Process for the preparation of rebeccamycin and analogs thereof

• US 20040248892A1
• Filed: 07/21/2004
• Published: 12/09/2004
• Est. Priority Date: 09/13/2001
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wang, Jianji
• Granted Patent: US 7,227,019 B2
• Time in Patent Office: Days
• US Class Current: 514/232.2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07H 19/23 Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

The present invention relates to a method for making an indolopyrrolocarbazole compound of the general formula [I], where the method includes the step of reacting a bisindolylmaleimide compound with an oxidizing agent in the presence of an oxygen containing gas at a temperature and for a time sufficient to yield the indolopyrrolocarbazole compound of the general formula [I]. Methods of making rebeccamycin analogs using the indolopyrrolocarbazole compound are also provided.

Claims

1. A method for making an indolopyrrolocarbazole compound according to general formula [I]:

2. The method according to claim 1, wherein said oxidizing agent is present in an amount of from about 5 mol % to about 100 mol %.

3. The method according to claim 2, wherein said oxidizing agent comprises a copper salt or a palladium salt having an oxidation number of 2+, wherein when said oxidizing agent is said copper salt, then said oxidizing agent is present in an amount of about 100 mol %, and when said oxidizing agent is said palladium salt, then said oxidizing agent is present in an amount of about 5 mol %.

4. The method according to claim 3, wherein said oxidizing agent is selected from the group consisting of CuCl₂, Cu(NO₃)₂, Cu(OAc)₂.

5. The method according to claim 4, wherein said oxidizing agent is CuCl₂.

6. The method according to claim 2, wherein said oxidizing agent is selected from the group consisting of Pd(OAc)₂, PdCl₂, Pd(OOCCF₃)₂, and PdSO₄.

7. The method according to claim 5, wherein said oxidizing agent also comprises Pd(OAc)₂.

8. The method according to claim 1, further comprising the step of regenerating said oxidizing agent by sequential oxidation reduction reactions converting Pd⁰ to Pd²⁺ or Cu⁰ to Cu²⁺.

9. The method according to claim 8, wherein said regeneration step comprises at least one of the following stoichiometric reactions:

10. The method according to claim 1, wherein X′

₁ is Cl at the 1-position, X′

_1a is Cl at the 11-position, and R″

₇ and R″

₈ together are ═

O.

11. The method according to claim 1, further comprising the steps of:

(a) reacting a dihalomaleic acid of the general formula [IV];

wherein each X is the same or different protecting group selected from a fluorine, a chlorine, a bromine and an iodine atom, with an R″

₆-substituted amine compound, to form a maleimide compound of the general formula [V];

wherein;

R″

₆, R″

₇ and R″

₈ are as defined previously in formula [I]; and

(b) reacting said maleimide compound of the general formula [V] with an indolylmetal halide compound of the general formula [VI];

wherein;

R₅ is independently selected from H, halogen, OH, —

CN, CF₃, —

COR″

_a, NO₂, OR″

₁₁, O(CH₂)_nNR″

₉R″

₁₀, O(CH₂)_nOR″

₉ and O(CH₂)_nCOOR″

₉, and is present at each of the 2-5 positions;

Y is an alkali metal; and

Z is selected from the group consisting of fluorine, bromine, chlorine, and iodine, to yield the bis-indolylmaleimide compound of the general formula [II].

12. The method according to claim 11, wherein Y is magnesium.

13. A method of synthesizing a rebeccamycin analog of general formula [III] or a pharmaceutically acceptable salt thereof:

14. The method according to claim 13, wherein said sugar moiety includes at least one protecting group, further including the step of deprotecting said sugar moiety selectively so as to remove said protecting group.

15. The method of claim 13, further comprising the step of reacting the rebeccamycin compound of general formula [I] wherein at least R″

₆ or one of R″

₁, and R″

_1a are H, first with a strong base followed by an R—

substituted amino- halide to form a rebeccamycin analog, said R—

being selected from the group consisting of;

C_1-7 alkyl, aryl, arylalkyl, OR″

₁₀, NR″

₉R″

₁₀, or OCO(CH₂)_nNR″

₉R″

₁₀,

wherein;

said C_1-7 alkyl is optionally substituted with one to six of the same or different halogen, NR″

₉R″

₁₀, CN, NO₂, aryl, said aryl being substituted with one or two groups independently selected from NR″

₉R″

₁₀, OH, COOR″

₉, SO₃R″

₉ or OCOR″

₉.

16. The method according to claim 13, further comprising the step of:

reacting said rebeccamycin analog of general formula [III], wherein at least one of R″

₆ and R″

₁, or R″

_1a are H, with a strong base followed by a substituted amine halide, said amine halide being substituted with —

(CH₂)_n′

NR′

″

₁R″

′

₂, wherein n′

is an integer of from 1 to 6, and R′

″

₁ and R′

″

₂ are each independently selected from H, unsubstituted and substituted C₁-C₆ alkyl, aralkyl having 1 to 3 carbons in the alkyl moiety and unsubstituted phenyl or phenyl substituted with 1 to 3 alkyl, alkoxy, hydroxy, halo, carboxyl, alkoxycarbonyl, and amino and mono- and di-lower-alkylamino groups in the aryl moiety, and aryl selected from unsubstituted phenyl and phenyl substituted with 1 to 3 alkyl, alkoxy, hydroxy, halo, amino, mono- and dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano groups provided that both R′

″

₁ and R′

″

₂ are not each aryl and, when taken together, R′

″

₁ and R′

″

₂ may be selected from —

(CH₂—

)₄— and

(CH₂)₂—

R′

″

₃—

(CH₂)₂—

to form a 5- or 6 membered ring together with the N-atom wherein R′

″

₃ is selected from CH₂, NH, O and S, to yield an R substituted rebeccamycin analog.

17. The method of claim 13 wherein the formula [II] compound is selected from the group consisting of:

18. The method according to claim 13, wherein said indolopyrrolocarbazole compound is general formula [XI]:

19. The method according to claim 13 wherein X′

″

is selected from H, Cl, Br, OH, OCH₃ and OCH₂C₆H₅.

20. The method according to claim 19 wherein n′

is selected from the integers 1, 2, and 3; and

, R′

″

₁ and R′

″

₂, are independently selected from H, C₁-C₃ alkyl, and —

(CH₂)₄—

.

21. The method according to claim 20 wherein X′

″

is Cl in each of the 1- and 11-positions.

22. The method according to claim 21 wherein n′

is an integer selected from 2 and 3; and

R′

″

₁ and R′

″

₂ are each C₂H₅.

23. The method according to claim 22 wherein the formula [IV] compound is: