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Pyrrolobenzodiazepines and antibody disulfide conjugates thereof

一种抗体、化合物的技术，应用在抗动物/人类的免疫球蛋白、抗受体/细胞表面抗原/细胞表面决定因子免疫球蛋白、药物组合等方向，能够解决无活性活性等问题

Inactive Publication Date: 2017-08-18
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some cytotoxic drugs tend to be inactive or less active when conjugated to larger antibodies or protein receptor ligands

Method used

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  • Pyrrolobenzodiazepines and antibody disulfide conjugates thereof
  • Pyrrolobenzodiazepines and antibody disulfide conjugates thereof
  • Pyrrolobenzodiazepines and antibody disulfide conjugates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0303] (25) GEDA (Genbank accession number AY260763); AAP14954 lipoma HMGIC fusion-partner protein / pid=AAP14954.1-Homo sapiens (human); WO2003 / 054152 (claim 20); WO2003 / 000842 (claim 1) ; WO2003 / 023013 (Example 3, Claim 20); US2003 / 194704 (Claim 45); Cross Reference: GI: 30102449; AAP14954.1; AY260763_1

[0304](26) BAFF-R (B cell activating factor receptor, BLyS receptor 3, BR3, Genbank accession number AF116456); BAFF receptor / pid=NP_443177.1-Homo sapiens: Thompson, J.S. et al. Science 293(5537), 2108-2111 (2001); WO2004 / 058309; WO2004 / 011611; WO2003 / 045422 (Examples; pp. 32-33); WO2003 / 014294 (claim 35; FIG. 6B); WO2003 / 035846 (claim 70; pp. pp. 615-616); WO2002 / 94852 (columns 136-137); WO2002 / 38766 (claim 3; p. 133); WO2002 / 24909 (example 3; figure 3); cross-references: MIM:606269; .1;NM_052945_1;AF132600

[0305] (27) CD22 (B cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814, Genbank accession number AK026467); Wilson et al. (1991) J.Exp.Med.173 :13...

Embodiment 1

[0696]

[0697] (a) (R)-2-((3-nitropyridin-2-yl)disulfanyl)propan-1-ol (3)

[0698] A solution of (R)-2-mercaptopropan-1-ol 1 (0.4 g, 4.35 mmol, 1.0 equiv) in anhydrous DCM (14 mL) was added dropwise to the A solution of 3-nitropyridin-2-ylhypochlorothioite 2 (1.0 g, 5.22 mmol, 1.2 eq) in anhydrous DCM (40 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure to yield a yellow gum. The gum was redissolved in water and the solution was basified with ammonium hydroxide solution (pH 12), extracted with DCM (4 x 50 mL) and the combined extracts were washed with saturated brine (100 mL), dried (MgSO 4 ) and evaporated to yield an orange oil / solid mixture. Purification by flash column chromatography [gradient elution DCM / MeOH 0% to 1%] gave the product (0.745 g, 70%) as a yellow semi-solid. Analytical data: RT 1.41 min; MS(ES + ) m / z (relative intensity) 247 ([M+H] +. ,100).

[0699] (b) (2-((S)-2-((tert-bu...

Embodiment 2

[0707]

[0708] (a) (R)-2-((5-nitropyridin-2-yl)disulfanyl)propan-1-ol (10)

[0709] Sulfuryl chloride (2.35 mL of a 1.0 M solution in DCM, 2.35 mmol) was added dropwise to 5-nitropyridine-2-thiol 9 (334 mg, 2.14 mmol) at 0 °C (ice / acetone) under argon atmosphere ) in a stirred suspension in anhydrous DCM (7.5 mL). The reaction mixture changed from a yellow suspension to a yellow solution and was allowed to warm to room temperature, then stirred for 2 hours, after which time the solvent was removed by evaporation in vacuo to afford a yellow solid. The solid was redissolved in DCM (15 mL) and treated with a solution of (R)-2-mercaptopropan-1-ol (213 mg, 2.31 mmol) in anhydrous DCM (7.5 mL) at 0 °C under argon atmosphere Process drop by drop. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, after which time analysis by LC / MS revealed substantial product formation at retention time 1.41 minutes (ES+) m / z 247 ([M+H] + , about 100% relati...

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Abstract

A compound of formula (I) is disclosed, wherein Y is selected from a single bond, and a group of formulae (A1) or (A2),and N shows where the group binds to the N10 of the PBD moiety.

Description

technical field [0001] The present invention relates to pyrrolobenzodiazepines (PBDs), especially pyrrolobenzodiazepines having a labile N10 protecting group suitable for forming linkers to cell-binding agents. The invention also relates to certain conjugates made from these PBDs. [0002] Background of the invention [0003] Pyrrolobenzodiazepines [0004] Some pyrrolobenzodiazepines (PBDs) have the ability to recognize and bind to specific sequences in DNA; the preferred sequence is PuGPu. The first PBD antitumor antibiotic, anthramycin, 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, many 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. 2011 111(4), 2815-2864). Family members include gibberellin (abbeymyci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68C07K16/18C07D487/04A61K45/06C07D519/00C07K16/28C07K16/32A61P35/00
CPCA61K45/06C07D487/04C07D519/00C07K16/18C07K16/28C07K16/2803C07K16/2851C07K16/32C07K2317/567C07K2317/522C07K2317/40A61K47/68035A61K47/6889A61K47/6855A61P35/00A61P43/00
Inventor 约翰·A·弗吕加勒托马斯·H·皮洛
Owner GENENTECH INC
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