Compounds

A compound and residue technology, applied in the field of novel polymyxin compounds, can solve problems such as reducing nephrotoxicity

Pending Publication Date: 2017-08-29
SPERO THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] WO 2010 / 075416 provides ureido-linked arylpolymyxin decapeptides including CB182,804 which are reported to have similar activity compared to polymyxin B, but with reduced nephrotoxicity

Method used

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Examples

Experimental program
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preparation example Construction

[0719] In one aspect of the present invention, there is provided a synthetic method comprising the steps of: digesting a halogenated polymyxin compound selected from the group consisting of halogenated decapeptides, halogenated nonapeptides and halogenated octapeptides, thereby producing halogenated heptapeptide polymyxins Bacteroid compounds. Digestion refers to the step of reducing the total number of amino acid residues within a polypeptide.

[0720] In one embodiment, a compound of formula (IVa) is digested to yield a compound of formula (IVb).

[0721] The compound of formula (IVa) is a halogenated decapeptide, halogenated nonapeptide or halogenated octapeptide. The compound of formula (IVa) is the compound of formula (IV), wherein-A 3 - is an amino acid residue. The compound of formula (IVa) is -R 6 or -R 7 Compounds containing haloaryl groups. After the cleavage reaction, the haloaryl group remains in the cleavage product.

[0722] The compound of formula (IVb) i...

Embodiment

[0919] The following examples are provided solely to illustrate the invention and are not intended to limit the scope of the invention described herein.

[0920] Nomenclature: Compounds are named based on the natural polymyxin core from which they are synthetically derived.

[0921]

[0922] Abbreviation Meaning

[0923] DCM dichloromethane

[0924] TFA trifluoroacetic acid

[0925] ND not determined

[0926] N / A not applicable

[0927] DMF N,N-Dimethylformamide

[0928] PMBH Polymyxin B Heptapeptide (3-10)

[0929] PMBD polymyxin B decapeptide

[0930] Pro Proline

[0931] Dap α,β-Diaminopropionic acid

[0932] Gly glycine

[0933] His Histidine

[0934] Phe Phenylalanine

[0935] DCHA dicyclohexylamine

[0936] X phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0937] NorLeu Norleucine

[0938] NorVal Norvaline

[0939] OctGly Octylglycine

[0940] Synthetic example

[0941] Preparation of comparative compounds C1 to C3.

[0942] Polymyxin B ...

Embodiment 24

[1007] Example 24: Polymyxin B[D-(4-cyano)Phe]-6

[1008] In anhydrous DMF (2ml) (Boc) 5 D-[(4-bromo)Phe]-6-polymyxin (100mg, 0.056mmol), zinc cyanide (45mg, 0.383mmol, 6.8mol equivalent) and 1,1'-bis(diphenylphosphino ) ferrocene (6 mg, 2 mol equiv) was degassed and then treated with tris(dibenzylideneacetone)dipalladium(0) (5 mg, 1 mol equiv). Seal the tube and heat to 100 °C for up to 3 days. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was chromatographed on silica eluting with 0-10% in ethyl acetate (1% .880 ammonia in methanol), followed by further purification by preparative HPLC with 20%-95% acetonitrile in water (additional 1% TFA) elution. Fractions containing product were combined and evaporated to an oil. This oil was dissolved in TFA (2 mL) and DCM (8 mL) and stirred at room temperature for 6 hours. Evaporation of the solv...

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Abstract

The present invention provides a compound of formula (I), and its use in methods of treatment, including the treatment of bacterial infections. Methods for the preparation of the compound of formula (I) are also provided. The compound of formula (I) has the structure shown below, where -R6 and -R7 are each together with the carbonyl group and nitrogen alpha to the carbon to which it is attached an amino acid residue, except that R6 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue and / or -R7 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue, and -T, -A1, -A2, -A3 and -R10 are as discussed in the application:

Description

[0001] related application [0002] This case involves GB 1421020.7 filed on November 26, 2014 (26.11.2014) and GB 1516059.1 filed on September 10, 2015 (10.09.2015). The contents of the above two applications are fully incorporated herein by reference . technical field [0003] The present invention relates to novel polymyxin compounds, combinations of compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds, pharmaceutical compositions and combinations in the treatment (e.g., of treating microbial infections, particularly caused by Gram Microbial infection caused by negative bacteria). Background technique [0004] In susceptible individuals, certain gram-negative bacteria (such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumanii) Serious infections (such as pneumonia, urinary tract infection, skin and skin tissue infection (such as wound infection), ear infection, eye infection, intra-abdo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/62A61K38/12A61P31/04
CPCC07K7/62A61K38/00A61P31/04Y02A50/30A61K38/12
Inventor 帕梅拉·布朗迈克尔·道森莫娜·西莫诺维克史蒂文·博克斯伊斯特·杜珀尔奇史蒂文·詹姆斯·斯坦威安托瓦妮特·威尔逊斯蒂芬·弗雷德里克·莫斯
Owner SPERO THERAPEUTICS INC
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