Renin inhibitory pentols showing improved enteral bioavailability

Abstract

Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.

Stereoselective Synthesis and Biological Evaluation of Anisomycin and 2-Substituted Analogues

“…In accord with results observed with other a-alkoxy-, 23 aaminoaldimines, 24 or 2-O-benzyllactaldimines, 15a,b but in contrast to our observations with 2-O-benzylglyceraldimines, 15 the reactions of 3 with organolithium compounds ( Table 1, entries 1-6) showed excellent 3,4-threoselectivity (1,2-asymmetric induction). In all cases except one (MeLi, entry 1), a single isomer with D-xylo configuration was found by 1 H and 13 C NMR analysis of the crude acetonide-protected material 4/5.…”

Renin inhibitors containing a pyridyl amino diol derived C-terminus

“…For the minor isomer: lH NMR (CDCls) = 3.96 (br m, 1H), 3.81 (br m, 1H), 3.08 (m, 1H), 2.83 (dd, J = 4.0, 4.4 Hz, 1H), 2.63 (dd, J = 2.2, 4.8 Hz, 1H), 1.90-0.85 (br m, 13H), 1.61 (s, 3H), 1.53 (s, 3H), 1.49 5). Oxazolidine 4a (9.3 g, 21.50 mmol) in 20 mL of CH2CI2 was treated with 10 mL of trifluoroacetic acid at room temperature for 1 h. After addition of 0.5 mL of water, stirring was continued for 3 h. The mixture was evaporated to dryness and the residue dissolved in ethyl acetate, washed with saturated NaHCOs solution and brine, and then dried and evaporated to afford 6.2 g (98.6%) of a pale yellow foam: TLC Rf = 0.10 (CHaCWmethanol (4:1)), [a]21D = +0.6°(c = 1, methanol); NMR (CDCls) = 8.45 (dd, J = 5.0 Hz, 1H), 7.74 (dt, J = 2.0, 7.5 Hz, 1H), 7.26 (m, 2H), 3.94 (br m, 1H), 3.63 (br m, 2H), 3.06 (br m, 2H), 1.92 (br m, 3H), 1.63 (br m, 8H), 1.42- 7.58 (dt, J = 1.6, 7.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 6.0 Hz, 1H),6.92 (s, 1H), 6.54 (br d,«7= 8.8Hz, 1H), 5.88 (br d,J = 6.4 Hz, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 3.28 (m, 2H), 3.05 (m, 3H), 2.83 (m, 1H), 2.20 (m, 1H), 1.88 (m, 1H), 1.75-0.78 (br m, 13H), 1.45 (s, 9H); FAB MS m/e 702 ( + Li)+.…”

“…(4S)-3-[3-(l-Naphthyl)propionyl]-4-benzyloxazolidin-2one (15). This compound was obtained in 63.3% yield (6.2 g) from 4.83 g (27.3 mmol) of 8l4c using the procedure described for the oxazolidinone 9 but replacing the 3-phenylpropionyl chloride with the 3-(l-naphthyl)propionyl chloride: TLC Rf = 0.52 (ethyl acetate/n-heptane (1:1)); [ ]2^= +78.2°(c = 1, methanol); 1H NMR (CDCls) = 8.11 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 1.2,8.0 Hz, 1H), 7.74 (dd, J = 2.0, 8.0 Hz, 1H), 7.57-7.18 (m, 9H), 4.68 (m, 1H), 4.17 (m, 2H), 3.53-3.28 (m, 5H), 2.78 (dd, J = 9.6,13.2 Hz, 1H); DCI MS m/e 360 (M + H)+.…”

“…The title compound was synthesized using general procedure C using dry DMF as solvent. Acid 17 (400.0 mg, 0.96 mmol) and 192.0 (0.96 mmol) of 4-[(tert-butyloxycarbonyl) amino] piperidine afforded after chromatographic purification (ethyl acetate/n-heptane (1:1)) 353.0 mg (61.3 %) of an oil: TLC Rf -0.38 (ethyl acetate/n-heptane (2:1)); NMR (CDCla) = 8.26 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 1.6, 7.6 Hz, 1H), 7.58-7.22 (m, 9H), 4.82 (m, 1H), 4.40 (m, 2H), 3.98 (dd, J = 2.0,8.8 Hz, 1H), 3.77-3.47 (br m, 4H), 3.33 (dd, J = 3.6,12.8 Hz, 1H), 3.20 (m, 1H), 3.02 (br m, 2H), 2.67 (br m, 2H), 2.36 (m, 1H), 1.86 (br m, 2H), 1.43 (s, 9H), 1.17 19). To a solution of 143.0 mg (0.24 mmol) of amide 18 in 4 mL of aqueous THF (20 % water) was added 20.1 mg (0.48n mmol) ofLiOHxHaO at 0 °C.…”

Hydroxycyclopentanone Derivativesfromd-Mannose via Ring Closing Metathesis:An Improved Synthesis of a Key Intermediate of Tricyclo-DNA

“…Diacetal 2 was prepared from D-mannose according to a known procedure. 6 The obtained material after evaporation of the solvents was pure enough to be used directly in the next step. As the protecting group for the anomeric hydroxyl function we preferred the acetate 7 (® 3) over the previously reported benzoate group 4 due to easier separation of byproducts during distillation.…”