# US 9,750,809 B2 · Cancer treatment

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- Number: US 9,750,809 B2
- Document ID: US9750809B2
- Status: Granted
- Kind: B2
- Application number: 14/413,949
- Filed: 2013-07-11
- Published: 2015-06-11
- Granted: 2017-09-05
- Earliest claimed: 2012-07-12
- Assignees: Morex Development Partners LLP C/O Blue Rock Services
- Applicants: Morex Development Partners LLP
- Inventors: Christopher Beattie; Anne Wadsworth; James Rennie
- Web page: https://patentgrep.com/patent/US9750809B2

## CPC

- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 31/409: having four such rings, e.g. porphine derivatives, bilirubin, biliverdine (hemin, hematin A61K31/555)
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/69: Boron compounds
- A61K 33/34: Copper; Compounds thereof
- A61K 41/0057: {Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent}
- A61K 41/0095: {Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins}
- A61K 51/0485: {Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal}
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- C07D 487/22: in which the condensed system contains four or more hetero rings
- 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

A carborane-comprising porphyrin of Formula (1) is provided for use in cancer therapy that extends the period of time between the doses required while the patient is undergoing radiation therapy. The compound can be given not more often than once every 2 or more weeks, avoiding repeated administration, while radiation therapy can continue regularly.

## Claims

### Claim 1

A method of treating cancer, comprising administering a compound of the formula (1) as defined below to a patient and repeatedly irradiating the patient, wherein a single dose of the compound is administered not more than once every two weeks:
wherein:
R1, R2, R3 and R4 are selected from an electron withdrawing group, —NO2, —NH2, halogen or a substituent represented by the following formula
wherein Y can be on the ortho, meta or para position on the phenyl rings, and is selected from hydrogen, hydrocarbyl, non-aromatic carbocyclic, non-aromatic heterocyclic, aryl, alkylaryl, arylalkyl; or
a hydrocarbyl, non-aromatic carbocyclic, non-aromatic heterocyclic, aryl, alkylaryl or an arylalkyl group substituted with 1 to 4 hydrophilic groups selected from hydroxy, alkoxy, —C(O)OR5, —SOR6, —SO2R6, nitro, amido, ureido, carbamato, —SR7, —NR8R9 or poly-alkyleneoxide; or a substituent represented by formula (3)
—X—(CR10R11)r—Z (3);
provided that at least one of R1, R2, R3 and R4 is the substituent represented by formula (2) wherein Y represents formula (3);
wherein:
X is selected from oxygen or sulfur;
R5, R6, R7, R8, R9, R10 and R11 are selected from hydrogen and C1 to C4 hydrocarbyl;
Z is a carborane cluster comprising at least two carbon atoms and at least three boron atoms, or at least one carbon atom and at least five boron atoms, within a cage structure;
r is 0 or an integer from 1 to 20;
a represents an integer from 1 to 4; and
provided also that at least one of R1, R2, R3 and R4 is an electron withdrawing group, —NO2, —NH2 or halogen; and
M is selected from two hydrogen ions, a single monovalent metal ion, two monovalent metal ions, a divalent metal ion, a trivalent metal ion, a tetravalent metal ion, a pentavalent metal ion or a hexavalent metal ion, wherein the porphyrin-metal complex derived from a single monovalent metal ion is charge-balanced by a counter cation, and the porphyrin-metal complex derived from a trivalent, tetravalent, pentavalent or hexavalent metal ion is charge-balanced by an appropriate number of counter anions, dianions or trianions.

### Claim 2 (depends on 1)

The method of claim 1, wherein the single dose is administered not more often than once every 3 to 12 weeks.

### Claim 3 (depends on 1)

The method of claim 1, wherein the single dose is administered not more often than once every 4 to 9 weeks.

### Claim 4 (depends on 1)

The method of claim 1, wherein the single dose is administered not more often than once every 5 to 8 weeks.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1, R2, R3, R4 are selected from —NO2, halogen and Formula (2).

### Claim 6 (depends on 1)

The method of claim 1, wherein two of R1, R2, R3, R4 are —NO2 and two of R1, R2, R3, R4 are Formula (2).

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 and R3 are NO2.

### Claim 8 (depends on 1)

The method of claim 1, wherein R2 and R4 are Formula (2).

### Claim 9 (depends on 1)

The method of claim 1, wherein Y is in the meta position, M is a divalent metal ion, R10 and R11 are hydrogen, r is 1 to 6 and a is 1 or 2.

### Claim 10 (depends on 1)

The method of claim 1, wherein Z comprises 2 carbon atoms and 10 boron atoms within a cage structure.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is copper meso-5, 15-bis[3-[(1,2-dicarba-closo-dodecaboranyl)methoxy]phenyl]-meso-10,20-dinitroporphyrin.

### Claim 12 (depends on 1)

The method of claim 1, comprising intra-tumoural administration of the compound.

### Claim 13 (depends on 1)

The method of claim 1, comprising irradiating the patient approximately daily.

### Claim 14 (depends on 1)

A method of treating cancer, comprising administering a compound of the formula (1) as defined in claim 1 to a patient and repeatedly irradiating the patient, wherein a single dose of the compound is administered for the entire course of the treatment.

### Claim 15 (depends on 14)

The method claim 14, wherein the entire course of treatment takes between 1 and 16 weeks.

### Claim 16 (depends on 14)

The method claim 14, wherein the entire course of treatment takes between 3 and 12 weeks.

### Claim 17 (depends on 14)

The method of claim 14, wherein R1, R2, R3, R4 are selected from —NO2, halogen and Formula (2).

### Claim 18 (depends on 14)

The method of claim 14, wherein two of R1, R2, R3, R4 are —NO2 and two of R1, R2, R3, R4 are Formula (2).

### Claim 19 (depends on 14)

The method of claim 14, wherein R1 and R3 are NO2.

### Claim 20 (depends on 14)

The method of claim 14, wherein R2 and R4 are Formula (2).

### Claim 21 (depends on 14)

The method of claim 14, wherein Y is in the meta position, M is a divalent metal ion, R10 and R11 are hydrogen, r is 1 to 6 and a is 1 or 2.

### Claim 22 (depends on 14)

The method of claim 14, wherein Z comprises 2 carbon atoms and 10 boron atoms within a cage structure.

### Claim 23 (depends on 14)

The method of claim 14, wherein the compound is copper meso-5, 15-bis[3-[(1,2-dicarba-closo-dodecaboranyl)methoxy]phenyl]-meso-10,20-dinitroporphyrin.

### Claim 24 (depends on 14)

The method of claim 14, comprising intra-tumoural administration of the compound.

### Claim 25 (depends on 1)

A method of treating cancer, comprising administering a single dose of a compound of the formula (1) as defined in claim 1 to a patient and repeatedly irradiating the patient, wherein a therapeutically effective amount of X-ray sensitizing compound is retained in the tumour tissue after administration of a single dose of the compound for a clinically relevant period to allow a course of radiation therapy for the clinically relevant period, wherein the clinically relevant period is any period during which radiation therapy can still be given to the patient or needs to be given to the patient to treat the cancer.

### Claim 26 (depends on 25)

The method of claim 25 wherein the clinically relevant period is between 1 and 16 weeks.

### Claim 27 (depends on 25)

The method of claim 25 wherein the clinically relevant period is between 4 and 9 weeks.

### Claim 28 (depends on 25)

The method of claim 25, comprising intra-tumoural administration of the compound.

### Claim 29 (depends on 1)

A method of imaging a tumour, comprising administration of a compound of formula (I) as defined in claim 1 not more often than once every 2 weeks, and imaging the tumour two or more times.

### Claim 30 (depends on 29)

The method of claim 29, comprising intra-tumoural administration of the compound.