# US 11,298,366 B2 · Ibandronate conjugates of nucleoside antimetabolites

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- Number: US 11,298,366 B2
- Document ID: US11298366B2
- Status: Granted
- Kind: B2
- Application number: 16/625,990
- Filed: 2018-01-05
- Published: 2020-05-28
- Granted: 2022-04-12
- Earliest claimed: 2017-06-26
- Assignees: Mbc Pharma, Inc.
- Applicants: MBC Pharma, Inc.
- Inventors: Alexander Karpeisky; Shawn Zinnen
- Web page: https://patentgrep.com/patent/US11298366B2

## CPC

- A61K 31/663: Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
- A61K 31/7042: Compounds having saccharide radicals and heterocyclic rings
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/7084: Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- A61P 35/00: Antineoplastic agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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

Provided herein are conjugates of nucleoside antimetabolites and their analogs with ibandronate, pharmaceutical compositions including one or more of said conjugates, methods of synthesizing the same as well as methods of treating diseases and or conditions using the same.

## Claims

### Claim 1

A compound comprising:
or a pharmaceutically acceptable acid addition salt thereof,
wherein;
X is an anticancer compound comprising a nucleoside antimetabolite having the structure:
wherein:
B is a natural or modified nucleic acid base,
R4=H, and
R2 and R3 are independently selected from the group consisting of H, OH, F, and Cl; and
Y is selected from the group consisting of H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

### Claim 2

A compound comprising:
or a pharmaceutically acceptable acid addition salt thereof,
wherein;
X is an anticancer compound comprising a nucleoside antimetabolite having the structure:
wherein:
B is a natural or modified nucleic acid base,
R2 and R3 are independently selected from the group consisting of H, OH, F, and Cl; and
Y is selected from the group consisting of H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

### Claim 3 (depends on 1)

A compound of claim 1, where X is selected from the group consisting of cytarabine, gemcitabine, clofarabine, cladribine, vidaza, dacogen, fludarabine, floxuridine, nelarabine and pentostatin.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 5 (depends on 1)

A method of treating cancer-induced bone disease or primary bone cancer, or preventing bone metastases, or treating or ameliorating at least one symptom of bone cancer or cancer-induced bone disease, or decreasing the frequency or severity of at least one symptom of bone cancer or cancer-induced bone disease, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

### Claim 6 (depends on 1)

A method for delivering of nucleoside antimetabolites to bone or surrounding tissues, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

### Claim 7 (depends on 5)

The method of claim 5, wherein the compound is administered in combination with one or more therapeutic agents.

### Claim 8 (depends on 5)

The method of claim 5, wherein the compound or the pharmaceutical composition is administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally, or orally.

### Claim 9

A method of synthesizing nucleoside antimetabolite ibandronate conjugates, the method comprising reacting nucleoside-5′-phosphate or nucleoside-2′- or 3′-phosphate with trifluoroacetic anhydride in the presence of tertiary amine base in organic solvent, followed by addition of nucleophilic catalyst, followed by addition of ibandronate, followed by addition of water and purification by ion-exchange or reverse-phase chromatography.

### Claim 10 (depends on 9)

The method of claim 9 where tertiary amine is selected from the group consisting of triethylamine, dimethylaniline, and pyridine.

### Claim 11 (depends on 9)

The method of claim 9, where said nucleophilic catalyst is selected from the group consisting of dimethylaminopyridine and N-methylimidazole.

### Claim 12 (depends on 9)

The method of claim 9, where organic solvent is selected from the group consisting of acetonitrile, pyridine, dimethylformamide, and dimethylacetamide.

### Claim 13 (depends on 5)

The method of claim 5, wherein the symptom of bone cancer or bone disease is pain.

### Claim 14 (depends on 5)

The method of claim 5, wherein the primary cancer is prostate cancer or breast cancer.

### Claim 15 (depends on 5)

The method of claim 5, wherein the treatment results in increased survival compared to a similarly situated subject without treatment.

### Claim 16 (depends on 5)

The method of claim 5, wherein the treatment results in decreased formation of secondary non-osseous metastases compared to a similarly situated subject without treatment.

### Claim 17 (depends on 2)

A compound of claim 2, where X is selected from the group consisting of cytarabine, gemcitabine, clofarabine, cladribine, vidaza, dacogen, fludarabine, floxuridine, nelarabine and pentostatin.

### Claim 18 (depends on 2)

A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier or diluent.