Compounds and methods for the prevention and treatment of tumor metastasis and tumorigenesis

Patent metadata

Field	Value
Publication number	US-10301314-B2
Application number	US-201715606740-A
Country	US
Kind code	B2
Filing date	May 26, 2017
Priority date	Dec 16, 2011
Publication date	May 28, 2019
Grant date	May 28, 2019

Abstract

The disclosure provides compounds for reducing the prevalence of the perinucleolar compartment in cells, for example, of formula (I), wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, that are useful in treating a disease or disorder associated with increased prevalence of the perinucleolar compartment, such as cancer. Also disclosed is a composition containing a pharmaceutically acceptable carrier and at least one compound embodying the principles of the invention, and a method of treating or preventing cancer in a mammal.

First claim

The invention claimed is:

1. A method for treating cancer in a mammal, comprising administering to a mammal in need thereof a compound of formula (I):

wherein R 1 is a 5 or 6-membered heterocyclyl group selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, pyrrolidinyl, piperidinyl, and morpholinyl; hydroxy C 3 -C 7 cycloalkyl; C 1 -C 6 hydroxyalkyl; N,N-di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl; C 1 -C 6 alkoxy C 1 -C 6 alkyl; heteroaryl C 1 -C 6 alkyl, wherein the heteroaryl is selected from the group consisting of furanyl; thiopheneyl; pyrrolyl; pyrazolyl; imidazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; isoxazolyl; oxazolyl; isothiazolyl; thiazolyl; 1,3,4-oxadiazol-2-yl; 1,2,4-oxadiazol-2-yl; 5-methyl-1,3,4-oxadiazole; 3-methyl-1,2,4-oxadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; triazinyl; benzofuranyl; benzothiopheneyl; indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzoxazolinyl; benzothiazolinyl; and quinazolinyl; heterocyclyl C 1 -C 6 alkyl, wherein the heterocyclyl group of heterocyclyl C 1 -C 6 alkyl is selected from the group consisting of selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, pyrrolidinyl, piperidinyl, and morpholinyl; phenyl C 1 -C 6 alkyl wherein the phenyl ring of phenyl C 1 -C 6 alkyl is substituted with one or more C 1 -C 6 alkoxy groups; N-phenyl piperazinylalkyl; or phenyl C 1 -C 6 alkyl where the alkyl of phenyl C 1 -C 6 alkyl is substituted with a hydroxy group,
R 2 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, thio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthioalkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthiocarbonyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, and (C 1 -C 6 )alkylcarbonyl,
R 3 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, thio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthioalkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthiocarbonyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, and (C 1 -C 6 )alkylcarbonyl,
R 4 is selected from the group consisting of cyclohexylmethyl, cyclopropylmethyl, benzyl, and phenylethyl, wherein the phenyl ring of benzyl and phenylethyl is optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, thio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthioalkyl, (C 1 -C 6 )alkoxy carbonyl, (C 1 -C 6 )alkylthiocarbonyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, hydroxyl, perfluoroalkoxy, and (C 1 -C 6 )alkylcarbonyl,
or a pharmaceutically acceptable salt thereof,
wherein R 1 is optionally substituted on the hydroxy C 3 -C 7 cycloalkyl group with one or more (C 1 -C 6 )alkyl groups,

wherein the cancer is a metastatic cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

2. The method of claim 1 , wherein R 1 is selected from the group consisting of the following:

3. The method of claim 2 , wherein R 2 is phenyl, R 3 is phenyl, and R 4 is benzyl.

4. The method of claim 1 , wherein R 4 is 4-methoxybenzyl, R 2 is phenyl, R 3 is phenyl, and R 1 is selected from the group consisting of the following:

5. The method of claim 1 , wherein R 4 is phenylethyl, R 2 is phenyl, R 3 is phenyl, and R 1 is selected from the group consisting of the following:

6. The method of claim 1 , wherein R 4 is selected from 4-trifluoromethoxybenzyl, 4-methoxybenzyl, and cyclopropylmethyl and wherein R 1 is selected from the following:

7. The method of claim 1 , wherein the cancer is pancreatic cancer.

8. The method of claim 1 , further comprising administering to the mammal a chemotherapeutic agent or subjecting the mammal to a radiation treatment.

9. The method of claim 1 , wherein the treating results in the disrupting a perinucleolar compartment in a cell in the mammal, reducing the prevalence of perinucleolar compartment in a cell in the mammal, reducing ATP levels produced by metastatic cancer cells in the mammal, reducing the colony formation of cancer cells in the mammal, or reducing the migration of cancer cells in the mammal.

Assignees

• Us Health
• Univ Kansas
• Univ Northwestern

Inventors

• Frankowski Kevin
• Patnaik Samarjit
• Huang Sui
• Marugan Juan Jose
• Norton John
• Schoenen Frank J
• Southall Noel Terrence
• Titus Steven
• Zheng Wei
• Wang Chen

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title