# US 2010/0168060 A1 · Salts of benzimidazolyl pyridyl ethers and formulations thereof

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- Number: US 2010/0168060 A1
- Document ID: US20100168060A1
- Status: Published application
- Kind: A1
- Application number: 12/377,901
- Filed: 2007-08-30
- Published: 2010-07-01
- Earliest claimed: 2006-08-30
- Assignees: Novartis AG
- Inventors: Rampurna Gullapalli; Ahmad Hashash; Piotr H. Karpinski; Kangwen L. Lin; Eric M. Loeser; Augustus O. Okhamafe; Paul Allen Sutton; Eduardo Sy
- Web page: https://patentgrep.com/patent/US20100168060A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Salts of benzimidazolyl pyridyl ethers are provided, particularly salts of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine. Compositions and formulations including such salts and surfactants as well as methods of preparing such compositions and formulations are provided.

## Claims

### Claim 1

A salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine selected from the group consisting of acetate, tosylate, succinate, lactate, malate, sulfate, maleate, citrate, hydrochloride, phosphate, ethanesulfonate, and methanesulfonate.

### Claim 2 (depends on 1)

The salt of claim 1 selected from {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine methanesulfonate, {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine ethanesulfonate, or {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine) trifluoromethyl-phenyl)amine maleate.

### Claim 3

A composition comprising a pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine and a surfactant.

### Claim 4 (depends on 3)

The composition of claim 3 wherein the cognate acid of the acid salt has a pKa of about 4.7 or less than 4.7.

### Claim 5 (depends on 3)

The composition of claim 3 wherein the cognate acid of the acid salt has a pKa of from about 4 to about −6.

### Claim 6 (depends on 3)

The composition of claim 3 wherein the cognate acid of the acid salt is a carboxylic acid, carbonic acid, acid salt of an amino acid, ascorbic acid, isoascorbic acid, amino acid, polyamino acid, alkanesulfonic acid, inorganic acid, polymeric acid, or a mixture of any two or more thereof.

### Claim 7 (depends on 3)

The composition of claim 3 wherein the cognate acid of the acid salt is malic acid, citric acid, tartaric acid, oxalic acid, succinic acid, adipic acid, fumaric acid, acetic acid, formic acid, lactic acid, maleic acid, phthalic acids, creatinine hydrochloride, pyridoxine hydrochloride, thiamine hydrochloride, cysteine hydrochloride, glycine hydrochloride, cystine dihydrochloride, peptides, toluene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, phosphoric acid, phosphonic acid, orthophosphoric acid, hydrochloric acid, sulfonic acid, sulfuric acid, nitric acid, sodium metabisulfite, potassium phosphate monobasic, polyphosphoric acid, polyvinylsulfuric acid, polyvinylsulfonic acid, or a mixture of any two or more thereof.

### Claim 8 (depends on 3)

The composition of claim 3 wherein the cognate acid of the acid salt is selected from the group consisting of acetic acid, toluene sulfonic acid, succinic acid, lactic acid, malic acid, sulfuric acid, maleic acid, citric acid, hydrochloric acid, ethanesulfonic acid, and methanesulfonic acid.

### Claim 9 (depends on 3)

The composition of claim 3 wherein the amount of pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine is from about 0.0025 wt % to about 80 wt % based upon the total weight of the composition.

### Claim 10 (depends on 3)

The composition of claim 3 wherein the surfactant has an HLB value of about 8 or higher than 8.

### Claim 11 (depends on 3)

The composition of claim 3 wherein the surfactant is selected from polyoxyethylene castor oil compounds, polyoxyethylene mono- and di-fatty acid esters, mixtures of polyoxyethylene mono- and di-esters of C8-C22 fatty acids and glyceryl mono-, di-, and tri-esters of C8-C22 fatty acids, α-tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sodium dioctyl sulfosuccinate, sodium lauryl sulfate, sorbitan fatty acid esters, sugar fatty acid esters, or a mixture of any two or more thereof.

### Claim 12 (depends on 3)

The composition of claim 3 wherein the surfactant is polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 40 stearate, polyoxyl 150 stearate, polyoxyl 150 distearate, d-α-tocopheryl polyethylene glycol 1000 succinate, poloxamer 124, poloxamer 188, poloxamer 407, sorbitan monolauryl ester, sorbitan monopalmityl ester, sorbitan monostearyl ester, or a mixture of any two or more thereof.

### Claim 13 (depends on 3)

The composition of claim 3 wherein the surfactant is d-α-tocopheryl polyethylene glycol 1000 succinate, poloxamer 188, or a mixture of any two or more thereof.

### Claim 14 (depends on 3)

The composition of claim 3 wherein the amount of surfactant is from about 0.01 wt % to about 60 wt % based upon the total weight of the composition

### Claim 15 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any one of claims 3-14 having a solubility of at least about 0.058 mg/mL in distilled water.

### Claim 16 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any one of claims 3-14 having a solubility of at least about 0.058 mg/mL in simulated gastric fluid.

### Claim 17 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any one of claims 3-14 wherein at least 90 wt % of a sample of the composition containing the equivalent of about 100 mg of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine dissolves in 900 mL of simulated gastric fluid at 37±0.5° C. in about 90 minutes or less than 90 minutes.

### Claim 18 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any one of claims 3-14 wherein the composition is solid.

### Claim 19 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any one of claims 3-14 further comprising a carrier.

### Claim 20 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any of claims 3-14 further comprising an antioxidant, a coloring agent, a cyclodextrin, a flavoring agent, a preservative, a sweetener, or a mixture of any two or more thereof.

### Claim 21 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The composition of any of claims 3-14 wherein the composition is contained within a capsule or tablet.

### Claim 22 (depends on 21)

The composition of claim 21 wherein the total mass of the pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine ranges from about 0.01 mg to about 400 mg.

### Claim 23 (depends on 3)

A method comprising combining a pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine and a surfactant to provide the composition of claim 3.

### Claim 24 (depends on 23)

The method of claim 23 further comprising combining a carrier with the acid salt and the surfactant.

### Claim 25 (depends on 23)

The method of claim 23 further comprising combining an antioxidant, a coloring agent, a cyclodextrin, a flavoring agent, a preservative, a sweetener, or a mixture of any two or more thereof with the acid salt and the surfactant.

### Claim 26 (depends on 3)

A method comprising combining a compound, a pharmaceutically acceptable acid, and a surfactant to provide the composition of claim 3, wherein the compound is {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine.

### Claim 27 (depends on 3, 26)

The method of claim 26 wherein the compound, acid, and surfactant are combined by mixing the compound and acid together to provide a salt of the compound, and subsequently mixing the salt of the compound with the surfactant to provide the composition of claim 3.

### Claim 28 (depends on 27)

The method of claim 27 wherein the compound and the acid are mixed by dissolving the compound and the acid in an organic solvent to form the salt of the compound.

### Claim 29 (depends on 28)

The method of claim 28 further comprising isolating the salt from the organic solvent.

### Claim 30 (depends on 29)

The method of claim 29 wherein the salt is isolated by precipitation from the organic solvent.

### Claim 31 (depends on 28)

The method of claim 28 wherein the organic solvent is a ketone, alcohol, ether, ester or a mixture of any two or more thereof.

### Claim 32 (depends on 28)

The method of claim 28 wherein the organic solvent is acetone, tetrahydrofuran, methanol, ethanol, isopropanol, or mixtures of any two or more thereof.

### Claim 33 (depends on 26)

The method of claim 26 wherein the pharmaceutically acceptable acid is a carboxylic acid, carbonic acid, acid salt of an amino acid, ascorbic acid, isoascorbic acid, amino acid, polyamino acid, alkanesulfonic acid, inorganic acid, polymeric acid, or a mixture of any two or more thereof.

### Claim 34 (depends on 26, 27, 28, 29, 30, 31, 32, 33)

The method of any one of claims 26-33 further comprising combining a carrier with the acid salt and the surfactant.

### Claim 35 (depends on 26, 27, 28, 29, 30, 31, 32, 33)

The method of any of claims 26-33 further comprising combining an antioxidant, a coloring agent, a cyclodextrin, a flavoring agent, a preservative, a sweetener, or a mixture of any two or more thereof with the acid salt and the surfactant.

### Claim 36 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any of claims 23-33 further comprising forming at least one capsule or tablet with the formulation.

### Claim 37 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any of claims 23-33 wherein the amount of pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine is from about 0.0025 wt % to about 80 wt % based upon the total weight of the composition.

### Claim 38 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any of claims 23-33 wherein the amount of surfactant is from about 0.01 wt % to about 60 wt % based upon the total weight of the composition.

### Claim 39 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any of claims 23-33 wherein the total mass of the pharmaceutically acceptable acid salt of {1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethyl-phenyl)amine ranges from about 0.01 mg to about 400 mg.

### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

A method of treating cancer and/or inhibiting angiogenesis comprising administering the salt of claim 1 or 2 or the composition of any one of claims 3-22 to a subject in need thereof.

### Claim 41 (depends on 40)

The method of claim 40 wherein the cancer to be treated is one or more selected from the group consisting of bladder, breast, brain, head and neck, liver, biliary tract, carcinomas, acute and chronic lymphoid leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemias colorectal, gastric, gastrointestinal stromal, glioma, lymphomas, melanomas, multiple myeloma, myeloproliferative diseases, neuroendocrine, lung, pancreatic, prostate, renal cell, sarcomas, and thyroid cancers.

### Claim 42 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 40, 41)

The method of claims 40 and 41 wherein the salt of claim 1 or 2 or the composition of any one of claims 3-22 to subject in need is to be administered as a single loading dose and then to be followed by once, twice, three-times, or four-times daily administration with the ratio of loading dose to daily dose of 3 to 20.