IP Library › Granted Patent US 8,258,145

Granted Patent B2

US 8,258,145 · App. 11/773,285 · Granted Sep 4, 2012

Method of treating brain cancer

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Quick Facts

Patent No.: US 8,258,145
App. No.: 11/773,285
Granted: Sep 4, 2012
Kind: B2

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Abstract

Disclosed are 4-arylamino-quinazolines and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, and in particular to the use of these compounds in treating brain cancer.

Claims (164)

1. A method of treating anaplastic astrocytoma, glioblastoma, meningioma, or mesenchymal tumor in a mammal in need of such treatment, comprising intravenously administering to the mammal an effective amount of a compound according to Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is C 1-3 alkyl;

R 2 is halo, R 14 , OR 14 , SR 14 , NR 15 R 14 , or NR 14 (C═O)C 1-6 alkyl wherein R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl and R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl;

R 3 , R 4 , R 6 -R 8 , R 10 -R 13 are independently halo, R 16 , NR 16 R 17 , OR 16 , or SR 16 wherein R 16 and R 17 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl provided that R 16 and R 17 are not both H;

R 5 is H or C 1-3 alkyl;

R 9 is H, halo, R 18 , OR 18 , SR 18 , NR 18 R 19 , or optionally R 9 and one of R 8 and R 10 together form a heterocycle, wherein R 18 and R 19 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl provided that R 18 and R 19 are not both H; and

B, D, W, X, Y and Z are independently C or N, provided that at least one of B and D is N, no more than one of W, X, Y and Z are N, and when B, D, W, X, Y or Z is N then there is no substituent at the N.

2. The method of claim 1 wherein B is C and D is N.

3. The method of claim 2 wherein X or Y is N.

4. The method of claim 2 wherein W or Z is N.

5. The method of claim 1 wherein R 2 is C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, C 3-8 heterocycle, NR 2a C 1-3 alkyl, NR 2a (C═O)C 1-3 alkyl, or NR 2a (arylalkyl) wherein R 2a is H or C 1-3 alkyl.

6. The method of claim 5 wherein R 1 is CH 3 .

7. The method of claim 6 wherein R 5 is H.

8. The method of claim 7 wherein R 3 , R 4 , R 6 —R 8 , R 10 , R 11 , and R 12 and R 13 if present, are independently H, C 1-3 alkyl, halo, NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , or —OC 1-3 alkyl.

9. The method of claim 8 wherein R 9 is H, OH, C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, —OC 1-3 haloalkyl, NR 9a R 9b wherein R 9a and R 9b are independently H or C 1-3 alkyl provided that R 9a and R 9b are not both H, or optionally R 9 and one of R 8 and R 10 together form a C 3-8 heterocycle.

10. The method of claim 1 wherein:

R 1 is CH 2 CH 3 , or CH 3 ;

R 2 is CH 2 CH 3 , CH 3 , Cl, CH 2 F, OCH 3 , SCH 3 , morpholino, NHCH 3 , NCH 3 (C═O)CH 3 , or NHCH 2 C 6 H 5 ;

R 3 , R 4 , R 6 , R 12 , and R 13 are independently H, CH 3 , Cl, NHCH 3 , N(CH 3 ) 2 , or OCH 3 ;

R 5 is H;

R 7 , R 8 , R 10 and R 11 are independently H, F, or OCH 3 ; and

R 9 is H, OH, Cl, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , SCH 3 , OCF 3 , OCHF 2 , OCH(CH 3 ) 2 , N(CH 3 ) 2 , NHCH 3 ; or optionally R 9 and one of R 8 and R 10 together form 1,3-dioxolane.

11. The method of claim 1 wherein the compound has the structure according to Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is C 1-3 alkyl;

R 3 , R 4 , R 6 -R 8 , R 10 and R 11 are independently halo, R 16 , NR 16 R 17 , OR 16 , or SR 16 wherein R 16 and R 17 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl provided that R 16 and R 17 are not both H;

R 5 is H or C 1-3 alkyl;

W, X, Y and Z are independently C or N, provided that no more than one of W, X, Y and Z are N, and when W, X, Y or Z is N, then there is no substituent at the N.

12. The method of claim 11 wherein X or Y is N.

13. The method of claim 11 wherein W or Z is N.

14. The method of claim 11 wherein R 2 is C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, C 3-8 heterocycle, NR 2a C 1-3 alkyl, NR 2a (C═O)C 1-3 alkyl, or NR 2a (arylalkyl) wherein R 2a is H or C 1-3 alkyl.

15. The method of claim 14 wherein R 1 is CH 3 .

16. The method of claim 15 wherein R 5 is H.

17. The method of claim 16 wherein R 3 , R 4 , R 6 —R 8 , R 10 and R 11 are independently H, C 1-3 alkyl, halo, NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , or —OC 1-3 alkyl.

18. The method of claim 17 wherein R 9 is H, OH, C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, —OC 1-3 haloalkyl, NR 9a R 9b wherein R 9a and R 9b are independently H or C 1-3 alkyl provided that R 9a and R 9b are not both H, or optionally R 9 and one of R 8 and R 10 together form a C 3-8 heterocycle.

19. The method of claim 11 wherein:

R 1 is CH 2 CH 3 , or CH 3 ;

R 2 is CH 2 CH 3 , CH 3 , Cl, CH 2 F, OCH 3 , SCH 3 , morpholino, NHCH 3 , NCH 3 (C═O)CH 3 , or NHCH 2 C 6 H 5 ;

R 3 , R 4 , and R 6 , are independently H, CH 3 , Cl, NHCH 3 , N(CH 3 ) 2 , or OCH 3 ;

R 5 is H;

R 7 , R 8 , R 10 and R 11 are independently H, F, or OCH 3 ; and

20. The method of claim 1 wherein the compound has the structure according to Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is C 1-3 alkyl;

R 2 is halo, R 15 , OR 14 , SR 14 , NR 15 R 14 , or NR 14 (C═O)C 1-6 alkyl wherein R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl and R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl;

R 5 is H or C 1-3 alkyl; and

21. The method of claim 20 wherein R 2 is C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, C 3-8 heterocycle, NR 2a C 1-3 alkyl, NR 2a (C═O)C 1-3 alkyl, or NR 2a (arylalkyl) wherein R 2a is H or C 1-3 alkyl.

22. The method of claim 21 wherein R 1 is CH 3 .

23. The method of claim 22 wherein R 5 is H.

24. The method of claim 23 wherein R 3 , R 4 , R 6 —R 8 , R 10 and R 11 are independently H, C 1-3 alkyl, halo, NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , or —OC 1-3 alkyl.

25. The method of claim 24 wherein R 9 is H, OH, C 1-3 alkyl, halo, C 1-3 haloalkyl, —OC 1-3 alkyl, —SC 1-3 alkyl, —OC 1-3 haloalkyl, NR 9a R 9b wherein R 9a and R 9b are independently H or C 1-3 alkyl provided that R 9a and R 9b are not both H, or optionally R 9 and one of R 8 and R 10 together form a C 3-8 heterocycle.

26. The method of claim 20 wherein:

R 1 is CH 2 CH 3 or CH 3 ;

R 2 is CH 2 CH 3 , CH 3 , Cl, CH 2 F, OCH 3 , SCH 3 , morpholino, NHCH 3 , NCH 3 (C═O)CH 3 , or NHCH 2 C 6 H 5 ;

R 3 , R 4 , and R 6 are independently H, CH 3 , Cl, NHCH 3 , N(CH 3 ) 2 , or OCH 3 ;

R 5 is H;

R 7 , R 8 , R 10 and R 11 are independently H, F, or OCH 3 ; and

27. The method of claim 20 wherein:

R 1 is CH 3 ;

R 2 is CH 3 , Cl, OCH 3 , NHCH 3 , or NCH 3 (C═O)CH 3 ;

R 3 -R 6 , R 7 , R 8 , R 10 and R 11 are H; and

R 9 is OCH 3 , N(CH 3 ) 2 , or NHCH 3 .

28. The method of claim 20 , wherein when R 9 is H then R 8 and R 10 are not both H or one H and the other halo.

29. The method of claim 20 , wherein when R 9 is H then R 8 and R 10 are not both H or one H and the other halo or alkyl or haloalkyl.

30. The method of claim 1 , wherein when R 9 is C 1-6 alkyl, halo, or C 1-6 haloalkyl, R 2 is not H.

31. The method of claim 1 , wherein when R 9 is H then R 8 and R 10 are not both H or one H and the other halo, and R 2 is not H.

32. The method of claim 1 , wherein the compound is chosen from:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;

(4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride;

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(4-methylamino-phenyl)-methylamine;

(4-Methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl)-methylamine;

and pharmaceutically acceptable salts or solvates thereof.

33. The method of claim 1 , wherein the compound is chosen from:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;

(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;

(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;

(2-Chloro-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine;

(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-phenyl-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;

(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

and pharmaceutically acceptable salts or solvates thereof.

34. The method of claim 1 , wherein the compound is chosen from:

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride;

(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(4-methylamino-phenyl)-methylamine;

(2-Methyl-6-nitroquinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine;

(4-Methylthio-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine;

(2-Dimethylamino-pyridine-5-yl)-(2-methyl-quinazolin-4-yl)-methylamine;

(6-Dimethylamino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine;

(3,4,5-Trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine;

and pharmaceutically acceptable salts or solvates thereof.

35. The method of claim 1 , wherein the compound is chosen from:

N 2 -Hydroxyl-N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;

(2-Methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;

(4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine;

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Benzylamino-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;

(2-Dimethylamino-6-nitroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine;

(2-Methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine;

[2-(N-Methyl-acetamido)-quinazolin-4-yl]-(4-dimethylaminophenyl)-methylamine;

(4-Methoxy-phenyl)-(2-N-methylacetamido-quinazolin-4-yl)-methylamine;

and pharmaceutically acceptable salts or solvates thereof.

36. The method of claim 1 , wherein a brain/plasma AUC ratio of said compound after administration is greater than about 5.

37. The method of claim 1 , wherein a brain/plasma AUC ratio of said compound after administration is greater than about 10.

38. The method of claim 1 , wherein a brain/plasma AUC ratio of said compound after administration is greater than about 15.

39. The method of claim 1 , wherein the compound has a calculated polar surface area of less than about 100 square Angstroms.

40. The method of claim 1 , wherein the compound has a calculated polar surface area of less than about 80 square Angstroms.

41. A method of treating a metastatic brain cancer in a mammal in need of such treatment, comprising intravenously administering to the mammal an effective amount of a compound according to Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is C 1-3 alkyl;

R 2 is halo, R 14 , OR 14 , SR 14 , NR 15 R 14 or NR 14 (C═O)C 1-6 alkyl wherein R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl and R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 carbocycle, C 3-8 heterocycle, C 6-10 aryl, or arylalkyl;

R 5 is H or C 1-3 alkyl;

R 9 is H, halo, R 18 , OR 18 , SR 18 , NR 18 R 19 , or optionally R 9 and one of R 8 and R 10 together form a heterocycle, wherein R 18 and R 19 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, or C 1-6 haloalkyl provided that R 18 and R 19 are not both H; and

Assignments (7)

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