Heat shock protein binding compounds, compositions, and methods for making and using same

Patent metadata

Field	Value
Publication number	US-10758538-B2
Application number	US-201816037160-A
Country	US
Kind code	B2
Filing date	Jul 17, 2018
Priority date	Aug 17, 2009
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present subject matter relates to a compound represented by the general formula (I) or (I′) or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).

First claim

We claim:

1. A method of treating a cancer or proliferative disorder in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula 2a:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
wherein:
X 5 -X 9 are independently selected from CH, C substituted with W 3 or W 4 , and N;
Y is S, SO, SO 2 , CH 2 , CHR, CRR, or CO, wherein R is a C 1 -C 6 alkyl or alkoxy chain;
Z is selected from the group consisting of alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, nitro, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, —SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN;
W 1 and W 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, unsaturated heterocycle, halogen, nitro, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, —SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN, and
W 3 and W 4 independently at each occurrence are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, —SO 2 -alkyl, —COO-alkyl, —COalkyl, and alkyl-CN.

2. The method of claim 1 , wherein the cancer or proliferative disorder is selected from the group consisting of breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, brain cancer, hematopoietic cancer, esophageal carcinoma, renal cell carcinoma, bladder cancer, head and neck cancer, leukemia, cholangiosarcoma, esophageal sarcoma, hepatocellular carcinoma, non-small- and small-cell lung cancer (NSCLC and SCLC), and lymphoma.

3. The method of claim 1 , wherein:
Y is S, SO, or SO 2 ;
Z is alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, alkoxy, dialkylamino, cycloalkylamino, arylamino, or diarylamino;
W 1 and W 2 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, amino, alkylamino, cycloalkylamino, arylamino, or diarylamino; and
W 3 and W 4 are independently hydrogen, halogen, hydroxyl, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, —SO 2 -alkyl, —COO-alkyl, —COalkyl, or alkyl-CN.

4. The method of claim 1 , wherein X 5 -X 9 are selected from:

5. The method of claim 1 , wherein Y is S, SO, or SO 2 .

6. The method of claim 1 , wherein Z is alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycle, halogen, hydroxyl, alkoxy, dialkylamino, cycloalkylamino, arylamino, or diarylamino.

7. The method of claim 1 , wherein W 1 and W 2 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, amino, alkylamino, cycloalkylamino, arylamino, or diarylamino.

8. The method of claim 1 , wherein W 3 and W 4 are independently hydrogen, halogen, hydroxyl, cyano, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, diarylamino, acylamino, carbamyl, amido, alkylamido, alkylsulfonamido, sulfonamido, —NHSO 2 alkenyl, —NHCOalkenyl, —NHCOalkynyl, —COalkenyl, —COalkynyl, trihalocarbon, thioalkyl, —SO 2 -alkyl, —COO-alkyl, —COalkyl, or alkyl-CN.

9. The method of claim 1 , wherein when W 1 or W 2 are alkoxy, the alkoxy is a substituted alkoxy group.

10. A method of treating a cancer or proliferative disorder in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula 2a″:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:
each R 1 is independently selected from the group consisting of H; optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; halogen; an optionally substituted C 2-22 acyl group; a C(O)R 6 group; and an -(ethoxy) n -R 6 group, wherein n is 1-12;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of H; optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; an optionally substituted C 2-22 acyl group; a C(O)R 6 group; and an optionally substituted alkoxycarbonyl group; and
X is selected from the group consisting of optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; halogen; an optionally substituted C 2-22 acyl group; a —NR 4 R 5 group; a —C(O)R 6 group; an -(ethoxy) n -R 6 group, wherein n is 1-12; an optionally substituted alkoxycarbonyl group; an optionally substituted alkyloxy group; an optionally substituted amino group; a nitro group; and a carboxyl group; and
each R 6 is independently selected from the group consisting of an optionally substituted straight or branched alkyl, alkenyl, or alkynyl; an optionally substituted carbocyclic, heterocyclic, aryl, or heteroaryl group; an optionally substituted alkyloxy group; and an alkylacrylate group;
provided that X does not comprise a bridged ring structure.

11. The method of claim 10 , wherein the cancer or proliferative disorder is selected from the group consisting of breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, brain cancer, hematopoietic cancer, esophageal carcinoma, renal cell carcinoma, bladder cancer, head and neck cancer, leukemia, cholangiosarcoma, esophageal sarcoma, hepatocellular carcinoma, non-small- and small-cell lung cancer (NSCLC and SCLC), and lymphoma.

12. The method of claim 10 , wherein:
each R 1 is independently selected from the group consisting of H; and optionally substituted straight or branched alkyl, alkenyl, or alkynyl;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of H; optionally substituted straight or branched C 1 -C 6 alkyl; and —C(O)R 6 wherein R 6 is an optionally substituted straight or branched C 1 -C 6 alkyl, alkenyl, or alkynyl; and
X is selected from the group consisting of an optionally subs

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Chiosis Gabriela
• Taldone Tony
• Rodina Anna
• Patel Pallav
• Kang Yanlong

Classifications

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D239/56

  One oxygen atom and one sulfur atom · CPC title