180715-99-5

Upstream product

• 20734-58-1 N,N,N',N'-tetramethyl-1,8-diaminonaphthalene 
• 133645-51-9 (4R,5S,2'R,3'R,2S)-3-[3'-(N-tert-butoxycarbonyl-2-pyrrolidinyl)-3-hydroxy-2'-methylpropanoyl]-4-methyl-5-phenyl-2-oxazolidinone 
• 54418-69-8 4-methyl-5-phenyl-2-oxazolidinone 
• 77877-20-4 (4R,5S)-4-methyl-5-phenyl-3-propionyloxazolidin-2-one 
• 69610-41-9 Boc-L-Pro-H 
• 69610-40-8 N-(tert-butoxycarbonyl)-L-prolinol 
• 15761-39-4 1-(tert-butoxycarbonyl)-L-proline 
• 37577-28-9 (1S,2R)-(+)-norphedrine 
• 77943-39-6 4-methyl-5-phenyloxazolidin-2-one 
• 420-37-1 trimethoxonium tetrafluoroborate 

Downstream Products

• 161485-82-1 tert-butyl (S)-2-((1R,2R)-1-methoxy-3-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methyl-3-oxopropyl)pyrrolidine-1-carboxylate 
• 1369427-40-6 (2R,3R)-3-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionic acid dicyclohexylamine salt 
• 646502-53-6 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate 
• 474645-27-7 [3H]-Vedotin 
• 149606-97-3 benzyl (2R,3R,2'S)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methoxy-2-methylpropanoate 

Relevant academic research and scientific papers

The dolastatins; 18: Stereospecific synthesis of dolaproine

Dolastatin 10 (1), isolated from the sea hare Dolabella auricularia, has proved to be an exceptionally promising antineoplastic substance. Synthesis of this new and important peptide has been achieved. However, a more convenient and stereoselective synthesis of its three chiral center dolaproine (2a) unit has become necessary. A practical solution to this challenging problem was realized by employment of the following key reaction steps. Chiral oxazolidinone 5 was condensed at -75°C with S-prolinal 4 using dibutylboron triflate to direct the stereochemical course of the aldol reaction. Methylation of the product (6, 60-80% yields) and cleavage of the amide, in 83 and 93% yields respectively, completed a facile route to N-Boc-dolaproine (2b). Pertinent aspects of the aldol reaction and cleavage of oxazolidinone amides are discussed.

NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG

PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT

EFFICIENT PREPARATION OF DOLASTATIN AND AURISTATIN ANALOGS THROUGH A COMMON INTERMEDIATE

Methods for making a dolastatin, auristatin or related compounds comprising the steps of providing a universal dolastatin core of Formula (I) reacting the C-terminal carboxylic acid group with an amine (A) to form an amide bond and reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond, wherein the steps can be performed in either order. Also provided are an isolated salt of the universal dolastatin core for use in preparation of dolastatins, auristatins and related compounds. Also provided are a number of intermediates and process steps which are useful for the preparation of high purity dolastatin core and high purity dolastatin and auristatin compounds.

CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP

Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.

CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE

What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.

CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS

The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.

LIGAND-CYTOTOXICITY DRUG CONJUGATE, PREPARING METHOD THEREFOR, AND APPLICATION THEREOF

Provide are a ligand-cytotoxicity drug conjugate with a general formula of PC-L-Dr, a preparing method thereof, and applications of the ligand-cytotoxicity drug conjugate and pharmaceutical compositions comprising the same in preparing drugs for treating cancers by means of receptor regulation.

SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF

The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.

AURISTATIN ANALOGUES AND THEIR CONJUGATES WITH CELL-BINDING MOLECULES

This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and /or proliferation.

NOVEL LINKERS AND THEIR USES IN SPECIFIC CONJUGATION OF DRUGS TO A BIOLOGICAL MOLECULE

The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic) group for conjugation of two or more compounds/cytotoxic agents per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.