Affinity medicant conjugates 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2015157578 A2 2015-10-15 [WO2015157578]WO2015157578 A3 2015-12-17 [WO2015157578] / 2015-10-152015-12-17
申请号/申请日
2015WO-US25208 / 2015-04-09
发明人
KELNER MICHAEL;MCMORRIS TREVOR C;
申请人
BASF;
主分类号
IPC分类号
A01N-047/10C07C-209/62C07D-235/02C07D-493/00
摘要
(WO2015157578) In an embodiment of the invention, a composition for treating a cell population comprises an Affinity Medicant Conjugate (AMC).  The medicant moiety can be a toxin including an acylfulvene or a drug moiety.  The affinity moiety can be an antibody, a binding protein, a steroid, a lipid, a growth factor, a protein, a peptide or non peptidic.  The affinity moiety can be covalently bound to the medicant via a linker.  Novel linkers that can be directed to cysteine, arginine or lysine residues based on solution pH allow greater flexibility in preserving and/or generating specific epitopes in the AMC.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2014US-61978195 2014-04-10
主权利要求
(WO2015157578) 11 A compound of the formula: where X denotes a heteroatom containing nitrogen (N), oxygen (O) or sulphur (S) including - NH-, -NR.7-, -S-, -0-, -CH2-, -CHR8-, -CHR7R8; Ri denotes a Linker Unit; R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide; and R3, R4, Rs, R6, R7, Rs each independently denote H, -, CH3, CH2- CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl. 2  13. A compound comprising: an illudinl including a first functional group; a bifunctional linker with a first terminus including a second functional group, and a second terminus including a third functional group, where the first functional group is covalently bonded to the second functional group; and an Affinity Moiety including one or both one or more primary amino groups and one or more hydroxy l groups, where the Affinity Moiety is selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, folate and an oligonucleotide, where the third functional group is covalently bonded to at least one of the one or more primary amino groups or one or more one or more hydroxy l groups of the Affinity Moiety, or a pharmaceutically acceptable salt thereof.   21. A method of ablating cancer cells comprising the steps of: selecting an Affinity Moiety which preferentially binds to a marker present on cancer cells; covalently binding a medicant moiety to the Affinity Moiety via a Linker Unit to generate an affinity medicant conjugate; and treating the cancer cells with the affinity medicant conjugate.  22. A compound comprising: an illudinl selected from the group consisting of analogs 189, 190, 217, 218, 219, 222 and 316 including a first functional group; and an Affinity Moiety including one or more of one or more primary amino groups, one or more hydroxy l groups, and one or more sulfhydryl groups, where the Affinity Moiety is selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, folate and an oligonucleotide, where the first functional group is covalently bonded to at least one of the one or more primary amino groups, one or more one or more hydroxy l groups or one or more sulfhydryl groups of the Affinity Moiety, or a pharmaceutically acceptable salt thereof.  23. An affinity medicant conjugate (AMC) comprising: a medicant moiety containing a hydroxy l group; 2: a FSB linker selected from the group consisting of 4-fluorosulfonyl benzoyl, 3 -fluorosulfonyl benzoyl and 2-fluorosulfonyl benzoyl forming a reactive fluorosulfonyl benzoyl group, where the reactive fluorosulfonyl benzoyl group forms a covalent bond with the hydroxy l group; and an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor a protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide, where the fluorosulfonyl benzoyl group forms a covalent bond with the Affinity Moiety.   25. A compound of formula selected from the group consisting of: 2 where X= oxygen (O) or sulfur (S); Ri, R2, R3, R4 each independently denote H, OH, -, CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, (-0-C=0)R9, (C=0)-0-R9, -0-R9, CH2OH, -CH2OR9, R9-OH, (C C4)alkyl, F, CI, Br, I; R5, R7, R8 each independently denote H, OH, -, CH3, CH2-CH3, CH-(CH3)2, - C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, (-0-C=0)R9, (C=0)-0-R9, -0-R9, CH2OH, -CH2OR9, R9-OH, (C C4)alkyl; R6 denotes H, OH, -, CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, (-0-C=0)R9, (C=0)-0-R9, -0-R9, CH2OH, -CH2OR9, R9-OH, -CH2-N3, (C C4)alkyl and R9 denotes CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH- (CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl.  31. A compound of formula selected from the group consisting of: C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, -C(=0)CH3, -C(=0)R7, - C(=0)-0-R7, (-0-C=0)-R7, 0-R7, CH2OH, -CH2OR7, R7-OH, (C C4)alkyl, F, CI, Br, I; R5 denotes a medicant moiety; R6 denotes an Affinity Moiety and R7 denotes CH , CH2-CH , CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl.   34. A compound of the formula: 2 where 3/4 denotes H, OH, -, CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2- CH-(CH3)2, -CH-C-(CH3)3, -C(=0)CH3, -C(=0)R7, -C(=0)-0-R7, (-0-C=0)-R7, 0-R7, CH2OH, -CH2OR7, R7-OH, (C C4)alkyl, F, CI, Br, I, or a heteroatom containing nitrogen (N) or oxygen (O); R2, R3, R4, R5, R6 each independently denote H, -, CH3, CH2OH; and R7 denotes CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C- (CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl.  35. A compound of the formula: where 3/4 denotes H, OH, -, CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, -CH2- CH-(CH3)2, -CH-C-(CH3)3, -C(=0)CH3, -C(=0)R7, -C(=0)-0-R8, (-0-C=0)-R7, 0-R8, CH2OH, -CH2OR8, Rs-OH, (C C4)alkyl, F, CI, Br, I, or a heteroatom containing nitrogen (N) or oxygen (O); R2, R3, R4, R5, R6 each independently denote H, -, CH3, CH2OH; R7 denotes an Affinity Moiety; and R8 denotes CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, -CH2-CH2-CH3, - CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl. 2 sting of: where Ri is selected from a linking unit, a heteroatom containing nitrogen (N), oxygen (O) or Sulphur (S), or -(CH2)n-, where n = 1 to 20, or a substituted alkyl -(CH2)n-C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, - CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, -C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, - C(0)NH2, -NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2, R3, R4, R5 denote H, -, CH3, CH2-CH3, CH-(CH3)2, -C(CH3)3, - CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl and R6 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide. 2 sting of: where Ri is selected from a linking unit, a heteroatom containing nitrogen (N), oxygen (O) or Sulphur (S), or -(CH2)n-, where n = 1 to 20, or a substituted alkyl -(CH2)n-C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, - CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, -C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, - C(0)NH2, -NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2, R3, R4, R5, R6 denote H, -, CH3, CH2-CH3, CH-(CH3)2, - C(CH3)3, -CH2-CH2-CH3, -CH2-CH-(CH3)2, -CH-C-(CH3)3, (C(=0)CH3, CH2OH, and (C C4)alkyl and R7 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide. 2  38. An affinity medicant conjugate (AMC) comprising: a medicant moiety containing a hydroxy l group; a maleimide linker forming a covalent bond with the hydroxy l group; and an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor a protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide, where the maleimide linker forms a covalent bond with the Affinity Moiety.  40. A compound of the formula: where Ri is selected from a linking unit, a heteroatom containing nitrogen (N) or oxygen (O), or -(CH2)n-, where n = 1 to 20, or a substituted alkyl -(CH2)"-C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, -CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, -C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, -C(0)NH2, - NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease 2 cleavable peptide, a glycopeptide, folate and an oligonucleotide; R3, R4, R5, R6, R7 each independently denote H, OH, -, CH3, CH2CH3, OCH3, OCH2CH3, OC(C=0)CH3, OC(C=0)CH2CH3. where Z denotes oxygen (O), -NH-, or -CH2- ; Ri is independently selected from a linking unit, a heteroatom containing nitrogen (N) or oxygen (O), -(CH2)n-, where n = 1 to 20, and a substituted alkyl -(CH2)n- C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, -CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, - C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, -C(0)NH2, -NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide; R3, R4, R5, R6, R7 each independently denote H, OH, -, CH3, CH2CH3, OCH3, OCH2CH3, OC(C=0)CH3, OC(C=0)CH2CH3.  42. A compound of formula selected from the group consisting of: where Ri denotes either an illudin or an acylfulvene analog selected from the group consisting of analogs 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 133, 134, 135, 136, 137, 138, 2^ 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 171, 172, 173, 174, 175, 177, 178, 179, 180, 181, 182, 183, 188, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201 202, 203, 204, 205, 206, 207, 208, 209, 210, 212, 213, 214, 215, 216, 221, 223, 224, 225, 226, 227, 228, 229, 230, 231, 236, 240, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259 , 262, 263, 267, 268, 269, 270, 272, 273, 274, 275, 276, 284, 285, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314 and 315; and R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide.  43. A compound of formula selected from the group consisting of: where Ri is independently selected from a linking unit, a heteroatom containing nitrogen (N) or oxygen (O), -(CH2)"-, where n = 1 to 20, and a substituted alkyl -(CH2)"- C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, - CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, -C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, - C(0)NH2, -NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide; and R3, R4, R5, R6 each independently denote H, OH, -, CH3, CH2CH3, OCH3, OCH2CH3, OC(C=0)CH3, OC(C=0)CH2CH3.  44. A compound of the formula: 2^ where Z denotes oxygen (O), -NH-, or -CH2- ; Ri is independently selected from a linking unit, a heteroatom containing nitrogen (N) or oxygen (O), -(CH2)n-, where n = 1 to 20, and a substituted alkyl -(CH2)"- C(X)H-(CH2)m-, where n = 0 to 20, where m = 0 to 20, and X independently denotes -F, -CI, -Br, -I, -CN, -CF3, -SH, -N(O), -N(0)2, -NH2, -C(0)H, - C(0)OH, -N=NH, -NH-C(0)H, -NH-C(0)-OH, -C(0)NH2, -NHS2H, -S(0)2NH2, -OH, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 denotes an Affinity Moiety selected from the group consisting of an antibody, a peptide, a receptor protein, a growth factor, a lipid, a steroid, a protease cleavable peptide, a glycopeptide, folate and an oligonucleotide; R3, R4, R5, R6, R7 each independently denote H, OH, -, CH3, CH2CH3, OCH3, OCH2CH3, OC(C=0)CH3, OC(C=0)CH2CH3. 2^
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