THYMIDINE ANALOGS FOR IMAGING

• US 20080170993A1
• Filed: 10/24/2007
• Published: 07/17/2008
• Est. Priority Date: 10/25/2006
• Status: Abandoned Application

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: SRINIVASAN, Ananth, Grahan, Keith, Zitzmann, Sabine, Berndt, Mathias, Lehmann, Lutz, Fitzner, Ansgar, Voigtmann, Ulrike
• Application Number:
  US11/923,219
• Publication Number:
  US 20080170993A1
• Time in Patent Office: Days
• US Class Current: 424/1.81
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

The present invention relates to nucleoside analogues and more particularly to labeled nucleoside analogues. It has been found new thymidine analogues can be stably labeled with a detectable label moiety. Further the present invention relates to methods of making above compounds and use of such compounds for diagnostic imaging of tumor cells and/or treatment of proliferative diseases. In addition, the present invention relates to the preparation and use of positron emitting compounds for positron emission tomography (PET). A kit is also disclosed.

Claims

1. A compound according to formula (I)

2. The compound according to claim 1 wherein R3 is a benzoyl.

3. The compound according to claim 1 wherein R3 is a higher alkyl.

4. The compound according to claim 3 wherein the higher alkyl is a C₈ to C₁₈ alkyl.

5. The compound according to claim 3 wherein the higher alkyl is a C₈ to C₁₂ alkyl.

6. The compound according to claim 1 wherein R3 is [alkoxyl]_n-alkyl wherein n is 1 to 10.

7. The compound according to claim 6 wherein [alkoxyl]_n-alkyl is selected from

i. —

(CH₂—

CH₂—

O)_m—

(CH₂—

CH₂)—

;

ii. —

(CH₂—

CH₂—

CH₂O)—

(CH₂—

CH₂—

O)_m—

(CH₂—

CH₂)—

; and

iii. —

(CH₂—

CH₂—

CH₂O)—

(CH₂—

CH₂—

O)_m—

(CH₂—

CH₂—

CH₂)—

wherein m is 1 to 6.

8. The compound according to claim 1 wherein the R3 is benzoyl-alkyl.

9. The compound according to claim 1 wherein R1 is selected from O, S and C(═

CH₂).

10. The compound according to claim 1 wherein R2 is a C₁ to C₄ alkyl.

11. The compound according to claim 1 wherein the linker R4 is a bond or Aryl-L

wherein L is selected from

a) —

C(O)N(H);

b) —

C((O)N(Me);

c) —

SO₂—

N(H)—

; and

d) —

SO₂—

N(Me)—

;

and wherein Aryl is an aromatic moiety optionally substituted with;

a) Hydrogen;

b) Halo;

c) Cyano;

d) Nitro;

e) Trifluormethyl;

f) —

S(O)₂-methyl;

g) —

S(O)₂-ethyl;

h) —

C(O)-Me or

a combination thereof.

12. The compound according to claim 11 wherein independently aromatic moiety is a phenyl and L is selected from —

C(O)N(H) and —

SO₂—

N(Me)-.

13. The compound according to claim 1 wherein the radioisotope label R5 is selected from ¹⁸F, ⁷⁷Br, ⁷⁶Br, ¹²³I, ¹²⁵I, and ¹¹C.

14. The compound according claim 1 wherein the radioisotope label R5 is ¹⁸F.

15. The compound according to claim 1

N³-(2-(2-[¹⁸F]Fluoroethoxy)-ethyl)-O,O-bis-(1′

-methoxy-1′

-cyclohexyl) thymidine 15,

N³-(3-(N-(4-[¹⁸F]-fluoro-3-cyano-benzoyl))aminopropyl)-thymidine 16,

N³-(2-(2-[¹⁸F]Fluoroethoxy)-ethyl)-thymidine 20,

N³-(3-(N-(4-[¹⁸F]-fluoro-3-cyano-benzoyl))aminopropyl)-thymidine 13aa,

N³-(3-(N-(4-[¹⁸F]-fluoro-3-trifluoromethyl-benzoyl))aminopropyl)-thymidine 13bb,

N³-(3-(N-(4-[¹⁸F]-fluoro-2-chloro-benzoyl))aminopropyl)-thymidine 13cc and

N³-(3-(N-(4-[¹⁸F]-fluorobenzoyl))amino-propyl)-thymidine.

16. The compound according to claim 1 for use as diagnostic imaging agent.

17. The compound according to claim 1 for use as diagnostic imaging agent for positron emission tomography (PET).

18. The compound according to claim 1 for use as medicament.

19. A composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier or diluent.

20. Use of a compound according to claim 1 for the manufacture of diagnostic imaging agent.

21. The use according to claim 20 for the manufacture of diagnostic imaging agent for imaging tissue proliferations, hyperplastic inflammation, benign tumours or malignant tumours.

22. Use of a compound according to claim 1 for the manufacture of medicament.

23. The use according to claim 22 for the manufacture of medicament for treating proliferative diseases.

24. The use according to claim 23 wherein proliferative disease is a disease developing malignant tumor selected from malignant lymphoma, pharyngeal cancer, lung cancer, liver cancer, bladder tumor, rectal cancer, prostatic cancer, uterine cancer, ovarian cancer, breast cancer, brain tumor, and malignant melanoma.

25. A compound according to formula (II)

26. The compound according to claim 25 wherein PG is (1-alkoxy)-cycloalkyl

27. The compound according to claim 25 wherein the leaving group (LG) is selected fromNO₂, (CH₃)₃N⁺ if R4 is aryl for radiofluorination;

2. (alkyl)₃Sn if R4 is aryl for radioiodination and ¹¹C-methyliodide (Stille-cross-coupling), and

3. Cl, Br, I, OTs, OMs, OTf, ONs if R4 is bond for radiofluorination.

4. hydroxy if R4 is aryl for ¹¹C alkylation;

28. The compound according to claim 25 wherein R6 is C₈-C₁₈ alkyl.

29. The compound according to claim 25 as followed

3-t-butyldimethylsilyloxybutyl-4-(1-methoxy-cyclohexyloxy)-5(1-methoxy-cyclohexyloxy-methyl)-thymidine 2^a,

3-t-butyldimethylsilyloxyhexyl-4-(1-methoxy-cyclohexyloxy)-5(1-methoxy-cyclohexyloxy-methyl)-thymidine 2b,

3-(4-Hydroxybutyl)-4′

-(1-methoxy-cyclohexyloxy)-5′

(1-methoxy-cyclohexyloxymethyl)-thymidine 3a,

3-(6-Hydroxyhexyl)-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 3b,

3-(4-O-Tosyl)butyl-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 4a,

3-(6-O-Tosyl)hexyl)-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 4b,

3-(4-O-Tosyl)butyl-thymidine 5a,

3-(6-O-Tosyl)hexyl-thymidine 5b,

3-(4-O-methanesulfonyl)butyl-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 6a,

3-(6-O-methanesulfonyl))hexyl)-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 6b,

3-(4-O-methanesulfonyl)butyl-thymidine 7a,

3-(6-O-methanesulfonyl)hexyl-thymidine 7b,

3-(3-(4-trimethylaminobenzoyl)amino)propyl-4′

-(1-methoxy-cyclohexyloxy)-5′

-(1-methoxy-cyclohexyloxymethyl)-thymidine 10 and 3-(3-(4-trimethylaminobenzoyl)amino)propyl-thymidine 11.

30. A method for obtaining compound of formula (III)

31. A method for obtaining compound of formula (III)

32. The method according to claim 30 wherein R6 is C₈-C₁₈ alkyl.

33. The method according to claim 30 wherein the radioisotope label R5 is ¹⁸F.

34. A kit comprising

iv. compound of formula I;

v. compound of formula II;

vi. compound of formula III or

vii. compound of formula IV and V.

35. A kit according to claim 34 for imaging tissue proliferations, hyperplastic inflammation, benign tumours or malignant tumours.

36. A method for diagnosing tissue proliferations, hyperplastic inflammation, benign tumours or malignant tumours comprising the steps of

a) administering to a patient a compound of formula I, and

b) measuring positron emission by PET.

37. The method according to claim 36 wherein the diagnosis is a diagnosis concerning localization, progress or determination of therapeutic effect of tissues proliferation, hyperplastic inflammation or benign or malignant tumours.

38. Compound selected from

N³-(3-(N-(4-[¹⁹F]-fluorobenzoyl))amino-propyl)-O,O-bis-(1′

-methoxy-1′

-cyclohexyl) thymidine 12,

N³-(3-(N-(4-[¹⁹F]-fluorobenzoyl))amino-propyl)-thymidine 13,

N³-(3-(N-(3-cyano-4-[¹⁹F]-fluorobenzoyl))amino-propyl)-O,O-bis-(1′

-methoxy-1′

-cyclohexyl) thymidine 12a,

N³-(3-(N-(3-trifluoromethyl-4-[¹⁹F]-fluorobenzoyl))amino-propyl)-O,O-bis-(1′

-methoxy-1′

-cyclohexyl) thymidine 12b,

N³-(3-(N-(2-chloro-4-[¹⁹F]-fluorobenzoyl))amino-propyl)-O,O-bis-(1′

-methoxy-1′

-cyclohexyl) thymidine 12c,

N³-(3-(N-(3-cyano-4-[¹⁹F]-fluorobenzoyl))amino-propyl)-thymidine 13a,

N³-(3-(N-(4-[¹⁹F]-fluoro-3-trifluormethyl-benzoyl))amino-propyl)-thymidine 13b,

N³-(3-(N-(2-chloro-4-[¹⁹F]-fluorobenzoyl))amino-propyl)-thymidine 13c,

3-(4-[¹⁹F]-Fluorobutyl)-thymidine 18,

3-(6-[¹⁹F]-Fluorohexyl)-thymidine 19,

3-(4-[¹⁸F]-Fluorobutyl)-thymidine 14, and

3-(6-[¹⁸F]-Fluorohexyl)-thymidine 17.