Compound useful as antiproliferative agents and GARFT inhibitors

Details Compound useful as antiproliferative agents and GARFT inhibitors Compound useful as antiproliferative agents and GARFT inhibitors

1995-06-07

1997-03-11

Dees, Jose G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549 72, 549 73, 549484, 549488, 548532, C07D33338, C07D30754, C07D207337

Patent

active

056103190

ABSTRACT:
The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: ##STR1## where n is 0 to 2; A is S, CH.sub.2, O, NH or Se, and when n is 0, A is not CH.sub.2, and when n is 1, A is not CH.sub.2 or NH; X is a substituted or unsubstituted C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R.sub.1 and R.sub.2 are hydrogen or a moiety that forms together with the attached CO.sub.2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such Compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

REFERENCES:
patent: 2453674 (1948-11-01), Scholz
patent: 2502344 (1950-03-01), Rosenberg et al.
patent: 2714111 (1955-07-01), Hermann
patent: 4123550 (1978-10-01), Untch et al.
patent: 4684653 (1987-08-01), Taylor et al.
patent: 4686223 (1987-08-01), Cohnen et al.
patent: 4831037 (1989-05-01), Taylor et al.
patent: 4845216 (1989-07-01), Taylor et al.
patent: 4871743 (1989-10-01), Taylor et al.
patent: 4871746 (1989-10-01), Taylor et al.
patent: 4880812 (1989-11-01), Kelley
patent: 4882333 (1989-11-01), Shih et al.
patent: 4882334 (1989-11-01), Shih et al.
patent: 4883799 (1989-11-01), Taylor et al.
patent: 4889859 (1989-12-01), Taylor et al.
patent: 4895946 (1990-01-01), Taylor et al.
patent: 4920125 (1990-04-01), Taylor et al.
patent: 4921836 (1990-05-01), Bigham et al.
patent: 4927828 (1990-05-01), Taylor et al.
patent: 4971973 (1990-11-01), Bigham et al.
patent: 4988813 (1991-01-01), Taylor et al.
patent: 5013738 (1991-05-01), Taylor et al.
patent: 5026851 (1991-06-01), Taylor et al.
patent: 5179123 (1993-01-01), Djuri et al.
patent: 5217974 (1993-06-01), Grindey et al.
patent: 5223503 (1993-06-01), Gossett et al.
Moran, "Folate antimetabolites inhibitory to de novo purine synthesis," New Drugs, Concepts and Results in Cancer Chemotherapy, Muggia (ed.), Kluwer Academic Publishers, Boston (1992), 65-87.
Young et al., "An Antibody Probe to Determine the Native Species of Glycinamide Ribonucleotide Transformylase in Chicken Liver," Biochemistry, vol. 23 (1984), 3979-3986.
Morrison, "Kinetics of the Reversible Inhibition of Enzyme-Catalysed Reactions by Tight-Binding Inhibitors," Biochem. Biophys. Acta, 185 (1969), 269-286.
Totani et al., "Synthesis of a Novel 5-Deaza-5-thia Analogue of Tetrahydrofolic Acid . . . ," J. Chem. Soc. Perkin Trans. 1 (Apr. 1994), 833-836.
Mosmann, "Rapid Colorimetric Assay for Cellular Growth and Survival . . . ," J. Immunol. Methods, vol. 65 (1983), 55-63.
Sako et al., "New and Facile Synthesis of 5,6,7,8-Tetrahydro-5-deaza-5-thiapterins . . . ," Chem. Pharm. Bull., vol. 42, No. 4 (1994), 806-810.
Antony, "The Biological Chemistry of Folate Receptors," Blood, The Journal of the American Society of Hematology, vol. 79, No. 11 (1992), 2807-2820.
Pizzorno et al., "5,10-Dideazatetrahydrofolic Acid (DDATHF) Transport in CCRF-CEM and MA104 Cell Lines," The Journal of Biological Chemistry, vol. 268, No. 2 (1993), 1017-1023.
Alati et al., "Evaluation of the Mechanism(s) of Inhibition of the Toxicity, but not the Antitumor Activity of Lometrexol . . . ," Proceedings of the Am. Assoc. for Cancer Res., Abstract 2432, vol. 33 (1992), 407.
Shih et al., "Synthesis and Biological Activity of Acyclic Analogues of 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid," J. Med. Chem., vol. 35 (1992), 1109-1116.
Nemec et al., "The Synthesis of 4-Substituted 2-Thiophenecarboxylic Acids," Collection Czechoslov. Chem. Commun., vol. 39 (1974), 3527-3531.
Taylor et al., "Convergent and Efficient Palladium-Effected Synthesis of . . . (DDATHF)," J. Org. Chem., vol. 54, No. 15 (1989), 3618-3624.
Habeck et al., "A Novel Class of Monoglutamated Antifolates Exhibits Tight-binding Inhibition of Human Glycinamide Ribonucleotide Formyltransferase and Potent Activity Against Solid Tumors," Cancer Research, vol. 54 (Feb. 15, 1994), 1021-1026.
Henrie II et al., "Preparation of 2-Amino-4(3H)-oxopyrimido[5,4-b][1,4]-thiazines . . . ," J. Med. Chem., vol. 26, No. 4 (1993), 559-563.
Okafer, "Studies in the Heterocyclic Series XVIII . . . ," J. Heterocyclic Chem., vol. 17, No. 7 (1980), 1587-1592.
Alley et al., "Feasibility of Drug Screening with Panels of Human Tumor Cell Lines Using Microculture Tetrazolium Assay," Cancer Res., vol. 48 (1988), 589-601.
Cleland, "The Kinetics of Enzyme-Catalyzed Reactions with Two or More Substrates or Products," Biochem. Biophys. Acta., vol. 67 (1963), 173-187.
Casarrubio et al., "On The Synthesis of Thiophene Analogs of Practolol and `Reversed` Practolol," J. Heterocyclic Chem., vol. 20, No. 6, Nov.-Dec. 1983, 1557-1560.

Affiliated with

Also associated with

Rating

Compound useful as antiproliferative agents and GARFT inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Compound useful as antiproliferative agents and GARFT inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compound useful as antiproliferative agents and GARFT inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-444774