Salinosporamides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10314818-B2
Application number	US-201715655739-A
Country	US
Kind code	B2
Filing date	Jul 20, 2017
Priority date	Jun 24, 2002
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

The present invention is based on the discovery that certain fermentation products of the marine actinomycete strains CNB392 and CNB476 are effective inhibitors of hyperproliferative mammalian cells. The CNB392 and CNB476 strains lie within the family Micromonosporaceae, and the generic epithet Salinospora has been proposed for this obligate marine group. The reaction products produced by this strain are classified as salinosporamides, and are particularly advantageous in treating neoplastic disorders due to their low molecular weight, low IC 50 values, high pharmaceutical potency, and selectivity for cancer cells over fungi.

First claim

What is claimed is:

1. A method of treating a central nervous system cancer in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the structure:

wherein:
R 1 to R 3 are each independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, hydroxy, halogen, amino, amido, carboxyl, —C(O)H, acyl, oxyacyl, carbamate, sulfonyl, sulfonamide or sulfuryl;
each R 4 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl;
E 1 to E 4 are each independently —O, —NR 5 , or —S, wherein R 5 is —H or C 1 -C 6 alkyl; and
x is 0 to 8.

2. The method of claim 1 , wherein
R 1 is a substituted alkyl; R 2 is methyl; R 3 is hydroxyl;
each R 4 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl;
E 1 , E 3 and E 4 are —O,
E 2 is —NR 5 , wherein R 5 is —H or C 1 -C 6 alkyl; and
x is 0 to 8.

3. The method of claim 1 , wherein the compound has the structure:

4. The method of claim 1 , wherein the compound has the structure:

Assignees

• Univ California

Inventors

• Fenical William
• Jensen Paul
• Mincer Tracy
• Feling Robert H R

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title

• C12P17/188

  Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms (ergot-alcaloids C12P17/183) · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title