Methods and reagents for radiolabeling

Patent metadata

Field	Value
Publication number	US-10329293-B2
Application number	US-201815971908-A
Country	US
Kind code	B2
Filing date	May 4, 2018
Priority date	Dec 23, 2013
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention provides methods for radiolabeling compounds useful as Hsp90 inhibitors. The present invention also provides intermediates useful in such methods, and compositions of radiolabeled compounds. The present invention provides, among other things novel methods for the synthesis of radiolabeled compounds. In certain embodiments, the present invention provides compounds of formula I.

First claim

What is claimed is:

1. A method comprising the steps of:
a) providing a trialkyltin compound of formula I:

wherein:
X is —CH 2 —, —O—, or —S—;
Y 1 and Y 2 are independently —CR 3a — or —N—;
Z 1 Z 2 , and Z 3 are independently —CH— or —N—;
R 1 is hydrogen or halogen;
L is a straight or branched, C 2-14 aliphatic group wherein one or more carbons are optionally and independently replaced by —Cy—, —NR—, —N(R)C(O)—, —C(O)N(R)—, —C(O)N(O)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, or —SO 2 —,
each -Cy- is independently an optionally substituted 3-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is hydrogen or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl;
wherein —L—R 2 does not contain a Boc-protected secondary amine;
each R 3 is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , or optionally substituted C 1-6 aliphatic or pyrrolyl; or
two R 3 groups are taken together with their intervening atoms to form Ring A, wherein Ring A is a 3- to 7-membered partially unsaturated carbocyclyl, phenyl, a 5- to 6-membered partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, or 6-membered aryl;

R 3a is R 3 or hydrogen;
R 4 is C 1-4 alkyl;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;

and
b) reacting the trialkyltin compound of formula I under suitable conditions to provide a compound of formula I L :

wherein R L is a radiolabel.

2. The method of claim 1 , further comprising the steps of:
a) providing an aryl iodide compound of formula A:

and
b) reacting the aryl iodide of formula A under suitable conditions to provide a trialkyltin compound of formula I:

3. The method of claim 1 , further comprising the steps of:
a) providing protected amine compound of formula C:

wherein —L—R 2 ′ comprises a methylene that is replaced with —NH— to form a secondary amine, and wherein the secondary amine is protected with a suitable protecting group;
and
b) reacting the protected amine compound of formula C under suitable deprotection conditions to provide trialkyltin compound of formula I:

4. The method of claim 3 , further comprising the steps of:
a) providing an aryl iodide compound of formula B:

and
b) reacting the aryl iodide of formula B under suitable conditions to provide protected amine compound of formula C:

5. The method of claim 4 , further comprising the steps of:
a) providing an aryl iodide of formula A:

and
b) reacting the aryl iodide of formula A under suitable reaction conditions to provide an aryl iodide compound of formula B:

6. The method of claim 1 , wherein the compound of formula I is of formula I-a:

7. The method of claim 1 , wherein the compound of formula I is of formula I-b, I-c, I-d, I-e, I-f, I-g, I-h, or I-j:

8. The method of claim 1 , wherein Y 1 is —CR 3a —.

9. The method of claim 8 , wherein Y 2 is —CR 3a —.

10. The method of claim 9 , wherein each of R 3a is hydrogen.

11. The method of claim 10 , wherein Z 1 , Z 2 , and Z 3 are —N—.

12. The method of claim 1 , wherein the compound of formula I is of formula I-i:

13. The method of claim 11 , wherein —L—R 2 does not contain a protected secondary amine.

14. The method of claim 13 , wherein X is —S—.

15. The method of claim 11 , wherein —L—R 2 comprises a methylene that is replaced with —NH— to form a secondary amine.

16. The method of claim 14 , wherein L is a C 2-14 aliphatic group wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.

17. The method of claim 16 , wherein L is a C 2-8 aliphatic group wherein a methylene of the aliphatic group is replaced with —NH— to form a secondary amine.

18. The method of claim 17 , wherein R 4 is methyl.

19. The method of claim 17 , wherein R 4 is butyl.

20. The method of claim 11 , wherein —L—R 2 is selected from the following:

21. The method of claim 20 , wherein —L—R 2 is selecte

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Ochiana Stefan O
• Pillarsetty Nagavarakishore
• Taldone Tony
• Chiosis Gabriela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D473/34 Primary

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

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07F7/2208

  Compounds having tin linked only to carbon, hydrogen and/or halogen · CPC title