Biodegradable drug-polymer conjugate
A technology of polymers and conjugates, applied in the direction of drug combination, drug delivery, active ingredients of heterocyclic compounds, etc., can solve the problems of few or no hydrogels with limited applications
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specific Embodiment
[0540] Specific examples include -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -and-CH 2 -CH 2 -O-CH 2 -CH 2 -.
[0541] In formulas (I), (II), (IV), (IVa), (IVb) and (V), the linking group M or M and M' is present in the backbone part of the monomer or polymer. The groups M and M' are independently selected, and the occurrence of M in part of the drug-monomer conjugate and comonomer is also independently selected. The drug-monomer conjugate contains two M linking groups that can be independently selected, but in many embodiments it is convenient that they be the same. M and M' are each selected from the group consisting of a bond, optionally substituted C 1to C 10 Linear or branched aliphatic, the group -O-(C 1 to C 10 straight-chain or branched-chain aliphatic), containing C through an oxygen interval (-O-) 1 to C 10 A linear or branched chain aliphatic ether linking group, the group –N(R w )-(C 1 to C 10 Straight chain or br...
Embodiment 1
[0615] Example 1 illustrates that 1-chloroethyl(2-(prop-2-yn-1-yl)pent-4-yn-1-yl)carbonate
[0616] To a solution of 2-(prop-2-yn-1-yl)pent-4-yn-1-ol (2.649 g, 21.7 mmol) in dry pyridine (50 mL) was added chloroformic acid dropwise at 0 °C 1-Chloroethyl ester (4.70 mL, 43.4 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 2 days. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, washed with water and brine. Then the organic phase was washed with Na 2 SO 4 Dry, filter and concentrate and dry in vacuo. The crude residue was purified by flash chromatography.
[0617] Method 9B
[0618] To 2-(prop-2-yn-1-yl)pent-4-yn-1-ol (2.0 g, 16.37 mmol) and DMAP (3.0 g, 24.55 mmol) in anhydrous dichloromethane (60 mL) To the ice-cold solution was added 1-chloroethyl chloroformate (3.4 mL, 31.4 mmol). The reaction mixture was warmed to room temperature and stirred for 18h. The solvent was removed unde...
Embodiment 65
[0622] To a 0° C. solution of latanoprost free acid (1.80 mmol) in DMF (5 mL) was added K 2 CO 3 (3.66 mmol). After 5 minutes, an alkyl chloride (eg, 1-chloroethyl(2-(prop-2-yn-1-yl)pent-4-yn-1-yl)carbonate 5.98 mmol) in DMF was added via cannula ( 20 mL) solution, the resulting solution was warmed to room temperature and stirred for 5 days or until the reaction was complete. Add EtOAc and saturated NH 4 Cl aqueous solution, the product was extracted (EtOAc), washed (H 2 O, then brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure. Flash chromatography (20%-100% EtOAc / petrol gradient elution) afforded 1-(((((2-(prop-2-yn-1-yl)pent-4-yn-1-yl)oxy)carbonyl )oxy)ethyl(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl base) hept-5-enoate (643.4 mg, 1.10 mmol, 61%) as a colorless viscous oil R f = 0.60 (EtOAc).
[0623] Method 10B Formation of [(alkoxycarbonyl)oxy]alkyl esters using NaH
[0624] To a solution of the carbox...
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