# US 8,541,460 B2 · PDK-1/Akt signaling inhibitors

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- Number: US 8,541,460 B2
- Document ID: US8541460B2
- Status: Granted
- Kind: B2
- Application number: 12/118,788
- Filed: 2008-05-12
- Published: 2008-10-30
- Granted: 2013-09-24
- Earliest claimed: 2003-10-03
- Assignees: The Ohio State University
- Applicants: Ching-Shih Chen
- Inventors: Ching-Shih Chen
- Web page: https://patentgrep.com/patent/US8541460B2

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- 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

Use of a new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of formula I for inducing apoptosis in unwanted rapidly proliferating cells, for treating, inhibiting, or delaying the onset of cancer, and for preventing restenosis in a subject that has undergone an angioplasty or stent: wherein X is selected from the group consisting of alkyl and haloalkyl; Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl; and wherein Ar is optionally substituted with one or more radicals selected from the group consisting of halo, C1-C4 alkyl, C1-C4 haloalkyl, azido, C1-C4 azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof; and R is selected from the group consisting of nitrile, acetonitrile, ethylnitrile, propylnitrile, carboxamide, amidine, tetrazole, oxime, hydrazone, acetamidine, aminoacetamide, guanidine, and urea.

## Claims

### Claim 1

A method of inducing apoptosis in unwanted rapidly proliferating cells, the method comprising the step of contacting a therapeutically effective amount of a compound of formula I:
wherein
X is selected from the group consisting of alkyl and haloalkyl;
Ar is selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthrenyl, and fluorenyl; wherein Ar is optionally substituted with one or more substituents at any suitable position;
R is selected from the group consisting of —CN, —CH2CN, —CH2CH2CN, —CH2CH2CH2CN,
or pharmaceutically acceptable salts thereof, with the rapidly proliferating cells.

### Claim 2 (depends on 1)

The method of claim 1, wherein the rapidly proliferating cells are cancer cells, wherein the cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.

### Claim 3 (depends on 1)

The method of claim 1 wherein the compound is selected from compounds IV and V:
or a combination thereof, pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein X is C1 to C4 haloalkyl.

### Claim 5 (depends on 4)

The method of claim 4, wherein X is CF3.

### Claim 6 (depends on 1)

The method of claim 1, wherein Ar is selected from the group consisting of 2-naphthyl, 4-biphenyl, 9-anthryl, 2-fluorenyl, 4-azidophenyl, 4-azidomethylphenyl, 4-(2-azidoethyl)phenyl, 4-(3-azidopropyl)phenyl, 4-(4-azidobutyl)phenyl, 4-(4-azidophenyl)phenyl, 4-(4-azidomethylphenyl)phenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-(2-bromoethyl)phenyl, 4-(3-bromopropyl)phenyl, 4-(4-bromobutyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(4-methylphenyl)phenyl, 4-(4-bromomethylphenyl)phenyl, 4-(4-butylphenyl)phenyl, 4-(4-tert-butylphenyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-(4-chlorophenyl)phenyl, 4-(3,5-dichlorophenyl)phenyl, 4-(2,3-dichlorophenyl)phenyl, 4-(3,5-dimethylphenyl)phenyl, 4-(2,4,5-trichlorophenyl)phenyl, 4-(4-trifluoromethylphenyl)phenyl, 2-phenanthrenyl, 3-indolyl, 2-pyrrolyl, and 4-(benzyl)phenyl.

### Claim 7 (depends on 6)

The method of claim 6, wherein Ar is 2-phenanthrenyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R is selected from aminoacetamide and guanidine.

### Claim 9 (depends on 1)

The method of claim 1, wherein X is CF3, Ar is 2-phenanthrenyl, and R is selected from aminoacetamide and guanidine.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is:
or pharmaceutically acceptable salts thereof, and
wherein the rapidly proliferating cells are cancer cells, wherein the cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.