Deoxycytidine kinase binding compounds

Patent metadata

Field	Value
Publication number	US-9688673-B2
Application number	US-201214002964-A
Country	US
Kind code	B2
Filing date	Mar 8, 2012
Priority date	Mar 8, 2011
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The invention provides compounds that bind to deoxycytidine kinase (dCK) and compositions including pharmaceutically acceptable compositions containing the compounds. The compounds are useful in treating diseases and disorders where dCK activity is implicated such as cancer and immune disorders. The compounds also find use in clinical methodologies including positron emission tomography (PET) imaging.

First claim

What is claimed is:

1. A compound of the formula (I):

or a salt thereof, wherein:
R 1 and R 2 are independently H, OH, OR 14 , NH 2 , NHC(O)R 15 or NHC(O)OR 17 ;
each Y 1 , Y 2 and Y 3 is independently N or CH, wherein at least one of Y 1 , Y 2 , and Y 3 is N;
L is O, S, SO, SO 2 , Se, NH or NR 16 ;
each m, n, p, q and r is independently 1, 2, 3, 4, 5 or 6;
n′ is 0, 1, 2, 3, 4, 5 or 6;
R 3 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl or OCH 3 ;
R 4 and R 8 are independently H, F, Cl, Br, I, CF 3 or OR 9 ;
R 5 and R 7 are independently H, F, Cl, Br, I, CF 3 , fluoropyridyl or OR 10 ;
Z is N or CR 6 ;
R 6 is H, F, Cl, Br, I, CF 3 or OR 11 ;
R 9 and R 11 are independently C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, (CH 2 ) m X, (CH 2 ) p OR 12 , or (CH 2 ) r X*,
R 10 is C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, (CH 2 ) m X, (CH 2 ) p OR 12 , (CH 2 ) q R 13 or (CH 2 ) r X*;
R 12 is H, tosyl or 2-tetrahydropyranyl;
R 13 is OCH 3 , NH 2 , NHCOCH 3 , CO 2 H, CO 2 CH 3 , SH or COCH 3 ;
R 14 is C 1 -C 4 alkyl;
R 15 is C 1 -C 6 alkyl or CF 3 ;
R 16 is C1-C4 alkyl or phenyl;
R 17 is C 1 -C 6 alkyl;
X is F, Cl, Br or I; and
X* is 18 F, 75 Br, 76 Br or 124 I.

2. The compound of claim 1 , wherein R 1 and R 2 are independently H, NH 2 , NHC(O)R 15 or NHC(O)OR 17 ; or a salt thereof.

3. The compound of claim 2 , wherein each R 1 and R 2 is NH 2 ; or a salt thereof.

4. The compound of claim 2 , wherein each R 1 and R 2 is NHC(O)R 15 ; or a salt thereof.

5. The compound of claim 4 , wherein R 15 is CH 3 ; or a salt thereof.

6. The compound of claim 4 , wherein R 15 is CF 3 ; or a salt thereof.

7. The compound of claim 1 , wherein R 5 is F, Cl, Br, I, CF 3 , fluoropyridyl or OR 10 ; or a salt thereof.

8. The compound of claim 7 , wherein R 5 is OR 10 ; or a salt thereof.

9. The compound of claim 8 , wherein R 10 is C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, (CH 2 ) m X, (CH 2 ) p OR 12 or (CH 2 ) r X*; or a salt thereof.

10. The compound of claim 9 , wherein R 10 is (CH 2 ) r X*; or a salt thereof.

11. The compound of claim 10 , wherein X* is 18 F; or a salt thereof.

12. The compound of claim 1 , wherein the compound is of the formula (A):

or a salt thereof, wherein:
R 1 and R 2 are independently NH 2 , OH, OCH 3 or OC 2 H 5 ;
each Y 1 , Y 2 and Y 3 is independently N or CH, wherein at least one of Y 1 , Y 2 , and Y 3 is N;
n is 1, 2, 3, 4, 5 or 6;
n′ is 0, 1, 2, 3, 4, 5 or 6;
R 3 is CH 3 , C 2 H 5 , C 3 H 7 or OCH 3 ;
each R 4 , R 5 , R 6 , R 7 and R 8 is independently H, F, Cl, Br, I or OR 9 ;
each R 9 is independently CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , CH 2 F, C 2 H 4 F, C 3 H 6 F, C 4 H 8 F, C 5 H 10 F, C 6 H 12 F, C 2 H 4 Br, C 2 H 4 I, CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 , C 5 F 11 , C 6 F 13 , CH 2 OTs, C 2 H 4 OTs, C 3 H 6 OTs, C 4 H 8 OTs, C 5 H 10 OTs, C 6 H 12 OTs, CH 2 OH, C 2 H 4 OH, C 3 H 6 OH, C 4 H 8 OH, C 5 H 10 OH, C 6 H 12 OH, CH 2 OTHP, C 2 H 4 OTHP, C 3 H 6 OTHP, C 4 H 8 OTHP, C 5 H 10 OTHP or C 6 H 12 OTHP, CH 2 X*, C 2 H 4 X*, C 3 H 6 X*, C 4 H 8 X*, C 5 H 10 X*, C 6 H 12 X*;
wherein Ts is tosyl;
wherein THP is 2-tetrahydropyranyl group; and
wherein X* is selected from: 18 F, 75 Br, 76 Br or 124 I.

13. The compound of claim 1 , wherein the compound binds to a deoxycytidine kinase polypeptide.

14. The compound of claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier.

15. A method for inhibiting a deoxycytidine kinase (dCK) activity comprising contacting a compound of claim 1 with the deoxycytidine kinase.

16. A compound, or salt thereof, wherein the compound is selected from the group consisting of:

17. A method of imaging, comprising:
administering a radiolabeled compound of claim 1 to an animal or human;
performing PET imaging to determine a local concentration of the compound in the animal or human; and
correlating the local concentration of the compound with a local immune response or the presence of neoplastic tissue.

18. The method of claim 17 , further comprising using the local concentration of the compound to diagnose cancer and/or monitor cancer treatment.

19. The method of claim 17 , wherein the animal or human has a condition selected from the group consisting of cancer, an autoimmune disorder, a development disorder, viral infection, bacterial infection, parasitical infection, infection, a metabolic disease, and inflammation.

20. The method of claim 17 , wherein the animal or human is undergoing a therapy selected from the group consisting of cancer immunotherapy, immunotherapy, interferon therapy, vaccination, radiation therapy, chemotherapy, and antibiotic therapy.

Assignees

• Radu Caius G
• Liao Hsiang-I
• Satyamurthy Nagichettiar
• Czernin Johannes
• Murphy Jennifer M
• Nathanson David A
• Univ California

Inventors

• Radu Caius G
• Liao Hsiang-I
• Satyamurthy Nagichettiar
• Czernin Johannes
• Murphy Jennifer M
• Nathanson David A

Classifications

• A61K31/426

  1,3-Thiazoles · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title