Processes for the convergent synthesis of calicheamicin derivatives

1. A trifunctional linker intermediate, of the formula

wherein:

Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;

Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;

Z 1 is H, or alkyl of 1 to 5 carbon atoms;

Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or a 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6-, or 2,7-naphthylidene optionally substituted with one, two, three, or four groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;

n is an integer from 0 to 5;

R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;

Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C1-C18) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C1-C18) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;

Q is selected from the group consisting of —NNHCO—, —NNHCS—, and —NNHCONH—;

Z is selected from the group consisting of

2. The trifunctional linker intermediate of claim 1 , wherein Z is N-hydroxysuccinimide.

3. The trifunctional linker intermediate of claim 1 , wherein Alk 1 is a branched or unbranched alkylene chain of 2 to 5 carbon atoms.

4. The trifunctional linker intermediate of claim 1 , wherein Alk 1 is a branched or unbranched alkylene chain of 3 carbon atoms.

5. The trifunctional linker intermediate of claim 1 , wherein Sp 1 is an oxygen atom.

6. The trifunctional linker intermediate of claim 1 , wherein Z 1 is alkyl of 1 to 3 carbon atoms.

7. The trifunctional linker intermediate of claim 1 , wherein Z 1 is methyl.

8. The trifunctional linker intermediate of claim 1 , wherein Ar is selected from the group consisting of 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylidene, 1,3-naphthylidene, 1,4-naphthylidene, 1,5-naphthylidene, 1,6-naphthylidene, 1,7-naphthylidene, 1,8-naphthylidene, 2,3-naphthylidene, 2,6-naphthylidene, and 2,7-aphthylidene.

9. The trifunctional linker intermediate of claim 1 , wherein Ar is 1,4-phenylene.

10. The trifunctional linker intermediate of claim 1 , wherein Q is —NNHCO—.

11. The trifunctional linker intermediate of claim 1 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 12 carbon atoms.

12. The trifunctional linker intermediate of claim 1 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 6 carbon atoms.

13. The trifunctional linker intermediate of claim 1 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 4 carbon atoms.

14. The trifunctional linker intermediate of claim 1 , having the formula:

15. A sodium salt of the trifunctional linker intermediate of claim 1 .

16. A bilinker carboxylic acid intermediate of the formula

wherein:

Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;

Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;

Z 1 is H, or alkyl of 1 to 5 carbon atoms;

Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or a 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6-, or 2,7-naphthylidene optionally substituted with one, two, three, or four groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;

n is an integer from 0 to 5;

R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;

Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups; and

Q is selected from the group consisting of —NNHCO—, —NNHCS—, and —NNHCONH—.

17. The bilinker carboxylic acid intermediate of claim 16 , wherein Alk 1 is a branched or unbranched alkylene chain of 2 to 5 carbon atoms.

18. The bilinker carboxylic acid intermediate of claim 16 , wherein Alk 1 is a branched or unbranched alkylene chain of 3 carbon atoms.

19. The bilinker carboxylic acid intermediate of claim 16 , wherein Sp 1 is an oxygen atom.

20. The bilinker carboxylic acid intermediate of claim 16 , wherein Z 1 is alkyl of 1 to 3 carbon atoms.

21. The bilinker carboxylic acid intermediate of claim 16 , wherein Z 1 is methyl.

22. The bilinker carboxylic acid intermediate of claim 16 , wherein Ar is selected from the group consisting of 1, 2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylidene, 1,3-naphthylidene, 1,4-naphthylidene, 1,5-naphthylidene, 1,6-naphthylidene, 1,7-naphthylidene, 1,8-naphthylidene, 2,3-naphthylidene, 2,6-naphthylidene, and 2,7-naphthylidene.

23. The bilinker carboxylic acid intermediate of claim 16 , wherein Ar is 1,4-phenylene.

24. The bilinker carboxylic acid intermediate of claim 16 , wherein Q is —NNHCO—.

25. The bilinker carboxylic acid intermediate of claim 16 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 12 carbon atoms.

26. The bilinker carboxylic acid intermediate of claim 16 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 6 carbon atoms.

27. The bilinker carboxylic acid intermediate of claim 16 , wherein Sp is a straight or branched-chain divalent or trivalent alkyl radical of 4 carbon atoms.

28. The bilinker carboxylic acid intermediate of claim 16 , having the formula: