# US 8,569,360 B2 · Compositions and methods for inhibition of hepatocyte growth factor receptor c-Met signaling

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,569,360 B2
- Document ID: US8569360B2
- Status: Granted
- Kind: B2
- Application number: 12/935,646
- Filed: 2009-03-31
- Published: 2011-11-17
- Granted: 2013-10-29
- Earliest claimed: 2008-04-01
- Applicants: Donald P. Bottaro; Megan Peach; Marc Nicklaus; Nelly Tan
- Inventors: Donald P. Bottaro; Megan Peach; Marc Nicklaus; Nelly Tan
- Web page: https://patentgrep.com/patent/US8569360B2

## CPC

- C07D 213/90: having more than three double bonds between ring members or between ring members and non-ring members
- A61P 35/00: Antineoplastic agents
- C07D 213/85: in position 3
- C07D 239/22: with hetero atoms directly attached to ring carbon atoms
- C07D 311/86: Oxygen atoms, e.g. xanthones
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Derivatives and analogs of inhibitors of receptor tyrosine kinase c-Met obtained by virtual screening, pharmaceutical compositions containing derivatives and analogs of c-Met inhibitors are provided. Methods of making derivatives and analogs of c-Met inhibitors and methods of use thereof are provided. Formula (I)

## Claims

### Claim 1

A compound that is 9-(2,3-dichloro-phenyl)-2,6,7-trihydroxy-xanthen-3-one, or a pharmaceutically acceptable salt thereof.

### Claim 2

A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient and 9-(2,3-dichloro-phenyl)-2,6,7-trihydroxy-xanthen-3-one.

### Claim 3

A method for treating a mammal having a neoplastic disease,
wherein the treatment delays the onset of symptoms, complications, or biochemical indicia of the disease; alleviates the symptoms of the disease, arrests further development of the disease; or inhibits further development of the disease;
wherein the neoplastic disease is characterized by a c-Met mutation or an overexpression of c-Met, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein
R1 and R2 are each independently H, —CN, S, O, N, F, —CH2—OH, —OH, C1-C4 alkyl, amine, or ethanone, and at least one of R1 and R2 is —CN, S, O, N, or F;
R3 is H; C1-C4 alkyl optionally substituted with halo or sulfonate; phenyl, phenoxy, or phenoxyalkyl, each optionally substituted with one or two substituents selected from hydroxyl, alkoxy, alkyl, halo, acetamido, acetamido alkoxy, carboxyl, and optionally-substituted amino; indolyl; pyridinyl; furanyl; thiophenyl; benzo[1,3]dioxolyl; or morpholinoalkyl, phenylalkyl or naphthylalkyl, each optionally substituted with alkyl, halo, or haloalkyl;
R4 and R5 are each independently H; —CN; S; O; N; F; OH; C1-C4 alkyl; amine; ethanone; phenyl optionally substituted with hydroxyl, alkyl, or halo; or morpholinoalkyl, and at least one of R4 and R5 is —CN, S, O, N, F, or OH;
R6 is O or N—R7; and
R7 and R8 are each independently H; C1-C4 alkyl; hydroxyalkyl; carboxyalkyl; phenyl optionally substituted with one or more substituent selected from hydroxyl, alkoxy, carboxyl, halo, and acetamide-oxy; phenylamido; phenylamido carboxyl; phenylalkyl; phenylalkenyl; phenylhydrazonoalkyl; morpholinoalkyl; piperidine-proprionyl optionally substituted with carboxyl; or chromen-5-one optionally substituted with alkyl, dialkyl, or amino; and
R9, R10, and R11 are each independently H, lower alkyl, or halo.

### Claim 4 (depends on 3)

The method of claim 3 wherein R6 is O and R8 is piperidine-proprionyl optionally substituted with carboxyl.

### Claim 5 (depends on 3)

The method of claim 3 wherein R1 is O and R2 is OH.

### Claim 6 (depends on 3)

The method of claim 3 wherein R4 and R5 are each OH.

### Claim 7 (depends on 3)

The method of claim 3 wherein R3 is phenyl substituted with two halogen atoms.

### Claim 8 (depends on 3)

The method of claim 3 wherein the halogen atoms are Cl, Br, F, or I.

### Claim 9 (depends on 3)

The method of claim 3 wherein the compound acts through c-Met protein down-regulation and TK inhibition.

### Claim 10 (depends on 3)

The method of claim 3 wherein the compound inhibits TK activity as a competitive ATP binding antagonist.

### Claim 11 (depends on 3)

The method of claim 3 wherein:
R1 is ═O,
R2, R4, and R5 are each OH,
R3 is phenyl di-substituted with chloro,
R6, is O, and
R8, R9, R10, and R11 are each H.

### Claim 12 (depends on 3)

The method of claim 3 comprising administering a therapeutically effective amount of 9-(2,3-dichloro-phenyl)-2,6,7-trihydroxy-xanthen-3-one, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 3)

The method of claim 3, wherein the neoplastic disease is renal cell carcinoma, lung cancer, thyroid cancer, or head and neck cancer.