29421-22-5

Upstream product

• 100-46-9 benzylamine 
• 30924-93-7 Boc-Glu-OBn 

Downstream Products

• 681857-36-3 (S)-4-(1-benzyl-1H-tetrazol-5-yl)-2-[(tert-butoxycarbonyl)amino]butyric acid benzyl ester 

Relevant academic research and scientific papers

HETEROCYCLIC PYRAZOLE-CARBOXAMIDES AS P2Y12 ANTAGONISTS

The present invention relates to compounds of the formula I, wherein R1; R2; Z; A; B; D; Q; J; V; G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong anti-aggregating effect on platelets and thus an anti-thrombotic effect and are suitable e.g. for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible antagonists of the platelet ADP receptor P2Y12, and can in general be applied in conditions in which an undesired activation of the platelet ADP receptor P2Y12 is present or for the cure or prevention of which an inhibition of the platelet ADP receptor P2Y12 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

Synthesis of Urea-Based Inhibitors as Active Site Probes of Glutamate Carboxypeptidase II: Efficacy as Analgesic Agents

The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII was originally cloned as PSMA, an Mr 100 000 type II transmembrane glycoprotein highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. Inhibition of brain GCPII may have therapeutic potential in the treatment of certain disease states arising from pathologically overactivated glutamate receptors. Recently, we reported that certain urea-based structures act as potent inhibitors of GCPII (J. Med. Chem. 2001, 44, 298). However, many of the potent GCPII inhibitors prepared to date are highly polar compounds and therefore do not readily penetrate the blood-brain barrier. Herein, we elaborate on the synthesis of a series of potent, urea-based GCPII inhibitors from the lead compound 3 and provide assay data for these ligands against human GCPII. Moreover, we provide data revealing the ability of one of these compounds, namely, 8d, to reduce the perception of inflammatory pain. Within the present series, the γ-tetrazole bearing glutamate isostere 7d is the most potent inhibitor with a Ki of 0.9 nM. The biological evaluation of these compounds revealed that the active site of GCPII likely comprises two regions, namely, the pharmacophore subpocket and the nonpharmacophore subpocket. The pharmacophore subpocket is very sensitive to structural changes, and thus, it appears important to keep one of the glutamic acid moieties intact to maintain the potency of the GCPII inhibitors. The site encompassing the nonpharmacophore subpocket that binds to glutamate's α-carboxyl group is sensitive to structural change, as shown by compounds 6b and 7b. However, the other region of the nonpharmacophore subpocket can accommodate both hydrophobic and hydrophilic groups. Thus, an aromatic ring can be introduced to the inhibitor, as in 8b and 8d, thereby increasing its hydrophobicity and thus potentially its ability to cross the blood-brain barrier. Intrathecally administered 8d significantly reduced pain perception in the formalin model of rat sensory nerve injury. A maximal dose of morphine (10 mg) applied in the same experimental paradigm provided no significant increase in analgesia in comparison to 8d during phase 1 of this pain study and modestly greater analgesia than 8d in phase 2. These urea-based inhibitors of GCPII thus offer a novel approach to pain management.

Methotrexate Analogues. 28. Synthesis and Biological Evaluation of New γ-Monoamides of Aminopterin and Methotrexate

Lipophilic γ-monoamide derivatives of aminopterin (AMT) were synthesized in high overall yield from 4-amino-4-deoxyN10-formylpteroic acid and γ-N-tert-alkyl-, γ-N-aralkyl, or γ-N-arylamides of α-benzyl L-glutamate via a modification of the mixed carboxylic-carbonic anhydride coupling method.Coupling was also accomplished with p-nitrophenyl 4-amino-4-deoxy-N10-formylpteroate.Compounds obtained in this manner included the γ-tert-butylamide, γ-(1-adamantylamide), γ-benzylamide, γ-(3,4-dichlorobenzylamide), γ-(2,6-dichlorobenzylamide, γ-anilide, γ-(3,4-methylened ioxyanilide), and γ-(3,4-dihydroxanilide) derivatives of AMT.Also prepared, from 4-amino-4-deoxy-N10-methylpteroic acid via diethyl phosphorocyanidate coupling, was the γ-(3,4-methylenedioxyanilide) of MTX.The methylenedioxyanilides were cleaved smoothly dihydroxyanilides with boron tri(trifluoroacetate) in trifluoroacetic acid.All the γ-monoamides were tested as inhibitors of purified dihydrofolate reductase (DHFR) from murine L1210 leukemia cells and as inhibitors of the growth of wild-type L1210 cells and a subline (L1210/R81) with high-level resistance to MTX and AMT based mainly on a defect in drug uptake via active transport.Several compounds were also tested against human leukemic lymphoblasts (CEM cells) and a resistant subline (CEM/MTX) whose resistance is like wise based on uptake.The IC50 of the γ-monoamides against DHFR was 1.5- to 5-fold higher than that of the parent acids, but the IC50 against cultured cells varied over a much broader range, suggesting that uptake and/or metabolism rather than DHFR binding are principal determinants of in vitro growth inhibitory activity for these compounds. γ-N-Aryl and γ-N-aralkyl derivatives appeared to be more potent than γ-N-tert-alkyl derivatives.Where comparison could be made, AMT γ-monoamides were more potent than MTX γ-monoamides.Several of the γ-monoamides showed potency comparable to that of the parent acid against wild-type L1210 and CEM cells; all of them were more potent than MTX against the L1210/R81 subline; and some of the AMT γ-monoamides were also more potent than the parent acid against resistant CEM/MTX cells.As a group, however, the γ-monoamides were considerably more active against the murine cells than against the human cells, suggesting that the former may take up the amides better or may be able to metabolize them more efficiently than the parent acids.All the γ-monoamides were tested in vivo against L1210 leukemia in mice.The γ-N-tert-alkylamides were inactive, whereas significant activity (>50percent increase in survival at optimal doses) was shown by every γ-N-aralkylamide and γ-N-arylamide in the series.The γ-N-arylamides were more toxic than the γ-N-aralkylamides.The most therapeutically effective compound was AMT γ-(3,4-dichlorobenzylamide), which produced an increase in lifespan (ILS) of 110percent at 70 mg/kg per day x 9 as compared with 122percent fot AMT itself at 0.5 mg/kg per day x 9.The fact that...

Methotrexate Analogues. 14. Synthesis of New γ-Substituted Derivatives as Dihydrofolate Reductase Inhibitors and Potential Anticancer Agents

The γ-tert-butyl ester (1), γ-hydrazide (2), γ-n-butylamide (3), and γ-benzylamide (4) derivatives of methotrexate (MTX) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid (APA) and the appropriate blocked L-glutamic acid precursors with the aid of the peptide bond forming reagent diethyl phosphorocyanidate.The affinity of these side chain modified products for dihydrofolate reductase (DHFR) from Lactobacillus casei and L1210 mouse leukemic cells was determined spectrophotometrically or by competitive radioligand binding assay, and their cytotoxicity was evaluated against L1210 leukemic cells in culture.The results provide continuing support for the view that the "γ-terminal region" of the MTX side chain is an attractive site for molecular modification of this anticancer agent.