Synthetic antineoplastic agents derived from dolastatin 15 and methods of making same
AssigneeArizona Board of Regents, acting for and on behalf of Arizona State University
InventorsGeorge R. Pettit, Erik J. Flahive
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Abstract
A composition of matter, denominated herein as 12a-r, having the structural formula set forth below: wherein R is selected from the group consisting of: a) R=NHPh; b) R=NHCH2Ph; c) R=NH(CH2)2Ph; d) R=NH(CH2)2‘-4-F-Ph; e) R=NH(CH2)2-4-Cl-Ph; f) R=NH(CH2)2-3-Cl-Ph; g) R=NH(CH2)2-2-Cl-Ph; h) R=NH(CH2)2-4-Br-Ph; i) R=NH(CH2)2-4-NO2-Ph; j) R=NH(CH2)2-3,4-(CH3O)2Ph; k) R=NH(CH2)2-2-pyridine; l) R=NH(CH2)3Ph; m) R=L-Phe-OCH3; n) R=L-Met-OCH3; o) R=L-Pro-OCH3; p) R=NH-2-thiazolyl; q) R=NH-2-benzothiazolyl; r) R=NH-3-quinolyl; and methods of making these compounds 12a-r.
Claims22
A dolastatin 15 derivative of formula 13
- wherein R3 is selected from the group consisting of:
- NHPh, NHCH2Ph, NH(CH2)2Ph, NH(CH2)2-4-F-Ph, NH(CH2)2-4-Cl-Ph, NH(CH2)2-3-Cl-Ph, NH(CH2)2-2-Cl-Ph, NH(CH2)2-4-Br-Ph, NH(CH2)2-4-NO2-Ph, NH(CH2)2-3,4-(CH3O)2Ph, NH(CH2)2-2-pyridine, NH(CH2)3-Ph, L-Phe-OCH3, L-Met-OCH3, L-Pro-OCH3, HN-2-thiazoly, NH-2-benzothiazolyl, and NH-3-quinolyl.
A method of synthesizing a dolastatin 15 derivative of formula 13
- wherein R3 is selected from the group consisting of:
- NHPh, NHCH2Ph, NH(CH2)2Ph, NH(CH2)2-4-F-Ph, NH(CH2)2-4-Cl-Ph, NH(CH2)2-3-Cl-Ph, NH(CH2)2-2-Cl-Ph, NH(CH2)2-4-Br-Ph, NH(CH2)2-4-NO2-Ph, NH(CH2)2-3,4-(CH3O)2Ph, NH(CH2)2-2-pyridine, NH(CH2)3-Ph, L-Phe-OCH3, L-Met-OCH3, L-Pro-OCH3, NH-2-thiazolyl, NH-2-benzothiazolyl, and NH-3-quinolyl;
- said method comprising:
- (a) reacting 2-hydroxyisovaleric acid with an amine of formula R3-H for a time and under conditions effective to form an amide of formula 14
- wherein R3 is as defined above;
- (b) reacting the amide of formula 14 with tBoc-L-proline for a time and under conditions effective to form an ester of formula 15
- (c) treating the ester of formula 15 with trifluoracetic acid for a time and under conditions effective to remove the tBoc group from the ester of formula 15, thereby generating a trifluoroacetic acid salt of formula 16
- (d) reacting the trifluoroacetic acid salt of formula 16 with the tripeptide of formula 17 for a time and under conditions effective to generate the tetrapeptide of formula 18
- wherein Z is carboxybenzyloxy;
- (e) removing the carboxybenzyloxy group from the tetrapeptide of formula 18 to form a deprotected tetrapeptide, and reacting said deprotected tetrapeptide with N,N′-dimethylvaline for a time and under conditions effective to generate said dolastatin 15 derivative of formula 13;
- and
- (f) recovering said dolastatin 15 derivative of formula 13.
A method of synthesizing a dolastatin 15 derivative of formula 13
- wherein R3 is selected from the group consisting of:
- NHPh, NHCH2Ph, NH(CH2)2Ph, NH(CH2)2-4-F-Ph, NH(CH2)2-4-Cl-Ph, NH(CH2)2-3-Cl-Ph, NH(CH2)2-2-Cl-Ph, NH(CH2)2-4Br-Ph, NH(CH2)2-4-NO2-Ph, NH(CH2)2-3,4-(CH3O)2Ph, NH(CH2)2-2-pyridine, NH(CH2)3-Ph, L-Phe-OCH3, L-Met-OCH3, L-Pro-OCH3, NH-2-thiazolyl, NH-2-benzothiazolyl, and NH-3-quinolyl;
- said method comprising:
- (a) reacting 2-hydroxyisovaleric acid with an amine of formula R3-H for a time and under conditions effective to form an amide of formula 14
- wherein R3 is as defined above;
- (b) reacting the amide of formula 14 with tBoc-L-proline for a time and under conditions effective to form an ester of formula 15
- (c) treating the ester of formula 15 with trifluoracetic acid for a time and under conditions effective to remove the tBoc group from the ester of formula 15, thereby generating a trifluoroacetic acid salt of formula 16
- (d) reacting the trifluoroacetic acid salt of formula 16 with the tripeptide of formula 17 for a time and under conditions effective to generate the tetrapeptide of formula 18
- wherein Z is tBoc;
- (e) removing the tBoc group from the tetrapeptide of formula 18 to form a deprotected tetrapeptide, and reacting said deprotected tetrapeptide with N,N′-dimethylvaline for a time and under conditions effective to generate said dolastatin 15 derivative of formula 13;
- and
- (f) recovering said dolastatin 15 derivative of formula 13.
Dependencies are inferred from the claim text.