# US 9,040,551 B2 · Small molecule inhibitors of polynucleotide kinase/phosphatase, poly(ADP-ribose) polymerase and uses thereof

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- Number: US 9,040,551 B2
- Document ID: US9040551B2
- Status: Granted
- Kind: B2
- Application number: 13/375,876
- Filed: 2010-06-04
- Published: 2012-06-07
- Granted: 2015-05-26
- Earliest claimed: 2009-06-04
- Assignees: The Governors of the University of Alberta; Alberta Health Services
- Applicants: Michael Weinfeld; Dennis G. Hall; Feridoun Karimi-Busheri; Gary Kenneth Freschauf; Todd Randall Mereniuk
- Inventors: Michael Weinfeld; Dennis G. Hall; Feridoun Karimi-Busheri; Gary Kenneth Freschauf; Todd Randall Mereniuk
- Web page: https://patentgrep.com/patent/US9040551B2

## CPC

- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- C07D 471/04: Ortho-condensed systems
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention generally relates to use of compounds and compositions as a chemosensitizers and/or radiosensitizers and/or inhibitors of PNKP phosphatase activity. The present invention provides pharmaceutical combinations and/or a pharmaceutically acceptable salt thereof, kits containing such compounds and/composition and methods of using such compounds and/or compositions.

## Claims

### Claim 1

A pharmaceutical composition comprising: a first amount of a topoisomerase I inhibitor and a second amount of a polynucleotide kinase/phosphatase (PNKP) inhibitor, and a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein said PNKP inhibitor is 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), 2-(hydroxy(phenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1Hpyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A1B4C3), 2-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7adihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A6B4C3), tert-butyl 2-(1-hydroxy-2,2-diphenylethyl)-6-methyl-5,7-dioxo-2,4-a,5,6,7,7a-hexahydro-1Hpyrrolo[3,4-b]pyridin-1-ylcarbamate A26B11C2) or 2-(hydroxy(thiophen-2-yl)methyl)-6-methyl-1-(phenylamino)-6,7a-dihydro-1Hpyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A39B1C2).

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein said PNKP inhibitor is A12B4C3.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein said topoisomerase I inhibitor is gimatecan, irinotecan, or camptothecin.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein said topoisomerase I inhibitor is camptothecin.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein said PNKP inhibitor is A12B4C3 and said topoisomerase I inhibitor is camptothecin.

### Claim 7

A combination comprising a topoisomerase I inhibitor and a polynucleotide kinase/phosphatase (PNKP).

### Claim 8 (depends on 7)

The combination of claim 7, wherein said PNKP inhibitor is 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1Hpyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), 2-(hydroxy(phenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1Hpyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A1B4C3), 2-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7adihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A6B4C3), tert-butyl 2-(1-hydroxy-2,2-diphenylethyl)-6-methyl-5,7-dioxo-2,4-a,5,6,7,7a-hexahydro-1Hpyrrolo[3,4-b]pyridin-1-ylcarbamate A26B11C2) or 2-(hydroxy(thiophen-2-yl)methyl)-6-methyl-1-(phenylamino)-6,7a-dihydro-1Hpyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A39B1C2).

### Claim 9 (depends on 7)

The combination of claim 7, wherein said PNKP inhibitor is A12B4C3.

### Claim 10 (depends on 7)

The combination of claim 7, wherein said topoisomerase I inhibitor is gimatecan, irinotecan, or camptothecin.

### Claim 11 (depends on 10)

The combination of claim 10, wherein said topoisomerase I inhibitor is camptothecin.

### Claim 12 (depends on 7)

The combination of claim 7, wherein said PNKP inhibitor is A12B4C3 and said topoisomerase I inhibitor is camptothecin.

### Claim 13

A method of treating a subject suffering from a disorder associated with a defect in DNA polymerase β, comprising administering to said subject an inhibitor of polynucleotide kinase/phosphatase (PNKP).