

A method, further comprising:
at least one of injecting into a recipient or taking orally by the recipient the anti-tumor compound with high CD169 affinity according to claim 6 for treating a tumor.