# US 2014/0194442 A1 · Anticancer therapy

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- Number: US 2014/0194442 A1
- Document ID: US20140194442A1
- Status: Published application
- Kind: A1
- Application number: 13/978,748
- Filed: 2012-01-12
- Published: 2014-07-10
- Earliest claimed: 2011-01-12
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Flavio Solca; Ulrich Guertler; Michael Sanderson; Ulrike Tontsch-Grunt; Irene Waizenegger
- Web page: https://patentgrep.com/patent/US20140194442A1

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- 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 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- 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

The invention describes anti-cancer therapies comprising using dual Aurora kinase/MEK inhibitors as described herein.

## Claims

### Claim 1

A method of treating a mammalian patient having cancer, said method comprising:
obtaining a nucleic acid sample from a cancer sample from said patient;
subjecting the sample to RAF or RAS mutational testing or PCR and identifying the presence of at least one mutation in the RAF or RAS gene; and
administering an effective amount of a dual Aurora kinase/MEK inhibitor to the patient in whose sample the presence of at least one mutation in the RAF or RAS gene is identified.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The method of claim 1, wherein said RAF is BRAF.

### Claim 4 (depends on 1)

The method of claim 1, wherein said RAS is KRAS or NRAS.

### Claim 5

A method of treating a mammalian, patient diagnosed with cancer which is dependent upon the MEK-signalling pathway or in which MEK is activated, in particular such cancer having at least one mutation in the BRAF or RAS (e.g. KRAS and/or NRAS) gene, said method comprising administering an effective amount of a dual Aurora kinase/MEK inhibitor.

### Claim 6 (depends on 1)

The method of claim 1, wherein said at least one mutation comprises a mutation in the BRAF gene, particularly a mutation in codons 464-469 and/or in codon V600 of BRAF gene.

### Claim 7 (depends on 6)

The method of claim 6, wherein the mutation in the BRAF gene is a mutation selected from V600E, V600G, V600A and V600K, or a mutation selected from V600E, V600D, V600K and V600R, or a mutation selected from V600E, V600D and V600K, or a mutation selected from V600E, V600D, V600M, V600G, V600A, V600R and V600K.

### Claim 8 (depends on 1)

The method of claim 1, wherein said at least one mutation comprises a mutation in the KRAS gene, such as e.g. a mutation in codons 12, 13 and/or 61, particularly a mutation in codons 12 and/or 13 of KRAS gene.

### Claim 9 (depends on 8)

The method of claim 8, wherein the mutation in the KRAS gene is selected from Gly12Asp, Gly12Val, Gly13Asp, Gly12Cys, Gly12Ser, Gly12Ala and Gly12Arg, or selected from 12D, 12V, 12C, 12A, 12S, 12R, 12F, 13D, 13C, 13R, 13S, 13A, 13V, 13I, 61H, 61L, 61R, 61K, 61E and 61P.

### Claim 10 (depends on 1)

The method of claim 1, wherein said at least one mutation comprises a mutation in the NRAS gene, particularly a mutation in codons 12, 13 and/or 61 of NRAS gene.

### Claim 11 (depends on 10)

The method of claim 10, wherein the mutation in the NRAS gene is selected from p.G12D, p.G12S, p.G12C, p.G12V, p.G12A, p.G13D, p.G13R, p.G13C, p.G13A, p.Q61R, p.Q61K, p.Q61L, p.Q61H and p.Q61P.

### Claim 12 (depends on 1)

The method of claim 1, wherein said cancer is selected from pancreas cancer (PAC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), ovarian cancer (OC), prostate cancer, breast cancer, hepatocellular cancer (HCC), melanoma, and thyroid cancer.

### Claim 13 (depends on 1)

The method of claim 1, wherein said dual Aurora kinase/MEK inhibitor is selected from the group consisting of:
1) N-ethyl-3-[3-[[4-(4-methylpiperazin-1-yl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
2) N-(2,2-difluoroethyl)-3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
3) N-(2,2-difluoroethyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
4) N-(2-fluoroethyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
5) N-ethyl-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
6) 3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-ethylprop-2-ynamide,
7) N-cyclobutyl-3-[3-[[4-(4-methylpiperazin-1-yl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
8) N-cyclopropyl-3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
9) 3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-phenylprop-2-ynamide,
10) N-cyclopentyl-3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
11) N-cyclopentyl-3-[3-[[4-(4-methylpiperazin-1-yl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
12) N-cyclobutyl-3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
13) 3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-(2-hydroxyethyl)prop-2-ynamide,
14) 3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-propan-2-ylprop-2-ynamide,
15) 3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]-N-propan-2-ylprop-2-ynamide,
16) N-(2-hydroxyethyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
17) N-(2-fluorophenyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
18) 3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-[(2S)-1-hydroxypropan-2-yl]prop-2-ynamide,
19) N-[(2S)-1-hydroxypropan-2-yl]-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
20) N-[(2R)-butan-2-yl]-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
21) N-(3-chlorophenyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
22) N-(3-chlorophenyl)-3-[3-[[4-(dimethylaminomethyl)anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]prop-2-ynamide,
23) 3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]-N-phenylprop-2-ynamide,
24) 3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]-N-pentan-3-ylprop-2-ynamide, and
25) N-(3-fluorophenyl)-3-[2-oxo-3-[phenyl-[4-(pyrrolidin-1-ylmethyl)anilino]methylidene]-1H-indol-6-yl]prop-2-ynamide,
or a pharmaceutically acceptable salt thereof.

### Claim at position 14

14-16. (canceled)

### Claim at position 15

17-19. (canceled)

### Claim at position 16

20-40. (canceled)