Abstract: The perception of pain precedes the manifestation of measurable and quantifiable clinical symptoms of most diseases. Pain is an early warning signal at the beginning of a physical abnormality. The present invention discloses novel methods to ameliorate or reverse diseases at their warning stages by therapeutic intervention of pain before a definite clinical diagnosis of the abnormality can be made. Unprecedented methods to eliminate pain caused by inflammatory autoimmune response or inflammatory allergic response or malignant and benign neoplastic growth by administering metabolism blocked antifolate compounds are described.

Abstract: New metabolism blocked antifolates and their salts are provided along with new indications (coronary heart disease, cardiovascular diseases, stroke and termination of tubal or ectopic pregnancy) and methods (sublingual dosage forms, filmstrips or patches) for their use and delivery. Sublingual dosage forms or trans-dermal patches of metabolically blocked entities of this invention offer superior alternatives to traditional oral dosage forms to achieve greater and predictable therapeutic efficacy, lower toxicity and to overcome drug resistance by virtue of elimination of oxidative deactivation and production of toxic metabolites. Metabolism blocked antifolates bearing a fluorinated benzene ring, a thiophene ring, a pyrrole ring, a furan ring or a 8-deazapteridine ring that are provided in this invention are not previously described.

Abstract: Several major new inflammatory diseases that respond to methotrexate are identified in this Invention. These newly identified indications that respond to methotrexate include a number of cardiovascular diseases, coronary heart disease and stroke. To optimize and improve therapeutic effectiveness, therapeutic responses and to minimize toxicity new sublingual dosage units and patches of methotrexate are taught in this Invention for direct delivery of the drug to the blood stream bypassing absorption through the human gut. The practice of this invention as provided herein should result in significant improvement of the therapeutic index of methotrexate in the treatment of a number of painful, crippling, disfiguring, and fatal diseases. This Invention therefore addresses an unmet need to treat the above diseases for which there are no curative treatments are available at the present time.

Abstract: Hether to unknown metabolically inert classical folate analog inhibitors of the enzyme Dihydrofolate Reductase ?DHFR! that are transported to tumor cells via the reduced folate receptors are provided. These compounds exhibit superior anti-asthmatic responses in rabbits relative to methotrexate and the standard drug theophylline. The title compound 4-amino-4-deoxy-5,8,10-trideaza-pteroyl-4'-methyleneglutamic acid (1) exhibited outstanding anti-tumor activity. Compound 1 was 1,000 to 10,000 times more active than methotrexate in causing total growth inhibition (TGI) of a number of human tumor cells in culture. Unlike methotrexate the the TGI values of 1 are in the range of therapeutically relevant concentrations. Tumor cells that are resistant to methotrexate by virtue of defective polyglutamylation were 3-4 times more collaterally sensitive to compound 1. 1 was completely inert on incubation with folylpolyglutamate synthetase.

Abstract: Several new 10-formyl and 10-hydroxymethyl derivatives of 5,8,10-trideazapteroic acid are provided, as well as procedures for their preparation. These compounds were shown to be powerful inhibitors of glycinamide ribonucleotide formyltransferase (GARFT), an enzyme that mediates the de novo biosynthesis of purine nucleotides that are required for DNA synthesis and cell division. Due to their ability to interfere with nucleotide biosynthesis and to penetrate microbial cells they are potential anti-microbial agents and are useful for the treatment of opportunistic infections in AIDS and other infections caused by micro-organisms that are resistant to conventional anti-bacterial and anti-fungal agents.

Abstract: The biologically active enantiomer of .gamma.-methylene-10-deazaaminopterin (L-MDAM) possessing the L configuration at the .gamma.-methyleneglutamate moiety, which is identical to the absolute configuration at the .alpha.-position of the .gamma.-methyleneglutamic acid isolated from peanut seedlings is provided as well as procedures for its preparation. The compound does not undergo polyglutamylation, is twice as effective as an inhibitor of recombinant human dihydrofolate reductase, and exhibits outstanding growth inhibitory activity in a large variety of human tumor cells in culture. The biochemical and pharmacological results established the utility of L-MDAM as a therapeutic agent for the treatment of human neoplastic diseases.

Abstract: A new thiophene substituted antitumor antifolate, N{[5-(2,4-diamino-6-pteridinyl)ethyl]2-theonyl}-L-glutamic acid having the structural formula 1 is provided, as well as methods for its preparation. The new thiophene substituted antifolate 1 is a very potent inhibitor of the enzyme dihydrofolate reductase, undergoes moderate polyglutamylation and is transported to tumor cells more effectively than methotrexate. Compound 1 is an excellent inhibitor of tumor cells growth in culture, the potency being superior to methotrexate against CCRF-CEM human lukemia cells.

Abstract: A 10-deaza-10-formyl folate analogue is a potent inhibitor of the enzyme glycinamide ribonucleotide formyltransferase and an antitumor agent. A typical embodiment is 10-formyl-5,8,10-trideazafolic acid (FTDF).

Abstract: Two new non-polyglutamatable glutamic acid derivatives in the antifolate series are provided as well as procedures for their preparation. These compounds are: 4-amino-4-deoxy-10-methylpteroyl-.tau.-methyleneglutamic acid (1) and 4-amino-4-deoxy-10-methylpteroyl-.beta.-hydroxyglutamic acid (2). Compounds 1 and 2 do not undergo polyglutamylation as determined by their inability to serve as substrates for folylpolyglutamate synthetase (FPGS), and they are powerful inhibitors of human dihydrofolate reductase (DHFR). Both compounds 1 and 2 are powerful inhibitors of the growth of Manca human lymphoma, human leukemia (CCRF-CEM) and H35 hepatoma cells.

Abstract: A double blind clinical trial of 10-deazaaminopterin versus the antirheumatoid drug methotrexate (MTX) established that 10-deazaaminopterin, in addition to being at least equally effective as methotrexate in all respects in ameliorating rheumatoid arthritis in humans, it is superior to methotrexate in controlling pain and joint stiffness and in improving grip strength. In accordance with this invention 10-deazaaminopterin is claimed as a more effective disease modifying arthritis remittive drug for the treatment of rheumatoid arthritis in humans.

Abstract: Three new non-polyglutamatable glutamic acid derivatives in the antifolate series are provided as well as procedures for their preparation. These compounds are: 4-amino-4-deoxy-10-deazapteroyl-.tau.-methyleneglutamic acid (1); 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-.tau.-methylene-glutamic acid (2); and 4-amino-4-deoxy-10-deazapteroyl-3-hydroxyglutamic acid (3). None of the compound undergo polyglutamylation as determined by their inability to serve as substrates for folylpolyglutamate synthetase (FPGS). Compounds 1 and 2 are transported more effectively to tumor cells and they are more powerful in inhibiting the growth of human leukemia cells in culture as compared to the standard anticancer drug methotrexate. All three compounds (1, 2, and 3) inhibit human dihydrofolate reductase to the same extent as methotrexate.