Chemically modified small molecules

Abstract

Methods of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from about 50 to about 20,000 Daltons, and wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 1.5-fold greater than the half-life of elimination from the lung of the drug, wherein the half-life of elimination from the lung is measured by bronchoalveolar lavage followed by assaying residual lung material.

1 - 38 . (canceled) 
     
     
         39 . A composition comprising conjugates, each conjugate comprised of a moiety derived from a small molecule drug having a molecular weight of less than about 1000 Daltons covalently attached by a hydrolytically and enzymatically stable linkage to a water-soluble oligomer with monodispersed molecular weight having from about 1 to about 30 monomers, wherein said conjugate exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer. 
     
     
         40 . The composition of  claim 39 , wherein the biological membrane is associated with the blood-brain barrier. 
     
     
         41 . The composition of  claim 39 , wherein the small molecule drug is orally bioavailable. 
     
     
         42 . The composition of  claim 39 , wherein the conjugate possess a molecular weight between about 300 and 1800 Daltons. 
     
     
         43 . The composition of  claim 39 , wherein the water-soluble oligomer is composed of monomers selected from the group consisting of alkylene oxide, olefinic alcohol, vinylpyrrolidone, hydroxyalkylmethacrylamide, hydroxyalkylmethacrylate, saccharide, α-hydroxy acid, phosphazene, oxazoline, amino acids, and N-acryloylmorpholine. 
     
     
         44 . The composition of  claim 39 , wherein the water-soluble oligomer is composed of ethylene oxide monomer subunits. 
     
     
         45 . The composition of  claim 39 , wherein the oligomer has a number of monomers of between 3 and 15. 
     
     
         46 . The composition of  claim 39 , wherein the stable linkage is selected from the group consisting of ether, amide, urethane, amine, thioether ether, urea, and a carbon-carbon bond. 
     
     
         47 . A pharmaceutical composition comprising: (i) conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer with monodispersed molecular weight, wherein said conjugate exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer; and (ii) a pharmaceutically acceptable excipient. 
     
     
         48 . The pharmaceutical composition of  claim 47 , in an oral dosage form. 
     
     
         49 . A method for optimizing the-selected membrane passage crossing of a small molecule drug having a molecular weight of less than about 1000 Daltons, said method comprising the step of conjugating a water-soluble oligomer with monodispersed molecular weight having from about 2 to about 30 monomers to a small molecule drug via a hydrolytically and enzymatically stable linkage, to thereby form a conjugate that exhibits a biological membrane crossing rate that is reduced when compared to the biological membrane crossing rate of the small molecule drug prior to said conjugating. 
     
     
         50 . A method for preparing a conjugate, said method comprising the step of covalently attaching a water-soluble oligomer with monodispersed molecular weight to a small molecule drug to provide a conjugate comprised of a stable linkage connecting the oligomer to the moiety derived from the small molecule drug. 
     
     
         51 . The method of  claim 50 , wherein the stable linkage is hydrolytically stable. 
     
     
         52 . The method of  claim 50 , wherein said linkage is enzymatically stable. 
     
     
         53 . The method of  claim 50 , wherein the attaching step comprises reacting, in one or more synthetic steps, the oligomer having a reactive group, A, with a small molecule comprising a reactive group, B, suitable for reaction with A, under conditions effective to form a stable linkage resulting from reaction of A with B. 
     
     
         54 . The method of  claim 53 , wherein the conjuga e co prises amixture of isomers. 
     
     
         55 . New) The method of  claim 54 . further comprising the step of separating the mixture of isomers to obtain a substantially pure composition of a single conjugate isomer. 
     
     
         56 . A method of preparing a monodisperse oligo (ethylene glycol) reagent composition, said method comprising the step of reacting a halo-terminated oligo (ethylene glycol) having (m) monomer subunits with a hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo (ethylene glycol) having (m)+(n) monomer subunits (OEG m+n ), where (m) and (n) each independently range from 1-10. 
     
     
         57 . The e hod of  claim 56 , wherein (m) ranges fro 1-3 and (n) ranges from 2-6. 
     
     
         58 . The method of  claim 56 , wherein the reacting step is carried out in the presence of a strong base. 
     
     
         59 . The method of  claim 56 , wherein the halo-terminated oligo (ethylene glycol) comprises and end-capping group. 
     
     
         60 . The method of  claim 56 , wherein the hydroxyl-terminated oligo (ethylene glycol) corresponds to the structure: HO—(CH 2 CH 2 O) n —H. 
     
     
         61 . The method of  claim 60 , further comprising the step of converting the terminal hydroxyl group of OEG m+n , into a halo group, —X, to form OEG m+n —X. 
     
     
         62 . The method of  claim 61 , further comprising the step of reacting OEG m+n —X with a second hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG m+2n ), where (m) and (n) each independently range from 1-10. 
     
     
         63 . The method of  claim 62 , wherein said second hydroxyl-terminated oligo (ethylene glycol) corresponds to the structure HO—(CH 2 C 2 O) n —H. 
     
     
         64 . The method of  claim 63 , wherein (OEG m+2n ) corresponds to the structure CH 3 O(CH 2 CH 2 O) m+2n H, and is present as part of a monodisperse composition of CH 3 O(CH 2 CH 2 O) m+2n H. 
     
     
         65 . The method of  claim 62 , wherein OEG m+2n , possesses a primary or secondary hydroxyl group. 
     
     
         66 . The method of  claim 65 , further comprising the step of converting said primary or secondary hydroxyl group into a halo group, —X, to form OEG m+2n —X. 
     
     
         67 . The method of  claim 66 , further comprising the step of reacting OEG m+2n —X with a third hydroxyl-terminated oligo (ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo (ethylene glycol) having m+3n monomer subunits (OEG m+3n ), where (m) and (n) each independently range from 1-10. 
     
     
         68 . The method of  claim 67 , where (OEG m+3n ) corresponds to he structure CH 3 O(CH 2 CH 2 O) m+3n H, and is present as a monodisperse composition of CH 3 O(CH 2 CH 2 O) m+3n H. 
     
     
         69 . A method for reducing the metabolism of an active agent, the method comprising the steps of:
 providing conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer with monodispersed molecular weight, wherein said conjugate exhibits a reduced rate of metabolism as compared to the rate of metabolism of the small molecule drug not attached to the water-soluble oligomer; and   administering said conjugate to a patient.   
     
     
         70 . The method of  claim 69 , wherein said administering step is carried our via one type of administration selected from the group consisting of oral administration, transdermal administration, buccal administration, transmucosal administration, vaginal administration, rectal administration, parenteral administration, and pulmonary administration. 
     
     
         71 . The method of  claim 70 , wherein the small omokculedrue is metabolized by a hepatic enzyme. 
     
     
         72 . The method of c aim 71, wherein the hepatic enzymes comprise one or more cytochrome P450 isoforms. 
     
     
         73 . The method of  claim 70 , wherein the administering step is carried out via oral administration. 
     
     
         74 . The method of  claim 73 , wherein the small molecule drug is metabolized by one or more intestinal enzymes.