# US 10,500,224 B2 · Mutual prodrug comprising short chain fatty acids and zebularine or 1'-cyano-cytarabine for cancer treatment

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- Number: US 10,500,224 B2
- Document ID: US10500224B2
- Status: Granted
- Kind: B2
- Application number: 15/029,852
- Filed: 2014-11-14
- Published: 2016-08-11
- Granted: 2019-12-10
- Earliest claimed: 2013-11-14
- Assignees: Kainos Medicine, Inc.
- Applicants: Kainos Medicine, Inc.
- Inventors: Sunmi Shin; Hyangmi Kim; Su-Sung Oh
- Web page: https://patentgrep.com/patent/US10500224B2

## CPC

- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 19/06: Pyrimidine radicals
- C07H 19/067: with ribosyl as the saccharide radical
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention provides mutual prodrugs comprising anti-cancer nucleosides and short chain fatty acids; methods for production of the mutual prodrugs; methods of treatment comprising administration of the mutual prodrugs; and pharmaceutical compositions comprising the mutual prodrugs. Further, the mutual prodrugs of the present invention can be used as therapeutic agents for the treatment of cancer diseases and conditions.

## Claims

### Claim 1

A compound consisting of a nucleoside of Formula (I) or (II) covalently linked to one or more short chain fatty acids (SCFAs) or a derivative thereof, wherein the SCFAs are selected from the group consisting of butyric acid and isobutyric acid, and the SCFAs are linked at 5′ position, or 2′, 3′, and 5′ positions of the nucleoside of formula (I) or (II):

### Claim 2 (depends on 1)

The compound of claim 1, which is selected from the group consisting of:
1) ((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl butyrate;
2) ((2R,3S,4R,5R)-3,4-dihydroxy-5-(2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl butyrate;
3) (2R,3R,4R,5R)-2-((butyryloxy)methyl)-5-(2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl dibutyrate; and
4) (2R,3R,4R,5R)-2-((isobutyryloxy)methyl)-5-(2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate).

### Claim 3 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier or an excipient.

### Claim 4 (depends on 1)

A method for inhibiting the growth of a cancer cell in a subject, which comprises administering a therapeutically effective amount of the compound of claim 1 to the subject in need thereof.

### Claim 5 (depends on 1)

A method for treating a disease, disorder, or condition modulated by an anti-cancer nucleoside and histone deacetylase inhibitor in a subject, which comprises administering a therapeutically effective amount of the compound of claim 1 to the subject in need thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein the disease, disorder, or condition is selected from the group consisting of an autoimmune disease, epithelial tumors, melanoma, leukemia, acute promyelocytic leukemia, lymphoma, osteogenic sarcoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, ovarian cancer, lung cancer and a combination thereof.