Inhibitors of NEDD8-activating enzyme

Patent metadata

Field	Value
Publication number	US-9850214-B2
Application number	US-201414326051-A
Country	US
Kind code	B2
Filing date	Jul 8, 2014
Priority date	Aug 24, 2011
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Disclosed are chemical entities which are inhibitors of Nedd8-activating enzyme (NAE), namely, the compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate and pharmaceutically acceptable salts thereof; solid state forms thereof; and prodrugs thereof. Also disclosed are methods of using the chemical entities to treat disorders such as cancer.

First claim

What is claimed is:

1. A chemical entity comprising a hydrochloride salt of the compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate or a pharmaceutically acceptable solvate thereof, wherein said chemical entity is substantially crystalline Form II.

2. A prodrug of a chemical entity, wherein:
the chemical entity is the compound {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate or a pharmaceutically acceptable salt thereof; and
the prodrug is a carbamate or amide of an NH group of the chemical entity, or an ether or ester of an OH group of the chemical entity.

3. A composition comprising the chemical entity of claim 1 , and a pharmaceutically acceptable carrier.

4. The composition of claim 3 suitable for oral administration.

5. The chemical entity of claim 1 , wherein at least 70% by weight is crystalline Form II.

6. The chemical entity of claim 1 , wherein at least 80% by weight is crystalline Form II.

7. The chemical entity of claim 1 , wherein at least 90% by weight is crystalline Form II.

8. The chemical entity of claim 1 , wherein at least 95% by weight is crystalline Form II.

9. The chemical entity of claim 1 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern having peaks at 2θ angles of 8.7°, 15.2°, 15.7°, 19.6°, and 24.2°, wherein each 2θ angle value is ±0.2°.

10. The chemical entity of claim 9 , wherein Form II is characterized by an XRPD pattern having peaks at 2θ angles of 4.3°, 8.7°, 15.2°, 15.7°, 19.6°, 20.0°, 20.8°, 22.5°, 23.1°, and 24.2°, wherein each 2θ angle value is ±0.2°.

11. The chemical entity of claim 9 , wherein Form II is characterized by an XRPD pattern having peaks at 2θ angles of 4.3°, 8.7°, 12.4°, 14.5°, 15.2°, 15.7°, 17.3°, 18.2°, 18.5°, 19.6°, 20.0°, 20.8°, 22.0°, 22.5°, 23.1°, 24.2°, 24.7°, 25.7°, 28.2° and 29.4°, wherein each 2θ angle value is ±0.2°.

12. The chemical entity of claim 1 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern having a reference peak with a 2θ angle of 8.7±0.3°, and having peaks at 2θ angles of −4.4°, 6.5°, 7.0°, 10.9°, 11.3°, 12.1°, 13.8°, 14.4°, and 15.5° relative to the reference peak.

13. The chemical entity of claim 1 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern having a reference peak with a 2θ angle of 8.7±0.3°, and having peaks at 2θ angles of −4.4°, 3.7°, 5.8°, 6.5°, 7.0°, 8.6°, 9.5°, 9.8°, 10.9°, 11.3°, 13.3°, 13.8°, 14.4°, 15.5°, 16.0°, 17.0°, 19.5° and 20.7° relative to the reference peak.

14. The chemical entity of claim 1 , wherein Form II is characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 10 .

15. A composition comprising the prodrug of claim 2 and a pharmaceutically acceptable carrier.

Assignees

• Millennium Pharm Inc

Inventors

• Mccarron Ashley Sue
• Sells Todd B
• Stirling Matthew
• Stroud Stephen G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/47 Primary

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D239/46

  Two or more oxygen, sulphur or nitrogen atoms · CPC title

• C07D473/02

  with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title