# US 9,518,062 B2 · Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers

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- Number: US 9,518,062 B2
- Document ID: US9518062B2
- Status: Granted
- Kind: B2
- Application number: 14/316,415
- Filed: 2014-06-26
- Published: 2014-12-18
- Granted: 2016-12-13
- Earliest claimed: 2009-07-16
- Assignees: Mallinckrodt Inc.
- Applicants: Mallinckrodt LLC
- Inventors: Gary L. Cantrell; Raghavan Rajagopalan; Amolkumar Karwa; Richard B. Dorshow
- Web page: https://patentgrep.com/patent/US9518062B2

## CPC

- C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/02: Suppositories; Bougies; Bases therefor; {Ovules}(apparatus for making A61J3/08; devices for introducing into the body A61M31/00)
- A61K 9/10: Dispersions; Emulsions
- A61K 9/145: {with organic compounds}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2022: {Organic macromolecular compounds}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- C07D 221/28: Morphinans
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

The invention relates generally to anti-angiogenesis agents and related methods of using to anti-angiogenesis agents for biomedical applications including direct monotherapy and combination therapy for treatment of an angiogenesis related condition. In an embodiment, the invention provides a class of opioid compounds and structurally related opioid derivatives exhibiting anti-VEGF activity for use in therapeutic procedures, including phototherapy. Opioid compounds and structurally related opioid derivatives of the invention may be administered alone or in combination with administration of a phototherapy agent and/or other therapeutic agent.

## Claims

### Claim 1

A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula (FX2):
wherein:
ring A is
X is —OH, —OCH3, or C2-C8 alkoxy;
Y is —H or —OH;
W is —(CR10R11)—, —(C═O)—, —(C═S)—, —(C═CR12R13)—, or —(CR14NR15R16—);
each of R1 and R2 is independently —H, —CH3, —(O−), C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C5-C10 aryl, C5-C10 heteroaryl, C5-C10 alkylaryl, C5-C10 alkylheteroaryl, C5-C10 carbonylalkenylaryl, or C5-C10 carbonylalkenylheteroaryl;
each of R3-R16 and R50-R54 is independently —H, —OH, —OCH3, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkoxy, C5-C10 aryl, C5-C10 heteroaryl, C5-C10 alkylaryl, C5-C10 alkylheteroaryl, halo, nitrile, C1-C8 haloalkyl, C1-C10 hydroxyalkyl, or C5-C10 carbonylalkenylheteroaryl; and
when n is 1, and the nitrogen to which R2 is attached has a positive charge and optionally is associated with an anion.

### Claim 2 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX12):
wherein:
A−z is independently an anion;
z is independently 1, 2 or 3; and
m is independently 0 or 1, wherein when m is 0, A−z is not present.

### Claim 3 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula:

### Claim 4 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula:

### Claim 5 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula:

### Claim 6 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX14):

### Claim 7 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX16):

### Claim 8 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX18):

### Claim 9 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX19):

### Claim 10 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX21):

### Claim 11 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX23):

### Claim 12 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX25):

### Claim 13 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX27):

### Claim 14 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX30):

### Claim 15 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX32):

### Claim 16 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX34):

### Claim 17 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX36):

### Claim 18 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX38):

### Claim 19 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX39):

### Claim 20 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX41):

### Claim 21 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX43):

### Claim 22 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX45).

### Claim 23 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX47):

### Claim 24 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX50):

### Claim 25 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX52):

### Claim 26 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX54):

### Claim 27 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX56):

### Claim 28 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX58):

### Claim 29 (depends on 1)

The method of claim 1 wherein said (+) enantiomer compound has the formula (FX60):

### Claim 30 (depends on 1)

The method for treating cancer of claim 1, further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula (FX2).

### Claim 31 (depends on 1)

The method of claim 1, comprising a method for treating pancreatic cancer.

### Claim 32 (depends on 1)

The method of claim 1, comprising a method of suppressing tumor growth or tumor metastasis.

### Claim 33 (depends on 1)

The method of claim 1, further comprising administering to said patient one or more chemotherapeutic agents.

### Claim 34 (depends on 1)

The method of claim 1, further comprising administering to said patient one or more VEGF inhibitors.

### Claim 35 (depends on 1)

The method of claim 1, further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.

### Claim 36

A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula:
wherein:
each of R1 and R2 is independently —H, —CH3, —(O−), C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C5-C10 aryl, C5-C10 heteroaryl, C5-C10 alkylaryl, C5-C10 alkylheteroaryl, C5-C10 carbonylalkenylaryl, or C5-C10 carbonylalkenylheteroaryl; and
n is 1, and the nitrogen to which R2 is attached has a positive charge and optionally is associated with an anion.

### Claim 37 (depends on 36)

The method for treating cancer of claim 36, further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula:

### Claim 38 (depends on 36)

The method of claim 36, comprising a method for treating pancreatic cancer.

### Claim 39 (depends on 36)

The method of claim 36, comprising a method of suppressing tumor growth or tumor metastasis.

### Claim 40 (depends on 36)

The method of claim 36, further comprising administering to said patient one or more chemotherapeutic agents.

### Claim 41 (depends on 36)

The method of claim 36, further comprising administering to said patient one or more VEGF inhibitors.

### Claim 42 (depends on 36)

The method of claim 36, further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.

### Claim 43

A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula (FX14):
wherein:
each of R1 and R2 is independently —H, —CH3, —(O−), C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C5-C10 aryl, C5-C10 heteroaryl, C5-C10 alkylaryl, C5-C10 alkylheteroaryl, C5-C10 carbonylalkenylaryl, or C5-C10 carbonylalkenylheteroaryl; and
n is 1, and the nitrogen to which R2 is attached has a positive charge and optionally is associated with an anion.

### Claim 44 (depends on 43)

The method for treating cancer of claim 43, further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula (FX14).

### Claim 45 (depends on 43)

The method of claim 43, comprising a method for treating pancreatic cancer.

### Claim 46 (depends on 43)

The method of claim 43, comprising a method of suppressing tumor growth or tumor metastasis.

### Claim 47 (depends on 43)

The method of claim 43, further comprising administering to said patient one or more chemotherapeutic agents.

### Claim 48 (depends on 43)

The method of claim 43, further comprising administering to said patient one or more VEGF inhibitors.

### Claim 49 (depends on 43)

The method of claim 43, further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.