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`
`with
`
`and the carbons
`
`to which they
`
`and the carbons to which they are
`
`SCHaOMe); or R7 together with R5 or R6 and the carbons to which they are attached,
`form an optionally substituted ring (e.g.,
`a cyclopropyl ring);
`R7a H or OH;
`a mesylate, or halo); or R8 taken together
`R8 is OH or a leaving group (e.g.,
`ring;
`
`R9a and the carbons to which they are attached form a
`R9a is an activated alkyl (e.g.CH2l);
`taken together with R8
`or R9a
`
`
`
`to which they are attached form a ring; or R9a, together with R9b and carbon the to which
`it is attached, forms a ring (forming a spirocyclic ring);
`R9b is OH, 0C(0)alkyl (e.g., Oacyl), 0C(0)0alkyl (e.g., OC(O)OMe), or
`OC(0)cycloalkyl; or R9b, taken together with R1
`and the carbons to which they
`are
`attached, form a ring; or R9b, together with R9a
`and the carbon to which it is attached,
`forms a ring (forming a spirocyclic ring);
`substituted for example
`R10 is OH, 0C(0)aryl (e.g., wherein aryl is optionally
`
`with halo, alkoxy, or N3) or 0C(0)alkyl; or R10
`taken together with R1
`or R11 and the
`carbons to which
`they are attached, forms a ring;
`R11 H or OH; or R11 taken together with R10 or R12 and the carbons
`are attached, forms a ring;
`R12 is H, or OH; or R12 taken together with R11
`attached, forms a ring;
`each Rla is independently halo (e.g., fluro), alkyl (e.g., methyl)
`each R2a and R2b is independently H, C(0)aryl (e.g, C(O)phenyl), C(0)alkyl (e.g.,
`acyl), C(0)H, C(0)0alkyl; wherein C(0)aryl (e.g, C(O)phenyl), C(0)alkyl
`(e.g., acyl),
`
`and C(0)0alkyl is each optionally further substituted, for example, with a substituent
`descdribed in Rla; and
`R2c is H or C(0)NHalkyl.
`example with
`is phenyl (e.g., optionally substituted for
`In some embodiments, R1
`halo such as fluoro).
`In some embodiments, R1
`is heteroaryl, for example, furanyl,
`thiophenyl, or pyridyl (e.g., an optionally substituted pyridyl).
`isobutyl or tert-butyl.
`In some embodiments, R1 is alkyl, e.g., butyl such as
`In some embodiments, R1
`is heterocyclcoalkyl (e.g., epoxyl optionally substituted,
`for example, with one or more alkyl
`groups such as methyl).
`
`as
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`In some embodiments, R1, taken together with R3b
`
`and the carbons to which they
`
`R2
`
`and the carbons to which they
`
`•3a R ).
`
`are attached form a bicyclic ring system (e.g.,
`In some embodiments, R1,
`taken together with R10 and the carbons to which they
`are attached, form a ring, e.g., a mono- or bi-cyclic ring system).
`In some embodiments, R1, taken together with R9b
`are attached, form a ring, e.g., a mono- or bi-cyclic ring system).
`is NR2aR2b. In some embodiments, at least one of R2a
`In some embodiments, R2
`
`or R2b is H. In some embodiments, R2a
`is H and R2b
`is C(0)aryl (e.g, C(O)phenyl),
`C(0)alkyl (e.g., acyl), C(0)H, or C(0)0alkyl.
`In some embodiments, R2
`is NHC(0)aryl
`or NHC(0)Oalkyl.
`is Opolymer. In
`In some embodiments, R3a is OH. In some embodiments, R3a
`some embodiments, polymer is polyglutamic acid.
`In some embodiments, R3a
`is
`0C(0)C2ialkenyl.
`In some embodiments, one of R3a or R3b is H and the other of R3a
`or R3b is OH.
`is OH. In some
`In some embodiments, R4 is OAcyl. In some embodiments, R4
`embodiments, R4 is methoxy. In some embodiments, R4
`together with R5 and the carbons
`
`
`
`^ In some embodiments, R4, together with the
`
`I X O O
`
`>-<
`
`to which they are attached forms ^
`
`carbon to which it is attached,
`forms
`carbon to which it is attached, forms an oxo.
`
`. In some embodiments, R4, together with the
`In some embodiments, R4 is
`
`CL
`
`heterocycloalkylalkyl (e.g..
`
`k- N 1
`
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`In some embodiments, R5, together with the carbon to which it is attached, forms
`
`
`an oxo. In some embodiments, R
`together with R
`and the carbons to which they are
`5
`7
`
`O
`N—JSIH
`6 O
`x^orV$-f
`attached forms
`In some embodiments, R6 is methyl. In some embodiments, R6
`
`
`and the carbons to which they are attached form a ring (e.g., cyclopropyl).
`In some embodiments, R is OH. In some embodiments, R
`7
`embodiments, when R7 is H, R7a is OH.
`is OH.
`In some embodiments, R7a is H. In some embodiments, R7a
`together with R 9a and the carbons to which they are
`In some embobodiments, R8
`
`is H. In some
`7 •
`
`together with R7
`
`/wv
`
`is H, alkyl.
`, wherein X is O, S, Se, or NR8a (e.g., O), wherein R8a
`attached form
`arylalkyl (e.g., benzyl), C(0)alkyl, or C(0)H.In some embobodiments, R8
`together with
`R9a and the carbons to which they
`are attached form a cyclopropyl ring.
`In some embodiments, R9b
`is OAc.
`In some embodiments, R10
`is 0C(0)phenyL In some embodiments, R10
`
`taken
`O
`O^o
`forms a ring such as ^
`
`or
`
`^
`
`together with R11 and the carbon to which it is attached,
`Ph
`
`X X"
`
`In some embodiments, R11
`
`is OH. In some embodiments, R11
`
`taken
`O
`oA,
`0-f,
`forms a ring such as ^ ^ or
`
`together with R12 and the carbon to which it is attached,
`OEt
`o^o
`
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`
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`is H.
`In some embodiments, R
`12
`In some embodiments, the variables defined above are chosen so as
`
`docetaxel, paclitaxel, larotaxel, or cabazitaxel or a structural analogue therof.
`In some embodiments, the taxane is a compound of formula (Xa)
`R
`
`O
`
`p7
`
`to form
`
`R2
`
`O
`
`1 R
`
`RSa
`
`s H
`•=:
`p9b
`%
`R10 R
`
`11 R
`
`8 R
`
`R9a
`
`formula (Xa).
`
`In some embodiments, the taxane is a compound of formula (Xb)
`
`R4
`
`/
`
`R7
`
`56
`
`\^V
`
`X
`
`i
`2- H
`%
`5-
`R9b
`Ri1 R10 R
`
`R2
`
`O
`
`1 R
`
`R3a
`
`formula (Xb).
`In some embodiments, the compound is a compound of formula Xc
`
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`
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`
`R4
`
`R7
`
`/ E6
`
`R2
`
`O
`
`HO
`
`\\^V
`
`•O^
`
`P
`
`AcO
`OH 0C(0)Ph
`
`(Xc).
`In some embodiments, R2 is NHC(0)aryl or NHC(0)Oalkyl.
`In some embodiments, R4 is OH or OAc.
`In some embodiments, R6 is methyl.
`In some embodiments, R is OH or OMe.
`7
`In some embodiments, R6 and R7, together with the carbons to which they are
`attached, form a ring.
`In some embodiments, the variables defined above are chosen so as
`
`docetaxel, paclitaxel, larotaxel, or cabazitaxel or a structural analogue therof.
`
`In one embodiment, the taxane is a compound of formula (XI)
`
`to form
`
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`
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`R4
`
`R5
`R6
`
`R7
`
`X
`
`R12
`
`i H
`c;
`5-
`R9b
`R10 R
`
`11 R
`
`R'
`
`R9a
`
`formula (XI)
`
`a
`
`double
`
`bond
`
`with the carbon
`
`wherein
`forming
`(i.e., when
`X is OH, oxo
`
`attached), alkoxy,
`0C(0)alkyl
`(e.g., Oacyl), or OPg;
`(e.g.,
`R is OH, alkoxy
`(e.g., methoxy),
`0C(0)alkyl
`to which
`OPg, heterocycloalkylalkyl;
`or
`
`together R4 with R5 and the carbons
`
`or
`attached, form
`an
`optionally
`substituted
`ring;
`spirocyclic
`a
`is attached, forms
`a
`ring
`(forming
`
`OPg; or together with R4 and the
`
`R5 is OH, 0C(0)alkyl
`(e.g.,
`Oacyl),
`substituted
`carbons to which
`
`they are attached,
`form
`an
`optionally
`with the carbon
`to which
`it
`attached,
`forms
`R6 is alkyl (e.g., methyl);
`methoxy),
`R7 is H, OH, alkoxy
`(e.g.,
`OTroc), or OC(0)alkenyl
`(wherein
`alkenyl
`y
`(e.g., OC(O)CHCHnapthyl),
`
`
`R or , together with
`the carbon
`an oxo;
`OC(0)arylalkyl
`substituted
`R8 is OH, optionally
`0C(0)CH2CH2phenyl),
`or
`0C(0)(CH2)i_3aryl
`(e.g.,
`halo); or R8
`
`taken together with R9a and the carbons
`to which
`ring;
`
`they
`R4,
`ring)
`or
`
`ring;
`an
`
`0C(0)alkyl
`is
`to
`
`(e.g.,
`substituted,
`
`which attached, forms it
`
`
`Oacyl),
`are
`
`together
`or
`
`R5
`
`or
`oxo;
`
`OAc); OPg
`e.g.,
`
`is
`
`is
`
`(e.g.,
`a
`
`they
`
`or
`are
`
`OC(O)CHCHphenyl),
`leaving
`attached
`
`R9a is an activated alkyl
`to which they are
`attached
`
`(e.g.CH2l);
`form
`
`or taken together with R8 R9a and the carbons
`
`
`
`a
`ring;
`
`or and the carbon
`R9a, to which
`
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`
`R9a taken together with R9b and
`
`0C(0)0alkyl
`R9a
`
`with
`
`ring); and the
`
`or
`
`optionally
`with
`R11
`
`is
`
`together the carbons
`
`it is attached,
`
`a (forming a spirocyclic ring)or ring
`
`
`forms
`
`
`are they attached form
`
`an
`alylenyl;
`the carbon
`to which
`R9b is OH, alkoxy,
`0C(0)alkyl
`(e.g.,
`OC(0)cycloalkyl,
`or
`OPg;
`or
`a
`attached, forms
`ring
`(forming
`carbon to which they are attached
`form
`R10 is OH, 0C(0)aryl
`(e.g.,
`with halo, alkoxy,
`or
`or 0C(0)alkyl;
`or
`N3)
`to which they are
`attached,
`forms
`R11 H, OH; or R11
`taken
`together
`are attached,
`forms
`a
`ring;
`12 R
`substituted
`is
`alkyl
`wherein
`is H, OH, or 0C(0)alkyl,
`11
`attached,
`are
`they
`to which
`
`taken together with R and the carbons
`
`
`Pg is a protecting
`
`
`a for group heteroatom such
`
`or as O (e.g., Bn, Bz, TES, N
`TMS,
`DMS, Troc, or Ac);
`and
`
`Oacyl),
`together
`spirocyclic
`alylenyl;
`wherein
`R10
`a
`
`
`R9b,
`a
`an
`
`aryl
`taken
`ring;
`
`R10or with and the carbons
`
`to
`
`
`
`R12 which
`
`they
`
`12
`R
`
`
`
`forms
`
`is a single or double bond
`In some embodiments,
`X
`embodiments, X
`is OAc.
`
`
`
`
`
`OH. is In some embodiments,
`
`X
`
`
`
`is In some
`
`oxo.
`
`is a single bond.
`In some embodiments,
`R4 is OH. In some
`
`
`R4 is OAcyl. In some embodiments,
`In some embodiments,
`OAc).
`embodiments, R4
`is
`
`methoxy. In some embodiments,
`
`R4 is OPg (e.g., OTroc
`or
`In
`
`some embodiments, R4 together with R5 and the carbons
`
`to which are attached they
`
`forms
`a ring.
`
`together
`R5,
`In some embodiments,
`R5
`is
`an oxo. In some embodiments,
`In some embodiments,
`
`R6 is methyl.
`7
`In some embodiments,
`
`R is H. In some embodiments,
`embodiments, R , together with
`the carbon
`to
`which
`
`7
`
`n
`
`with
`OH
`
`the
`or
`
`carbon
`OPg.
`
`to
`
`
`R is OH or OPg. In some
`it
`is
`
`attached,
`
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`
`O
`
`O
`
`In some embodiments,
`
`8
`
`
`
`R is
`
`. In some embodiments,
`
`R'
`
`/wir
`
`are
`they
`to which
`together with R9a and the carbons
`alkyl,
`H,
`O, S, Se, or NR8a (e.g., O), wherein R8a
`is
`Pg, or C(0)H. In some embodiments,
`R8 together with R9a and the carbons
`
`O
`
`N
`
`is
`, wherein X
`attached
`arylalkyl
`
`to which they
`
`form
`(e.g.,
`
`:~0'
`
`the carbon
`
`to
`
`which
`
`are attached
`cyclopropyl ring. In some embodiments,
`
`a
`form
`In some embodiments,
`
`R9a and R9b, together with
`JL
`attached form ^ ^.
`In some embodiments,
`In some embodiments,
`
`R9b is OAc.
`
`R10
`
`is
`
`
`
`0C(0)phenyl. In some embodiments,
`
`R10 taken
`
`O
`oA O
`
`forms attached, a ring such as ^ ^ or
`
`to which
`
`it
`
`is
`
`
`
`
`
`and the carbon
`
`together with R11
`Ph
`o^o
`X X
`In some embodiments,
`In some embodiments,
`
`is In some embodiments, H.
`
`
`R11
`
`
`is In some embodiments, H.
`R12
`O NHR8a
`
`R11
`R12
`
`is
`
`is In some
`
`OH.
`OH.
`
`12
`embodiments, R is
`
`ro-
`
`OH
`
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`
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`
`is
`
`a
`
`compound
`
`of
`
`formula
`
`R7 <sX
`
`R
`
`i
`
`R 1 1
`
`i H 5 ^R9a
`R l O O.
`
`8 R
`
`O
`
`In one embodiment, the
`
`taxane
`
`O
`
`HQ
`
`Rx
`
`R4
`
`R12
`
`-£
`
`-CHRX;
`Oacyl),
`
`formula (Xlla)
`wherein
`to
`attached
`linking O with the atom X
`
`by
`ring
`Z forms a
`4 R is OH, alkoxy
`(e.g.,
`(e.g., methoxy),
`0C(0)alk:yl
`heterocycloalkylalkyl;
`
`or together with R5 and the carbons R4
`
`
`
`they to which are attached,
`form an optionally
`substituted
`ring;
`or
`R4,
`together
`a
`attached, forms
`a
`ring
`(forming
`spirocyclic
`ring)
`Oacyl);
`R5 is OH, 0C(0)alkyl
`(e.g.,
`
`R5 or with R4 or R7 and the carbons together
`
`
`an
`to which they are
`attached,
`form
`optionally
`substituted
`forms
`carbon to which
`it
`is
`attached,
`a
`(forming
`ring
`R6
`R6 is alkyl (e.g., methyl);
`or
`
`together and the carbons
`they
`
`with to which
`attached, form
`an
`optionally
`substituted
`ring
`(e.g.,
`7 R is H, OH, alkoxy
`(e.g.,
`methoxy),
`0C(0)0alkyl,
`OCH2SMe), or OalkylOalkyl
`(e.g.,
`0CH20Me),
`thioalkyl, (e.g.,
`
`SC^OMe); or R7 together with R5 or R6 and the carbons
`are
`to which
`they
`form an optionally
`substituted
`ring
`
`(e.g., ring);
`a
`cyclopropyl
`R7a H or OH;
`
`with
`or
`
`ring;
`
`R7
`a
`
`are
`cyclopropyl
`OalkylSalkyl
`SalkylOalkyl
`attached,
`
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`8
`
`
`
`is
`aryl
`together R1 or R11 and the
`
`
`
`taken
`
`with
`
`or
`
`R12
`
`
`
`and which they
`
`
`
`R and the carbons
`
`to which
`
`8
`R is OH or a
`mesylate, taken together with or
`
`a
`(e.g.,
`group
`leaving
`attached
`form a
`are
`they
`to which
`R9a and the carbons
`
`
`or taken together with R8 R9a and the carbons
`
`R9a is an activated alkyl
`(e.g.CH^I);
`a
`ring;
`to which they are
`attached
`form
`wherein
`R10 is OH, 0C(0)aryl
`(e.g.,
`with halo, alkoxy,
`or
`or 0C(0)alkyl;
`or R10
`N3)
`carbons to which
`
`they are attached,
`forms
`a
`ring;
`R11 H or OH; or R11 taken together with R10
`are attached,
`forms
`a
`ring;
`12
`12
`11
`R
`
`is H, or OH; or R taken together with
`attached, forms
`a
`ring;
`Rx is NHPg or aryl;
`X is C or N; and
`
`Pg is a protecting
`
`a for group heteroatom such
`DMS, Troc, Boc
`or Ac).
`In some embodiments,
`In some embodiments,
`In some embodiments,
`
`
`
`
`
`or as O (e.g., Bn, Bz, TES, N
`
`halo);
`ring;
`
`optionally
`
`the
`
`they
`
`are
`
`TMS,
`
`phenyl
`double
`heteroatoms.
`
`
`
`
`
`Z
`Z
`Z
`
`includes
`includes
`includes
`
`one
`one
`one
`
`or
`or
`or
`
`more
`more
`more
`
`,**
`
`In some embodiments,
`Z
`attached to CHRX and **
`indicates
`,**
`
`is
`the
`
`, wherein *
`indicates
`the
`atom
`carbon
`
`
`
`attached In some embodiments, to C(O).
`
`Z
`
`X
`
`^ /r0\ //
`
`is
`
`, wherein *
`
`indicates
`
`the
`
`atom
`
`
`
`X and * * indicates attached
`
`
`
`to
`
`the carbon attached
`to C(O). In some embodiments,
`
`indicates the atom X
`attached
`to
`In some embodiments,
`the
`taxane
`
`is
`
`Z
`CHRX
`is
`
`, wherein *
`and
`**
`a
`compound
`
`indicates
`of
`
`**
`
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`R4
`
`R
`
`R7
`
`O
`
`HO,
`
`Rx
`
`\\\^
`
`R12
`
`8 R
`
`H
`R9a
`
`i
`% R9b
`
`11 R
`
`O
`
`formula(XIIb)
`
`wherein
`the
`with
`linking
`by
`ring
`Z' forms a
`4 R is OH, alkoxy
`(e.g.,
`0C(0)aIk:yl
`(e.g., methoxy),
`heterocycloalkylalkyl;
`
`or together with R5 and the carbons R4
`
`
`they to which are attached,
`
`form an optionally
`substituted
`ring;
`or
`R4,
`together
`a
`attached, forms
`a
`ring
`(forming
`spirocyclic
`ring)
`Oacyl);
`R5 is OH, 0C(0)alkyl
`(e.g.,
`
`R5 or with R4 or R7 and the carbons together
`
`
`an
`to which they are
`attached,
`form
`optionally
`substituted
`forms
`carbon to which
`it
`is
`attached,
`a
`(forming
`ring
`R6
`R6 is alkyl (e.g., methyl);
`or
`
`together and the carbons
`they
`
`with to which
`attached, form
`an
`optionally
`substituted
`ring
`(e.g.,
`7 R is H, OH, alkoxy
`(e.g.,
`methoxy),
`0C(0)0alkyl,
`OCH2SMe), or OalkylOalkyl
`(e.g.,
`0CH20Me),
`thioalkyl, (e.g.,
`
`are
`SC^OMe); or R7 together with R5 or R6 and the carbons
`to which
`they
`form an optionally
`substituted
`ring
`
`(e.g., ring);
`a
`cyclopropyl
`R7a H or OH;
`8
`R is OH or a
`R9a and the carbons
`
`O
`
`leaving
`to which
`
`group
`they
`
`(e.g.,
`are
`
`152
`
`8
`
`atom
`Oacyl),
`
`X,
`
`ring;
`
`with
`or
`
`R7
`a
`
`are
`cyclopropyl
`OalkylSalkyl
`SalkylOalkyl
`attached,
`
`mesylate, taken together with or
`
`a
`attached
`form a
`
`
`
`halo);
`ring;
`
`00715
`
`

`
`or taken together with R8 R9a and the carbons
`
`
`
`R9a is an activated alkyl
`a
`ring;
`
`or and the carbon
`R9a, to which
`
`to which they are
`attached
`(forming
`a
`spirocyclic
`ring);
`it is attached,
`forms
`a
`ring
`(e.g.,
`Oacyl),
`0C(0)0alkyl
`R9b is OH, 0C(0)aLkyl
`together
`with the carbon
`
`
`R9a to which
`it
`OC(0)cycloalkyl;
`or
`R9b,
`ring);
`ring (forming a
`spirocyclic
`R11 H or OH; or R11 taken together with R10
`are attached,
`forms
`a
`ring;
`12
`12
`11
`R
`
`is H, or OH; or R taken together with
`attached, forms
`a
`ring;
`Rx is NHPg or aryl;
`X is C or N; and
`
`Pg is a protecting
`
`a for group heteroatom such
`DMS, Troc, Boc
`or Ac).
`In some embodiments,
`In some embodiments,
`In some embodiments,
`
`or as O (e.g., Bn, Bz, TES, N
`
`
`
`TMS,
`
`more
`more
`more
`
`WO 2011/063421
`
`PCT/US2010/057913
`
`(e.g.CH^I);
`form
`
`
`
`and is
`
`attached,
`
`or
`
`R12
`
`
`
`and which they
`
`the
`
`
`
`R and the carbons
`
`to which
`
`they
`
`(e.g.,
`
`forms
`
`are
`
`
`
`
`
`
`
`Z'
`Z'
`Z'
`
`one rings.
`
`includes
`
`one bonds.
`includes
`
`
`one includes heteroatoms.
`
`or
`or
`or
`
`**,
`
`In some embodiments,
`Z'
`attached to CHRX and **
`indicates
`
`the
`
`
`is , wherein *
`indicates
`the
`atom
`carbon
`
`
`
`attached In some embodiments, to C(O).
`
`X
`
`**
`
`*
`
`Z' is
`indicates the carbon
`O
`
`, wherein *
`
`
`indicates
`
`the X attached atom to CHRX and **
`
`
`attached
`C(O). to In some embodiments,
`Z'
`is
`
`HN
`
`**
`
`, wherein *
`attached
`indicates the carbon
`In some embodiments,
`the
`
`atom
`
`
`
`X and * *
`
`attached
`
`to
`
`a
`
`compound
`
`of
`
`indicates
`to
`taxane
`
`the
`C(O).
`is
`
`153
`
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`
`

`
`WO 2011/063421
`
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`
`R2
`
`O
`
`R
`
`o^'
`
`R3a
`
`O
`
`OH
`
`R7
`
`%
`
`i H i
`
`%o Ri*
`
`R9a
`
`R
`
`R11
`
`R12
`formula (XIII)
`
`heteroaryl
`or
`
`(e.g.,
`tert-butyl),
`together
`with
`mono-
`
`wherein;
`R1 is aryl (e.g., phenyl),
`(e.g., butyl such
`as
`isobutyl
`(epoxyl), or R1, when
`taken
`they are attached,
`forms
`a
`substituted with 1-3
`Rla;
`R2 is NR2aR2b or OR2c;
`OC(0)alkenyl;
`R3a is H, OH, Opolymer, 0C(0)alkyl,
`0C(0)0alkyl;
`R7 is OH, alkoxy
`(e.g.,
`methoxy),
`
`mesylate, or halo); or R8 taken together with
`
`R8 is OH or a leaving group
`(e.g.,
`a
`R9a and the carbons
`attached
`to which
`they
`are
`form
`R9a is an activated
`alkyl
`(e.g.C^I);
`or together with R8 and the carbons R9a
`
`
`to which they
`are
`attached
`form
`a
`or and the carbon
`R9a, to which
`ring;
`
`
`it is attached,
`forms
`a
`ring
`(forming
`a
`spirocyclic
`ring)
`R9b is OH, 0C(0)alkyl
`(e.g.,
`Oacyl),
`0C(0)0alkyl
`OC(0)cycloalkyl;
`or
`
`
`R9b, taken together with R1 and the carbons
`to
`which
`attached, form a
`
`
`
`R9a ring; or R9b, together with and the carbon
`to
`which
`forms a
`ring
`
`a (forming spirocyclic
`
`ring);
`aryl
`wherein
`R10 is OH, 0C(0)aryl
`(e.g.,
`
`0C(0)alkyl; together with R1
`with halo, alkoxy,
`or
`or
`carbons to which
`they
`attached,
`forms
`
`
`furanyl, or pyridyl), alkyl thiophenyl,
`
`(e.g.,
`cycloalyl
`
`one and the carbons
`of to which
`
`bi-cyclic
`ring
`
`R3b, R9b,
`
`a
`taken
`
`they
`
`are
`
`it
`
`is
`
`(e.g.,
`
`attached,
`
`is
`the
`
`R11
`
`
`
`or or
`
`a
`
`optionally
`
`R10 and
`ring;
`
`or
`
`or
`
`N3)
`are
`
`154
`
`00717
`
`

`
`WO 2011/063421
`
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`
`or
`
`R12
`
`
`
`and which they
`
`
`
`R and the carbons
`
`to which
`
`methyl)
`
`C(O)phenyl), (e.g.,
`(e.g.,
`substituent
`
`and
`(e.g.,
`
`benzyl),
`
`C(0)alkyl,
`
`the
`
`they
`
`are
`
`C(0)alkyl
`acyl),
`as
`
`or
`
`docetaxel,
`tesetaxel,
`
`Design,
`2008,
`incorporated
`
`different
`
`linkers
`
`R11 H or OH; or R11 taken together with R10
`are attached,
`forms
`a
`ring;
`12
`12
`11
`
`is H, or OH; or R taken together with
`R
`attached, forms
`a
`ring;
`(e.g.,
`alkyl
`independently halo (e.g., fluro),
`each Rla
`is
`
`(e.g,
`each R2a and R2b is independently H, C(0)aryl
`acyl), C(0)H,
`C(0)0alkyl;
`
`wherein (e.g, C(O)phenyl), C(0)alkyl C(0)aryl
`
`and C(0)0alkyl is each optionally
`further
`
`substituted, for example, with
`a
`descdribed
`in Rla;
`2 c is H or C(0)NHalkyl;
`R
`R8a is H, alkyl,
`arylalkyl
`7
`In some embodiments,
`
`R is OH.
`taxane
`the
`In some preferred
`embodiments,
`BMS-188797,
`287, TL-310, BMS-275183, BMS-184476,
`cabazitaxel. Additional
`taxanes
`are
`provided
`in
`Chemistry, 2005,
`5,
`1-12;
`Gueritte,
`Current
`Kingston, J. Nat.
`Prod.,
`2009,
`
`72, and Ferlini, Exper Opin. 507-515;
`
`17, 3, 335-347;
`the
`contents
`of
`each
`of
`which
`entirety.
`
`Fan,
`
`is
`ortataxel,
`Mini-Reviews
`Pharmaceutical
`Invest.
`
`Drugs,
`
`is
`
`Exemplary CDP-taxane
`
`conjugates
`
`be
`can
`CDP-taxane conjugates
`components described
`
`herein. For example, various
`beta-cyclodextrin),
`comonomers
`(e.g.,
`PEG
`cyclodextrins and
`comonomers,
`and/or
`linkers
`described herein.
`
`many
`of
`using
`made
`cyclodextrins
`of
`combinations
`
`containing comonomers), linking the
`tethering
`
`the
`
`table
`Fig. 2 is a
`CDP-taxane conjugates
`
`examples
`depicting
`
`in
`Fig. are represented by 2
`
`CDP-CO-ABX-Taxane
`
`the
`
`different
`of
`following
`
`CDP-taxane
`formula:
`
`In this formula.
`
`155
`
`00718
`
`

`
`WO 2011/063421
`
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`
`CDP is the cyclodextrin-containing
`
`polymer
`
`
`
`shown well as in
`
`below
`
`Figure 1):
`
`O^/OH
`•s.
`
`N
`H
`
`HO'
`
`HO
`
`o
`
`HO-
`OHHO 1/°
`
`•S'
`
`(J
`
`H
`•N
`
`o
`OH
`
`O
`
`O-
`
`O
`
`m
`
`DH
`
`O H
`
`H O
`
`•OH
`
`OH O-
`
`HO
`
`O H
`
`•OH
`
`OH
`
`OH
`
`HO.
`
`HO'
`
`OH
`
`O.
`
`wherein the group
`
`4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
`conjugated
`to
`the
`CDP
`above. Full loading of
`the
`least one, e.g.,
`at
`least
`with the taxane
`after
`unreacted).
`
`n
`and
`less
`m has a Mw of 3.4kDa or
`is
`taxane
`
`
`17, 15, 16, 18, 19 or 20. Note that the
`14,
`through
`carboxylic the acid moieties of the polymer as provided
`
`
`taxane
`onto
`
`CDP In some embodiments, is
`the
`
`2,
`3,
`4,
`5,
`6
`conjugation
`(e.g.,
`a
`plurality
`
`at
`
`least
`
`not
`
`is
`
`at
`or
`
`of
`
`the
`
`CO represents
`the
`of
`residue
`carbonyl group of the cysteine
`
`the
`
`
`the Position A is either CDP
`the
`link
`between
`A and B represent
`
`bond between
`linker
`
`and B the cysteine acid carbonyl of CDP
`
`(represented in
`as
`Fig. 2), a bond between
`the taxane
`and
`the
`cysteine
`a "-"in Fig. 2)
`or
`depicts
`a
`via
`portion of
`the
`linker
`that
`attached
`acid carbonyl of
`the
`
`CDP. Position B
`is
`either
`not
`
`(represented in Fig. 2)
`or represents
`the
`linker
`or
`the
`portion
`the
`taxane; and
`X represents
`As provided
`taxane is
`included
`
`to
`heteroatom
`the
`the
`in Fig.
`2,
`
`
`the in CDP-taxane conjugate.
`
`which
`column
`
`the taxane.
`
`with
`
`linker
`the
`
`is
`occupied
`of
`
`a
`
`CDP;
`and
`a
`
`acid
`
`a
`by
`linker
`
`is
`heading
`
`156
`
`00719
`
`

`
`WO 2011/063421
`
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`
`table
`
`The three columns
`the on right of the
`
`to
`are
`any, protecting groups
`used
`for producing
`the CDP-taxane
`conjugate,
`producing
`the CDP-taxane
`conjugate.
`Fig. letter
`The processes
`referred
`to
`
`in given a
`
`in
`A, Process B, etc.
`as
`seen
`the
`processes respectively
`are
`provided
`below.
`of to
`
`Process A: Couple
`the
`
`protected linker position B
`linker
`and
`couple
`
`to carboxylic acid group CDP
`
`linked
`to
`CDP.
`
`indicate
`2
`Fig.
`in
`respectively,
`protect the taxane, the the
`indicated process
`
`
`
`
`
`
`the and product of the process
`for
`final
`
`2 representation,
`
`
`second The steps for
`
`e.g..
`are
`
`
`column each these
`
`Process
`from
`
`the
`
`via of
`
`taxane,
`the
`
`
`
`the CDP
`
`to
`
`deprotect the
`the 2'-taxane
`
`Process B: Couple the activated
`taxane, and couple
`
`to CDP containing
`linker
`of
`the 2'-
`
`taxane linked to CDP.
`
`position of to the 2'-hydroxyl of
`
`
`linker
`
`
`position via the linker of A A
`to
`
`B
`
`afford
`
`Process C: Protect
`protected linker
`of
`position
`CDP via
`the
`group, and couple
`to
`linked to CDP.
`
`C2'
`the
`to
`B
`carboxylic
`
`group
`
`of
`hydroxy
`deprotect
`taxane,
`
`
`group to afford the 7-taxane of the
`
`
`the
`acid
`
`the
`
`CDP
`
`Process D: Protect the C2'
`
`activated linker of position B to the 7-hydroxyl
`group and couple
`to
`CDP
`containing
`afford the 7-taxane
`linked
`CDP.
`
`to
`
`hydroxy group
`of
`the
`linker
`
`the
`of
`deprotect
`taxane,
`
`of to afford
`position
`
`taxane,
`
`the
`
`in
`
`Fig.
`
`
`
`
`CDP-taxane prepared
`2, conjugates can be the
`
`As shown specifically
`art,
`
`including In some
`the
`in
`a variety of methods
`known
`prepared
`using
`embodiments,
`the
`
`CDP-taxane conjugates can be
`the taxane
`(see,
`e.g.,
`
`examples 3 and 4). For taxanes having 1,
`
`hydroxyl
`the 2' and
`the
`7-positions,
`one
`of
`skill
`in
`more reactive,
`and
`therefore
`when
`using
`reaction(s) will be
`that which
`linked
`
`no
`groups
`the
`the
`protecting
`the
`
`no
`
`via
`
`is
`
`157
`
`using
`those
`protecting
`at
`
`both
`art
`groups,
`2'
`
`00720
`
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`
`WO 2011/063421
`
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`
`used
`
`be
`
`in
`used
`
`be
`can
`protecting groups
`One or more
`can
`group
`make the CDP-taxane conjugates described herein. A protecting
`
`to position
`A. In some
`control
`the
`point
`of
`
`attachment the taxane
`
`of and/or
`
`taxane linker
`
`removed protecting
`embodiments,
`the
`protecting
`group
`is
`so
`
`
`not it can be removed, selected
`
`is
`group is not
`
`removed. If a protecting
`group
`in
`vivo
`acid
`hexanoic
`is
`
`it is removed
`(e.g., acting
`as
`a
`prodrug). An example
`in
`group
`been shown
`to
`removed
`be
`lipases to protect a
`
`by
`hydroxyl
`
`for the
`doxorubicin. Protecting groups
`are
`generally
`selected
`
`linker the coupling
`the
`reactive
`taxane and
`groups
`of
`the
`will
`
`reaction. The protecting
`group
`should
`
`be conditions which removable
`degrade
`the
`taxane
`and/or
`
`linker Examples
`material. include t-butyldimethylsilyl
`
`
`("TBDMS")
`and
`TROC
`(derived
`from
`2,2,2-trichloroethoxy
`in
`Carboxybenzyl
`("CBz")
`can
`also
`be
`used
`for
`of TROC
`selectivity
`seen
`if there is
`removal over
`olefin
`
`reduction. This can be
`addressed
`using
`by
`a group
`
`readily removed
`by
`hydrogenation
`such
`as Other protecting
`-methoxybenzyl
`groups may
`also
`be
`acceptable. One of skill
`
`the
`select
`art
`can
`in
`groups for
`the
`products
`and
`methods
`described
`herein.
`
`and,
`then that
`
`which has
`in
`
`vivo
`
`both
`that
`
`not
`
`under
`
`characteristics
`CDP-taxane conjugate
`the
`CDP
`In some embodiments,
`less
`
`
`herein have
`polydispersities
`than or even less
`the
`present
`One embodiment
`of
`taxanes
`by
`covalently conjugating
`certain
`aqueous solubility
`and
`hence
`the
`embodiment
`of
`the
`invention,
`the
`In other embodiments,
`>0.6, >0.8, >1, >2,
`>3,
`>4,
`or
`to another compound,
`such
`an
`as
`onto the CDP.
`have
`preferably
`conjugates described herein
`
`The CDP-taxane
`to
`in the range
`of
`10,000
`to
`
`500,000; or even 70,000 30,000
`
`certain embodiments
`as
`disclosed
`herein,
`the
`
`molecular
`
`amu.
`compound
`
`to 150,000
`
`158
`
`described
`and/or
`
`than
`about about
`invention
`
`them Such conjugation
`
`
`taxane
`a
`even
`amino
`
`CDP-taxane
`3,
`2.
`provides an
`to improves
`the
`
`bioavailability Accordingly, in
`one
`of
`is
`taxane
`>5.
`acid,
`
`a
`
`a
`
`may
`
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`
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`
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`
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`
`to
`
`500,000
`molecular
`mixed
`
`known
`
`herein, conjugate
`
`in
`is
`
`to
`1,000
`between
`molecular weight
`determine
`to
`
`100,000 amu. One method
`between 10,000
`e.g.,
`permeation
`chromatography
`("GPC"),
`dn/dc.
`scattering detector,
`and
`off-line
`are
`Other methods
`In certain embodiments
`as
`disclosed
`biodegradable
`or
`bioerodable.
`herein,
`disclosed
`as
`In certain embodiments
`
`15%,
`or by weight of the compound. 20%)
`
`
`least 10%,
`up at least
`3%
`(e.g.,
`at about 5%,
`
`
`prodrug 15% or 20%
`or
`taxane
`In certain embodiments,
`the
`17-21%
`from
`(e.g.,
`weight of
`the
`compound
`
`be or flowable
`may
`conjugate
`
`the CDP-taxane
`In other embodiments,
`
`itself CDP composition flowable, of
`
`
`the
`used
`is
`material. When the CDP
`even when viscous,
`
`
`not need include a biocompatible
`
`solvent flowable, although to
`
`
`trace or
`residual
`amounts
`of
`biocompatible
`solvents
`
`amu,
`weight
`bed columns,
`the
`the
`
`the
`
`by
`
`thereof
`
`by
`
`a
`
`flexible
`the invention,
`
`be
`
`may
`
`mixing
`otherwise
`solvents,
`
`
`
`
`acid,
`2-
`
`their
`
`used
`is
`solvent
`When a
`facilitate
`to
`it should
`CDP-taxane
`conjugate,
`non-toxic,
`be
`Examples of
`biocompatible
`suitable
`amounts.
`used in
`relatively small
`used, include N-methyl-2-pyrrolidone,
`
`2-pyrrolidone, propylene glycol, ethanol, acetone,
`methyl acetate,
`ethyl
`
`acetate, ethyl ketone, methyl dimethylformamide,
`
`
`dimethylsulfoxide,
`tetrahydrofuran,
`caprolactam,
`oleic
`dodecylazacylcoheptanone. Preferred solvents
`include
`N-methylpyrrolidone,
`pyrrolidone,
`dimethylsulfoxide,
`and
`acetone because
`of
`biocompatibility.
`In certain embodiments,
`common organic
`solvents
`solvents
`include
`such solvents
`butanone, butyl
`acetate,
`ethyl
`methylpyrrolidone,
`dimethylformamide,
`In certain embodiments,
`the
`contact with
`body
`fluids,
`undergo
`
`the
`for
`
`as
`
`CDP-taxane conjugates in one or more are
`
`
`ease
`
`of Common organic fabrication
`
`chloroform,
`dichloromethane,
`butyrate,
`acetone,
`ethyl
`and
`dimethylsulfoxide.
`CDP-taxane conjugates
`
`gradual The life of a biodegradable degradation.
`
`described herein,
`
`
`159
`
`00722
`
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`
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`
`things,
`molecular
`
`the
`
`the
`
`greater
`
`in
`
`about
`0.0001
`
`mg/kg/hour, taxane
`
`of
`
`the
`
`hydrolysis
`of
`
`be
`
`obtained
`
`or
`
`Such a
`use
`For
`various
`backbone
`
`is
`
`encouraged
`
`the
`hydrophobic
`cleavage
`
`accepted
`generally
`therapeutic
`agent
`the
`present
`
`7.4) (pH 37 0C, an assay
`
`term
`"PBS
`
`160
`
`in vivo
`other
`among
`upon,
`depends
`polymer
`
`the
`degree
`of In general,
`
`crosslinking. the greater
`
`biostability,
`and
`degree
`of
`crystallinity,
`and
`the higher
`the
`biodegradation will
`be.
`with
`a
`formulated
`If a subject
`composition
`is
`or
`extended the release
`
`sustained
`the taxane or other material
`for
`a
`profile
`
`result
`results. may
`generally Such release
`
`from an
`isotonic
`saline
`solution
`alternatively
`1 hours,
`or
`
`prolonged delivery
`
`
`(over, to about 2,000 say
`about
`(e.g.,
`800 hours)
`of
`effective
`amounts
`
`
`mg/kg/hour, 1.0 mg/kg/hour) 0.1
`e.g., 0.001 mg/kg/hour,
`0.01
`with the
`polymer.
`or any other material associated
`of
`the
`desired
`rate
`A variety of
`factors may affect
`flexibility
`conjugates,
`the
`desired
`softness
`and
`selection/identity
`the
`include
`Some of such
`factors
`extent of bioactive material
`release.
`diastereomeric
`
`or the monomeric
`of the various
`subunits,
`the
`enantiomeric
`of
`
`the polymer.
`found the length of in
`
`the
`subunits, homogeneity
`subunits
`
`present
`heteropolymers
`For instance,
`the
`invention
`contemplates
`order to control,
`for
`of
`and/or the
`inclusion
`other
`monomeric
`in
`elements
`of
`example,
`the
`rate
`biodegradation
`of
`the
`matrix.
`further,
`To illustrate
`
`a range of degradation wide
`
`rates
`may
`adjusting
`the
`hydrophobicities
`of
`the
`backbones
`maintaining
`sufficient
`biodegradability
`for
`the
`result may be
`achieved
`by
`varying
`example,
`the
`combination
`of
`a
`heterogeneous
`degradation
`because
`resisted.
`One protocol
`a
`release rate
`of
`of
`taxane conjugates
`0.1 M PBS
`solution
`present
`invention,
`the
`
`in
`
`the
`
`field
`
`as
`such
`any such matrix
`in
`invention
`involves
`
`at known
`in For purposes
`
`the of
`the
`
`
`protocol" to such protocol.
`is
`
`a
`
`a
`art.
`
`used
`
`00723
`
`

`
`WO 2011/063421
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`
`different
`them
`polymeric
`
`of
`rates
`by subjecting In certain
`
`process
`different
`of
`For example,
`different
`methods
`
`that
`any releases
`to
`1000
`
`about
`
`one
`or
`
`
`
`a 10, 25,
`
`rate
`contemplated
`
`are
`
`the
`be
`
`or
`
`may
`rate
`rate
`
`when
`
`release
`instances,
`In certain
`compared
`may
`present
`invention
`to
`necessary
`be
`instances,
`it may
`accurate
`comparisons
`direct and
`relatively
`teaches
`several
`the present
`invention
`conjugates. Such comparisons
`may
`indicate
`
`
`at incorporated material a rate from about 2 or
`less
`than another
`polymeric
`system.
`Alternatively,
`a
`comparison
`50, 100, 250,
`
`500 or 750
`times. Even higher
`present
`invention
`and
`release
`formulated
`In certain embodiments,
`present
`the
`CDP-taxane conjugates
`of
`Release of any
`material incorporated
`
`provided as a
`
`may microsphere, be characterized
`
`in certain
`increased
`release
`rate,
`which
`may
`incorporated material,
`alternatively
`release rate
`of
`lesser
`magnitude.
`characterized
`material may also be
`
`The release rate of any
`incorporated
`
`amount of
`
`
`per such material released per day mg of polymer matrix. For example,
`certain embodiments,
`the
`release
`rate
`may or less of any
`
`incorporated material
`per
`
`day mg of polymeric per
`system
`to or more about
`
`
`
`ng/day/mg. Alternatively,
`the
`release
`rate
`
`
`
`may 5, 10, 25, 50, be 75, 100,
`125, 150, 175,
`200,
`
`
`
`300, 350, 250, 400, 450, or 500
`
`ng/day/mg. In still other
`embodiments,
`the
`
`rate release of any incorporated material may
`
`be
`10,000
`even higher. In certain
`instances,
`materials
`incorporated
`
`and such
`release rate
`protocols
`may
`include
`
`therapeutic fillers, and other
`agents, substances.
`
`In another aspect,
`the
`rate
`release
`of
`of
`conjugate of
`the
`present
`invention
`may as the half-life
`of
`presented material
`the matrix.
`
`reveal
`differences
`protocols.
`in release rate for
`
`invention
`the
`
`into
`instances
`release
`about
`or 40%,
`
`by
`
`an
`
`10,
`followed
`
`a
`may
`polymer
`initial
`from
`by
`
`a
`
`15,
`
`by
`
`the
`
`in
`
`vary
`500
`about
`
`ng/day/mg,
`characterized
`
`
`
`
`
`be such
`
`
`
`any
`in
`
`161
`
`00724
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`
`In addition
`in
`release rates,
`systems may
`be
`Other assays
`useful
`present system
`are
`
`involving
`embodiment
`the
`to
`vivo
`whereby
`protocols,
`vivo,
`in