Substituted 6-aminopurines for targeting HSP90

Patent metadata

Field	Value
Publication number	US-10112947-B2
Application number	US-201715653338-A
Country	US
Kind code	B2
Filing date	Jul 18, 2017
Priority date	Aug 6, 2012
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

Described herein are 6-aminopurine compounds comprising formula (III) that may selectively bind to Hsp90, methods of using the compounds, and kits including the compounds. Formula (III) may link to detection moieties such as fluorophores that may allow for selective detection of Hsp90 in a sample.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
A is a heat shock protein 90 binding component of formula (III):

wherein:
R is alkylenyl or heteroalkylenyl;
each Y 1 is independently —CH or —N;
each Z 1 is taken together with the carbon atoms to which they are attached to form a heterocyclic ring;
Z 2 is —H or halo;
Z 3 is —CH 2 —, —S—, —O—or —NH—;
Z 4 is —H or halo; and

is the point of attachment in formula (I);
X 1 is —NH—, —O—, —S—, —C(O)—or —S(O) 2 —;
L is a divalent linker of the following formula:
—(CH 2 ) m —(OCH 2 CH 2 ) n —O—(CH 2 ) p —,

wherein:
m is 2 or 3;
n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and
p is 2 or 3;

X 2 is —NR—, —O—, —S—, —C(O)—or —S(O) 2 —;
R is —H or a detection moiety; and
B is a detection moiety, an anti-cancer agent, or a heat shock protein 90 binding component of formula (II):

wherein:
R 1 is —H or —C 1-8 -alkyl;
R 2 is —H or —C 1-8 -alkyl;
Y is —CR 3 or —N;
R 3 is —H, —F or —OCH 3 ;
R 4 is —H, —F or —OCH 3 ;
R 5 is —H, —F or —OCH 3 ;
R 6 is —C 1-8 -alkyl, —C 2-8 -alkenyl, —C 2-8 -alkynyl, —C 3-8 -cycloalkenyl, —C 3-8 -cycloalkenyl-C 1-8 -alkyl, —C 3-8 -cycloalkyl, —C 3-8 -cycloalkyl-C 1-8 -alkyl, aryl, aryl-C 1-8 -alkyl, halo-C 1-8 -alkyl, heteroaryl, heteroaryl-C 1-8 -alkyl, heterocyclyl, heterocyclyl-C 1-8 -alkyl, or hydroxy-C 1-8 -alkyl;
R 7 is —H or —C 1-8 -alkyl;
R 8 is —H or —C 1-8 -alkyl; or
R 7 and R 8 , taken together with the carbon atom to which they are attached, form a —C 3-8 -cycloalkyl;
X is —CR 9 or —N;
R 9 is —H or —C 1-8 -alkyl; and

is the point of attachment in formula (I); or
B is a detection moiety, an anti-cancer agent, or a heat shock protein 90 binding component of formula (III):

wherein:
R is alkylenyl or heteroalkylenyl;
each Y 1 is independently —CH or —N;
each Z 1 is taken together with the carbon atoms to which they are attached to form a heterocyclic ring;
Z 2 is —H or halo;
Z 3 is —CH 2 —, —S—, — 0 —or —NH—;
Z 4 is —H or halo; and

is the point of attachment in formula (I);
wherein each detection moiety independently comprises a fluorophore or a radioactive compound;
wherein the fluorophore is a fluorescein, a rhodamine, a coumarin, a cyanine or a boron-dipyrromethene;
wherein the radioactive compound is a radioisotope; and
wherein the anti-cancer agent is an alkylating agent, an anti-epidermal growth factor receptor antibody, an anti-Her-2 antibody, an antimetabolite, a vinca alkaloid, an anthracycline, a platinum-based agent, a topoisomerase inhibitor, a taxane, an anti-cancer antibiotic, an immune cell antibody, an interferon, an interleukin, a heat shock protein 90 inhibitor, an anti-androgen, an anti-estrogen, an antihypercalcemia agent, an apoptosis inducer, an aurora kinase inhibitor, a Bruton's tyrosine kinase inhibitor, a calcineurin inhibitor, a Ca 2+ -calmodulin-dependent protein kinase II inhibitor, a CD45 tyrosine phosphatase inhibitor, a cell division cycle 25 phosphatase inhibitor, a checkpoint kinase inhibitor, a cyclooxygenase inhibitor, a cRAF kinase inhibitor, a cyclin dependent kinase inhibitor, a cysteine protease inhibitor, a deoxyribonucleic acid intercalator, a deoxyribonucleic acid strand breaker, an E3 ligase inhibitor, an epidermal growth factor pathway inhibitor, a farnesyltransferase inhibitor, a fetal liver kinase-1 inhibitor, a glycogen synthase kinase-3 inhibitor, a histone deacetylase inhibitor, an I-kappa B-alpha kinase inhibitor, an imidazotetrazinone, an insulin tyrosine kinase inhibitor, a c-Jun N-terminal kinase inhibitor, a mitogen-activated protein kinase inhibitor, a mouse double minute 2 inhibitor, an MEK inhibitor, a matrix metalloproteinase inhibitor, a mammalian target of rapamycin inhibitor, a nerve growth factor receptor tyrosine kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, a p56 tyrosine kinase inhibitor, a platelet-derived growth factor pathway inhibitor, a phosphatidylinositol 3-kinase inhibitor, a phosphatase inhibitor, a protein phosphatase inhibitor, a protein kinase C inhibitor, a protein kinase C delta kinase inhibitor, a polyamine synthesis inhibitor, a protein tyrosine phosphatase 1B inhibitor, a protein tyrosine kinase inhibitor, an SRC family tyrosine kinase inhibitor, a spleen tyrosine kinase inhibitor, a Janus tyrosine kinase inhibitor, a retinoid, a ribonucleic acid polymerase II elongation inhibitor, a serine/threonine kinase inhibitor, a sterol biosynthesis inhibitor, a vascular endothelial growth factor pathway inhibitor, alitretinon, altretamine, aminopterin, aminolevulinic acid, amsacrine, asparaginase, atrasentan, bexarotene, carboquone, demecolcine, efaproxiral, elsamitrucin, etoglucid, a Gliadel implant, hydroxycarbamide, leucovorin, lonidamine, lucanthone, masoprocol, methyl aminolevulinate, mitoguazone, mitotane, oblimersen, omacetaxine, pegaspargase, porfimer sodium, prednimustine, sitimagene ceradenovec, talaporfin, temoporfin, trabectedin or verteporfin.

2. The compound of claim 1 , wherein A has the following formula:

3. The compound of claim 1 , wherein B is the detection moiety.

4. The compound of claim 1 , wherein B is the detection moiety comprising the fluorophore.

5. The compound of claim 4 , wherein B has the following formula:

and

is the point of attachment to the —X 2 -L-X 1 -A moiety of the compound of formula (I).

6. The compound of claim 4 , wherein the fluorophore is a fluorescein.

7. The compound of claim 1 , wherein B is the anti-cancer agent.

8. The compound of claim 7 , wherein the anti-cancer agent is methotrexate, topotecan, irinotecan, etoposide, teniposide, lamellarin D, SN-38, camptothecin, belotecan, rubitecan, thalidomide, or verteporfin.

9. The compound of claim 1 , wherein B is the heat shock protein 90 binding component of formula (II) or formula (III).

10. The compound of claim 9 , wherein B is the heat shock protein 90 binding component of formula (II).

11. The compound of claim 9 , wherein B is the heat shock protein 90 binding component of formula (III).

12. The compound of claim 1 , wherein m is 3 and p is 3.

13. The compound of claim 1 , wherein n is 4.

14. A kit comprising a compound of claim 1 .

Assignees

• Univ Duke

Inventors

• Haystead Timothy
• Hughes Philip Floyd

Classifications

• G01N33/57595

  involving intracellular compounds · CPC title

• G01N33/575

  for cancer · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D413/12

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

• C07D493/10

  Spiro-condensed systems · CPC title