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Some cytotoxic drugs tend to be inactive or less active when conjugated to larger antibodies or protein receptor ligands
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[0570] Preparation of Antibody Drug Conjugates
[0571] Antibody drug conjugates can be prepared by several routes using those organic chemical reactions, conditions and reagents well known to those skilled in the art, including: (1) reacting the nucleophilic group of the antibody with a divalent linker reagent to pass covalently bonding to form the antibody-linker intermediate Ab-L, followed by reaction with the activated drug moiety reagent; and (2) reacting the drug moiety reagent with the linker reagent to covalently form the drug-linker reagent D-L, which is then reacted with the antibody nucleophilic group reaction. Conjugation Methods (1) and (2) Various antibodies and linkers can be employed to prepare the antibody-drug conjugates of the present invention.
[0572] Nucleophilic groups of antibodies include, but are not limited to, side chain sulfhydryl groups such as cysteine. Thiol groups are nucleophilic and are capable of reacting with electrophilic groups on the ...
[0602] Potassium carbonate (19.92 g, 14 mmol, 3 eq.) was added to a stirred solution of carboxylic acid (1) (10.92 g, 48 mmol, 1 eq.) in DMF (270 mL). The resulting white suspension was stirred at room temperature for 30 min, at which time iodomethane (21.48 g, 9.5 mL, 151 mmol, 3.15 eq.) was added. The reaction mixture was stirred at room temperature for 3 days. DMF was removed by rotary evaporation under reduced pressure to give a yellow residue which was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. Ethyl acetate was removed by rotary evaporation under reduced pressure to yield the crude product as a yellow oil. The crude pro...
[0633] Thioacetic acid (1.99 g, 1.86 mL, 26.1 mmol, 1.1 eq.) was added to a suspension of cesium carbonate (7.73 g, 23.72 mmol, 1.0 eq.) in dry DMF (40 mL). After 30 minutes, (S)-methyl 2-chloropropionate (15) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between diethyl ether (150 mL) and water (150 mL); the water was separated and washed with another portion of diethyl ether (150 mL). The combined organic fractions were washed with water (6×100 mL), brine (200 mL), dried (MgSO 4 ) and evaporated under reduced pressure. Purification by flash column chromatography [10% ethyl acetate / 90% n-hexane] gave the product as a colorless oil (3.01 g, 82%). Analytical data: RT 2.25 min; MS (ES + ) m / z (relative intensity) 163 ([M+H] +. ,10),185([M+Na] +. ,65); [α] t d =[+141] 17.8℃ d (c, 2.26C...
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Abstract
A conjugate of formula (A): the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 is independently selected from H, OH, =0, =CH2, CN, R, OR, =CH-RD, =C(RD)2, 0-S02-R, C02R and COR, and optionally further selected from halo or dihalo; where RD is independently selected from R, C02R, COR, CHO, C02H, and halo; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', NO2, Me3Sn and halo; R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', N02, Me3Sn and halo; Y is selected from a single bond, and a group of formulae A1 or A2: where N shows where the group binds to the N10 of the PBD moiety; RL1 and RL2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene group; CBA represents a cell binding agent; Q is independently selected from O, S and NH; R11 is either H, or R or, where Q is O, S03M, where M is a metal cation; R and R' are each independently selected from optionally substituted C1-12alkyl, C3-20 heterocyclyl and C5-20aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-; 6- or 7-metfibered heteracyciie ring; wherein R12 R16, R19 and R17 are as defined for R2, R6, R9 and R7 respectively: wherein R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H}; NMe and / or aromatic rings, e.g. benzene or pyridine, which rings are optional y substituted; X and X' are independently selected from O, S and N(H).
Description
technical field [0001] The present invention relates to pyrrolobenzodiazepines (PBDs), in particular pyrrolobenzodiazepines with a labile N10 protecting group in the form of a cell binding agent linker. Background technique [0002] Pyrrolobenzodiazepines [0003] Some pyrrolobenzodiazepines (PBDs) have the ability to recognize and bind specific DNA sequences; the preferred sequence is PuGPu. The first PBD antitumor antibiotic, anthranilidine, was discovered in 1965 (Leimgruber et al., J.Am.Chem.Soc., 87, 5793-5795 (1965); Leimgruber et al., J.Am.Chem.Soc. ., 87, 5791-5793 (1965)). Since then, a large number of naturally occurring PBDs have been reported, and more than 10 synthetic routes have been developed for various analogs (Thurston et al., Chem. Rev. 1994, 433-465 (1994); Antonow, D. and Thurston, D.E., Chem. Rev. 2011111(4), 2815-2864). Family members include abbeymycin (Hochlowski et al, J. Antibiotics, 40, 145-148 (1987)), chikamycin (Konishi et al, J. Antibioti...
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