US2007197455A1PendingUtilityA1
Processes for the convergent synthesis of calicheamicin derivatives
Est. expiryFeb 21, 2026(expired)· nominal 20-yr term from priority
A61P 35/00C07D 309/14C07H 15/203C07C 323/60C07D 207/404C07D 405/14C07C 319/20C07H 15/26C07D 207/46C07H 15/20
63
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Claims
Abstract
This invention describes processes for the convergent synthesis of calicheamicin derivatives, and similar analogs using bifunctional and trifunctional linker intermediates.
Claims
exact text as granted — not AI-modified1 . A process to prepare compounds of Formula (I):
wherein:
Z is selected from the group consisting of
Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;
Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;
Z 1 is H, or alkyl of 1 to 5 carbon atoms;
Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or 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 alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;
n is an integer from 0 to 5;
R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;
Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;
W′ is
R 5 is —CH 3 , —C 2 H 5 , or —CH(CH 3 ) 2 ;
X is an iodine or bromine atom;
R 5′ 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 (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) 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, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms; and
Q is selected from the group consisting of —NNHCO—, —NNHCS—, —NNHCONH—, —NNHCSNH—, and —NO—;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
H 2 -Q-Sp-SH
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, wherein Alk 1 , Sp 1 , Ar, Z 1 , Q, and Sp are as defined above, to produce a bilinker-carboxylic acid of the formula, wherein the mercapto compound and carboxylic acid are present in a ratio of about 1.2:1
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with an at least a 3 fold molar excess of N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula
where Z is hereinbefore defined;
d. reacting the trilinker-activated ester formed in step c with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent to generate an activated ester of the formula below, wherein the trilinker-activated ester in step c and the CH 3 —S—S—S—W′ are in a ratio of 3.3:1 and the temperature of the reaction is ≦5° C.
e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of Formula (I)
2 . The process of claim 1 wherein the purifying of step (e) comprises the use of reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed by normal phase chromatography.
3 . A process according to claim 1 , wherein
alk 1 is 3 carbon atoms; Sp 1 is —O—; Z 1 is methyl; Ar is unsubstituted 1,4-phenylene; Sp is 4 carbon atoms; R 3 is H; Q is NNHC(O)—;
R 5 is C 2 H 5 ;
R 5 ′ is —C(O)—R;
R is methyl; and
Z is
4 . A process to prepare antitumor antibiotics of Formula (I):
wherein:
Z is selected from the group consisting of
Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;
Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;
Z 1 is H, or alkyl of 1 to 5 carbon atoms;
Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or 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 alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;
n is an integer from 0 to 5;
R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;
Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;
W′ is
R 5 is —CH 3 , —C 2 H 5 , or —CH(CH 3 ) 2 ;
X is an iodine or bromine atom;
R 5′ 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 (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) 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, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms; and
Q is selected from the group consisting of —NNHCO—, —NNHCS—, —NNHCONH—, —NNHCSNH—, and —NO—;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
H 2 Q-Sp-SH
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, wherein Alk 1 , Sp 1 , Ar, Z 1 , Q, and Sp are as defined above, to produce a bilinker-carboxylic acid of the formula, wherein the mercapto compound and carboxylic acid are present in a ratio of about 1.2:1
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent;
d. reacting the compound of step (c) with an at least a 3 fold molar excess of N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) and purifying to yield antitumor antibiotics of Formula (I)
5 . The process of claim 4 wherein the purifying of step (e) comprises the use of a reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed with a normal phase chromatography.
6 . A process according to claim 4 , wherein
alk 1 is 3 carbon atoms; Sp 1 is —O—; Z 1 is methyl; Ar is unsubstituted 1,4-phenylene; Sp is 4 carbon atoms; R 3 is H; Q is NNHC(O)—;
R 5 is C 2 H 5 ;
R 5 ′ is —C(O)—R;
R is methyl; and
Z is
7 . A process to prepare antitumor antibiotics of Formula (I):
wherein:
Z is selected from the group consisting of
Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;
Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;
Z 1 is H, or alkyl of 1 to 5 carbon atoms;
Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or 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 alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;
n is an integer from 0 to 5;
R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;
Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;
W′ is
R 5 is —CH 3 , —C 2 H 5 , or —CH(CH 3 ) 2 ;
X is an iodine or bromine atom;
R 5′ 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 (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) 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, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms; and
Q is selected from the group consisting of —NNHCO—, —NNHCS—, —NNHCONH—, —NNHCSNH—, and —NO—;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
H 2 -Q-Sp-SH
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, wherein Alk 1 , Sp 1 , Ar, Z 1 , Q, and Sp are as defined above, to produce a bilinker-carboxylic acid of the formula,
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with an at least of N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula
where Z is hereinbefore defined
d. reacting the trilinker-activated ester in step c in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent to generate an activated ester of the formula
e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of Formula (I)
8 . A process according to claim 1 , wherein
alk 1 is 3 carbon atoms; Sp 1 is —O—; Z 1 is methyl; Ar is unsubstituted 1,4-phenylene; Sp is 4 carbon atoms; R 3 is H; Q is NNHC(O)—;
R 5 is C 2 H 5 ;
R 5 ′ is —C(O)—R;
R is methyl; and
Z is
9 . A process according to claim 1 , wherein Alk 1 is an alkylene of 2 to 5 carbon atoms, and Sp 1 is an oxygen atom.
10 . A process according to claim 9 , wherein Alk 1 is an alkylene of 3 carbon atoms.
11 . A process according to claim 1 , wherein Z 1 is alkyl of 1 to 3 carbon atoms.
12 . A process according to claim 1 , wherein Ar is 1,2-, 1,3-, or 1,4-phenylene, or 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6-, or 2,7-naphthylidene.
13 . A process according to claim 12 , wherein Ar is 1,4-phenylene.
14 . A process according to claim 1 , wherein Q is —NNHCO—.
15 . A process according to claim 1 , wherein Sp is straight or branched-chain divalent or trivalent alkyl radical of 1 to 12 carbon atoms.
16 . A process according to claim 15 , wherein Sp is straight or branched-chain divalent or trivalent alkyl radical of 1 to 6 carbon atoms.
17 . The process according to claim 1 , wherein the alcohol solvent is methanol.
18 . The process according to claim 1 , wherein the inert solvent is acetonitrile.
19 . The process according to claim 1 , wherein alkyl carboxylic acid is acetic acid.
20 . The process according to claim 1 , wherein the inert organic solvent is acetonitrile.
21 . A process according to claim 1 , wherein Z is
22 . A process to prepare trilinker-activated esters of the formula:
wherein:
Z is selected from the group consisting of
Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;
Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;
Z 1 is H, or alkyl of 1 to 5 carbon atoms;
Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or 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 alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;
n is an integer from 0 to 5;
R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;
Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;
W′ is
R 5 is —CH 3 , —C 2 H 5 , or —CH(CH 3 ) 2 ;
X is an iodine or bromine atom;
R 5′ 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 (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) 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, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms; and
Q is selected from the group consisting of —NNHCO—, —NNHCS—, —NHNCONH—, —NNCSNH—, and —NO—;
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
H 2 Q-Sp-SH
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, wherein Alk 1 , Sp 1 , Ar, Z 1 , Q, and Sp are as defined above, to produce a bilinker-carboxylic acid of the formula
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the bilinker-carboxylic acid from step (b) in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ in an inert organic solvent to generate a bilinker-methyltrithio antitumor antibiotic of the formula
d. reacting the isolated bilinker-methyltrithio antitumor antibiotic of step (c) with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula
23 . The process according to claim 17 , wherein Alk 1 is an alkylene of 2 to 5 carbon atoms, and Sp 1 is an oxygen atom.
24 . A process for the preparation of trifunctional linker intermediates, of the formula
wherein:
Alk 1 is a branched or unbranched alkylene chain of 2 to 6 carbon atoms;
Sp 1 is selected from —S—, —O—, —CONH—, —NHCO—, and —NR′—;
Z 1 is H, or alkyl of 1 to 5 carbon atoms;
Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′ or 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 alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH 2 ) n COOR′, —S(CH 2 ) n COOR′, —O(CH 2 ) n CONHR′, and —S(CH 2 ) n CONHR′;
n is an integer from 0 to 5;
R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms;
Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C 1 -C 18 ) radical, divalent or trivalent cycloalkyl- or heterocyclo-alkyl-alkyl (C 1 -C 18 ) radical or divalent or trivalent unsaturated alkyl radical of 2 to 18 carbon atoms, wherein heteroaryl is furyl, thienyl, N-methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocoumarinyl, or phenazinyl and wherein if Sp is a trivalent radical, it can be additionally substituted by dialkylamino of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, hydroxy, or alkylthio of 1 to 5 carbon atoms groups;
Q is selected from the group consisting of —NNHCO—, —NNHCS—, and —NNHCONH—;
Z is selected from the group consisting of
comprising the steps of:
a. reacting a carboxylic acid of the formula
with a mercapto compound of the formula
H 2 Q-Sp-SH
in an alcohol solvent in the presence of an alkyl carboxylic acid, alk 2 CO 2 H, where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, wherein Alk 1 , Sp 1 , Ar, Z 1 , Q, and Sp are as defined above, to produce a bilinker-carboxylic acid of the formula
b. isolating the bilinker-carboxylic acid of step (a);
c. reacting the isolated bilinker-carboxylic acid of step (b) with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimidyl carbonate in an inert solvent containing 0-50% DMF to generate trifunctional linker intermediates, of the formulaJoin the waitlist — get patent alerts
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