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A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of our biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamide-based fXa inhibitors. Highly potent 2-naphthyl-P1 fXa inhibitors (K(i)or =2 nM) with improved in vitro anticoagulant activity (2xTGor =1 microM) and respectable pharmacokinetic properties have been discovered.

To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.

The Hofmann rearrangement is an excellent synthetic method to introduce amino functions into aromatic molecules; however, it becomes less efficient in electron-deficient systems because of competitive hydrolytic reactions. This report describes the preparation of the aminodinitrotoluenes (ADNTs) 2-(15N)-amino-4,6-dinitrotoluene and 4-(15N)-amino-2,6-dinitrotoluene by developing conditions using HPLC as a reaction monitoring technique. Both ADNTs were prepared in >70% yield and >95% isotropic purity by using organic solvents and controlling pH during the formation of N-chlorobenzamides and then performing the rearrangement. © 1998 John Wiley & Sons, Ltd.

Synthesis of the anthracycline anticancer agent, 14-O(β-alanyl-N-HC)-7-O (2',6'-dideoxy-2'-fluoro-α-L-talopyranosyl) Adriamycinone (DA-125- 14 C) labeled with carbon-14 regiospecifically for ADME (absorption, distribution, metabolism, and excretion) studies is described. Unlabeled 7-O(2',6'-dideoxy-2'-fluoro-α-L-talopyranosyl) adriamycinone (Dong-A Pharm. Lot MI-8008)(B-1) was employed as the starting material in this nine-step radiosynthesis. The 14 C-labeled N-methyl-N-nitroso-p-toluene sulfonamide (methyl -14 C), prepared in five steps from 14 CH 3 I, served as the source of the label. A total of 335 μCi of 14- 14 C - DA-125 (specific activity 6.63 mCi/mmol, radiochemical purify or 98%, and overall isolated radiochemical yield >1 % based on N-methyl- 14 C-N-nitroso-p-toluenesulfonamide,A-5) was prepared.

An operationally simple preparation of glycolic-1-14C acid from 14CO2 has been developed using a tin-lithium exchange reaction to generate the required hydroxymethyl anion equivalent. Glycolic-1-14C acid was then produced in high yield and good radiochemical purity upon hydrogenolytic removal of the benzyl group.

Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.

Convenient methods for the selective hydrolysis of the thioester groups of dithiopyr to the corresponding carboxylic acid are described. 2-(Difluoromethyl)-4-(2-methylpropyl)-5-[(methylthio)carbonyl]-6-(trifluoromethyl)-3-pyridine-4-14C-carboxylic acid (2) was obtained by simple potassium hydroxide hydrolysis of 14C-labelled dithiopyr. A more involve strategy was necessary for the preparation of the isomeric carboxylic acid 6-(difluoromethyl)-4-(2-methylpropyl)-5-[(methylthio) carbonyl]-2-(trifluoromethyl)-3-pyridine-4-14C-carboxylic acid (3)

This report describes the synthesis of the 13C-enriched and 14C-labelled title compound starting from isotopically labelled isovaleraldehyde.

A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.

Allylically transposed amines from allylic alcohols: 3,7-dimethyl-1,6-octadien-3-amine intermediate: Geraniol trichloroacetimidate (1) intermediate: 3,7-Dimethyl-3-trichloroacetamido-1,6-octadiene (2) solvent: 300 ml. of xylene product: 3,7-Dimethyl-1,6-octadien-3-amine (3) product: 3-Trichloroacetamido-1-hexene product: 3-Phenyl-3-trichloroacetamido-1-propene product: (E)-1-Trichloroacetamido-2-heptene product: 3-Trichloroacetamido-1-cyclohexene product: 3,7-Dimethyl-1-trichloroacetamido-2,6-octadiene product: 3,5,5-Trimethyl-3-trichloroacetamido-1-cyclohexene product: 3-(4,4-Ethylenedioxybutyl)-3-trichloroacetamido-1-cyclohexene Keywords: trichloroacetonitrile

A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3 , a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency ( 14 , IC 50 =0.028 μM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.

Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.

Novel non-nucleoside tricyclic platelet ADP receptor (P2Y12) antagonists have been discovered that bind reversibly and with high affinity to the platelet receptor. Condensation of various 2-aminobenzothiazoles with chlorosulfonylacetyl chloride affords these novel tricyclic heterocycles, which are novel and unpredicted products of this reaction.