Unlock instant, AI-driven research and patent intelligence for your innovation.

Albumin-binding prodrugs of auristatin e derivatives

A technology of drugs and compounds, applied in the field of albumin-binding products of auristatin E derivatives, which can solve the problems of lack of anti-tumor activity and unacceptable systemic toxicity

Pending Publication Date: 2020-09-25
CYTRX BIOPHARMA CORP
View PDF9 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In phase 1 and 2 trials, dolastatin10, dolastatin15, and auristatin PE resulted in unacceptable systemic toxicity and lack of antitumor activity, leading to discontinuation

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Albumin-binding prodrugs of auristatin e derivatives
  • Albumin-binding prodrugs of auristatin e derivatives
  • Albumin-binding prodrugs of auristatin e derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0140] Example 1 describes a new synthetic method and novel linker Sulf07,5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) achieved according to routes A and B Characterization of hexanoamido)-2-(hydrazinocarbonyl)-benzenesulfonic acid.

[0141] Linker Sulf07 reacts with:

[0142]

[0143]

[0144] AE-Ester In order to obtain compounds of formula III (abbreviation of AE-Keto-Sulf07) and formula IV (abbreviation of AE-Ester-Sulf07) respectively:

[0145]

[0146] Examples 2 and 3 describe the synthesis and characterization of AE-Keto-Sulf07 (Formula III) and AE-Ester-Sulf07 (Formula IV).

[0147] Structural analysis of AE-Keto-Sulf07 and AE-Ester-Sulf07 revealed that there are two moieties (-SO 3 H and -N(CH 3 ) 2 group) exists as an acid-base pair to form the zwitterions described in Scheme 3 and Scheme 4.

[0148]

[0149] Option 3

[0150]

[0151] Option 4

[0152] The sulfonic acid moiety integrated on the linker Sulf07 and the zwitterionic properties of t...

Embodiment

[0201] Materials and methods for the preparation and analysis of compounds

[0202] All reactions were performed under an inert atmosphere of nitrogen unless otherwise stated. Unless otherwise stated, commercially available reagents were used without further purification. Anhydrous solvents were purchased in anhydrous form (dichloromethane, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, etc.), and all other solvents used were reagent grade or HPLC or LCMS grade.

[0203] Where applicable, glassware and stir bars were typically dried in an oven at 110 °C for at least 12 h, then cooled under a nitrogen atmosphere before use. All other reactions were performed in round bottom flasks sealed with rubber septa. Use plastic syringes or glass pipettes to transfer liquid reagents. The reaction was stirred magnetically using a Teflon-coated magnetic stir bar. The organic solution was concentrated under reduced pressure using a rotary evaporator KNF RC 600 and a Heidolph ...

example 2

[0271] Compound AE-Keto-Sulf07, 2-(2-((R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S) -2-((S)-2-(Dimethylamino)-3-methylbutanylamino)-N,3-dimethylbutanylamino)-3-methoxy-5-methylheptanoyl )pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-1-phenylpropylene)hydrazine-1-carbonyl)-5-(6-(2,5-di Oxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoamido)benzenesulfonic acid, synthesized as described below and shown in Scheme 5.

[0272]

[0273] Option 5

[0274] (S)-1-(((S)-1-(((3R, 4S, 5S)-3-methoxy-1-((S)-2-((IR, 2R)-1-methoxy Base-2-methyl-3-oxo-3-(((R)-1-oxo-1-phenylpropan-2-yl)amino)propyl)pyrrolidin-1-yl)-5- Methyl-1-oxoheptyl-4-yl)(methyl)amino)-3-methyl-1-oxobut-2-yl)amino)-N,N,3-trimethyl-1- Synthesis of oxobutan-2-ammonium 2,2,2-trifluoroacetate (AE-Keto TFA salt)

[0275]

[0276] Route A: Synthesize according to the improved method of patent US6884869-B2

[0277] Pyridinium chlorochromate (PCC) (382 mg, 1.772 mmol, 1.5 equiv, SigmaAldrich) was added to auristatin E TFA salt (100...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
weightaaaaaaaaaa
weightaaaaaaaaaa
weightaaaaaaaaaa
Login to View More

Abstract

The present disclosure provides for albumin-binding prodrugs of auristatin E derivatives and uses thereof.

Description

[0001] This application claims priority to US Provisional Application 62 / 592,721, filed November 30, 2017, the entire disclosure of which is incorporated herein by reference. Background technique [0002] Low-molecular-weight anticancer drugs usually have a narrow therapeutic window, which limits their clinical efficacy. These low molecular weight compounds show a high tendency to penetrate into human tissues by diffusion, resulting in uniform biodistribution. Therefore, only a small amount of the drug reaches the site of action, and due to distribution on healthy tissues of the body, the drug causes undesirable side effects. [0003] These disadvantages are especially pronounced for those drugs with high cytotoxicity and very narrow therapeutic window. Auristatins are drugs based on tubulin-binding peptides, representative examples such as dolastatin10, dolastatin15, auristatin PE, auristatin E or auristatin F exhibit high cytotoxicity effect. In phase 1 and 2 clinical tri...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02A61K47/64A61P35/00
CPCC07K5/0205A61K47/643A61K47/40A61K9/0019A61P35/00A61P31/00A61P37/00A61P29/00A61K38/07A61K47/54
Inventor F·克拉茨K·阿布阿贾伊A·瓦尔内克F·I·诺尔曼S·D·克斯特J·加西亚费尔南德斯L·帕斯H-K·瓦尔特J·P·马格努松S·切尔切亚P·佩雷斯加兰F·梅达S·J·道姆
Owner CYTRX BIOPHARMA CORP