Anthranilamide-based N,N-dialkylbenzamidines as potent and orally bioavailable factor Xa inhibitors: P4 SAR

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 8, 2009, Pages 2186-2189

  Zhang, Penglie ^a   Bao, Liang ^a   Fan, Jingmei ^a   Jia, Zhaozhong J ^a   Sinha, Uma ^a   Wong, Paul W ^a   Park, Gary ^a   Hutchaleelaha, Athiwat ^a   Scarborough, Robert M ^a   Zhu, Bing Yan ^a  

^a MILLENNIUM PHARMACEUTICALS INC   (United States)

Author keywords

Anthranilamide; Anticoagulant; Benzamidine; Factor Xa inhibitor; N,N Dialkylbenzamidine

Indexed keywords

2 AMINOBENZAMIDE; BENZAMIDINE DERIVATIVE; BLOOD CLOTTING FACTOR 10A INHIBITOR; N (5 CHLOROPYRIDIN 2 YL) 2 [4 (N,N DIMETHYL)BENZAMIDO]BENZAMIDE; N (5 CHLOROPYRIDIN 2 YL) 2 [4 (N,N DIMETHYLCARBAMIMIDOYL)BENZAMIDO]BENZAMIDE; N (5 CHLOROPYRIDIN 2 YL) 2 [4 (N,N DIPIPERIDINYLCARBAMIMIDOYL)BENZAMIDO]BENZAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTICOAGULATION; ARTICLE; CONTROLLED STUDY; DOG; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG STRUCTURE; NONHUMAN; RAT;

ADMINISTRATION, ORAL; ANIMALS; ANTHRANILIC ACIDS; ANTICOAGULANTS; BENZAMIDINES; BIOLOGICAL AVAILABILITY; DOGS; FACTOR XA; HUMANS; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 63149179306     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.114     Document Type: Article

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37. Human plasma protein binding, expressed as unbound fraction, was determined by this protocol: The compound stock solutions were diluted in 1.0 M HEPES (pH 7.4) to yield a 1.0 mM working solution. The working solution was added to plasma samples (EDTA was used as anticoagulant) in a ratio of 1/100 yielding a final concentration of 10 μM. The mixture was gently mixed and incubated at 37 °C for 30 min. At the conclusion of the incubation 3 aliquots (450 μL) each were added to a centrifugal filter device fitted to a 96 well plate. Standards were prepared in protein free human plasma and transferred to the centrifugal filter device fitted to the same plate. The plates were centrifuged for 25 min at 32 °C in a centrifuge. 15 μL each of the filtrate was transferred to a round bottom 96 well plate and 15 μL of acetonitrile including KN1022 (1 μg/mL) as internal standard was added followed by 60 μL of DI water. Plates were placed on a Multi-Tube Vortexer for 30 s and vortexed. Concentrations in the filtrate were determined by LC/MS/MS and using standard curves prepared in ultra filtrated plasma.
38. t (224 mg, 2 mmol) in 10 mL of THF was added 2-amino-5-chloropyridine (128 mg, 1 mmol). After 10 min, isatoic anhydride 28 (163 mg, 1 mmol) was added in three portions. Stirring was allowed to continue for 10 more minutes and the mixture became gelatinous. The reaction was quenched with 10 mL of water, and the resulting slurry was filtered and air-dried to give compound 29 (170 mg) as a pale yellow solid. (b) Compound 29 (123 mg) suspended in 5 mL of THF was treated with 4-cyanobenzoyl chloride (83 mg) at rt for 30 min. The mixture was filtered and washed with small amount of chilled methanol to give compound 30 (145 mg) as a grey solid. (c) Hydrogen sulfide (gas) was bubbled into a suspension of compound 30 (0.1 g) in 5 mL of pyridine and 0.5 mL of triethylamine until saturation. The mixture was stirred at rt for overnight and the volatile was evaporated. The residue was taken up by 3 mL of acetone and to it 0.5 mL of iodomethane was added. The resulting mixture was refluxed for 30 min and evaporated to give a yellow solid, which was treated with a premixed solution of 2 mL of 2 N dimethylamine in THF and 0.2 mL of acetic acid. The reaction mixture was refluxed for 10 min. The desired product 11 was isolated using reverse phase HPLC with water-acetonitrile (0.1% TFA) as its TFA salt (70 mg).
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