WO2013162922A1 - Composés taxane, compositions et procédés - Google Patents

Composés taxane, compositions et procédés Download PDF

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Publication number
WO2013162922A1
WO2013162922A1 PCT/US2013/036392 US2013036392W WO2013162922A1 WO 2013162922 A1 WO2013162922 A1 WO 2013162922A1 US 2013036392 W US2013036392 W US 2013036392W WO 2013162922 A1 WO2013162922 A1 WO 2013162922A1
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Prior art keywords
acid
compound
formula
tesetaxel
compound represented
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PCT/US2013/036392
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English (en)
Inventor
John K. Thottathil
Raymond P. Warrell, Jr.
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Genta Incorporated
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Priority claimed from US13/455,455 external-priority patent/US8697892B2/en
Application filed by Genta Incorporated filed Critical Genta Incorporated
Priority to SG11201406885VA priority Critical patent/SG11201406885VA/en
Publication of WO2013162922A1 publication Critical patent/WO2013162922A1/fr
Priority to IL235312A priority patent/IL235312A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates generally to methods for preparation of taxane derivatives that have antitumor activity and can be orally administered, in particular pentacyclic taxanes .
  • Taxol is a natural substance represented by the following chemical structural formula, which can be obtained in small amounts from the bark or other parts of Taxus brevifolia.
  • taxol has antitumor activity, and its mechanism of action is believed to be based on its ability to inhibit depolymerization of microtubules during cell division. At the time of the discovery of taxol this mechanism of action was different from the conventional antitumor agents, so it became of great interest for its potential clinical application as an antitumor agent.
  • Taxol can be obtained from natural sources, but only in very small amounts.
  • taxol derivatives can now be synthesized using a taxol precursor, 10-O-deacetylbaccatine III ("10-DAB III"), which can be obtained from leaves and other parts of Taxus plants in relatively larger amounts.
  • 10-DAB III 10-O-deacetylbaccatine III
  • docetaxel is marketed by Sanofi under the tradename Taxotere® and has been approved for the treatment of various cancers, including breast cancer.
  • Cremophor EL a polyoxyethylated castor oil
  • polysorbate 80 to solubilize taxanes for intravenous administration.
  • Cremophor EL a polyoxyethylated castor oil
  • tesetaxel having the following structure.
  • one aspect of the present invention is directed to a compound represented by formula (la) and methods for preparing a taxane, including tesetaxel, comprising reacting the compound represented by formula (la)
  • C13 of the compound represented by formula (la) is coupled with a side chain precursor compound represented by f rmula (II)
  • R is an alkoxy group having from 1 to 6 carbon atoms or a halogen atom such as fluorine (F) , bromine (Br), iodine (I) or chlorine (CI) and R 33 is a protected hydroxyl group.
  • the dimethylaminomethyl group of the compound represented by formula (la) is replaced with any of the R4 and R5 substituents disclosed in US Patent No. 6,646,123, discussed above.
  • the dimethylaminomethyl group is replaced with another amino-containing group such as morpholinomethyl .
  • R 33 is triisopropylsilyl , while in others R 33 is methoxy methylethoxy (also referred to as 2- methoxy propyloxy or MOP) .
  • the compound represented by formula (lb) is provided.
  • the compound represented by formula (la) can be derived from the precursor compound represented by formula (lb)
  • the compound represented by formula (la) can be derived from a precursor compound represented by formula (III)
  • formula (III) by converting the terminal olefin (vinyl) group to an aldehyde and reacting the product aldehyde with an amine to form a dimethylaminomethyl group.
  • Yet another aspect of the present invention provides a compound represented by formula (VII) which is useful as an intermediate compound in the synthesis of tesetaxel and other pentacyclic taxanes:
  • Yet another aspect of the present invention provides a method for the preparation of DOH which involves reduction of the C6-C7 double bond of the compound represented by formula (VII) to obtain DOH.
  • Another aspect of the present invention is directed to a compounds represented by formula (XI) which is useful as an intermediate compound in the synthesis of tesetaxel and other pentacyclic taxanes:
  • the compound represented by formula (XI) can be derived from the compound represented by formula (IX) as described herein.
  • Another aspect of the present invention is directed to pharmaceutically acceptable acid addition salts of tesetaxel, including, for example, monobasic, dibasic, tribasic or polybasic acid salts.
  • the salt forms of tesetaxel may comprise only tesetaxel and the acid, or they may be hydrates and/or solvates of the acid addition salt of tesetaxel.
  • These acid addition salts of tesetaxel are represented by the following structural formula:
  • TT is tesetaxel
  • HX is a monobasic, dibasic, tribasic or polybasic acid
  • Sol is an organic solvent
  • n are each independently an integer from about 1 to about 5;
  • y and z are each independently an integer from 0 to about 5.
  • the acid addition salts of tesetaxel may be comprised only of tesetaxel and the acid (i.e., y and z are both 0) or they may be hydrates and/or solvates of the acid addition salt (i.e., y and z are each independently integers from about 1 to about 5, y is 0 and z is an integer from about 1 to about 5, or z is 0 and y is an integer from about 1 to about 5.) .
  • the present invention provides methods of treating cancer using the foregoing acid addition salts of tesetaxel.
  • the acid addition salt is administered to a cancer patient in an amount effective to treat the cancer.
  • Administration may be by any appropriate route, including injection, infusion or oral administration.
  • the compounds and methods employed in the syntheses of the invention provide several advantages and improvements over prior art compounds and methods for synthesis of Pentacyclic taxanes.
  • active taxanes require handling and processing in high containment facilities due to their potency and toxicity.
  • Such specialized handling substantially increases the cost of manufacture.
  • the synthesis methods of the invention decrease the amount of time and handling under high containment conditions by making attachment of the side chain the last key synthetic step of the method.
  • special handling is only required for attachment of the side chain and purification of the final product. This substantially reduces the cost of taxane manufacture.
  • Fig. 1 is an illustration of a reaction scheme for synthesis of a pentacyclic taxane core structure, including alternative steps for synthesis of intermediates.
  • FIG. 2 is an illustration of a general reaction scheme for synthesis of a ⁇ -lactam intermediate for preparation of taxanes .
  • Fig. 3 is an illustration of a specific reaction scheme for synthesis of the compound represented by formula (la) and conversion of formula (la) to tesetaxel.
  • FIG. 4 is an illustration of an alternative specific reaction scheme for synthesis of the compound represented by formula ( la) .
  • Fig. 5 is an illustration of an alternative reaction scheme for coupling the compound represented by formula (la) to the side chain precursor to produce tesetaxel.
  • Fig. 6 is an HPLC analysis of tesetaxel produced according to the methods of the invention.
  • the designation "Me” means methyl
  • the designation “Bz” means benzoyl
  • the designation “Ac” means acetyl
  • the designation “Boc” means t-butoxycarbonyl .
  • the term "derived” or “derivable” in connection with synthesis of a compound from a precursor compound means that the compound can be obtained by chemical synthesis from the identified precursor, either directly in a single step or in a multi-step process starting with the identified precursor compound.
  • One aspect of the present invention is directed to a method for the preparation of tesetaxel.
  • tesetaxel is prepared by coupling the side chain to C13 of a polycyclic taxane core compound before completing synthesis of the tesetaxel fifth ring.
  • the method for synthesis of a taxane compound comprises coupling a taxane side chain precursor compound to the C13 hydroxyl group f the compound represented by formula (la)
  • formula (la) to produce a protected taxane reaction product, deprotecting the protected taxane reaction product, and isolating the taxane compound .
  • a taxane side chain precursor compound represented by formula (II) represented by formula (II) :
  • R 2 is an alkoxy group having from 1-6 carbon atoms or a halogen atom and R 33 is a protected hydroxyl group, is coupled to the C13 hydroxyl of the compound represented by formula (la) .
  • a preferred R 2 substituent is fluorine at the 3-position of pyridine.
  • Compounds represented by formula (II) can be prepared by methods known in the art as well as the inventive methods described herein.
  • R 33 is triisopropylsilyl
  • the compound can be prepared using the method described in Example 13 of U.S. Patent No. 6,677,456 and in US Patent Number 7, 126, 003 B2.
  • Other pentacyclic taxanes according to the invention can be synthesized by reacting a compound having a desired amino- containing group in place of the dimethylaminomethyl group of the compound represented by formula (la) with a compound having a desired pyridine or pyridine derivative in place of the fluoropyridine group of the compound represented by formula (II) .
  • R 2 of formula (II) may be an alkoxy group having from 1 to 6 carbon atoms or an alternative halogen atom such as chlorine.
  • the compound represented by formula (la) can be derived from either the compound represented by formula (III) :
  • the compound represented by formula (la) may be prepared by converting the terminal olefin group of the cyclic acetal of the compound represented by formula (III) or formula (IV) to a diol group, for example using an alkali metal permanganate or osmium tetroxide.
  • the diol is oxidatively cleaved to an aldehyde (e.g., using periodate) and converted to a dimethylaminomethyl group.
  • the cyclic acetal ring of the compounds represented by formulas (III) and (IV) can be formed using the same or similar methodology as described in connection with different intermediate compounds in U.S. Patent No. 6,646,123, hereby incorporated by reference in its entirety.
  • the method includes the use of acrolein dialkyl acetals (such as acrolein dimethyl acetal, acrolein diethyl acetal) with an acid catalyst (for example, camphorsulfonic acid) and, optionally, triethylamine, or with a Lewis acid catalyst (for example, zinc chloride) .
  • the invention provides an alternative method for synthesis of the pentacyclic core of tesetaxel (i.e., the compound represented by formula la) which is more economical and practical than methods of the prior art. It will also be appreciated by one of skill in the art that the synthesis methods of the invention can be adapted to produce the core structures of other pentacyclic taxanes. Included in the reactions of the invention are syntheses for the novel intermediates represented by formula (la), formula (lb), formula (III), formula (VII), formula (IX), formula (X) and formula (XI ) .
  • the method of making a taxane compound according to the invention comprises coupling a taxane side chain precursor compound to the C13-hydroxyl of the compound represented by formula (la) to produce a protected taxane reaction product, deprotecting the protected taxane reaction product, and isolating the taxane compound.
  • a specific example of a reaction scheme for synthesis of the pentacyclic tesetaxel core i.e., the compound represented by formula (la)
  • Fig . 1 A specific example of a reaction scheme for synthesis of the pentacyclic tesetaxel core (i.e., the compound represented by formula (la)) is illustrated in Fig . 1.
  • the compound represented by formula (la) can be synthesized according to Steps 1-7, starting with 10-DAB III.
  • the compound represented by formula (la) is derived from the compound represented by formula (lb), which is derived from the compound represented by formula (VII), which is derived from the compound represented by formula (IX) :
  • Step-1 Formylation of CIO of 10-DAB III. (e.g., using Tf 2 0/DMAP/DMF) ;
  • Step-2 Triflic anhydride reaction of the C7 hydroxyl.
  • Step-3 Formation of a C6-7 double bond and hydrolysis of the CIO formyl ester to produce the compound represented by formula (IX) .
  • a. Base such as Me 2 H/THF, b.
  • Base such as DBU/THF
  • Step-4 Reduction of the C9 ketone to form a diol compound having hydroxyls at C9 and CIO, producing the compound represented by formula (VII). (e.g., hydride reduction such as BH 3 , NaBH 4 or (Bu) 4 NBH 4 );
  • Step-5 Formation of a C9-C10 cyclic acetal attached to a terminal olefin group, producing DHB .
  • acroline acetal and acid catalyst e.g., camphor sulfonic acid, TFA or TSA
  • Lewis acid e.g., anhydrous zinc chloride
  • Step-6 Oxidative cleavage of the terminal olefin group of the cyclic acetal to form an aldehyde, and reductive amination of the aldehyde, producing the compound represented by formula (lb) .
  • Step-7 Hydrogenat ion of the C6-7 double bond to produce the compound represented by formula (la) .
  • a e.g., Rh- A1203/H2, Pd-C/H 2 or Pd-C/HCOONH 4
  • a e.g., Rh- A1203/H2, Pd-C/H 2 or Pd-C/HCOONH 4
  • the reaction proceeds as described above from Steps 1-4.
  • the compound represented by formula (la) is derived from the compound represented by formula (III), which is derived from the compound represented by formula (VII), which is derived from the compound represented by formula (IX) .
  • the synthesis proceeds as follows to produce the compound represented by formula (III) :
  • Step-8 Hydrogenat ion of the C6-7 double bond of the diol compound represented by formula (VII) to produce DOH .
  • DOH e.g., Rh-Al 2 0 3 /H 2 or Pd-C/H 2 or Pd-C/HCOONH 4
  • Rh-Al 2 0 3 /H 2 or Pd-C/H 2 or Pd-C/HCOONH 4 e.g., Rh-Al 2 0 3 /H 2 or Pd-C/H 2 or Pd-C/HCOONH 4
  • Step-9 Formation of a C9-C10 cyclic acetal attached to a terminal olefin group, producing the compound represented by formula (III) .
  • acroline acetal/CSA camphor sulfonic acid
  • other acid catalyst for example, TFA or TSA or Lewis acids such as anhydrous zinc chloride
  • the compound represented by formula III is then converted directly to the compound represented by formula (la) by oxidative cleavage of the terminal olefin group to form an aldehyde and reductive amination of the aldehyde.
  • oxidative cleavage of the terminal olefin group to form an aldehyde and reductive amination of the aldehyde.
  • oxidative cleavage of the diol to aldehyde e.g., periodate, e.g., NaI0 4
  • c conversion of aldehyde to a dimethylaminomethyl group, e.g., Me 2 NH/AcONa/NaBH (OAc) 3
  • Further alternative syntheses provided by the invention for producing the compound represented by formula (la) include alternative methods for deriving the compound represented by formula (IX) (the precursor of the compound represented by formula (VII) from 10-DAB III.
  • 10-DAB III is converted to the compound represented by formula (IX) by formation of a C6-C7 double bond.
  • the double bond may be formed, for example, by reaction of the C7 hydroxyl of 10-DAB III with triflic anhydride (e.g., Tf 2 0/Pyridine/CH 2 Cl 2 ) followed by base such as (DBU) /THF) to form the C6-C7 double bond of the compound represented by formula (IX) .
  • triflic anhydride e.g., Tf 2 0/Pyridine/CH 2 Cl 2
  • base such as (DBU) /THF
  • the reaction then proceeds through Steps 4-7 of Fig. 1 as described above to obtain the compound represented by formula (la) .
  • the reaction steps can proceed through Step 4, Step 8, Step 9 and Step 11 of Fig. 1 as previously described.
  • Fig. 3 an alternative reaction scheme for synthesis of a pentacyclic taxane is illustrated using tesetaxel as an example. This synthesis does not involve the CIO formyl ester intermediate of Fig. 1.
  • the compound represented by formula (la) is derived from the compound represented by formula (III), which is derived from the compound represented by formula (IX) .
  • the compound represented by formula (la) can be synthesized according to Steps 1-8 of Fig. 3, starting with 10-DAB III: Step 1: Reaction of the C7 hydroxyl of 10-DAB III with triflic anhydride. (e.g., Tf 2 0/Pyridine/CH 2 Cl 2 ) ;
  • Step 2 Formation of a C6-7 double bond by base elimination to form the compound represented by formula IX. (e.g. , DBU) ;
  • Step 3 Reduction of the C6-7 double bond by hydrogenation of compound IX to produce the compound represented by formula (XI). (e.g., with Rh-Al 2 0 3 /H 2 or Pd-C/H 2 or Pd- C/HCOONH4) ;
  • Step 4 Reduction of the C9 ketone to produce a diol compound having hydroxyls at C9 and CIO (DOH) . (e.g., using BH 3 , NaBH 4 or (Bu) 4 NBH 4 );
  • Step 5 Formation of a C9-C10 cyclic acetal from the diol DOH to produce the compound represented by formula (III), wherein the cyclic acetal is attached to a terminal olefin group.
  • acroline acetal and acid catalyst e.g., camphor sulfonic acid, TFA or TSA
  • Lewis acid e.g., anhydrous zinc chloride
  • Steps 6-8 can be accomplished in a single operation without any purification of intermediates.
  • Fig. 4 Yet another alternative approach to synthesis of the compound represented by formula (la) is illustrated in Fig. 4. This synthesis also eliminates formation of the CIO formyl ester shown in Fig. 1.
  • the compound represented by formula (la) is derived from the compound represented by formula (lb), which is derived from the compound represented by formula (IV), in a reaction scheme with early formation of the cyclic acetal. This first reaction scheme is shown in Fig. 4 as follows, starting with 10-DAB III:
  • Step 1 Reduction of the C9 ketone of 10-DAB III, producing a triol compound (formula 10) having hydroxyls at C9 and CIO (e.g., using borohydride) ;
  • Step 2 Formation of a C9-C10 cyclic acetal from the triol compound (formula 10), wherein the cyclic acetal is attached to a terminal olefin group.
  • acroline acetal and acid catalyst e.g., camphor sulfonic acid, TFA or TSA
  • Lewis acid e.g., anhydrous zinc chloride
  • Step 3 Triflic anhydride reaction of the C7 hydroxyl (e.g., Tf 2 0/Pyridine/CH 2 Cl2 ) , followed by base elimination to form a C6-C7 double bond, producing the compound represented by formula (IV);
  • Step 4 Oxidatively cleaving the terminal olefin group of the cyclic acetal to an aldehyde, and reductively aminating the aldehyde to produce the compound represented by formula (lb) .
  • These reactions can be accomplished in a single operation without purification of any intermediates to produce the compound represented by formula (lb);
  • Step 5 Hydrogenation of the C6-C7 double bond of the compound represented by formula (lb) to produce the compound represented by formula (la).
  • the compound represented by formula (la) e.g., Rh-Al 2 0 3 /H 2 or Pd-C/H 2 or Pd-C/HCOONH 4 .
  • the compound represented by formula (IV) is derived from the compound represented by formula (VII), which is derived from the compound represented by formula (X) . That is, as further illustrated in Fig. 4, the triol compound 10 obtained by reduction of the C9 ketone in Step 1 may be further reacted as follows:
  • Step 6 Triflic anhydride reaction of the C7 hydroxyl of the triol compound 10 to produce the compound represented by formula (X). (e.g., Tf 2 0/Pyridine/CH 2 Cl2 ) ;
  • Step 7 Base elimination to form a C6-C7 double bond in the compound represented by formula (X) , producing the compound represented by formula (VII);
  • Step 8 Formation of a C9-C10 cyclic acetal attached to a terminal olefin group, producing the compound represented by formula (IV) .
  • acroline acetal and acid catalyst e.g., camphor sulfonic acid, TFA or TSA
  • Lewis acid e.g., anhydrous zinc chloride
  • the compound represented by formula (la), produced by any of the foregoing methods, can then be coupled at the C13 hydroxyl position to a taxane side chain precursor compound using any appropriate method known in the art.
  • a side chain precursor compound according to formula (II) can be coupled to the compound represented by formula (la) to produce a variety of pentacyclic taxane final products
  • FIG. 3 A specific example of such coupling using a ⁇ -lactam side chain precursor to obtain tesetaxel is illustrated in Fig. 3, wherein a protected ⁇ -lactam precursor (+)-THA is converted to ( + )-TBA) (Step 9), coupled to the C13 hydroxyl group of the pentacyclic taxane core compound represented by formula (la) using a hindered soluble alkaline metal base, e.g., LHMDS (Step) 10, and the protecting group of the side chain of the coupled product is deprotected (Step 11) using e.g., TBAF .
  • a hindered soluble alkaline metal base e.g., LHMDS
  • the ⁇ -lactam precursor TBA 1- ( tert-butoxycarbonyl ) -4- ( 3-fluoro-2- pyridyl ) -3-triisopropylsilyloxy-2-azetidinone ) , is disclosed in US Patent 7, 126, 003 B2 and in the US Patent 6, 677, 456 ( Soga) .
  • the side chain precursor may be a functional straight chain equivalent of the ⁇ -lactam such as TBBE ( S- ( 4-Bromophenyl ) ( 2R, 3 S ) -3- [ ( tert-butoxycarbonyl ) amino ] - 3- (3-fluoro-2-pyridinyl) -2- [ ( triisopropylsilyl )
  • TBBE S- ( 4-Bromophenyl ) ( 2R, 3 S ) -3- [ ( tert-butoxycarbonyl ) amino ] - 3- (3-fluoro-2-pyridinyl) -2- [ ( triisopropylsilyl )
  • the invention provides a method for synthesis of the ⁇ -lactam side chain precursor for use in taxane synthesis which employs methoxy methylethoxy (MOP, or methoxydimethyl propyloxy) or other acetal groups for protection of the 3-OH of the ⁇ -lactam side chain precursor as disclosed in US Patent 6, 310, 201 ( Thottathil ) , which is incorporated by reference herein.
  • MOP methoxy methylethoxy
  • acetal groups for protection of the 3-OH of the ⁇ -lactam side chain precursor as disclosed in US Patent 6, 310, 201 ( Thottathil ) , which is incorporated by reference herein.
  • taxane side chain precursor compounds represented by formula (V) and formula (VI) :
  • the invention provides an alternative synthesis that avoids the use of CAN while producing a crystalline solid ⁇ -lactam side chain precursor for linkage to C13 of the taxane polycyclic core structure.
  • the synthesis is performed according to the general reaction scheme illustrated in Fig. 2, wherein Py is pyridine or substituted pyridine; Ac is acetyl; Me is methyl; MOP is 2-methoxypropyl ; and BOC is tert-butoxycarbonyl.
  • Py is pyridine or substituted pyridine
  • Ac is acetyl
  • Me is methyl
  • MOP 2-methoxypropyl
  • BOC is tert-butoxycarbonyl.
  • Py is a halo-substituted pyridine, such as fluoropyridine, or a methoxy-substituted pyridine.
  • Py is 3-fluoropyridine .
  • compound 18 of the above reaction scheme is the compound represented by formula (VI) and compound 17 is the compound represented by formula (V) .
  • Py is also intended to encompass aromatic substituents and other suitable heteroaromatic moieties.
  • the invention also provides a compound represented by formula (VIII) which is a novel intermediate in the reaction scheme of Fig. 2 for synthesis of the compounds represented by formula (V) and formula (VI) .
  • Compound 20 is treated with lipase, pen-amidase or esterase and the desired enantiomer is recovered by recrystallization .
  • Base hydrolysis of Compound 20a removes the acetyl to produce the 3-OH (Compound 21), which is then protected by addition of methoxypropene and pyridinium p- toluene sulfonate (PPTS), generally as described in US Patent 6,130,201, resulting in Compound 17.
  • PPTS pyridinium p- toluene sulfonate
  • compound 17 is prepared by addition of methoxypropene/CSA or 2,2- dimethoxypropane/CSA .
  • BOC is added to Compound 17 by addition of (BOC) 2 0/DMAP to form the final product Compound 18.
  • the aldehyde starting compound is a derivative of 3-fluoropyridine and the reaction scheme is as illustrated in Fig. 2.
  • the 2-aldehyde of FFP (3-fluoropyridine) is reacted with ammonia (Step 1) .
  • Step 1 Subsequent steps to prepare the compound represented by formula (VI) are as described above.
  • the compound represented by formula (V) is prepared using methoxypropene/CSA or 2,2- dimethoxypropane/CSA and the BOC group is added using (BOC 2 ) O/DMAP.
  • the compound represented by formula (VI) is coupled to the C13 hydroxyl of the compound represented by formula (la) to produce protected tesetaxel or another related pentacyclic taxane compound.
  • the side chain linking reaction is preferably accomplished using a hindered soluble alkaline metal base such as lithium hexamethyl disilazide (LHMDS), which has been described in US Patent Publication 2002/0091274 (Holton) , US Patent 6,794,523 (Holton) and US Patent 6,350,887 (Thottathil) for linkage of side chains to the C13 hydroxyl of 7-protected taxanes.
  • LHMDS lithium hexamethyl disilazide
  • other metallic bases may also be used for coupling of taxane side chains as disclosed in US Patent 6,350,887.
  • attachment of the of the ⁇ -lactam intermediate represented by formula (VI) to the 13-position of the pentacyclic taxane intermediate represented by formula (la) can be performed as described in Example 6 in U.S. Patent No. 6 , 6 77 , 456 .
  • HTX refers to the intermediate compound in which the 2 ' hydroxyl is protected by R and R is as indicated in the reaction scheme above.
  • the compound represented by formula (la) is first reacted with LHMDS or another suitable alkaline metal base in a solvent such as tetrahydrofuran (THF) as taught in Examples 7 and 9 of U.S. Patent No. 6 , 6 77 , 456 .
  • THF tetrahydrofuran
  • the 2 ' -OH of HTX is deprotected by treatment with mild acid or TBAF (tetrabutylammonium fluoride) generally as taught in Examples 7 and 9 in U.S. Patent No. 6 , 6 77 , 456 .
  • TBAF tetrabutylammonium fluoride
  • the tesetaxel final product is purified and, optionally, crystallized to obtain the desired polymorph.
  • the ⁇ -lactam intermediate represented by formula (VI) can be converted to the functional equivalent TBBE as described below with respect to Fig. 5 , and coupled to the taxane core compound represented by formula (la) .
  • TBA is synthesized by conversion of 4 - ( 3-fluoro-2 - pyridyl ) -3-triisopropylsilyloxy-2-azetidinone (THA) to TBA by reaction with a butoxycarbonyl group.
  • THA triisopropylsilylether
  • TIPS triisopropylsilylether
  • TBBE can be derived from TBA by thio-esterification of TBA (the compound represented by formula (II)) with a thiol compound such as 4-bromothiophenol or 4-bromobenzenethiol in the presence of a base. This process is described in US Patent 7, 678, 919 (Imura) . TBBE is then coupled to C13 hydroxyl group of the pentacyclic taxane core compound (e.g., the compound represented by formula (la)) in an inert solvent in the presence of base to produce a taxane with a hydroxyl-protected side chain.
  • a thiol compound such as 4-bromothiophenol or 4-bromobenzenethiol
  • Coupling may be mediated by either bases such as sodium hydride or by soluble hindered bases such as LHMDS, and is preferably carried out in an inert gas atmosphere, such as nitrogen or argon.
  • bases such as sodium hydride or by soluble hindered bases such as LHMDS
  • the coupled, protected product (9 in Fig. 3 and Fig. 5) is isolated and purified, and the side chain is deprotected to produce the final taxane compound.
  • the final product may optionally be crystallized to obtain the desired polymorph .
  • steps may be taken to control and minimize hydrolysis of the BOC group of HTX by the acid deprotection reaction. For example, reducing the reaction temperature, shortening the reaction time and varying the reaction conditions may be employed to minimize hydrolysis of the BOC group if necessary. Alternatively, in the event of an undesirable amount of BOC hydrolysis the BOC group may simply be re-added by reaction of HTX with B0C 2 O in DMAP as described above .
  • the compound represented by formula (II) or formula (VI) can be coupled to the C13 hydroxyl of any of the compounds represented by formula (lb), formula (III) or formula (IV) using an alkaline metal base as described above to produce alternative intermediates in the tesetaxel synthesis schemes described above.
  • the coupled, protected product is then deprotected and purified as described above.
  • Coupling the side chain precursor to the alternative intermediates (represented by formula (III), formula (IV) and formula (lb)) means that the side chain is added to the taxane core structure before completion of the tesetaxel core.
  • the final tesetaxel product may also be converted to various pharmaceutically acceptable salt forms using methods well known in the art. These salt forms will provide a variety of useful physico-chemical and pharmacological properties to tesetaxel which will be useful in different medical applications.
  • acid addition salts of tesetaxel may be prepared through dissolution thereof in an appropriate solvent in the presence of an appropriate acid prior to purification and/or crystallization.
  • the salt forms of tesetaxel may comprise only tesetaxel and the acid, or they may be hydrates and/or solvates of the acid addition salt of tesetaxel. These acid addition salts of tesetaxel are represented by the following structural formula:
  • TT is tesetaxel
  • HX is a monobasic, dibasic, tribasic or polybasic acid
  • Sol is an organic solvent
  • n are each independently an integer from about 1 to about 5;
  • y and z are each independently an integer from 0 to about 5.
  • the salt forms of tesetaxel which are not hydrates and/or solvates may have the general structure (TT) m .(HX) n wherein TT is tesetaxel, HX is an acid, and m and n are each independently an integer from about 1 to about 5. That is, in these compounds both y and z of the compound represented by formula (XII) are 0.
  • the salts of tesetaxel and a monobasic acid may be represented by formula (XII), wherein both m and n are 1, or wherein m is 1 and n is 2. These compounds may also be designated TT.HX or TT.2HX, respectively.
  • the useful monobasic acids for forming salts of tesetaxel having these structures include HC1 (hydrochloric acid) , HBr (hydrobromic acid) , HI (hydroiodic acid) , HNO 3 (nitric acid) , HOAc (acetic acid) , benzoic acid, toluic acid (ortho, meta, para) , lactic acid (both D and L) , MSA (methane sulphonic acid) , BSA (benzene sulphonic acid) , esylate (ethane sulphonic acid) , sulfuric acid, CSA (camphor sulphonic acid) , TSA (toluene sulphonic acid ortho, meta, para), ( S ) - ( + ) -mandelic acid, (R) - ( - ) -mandelic acid, gentisic acid, hippuric acid, glycolic acid 2-hydroxyethanesulfonic acid, 2-naphthal
  • the salts of tesetaxel and a dibasic acid may be represented by structural formula (XII), wherein m and n are both 1, or wherein m is 2 and n is 1. These compounds may also be designated TT.HX or 2TT.HX, respectively.
  • the useful dibasic acids for forming salts of tesetaxel having the TT.HX or 2TT.HX structure include malic acid, maleic acid, fumaric acid, oxalic acid, succinic acid , tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid (1,2; 1,3; 1,4; both cis and trans), phthalic acid (1,2; 1,3; and 1,4,), edisylate ( 1 , 2-ethanedisulfonate ) , phenyl phosphonic acid, digluconic acid, natural di-basic amino acids, and other pharmaceutically acceptable acids.
  • the salts of tesetaxel and a dibasic acid may be represented by structural formula (XII), wherein m is 1 and n is 2. These compounds may also be designated TT.2HX.
  • Useful dibasic acids for forming salts of tesetaxel having the TT.2HX structure include malic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid (1,2; 1,3; 1,4; both cis and trans), phthalic acid (1,2; 1,3; and 1,4, edisylate (1,2 ethanedisulfonate ) , phenyl phosphonic acid, digluconic acid, natural dibasic amino acids, and other pharmaceutically acceptable dibasic acids.
  • the salts of tesetaxel and tribasic or polybasic acids may be represented by structural formula (XII), wherein m and n are each independently an integer from about 1 to about 5.
  • Useful tribasic and polybasic acids for forming salts of tesetaxel include citric acid, phosphoric acid, and other pharmaceutically acceptable tribasic and polybasic acids.
  • the salts of tesetaxel and a monobasic, dibasic, tribasic or polybasic acid can also exist as a hydrate or solvate, or a combination of hydrate and solvate, which may be designated generally as ( TT ) m . (HX) n . (H 2 0) y .
  • hydrates and solvates of salts of tesetaxel and a monobasic acid may have the structure (TT) . (HX) . (H 2 0) y . (Sol) z (i.e., m and n are both 1) or (TT) .2 (HX) . (H 2 0) y . (Sol) z (i.e., m is 1 and n is 2).
  • the compounds may have the structure (TT) . (HX) . (H 2 0) y .
  • Hydrates and solvates of salts of tesetaxel and tribasic or polybasic acids are more variable in structure, but typically will be represented by formula (XII) wherein wherein m and n are each independently an integer from about 1 to about 5, and; y and z are each independently integers from about 1 to about 5, y is 0 and z is an integer from about 1 to about 5, or z is 0 and y is an integer from about 1 to about 5.
  • Appropriate organic solvents for formation of the solvate include acetone, methanol, ethanol, propanol, butanol, acetonitrile, tetrahydrofuran, isopropyl alcohol, toluene, N,N- dimethylformamide, and other pharmaceutically acceptable solvents.
  • the foregoing acid addition salts of tesetaxel may be used in methods for treating cancer.
  • the acid addition salt is administered to a cancer patient (human or other mammal) in an amount effective to treat the cancer.
  • Administration may be by any appropriate route, including parenteral administration, intra-cavitary administration, oral administration, injection, or infusion. Dosing is typically at or near the maximum tolerated dose in order to increase the response rate.
  • the acid addition salt of tesetaxel will typically be formulated as a pharmaceutical preparation by addition of appropriate pharmaceutically acceptable excipients, which may include solubilizers, stabilizers, and the like.
  • the form of the pharmaceutical preparation is considered in the choice of excipients.
  • the pharmaceutical preparation may be in the form of a powder, tablet, solution, emulsion or capsule designed for the desired route of administration.
  • Specific examples of such pharmaceutical preparations include formulations for oral administration, extended release, parenteral administration and intra-cavitary administration.
  • the monobasic, dibasic, tribasic or polybasic acid selected for crystallization is added to the reaction mixture for linking the taxane side chain precursor to the compound represented by formula (la), followed by deprotection of the 2'-0 group.
  • the final acid salt product is then subsequently purified and crystallized from the crude reaction mixture as illustrated in the following reaction scheme:
  • the monobasic, dibasic, tribasic or polybasic acid selected for crystallization is added to a solution of purified and isolated tesetaxel, and the acid salt form is crystallized from the mixture.
  • the acid for crystallization may be in solution in a suitable solvent which is added to the purified and isolated tesetaxel (also dissolved in a solvent) followed by crystallization of the salt form. This process is illustrated in the following reaction scheme:
  • Tesetaxel The TBAF method.
  • the crude tesetaxel at this point can be purified either by chromatography or by crystallization or by a combination of chromatography and crystallization.
  • the yield was 535 mg with HPLC purity of 95%.
  • Example 7 Preparation of TBBE [0092] Crude TBA and 1.1 equivalent of 4-BTP (4-bromomo- thiophenol) were dissolved in 13 v/w of IPE (isopropyl ether), 0.3 equivalent of potassium carbonate was added, and the mixture was stirred at room temperature for 0.5 to 3 hours. Completion of the reaction was checked by HPLC.
  • IPE isopropyl ether
  • HPLC chemical purity was 67%. The yield was 95%. MS MW 525. HPLC Retention time (RT) 10.7 minutes.
  • HPLC chemical purity was 77%. The yield was 90%. MS MW 531. HPLC retention time (RT) 10.0 minutes.
  • the mixture was chilled to between 10°C and 0°C and stirred for from 1 to 3 hours while maintaining the temperature.
  • the precipitate was obtained by filtration using a 60 cm Nutsche filter.
  • the precipitate was washed with 15 L of IPE.
  • the precipitate was then dissolved in 74 L of AcOEt .
  • the organic layer was washed with 37 L of water followed by 18 L of water (twice) .
  • 9 L of 4% NaHCC>3 and 9 L of saturated NaCl solution were mixed and used to wash the organic layer.
  • the organic layer was then dried with 2 kg of MgSC>4. It was filtered and the residue was washed with 18 L of AcOEt.
  • the organic layer was washed with a mixture of 3 v/w of a 10% aqueous citric acid solution and 3 v/w of saturated saline, followed by a wash with a mixture of 5 v/w of 4% sodium bicarbonate solution and 3 v/w of saturated saline.
  • the washed organic layer was then concentrated under reduced pressure at 50°C or less to obtain the diol intermediate as a residue.
  • the diol intermediate residue was dissolved in 7 v/w of acetonitrile, 0.15 w/w of activated carbon was added, and the mixture was stirred at 15 to 50°C for 0.5 to 2 hours. Insoluble substances were removed, followed by addition of 3 volumes of acetonitrile and 1 v/w of pyridine, and then 3.3 v/w of tap water in which 0.426 w/w of sodium periodate was dissolved. The reaction was allowed to proceed at 15 to 50°C for 2 hours or more. Completion of the reaction was checked by HPLC.
  • the reaction was quenched by adding 7 v/w of a 15% aqueous potassium hydrogen carbonate solution and 3 v/w of saturated saline.
  • the organic layer was separated and washed with 5 v/w of tap water and with 3 v/w of saturated saline, and dried with an appropriate amount of magnesium sulfate.
  • Insoluble substances were removed by filtration and the residue was washed with 3 v/w of ethyl acetate.
  • the filtrate was then concentrated under reduced pressure at 50°C or less to obtain compound (la) as the residue.
  • the residue was further purified by chromatography and/or crystallization.
  • the organic layer was washed with a mixture of 3 v/w of a 10% aqueous citric acid solution and 3 v/w of saturated saline, followed by a wash with a mixture of 5 v/w of 4% sodium bicarbonate solution and 3 v/w of saturated saline.
  • the product was concentrated under reduced pressure at 50°C or less to obtain the diol intermediate as a residue.
  • the diol intermediate residue was dissolved in 7 v/w of acetonitrile, 0.15 w/w of activated carbon was added, and the mixture was stirred at 15 to 50°C for 0.5 to 2 hours. Insoluble substances were removed, then 3 volumes of acetonitrile and 1 v/w of pyridine were added, followed by addition of 3.3 v/w of tap water in which 0.426 w/w of sodium periodate (compared to the amount of acetal) was dissolved. The reaction was allowed to proceed at 15 to 50°C for 2 hours or more. Completion of the reaction was checked by HPLC.
  • the reaction product was then concentrated under reduced pressure at 50°C or less.
  • 15 v/w of ethyl acetate, 7 v/w of 4% sodium hydrogen carbonate and 3 v/w of saturate saline were added.
  • the organic layer was separated and washed with 7 v/w of saturated saline, then dried over an appropriate amount of magnesium sulfate.
  • Insoluble substances were removed and washed with 3 v/w of ethyl acetate.
  • the reaction product was then concentrated under reduced pressure at 50°C or less. Further purification by chromatography and/or crystallization gave compound (la).
  • the combined organic layer was first washed with 20 L of water and with 20 L of 5% aqueous NaCl solution (twice) , followed by washing with 20 L of 4% NaHC0 3 . 10 L of 4% NaHC0 3 and 10 L of saturated NaCl solution were mixed, and the organic layer was washed with this solution. After washing, 2 kg of MgS0 4 , 6.0 kg of SiC>2 (florisil), and 4.0 kg of alumina were added to the organic layer. After drying and de-coloring, the organic layer was recovered by filtration. The precipitate was washed with 20 L of CPME. Combined organic layer was evaporated under controlled temperatures between 20 °C and 40 °C.
  • the obtained residue was dissolved in 8.0 L of chloroform and heated to a maximum temperature of 55°C. If the residue did not dissolve completely, several additional amounts of chloroform were added (up to 5 v/v volume) . After slowly chilling to between 30°C to 20°C, 16 L of IPE and 16 L of n-hexane were added. After 1 hour stirring at a temperature between 20°C and 30°C the precipitate was recovered by filtration with a 60 cm Nutsche(SUS) filter. The precipitate was washed with 6 L of IPE/hexane (1:1) solution. After drying with a vacuum drier at temperatures controlled between 20°C to 40°C for from 3 hours to 72 hours, crystalline compound VII was obtained. (Standard 1.56 kg (Yield 80.0%), Theoretical 1.95 kg, Specification; not less than 95% by HPLC) .
  • Example 23 Conversion of compound intermediate VII to intermediate IV [00134] 15 L of ethyl acetate, 1.8 kg of alcohol compound VII, 0.23 kg of triethylamine HCl salt (TEA. HCl), and 1.3 kg of acrolein diethyl acetal (ADA) was added to the reactor. 7 g of camphorsulfonic acid(CSA) was dissolved in 1 L of AcOEt, and the solution was added to the reaction mixture, maintaining the temperature between 15°C and 25°C for several hours (from 4 hours to 28 hours) . The reaction mixture was checked by HPLC for completion. Upon completion, 15 L of isopropyl ether (IPE) and 15 L of n-hexane was added.
  • IPE isopropyl ether
  • the mixture was chilled to between 10°C and 0°C, and stirred for from 1 to 3 hours while maintaining the temperature. After stirring, the precipitate was obtained by filtration using a 60 cm Nutsche filter.
  • the precipitate (crude acetal wet) was washed with 15 L of IPE and dissolved in 30 L of AcOEt .
  • the organic layer was washed with 15 L of water, and twice with 9 L of water.
  • 5 L of 4% NaHCC>3 and 5 L of saturated NaCl solution were mixed and used to wash the organic layer.
  • the organic layer was then dried with 1 kg of MgS0 4 . It was filtered and the residue was washed 9 liter of AcOEt.

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Abstract

La présente invention concerne un procédé de préparation de composés pentacycliques taxane disponibles pour une administration par voie orale, ainsi que des intermédiaires utiles dans leur préparation.
PCT/US2013/036392 2012-04-25 2013-04-12 Composés taxane, compositions et procédés WO2013162922A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013530234A (ja) * 2010-06-30 2013-07-25 ジェンタ インコーポレイテッド テセタキセルおよび関連化合物ならびに対応する合成中間体の調製

Citations (3)

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US6858644B2 (en) * 2001-11-30 2005-02-22 Bristol-Myers Squibb Co. Paclitaxel solvates
US7678919B2 (en) * 2004-04-30 2010-03-16 Daiichi Pharmaceutical Co., Ltd. Method for producing pentacyclic taxans
WO2012003199A1 (fr) * 2010-06-30 2012-01-05 Genta Incorporated Synthèse du tésétaxel et de composés apparentés et intermédiaire de synthèse correspondant

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US6858644B2 (en) * 2001-11-30 2005-02-22 Bristol-Myers Squibb Co. Paclitaxel solvates
US7678919B2 (en) * 2004-04-30 2010-03-16 Daiichi Pharmaceutical Co., Ltd. Method for producing pentacyclic taxans
WO2012003199A1 (fr) * 2010-06-30 2012-01-05 Genta Incorporated Synthèse du tésétaxel et de composés apparentés et intermédiaire de synthèse correspondant

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013530234A (ja) * 2010-06-30 2013-07-25 ジェンタ インコーポレイテッド テセタキセルおよび関連化合物ならびに対応する合成中間体の調製
US9434740B2 (en) 2010-06-30 2016-09-06 Odonate Therapeutics, Llc Taxane compounds, compositions and methods

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