# US 10,307,465 B2 · Pharmaceutical compositions and methods

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- Number: US 10,307,465 B2
- Document ID: US10307465B2
- Status: Granted
- Kind: B2
- Application number: 15/618,344
- Filed: 2017-06-09
- Published: 2017-09-28
- Granted: 2019-06-04
- Earliest claimed: 2012-01-17
- Assignees: Tyme, Inc.
- Applicants: Tyme, Inc.
- Inventors: Steven Hoffman
- Web page: https://patentgrep.com/patent/US10307465B2

## CPC

- A61K 38/34: Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/787: containing heterocyclic rings having nitrogen as a ring hetero atom
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61P 35/00: Antineoplastic agents
- 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

Pharmaceutical compositions and kits including a tyrosine hydroxylase inhibitor; melanin, a melanin promoter, or a combination thereof; a p450 3A4 promoter; and a leucine aminopeptidase inhibitor are provided. Also provided are methods of treating cancer in a subject, comprising administering an effective amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, and a leucine aminopeptidase inhibitor to the subject in need thereof. Also provided are methods of reducing cell proliferation in a subject comprising administering an effective amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter, and a leucine aminopeptidase inhibitor to the subject in need thereof.

## Claims

### Claim 1

A method of making cancer cells more accessible to oxidative stress, comprising contacting said cancer cells with an effective amount of a tyrosine hydroxylase inhibitor and assessing oxidative stress in said cancer cells.

### Claim 2 (depends on 1)

The method of claim 1, wherein said tyrosine hydroxylase inhibitor accumulates in said cancer cells.

### Claim 3 (depends on 1)

The method of claim 1, wherein said tyrosine hydroxylase inhibitor prevents formation of a coating of lipids in said cancer cells.

### Claim 4 (depends on 1)

The method of claim 1, wherein said tyrosine hydroxylase inhibitor prevents formation of a coating of hyaluronan in said cancer cells.

### Claim 5 (depends on 1)

The method of claim 1, wherein said contacting is effected by administering said effective amount of said tyrosine hydroxylase inhibitor to a subject in whom said cancer cells reside.

### Claim 6 (depends on 1)

The method of claim 1, wherein said tyrosine hydroxylase inhibitor is administered orally, subcutaneously, intravenously, transdermally, vaginally, or rectally.

### Claim 7 (depends on 1)

The method of claim 1, wherein said tyrosine hydroxylase inhibitor is a tyrosine derivative.

### Claim 8 (depends on 7)

The method of claim 7, wherein the tyrosine derivative is one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6- dichloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OMe HCl, H-3,5-diiodo-tyr-Ome HCl, H-D-3,5-diiodo-tyr-OMe HCl, H-D-tyr-OMe HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-OMe HCl, methyl D-tyrosinate hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr (3,5-I2)-OSu, Fmoc-tyr(3-NO2)-OH, and α-methyl-DL-tyrosine.

### Claim 9 (depends on 7)

The method of claim 7, wherein the tyrosine derivative is α-methyl-DL tyrosine.

### Claim 10

A method of treating cancer in a subject comprising administering to the subject an amount of α-methyl-DL-tyrosine that is effective to make cancer cells in said subject more accessible to oxidative stress.

### Claim 11 (depends on 10)

The method of claim 10, wherein the cancer is non-small cell lung cancer, ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer, testicular cancer, prostate cancer, leukemia, or lymphoma.

### Claim 12 (depends on 10)

The method of claim 10, wherein the cancer is metastatic cancer.

### Claim 13 (depends on 10)

The method of claim 10, wherein the cancer is breast cancer.

### Claim 14 (depends on 10)

The method of claim 10, wherein the cancer is prostate cancer.

### Claim 15 (depends on 10)

The method of claim 10, wherein the α-methyl-DL-tyrosine accumulates in the cancer cells and prevents the cancer cells from forming a coating of lipids.

### Claim 16 (depends on 10)

The method of claim 10, wherein the α-methyl-DL-tyrosine accumulates in the cancer cells and prevents the cancer cells from forming a coating of hyaluronan.

### Claim 17 (depends on 10)

The method of claim 10, wherein the cancer is non-small cell lung cancer.

### Claim 18 (depends on 10)

The method of claim 10, wherein the cancer is ovarian cancer.

### Claim 19 (depends on 10)

The method of claim 10, wherein the cancer is cervical cancer.

### Claim 20 (depends on 10)

The method of claim 10, wherein the cancer is pancreatic cancer.

### Claim 21 (depends on 10)

The method of claim 10, wherein the cancer is stomach cancer.

### Claim 22 (depends on 10)

The method of claim 10, wherein the cancer is brain cancer.

### Claim 23 (depends on 10)

The method of claim 10, wherein the cancer is liver cancer.

### Claim 24 (depends on 10)

The method of claim 10, wherein the cancer is testicular cancer.

### Claim 25 (depends on 10)

The method of claim 10, wherein the cancer is leukemia.

### Claim 26 (depends on 10)

The method of claim 10, wherein the cancer is lymphoma.