Salinosporamides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10912764-B2
Application number	US-201916418801-A
Country	US
Kind code	B2
Filing date	May 21, 2019
Priority date	Jun 24, 2002
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

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 IC50 values, high pharmaceutical potency, and selectivity for cancer cells over fungi.

First claim

What is claimed is:

1. A method of treating a mammalian cell proliferative disorder comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of the structure (I):

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, 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 of formula (V):

4. The method of claim 1 , wherein the mammalian cell proliferative disorder is a neoplasm.

5. The method of claim 4 , wherein the neoplasm is a cancer.

6. The method of claim 5 , wherein the cancer is myeloma.

7. The method of claim 5 , wherein the cancer is central nervous system (CNS) cancer.

8. The method of claim 5 , wherein the cancer is Hodgkin's disease.

9. The method of claim 5 , wherein the cancer is non-Hodgkin's disease.

10. The method of claim 5 , wherein the cancer is renal cancer.

11. The method of claim 5 , wherein the cancer is sarcoma cell of bone.

12. The method of claim 5 , wherein the cancer is leukemia.

Assignees

• Univ California

Inventors

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

Classifications

• C12P17/18

  containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin {(e.g. Rifamycin C12P17/189)} · CPC title

• C07D491/044 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61K31/407 Primary

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title