EP0248573A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Diastereoisomeric tetrahydropyrido(2,3-d)pyrimidine derivatives
Assignee: Princeton University
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Filing: 1987-05-22
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Granted: —
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Expires: 2007-05-22
Abstract
Abstract The diastereoisomeric forms of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-dJ -pyrimidin-6-yl)ethyl]-benzoyl)-L-glutamic acid are antineoplastic agents. The compounds are prepared by separation of the diastereoisomeric form of the correspondingly protected glutamic derivatives and hydrolytic or hydrogenolytic removal of carboxylic acid and/or amino protecting groups.
Inventors
- 👤 Edward C. Taylor
- 👤 Chuan Shih
- 👤 George Peter Beardsley
- 👤 Stephen R. Fletcher
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-02 03:32
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/02; C07D471/04; A; A61; A61P; A61P35/00; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 10
Claim 1
Independent Claim
187 words
The process which comprises treating a solution of a mixture of diastereoisomeric compounds of the formula: wherein R l and R 2 are the same or different carboxylic acid protecting group; R 3 is hydrogen or an amino protecting group; and the configuration about the carbon atom designated * is L; with a chiral acid operable to form a salt with said mixture, separating the resultant two diastereoisomeric salts of said acid and said compound, and thereafter liberating as the free base the cationic moiety of at least one of said separated salts through treatment with a base and removing said protecting groups, said liberation being performed either as a discrete step before or after said removal of the protecting groups, or concomitantly with said removal, to yield at least one of (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid which has a of -21.06° substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of +31.09° and (ii) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid which has a [α] 25 589nm of +31.09° substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8- .tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L- glutamic acid which has a of -21.06°.
Claim 2
Dependent Claim
187 words
The process which comprises treating a solution of a mixture of diastereoisomeric compounds of the formula: wherein R l and R 2 are the same or different carboxylic acid protecting group; R 3 is hydrogen or an amino protecting group; and the configuration about the carbon atom designated * is L; with a chiral acid operable to form a salt with said mixture, separating the resultant two diastereoisomeric salts of said acid and said compound, and thereafter liberating as the free base the cationic moiety of at least one of said separated salts through treatment with a base and removing said protecting groups, said liberation being performed either as a discrete step before or after said removal of the protecting groups, or concomitantly with said removal, to yield at least one of (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid which has a of -21.06° substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of +31.09° and (ii) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid which has a [α] 25 589nm of +31.09° substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8- .tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L- glutamic acid which has a of -21.06°.
Claim 3
Dependent Claim
81 words
A compound selected from the group consisting of: (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-y l )et h y l] -benzoyl)-L-glutamic acid having a of -21.06° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L -glutamic acid which has a of +31.09 °; (ii) the 4(3H)-oxo tautomeric form thereof; and (iii) a pharmaceutically acceptable alkali metal, alkaline earth, non-toxic metal, ammonium, or substituted ammonium salt thereof which is substantially free of the corresponding salt of that diastereoisomer which has a of +31.09°.
Claim 4
Dependent Claim
81 words
A compound selected from the group consisting of: (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-y l )et h y l] -benzoyl)-L-glutamic acid having a of -21.06° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L -glutamic acid which has a of +31.09 °; (ii) the 4(3H)-oxo tautomeric form thereof; and (iii) a pharmaceutically acceptable alkali metal, alkaline earth, non-toxic metal, ammonium, or substituted ammonium salt thereof which is substantially free of the corresponding salt of that diastereoisomer which has a of +31.09°.
Claim 5
Dependent Claim
26 words
The diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid having a of -21.06° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetra- hydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of +31. 09°.
Claim 6
Dependent Claim
26 words
The diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid having a of -21.06° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetra- hydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of +31. 09°.
Claim 7
Dependent Claim
76 words
A compound selected from the group consisting of: (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-y l )ethyl]-benzoyl)-L-glutamic acid having a of +31.09° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L -glutamic acid which has a of -21.06°; (ii) the 4(3H)-oxo tautomeric form thereof; and (iii) a pharmaceutically acceptable alkali metal, alkaline earth, non-toxic metal, ammonium, or substituted ammonium salt thereof which is substantially free of the corresponding salt of that diastereoisomer which has a of -21.06°.
Claim 8
Dependent Claim
76 words
A compound selected from the group consisting of: (i) the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-y l )ethyl]-benzoyl)-L-glutamic acid having a of +31.09° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoyl)- L -glutamic acid which has a of -21.06°; (ii) the 4(3H)-oxo tautomeric form thereof; and (iii) a pharmaceutically acceptable alkali metal, alkaline earth, non-toxic metal, ammonium, or substituted ammonium salt thereof which is substantially free of the corresponding salt of that diastereoisomer which has a of -21.06°.
Claim 9
Dependent Claim
29 words
The diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5 f 6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid having a of +31.09° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetra- hydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of - 21.06 °.
Claim 10
Dependent Claim
29 words
The diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5 f 6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-ethyl]-benzoyl)-L-glutamic acid having a of +31.09° and being substantially free of the diastereoisomer of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetra- hydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid which has a of - 21.06 °.
References Cited (Backward Citations)
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