Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-26
2000-05-23
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544279, A61K 31519, C07D40114
Patent
active
060666390
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines of the formula: ##STR1## in which R.sup.1 is hydroxy or amino; system optionally containing a sulfur or nitrogen atom as a second hetero ring member, the valence bonds originating from nonadjacent carbon atoms of the heterocyclic ring; and
The present invention also pertains to the pharmaceutically acceptable salts of the 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines of Formula I.
In addition, the invention pertains to a method of inhibiting neoplastic growth in a mammal in which the growth is dependent on folic acid, or a metabolic derivative of folic acid (such as N.sup.5,N.sup.10 -methylenetetrahydrofolate), as a substrate. The method comprises administering, in a single or multiple dose regimen, an effective amount of a compound according to Formula I to a mammal in need of such therapy.
Finally, the invention pertains to pharmaceutical compositions for inhibiting such neoplastic growth in a mammal through inhibition of folate enzymes which comprises a compound according to Formula I in combination with a pharmaceutically acceptable carrier.
The compounds of Formula I are named herein as derivatives of the pyrido[2,3-d]-pyrimidine fused ring system which is numbered as follows: ##STR2##
It will be appreciated that the pyrido[2,3-d]pyrimidines of Formula I are the tautomeric equivalent of the corresponding 3-H-4-oxo or 3-H-4-imino structures. For simplicity's sake, the compounds are depicted herein as 4-hydroxy and 4-amino compounds, it being understood the corresponding and tautomeric keto and imino structures, respectively, are fully equivalent; e.g.: ##STR3##
The compounds of Formula I can be employed in the form of the free dicarboxylic acid, in which case both R.sup.2 groups are hydroxyl. Alternatively, the compounds often can be employed in the form of a pharmaceutically acceptable salt, in which case the hydrogen atom when R.sup.2 is hydroxy is replaced by a pharmaceutically acceptable cation. Such salt forms, including hydrates thereof, are often crystalline and advantageous for forming solutions or formulating pharmaceutical compositions. Pharmaceutically acceptable salts with bases include those formed from the alkali metals, alkaline earth metals, non-toxic metals, ammonium, and mono-, di- and trisubstituted amines, such as for example the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethanolammonium, pyridinium, and substituted pyridinium salts. The mono and disodium salts, particularly the disodium salt, are advantageous.
In addition to the center of chirality about the carbon atom on the glutamic acid designated *, a second chiral center is present in the 6-position of the 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine ring system. Both the therapeutically active diastereomeric mixtures and the individual diastereomers are included in the scope of this invention. When both individual diastereomers are formed, they can be separated mechanically as by chromatography or chemically by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alphabromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the individual diastereomeric bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.
The protecting groups designated by R.sup.2 and R.sup.3 utilized herein denote groups which generally are not found in the final therapeutic compounds but which are intentionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed at a later stage of the synthesis and compounds bearing such protecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly
REFERENCES:
patent: 5473071 (1995-12-01), Taylor et al.
patent: 5508281 (1996-04-01), Gangjee
patent: 5516776 (1996-05-01), Barnett et al.
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patent: 5786358 (1998-07-01), Shih et al.
Gossett Lynn S.
Lee Koo
Shih Chuan
Taylor Edward C.
Balasubramanian V
Eli Lilly and Company
Shah Mukund J.
The Trustees of Princeton University
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