Analogues of N-acetylardeemin, method of preparation and uses thereof

• US 6,147,076 A
• Filed: 11/15/1996
• Issued: 11/14/2000
• Est. Priority Date: 11/15/1995
• Status: Expired due to Fees

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center), Telxon Corporation (Zebra Technologies Corporation)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Bornmann, William, Depew, Kristopher, Chou, Ting Chao, Marsden, Stephen P., Zatorski, Andrej, Danishefsky, Samuel J.
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/749,908
• Time in Patent Office: 1,460 Days
• Field of Search: 544/245, 514/250
• US Class Current: 514/250
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention provides a compound having the structure: ##STR1## wherein R₁ R₆ and R₇ are independently hydrogen, OH, NH₂, SH, halogen, C₁ -C₉ linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, etc.; wherein R₀ and R₂ are independently hydrogen, OH, linear or branched chain alkyl, --CR₃ R₃ --CH(O)CH₂, --CR₃ R₃ --CH₂ CH₃, --CR₃ R₃ --CH₂ CH₂ OH, --CR₃ R₃ --CH(OH)R₄ or --CR₃ R₃ --CH═CHR₄ ; wherein R₃ and R₄ are independently hydrogen, halogen, C₁ -C₉ linear or branched chain alkyl, phenyl, etc.; wherein R₅ is hydrogen, C₁ -C₉ linear or branched chain alkyl, phenyl, etc.; and wherein R₈ is hydrogen, C₁ -C₉ linear or branched chain acyl, benzoyl, etc.; with the proviso that (a) when R₂ is --CR₃ R₃ --CH(O)CH₂, --CR₃ R₃ --CH₂ CH₃, --CR₃ R₃ --CH₂ CH₂ OH, --CR₃ R₃ --CH(OH)R₄ or --CR₃ R₃ --CH═CHR₄, then R₂ is hydrogen; (b) when R₀ is --CR₃ R₃ --CH(O)CH₂, --CR₃ R₃ --CH₂ CH₃, --CR₃ R₃ --CH₂ CH₂ OH, --CR₃ R₃ --CH(OH)R₄ or --CR₃ R₃ --CH═CHR₄, then R₂ is OH; and (c) when (i) R₀ or R₂ is --CR₃ R₃ --CH═CHR₄, (ii) R₃ and R₅ are CH₃ and (iii) R₄ is hydrogen, then R₁, R₆ and R₇ are not all hydrogen. Also provided are related compounds and compositions, and methods of inhibiting the growth of multidrug resistant cells by means of MDR reversal, collateral sensitivity and quantitative synergism.

Claims

1. A compound having the structure:

##STR45## wherein R₀, R₁, R₃, R₄, R₆ and R₇ are hydrogen;

wherein R₂ is --CR₃ R₃ --CH═

CHR₄ ;

wherein R₅ is CH₃ ; and

wherein R₈ is --(C═

O)CH₃.

2. A process for synthesizing an N-acylardeemin having the structure:

##STR46## wherein R₁ is hydrogen or C₁ -C₉ linear or branched chain alkyl;

wherein R₃ and R₄ are independently hydrogen or C₁ -C₉ linear or branched chain alkyl;

wherein R₅ is hydrogen or C₁ -C₉ linear or branched chain alkyl; and

wherein R₆ and R₇ are independently hydrogen or C₁ -C₉, linear or branched chain alkyl; and

wherein R₈ is C₁ -C₉ linear or branched chain alkyl;

which comprises;

(a) (i) reacting a compound having the structure;

##STR47## wherein X is Br, Cl, F, I, mesylate, triflate, tosylate, perchlorate, hydrogensulfate, carbonate, bicarbonate or tetrafluoroborate; and

R is C₁ -C₉ linear or branched chain alkyl, phenyl, alkylphenyl, alkylphenyl, alkoxyphenyl, benzyl or alkoxybenzyl, with an acyl halide having the structure R₀ (C═

O)--Z, wherein Z is F, Cl, Br or I, or an acyl anhydride having the structure {R₀ O(C═

O)}₂ O, wherein R₀ is C₁ -C₉ linear or branched chain alkyl, phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain dialkylphenyl, C₁ -C₉ linear or branched chain alkoxyphenyl, benzyl or 9-fluorenemethyl, to form a dicarbamate having the structure;

##STR48## (ii) treating the dicarbamate formed in step (a)(i) with a suitable phenylselenenide reagent to form a mixture of phenylselenide dicarbamates having the structures;

##STR49## wherein R₂ is phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain alkylphenyl or C₁ -C₉ linear or branched chain trialkylphenyl; and

(iii) cross-coupling the mixture of phenyl-selenide dicarbamates formed in step (a)(ii) with (1) an organostannane having the structure R₃ R₃ C═

CHCHR₄ SnR'"'"'R"R'"'"'" wherein R₃ and R₄ are independently hydrogen, C₁ -C₉ linear or branched chain alkyl; and

wherein R'"'"', R" and R'"'"'" are independently a C₁ -C₉ linear or branched chain alkyl, phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain alkoxyphenyl or benzyl, or (2) a Grignard reagent having the structure Z₀ MgR₃ R₃ C--CH═

CHR₄ and an organometallic catalyst having the structure NiQ₂ (PR^iv₃)₂ where Q and Z₀ are independently F, Cl, Br or I and R^iv is C₁ -C₉ linear or branched chain alkyl, phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain dialkylphenyl, C₁ -C₉ linear or branched chain alkoxyphenyl or benzyl, to form a mixture of cross-coupled dicarbamates respectively having the structure;

##STR50## (b) (i) hydrolzying the mixture of cross-coupled dicarbarmates formed in step (a)(iii) to form a mixture of dicarbamate acids;

(ii) purifying the mixture of dicarbamate acids formed in step (b)(1); and

(iii) isolating the dicarbamate acid having the structure;

##STR51## (c) coupling the dicarbamate acid with an amino acid ester having the structure;

##STR52## wherein wherein R₅ is as defined above and R₉ is C₁ -C₉ linear or branched chain alkyl, phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain dialkylphenyl, C₁ -C₉ linear or branched chain alkoxyphenyl or benzyl;

to form a peptide dicarbamate having the structure;

##STR53## (d) (i) deprotecting and lactamizing the peptide dicarbamate, formed in step (c) to form a diketopiperazine having the structure;

##STR54## (ii)acylating the diketopiperazine formed in step (d)(i) with a compound having the structure;

##STR55## wherein Y is Cl Br, F or I, to form an N-benzoylated diketopiperazine having the structure;

##STR56## (iii)cyclizing the compound formed in step (d)(ii) to form an ardeemin having the structure;

##STR57## and (iv) acylating the ardeemin formed in step (d)(iii) with (A) an acyl halide having the structure R₈ (C═

O)--Z'"'"' wherein R₈ is C₁ -C₉ linear or branched chain alkyl, and Z'"'"' is Cl, Br, F, I, or where R is a C₁ -C₉ linear or branched chain alkyl, phenyl, C₁ -C₉ linear or branched chain alkylphenyl, C₁ -C₉ linear or branched chain dialkylphenyl, C₁ -C₉ linear or branched chain alkoxyphenyl, hydroxyphenyl or benzyl;

or with (B) an acyl anhydride having the structure [R₈ (C═

O)]₂ O, wherein R₈ is C₁ -C₉ linear or branched chain alkyl, to form an N-acylardeemin.

3. The process of claim 2, wherein R₁, R₆ and R₇ are hydrogen.

4. The process of claim 2, wherein R₀ is t-Bu, R and R₅ are CH₃, and X, Y and Z are Cl.

5. The process of claim 2, wherein R₈ is CH₃.

6. The process of claim 2, wherein R₃ is CH₃ and R₄ is hydrogen.

7. The process of claim 2, wherein R₂ is phenyl.

8. The process of claim 2, wherein R'"'"', R" and R'"'"'" are n-Bu.

9. A compound having the structure:

##STR58## wherein R₀ is hydrogen;

wherein R₄ and R₅ are independently hydrogen or methyl;

wherein R₂ is --CR₃ R₃ --CH--CHR₄ ;

wherein R₈ is acetyl; and

wherein R₃ is hydrogen or methyl;

with the proviso that when R₄ is methyl, R₈ is acetyl and R₅ is hydrogen, then R₃ is hydrogen.

10. A composition comprising an amount of the compound of claim 9 effective to inhibit the growth of P-glycoprotein-mediated multidrug resistant cancer cells and a pharmaceutically acceptable carrier.

11. The composition of claim 10, further comprising a cytotoxic agent, wherein the cytotoxic agent is an anticancer agent.

12. The composition of claim 11, wherein the anticancer agent is adriamycin.

13. The composition of claim 11, wherein the anticancer agent is vinblastine.

14. The composition of claim 11, wherein the anticancer agent is paclitaxel.

15. The composition of claim 10, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

16. The composition of claim 10, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight.

17. A method of inhibiting the growth of P-glycoprotein-mediated multidrug resistant cancer cells comprising contacting the multidrug resistant cells with an amount of an ardeemin effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein said cells are collaterally sensitive and wherein the ardeemin has the structure:

##STR59## wherein R₀ is hydrogen;

wherein R₄ and R₅ are independently hydrogen or methyl;

wherein R₂ is --CR₃ R₃ --CH═

CHR₄ ;

wherein R₈ is acetyl; and

wherein R₃ is hydrogen or methyl;

with the proviso that when R₄ is methyl, R₈ is acetyl and R₅ is hydrogen, then R₃ is hydrogen.

18. The method of claim 17, further comprising administering an amount of a cytotoxic agent, wherein the cytotoxic agent is an anticancer agent.

19. The method of claim 18, wherein the anticancer agent is adriamycin.

20. The method of claim 18, wherein the anticancer agent is vinblastine.

21. The method of claim 18, wherein the anticancer agent is paclitaxel.

22. The method of claim 17, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

23. The method of claim 17, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight.

24. A compound having the structure:

##STR60## wherein R₀ is hydrogen;

wherein R₄ is hydrogen and R₅ methyl;

wherein R₂ is --CR₃ R₃ --CH═

CHR₄ ;

wherein R₈ is trifluoroacetyl; and

wherein R₃ is methyl.

25. A composition comprising an amount of the compound of claim 24 effective to inhibit the growth of P-glycoprotein-mediated multidrug resistant cancer cells and a pharmaceutically acceptable carrier.

26. The composition of claim 25, further comprising a cytotoxic agent, wherein the cytotoxic agent is an anticancer agent.

27. The composition of claim 26, wherein the anticancer agent is adriamycin.

28. The composition of claim 26, wherein the anticancer agent is vinblastine.

29. The composition of claim 26, wherein the anticancer agent is paclitaxel.

30. The composition of claim 25, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

31. The composition of claim 25, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight.

32. A method of inhibiting the growth of P-glycoprotein-mediated multidrug resistant cancer cells comprising contacting the multidrug resistant cells with an amount of an ardeemin effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein said cells are collaterally sensitive and wherein the ardeemin has the structure:

##STR61## wherein R₄ is hydrogen and R₅ is methyl;

wherein R₂ is --CR₃ R₃ --CH═

CHR₄ ;

wherein R₈ is trifluoroacetyl; and

wherein R₃ is methyl.

33. The method of claim 32, further comprising administering an amount of a cytotoxic agent, wherein the cytotoxic agent is an anticancer agent.

34. The method of claim 33, wherein the anticancer agent is adriamycin.

35. The method of claim 33, wherein the anticancer agent is vinblastine.

36. The method of claim 33, wherein the anticancer agent is paclitaxel.

37. The method of claim 32, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

38. The method of claim 32, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight.