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US4871746A
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N-[N-(tetrahydropyrido[2,3-D]pyrimidinylmethyl)-aminomethylbenzoyl]glutamic acid derivatives as neoplastic growth inhibitors
Assignee: Eli Lilly and Co
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Filing: 1988-05-31
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Granted: 1989-10-03
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Expires: 2008-05-31
Abstract
Abstract N-[N-(Tetrahydropyrido[2,3-d]pyrimidinylmethyl)aminomethylbenzoyl]glut amic acid derivatives of formula <CHEM> are anti-neoplastic agents with an effect on one or more enzymes which utilize metabolic derivatives of folic acid. The compounds can be prepared by allowing a protected aminomethylbenzoylglutamic acid derivative to react with 2-amino-4-hydroxy-6-formylpyrido[2,3-d]pyrimidine, reducing the intermediate Schiff base, and subjecting the intermediate to catalytic hydrogenation. A typical embodiment is (S,S) N-[N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl methyl)-4-aminomethylbenzoyl]-glutamic acid.
Inventors
- 👤 Edward C. Taylor
- 👤 James M. Hamby
- 👤 Chuan Shih
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-25 14:54
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/02; C07D471/04; A; A61; A61P; A61P35/00
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
50 words
A compound selected from the group consisting of a glutamic acid derivative having the formula: ##STR6## in which: R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkanoyl of 1 to 6 carbon atoms; and R 3 is hydrogen or halo; and a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
50 words
A compound selected from the group consisting of a glutamic acid derivative having the formula: ##STR6## in which: R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkanoyl of 1 to 6 carbon atoms; and R 3 is hydrogen or halo; and a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
29 words
A compound according to claim 1 wherein in said glutamic acid derivative R 1 is hydrogen, methyl, ethyl, formyl, or acetyl and R 3 is hydrogen, chloro, or fluoro.
Claim 4
Dependent Claim
22 words
A compound according to claim 2 wherein each of R 1 and R 3 is hydrogen, and the pharmaceutically acceptable salts thereof.
Claim 5
Dependent Claim
11 words
The compound according to claim 3 which is (S,S) N-[N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamic acid.
Claim 6
Dependent Claim
11 words
The compound according to claim 3 which is (R,S) N-[N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamic acid.
Claim 7
Dependent Claim
22 words
A compound according to claim 2 wherein R 1 is formyl and R 3 is hydrogen, and the pharmaceutically acceptable salts thereof.
Claim 8
Dependent Claim
11 words
The compound according to claim 6 which is (S,S) N-[N-formyl-N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamic acid.
Claim 9
Dependent Claim
11 words
The compound according to claim 6 which is (R,S) N-[N-formyl-N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamic acid.
Claim 10
Dependent Claim
49 words
The method of inhibiting neoplastic growth in a mammal which growth is dependent on folic acid or a metabolic derivative of folic acid as a substrate, which comprises administering to the mammal in a single or multiple dose regimen an effective amount of a compound according to claim 1.
Claim 11
Dependent Claim
64 words
A pharmaceutical composition for inhibiting neoplastic growth in a mammal which growth is dependent on folic acid or a metabolic derivative of folic acid as a substrate, which comprises an amount of a compound according to claim 1 which upon administration to the mammal in a single or multiple dose regimen is effective to inhibit said growth, in combination with a pharmaceutically acceptable carrier.
Claim 12
Dependent Claim
140 words
A compound selected from the group consisting of a glutamic acid derivative having the formula: ##STR7## in which: R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkanoyl of 1 to 6 carbon atoms; R 2 is hydrogen or a carboxy protecting group selected from the group consisting of (a) a straight or branched lower alkyl ester which is unsubstituted or substituted in the 1- or 2-position with (i) lower alkoxy, (ii) lower alkylthio, (iii) halogen, (iv) phenyl which is unsubstituted or mono-, di- or tri-substituted with lower alkyl, lower alkoxy, hydroxy, halo, or nitro, or (v) aroyl, or (b) a silyl group; R 3 is hydrogen or halo; and R 4 is hydrogen or an unsubstituted or substituted lower alkanoyl amino protecting group, at least one of R 2 and R 4 being other than hydrogen.
Claim 13
Dependent Claim
140 words
A compound selected from the group consisting of a glutamic acid derivative having the formula: ##STR7## in which: R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkanoyl of 1 to 6 carbon atoms; R 2 is hydrogen or a carboxy protecting group selected from the group consisting of (a) a straight or branched lower alkyl ester which is unsubstituted or substituted in the 1- or 2-position with (i) lower alkoxy, (ii) lower alkylthio, (iii) halogen, (iv) phenyl which is unsubstituted or mono-, di- or tri-substituted with lower alkyl, lower alkoxy, hydroxy, halo, or nitro, or (v) aroyl, or (b) a silyl group; R 3 is hydrogen or halo; and R 4 is hydrogen or an unsubstituted or substituted lower alkanoyl amino protecting group, at least one of R 2 and R 4 being other than hydrogen.
References Cited (Backward Citations)
US4596805A
Cited
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