Pharmaceutically active ornithine derivatives, ammonium salts thereof and methods of making same
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Abstract
The present invention relates to pharmaceutically active ornithine compounds, particularly to pharmaceutically acceptable ammonium salts of Nδ-acyl derivatives of Nα(4-amino-4-deoxypteroyl)-L-ornithine compounds; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such ammonium salts. The ammonium salts provided by the invention exhibit superior chemical stability than corresponding acidic Nδ-acyl derivatives of Nδ-acyl derivatives of Nα(4-amino-4-deoxypteroyl)-L-ornithine compounds.
11 Citations
92 Claims
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1-52. -52. (canceled)
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53. A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula II:
wherein;
R represents up to four groups independently selected at each occurrence of R2 from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, chloro, fluoro, hydroxy, and —
COOH;
R3, R4, and R5 are each independently selected from hydrogen and C1-6 alkyl;
or NR3R4 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. - View Dependent Claims (54, 55, 56, 57, 58)
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59. A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula III:
wherein;
R2 represents up to four groups each independently selected at each occurrence of R2 from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, chloro, fluoro, hydroxy, and —
COOH;
R3, R4, and R5 are each independently selected from hydrogen and C1-6 alkyl;
or NR3R4 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. - View Dependent Claims (60, 61, 62, 63, 64)
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65. A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula IV:
wherein;
R3, R4, and R5 are each independently selected from hydrogen and C1-6alkyl or NR3R4 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. - View Dependent Claims (66, 67, 68, 69, 70)
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71. A method of inhibiting growth of a cancer cell comprising contacting the cell with 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. - View Dependent Claims (72, 73, 74, 75, 76)
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77. A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula II:
wherein;
R represents up to four groups independently selected at each occurrence of R2 from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, chloro, fluoro, hydroxy, and —
COOH;
R3, R4, and R5 are each independently selected from hydrogen and C1-6 alkyl;
or NR3R4 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. - View Dependent Claims (78, 79, 80)
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81. A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula III:
wherein;
R2 represents up to four groups each independently selected at each occurrence of R2 from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, chloro, fluoro, hydroxy, and —
COOH;
R3, R4, and R5 are each independently selected from hydrogen and C1-6 alkyl;
or NR3R4 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. - View Dependent Claims (82, 83, 84)
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85. A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula IV:
wherein;
R3, R4, and R5 are each independently selected from hydrogen and C1-6alkyl or NR3R4 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. - View Dependent Claims (86, 87, 88)
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89. A method of treating a methotrexate-resistant tumor in a mammal in need thereof, 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. - View Dependent Claims (90, 91, 92)
Specification