# US 2017/0283374 A1 · Compositions and methods for treatment of prostate carcinoma

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- Number: US 2017/0283374 A1
- Document ID: US20170283374A1
- Status: Published application
- Kind: A1
- Application number: 15/508,391
- Filed: 2015-09-11
- Published: 2017-10-05
- Earliest claimed: 2014-09-12
- Assignees: Pellficure Pharmaceuticals, Inc.
- Applicants: Pellficure Pharmaceuticals, Inc.
- Inventors: Per Borgström; Adrian Chrastina; Veronique Therese Baron; Parisa Abedinpour
- Web page: https://patentgrep.com/patent/US20170283374A1

## CPC

- C07C 323/61: having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- A61K 31/05: Phenols {(cannabinoids A61K31/658)}
- A61K 31/105: Persulfides (thiuram disulfides A61K31/145; thiosulfonic acids A61K31/185)
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/222: with compounds having aromatic groups, e.g. dipivefrine, ibopamine
- A61K 31/235: having an aromatic ring attached to a carboxyl group
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/325: Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145)
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
- A61K 31/45: having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/661: Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos}
- A61P 35/00: Antineoplastic agents
- C07C 50/32: the quinoid structure being part of a condensed ring system having two rings
- C07C 69/63: of saturated acids
- C07C 69/92: with etherified hydroxyl groups
- C07C 205/36: to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C 217/60: linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
- C07C 225/30: of condensed quinone ring systems formed by two rings
- C07C 233/23: with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
- C07C 233/25: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- C07C 271/46: to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
- C07C 311/16: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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

Disclosed herein are 1,4-naphthoquinone analogs, pharmaceutical compositions that include one or more of such 1,4-naphthoquinone analogs, and methods of treating and/or ameliorating diseases and/or conditions associated with a cancer, such as prostate cancer with such 1,4-naphthoquinone analogs. Also included are combination therapies wherein a 1,4-naphthoquinone analog disclosed herein, and a hormone therapy agent are provided to a subject suffering from a condition such as cancer.

## Claims

### Claim 1

A 1,4-naphthoquinone analog compound having the chemical structure of:

### Claim 2

A method of inhibiting or delaying the growth of prostate cancer, comprising administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1 is —O—R3 or —NR4R5;
R2 is selected from the group consisting of hydrogen, halogen, and —O—R3;
R3 is an optionally substituted aryl, wherein the aryl is optionally substituted with one to five groups independently selected from the group consisting of —OH, —COOH, —NR6R7, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-C14 aryloxy, C6-C14 aralkyloxy, C6-C14 aralkyl, —(C═O)—C1-6 alkyl, —(C═O)—O—C1-6 alkyl, —N—(C═O)—C1-6 alkyl, —C1-6 alkyl-N(R6)(R7), —O(C═O)—NH—C1-6 alkyl, and —O(C═O)—NH—C1-6 haloalkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, —(C═O)—C1-6 alkyl, and an optionally substituted aryl, wherein the aryl is optionally substituted with one to five groups independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-C14 aryloxy, C6-C14 aralkyloxy, C6-C14 aralkyl, —(C═O)—C1-6 alkyl, —SO2N—C(═O)—C1-6 alkyl, and —SO2NH2;
R6 and R7 are independently selected from hydrogen and an optionally substituted C1-6 alkyl;
wherein the growth of prostate cancer is inhibited or delayed; and, optionally,
wherein the compound of Formula (I) is administered to the subject in combination with, subsequent to, or concomitantly with, an androgen deprivation therapy.

### Claim at position 3

3-30. (canceled)

### Claim 31 (depends on 2)

The method of claim 2, wherein the compound of Formula (I) is selected from the group consisting of:
2-(phenylamino)naphthalene-1,4-dione;
4-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)benzenesulfonamide;
2-(2,3,4,5,6-pentafluorophenoxy)-1,4-naphthoquinone;
2,3-dimethoxy-1,4-naphthoquinone; and
2-(4-hydroxyphenoxy)-1,4-naphthoquinone.

### Claim 32 (depends on 2)

The method of claim 2, wherein said androgen deprivation therapy is surgical orchiectomy.

### Claim 33 (depends on 2)

The method of claim 2, wherein said androgen deprivation therapy is administration of one or more agents selected from the group consisting of cyproterone acetate, abiraterone, finasteride, flutamide, nilutamide, bicalutamide, diethylstilbestrol (DES), megestrol acetate, fosfestrol, estamustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, orteronel, VT-464, enzalutamide, ARN-509, vinclozolin, galeterone, ketoconazole, L-39, aminoglutethimide, prochloraz, dutasteride, izonsteride, turosteride, epristeride, genisterin, gossypol, equol, 18β-glycyrrhetinic acid, altraric acid, N-butylbenzene-sulfonamide, 3,3′-diindolylmethane, deslorelin, nafarelin, cetrorelix, and ganirelix.

### Claim 34 (depends on 2)

The method of claim 2, wherein said androgen deprivation therapy reduces the production of testosterone and/or inhibits the conversion of testosterone to DHT.

### Claim 35 (depends on 2)

The method of claim 2, wherein said androgen deprivation therapy is administration of one or more agents selected from the group consisting of abiraterone, finasteride, diethylstilbestrol (DES), megestrol acetate, fosfestrol, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, orteronel, VT-464, ketoconazole, L-39, aminoglutethimide, prochloraz, dutasteride, izonsteride, turosteride, epristeride, equol, deslorelin, nafarelin, cetrorelix, and ganirelix.

### Claim 36 (depends on 35)

The method of claim 35, wherein said androgen deprivation therapy is administration of one or more agents selected from the group consisting of abiraterone, leuprolide, degarelix, and dutasteride.

### Claim 37 (depends on 2)

The method of claim 2, wherein the androgen deprivation therapy decreases the subject's serum testosterone level to about 1-2%, 2-4%, 1-5%, 4-6%, 4-8%, or 5-10% of a healthy male subject.

### Claim 38 (depends on 2)

The method of claim 2, wherein the androgen deprivation therapy decreases the subject's serum testosterone level to at least about ≦20 ng/dL.

### Claim 39

A method of inhibiting or delaying the growth of prostate cancer, comprising administering to a subject having prostate cancer a therapeutically effective amount of a compound of Formula (III) or a compound having the following chemical structure or a pharmaceutically acceptable salt thereof:
wherein R11 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, —(C═O)—C1-6 alkyl, and —(C═O)—C1-6haloalkyl;
wherein the growth of prostate cancer is inhibited or delayed; and, optionally,
wherein the compound of Formula (III) or Formula (F51) is administered to the subject in combination with, subsequent to, or concomitantly with, an androgen deprivation therapy.

### Claim 40 (depends on 39)

The method of claim 39, wherein the compound of Formula (III) is 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalen-1-yl 2-chloroacetate.

### Claim 41 (depends on 39)

The method of claim 39, wherein said androgen deprivation therapy is surgical orchiectomy.

### Claim 42 (depends on 39)

The method of claim 39, wherein said androgen deprivation therapy is administration of one or more agents selected from the group consisting of cyproterone acetate, abiraterone, finasteride, flutamide, nilutamide, bicalutamide, diethylstilbestrol (DES), megestrol acetate, fosfestrol, estamustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, orteronel, VT-464, enzalutamide, ARN-509, vinclozolin, galeterone, ketoconazole, L-39, aminoglutethimide, prochloraz, dutasteride, izonsteride, turosteride, epristeride, genisterin, gossypol, equol, 18β-glycyrrhetinic acid, altraric acid, N-butylbenzene-sulfonamide, 3,3′-diindolylmethane, deslorelin, nafarelin, cetrorelix, and ganirelix.

### Claim 43 (depends on 39)

The method of claim 39, wherein the androgen deprivation therapy decreases the subject's serum testosterone level to about 1-2%, 2-4%, 1-5%, 4-6%, 4-8%, or 5-10% of a healthy male subject.

### Claim 44 (depends on 39)

The method of claim 39, wherein the androgen deprivation therapy decreases the subject's serum testosterone level to at least about ≦20 ng/dL.

### Claim 45

A product combination that inhibits prostate cancer in a subject, wherein the product combination comprises a compound of Formula (I), Formula (III), or Formula (F51), or a pharmaceutically acceptable salt thereof, and a hormone therapy agent; and
wherein the compound of Formula (I), Formula (III), and Formula (F51) have the following structures:
wherein:
R1 is —O—R3 or —NR4R5;
R2 is selected from the group consisting of hydrogen, halogen, and —O—R3;
R3 is an optionally substituted aryl, wherein the aryl is optionally substituted with one to five groups independently selected from the group consisting of —OH, —COOH, —NR6R7, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-C14 aryloxy, C6-C14 aralkyloxy, C6-C14 aralkyl, —(C═O)—C1-6 alkyl, —(C═O)—O—C1-6 alkyl, —N—(C═O)—C1-6 alkyl, C1-6 alkyl-N(R6)(R7), —O(C═O)—NH—C1-6 alkyl, and —O(C═O)—NH—C1-6 haloalkyl;
R4 and R5 can be independently selected from the group consisting of hydrogen, —(C═O)—C1-6 alkyl, and an optionally substituted aryl, wherein the aryl is optionally substituted with one to five groups independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-C14 aryloxy, C6-C14 aralkyloxy, C6-C14 aralkyl, —(C═O)—C1-6 alkyl, —SO2N—C(═O)—C1-6 alkyl, and —SO2NH2;
R6 and R7 are independently selected from hydrogen and an optionally substituted C1-6 alkyl; and
R11 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, —(C═O)—C1-6 alkyl, and —(C═O)—C1-6haloalkyl.

### Claim 46 (depends on 45)

The product combination of claim 45, wherein said hormone therapy agent comprises one or more agents selected from the group consisting of cyproterone acetate, abiraterone, finasteride, flutamide, nilutamide, bicalutamide, diethylstilbestrol (DES), megestrol acetate, fosfestrol, estamustine phosphate, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, orteronel, VT-464, enzalutamide, ARN-509, vinclozolin, galeterone, ketoconazole, L-39, aminoglutethimide, prochloraz, dutasteride, izonsteride, turosteride, epristeride, genisterin, gossypol, equol, 18β-glycyrrhetinic acid, altraric acid, N-butylbenzene-sulfonamide, 3,3′-diindolylmethane, deslorelin, nafarelin, cetrorelix, and ganirelix.

### Claim 47 (depends on 45)

The product combination of claim 45, wherein said hormone therapy agent reduces the production of testosterone and/or inhibits the conversion of testosterone to DHT.

### Claim 48 (depends on 45)

The product combination of claim 45, wherein said hormone therapy agent comprises one or more agents selected from the group consisting of abiraterone, finasteride, diethylstilbestrol (DES), megestrol acetate, fosfestrol, leuprolide, triptorelin, goserelin, histrelin, buserelin, abarelix, degarelix, orteronel, VT-464, ketoconazole, L-39, aminoglutethimide, prochloraz, dutasteride, izonsteride, turosteride, epristeride, equol, deslorelin, nafarelin, cetrorelix, and ganirelix.

### Claim 49 (depends on 45)

The product combination of claim 45, wherein said hormone therapy agent comprises one or more agents selected from the group consisting of abiraterone, leuprolide, degarelix, and dutasteride.