Patent ID: 11873281
Assignee: HANGZHOU DAC BIOTECH CO., LTD.
Field: Pharmaceuticals (Chemistry)
Classification: CPC A  C  Y | IPC A  C

Claim 0:
1. A conjugate of a cell binding molecule with a cytotoxic agent having a structure of Formula (I):, or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof; or a polymorphic crystalline structure thereof, or an optical isomer, racemate, diastereomer or enantiomer thereof;
wherein T is a targeting or cell-binding molecule; L is a releasable linker;  is a linkage bond that L connects to an atom inside the bracket independently; n is 1˜20 and m is 1˜10;
wherein T is an antibody; a single chain antibody; an antibody fragment that binds to the target cell; a monoclonal antibody; a single chain monoclonal antibody; or a monoclonal antibody fragment that binds the target cell; a chimeric antibody; a chimeric antibody fragment that binds to the target cell; a domain antibody; a domain antibody fragment that binds to the target cell; lymphokine; a hormone; a vitamin; a growth factor; a colony stimulating factor; or a transferrin; a binding peptide, or protein, or antibody, or molecule attached on an albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or a capsid;
wherein the linker L has the formula: —Ww-(Aa)r-Vv-; wherein: —W— is a Stretcher unit; w is 0 or 1; each -Aa-is independently an Amino Acid unit; r is independently an integer ranging from 0 to 12; —V— is a Spacer unit; and v is 0, 1 or 2; the Stretcher unit (—W—), when present, links a targeted binding molecular unit (T) to an amino acid unit (-Aa-), or links V when an Aa is not present; the Stretcher unit W independently contains a self-immolative spacer, peptide unit, a hydrazone bond, disulfide or thiolether bond; W linked to T has a structure of:, , wherein R20 and R21 are selected from —C1˜C9 alkylene-, —C1˜C7 carbocyclo-, —O—(C1˜C8 alkyl)-, -arylene-, —C1˜C9 alkylene-arylene-, -arylene, —C1˜C9 alkylene-, —C1˜C9 alkylene-(C1˜C8 carbocyclo)-, —(C3˜C7 carbocyclo)-C1˜C9 alkylene-, —C3˜C8 heterocyclo-, —C1˜C10 alkylene-(C3˜C8 heterocyclo)-, —(C3-C8 heterocyclo)-C1˜C9 alkylene-, —(CH2CH2O)k—, —(CH(CH3)CH2O)k—, and —(CH2CH2O)k—CH2—; k is an integer ranging from 1˜20; R′ and R″ are independently H or CH3;
the Spacer unit (—V—), when present, links an Amino Acid unit to the antimitotic agent when an Amino Acid unit is present or the Spacer unit links the Stretcher unit to antimitotic agent when the Amino Acid unit is absent, or the Spacer unit links antimitotic agent to the binding molecule (T) when both the Amino Acid unit and Stretcher unit are absent; the spacer unit contains a function group that substantially increases the water solubility, biological transport, preferential renal clearance, uptake, absorption, biodistribution, and/or bioavailability of the conjugate; the Spacer unit includes a self-immolative or non-self-immolative; the non-self-immolative Spacer unit is one in which part or all of the Spacer unit remains bound to the antimitotic agent after cleavage of the Amino Acid unit from the conjugate; the self-immolative unit includes an aromatic compound that is electronically similar to a para-aminobenzyl-carbamoyl (PAB) group, 2-aminoimidazol-5-methanol group, heterocyclic PAB group, beta-glucuronide, or ortho or para-aminobenzylacetal; or one of the following structures:, wherein the (*) atom is the point of attachment of additional spacer or releasable linker unit, the antimitotic agent, and/or the binding molecule (T); X, Y and Z3 are independently NH, O, or S; Z2 is H, NH, O or S independently; v is 0 or 1; Q is independently H, OH, C1˜C6 alkyl, (OCH2CH2)n F, Cl, Br, I, OR17, or SR17, NR17R18, N═NR17, N═R17, NR17R18, NO2, SOR17R18, SO2R17, SO3R17, OSO3R17, PR17R18, POR17R18, PO2R17R18, OPO(OR17)(OR18), or OCH2PO(OR17(OR18) wherein R17 and R18 are independently H, C1˜C8 alkyl; C2-C8 alkenyl, alkynyl, or heteroalkyl; C3˜C aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, or alkylcarbonyl; or a pharmaceutical cation salt thereof;
the non-self-immolative spacer unit having a structure of:, or L- or D-, natural or unnatural peptides containing 1˜20 the same or different amino acids;
wherein the “*” and “” atom are the point of attachment of additional spacer or releasable linker, the antimitotic agent, and/or the binding molecule; m is 1˜10; n is 1˜20; X2, X3, X4, X5, or X6 are independently NH; NHNH; N(R12); N(R12)N(R12′); O; S; C1˜C6 alkyl; C2˜C6 of heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; C3˜C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; CH2OR12, CH2SR12, CH2NHR12, or 1˜8 amino acids; wherein R12 and R12′ are independently H; C1˜C8 alkyl; C2˜C8 hetero-alkyl, alkylcycloalkyl, or heterocycloalkyl; C3˜C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or C1˜C8 ester, ether, or amide; or polyethyleneoxy unit of formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 0 to about 1000, or a combination of two or more thereof;
a releasable component of the linker L that at least one bond in L can be broken under physiological conditions: a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond, which having one of the following structures: —(CR15R16)m(Aa)r(CR17R18)n(OCH2C12)t—, —(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t—, - (Aa)r-(CR15R16)m(CR17R18)n(OCH2CH2)t—, —(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-, —(CR15R16)m(CR17═CR18)(CR19R20)n(Aa)t(OCH2CH2)r—, —(CR15R16)m(NR21CO)(Aa)t(CR19R20)n—(OCH2CH2)r—, —(CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r—, —(CR15R16)m(OCO)(Aa)t-(CR19R20)n(OCH2CH2)r—, —(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r—, —(CR15R16)m—(CO)(Aa)t-(CR19R20)n(OCH2CH2)r—, —(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r—, —(CR15R16)m—(OCO)(Aa)t(CR19R20)n—(OCH2CH2)r—, —(CR15R16)m(OCNR17)(Aa)t(CR19R20)n—(OCH2CH2)r—, —(CR15R16)m(CO)(Aa)t(CR19R20)n—(OCH2CH2)r—, —(CR15R16)m-phenyl-CO(Aa)t-(CR17R18)n—, —(CR15R16)m-furyl-CO(Aa)t(CR17R18)n—, —(CR15R6)m-oxazolyl-CO(Aa)t(CR17R18)n—, —(CR15R16)m-thiazolyl-CO(Aa)t(CCR17R18)n—, —(CR15R16)t-thienyl-CO(CR17R18)n—, —(CR15R16)t-imidazolyl-CO—(CR17R18)n—, —(CR15R16)t-morpholino-CO(Aa)t-(CR17R18)n—, —(CR15R16)t-piperazino-CO(Aa)t(CR17R18)n—, —(CR15R16)t—N-methylpiperazin-CO(Aa)t(CR17R18)n—, —(CR15R16)m-(Aa)tphenyl-, —(CR15R16)m-(Aa)tfuryl-, —(CR15R16)m-oxazolyl(Aa)t-, —(CR15R16)m-thiazolyl(Aa)t-, —(CR15R16)m-thienyl-(Aa)t-, —(CR15R16)m-imidazolyl(Aa)t-, —(CR15R16)m-morpholino-(Aa)t-, —(CR15R16)m-piperazino-(Aa)t-, —(CR15R16)m—N-methylpiperazino-(Aa)t-, —K(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t—, —K(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t—, —K(Aa)r-(CR15R16)m(CR17R18)n(OCH2CH2)t—, —K(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-, —K(CR15R16)m—(CR17═CR18)(CR19R20)n(Aa)t(OCH2CH2)r, —K(CR15R16)m(NR11CO)(Aa)t-(CR19R20)n(OCH2CH2)r—, —K(CR5R6)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r—, —K(CR15R16)m—(OCO)(Aa)t(CR19R20)n—(OCH2CH2)r—, —K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n—(OCH2CH2)r—, —K(CR15R16)m(CO)(Aa)t- (CR19R20)n(OCH2CH2)r—, —K(CR15R16)m(NR21CO)(Aa)t-(CR19R20)n—(OCH2CH2)r—, —K(CR15R16)m—(OCO)(Aa)t(CR19R20)n(OCH2CH2)r—, —K(CR15R16)m—(OCNR17)(Aa)t-(CR19R20)n(OCH2CH2)r—, —K—(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r—, —K(CR15R16)m-phenyl-CO(Aa)t(CR17R18)n—, —K—(CR15R16)m-furyl-CO(Aa)t(CR17R18)n—, —K(CR15R16)m-oxazolyl-CO(Aa)t(CR17R18)n—, —K(CR15R16)m-thiazolyl-CO(Aa)t-(CR17R18)n—, —K(CR15R16)t-thienyl-CO(CR17R18)n—, —K(CR15R16)timidazolyl-CO—(CR17R18)n—, —K(CR5R6)tmorpholino-CO(Aa)t-(CR17R18)n—, —K(CR15R16)t-piperazino-CO(Aa)t-(CR17R18)n—, —K(CR15R16)t—N-methylpiperazin-CO(Aa)t(CR17R18)n—, —K(CR15R16)m-(Aa)tphenyl, —K—(CR15R16)m-(Aa)tfuryl-, —K(CR15R16)m-oxazolyl-(Aa)t-, —K(CR15R16)m-thiazolyl(Aa)t-, —K(CR15R16)m-thienyl-(Aa)t-, —K(CR15R16)m-imidazolyl(Aa)t-, —K(CR15R16)m-morpholino(Aa)t-, —K(CR15R16)mpiperazino(Aa)tG, —K(CR5R6)m—N-methyl-piperazino(Aa)t-; wherein m, Aa, R13, R14, and R15 are described above; t and r here are 0-100 independently; R16, R17, R18, R19, and R20 are independently H; halide; C1˜C8 alkyl or heteroalkyl, C2˜C8 aryl, alkenyl, alkynyl, ether, ester, amine or amide, C3˜C8 aryl, which optionally substituted by one or more halide, CN, NR12R12′, CF3, OR12, Aryl, heterocycle, S(O)R12, SO2R12, —CO2H, —SO3H, —OR12, —CO2R12, —CONR12, —PO2R12R13, —PO3H or P(O)R12R12′R13; K is NR12, —SS—, —C(═O)—, —C(═O)NH—, —C(═O)O—, —C═NH—O—, —C═N—NH—, —C(═O)NH—NH—, O, S, Se, B, Het (heterocyclic or heteroaromatic ring having C3˜C12); or a peptide containing the same or different 1-20 amino acids;
inside the bracket of the Formula (I) is an antimitotic agent wherein R1, R2, R3, and R4 are independently linear or branched C1-C8 alkyl, or alkylalcohol; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, alkyl ether, alkyl carboxylate, alkyl amine, alkyl ester, or alkyl amide; C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, or alkylcarbonyl; or two R's: R1R2, R3R4, R5R6, or R12R13 together form a 3˜7 membered carbocyclic, cycloalkyl, heterocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system; Y is N or C; R1, R2, R3, and R4 may optionally be independently absent;
wherein R5, R6, R8 and R10 are independently H, linear or branched C1-C4 alkyl or C2-C4 heteroalkyl;
wherein R7 is H, R14, —R14C(═O)X1R15; or —R14X1R15; X1 is O, S, S—S, NH, or NR14;
wherein R9 is H, —O—, —OR14, —OC(═O)R14—, —OC(═O)NHR14—, —OC(═O)NR14R15—, —OC(═O)R14SSR15—, OP(═O)(OR14)—, or OR14OP(═O)(OR15);
wherein R11 is H, R14, —R14C(═O)R16, —R14C(═O)X2R16, —R14X2R16, or —R14C(═O)X2, wherein X2 is —O—, —S—, —NH—, —NHS(O2), —NHS(O), —N(R14)—, —O—R14—, —S—R14—, —S(═O)—R14—, or —NHR14—, provided that when R11 is —R14C(═O)X2— and connects to L, wherein X2 is —O—, R14 is not C1-C8 alkyl;
wherein R12 is H, R14, —O—, —S—, —N—, ═N—, ═NNH—, —OH, —SH, —NH2, ═NH, ═NNH2, —NH(R14), —OR14, —C(O)O—, —C(O)OR16—, —COR16, —COOR14—, C(O)NH—, C(O)NH2, C(O)NHR14, —SR14, —S(═O)R14, —P(═O)(OR16)2, —OP(═O)(OR16)2, —CH2OP(═O)(OR16)2, or —SO2R16;
wherein R13 is linear or branched C1˜C10 alkyl, alkyl acid, alkyl amide, or alkyl amine; or C2-C10 heteroalkyl; or C3-C10 Ar; Ar is an aromatic or hetero aromatic group, composed of one or several rings, comprising four to ten carbon atoms, the hetero aromatic group is an aromatic group that has one or several carbon atoms replaced by hetero atoms, the aryl or Ar is an aromatic group, wherein one or several H atoms can be replaced independently by R17, F, Cl, Br, I, OR16, SR16, NR16R17, N═NR16, N═R16, NR16R17, NO2, SOR16R17, SO2R16, SO3R16, OSO3R16, PR16R17, POR16R17, PO2R16R17, OP(O)(OR17)2, OCH2OP(O)(OR17)2, OC(O)OP(O)(OR17)2, PO(OR16)(OR17), OP(O)(OR17)OP(O)(OR17)2, OC(O)R17 or OC(O)NHR17;
wherein R14 and R15 are independently H; linear or branched C1-C8 alkyl; C2-C8 alkenyl, alkynyl, heteroalkyl, heterocyclic, or carbocyclic; C3-C8 aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl;
wherein when R14 is bivalent, R14 is further connected to an additional functional group of one to four amino acid units, or (CH2CH2O)r, r is an integer ranging from 0 to 12, or C4-C12 glycoside, or C1-C8 carboxylic acid;
wherein R16 is H, OH, R14 or one to four amino acid units;
wherein R17 is H, linear or branched C1-C8 alkyl; C2-C8 alkenyl, alkynyl, heteroalkyl, or heterocyclic; C3-C8 aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, or alkylcarbonyl, or C4-C12 glycoside, or a pharmaceutical salt.