Conjugates of SN-38 that provide optimal drug release rates and minimize the formation of the corresponding glucuronate are described. The conjugates release SN-38 from a polyethylene glycol through a -elimination mechanism.

A fluorine-containing ether compound represented by formula (1) or (2):

A.sup.1-(OR.sup.f1).sub.y1R.sup.1-Q.sup.1-R.sup.2-L.sup.1-(R.sup.3-T.sup.1).sub.x1Formula (1)

(T.sup.3-R.sup.9).sub.x3-L.sup.3-R.sup.8-Q.sup.3-R.sup.7R.sup.f(OR.sup.f2).sub.y2R.sup.4-Q.sup.2-R.sup.5-L.sup.2-(R.sup.6-T.sup.2).sub.x2 Formula (2)

where each symbol in the formula is as described in the description.

A heterobifunctional monodispersed polyethylene glycol represented by the formula (1): ##STR00001##
wherein X.sup.1 and Y.sup.1 are each an atomic group containing a functional group capable of forming a covalent bond upon a reaction with a functional group present in a biofunctional molecule, the functional group contained in the atomic group X.sup.1 and the functional group contained in the atomic group Y.sup.1 are different from each other; R.sup.1 is a hydrocarbon group having from 1 to 7 carbon atoms or a hydrogen atom; n is an integer of 3 to 72; 1 is an integer of 2 to 72; and A.sup.1, B.sup.1 and C.sup.1 are as defined herein.

The present disclosure is directed to certain polyethers copolymers, and polyether derivatives thereof, and methods of making and using the same. For example, the starting materials may include such species as citronellol, geraniol, dihydromyrcene, adipic acid, propanediol, ethylene glycol, glycerol, 1,9-nonanediol, and 1,6-hexanediol.

Provided are methods of preparing heterobifunctional poly(ethylene glycol) derivatives (e.g., HO-PEG-OCH.sub.2CO.sub.2H) by alkylating poly(ethylene glycol). A method comprises: (a) synthesizing ArCR.sub.1R.sub.2O-Poly-OH (e.g., Bz-PEG-OH, where Bz is benzyl) by forming a polymer Poly (e.g., HO-PEG-OH) onto the aryl methyl oxide ion, ArCR.sub.1R.sub.2O; (b) alkylating ArCR.sub.1R.sub.2O-Poly-OH to form ArCR.sub.1R.sub.2O-poly-OR.sub.9 (e.g., Bz-O-PEG-OCH.sub.2CO.sub.2(CH.sub.3).sub.3); (c) converting the ArCR.sub.1R.sub.2O moiety to OH by acid-catalyzed hydrolysis or hydrogenolysis to form a new mixture of R.sub.9O-PEG-OH and R.sub.9O-PEG-OR.sub.9 (e.g., HO-PEG-OCH.sub.2CO.sub.2H and HO.sub.2CCH.sub.2O-PEG-OCH.sub.2CO.sub.2H); and (d) optionally, isolating the R.sub.9O-PEG-OH product formed in (c).
The method of the present invention obviates the extensive and laborious purification prior art steps normally required to remove HO-Poly-OH (e.g., HO-PEG-OH) from a preparation of the PEG derivatives.

Provided are methods of preparing heterobifunctional poly(ethylene glycol) derivatives (e.g., HO-PEG-OCH.sub.2CO.sub.2H) by alkylating poly(ethylene glycol). A method comprises: (a) synthesizing ArCR.sub.1R.sub.2O-Poly-OH (e.g., Bz-PEG-OH, where Bz is benzyl) by forming a polymer Poly (e.g., HO-PEG-OH) onto the aryl methyl oxide ion, ArCR.sub.1R.sub.2O; (b) alkylating ArCR.sub.1R.sub.2O-Poly-OH to form ArCR.sub.1R.sub.2O-poly-OR.sub.9 (e.g., Bz-O-PEG-OCH.sub.2CO.sub.2(CH.sub.3).sub.3); (c) converting the ArCR.sub.1R.sub.2O moiety to OH by acid-catalyzed hydrolysis or hydrogenolysis to form a new mixture of R.sub.9O-PEG-OH and R.sub.9O-PEG-OR.sub.9 (e.g., HO-PEG-OCH.sub.2CO.sub.2H and HO.sub.2CCH.sub.2O-PEG-OCH.sub.2CO.sub.2H); and (d) optionally, isolating the R.sub.9O-PEG-OH product formed in (c).
The method of the present invention obviates the extensive and laborious purification prior art steps normally required to remove HO-Poly-OH (e.g., HO-PEG-OH) from a preparation of the PEG derivatives.

A fluorinated ether compound is represented by formula: [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C-R.sup.21[N(R.sup.2)C(O)].sub.p2(R.sup.f2O).sub.m2-Q.sup.2-[C(O)N(R.sup.2)].sub.p2R.sup.21C[R.sup.22SiR.sup.2.sub.3-n2X.sup.2.sub.3-n2].sub.3. R.sup.f2 is a fluoroalkylene group having no branched structure, Q.sup.2 is a fluoroalkylene group having no branched structure, R.sup.2 is a hydrogen atom or an alkyl group, R.sup.21 is a single bond, an alkylene group, an alkylene group comprising an etheric oxygen atom at its terminal on the side bonded to [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C, an alkylene group with at least two carbon atoms comprising an etheric oxygen atom between its carbon-carbon atoms, or an alkylene group with at least two carbon atoms comprising an etheric oxygen atom between its carbon-carbon atoms and at its terminal on the side bonded to [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C, R.sup.22 is an alkylene group, or the like, R.sup.23 is a hydrogen atom or a monovalent hydrocarbon group, and X.sup.2 is a hydrolyzable group.

A fluorinated ether compound is represented by formula: [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C-R.sup.21[N(R.sup.2)C(O)].sub.p2(R.sup.f2O).sub.m2-Q.sup.2-[C(O)N(R.sup.2)].sub.p2R.sup.21C[R.sup.22SiR.sup.2.sub.3-n2X.sup.2.sub.3-n2].sub.3. R.sup.f2 is a fluoroalkylene group having no branched structure, Q.sup.2 is a fluoroalkylene group having no branched structure, R.sup.2 is a hydrogen atom or an alkyl group, R.sup.21 is a single bond, an alkylene group, an alkylene group comprising an etheric oxygen atom at its terminal on the side bonded to [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C, an alkylene group with at least two carbon atoms comprising an etheric oxygen atom between its carbon-carbon atoms, or an alkylene group with at least two carbon atoms comprising an etheric oxygen atom between its carbon-carbon atoms and at its terminal on the side bonded to [X.sup.2.sub.3-n2R.sup.23.sub.n2SiR.sup.22].sub.3C, R.sup.22 is an alkylene group, or the like, R.sup.23 is a hydrogen atom or a monovalent hydrocarbon group, and X.sup.2 is a hydrolyzable group.

Conjugates of SN-38 that provide optimal drug release rates and minimize the formation of the corresponding glucuronate are described. The conjugates release SN-38 from a polyethylene glycol through a -elimination mechanism.

The invention provides poly(ethylene glycol)-lipid conjugates for use in drug delivery.