Intermediates and methods for synthesizing calicheamicin derivatives

Patent metadata

Field	Value
Publication number	US-2018134656-A1
Application number	US-201815870014-A
Country	US
Kind code	A1
Filing date	Jan 12, 2018
Priority date	Nov 4, 2013
Publication date	May 17, 2018
Grant date	—

Abstract

The present invention relates to intermediates of Formula I

and to methods of synthesizing and purifying calicheamicin derivatives.

First claim

1 - 91 . (canceled)

92 . A method for synthesizing a compound of Formula I

wherein R 12 is selected from straight and branched-chain C 1 -C 8 alkyl;
each R 10 is independently selected from hydrogen, R 12 and —OR 12 ;
R 8 and R 9 are each independently selected from hydrogen and straight and branched-chain C 1 -C 8 alkyl, wherein each said alkyl for R 8 and R 9 is independently optionally substituted by —NH 2 , —NHR 11 , —NR 11 R 13 , —OR 11 , —OH, or —SR 11 , wherein each R 11 and each R 13 are independently selected from straight and branched-chain C 1 -C 5 alkyl;
r is an integer 0 or 1;
G is oxygen or sulfur;
Z 1 is H or straight or branched-chain C 1 -C 5 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 , 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 ;
wherein each R 14 is independently selected from (C 1 -C 5 )alkyl and each R 14 is independently optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )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 —NR 15 —, wherein R 15 is a (C 1 -C 5 )alkyl and R 15 is optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )alkyl; and Y is a straight or branched-chain (C 1 -C 6 )alkylene group or a straight or branched-chain (C 2 -C 6 )alkenylene group; which method comprises reacting a compound of Formula II

with a compound of Formula III

93 . A method according to claim 92 , wherein r is 0, G is oxygen, Z 1 is methyl, Ar is 1,4-phenylene, W is —O—, and Y is —(CH 2 ) 3 —.

94 . A method according to claim 92 , wherein R 8 and R 9 are methyl.

95 . A method according to claim 92 , wherein each R 10 is hydrogen.

96 . A method according to claim 95 , wherein R 12 is methyl.

97 . A method for synthesizing a compound of Formula IV

which method comprises treating a compound of Formula I

wherein R 12 is selected from straight and branched-chain C 1 -C 8 alkyl;
each R 10 is independently selected from hydrogen, R 12 and —OR 12 ;
R 8 and R 9 are each independently selected from hydrogen and straight and branched-chain C 1 -C 8 alkyl, wherein each said alkyl for R 8 and R 9 is independently optionally substituted by —NH 2 , —NHR 11 , —NR 11 R 13 , —OR 11 , —OH, or —SR 11 , wherein each R 11 and each R 13 are independently selected from straight and branched-chain C 1 -C 5 alkyl;
r is an integer 0 or 1;
G is oxygen or sulfur;
Z 1 is H or straight or branched-chain C 1 -C 5 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 , 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 ;
wherein each R 14 is independently selected from (C 1 -C 5 )alkyl and each R 14 is independently optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )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 —NR 15 —, wherein R 15 is a (C 1 -C 5 )alkyl and R 15 is optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )alkyl; and
Y is a straight or branched-chain (C 1 -C 6 )alkylene group or a straight or branched-chain (C 2 -C 6 )alkenylene group, with a strong acid to form a mixture comprising the compound of Formula IV.

98 . A method according to claim 97 , wherein the strong acid is trifluoroacetic acid or sulfuric acid.

99 . A method according to claim 97 , wherein R 8 and R 9 are methyl, r is 0, G is oxygen, Z 1 is methyl, Ar is 1,4-phenylene, W is —O—, and Y is —(CH 2 ) 3 —.

100 . A method according to claim 97 , wherein each R 10 is hydrogen.

101 . A method according to claim 100 , wherein R 12 is methyl.

102 . A method for synthesizing a linker intermediate of Formula V

wherein R 8 and R 9 are each independently selected from hydrogen and straight and branched-chain C 1 -C 8 alkyl, wherein each said alkyl for R 8 and R 9 is independently optionally substituted by —NH 2 , —NHR 11 , —NR 11 R 13 , —OR 11 , —OH, or —SR 11 , wherein each R 11 and each R 13 are independently selected from straight and branched-chain C 1 -C 5 alkyl;
r is an integer selected from 0 and 1;
G is oxygen or sulfur;
Z 1 is H or straight or branched-chain C 1 -C 5 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 , 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 C 1 -C 6 alkyl, —OR 14 , —SR 14 , halogen, nitro, —COOR 14 , —C(═O)NHR 14 , —O(CH 2 ) n COOR 14 , —S(CH 2 ) n COOR 14 , —O(CH 2 ) n C(═O)NHR 14 , and —S(CH 2 ) n C(═O)NHR 14 ;
wherein each R 14 is independently selected from (C 1 -C 5 )alkyl and each R 14 is independently optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )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 —NR 15 —, wherein R 15 is a (C 1 -C 5 )alkyl and R 15 is optionally substituted with one or two groups selected from —OH, —(C 1 -C 4 )alkyl, and —S(C 1 -C 4 )alkyl;
Y is a straight or branched-chain (C 1 -C 6 )alkylene group or a straight or branched-cha

Assignees

• Pfizer

Inventors

• Dugger Robert Wayne
• Letendre Leo Joseph
• Patel Vimalkumar Babubhai
• Prashad Amarnauth Shastrie
• Zhang Chunchun

Classifications

• C07C319/28 Primary

  Separation; Purification · CPC title

• C07C319/20 Primary

  by reactions not involving the formation of sulfide groups · CPC title

• A61K47/6809

  Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin · CPC title

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07C319/06

  from sulfides, hydropolysulfides or polysulfides · CPC title