NOVEL PYRIMIDINE DERIVATIVES 698

• US 20080242663A1
• Filed: 02/28/2008
• Published: 10/02/2008
• Est. Priority Date: 02/28/2007
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Ducray, Richard, Kettle, Jason Grant, Barlaam, Bernard Christophe, Wedge, Stephen Robert, Ashton, Susan Elizabeth, Cross, Darren Anthony Edward, Pearson, Mark Andrew, Purkiss, Stuart Charles, East, Simon John
• Application Number:
  US12/039,030
• Publication Number:
  US 20080242663A1
• Time in Patent Office: Days
• US Class Current: 514/232.2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention concerns compounds of Formula I, or a pharmaceutically acceptable salt thereof,

where R¹, n, R², R³, and R⁴ are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours or other proliferative conditions which are sensitive to the inhibition of EphB4 kinases.

Claims

1. A compound of formula I

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a (1-4C)alkyl group which is optionally substituted by one or more substituent groups selected from —

OR⁵ (wherein R⁵ is selected from hydrogen or (1-2C)alkyl).

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R² group present is independently selected from (1-2C)alkyl, (1-2C)alkoxy, fluoro, chloro, cyano, hydroxy(1-2C)alkyl, or a group of sub-formula:

-Q-R⁸

where Q is selected from —

CO—

, —

NR^a—

CO—

, —

S(O)_z—

(where z is 0, 1 or

     2);

R^a is selected from hydrogen or methyl, and R⁸ is hydrogen or (1-2C)alkyl.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is a group —

NR¹²R¹³, wherein R¹² and R¹³ are each independently selected from hydrogen or (1-6C)alkyl, or R¹² and R¹³ are linked to form a 5, 6 or 7-membered heterocyclic ring, and wherein, in addition to the nitrogen atom to which R¹² and R¹³ are attached, the ring optionally comprises one or two further heteroatoms selected from O, N or S, and wherein the ring is optionally substituted on any available carbon atom by one or two substituent groups selected from oxo, halo, hydroxy, cyano, (1-4C)alkyl, or (1-4C)alkanesulfonyl, and any available nitrogen atom present in the ring is optionally substituted by (1-4C)alkyl or (1-4C)alkanoyl.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a group —

NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are linked to form a 6 membered heterocyclic ring which optionally comprises, in addition to the nitrogen atom to which R¹⁷ and R¹⁸ are attached, one or two further heteroatoms selected from O, N or S, and wherein the ring is optionally substituted on any available carbon atom by one or two substituent groups selected from oxo, halo, hydroxy, cyano, or (1-4C)alkyl, and any available nitrogen atom is optionally substituted by (1-4C)alkyl, hydroxy(1-4C)alkyl or (1-4C)alkanoyl.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is any one of Examples 1 to 25.

8. A compound according to claim 1 which is [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8, which is:

the freebase form of [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol;

the besylate salt of [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol;

or

the tosylate salt of [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol.

10. A compound according to claim 8 in crystalline form.

11. A compound according to claim 10 which is [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol freebase Form 1 and has an X-ray powder diffraction pattern with specific peaks at about 2θ

=7.5, 22.2, 22.7 and 24.7°

when measured using CuKa radiation.

12. A compound according to claim 10 which is:

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol freebase, Form 1, which has an X-ray powder diffraction pattern with specific peaks at 2θ

=7.5, 10.1, 11.9, 12.3, 13.0, 13.6, 15.2, 16.3, 16.6, 17.4, 18.0, 18.6, 19.0, 19.8, 20.2, 20.6, 21.1, 22.2, 22.7, 23.8, 24.2, 24.7, 25.2, 26.2, 26.7, 27.6, 28.1, 28.8, 29.4, 31.5, 32.3, 34.0, 35.6, 36.2, 37.5 and 38.1°

when measured using CuKa radiation;

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol besylate, Form 1, which has an X-ray powder diffraction pattern with specific peaks at 2θ

=5.6, 8.7, 9.5, 10.3, 11.0, 11.3, 12.9, 14.8, 15.1, 15.4, 15.9, 16.3, 17.3, 18.2, 19.0, 19.6, 20.4, 20.8, 21.1, 21.4, 22.1, 23.0, 23.7, 24.3, 24.6, 25.2, 26.1, 26.7, 27.7, 28.5, 30.1, 31.0, 31.9 and 33.8°

when measured using CuKa radiation;

or

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol besylate, Form 2, which has an X-ray powder diffraction pattern with specific peaks at 2θ

=5.6, 8.6, 9.8, 11.1, 16.0, 16.7, 17.3, 17.7, 18.6, 20.9, 23.3, 23.9, 26.0 and 27.7°

when measured using CuKa radiation.

13. A compound according to claim 10 which is:

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol freebase, Form 1, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure A;

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol besylate, Form 1, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure B;

or

[3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol besylate, Form 2, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure C.

14. A pharmaceutical product which comprises a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a VEGF receptor tyrosine kinase inhibitor.

15. A pharmaceutical product according to claim 14 which comprises [3-[[2-[(3,5-dimorpholin-4-ylphenyl)amino]pyrimidin-4-yl]-methyl-amino]-4-methyl-phenyl]methanol, or a pharmaceutically acceptable salt thereof, and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition which comprises a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

17. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use as a medicament.

18. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

19. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

20. A process for the manufacture of a compound of formula I as defined in claim 1 provided that any functional groups can be optionally protected and L is a suitable leaving group, which comprises the reaction of a compound of formula (VII)

2. A compound of formula I