# US 9,040,501 B2 · Compositions and methods for treating cancer

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- Number: US 9,040,501 B2
- Document ID: US9040501B2
- Status: Granted
- Kind: B2
- Application number: 14/079,944
- Filed: 2013-11-14
- Published: 2014-08-07
- Granted: 2015-05-26
- Earliest claimed: 2009-04-06
- Assignees: Otsuka Pharmaceutical Co., Ltd.
- Applicants: Eisai Inc.
- Inventors: Sergel Belyakov; Bridget Duvall; Dana Ferraris; Gregory Hamilton; Mark Vaal
- Web page: https://patentgrep.com/patent/US9040501B2

## CPC

- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07H 19/04: Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- 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)
- 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

Provided herein are compounds used to inhibit the deamination enzyme responsible for the inactivation of therapeutic compounds, and methods of using them.

## Claims

### Claim 1

A composition comprising:
(i) a compound of Formula I:
wherein:
R1 and R2 is F, and the other is selected from H and F;
R3 and R4 are H;
where—is a covalent bond or absent, and R4 is absent when—is a covalent bond;
or a pharmaceutically acceptable salt, a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof;
(ii) a cytidine deaminase (CDA) substrate drug; and
(iii) at least one additional pharmaceutical agent, wherein the pharmaceutical agent is selected from an anti-emetic, an agent that increases appetite, a cytotoxic or chemotherapeutic agent, and an agent that relieves pain;
as a combination for simultaneous, separate, or sequential administration.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the CDA substrate drug is selected from the group consisting of decitabine, 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.

### Claim 3 (depends on 2)

The composition of claim 2, wherein the CDA substrate drug is 5-azacytidine, gemcitabine, or ara-C.

### Claim 4 (depends on 2)

The composition of claim 2, wherein the CDA substrate drug is decitabine.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the compound of Formula I is a compound of Formula VIII:
or a pharmaceutically acceptable salt, a C1-6 alkyl ester, or a C2-6alkenyl ester thereof.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the pharmaceutical agent is selected from a cytotoxic or chemotherapeutic agent.

### Claim 7 (depends on 4)

The composition of claim 4, wherein the compound of Formula I is a compound of Formula VIII:
or a pharmaceutically acceptable salt , a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof.

### Claim 8

A method for treating cancer in a mammal in need thereof, comprising:
(i) administering to said mammal a compound of Formula 1:
wherein:
one of R1 and R2 is F, and the other is selected from H and F;
R3 and R4 are H;
where—is a covalent bond or absent, and R4 is absent when—is a covalent bond;
or a pharmaceutically acceptable salt, a C1-6alkyl ester, or a C2-6alkenyl ester thereof;
(ii) administering to said mammal a CDA substrate drug; and
(iii) administering to said mammal at least one additional pharmaceutical agent, wherein the pharmaceutical agent is selected from an anti-emetic, an agent that increases appetite, a cytotoxic or chemotherapeutic agent, and an agent that relieves pain.

### Claim 9 (depends on 8)

The method of claim 8, wherein the CDA substrate drug is selected from the group consisting of decitabine, 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.

### Claim 10 (depends on 8)

The method of claim 8, wherein the CDA substrate drug is 5-azacytidine, gemcitabine, or ara-C.

### Claim 11 (depends on 8)

The method of claim 8, wherein the CDA substrate drug is decitabine.

### Claim 12 (depends on 8)

The method of claim 8, wherein the pharmaceutical agent is selected from a cytotoxic or chemotherapeutic agent.

### Claim 13 (depends on 8)

The method of claim 8, wherein the cancer is selected from hematological cancers and solid cancers.

### Claim 14 (depends on 8)

The method of claim 8, wherein the cancer is a hematological cancer selected from myelodysplastic syndrome and leukemia.

### Claim 15 (depends on 8)

The method of claim 8, wherein the cancer is a solid cancer selected from the group consisting of pancreatic cancer, ovarian cancer, peritoneal cancer, metastatic breast cancer, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, gynecological cancer, fallopian tube carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cervical carcinoma, genitourinary tract cancer, and gastrointestinal cancer.

### Claim 16 (depends on 8)

The method of claim 8, wherein the compound of Formula I is a compound of Formula VIII:
or a pharmaceutically acceptable salt , a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof.

### Claim 17 (depends on 8)

The method of claim 8, wherein the compound is administered at substantially the same time with the CDA substrate drug, prior to the CDA substrate drug or after the CDA substrate drug.

### Claim 18 (depends on 8)

The method of claim 8, wherein the compound and the CDA substrate drug are administered in a single unit dosage form or in multiple, separate unit dosage forms.

### Claim 19 (depends on 11)

The method of claim 11, wherein the compound of Formula I is a compound of Formula VIII:
or a pharmaceutically acceptable salt , a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 14)

The method of claim 14, wherein the leukemia is acute myeloid leukemia or chronic myeloid leukemia.

### Claim 22 (depends on 15)

The method of claim 15, wherein the lung cancer is non small cell lung cancer.

### Claim 23

A composition comprising:
(i) a compound of Formula I:
wherein:
one of R1 and R2 is F and the other is H;
one of R3 and R4 is H, and the other is selected from H and OH;
where —is a covalent bond or absent, and R4 is absent when —is a covalent bond;
or a pharmaceutically acceptable salt, a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof;
(ii) a cytidine deaminase (CDA) substrate drug; and
(iii) at least one additional pharmaceutical agent, wherein the pharmaceutical agent is selected from an anti-emetic, an agent that increases appetite, a cytotoxic or chemotherapeutic agent, and an agent that relieves pain;
as a combination for simultaneous, separate, or sequential administration.

### Claim 24 (depends on 23)

The composition of claim 23, wherein the CDA substrate drug is selected from the group consisting of decitabine, 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.

### Claim 25 (depends on 24)

The composition of claim 24, wherein the CDA substrate drug is 5-azacytidine, gemcitabine, or ara-C.

### Claim 26 (depends on 24)

The composition of claim 24, wherein the CDA substrate drug is decitabine.

### Claim 27 (depends on 23)

The composition of claim 23, wherein the pharmaceutical agent is selected from a cytotoxic or chemotherapeutic agent.

### Claim 28

A method for treating cancer in a mammal in need thereof, comprising:
(i) administering to said mammal a compound of Formula 1:
wherein:
one of R1 and R2 is F and the other is H;
one of R3 and R4 is H, and the other is selected from H and OH;
where—is a covalent bond or absent, and R4 is absent when—is a covalent bond;
or a pharmaceutically acceptable salt, a C1-6 alkyl ester, or a C2-6 alkenyl ester thereof;
(ii) administering to said mammal a CDA substrate drug; and
(iii) administering to said mammal at least one additional pharmaceutical agent, wherein the pharmaceutical agent is selected from an anti-emetic, an agent that increases appetite, a cytotoxic or chemotherapeutic agent, and an agent that relieves pain.

### Claim 29 (depends on 28)

The method of claim 28, wherein the CDA substrate drug is selected from the group consisting of decitabine, 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.

### Claim 30 (depends on 28)

The method of claim 28, wherein the CDA substrate drug is 5-azacytidine, gemcitabine, or ara-C.

### Claim 31 (depends on 28)

The method of claim 28, wherein the CDA substrate drug is decitabine.

### Claim 32 (depends on 28)

The method of claim 28, wherein the pharmaceutical agent is selected from a cytotoxic or chemotherapeutic agent.

### Claim 33 (depends on 28)

The method of claim 28, wherein the cancer is selected from hematological cancers and solid cancers.

### Claim 34 (depends on 28)

The method of claim 28, wherein the cancer is a hematological cancer selected from myelodysplastic syndrome and leukemia.

### Claim 35 (depends on 28)

The method of claim 28, wherein the cancer is a solid cancer selected from the group consisting of pancreatic cancer, ovarian cancer, peritoneal cancer, metastatic breast cancer, bladder cancer, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, gynecological cancer, fallopian tube carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, cervical carcinoma, genitourinary tract cancer, and gastrointestinal cancer.

### Claim 36 (depends on 28)

The method of claim 28, wherein the compound is administered at substantially the same time with the CDA substrate drug, prior to the CDA substrate drug or after the CDA substrate drug.

### Claim 37 (depends on 28)

The method of claim 28, wherein the compound and the CDA substrate drug are administered in a single unit dosage form or in multiple, separate unit dosage forms.

### Claim 38 (depends on 23)

A pharmaceutical composition comprising the composition of claim 23 and a pharmaceutically acceptable excipient.

### Claim 39 (depends on 34)

The method of claim 34, wherein the leukemia is acute myeloid leukemia or chronic myeloid leukemia.

### Claim 40 (depends on 35)

The method of claim 35, wherein the lung cancer is non small cell lung cancer.