Asymmetric Fluorination of Enolates with Nonracemic <i>N</i>-Fluoro-2,10-Camphorsultams

The asymmetric “electrophilic” fluorination of tertiary enolates by nonracemic N-fluoro-2,10-camphorsultams 3 affords quaternary α-fluoro carbonyl compounds in modest yield and ee. The highest asymmetric induction was observed for the fluorination of the sodium enolate of 2-methyl-1-tetralone (8a) by (−)-N-fluoro-2,10-(3,3-dichlorocamphorsultam) (3b) to give (S)-(+)-2-fluoro-2-methyl-1-tetralone (9a) in 70% ee. The absolute configuration was established by X-ray crystallography of the corresponding diastereomeric β-hydroxy sulfoximine prepared from (±)-9a and the Johnson reagent. The asymmetric induction exhibited by 3 is opposite to that of the closely related enolate hydroxylation reagents nonracemic (camphorylsulfonyl)oxaziridines 4. The N-fluoro sultams 3 were prepared by fluorination (10% F2/N2) of the corresponding sultams 5

AlMe₃-Promoted Formation of Amides from Acids and Amines

In the presence of AlMe3, amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected secondary amino acids, and acids with poor solubility were coupled smoothly to give the desired products in 55–98% yields

An Efficient Fischer Indole Synthesis of Avitriptan, a Potent 5-HT_1D Receptor Agonist

An efficient synthesis of the antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization reaction between hydrazine 6 and 5-chlorovaleraldehyde, 20, to give the chloropropylindole 35, which is susceptible to acid-catalyzed degradation under the reaction conditions required for its formation. Sequential coupling of 35 with piperazine, 26, and 4-chloro-5-methoxypyrimidine, 24, gives the title compound in 40−45% overall yield. Significant improvements in the syntheses of the known starting materials, hydrazine 6, 5-chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved

An Efficient Fischer Indole Synthesis of Avitriptan, a Potent 5-HT_1D Receptor Agonist

An efficient synthesis of the antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization reaction between hydrazine 6 and 5-chlorovaleraldehyde, 20, to give the chloropropylindole 35, which is susceptible to acid-catalyzed degradation under the reaction conditions required for its formation. Sequential coupling of 35 with piperazine, 26, and 4-chloro-5-methoxypyrimidine, 24, gives the title compound in 40−45% overall yield. Significant improvements in the syntheses of the known starting materials, hydrazine 6, 5-chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved

A Synthesis of <i>N</i>-Bridged 5,6-Bicylic Pyridines via A Mild Cyclodehydration Using the Burgess Reagent and Discovery of A Novel Carbamylsulfonylation Reaction

Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct

Arylcyclopropanecarboxyl Guanidines as Novel, Potent, and Selective Inhibitors of the Sodium Hydrogen Exchanger Isoform-1

A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC50 = 3.5 μM) shows inhibitory activity comparable to cariporide (IC50 = 3.4 μM). Structure−activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC50 = 0.003 μM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide

Discovery of <i>N</i>-[2-[2-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-<i>N</i>-methyl-4- morpholineacetamide as a Novel and Potent Inhibitor of Inosine Monophosphate Dehydrogenase with Excellent in Vivo Activity

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats

<i>N</i>-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. <i>N</i>-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032}, has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC50 = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC50 = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5−7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a sc/ip A2780 human ovarian carcinoma xenograft model

Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y₁₂ and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed

Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor α Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) α agonist, with an EC50 of 10 nM for human PPARα and ∼410-fold selectivity vs human PPARγ in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARδ. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARα ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARα in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed