Intermediates and methods for synthesizing calicheamicin derivatives

A method for synthesizing a compound of Formula IV

• which method comprises treating a compound of Formula I
• wherein R12 is selected from straight and branched-chain C1-C8 alkyl;
• each R10 is independently selected from hydrogen, R12 and —OR12;
• R8 and R9 are each independently selected from hydrogen and straight and branched-chain C1-C8 alkyl, wherein each said alkyl for R8 and R9 is independently optionally substituted by —NH2, —NHR11, —NR11R13, —OR11, —OH, or —SR11, wherein each R11 and each R13 are independently selected from straight and branched-chain C1-C5 alkyl;
• r is an integer 0 or 1;
• G is oxygen or sulfur;
• Z1 is H or straight or branched-chain C1-C5 alkyl;
• Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two or three groups independently selected from straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14, or Ar is 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 straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14;
• wherein each R14 is independently selected from (C1-C5)alkyl and each R14 is independently optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• each n is an integer independently selected from 0, 1, 2, 3, 4, and 5;
• W is selected from —O—, —S—, —C(═O)NH—, —NHC(═O)—, and —NR15—, wherein R15 is a (C1-C5)alkyl and R15 is optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• and
• Y is a straight or branched-chain (C1-C6)alkylene group or a straight or branched-chain (C2-C6)alkenylene group, with a strong acid to form a mixture comprising the compound of Formula IV.

A method for synthesizing a linker intermediate of Formula V

• wherein R8 and R9 are each independently selected from hydrogen and straight and branched-chain C1-C8 alkyl, wherein each said alkyl for R8 and R9 is independently optionally substituted by —NH2, —NHR11, —NR11R13, —OR11, —OH, or—SR11, wherein each R11 and each R13 are independently selected from straight and branched-chain C1-C5 alkyl;
• r is an integer selected from 0 and 1;
• G is oxygen or sulfur;
• Z1 is H or straight or branched-chain C1-C5 alkyl;
• Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two or three groups independently selected from straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, or Ar is 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 straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14;
• wherein each R14 is independently selected from (C1-C5)alkyl and each R14 is independently optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• each n is an integer independently selected from 0, 1, 2, 3, 4, and 5;
• W is selected from —O—, —S—, —C(═O)NH—, —NHC(═O)—, and —NR15-, wherein R15 is a (C1-C5)alkyl and R15 is optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• Y is a straight or branched-chain (C1-C6)alkylene group or a straight or branched-chain (C2-C6)alkylene group;
• and
• Z is selected from the group consisting of
• which method comprises
• a) treating a compound of Formula I
• wherein R12 is selected from straight and branched-chain C1-C8 alkyl, and each R10 is independently selected from hydrogen, R12 and —OR12;
• with a strong acid to form a mixture comprising a compound of Formula IV
• and
• b) reacting the compound of Formula IV with a compound ZH;
• thereby synthesizing the linker intermediate of Formula V.

A method of synthesizing a calicheamicin derivative of Formula VI

• wherein J is
• R1 is
• or CH 3;
• R2 is
• or H;
• R3 is
• or H;
• R4 is
• or H;
• R5 is —CH3, —C2H5, or —CH(CH3)2;
• X is an iodine or bromine atom;
• R5′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C6-C11) aryl-alkyl (C1-C5) group, or a heteroaryl or heteroaryl-alkyl (C1-C5) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C1-C3) alkoxy, or thioalkoxy of 1 to 5 carbon atoms;
• R6 and R7 are each independently selected from H and
• R8 and R9 are each independently selected from hydrogen and straight and branched-chain C1-C8 alkyl, wherein each said alkyl for R8 and R9 is independently optionally substituted by —NH2, —NHR11, —NR11R13, —OR11, —OH, or —SR11, wherein each R11 and each R13 are independently selected from straight and branched-chain C1-C5 alkyl;
• r is an integer 0 or 1;
• G is oxygen or sulfur;
• Z1 is H or straight or branched-chain C1-C5 alkyl;
• Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two or three groups independently selected from straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14, or Ar is 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 straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14;
• wherein each R14 is independently selected from (C1-C5)alkyl and each R14 is independently optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• each n is an integer independently selected from 0, 1, 2, 3, 4, and 5;
• W is selected from —O—, —S—, —C(═O)NH—, —NHC(═O)—, and —NR15-, wherein R15 is a (C1-C5)alkyl and R15 is optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• Y is a straight or branched-chain (C1-C6)alkylene group or a straight or branched-chain (C1-C6)alkenylene group;
• and
• Z is selected from the group consisting of
• which method comprises
• a) treating a compound of Formula I
• wherein R12 is selected from straight and branched-chain C1-C8 alkyl, and each R10 is independently selected from hydrogen, R12 and —OR12;
• with a strong acid to form a mixture comprising a compound of Formula IV
• b) reacting the compound of Formula IV with a compound ZH;
• to form a linker intermediate of Formula V
• and
• c) reacting the linker intermediate of Formula V resulting from step (b) with a methyltrisulfide compound CH3—S—S—S-J;
• thereby synthesizing a calicheamicin derivative of Formula VI.

A method of synthesizing a calicheamicin derivative of Formula VI

• wherein J is
• R1 is
• or CH3;
• R2 is
• or H;
• R3 is
• or H;
• R4 is
• or H;
• R5 is —CH3, —C2H5, or —CH(CH3)2;
• X is an iodine or bromine atom;
• R5′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C6-C11) aryl-alkyl (C1-5) group, or a heteroaryl or heteroaryl-alkyl (C1-C5) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N -methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C1-C3) alkoxy, or thioalkoxy of 1 to 5 carbon atoms;
• R6 and R7 are each independently selected from H and
• R8 and R9 are each independently selected from hydrogen and straight and branched-chain C1-C8 alkyl, wherein each said alkyl for R8 and R9 is independently optionally substituted by —NH2, —NHR11, —NR11R13, —OR11, —OH, or —SR11, wherein each R11 and each R13 are independently selected from straight and branched-chain C1-5 alkyl;
• r is an integer 0 or 1;
• G is oxygen or sulfur;
• Z1 is H or straight or branched-chain C1-C5 alkyl;
• Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two or three groups independently selected from straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14, or Ar is 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 straight or branched-chain C1-C6 alkyl, —OR14, —SR14, halogen, nitro, —COOR14, —C(═O)NHR14, —O(CH2)nCOOR14, —S(CH2)nCOOR14, —O(CH2)nC(═O)NHR14, and —S(CH2)nC(═O)NHR14;
• wherein each R14 is independently selected from (C1-C5)alkyl and each R14 is independently optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• each n is an integer independently selected from 0, 1, 2, 3, 4, and 5;
• W is selected from —O—, —S—, —C(═O)NH—, —NHC(═O)—, and —NR15-, wherein R15 is a (C1-C5)alkyl and R15 is optionally substituted with one or two groups selected from —OH, —(C1-C4)alkyl, and —S(C1-C4)alkyl;
• Y is a straight or branched-chain (C1-C6)alkylene group or a straight or branched-chain (C2-C6)alkenylene group;
• and
• Z is selected from the group consisting of
• which method comprises reacting a linker intermediate of Formula V
• with a methyltrisulfide compound CH3—S—S—S-J, in the presence of a carbodiimide;
• thereby synthesizing a calicheamicin derivative of Formula VI.

A method of synthesizing a compound of Formula II

• wherein R12 is selected from straight and branched-chain C1-C8 alkyl;
• each R10 is independently selected from hydrogen, R12 and —OR12;
• R8 and R9 are each independently selected from hydrogen and straight and branched-chain C1-C8 alkyl, wherein each said alkyl for R8 and R9 is independently optionally substituted by —NH2, —NHR11, —NR11R13, —OR11, —OH, or —SR11, wherein each R11 and each R13 are independently selected from straight and branched-chain C1-C5 alkyl;
• r is an integer selected from 0 and 1;
• and
• G is oxygen or sulfur;
• which method comprises treating a compound of Formula VII
• wherein R16 is —C(═O)OH or —C(═V)SH, wherein V is oxygen or sulfur, or R16 is —NH2;
• with an azole activating agent of Formula IX
• wherein V′ is oxygen or sulfur;
• and
• wherein E is
• wherein m is an integer 0, 1, 2, or 3;
• q is an integer 0, 1 or 2;
• and p is an integer 0, 1, 2, 3, or 4;
• and wherein each R17 attached to E is independently selected from straight and branched-chain (C1-C6)alkyl groups;
• in an organic solvent to form a compound of Formula VIII
• wherein when R16 is —C(═O)OH, r is 0 and G is oxygen;
• when R16 is —C(═V)SH, r is 0 and G is V;
• and when R16 is —NH2, r is 1 and G is V′;
• followed by combining the compound of Formula VIII with hydrazine, thereby forming a compound of Formula II.