Peloruside analogs

Patent metadata

Field	Value
Publication number	US-9771344-B2
Application number	US-201415036743-A
Country	US
Kind code	B2
Filing date	Nov 28, 2014
Priority date	Nov 28, 2013
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention provides new therapeutic compounds for treatment of diseases caused or influenced by microtubule stability, such as proliferative diseases. The compounds are phenyl-analogs of the naturally occurring peloruside. The analogs are easier to synthesize, and hence open up the possibility to produce said compounds in large quantities for therapeutic use.

First claim

The invention claimed is:

1. A compound of Formula I:

wherein:
X 1 is CR 1a R 1b , X 2 is CR 2a R 2b , X 3 is CR 3a R 3b , X 4 is CR 4a R 4b , and wherein:
R 1a is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy;
R 2a is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy,
R 3a is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy
R 4a is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy; and wherein:
R 1b is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy,
R 2b is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy,
R 3b is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy,
R 4b is selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group independently being independently optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy;

or wherein R 1a and R 1b , or R 2a and R 2b , or R 3a and R 3b , or R 4a and R 4b taken together represent an oxo (═O) group; and wherein the bond represented by a dashed and solid line represents a single bond or a double bond and wherein in case of a double bond, R 1b and R 2b are absent and at least one of R 1a and R 2a is not OH or —NR 10 R 11 ; and wherein:
R 10 and R 11 are each independently selected from hydrogen and C 1-6 alkyl; and wherein:
when R 1a , R 2a , R 3a or R 4a is hydroxyl, the corresponding R 1b , R 2b , R 3b or R 4b is not hydroxyl, is not —NR 10 R 11 , is not halogen, or is not C 1-6 alkoxy,
when R 1a , R 2a , R 3a or R 4a is —NR 10 R 11 , the corresponding R 1b , R 2b , R 3b or R 4b is not hydroxyl, is not —NR 10 R 11 , is not halogen, or is not C 1-6 alkoxy,
when R 1a , R 2a , R 3a or R 4a is halogen, the corresponding R 1b , R 2b , R 3b or R 4b is not hydroxyl, or is not —NR 10 R 11 ,
when R 1b , R 2b , R 3b or R 4b is hydroxyl, the corresponding R 1a , R 2a , R 3a or R 4a is not hydroxyl, is not —NR 10 R 11 , is not halogen, or is not C 1-6 alkoxy, and
when R 1b , R 2b , R 3b or R 4b is —NR 10 R 11 , the corresponding R 1a , R 2a , R 3a or R 4a is not hydroxyl, is not —NR 10 R 11 , is not halogen, or is not C 1-6 alkoxy,
when R 1b , R 2b , R 3b or R 4b is halogen, the corresponding R 1a , R 2a , R 3a or R 4a is not hydroxyl, or is not —NR 10 R 11 ,

and the stereoisomers, prodrugs, tautomers, racemates, salts, hydrates, or solvates thereof.

2. The compound according to claim 1 , wherein R 1b R 2b R 3b , and R 4b each independently are selected from hydrogen, halogen, and a group selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, and C 1-6 alkoxy, each group being optionally substituted with one or more substituent(s) selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy; or wherein R 1a and R 1b , and/or R 2a and R 2b , and/or R 3a and R 3b , and/or R 4a and R 4b taken together form an oxo (═O) group.

3. The compound according to claim 1 , having structural Formula Ia,

wherein
R 1b , R 2b , R 3b , and R 4b are each independently selected from hydrogen, hydroxyl, halogen, and a group selected from —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl,
C 6-10 arylC 1-6 alkyl and C 1-6 alkoxy, each group independently being optionally substituted with one or more substituent(s) each independently selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy;

R 1b and R 2b each independently can represent an oxo (═O) group, in which case the bond represented by a dashed and solid line is a single bond and the geminal hydrogen is absent;
R 3b and R 4b each independently can represent an oxo (═O) group, in which case the geminal hydrogen is absent; and
wherein when the bond represented by a dashed and solid line is a double bond with E- or Z-geometry, at least one of R 1b and R 2b is not hydroxyl or —NR 10 R 11 ;

and the stereoisomers, prodrugs, tautomers, racemates, salts, hydrates, or solvates thereof.

4. The compound according to claim 3 , having structural Formula Ib, Ic or Id,

wherein R 1b , R 2b , R 3b , and R 4b each independently are selected from hydrogen, halogen, and a group selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, and C 1-6 alkoxy, each group being optionally substituted with one or more substituent(s) selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy; or wherein R 1a and R 1b , and/or R 2a and R 2b , and/or R 3a and R 3b , and/or R 4a and R 4b taken together form an oxo (═O) group, and wherein in structure Ic, the double bond can have the E- or Z-geometry.

5. The compound according to claim 3 , having structural Formula Ie, If, or Ig,

wherein R 1b , R 2b , R 3b , and R 4b each independently are selected from hydrogen, halogen, and a group selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, and C 1-6 alkoxy, each group being optionally substituted with one or more substituent(s) selected from hydroxyl, halogen, C 1-6 alkyl, or C 1-6 alkoxy; or wherein R 1a and R 1b , and/or R 2a and R 2b , and/or R 3a and R 3b , and/or R 4a and R 4b taken together form an oxo (═O) group, and the stereoisomers, p

Assignees

• Univ Gent

Inventors

• Van Der Eycken Johan
• Smans Gert
• Cornelus Jelle
• Van Den Bossche Dries
• Jacobs Nick

Classifications

• C07D313/00 Primary

  Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom · CPC title

• A61K31/365

  Lactones · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title