N,N-disubstituded amide for inhibit binding of integrins to their receptors protein
An integer, compound technology, applied in the field of compounds that inhibit this combination, can solve problems such as runaway, white blood cell overflow, tissue damage, etc.
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[0108] Methods of preparing liposomes are known in the art. See, eg, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 etseq.
[0109] The term "pharmaceutically acceptable prodrugs" as used herein means prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with human and lower animal tissues without undue toxicity, irritation Sex, allergic reaction, etc., with a reasonable benefit / risk ratio, effective for its intended use, and if possible, the zwitterionic form of the compounds of the invention. The prodrugs of the present invention can be rapidly converted in vivo to the parent compound of the above general formula by, for example, hydrolysis in blood. In T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Assoc...
Embodiment 1
[0121]Example 1 (9S, 13S)-13-(1,3-benzodioxol-5-yl)-9-{[benzyl (2-thienylmethyl)amino]carbonyl}-3 , Synthetic Step 1 of 11-dioxo-1-phenyl-2-oxa-4,10,12-triazpentadecane-15-acid (6): Thiophene-2-methylamine (1.36 ml, 13.26mmol) was dissolved in methanol (20mL). To this solution were added benzaldehyde (1.34 mL, 13.26 mmol), sodium cyanoborohydride (832 mg, 13.26 mmol) and 2 drops of acetic acid. The reaction was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, then dissolved in ethyl acetate (500ml). The organic layer was washed with water (200ml), saturated sodium bicarbonate (200ml) and brine (200ml). The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with silica gel and eluted with ethyl acetate:hexane (1:3) to obtain compound 1 (1.305 g, 48%). Step 2: Dissolve compound 1 (50mg, 0.246mmol) and Na-BOC-Ne-Cbz-L-lysine (94mg, 0.246mmol) in DMF (3ml), ad...
Embodiment 23
[0122] Example 23-({[((1S)-1-{[benzyl(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-3-(4-butoxyphenyl ) Synthetic step 1 of propionic acid (12): (1S,2R,5S)-(+)menthyl (R)-p-toluenesulfinate (0.59g, 2.0mmol) was dissolved in THF (5ml), and cooled to -78°C under a nitrogen atmosphere. Treat by dropwise addition of lithium N,N-bis(trimethylsilyl)amide (3.0 ml, 1.0 M in THF). After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 5 hours. The solution was cooled to 0°C and thiophene-2-carbaldehyde (0.37ml, 4.0mmol) was added via syringe, followed rapidly by cesium fluoride powder (0.61g, 4.0mmol). The resulting suspension was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The organic solution was filtered and concentrated under reduced pres...
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