Pharmaceutically active ornithine derivatives, ammonium salts thereof and methods of making same
View Patent ↗In one embodiment, the present invention relates to a new class of ammonium salts of N δ -acyl derivatives of N α -(4-amino-4-deoxypteroyl)-L-ornithine compounds having a structure according to formula II-IV. Formula II has the structure of: wherein: R 2 represents up to four groups independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH; R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and x is a real number greater than 0 and less than about 4. The ammonium salts provided by the invention exhibit high inhibitory activity against the growth o methotrexate-resistant cells, and also exhibit superior chemical stability than corresponding acidic N δ -acyl derivatives of N δ -acyl derivatives of N α (4-amino-4-deoxypteroyl)-L-ornithine compounds.
1. An ammonium salt of the compound of formula II:
wherein:
R 2 represents up to four groups independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
2. The compound of claim 1 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
3. The compound of claim 2 , wherein NR 3 R 4 R 5 represents ammonia.
4. An ammonium salt of the compound of formula III:
wherein:
R 2 represents up to four groups each independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
5. The compound of claim 4 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
6. The compound of claim 5 , wherein NR 3 R 4 R 5 represents ammonia.
7. The compound of claim 6 , wherein x is a real number between about 0.5 and 3.
8. The compound of claim 7 , wherein x is a real number between about 1 and about 2.
9. An ammonium salt of the compound of formula IV:
wherein:
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
10. The compound of claim 9 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
11. The compound of claim 10 , wherein NR 3 R 4 R 5 represents ammonia.
12. The compound of claim 11 , wherein x is a real number between about 0.5 and 3.
13. The compound of claim 12 , wherein x is a real number between about 1 and about 2.
14. The compound of claim 9 , further comprising at least about 0.5 equivalents of water.
15. The compound of claim 14 , wherein the water is present in an amount of from about 0.5 to about 5 equivalents.
16. An ammonium salt of the compound of formula V:
wherein x is a real number greater than 0 and less than about 4.
17. The compound of claim 16 , wherein x is a real number between about 0.5 and 3.
18. The compound of claim 17 , wherein x is a real number between about 1 and about 2.
19. The compound of claim 16 , further comprising at least about 0.5 equivalents of water.
20. The compound of claim 19 , wherein the water is present in an amount of from about 0.5 to about 5 equivalents.
21. The compound of claim 1 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 μM or less.
22. The compound of claim 21 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 500 nM or less.
23. The compound of claim 22 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 100 nM or less.
24. The compound of claim 23 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 10 nM or less.
25. The compound of claim 24 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 nM or less.
26. The compound of claim 4 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 μM or less.
27. The compound of claim 26 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 500 nM or less.
28. The compound of claim 27 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 100 nM or less.
29. The compound of claim 28 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 10 nM or less.
30. The compound of claim 29 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 nM or less.
31. The compound of claim 9 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 μM or less.
32. The compound of claim 31 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 500 nM or less.
33. The compound of claim 32 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 100 nM or less.
34. The compound of claim 33 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 10 nM or less.
35. The compound of claim 34 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 nM or less.
36. The compound of claim 16 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 μM or less.
37. The compound of claim 36 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 500 nM or less.
38. The compound of claim 37 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 100 nM or less.
39. The compound of claim 38 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 10 nM or less.
40. The compound of claim 39 , wherein the compound is capable of inhibiting the growth of methotrexate-resistant cells with an IC 50 of 1 nM or less.
41. A pharmaceutical composition comprising
(i) an ammonium salt of the compound of formula II:
wherein:
R 2 represents up to four groups independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4; and
(ii) a pharmaceutically acceptable carrier.
42. A pharmaceutical composition comprising
(i) an ammonium salt of the compound of formula III:
wherein:
R 2 represents up to four groups each independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4; and
(ii) a pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising
(i) an ammonium salt of the compound of formula IV:
wherein:
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4; and
(ii) a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising
(i) an ammonium salt of the compound of formula V:
wherein x is a real number greater than 0 and less than about 4; and
(ii) a pharmaceutically acceptable carrier.
45. The pharmaceutical composition of claim 41 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
46. The pharmaceutical composition of claim 41 , wherein NR 3 R 4 R 5 represents ammonia.
47. The pharmaceutical composition of claim 42 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
48. The pharmaceutical composition of claim 47 , wherein NR 3 R 4 R 5 represents ammonia.
49. The pharmaceutical composition of claim 48 , wherein x is a real number between about 0.5 and 3.
50. The pharmaceutical composition of claim 49 , wherein x is a real number between about 1 and about 2.
51. The pharmaceutical composition of claim 43 , wherein NR 3 R 4 R 5 represents ammonia, piperazinium, or 2-hydroxyethylammonium.
52. The pharmaceutical composition of claim 51 , wherein NR 3 R 4 R 5 represents ammonia.
53. The pharmaceutical composition of claim 52 , wherein x is a real number between about 0.5 and 3.
54. The pharmaceutical composition of claim 53 , wherein x is a real number between about 1 and about 2.
55. The pharmaceutical composition of claim 43 , wherein the compound comprises at least about 5 equivalents of water.
56. The pharmaceutical composition of claim 55 , wherein the water is present in an amount of from about 0.5 to about 5 equivalents.
57. The pharmaceutical composition of claim 44 , wherein x is a real number between about 0.5 and 3.
58. The pharmaceutical composition of claim 57 , wherein x is a real number between about 1 and about 2.
59. The pharmaceutical composition of claim 44 , wherein the compound comprises at least about 5 equivalents of water.
60. The pharmaceutical composition of claim 59 , wherein the water is present in an amount of from about 0.5 to about 5 equivalents.
61. A method of treating leukemia or cancer involving lymphoblasts in a mammal comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula II:
wherein:
R 2 represents up to four groups independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
62. The method of claim 61 , wherein the mammal is a human.
63. A method of treating leukemia or cancer involving lymphoblasts in a mammal comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula III:
wherein:
R 2 represents up to four groups each independently selected at each occurrence of R 2 from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, chloro, fluoro, hydroxy, and —COOH;
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl; or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
64. The method of claim 63 , wherein the mammal is a human.
65. A method of treating leukemia or cancer involving lymphoblasts in a mammal comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula IV:
wherein:
R 3 , R 4 , and R 5 are each independently selected from hydrogen and C 1-6 alkyl or NR 3 R 4 taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and
x is a real number greater than 0 and less than about 4.
66. The method of claim 65 , wherein the mammal is a human.
67. A method of treating leukemia or cancer involving lymphoblasts in a mammal comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula V:
wherein x is a real number greater than 0 and less than about 4.
68. The method of claim 51 , wherein the mammal is a human.