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

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

• ##STR46## wherein R.sub.1 is hydrogen or C.sub.1 -C.sub.9 linear or branched chain alkyl;
• wherein R.sub.3 and R.sub.4 are independently hydrogen or C.sub.1 -C.sub.9 linear or branched chain alkyl;
• wherein R.sub.5 is hydrogen or C.sub.1 -C.sub.9 linear or branched chain alkyl;
• and wherein R.sub.6 and R.sub.7 are independently hydrogen or C.sub.1 -C.sub.9, linear or branched chain alkyl;
• and wherein R.sub.8 is C.sub.1 -C.sub.9 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 C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, alkylphenyl, alkylphenyl, alkoxyphenyl, benzyl or alkoxybenzyl, with an acyl halide having the structure R.sub.0 (C.dbd.O)--Z, wherein Z is F, Cl, Br or I, or an acyl anhydride having the structure {R.sub.0 O(C.dbd.O)}.sub.2 O, wherein R.sub.0 is C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain dialkylphenyl, C.sub.1 -C.sub.9 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 R.sub.2 is phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl or C.sub.1 -C.sub.9 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 R.sub.3 R.sub.3 C.dbd.CHCHR.sub.4 SnR'R"R'" wherein R.sub.3 and R.sub.4 are independently hydrogen, C.sub.1 -C.sub.9 linear or branched chain alkyl;
• and wherein R', R" and R'" are independently a C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain alkoxyphenyl or benzyl, or (2) a Grignard reagent having the structure Z.sub.0 MgR.sub.3 R.sub.3 C--CH.dbd.CHR.sub.4 and an organometallic catalyst having the structure NiQ.sub.2 (PR.sup.iv.sub.3).sub.2 where Q and Z.sub.0 are independently F, Cl, Br or I and R.sup.iv is C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain dialkylphenyl, C.sub.1 -C.sub.9 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 R.sub.5 is as defined above and R.sub.9 is C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain dialkylphenyl, C.sub.1 -C.sub.9 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 R.sub.8 (C.dbd.O)--Z' wherein R.sub.8 is C.sub.1 -C.sub.9 linear or branched chain alkyl, and Z' is Cl, Br, F, I, or where R is a C.sub.1 -C.sub.9 linear or branched chain alkyl, phenyl, C.sub.1 -C.sub.9 linear or branched chain alkylphenyl, C.sub.1 -C.sub.9 linear or branched chain dialkylphenyl, C.sub.1 -C.sub.9 linear or branched chain alkoxyphenyl, hydroxyphenyl or benzyl;
• or with (B) an acyl anhydride having the structure [R.sub.8 (C.dbd.O)].sub.2 O, wherein R.sub.8 is C.sub.1 -C.sub.9 linear or branched chain alkyl, to form an N-acylardeemin.

A compound having the structure:

• ##STR58## wherein R.sub.0 is hydrogen;
• wherein R.sub.4 and R.sub.5 are independently hydrogen or methyl;
• wherein R.sub.2 is --CR.sub.3 R.sub.3 --CH--CHR.sub.4 ;
• wherein R.sub.8 is acetyl;
• and wherein R.sub.3 is hydrogen or methyl;
• with the proviso that when R.sub.4 is methyl, R.sub.8 is acetyl and R.sub.5 is hydrogen, then R.sub.3 is hydrogen.

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 R.sub.0 is hydrogen;
• wherein R.sub.4 and R.sub.5 are independently hydrogen or methyl;
• wherein R.sub.2 is --CR.sub.3 R.sub.3 --CH.dbd.CHR.sub.4 ;
• wherein R.sub.8 is acetyl;
• and wherein R.sub.3 is hydrogen or methyl;
• with the proviso that when R.sub.4 is methyl, R.sub.8 is acetyl and R.sub.5 is hydrogen, then R.sub.3 is hydrogen.

A compound having the structure:

• ##STR60## wherein R.sub.0 is hydrogen;
• wherein R.sub.4 is hydrogen and R.sub.5 methyl;
• wherein R.sub.2 is --CR.sub.3 R.sub.3 --CH.dbd.CHR.sub.4 ;
• wherein R.sub.8 is trifluoroacetyl;
• and wherein R.sub.3 is methyl.

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 R.sub.4 is hydrogen and R.sub.5 is methyl;
• wherein R.sub.2 is --CR.sub.3 R.sub.3 --CH.dbd.CHR.sub.4 ;
• wherein R.sub.8 is trifluoroacetyl;
• and wherein R.sub.3 is methyl.