Patent Application: US-22139105-A

Abstract:
methods and compositions for treating cancer patients that include administering at least one or more hybrid derivatives of paclitaxel that simultaneously display improved aqueous solubility , chemical stability under physiological conditions , a decreased liability toward multi - drug resistance , and in certain instances enhanced selective toxicity toward cancer cells compared to normal cells . the derivative , paclitaxel substituted with at least one or more polar appendages at either the 7 - or 10 - positions as defined by a formula “ 7 - or - 10 - or ′- paclitaxel ”, is either deployed alone or in combination protocols with other chemotherapeutic agents .

Description:
in one aspect , the present invention relates to the structural features in drugs that pertain to interaction with a p - glycoprotein transporter system ( pgp ) that is largely responsible for pac - related mdr . uniquely distinguishable from all prior art in this area , however , the present invention relates to structural features that reduce pgp binding so that those features are incorporated into drugs , such as pac , in order to help such drugs avoid pgp and the accompanying mdr - related fall - off in their chemotherapeutic efficacies . to attach the mdr - avoiding features onto pac it was necessary to first identify a neutral region on pac where the addition of appendages do not alter pac &# 39 ; s inherent anticancer mechanism , namely an over - stabilization of the microtubule system within cells that then interrupts the cell cycle process for which rapidly dividing cells are extremely dependent . the appendages can be placed along the northern edge of pac without significantly altering its inherent anticancer activity , as shown in fig1 . chemical methods are established that can be used to readily manipulate pac along its northern edge . the latter requires initial protection of pac &# 39 ; s 2 ′- position followed by its de - protection subsequent to such manipulations . the 2 ′- protection and de - protection chemistry was accomplished by the present co - inventors , as disclosed in pending patent application entitled “ selective conversion of 2 ′, 7 - bis - monochloracetylpaclitaxel analogs to 7 - monochloroacetyl derivatives by solvolysis in methanol , pct / us02 / 30727 , which is expressly incorporated herein by reference along with all other references mentioned herein . in terms of the chemical manipulations needed along the northern edge , the present invention relates to ester connections deployed at the 7 - or 10 - positions of pac in that such systems demonstrate remarkable aqueous stability at ph 7 . 4 and good stability within cell culture assays as shown in table 1 below . even more surprising is that some of these simple ester arrangements also reduce pac &# 39 ; s mdr liability from about 1000 - fold to about 150 - fold . in another aspect of the present invention , highly polar functionalities are included as part of the ester - appended features . both an acidic and a basic functionality have been added as well as an amino acid containing moiety , as shown in fig2 . although several other investigators have previously explored the northern edge of ac , and especially of baccatin iii ( fig1 ), in terms of non - polar appendages ( e . g . alstadt , t . j ., et al , synthesis and antitumor activity of novel c - 7 paclitaxel ethers : discovery of bms - 184476 , journal of medicinal chemistry , 2001 , 44 : 4577 - 4583 ; ojima , i ., et al ., new taxanes as highly efficient reversal agents for multi - drug resistance in cancer cells , bioorganic & amp ; medicinal chemistry letters , 1998 , 8 : 189 - 194 ), very little work has been done using even moderately polar groups ( georg , g . i ., y . liu , and t . c . boge , 7 - o - acylpaclitaxel analogues : potential probes to map the paclitaxel binding site , bioorganic & amp ; medicinal chemistry letters , 1997 , 7 : 1829 - 1832 ; bhat , l ., et al ., synthesis and evaluation of paclitaxel c7 derivatives : solution phase synthesis of combinatorial libraries , bioorganic & amp ; medicinal chemistry letters , 1998 , 8 : 3181 - 3186 ). moderately polar functionality has been placed along the northern edge of docetaxel , a closely related drug ( fig1 ), but again , studies in this regard have been very limited ( uoto , k , et al ., synthesis and evaluation of water - solublie non - prodrug analogs of docetaxel bearing sec - aminoethyl group at the c - 10 position , chem . pharm . bulletin , 1998 , 46 : 770 - 776 ). to the inventors &# 39 ; knowledge , the highly polar features utilized in the present invention have not been previously reported within the published pac - related literature . furthermore , while others have concluded that “ modifications at the 7 - position of pac are detrimental to activity ” ( 5 ), the unexpected and unique attributes of the novel arrangements of the present invention include : ( i ) increased aqueous solubility making the present analogs very amendable to improved clinical formulations ; ( ii ) significantly decreased liability toward mdr - related reductions in potency ; and , ( iii ) the capability to selectively enhance toxicity toward cancer cells versus healthy , rapidly dividing cells by either utilizing certain polar adducts directly linked to pac via the ester arrangements with the present invention and / or by further utilizing the acidic , basic or amino acid containing , appendages of the present invention as connecting linkages to various of such polar or non - polar adducts . fig3 provides examples of the adducts that are readily appended to pac according to the methods of the present invention so as to provide stable ac hybrid derivatives that exhibit all three of the attributes listed above . fig3 also shows the type of pharmacological selectivity that accompanies each adduct along with a reference in that regard , and an arrow indicative of the chemical connection that can be deployed during synthesis based upon the chemical methods of the present invention . the various adducts are either joined to pac directly according to one preferred mdr - lowering substitution pattern along the northern edge , or they are joined to the polar appendages shown in fig2 according to one preferred mdr - lowering substitution pattern . in both cases , an additional linking fragment may also be incorporated as part of the connection . the above detailed description of the present invention is given for explanatory purposes . it will be apparent to those skilled in the art that numerous changes and modifications can be made without departing from the scope of the invention . accordingly , the whole of the foregoing description is to be construed in an illustrative and not a limitative sense , the scope of the invention being defined solely by the appended claims . 1 . erhardt , p . w ., w . a . klis , and j . g . sarver , selective conversion of 2 ′, 7 - 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