Small-molecule Hsp90 inhibitors

Patent metadata

Field	Value
Publication number	US-10000494-B2
Application number	US-201615218524-A
Country	US
Kind code	B2
Filing date	Jul 25, 2016
Priority date	Feb 1, 2005
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

First claim

What is claimed is:

1. A method of treating cancer in an individual, comprising administering to the individual a compound of the formula:

wherein:
X 6 is NH 2 ;
X 3 is hydrogen or halogen;
X 1 is a C 1 to C 10 alkyl, alkenyl, or alkynyl group, wherein the alkyl, alkenyl, or alkynyl group includes a heteroatom;
the linker is selected from the group consisting of CH 2 , O, NH and S;
Y is independently CH or N;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2 , NHSO 2 X 7 , C═OR 2 where X 7 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and
n is 1 or 2,
or a pharmaceutically acceptable salt thereof,
wherein the cancer is breast cancer, prostate cancer, colon cancer, myelocytic leukemia, small cell lung cancer, non-small cell lung cancer, neuroblastoma, or vulvar cancer.

2. The method of claim 1 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

3. The method of claim 1 , wherein X 1 is an amino alkyl moiety, optionally substituted on the amino nitrogen with one or two carbon-containing substituents selected independently from the group consisting of alkyl, alkenyl and alkynyl substituents, wherein the total number of carbons in the amino alkyl moiety is from 1 to 10.

4. The method of claim 1 , wherein X 1 contains at least one nitrogen heteroatom.

5. The method of claim 1 , wherein X 1 contains at least one oxygen heteroatom.

6. The method of claim 1 , wherein X 1 includes a cyclic portion.

7. The method of claim 1 , wherein the linker is CH 2 or S.

8. The method of claim 1 , wherein X 1 comprises a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

9. The method of claim 1 , wherein X 1 is —(CH 2 ) n —N—R 10 R 11 , wherein n is 2 or 3 and R 10 and R 11 are independently selected from hydrogen, methyl, ethyl, ethene, ethyne, propyl, isopropyl, isobutyl, ethoxy, cyclopentyl, an alkyl group forming a 3 or 6-membered ring including the N, or a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

10. The method of claim 1 , wherein X 2 is halogen.

11. The method of claim 10 , wherein X 1 is —(CH 2 ) n —N—R 10 R 11 , wherein n is 2 or 3 and R 10 and R 11 are independently selected from hydrogen, methyl, ethyl, ethene, ethyne, propyl, isopropyl, isobutyl, ethoxy, cyclopentyl, an alkyl group forming a 3 or 6-membered ring including the N, or a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

12. The method of claim 10 , wherein the linker is CH 2 or S.

13. The method of claim 10 , wherein X 1 is selected from the following:

14. The method of claim 1 , wherein the compound is administered in combination with radiation and/or chemotherapy.

15. The method of claim 1 , wherein the cancer is breast cancer, prostate cancer, neuroblastoma, myelocytic leukemia, colon cancer, or non-small cell lung cancer.

16. A method of treating cancer in an individual, comprising administering to the individual a compound of the formula:

wherein:
X 6 is NH 2 ;
X 3 is hydrogen or halogen;
X 1 is hydrogen or a C 1 to C 10 alkyl, alkenyl, or alkynyl group, optionally including a heteroatom;
the linker is selected from the group consisting of CH 2 , O, NH and S;
Y is independently CH or N;
X 2 is alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2 , NHSO 2 X 7 , C═OR 2 where X 7 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and
n is 1 or 2,
or a pharmaceutically acceptable salt thereof,
wherein the cancer is breast cancer, prostate cancer, colon cancer, myelocytic leukemia, small cell lung cancer, non-small cell lung cancer, neuroblastoma, or vulvar cancer.

17. The method of claim 16 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

18. The method of claim 16 , wherein X 1 includes a cyclic portion which optionally includes at least one heteroatom.

19. The method of claim 16 , wherein the linker is CH 2 or S.

20. The method of claim 16 , wherein the compound is administered in combination with radiation and/or chemotherapy.

21. The method of claim 16 , wherein the cancer is breast cancer, prostate cancer, neuroblastoma, myelocytic leukemia, colon cancer, or non-small cell lung cancer.

Assignees

• Sloan Kettering Inst Cancer Res

Inventors

• Chiosis Gabriela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title