Note: Descriptions are shown in the official language in which they were submitted.
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BAZEDOXIFENE BIS-PHOSPHORATES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
60/892,044
filed February 28, 2007, which is incorporated herein by reference in its
entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure relates to bis-phosphoric acid esters of the selective
estrogen
receptor modulator 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-
methyl-1 H-
indol-5-ol (bazedoxifene), as well as compositions thereof, preparations
thereof and uses
thereof.
BACKGROUND
[0003] Bazedoxifene (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-
3-
methyl-1 H-indol-5-ol; or bazedoxifene free base), having the chemical formula
shown below:
CH3
HO
I \ \ / OH
N
O
0
belongs to the class of drugs typically referred to as selective estrogen
receptor modulators
(SERMs). Consistent with its classification, bazedoxifene and its salts
demonstrate affinity
for estrogen receptors (ER) but show tissue selective estrogenic effects. For
example,
bazedoxifene acetate demonstrates little or no stimulation of uterine response
in preclinical
models of uterine stimulation. Conversely, bazedoxifene acetate demonstrates
an estrogen
agonist-like effect in preventing bone loss and reducing cholesterol in an
ovariectomized rat
model of osteopenia. In an MCF-7 cell line (human breast cancer cell line),
bazedoxifene
acetate behaves as an estrogen antagonist. These data demonstrate that
bazedoxifene is
estrogenic on bone and cardiovascular lipid parameters and antiestrogenic on
uterine and
mammary tissue and thus has the potential for treating a number of different
disease or
disease-like states wherein the estrogen receptor is involved.
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[0004] U.S. Pat. Nos. 5,998,402 and 6,479,535 report the preparation of
bazedoxifene
and salts thereof. The synthetic preparation of bazedoxifene and its salts has
also appeared
in the general literature. See, for example, Miller et al., J. Med. Chem.,
2001, 44, 1654-
1657. Further description of the drug's biological activity has appeared in
the general
literature as well (e.g., Miller et al., Drugs of the Future, 2002, 27(2), 117-
121). Furthermore,
U.S. Pat. Pub. No. 2005/0227964 reports bazedoxifene ascorbate, compositions
containing
the same, dispersions thereof, preparations thereof, and uses thereof. Each of
these above-
mentioned references is incorporated herein by reference in its entirety.
[0005] Because drug formulations showing, for example, improved solubility and
bioavailability are consistently sought, there is an ongoing need for new
forms of existing
drug molecules. The bis-phosphoric acid esters of bazedoxifene (bazedoxifene
bis-
phosphorates) and compositions containing the same described herein help meet
these and
other needs.
SUMMARY
[0006] This disclosure provides bis-phosphoric acid esters of bazedoxifene
(bazedoxifene bis-phosphorates) and pharmaceutical compositions containing the
same.
[0007] Certain embodiments provide methods of preparing bazedoxifene bis-
phosphorates.
[0008] Other embodiments provide methods of treating a disease, condition or
disorder
associated with estrogen deficiency or excess of estrogen in a mammal in need
thereof,
which comprise administering an effective dose of a bazedoxifene bis-
phosphorate, or a
pharmaceutically acceptable salt or hydrate thereof.
[0009] Some embodiments provide methods of treating a disease or disorder
associated
with proliferation or abnormal development of endometrial tissues in a mammal
in need
thereof, which comprise administering an effective dose of a bazedoxifene bis-
phosphorate,
or a pharmaceutically acceptable salt or hydrate thereof.
[0010] Some embodiments provide methods of contraception in a mammal in need
thereof, which comprise administering an effective dose of a bazedoxifene bis-
phosphorate,
or a pharmaceutically acceptable salt or hydrate thereof.
[0011] Some embodiments provide methods of lowering cholesterol in a mammal in
need thereof, which comprise administering an effective dose of a bazedoxifene
bis-
phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
[0012] Some embodiments provide methods of treating one or more vasomotor
disturbances in a mammal in need thereof, which comprise administering an
effective dose
of a bazedoxifene bis-phosphorate, or a pharmaceutically acceptable salt or
hydrate thereof.
[0013] Some embodiments provide methods of inhibiting or retarding bone
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demineralization or treating or inhibiting osteoporosis in a postmenopausal or
estrogen
deficient woman in need thereof, which comprise administering an effective
dose of a
bazedoxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate
thereof, and
conjugated estrogens.
[0014] Some embodiments provide methods of treating or inhibiting menopausal
or
postmenopausal disorders in a postmenopausal or estrogen deficient woman in
need
thereof, which comprise administering an effective dose of a bazedoxifene bis-
phosphorate,
or a pharmaceutically acceptable salt or hydrate thereof, and conjugated
estrogens.
[0015] Some embodiments provide methods of inhibiting bone loss in a mammal in
need
thereof, which comprise administering an effective dose of a bazedoxifene bis-
phosphorate,
or a pharmaceutically acceptable salt or hydrate thereof.
[0016] Some embodiments provide methods of treating breast cancer in a mammal
in
need thereof, which comprise administering an effective dose of a bazedoxifene
bis-
phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
DETAILED DESCRIPTION
[0017] Certain embodiments provide compounds which are bis-phosphoric acid
esters of
bazedoxifene (bazedoxifene bis-phosphorates) having the structure of Formula
I:
CH3
R13_O
O-R1a
N
~ /
0~~~ No
I
or pharmaceutically acceptable salts thereof, wherein:
[0018] R13 and R14 are each independently selected from -P(=O)(OR')(OR2) and -
P(=0)(OR3)(OR4);
[0019] R1, R2, R3 and R4 are each independently selected from H, a protecting
group, C,_
1o alkyl, Cl_lo haloalkyl, C2_10 alkenyl, C2_10 alkynyl, aryl, cycloalkyl,
heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein
each of said Cl_lo alkyl, Cl_lo haloalkyl, C2_10 alkenyl, C2_10 alkynyl, aryl,
cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl is
optionally substituted by 1, 2, 3, 4 or 5 R5;
[0020] each R5 is independently selected from halo, Cl_6 alkyl, Cl_6
haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(=O)Rb, C(=O)NR
Rd,
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C(=O)ORa, OC(=O)R', OC(=O)NR Rd, NR Rd, NR C(=O)R', NR C(=O)ORa, NR S(=O)2R',
S(=0)R', S(=0)NR Rd, S(=0)2Rb, and S(=O)2NR Rd;
[0021] each Ra is independently selected from H, Cl_6 alkyl, Cl_6 haloalkyl,
C2_6 alkenyl,
C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Cl_6 alkyl,
Cl_6 haloalkyl, C2_6
alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH,
Cl_6 alkoxy, Cl_6
haloalkoxy, amino, halo, C,_6 alkyl, C,_6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl,
cycloalkyl or heterocycloalkyl;
[0022] each Rb is independently selected from H, Cl_6 alkyl, Cl_6 haloalkyl,
C2_6 alkenyl,
C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Cl_6 alkyl,
Cl_6 haloalkyl, C2_6
alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH,
Cl_6 alkoxy, Cl_6
haloalkoxy, amino, halo, Cl_6 alkyl, Cl_6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl,
cycloalkyl or heterocycloalkyl; and
[0023] R and Rd are each, independently, selected from H, Cl_lo alkyl, Cl_6
haloalkyl, C2_
6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Cl_lo alkyl,
Cl_6 haloalkyl, C2_6
alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH,
Cl_6 alkoxy, Cl_6
haloalkoxy, amino, halo, Cl_6 alkyl, Cl_6 haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl,
cycloalkyl or heterocycloalkyl;
[0024] or R and Rd together with the N atom to which they are attached form a
4-, 5-, 6-
or 7-membered heterocycloalkyl group.
[0025] In some embodiments, R1, R2, R3 and R4 are each independently selected
from
H, a protecting group, Cl_lo alkyl, Cl_lo haloalkyl, C2_1o alkenyl, C2_1o
alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of said Cl_lo alkyl, Cl_lo haloalkyl,
C2_10 alkenyl, C2_1o
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalky is optionally substituted by 1, 2, 3, 4 or 5
substituents
independently selected from halo, Cl_4 alkyl, C,_4 haloalkyl, aryl,
cycloalkyl, heteroaryl,
heterocycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl,
heterocycloalkylalkyl, CN, NO2, OH, Cl_4 alkoxy, Cl_4 haloalkoxy, aryloxy,
heteroaryloxy,
arylalkyloxy, heteroarylalkyloxy, amino, Cl_4 alkylamino, C2_$ dialkylamino,
SH, -S-(Cl_4 alkyl),
C(=O)H, C(=O)-(Cl_4 alkyl), C(=O)-(aryl), C(=O)-(arylalkyl), C(=O)NH2,
C(=O)NH(Cl_4 alkyl),
C(=O)N(C,_4 alkyl)2, C(=O)OH, C(=O)O-(C1_4 alkyl), C(=O)O-(arylalkyl),
OC(=O)H, OC(=O)-
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(C,_4 alkyl), OC(=O)-(aryl), OC(=O)-(arylalkyl), OC(=O)NH2, OC(=O)NH(C,_4
alkyl),
OC(=O)NH-(arylalkyl), OC(=O)N(Cl_4 alkyl)2, NHC(=O)-(Cl_4 alkyl), NHC(=O)-
(aryl),
NHC(=O)-(arylalkyl), NP_4 alkyl)C(=O)-(Cl_4 alkyl), NP_4 alkyl)C(=O)-(aryl),
NP_4
alkyl)C(=O)-(arylalkyl), NHC(=O)O-(arylalkyl), NHC(=O)O-(Cl_4 alkyl), NHC(=O)O-
(arylalkyl),
NHC(=O)NH(Cl_4 alkyl), NHC(=O)NH-(aryl), NHC(=O)NH-(arylalkyl), NHC(=O)NH(Cl_a
alkyl)2, N(Cl_4 alkyl)C(=O)NH(Cl_4 alkyl), NP_4 alkyl)C(=O)NH-(aryl), NP_4
alkyl)C(=O)NH-
(arylalkyl), NP_4 alkyl)C(=O)NH(Cl_4 alkyl)2, NHS(=O)2-(Cl_4 alkyl), NHS(=O)2-
(aryl),
NHS(=O)2-(arylalkyl), S(=O)2-(C,_4 alkyl), S(=O)2-(aryl), S(=O)2-(arylalkyl),
S(=O)2NH(C,_4
alkyl), S(=O)2NH(aryl), and S(=O)2NH(arylalkyl).
[0026] In some embodiments, R1, R2, R3 and R4 are each independently selected
from
H, a protecting group, Cl-lo alkyl, Cl-lo haloalkyl, C2_1o alkenyl, C2_1o
alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of said Cl-lo alkyl, Cl-lo haloalkyl,
C2_10 alkenyl, C2_1o
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents
independently
selected from halo, Cl_4 alkyl, Cl_4 haloalkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, CN, NO2,
OH, Cl_4 alkoxy, Cl_4 haloalkoxy, amino, Cl_4 alkylamino and C2_$
dialkylamino.
[0027] In some embodiments, R1, R2, R3 and R4 are each independently selected
from
H, a protecting group, Cl-lo alkyl, Cl-lo haloalkyl, C2_1o alkenyl, C2_1o
alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl.
[0028] In some embodiments, R1, R2, R3 and R4 are each independently selected
from
H, a protecting group, Cl-lo alkyl and Cl-lo haloalkyl. In some embodiments,
R1, R2, R3, and
R4 are each independently selected from H, a protecting group, Cl_6 alkyl and
Cl_6 haloalkyl.
[0029] In some embodiments, R1, R2, R3 and R4 are each independently selected
from
H, a protecting group and Cl_6 alkyl. In some embodiments, R1, R2, R3, and R4
are each
independently selected from H, a protecting group, and C,_4 alkyl. In some
embodiments, R1,
R2, R3, and R4 are each independently selected from H and tert-butyl. In some
embodiments, R1, R2, R3, and R4 are each Cl_6 alkyl. In some embodiments, R1,
R2, R3, and
R4 are each tert-butyl.
[0030] In some embodiments, the compounds of this disclosure have the
structure of
Formula la:
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0
II CH3
R'O-i-O ~ \ _ ~ 1
OR2 I/ N ~~ O- i-OR
OR2
v)
Oe N
la
or are pharmaceutically acceptable salts thereof.
[0031] In some embodiments, the compounds of this disclosure have the
structure of
Formula II:
0
II CH3 0
HO-P-O _
OH I / N ~ ~ O-i-OH
OH
d
O'-~ No
I I
or are pharmaceutically acceptable salts thereof.
Definitions
[0032] The term "optionally substituted," as used herein, means that
substitution is
optional and therefore it is possible for the designated atom or moiety to be
unsubstituted. In
the event a substitution is desired then such substitution means that any
number of
hydrogens on the designated atom or moiety is replaced with a selection from
the indicated
group, provided that the normal valency of the designated atom or moiety is
not exceeded,
and that the substitution results in a stable compound. For example, if a
methyl group (i.e.,
CH3) is optionally substituted, then from 1 up to 3 hydrogens on the carbon
atom can be
replaced. Examples of suitable substituents include, but are not limited to:
halogen, CN,
NH2, OH, SO, SO2, COOH, OC,_6 alkyl, CH2OH, S02H, C,_6 alkyl, OC,_6 alkyl,
C(=O)C,_6 alkyl,
C(=0)O-Cl_6 alkyl, C(=0)NH2, C(=0)NHC,_6 alkyl, C(=0)N(Cl_6 alkyl)2, S02C1_6
alkyl, SO2NH-
Cl_6 alkyl, S02N(C1_6 alkyl)2, NHP_6alkyl), NP_6 alkyl)2, NHC(=O)Cl_6 alkyl,
NC(=O)(Cl_6
alkyl)2, aryl, 0-aryl, C(=O)-aryl, C(=O)O-aryl, C(=O)NH-aryl, C(=O)N(aryl)2,
S02-aryl,
SO2NH-aryl, S02N(aryl)2, NH(aryl), N(aryl)2, NC(=O)aryl, NC(=O)(aryl)2,
heterocyclyl, 0-
heterocyclyl, C(=O)-heterocyclyl, C(=O)O-heterocyclyl, C(=O)NH-heterocyclyl,
C(=O)N(heterocyclyl)2, S02-heterocyclyl, SO2NH-heterocyclyl,
S02N(heterocyclyl)2,
NH(heterocyclyl), N(heterocyclyl)2, NC(=O)-heterocyclyl, and
NC(=O)(heterocyclyl)2.
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[0033] As used herein, "alkyl", "alkylenyl" or "alkylene" used alone or as a
suffix or prefix,
is intended to include both branched and straight-chain saturated aliphatic
hydrocarbon
groups having from 1 to 12 carbon atoms or if a specified number of carbon
atoms is
provided then that specific number would be intended. For example "C,_6 alkyl"
denotes alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are not
limited to,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,
pentyl, and hexyl, or any
subset thereof. As used herein, "Cl_3 alkyl", whether a terminal substituent
or an alkylene (or
alkylenyl) group linking two substituents, is understood to specifically
include both branched
and straight-chain methyl, ethyl, and propyl.
[0034] As used herein, "alkenyl" refers to an alkyl group having one or more
double
carbon-carbon bonds. Exemplary alkenyl groups include ethenyl, propenyl, and
cyclohexenyl. The term "alkenylenyl" refers to a divalent linking alkenyl
group.
[0035] As used herein, "alkynyl" refers to an alkyl group having one or more
triple
carbon-carbon bonds. Exemplary alkynyl groups include ethynyl and propynyl.
The term
"alkynylenyP' refers to a divalent linking alkynyl group.
[0036] As used herein, "aromatic" refers to groups having one or more
polyunsaturated
rings having aromatic character (e.g., 4n + 2 delocalized electrons) and
having up to about
20 ring-forming atoms.
[0037] As used herein, the term "aryl" refers to an aromatic ring structure
made up of
from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon
atoms would be
single-ring aromatic groups, for example, phenyl. Ring structures containing
8, 9, 10, 11, 12,
13, or 14 would be a polycyclic moiety in which at least one carbon is common
to any two
adjoining rings therein (for example, the rings are "fused rings"), for
example naphthyl. The
term "aryl" also includes polycyclic ring systems having two or more adjoining
rings in which
two or more carbons are common (the rings are "fused rings"), wherein at least
one of the
rings is aromatic (for example, the other ring(s) can be cycloalkyl,
cycloalkenyl or
cycloalkynyl). The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-
disubstituted
benzenes, respectively. For example, the names 1,2-dimethylbenzene and
ortho-dimethylbenzene are synonymous.
[0038] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons
including
cyclized alkyl, alkenyl, and/or alkynyl groups, having the specified number of
carbon atoms
(wherein the ring structure has 3 to 20 ring-forming carbon atoms). Cycloalkyl
groups can
include mono- or polycyclic (e.g., having 2, 3 or 4 fused or bridged rings)
groups. Exemplary
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl,
norpinyl,
norcarnyl, and adamantyl. Also included in the definition of cycloalkyl are
moieties that have
one or more aromatic rings fused (i.e., having a bond in common with) to the
cycloalkyl ring,
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for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene,
and
cyclohexane.
[0039] As used herein, the term "heterocyclyl" or "heterocyclic" or
"heterocycle" refers to
ring-containing monovalent and divalent structures having one or more
heteroatoms,
independently selected from N, 0 and S, as part of the ring structure and
having from 3 to 20
ring-forming atoms, for example making up 3- to 7- membered rings.
Heterocyclic groups
may be saturated or partially saturated or unsaturated, containing one or more
double
bonds, and heterocyclic groups may contain more than one ring as in the case
of polycyclic
systems. If specifically noted, nitrogen in the heterocyclyl may optionally be
quaternized. It
is understood that when the total number of S and 0 atoms in the heterocyclyl
exceeds 1,
then these heteroatoms are not adjacent to one another.
[0040] Examples of heterocyclyls include, but are not limited to, 1 H-
indazole,
2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-
piperidonyl,
4aH-carbazole, 4H-quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azabicyclo,
azetidine,
azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl,
benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-
carbazolyl, b-carbolinyl,
chromanyl, chromenyl, cinnolinyl, diazepane, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl,
dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran, dihydrofuro[2,3-
b]tetrahydrofuran,
furanyl, furazanyl, homopiperidinyl, imidazolidine, imidazolidinyl,
imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,
isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxirane,
oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,
4-piperidonyl,
purinyl, pyranyl, pyrrolidinyl, pyrroline, pyrrolidine, pyrazinyl,
pyrazolidinyl, pyrazolinyl,
pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl,
N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl dione,
pyrrolinyl, pyrrolyl,
pyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl,
tetrahydrofuranyl, tetramethylpiperidinyl, tetrahydroquinoline,
tetrahydroisoquinolinyl,
thiophane, thiotetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-
thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl,
thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiopheneyl, thiirane,
triazinyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and
xanthenyl, or any subset
thereof.
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[0041] As used herein, "heteroaryl" refers to an aromatic heterocycle (wherein
the ring
structure has up to about 20 ring-forming atoms) having at least one
heteroatom ring
member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include
monocyclic and
polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of
heteroaryl groups
include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl,
furyl (i.e., furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl,
indolyl, pyrryl, oxazolyl,
benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl,
1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl,
benzimidazolyl, and
indolinyl. In some embodiments, the heteroaryl group has from 1 to about 20
ring-forming
atoms, and in further embodiments from about 3 to about 20 ring-forming atoms.
In some
embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to
about 7, or 5
to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to
about 4, 1 to
about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has
1
heteroatom.
[0042] As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles
(wherein
the ring structure has about 3 to about 20 ring-forming atoms) including
cyclized alkyl,
alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms
is replaced
by a heteroatom such as an 0, N, or S atom. Heterocycloalkyl groups can be
mono or
polycyclic (e.g., fused-, bridged- and spiro- systems). Suitable
"heterocycloalkyl" groups
include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,
tetrahydrothienyl, 2,3-
dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,
pyrrolidinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,
and imidazolidinyl.
Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be
optionally
substituted by oxo or sulfido. Also included in the definition of
heterocycloalkyl are moieties
that have one or more aromatic rings fused (i.e., having a bond in common
with) to the non-
aromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and
benzo derivatives of
heterocycles such as indolene and isoindolene groups. In some embodiments, the
heterocycloalkyl group has from about 3 to about 20 ring-forming atoms. In
some
embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7,
or 5 to 6 ring-
forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about
4, 1 to
about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl
group contains
0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains
0 to 2 triple
bonds.
[0043] As used herein, "alkoxy" or "alkyloxy" represents an alkyl group as
defined above
with the indicated number of carbon atoms attached through an oxygen bridge.
Examples of
alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy,
isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and
propargyloxy.
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Similarly, "alkylthio" or "thioalkyl" represent an alkyl group as defined
above with the
indicated number of carbon atoms attached through a sulphur bridge.
[0044] As used herein, "amino" refers to NH2.
[0045] As used herein, "alkylamino" refers to an amino group substituted by an
alkyl
group.
[0046] As used herein, "dialkylamino" refers to an amino group substituted by
two alkyl
groups.
[0047] As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and
iodo.
[0048] As used herein, "haloalkyl" refers to an alkyl group having one or more
halogen
substituents. Exemplary haloalkyl groups include CF3, C2F5, CH2CF3, CHF2,
CC13, CHC12,
and C2C15. The term "perhaloalkyl" is intended to denote an alkyl group in
which all of the
hydrogen atoms are replaced with halogen atoms. Exemplary perhaloalkyl groups
include
CC13 and CF3. The term "perfluoroalkyP" is intended to denote an alkyl group
in which all of
the hydrogen atoms are replaced with fluorine atoms. One example of
perfluoroalkyl is CF3
(i.e., trifluoromethyl).
[0049] As used herein, "haloalkoxy" refers to an -0-haloalkyl group. An
example of a
haloalkoxy group is OCF3.
[0050] As used herein, "aryloxy" refers to -0-aryl. An example of an aryloxy
group is
phenoxy.
[0051] As used herein, "heteroaryloxy" refers to -0-heteroaryl. An example of
a
heteroaryloxy group is pyridine-2-yloxy [i.e., -O-(pyridine-2-yl)].
[0052] As used herein, "arylalkyl" refers to Cl_lo alkyl substituted by aryl
and
"cycloalkylalkyP' refers to Cl_lo alkyl substituted by cycloalkyl. An example
of an arylalkyl
group is benzyl.
[0053] As used herein, "heteroarylalkyl" refers to Cl_lo alkyl substituted by
heteroaryl and
"heterocycloalkylalkyl" refers to Cl_lo alkyl substituted by heterocycloalkyl.
[0054] As used herein, "arylalkyloxy" refers to -O-(arylalkyl) and
"heteroarylalkyloxy"
refers to -O-(heteroarylalkyl). An example of an arylalkyloxy group is
benzyloxy and an
example of a heteroarylalkyloxy group is (pyridin-2-yl)-methoxy.
[0055] As used herein, some substituents are described as a combination of two
or more
groups. For example, the expression "C(=O)-C3_9 cycloalkylRd" is meant to
refer to a
structure:
O
Rd
P
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wherein p is 1, 2, 3, 4, 5, 6 or 7 (i.e., C3_9 cycloalkyl), the C3_9
cycloalkyl is substituted by Rd;
and the point of attachment of the "C(=O)-C3_9 cycloalkylRd" is through the
carbon atom of
the carbonyl group, which is on the left of the expression.
[0056] The compounds of the disclosure may be derivatised in various ways. As
used
herein "derivatives" of the compounds include salts (e.g., pharmaceutically
acceptable salts),
any complexes (e.g., inclusion complexes or clathrates with compounds such as
cyclodextrins, or coordination complexes with metal ions such as Mn2+ and
Zn2+), esters
such as in vivo hydrolysable esters, polymorphic forms of the compounds,
solvates (e.g.,
hydrates), or lipids, and compounds having coupling partners and protecting
groups (such as
protecting groups for amino and/or hydroxyl groups).
[0057] As used herein, the phrase "protecting group" means a temporary
substituent
which protects a potentially reactive functional group from undesired chemical
transformations. Non-limiting examples of such protecting groups include
esters of
phosphoric acids, esters of carboxylic acids, silyl ethers of alcohols, and
acetals and ketals
of aldehydes and ketones respectively. The field of protecting group chemistry
has been
reviewed (see, e.g., Greene, T.W. and Wuts, P.G.M. Protective Groups in
Organic
Synthesis, 3rd Ed.; Wiley & Sons, 1999, which is incorporated herein by
reference in its
entirety), and protecting groups are well known to those skilled in the art.
[0058] The compounds of this disclosure are intended to be stable compounds
(compounds with stable structure). As used herein "stable compound" and
"stable structure"
are meant to indicate a compound that is sufficiently robust to survive
isolation to a useful
degree of purity from a reaction mixture, and formulation into an efficacious
therapeutic
agent.
[0059] A variety of compounds in this disclosure may exist in particular
stereoisomeric
forms. This disclosure takes into account all such compounds, including cis-
and trans
isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic
mixtures thereof, and other mixtures thereof, as being covered within the
scope of this
disclosure. Additional asymmetric carbon atoms may be present in a substituent
such as an
alkyl group. All such isomers, as well as mixtures thereof, are intended to be
included in this
disclosure. The compounds herein described may have asymmetric centers.
Compounds
of this disclosure containing an asymmetrically substituted atom may be
isolated in optically
active or racemic forms. It is well known in the art how to prepare optically
active forms,
such as by resolution of racemic forms or by synthesis from optically active
starting
materials. When required, separation of the racemic material can be achieved
by methods
known in the art. Many stereoisomers of olefins, C=N double bonds, and the
like can also
be present in the compounds described herein, and all such stable isomers are
contemplated in this disclosure. Cis and trans isomers of the compounds of
this disclosure
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are described and may be isolated as a mixture of isomers or as separated
isomeric forms.
Where the compounds contain chiral centres, all individual optical forms of a
structure such
as enantiomers, epimers and diastereoisomers, as well as racemic mixtures of
the
compounds are intended, unless the specific stereochemistry or isomeric form
is specifically
indicated.
[0060] Compounds may exist in a number of tautomeric forms and references
herein to
compounds include all such forms. For the avoidance of doubt, where a compound
can
exist in one of several tautomeric forms and only one is specifically
described or shown, all
others are nevertheless embraced by the scope of this disclosure. As used
herein,
"tautomer" means other structural isomers that exist in equilibrium resulting
from the
migration of a hydrogen atom. For example, keto-enol tautomerism where the
resulting
compound has the properties of both a ketone and an unsturated alcohol.
[0061] This disclosure further includes isotopically-labeled compounds of the
disclosure.
An "isotopically" or "radio-labeled" compound is a compound in which one or
more atoms are
replaced or substituted by an atom having an atomic mass or mass number
different from
the atomic mass or mass number typically found in nature (i.e., naturally
occurring). Suitable
radionuclides that may be incorporated in compounds of this disclosure include
but are not
limited to 2H (also written as D for deuterium), 3H (also written as T for
tritium), 11C, 13C, 14C
13N 15N 150, 170, 180, 18F 35S 36C182Br 75Br 76Br 77Br 123I 124I 125I and
131I, or any subset
thereof. In some embodiments the radionuclide is selected from the group
consisting of 3H,
14C 1251 35S and 82Br. The radionuclide that is incorporated in the instant
radio-labeled
compounds will depend on the specific application of that radio-labeled
compound. For
example, for in vitro receptor labeling and competition assays, compounds that
incorporate
3H 14C, 82Br 1251 1311, 35S or will generally be most useful. For radio-
imaging applications
11C ,8F 1251, 1231, 1241, 1311, 75Br, 76Br or 77Br will generally be most
useful.
[0062] In certain embodiments, salts of the compounds are physiologically well
tolerated
and non toxic. Many examples of salts are known to those skilled in the art.
All such salts
are within the scope of various embodiments, and references to compounds
include the salt
forms of the compounds.
[0063] Compounds having acidic groups, such as carboxylic, phosphoric,
sulfuric or
sulfonic acid groups, can form salts with alkaline or alkaline earth metals
such as Na, K, Mg
and Ca, and with organic amines such as triethylamine and Tris (2-
hydroxyethyl)amine.
Salts can be formed from compounds with basic groups, e.g. amines, with
inorganic acids
such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids
such as acetic
acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds
having both acidic
and basic groups can form internal salts.
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[0064] Acid addition salts may be formed with a wide variety of acids, both
inorganic and
organic. Examples of acid addition salts include salts formed with
hydrochloric, hydriodic,
phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic,
isethionic, fumaric,
benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic,
naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,
glucuronic and
lactobionic acids.
[0065] If the compound is anionic, or has a functional group which may be
anionic (e.g.,
COOH may be COO-, and P03H2 may be P03H-), then a salt may be formed with a
cation as
counterion. Examples of cations include, but are not limited to, alkali metal
ions such as Na+
and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such
as AI3+, as well
as ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+,
NH2R2+, NHR3+,
NR4+). Non-limiting examples of substituted ammonium ions include those
derived from:
ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine,
ethylenediamine,
ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine,
choline,
meglumine, and tromethamine, as well as amino acids, such as lysine and
arginine. An
example of a common quaternary ammonium ion is N(CH3)4+.
[0066] Where the compounds contain an amine function, these may form
quaternary
ammonium salts, for example by reaction with an alkylating agent according to
methods well
known to the skilled person. Such quaternary ammonium compounds are within the
scope
of this disclosure.
[0067] Where the compounds contain an amine function, acid addition salts may
also be
formed with a wide variety of acids, both inorganic and organic. Examples of
acid addition
salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric,
sulphuric, citric,
lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,
toluenesulphonic,
methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic,
propanoic,
butanoic, malonic, glucuronic and lactobionic acids. In such instances, the
counterions are
from the acids used (e.g., when hydrochloric acid is used, the counterion will
be chloride).
[0068] "Counterion" is used to represent a small, negatively or positively
charged
species such as chloride (CI-), bromide (Br ), hydroxide (OH-), acetate
(CH3COO-) , sulfate
(S042-), tosylate (CH3-phenyl-S03 ), benezensulfonate (phenyl-S03-), sodium
ion (Na+),
potassium (K+), and ammonium (NH4+)
[0069] As used herein, "pharmaceutically acceptable" refers to those
compounds,
materials, compositions, and/or dosage forms which are, within the scope of
sound medical
judgment, suitable for use in contact with the tissues of human beings and
animals without
excessive toxicity, irritation, allergic response, or other problem or
complication,
commensurate with a reasonable benefit/risk ratio.
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[0070] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or
base
salts thereof (i.e., also including counterions). Examples of pharmaceutically
acceptable
salts include, but are not limited to, mineral or organic acid salts of basic
residues such as
amines; and alkali or organic salts of acidic residues such as carboxylic
acids. The
pharmaceutically acceptable salts include the conventional non-toxic salts or
the quaternary
ammonium salts of the parent compound formed, for example, from non-toxic
inorganic or
organic acids. For example, such conventional non-toxic salts include those
derived from
inorganic acids such as hydrochloric and phosphoric; and the salts prepared
from organic
acids such as lactic, maleic, citric, benzoic, and methanesulfonic.
[0071] The pharmaceutically acceptable salts can be synthesized from the
parent
compound that contains a basic or acidic moiety by conventional chemical
methods.
Generally, such salts can be prepared by reacting the free acid or base forms
of these
compounds with a stoichiometric amount of the appropriate base or acid in
water or in an
organic solvent, or in a mixture of the two; nonaqueous media like ether,
ethyl acetate,
ethanol, isopropanol, or acetonitrile can be used.
[0072] Compounds containing an amine function may also form N-oxides. A
reference
herein to a compound that contains an amine function also includes the N-
oxide. Where a
compound contains several amine functions, one or more than one nitrogen atom
may be
oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides
of a tertiary
amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be
formed by
treatment of the corresponding amine with an oxidizing agent such as hydrogen
peroxide or
a per-acid (e.g. a peroxycarboxylic acid); see, for example, March, J.
Advanced Organic
Chemistry, 4 th Ed., Wiley & Sons, 1999. More particularly, N-oxides can be
made by the
procedure of Deady, L.W. Syn. Comm., 1977, 7, 509-514 in which the amine
compound is
reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert
solvent such as
dichloromethane.
[0073] Esters can be formed between hydroxyl or carboxylic acid groups present
in the
compound and an appropriate carboxylic acid or alcohol reaction partner, using
techniques
well known in the art. Examples of esters are compounds containing the group
C(=O)OR,
wherein R is an ester substituent, for example, a Cl_, alkyl group, a C3_20
heterocyclyl group,
or a C5_20 aryl group. Particular examples of ester groups include, but are
not limited to,
C(=O)OCH3, C(=O)OCH2CH3, C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy
(reverse ester) groups are represented by OC(=O)R, wherein R is an acyloxy
substituent, for
example, a C,_, alkyl group, a C3_20 heterocyclyl group, or a C5_20 aryl
group. Particular
examples of acyloxy groups include, but are not limited to, OC(=O)CH3
(acetoxy),
OC(=O)CH2CH3, OC(=O)C(CH3)3, OC(=O)Ph, and OC(=O)CH2Ph.
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[0074] Derivatives which are prodrugs of the compounds are convertible in vivo
or in
vitro into one of the parent compounds. Typically, at least one of the
biological activities of
compound will be reduced in the prodrug form of the compound, and can be
activated by
conversion of the prodrug to release the compound or a metabolite of it. Some
prodrugs are
esters of the active compound (e.g., a physiologically acceptable
metabolically labile ester).
During metabolism, the ester group is cleaved to yield the active drug. Such
esters may be
formed by esterification, for example, of any of the carboxylic acid groups (-
C(=O)OH) in the
parent compound, with, where appropriate, prior protection of any other
reactive groups
present in the parent compound, followed by deprotection if required.
[0075] Non-limiting examples of such metabolically labile esters include those
of the
formula -C(=O)OR, wherein R is, for example, C1_7alkyl (e.g., Me,
Et, -nPr, -iPr, -nBu, -sBu, -iBu, tBu); C1_7aminoalkyl (e.g., aminoethyl;
2-(N,N-diethylamino)ethyl; 2(4morpholino)ethyl); or acyloxy-Cl_,alkyl (e.g.,
acyloxymethyl;
acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1 acetoxyethyl;
1-(1-methoxy-l-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl;
isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;
cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;
cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;
(4-tetrahydropyranyloxy) carbonyloxymethyl;
1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-
tetrahydropyranyl)carbonyloxymethyl; or 1-(4-
tetrahydropyranyl)carbonyloxyethyl).
[0076] Some prodrugs are activated enzymatically to yield the active compound,
or a
compound which, upon further chemical reaction, yields the active compound
(for example,
as in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme
prodrug
therapy (GDEPT) and ligand-directed enzyme prodrug therapy (LIDEPT)). For
example, the
prodrug may be a sugar derivative or other glycoside conjugate, or may be an
amino acid
ester derivative.
[0077] Other derivatives include coupling partners of the compounds in which
the
compound is linked to a coupling partner, e.g., by being chemically coupled to
the compound
or physically associated with it. Examples of coupling partners include a
label or reporter
molecule, a supporting substrate, a carrier or transport molecule, an
effector, a drug, an
antibody or an inhibitor. Coupling partners can be covalently linked to
compounds of this
disclosure via an appropriate functional group on the compound such as a
hydroxyl group, a
carboxyl group or an amino group. Other derivatives include formulating the
compounds
with liposomes.
[0078] As used herein, the term "leaving group" refers to a moiety that can be
displaced
by another moiety, such as by nucleophilic attack, during a chemical reaction.
Leaving
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groups are well known in the art and include, for example, halogen, hydroxy,
alkoxy, -
O(C=O)Ra, -OSO2-Rb, and -OSi(R )3 wherein Ra is Cl_$ alkyl, C3_7 cycloalkyl,
aryl, heteroaryl,
or heterocycloalkyl, Rb is Cl_$ alkyl, aryl (optionally substituted by one or
more halo, cyano,
nitro, Cl_4 alkyl, Cl_4 haloalkyl, Cl_4 alkoxy, or Cl_4 haloalkoxy), or
heteroaryl (optionally
substituted by one or more halo, cyano, nitro, Cl_4 alkyl, Cl_4 haloalkyl, Cl-
C4 alkoxy, or Cl_4
haloalkoxy), and R is Cl_$ alkyl. Exemplary leaving groups include chloro,
bromo, iodo, 4-
nitrophenylcarbonate, mesylate, tosylate, and trimethylsilyl.
Synthesis
[0079] Compounds as described herein can be prepared in a variety of ways
known to
one skilled in the art of organic synthesis. The compounds can be synthesized
using the
methods as hereinafter described below, together with synthetic methods known
in the art of
synthetic organic chemistry or variations thereon as appreciated by those
skilled in the art.
[0080] The compounds can be prepared from readily available starting materials
using
the following general methods and procedures. It will be appreciated that
where typical or
exemplary process conditions (i.e., reaction temperatures, times, mole ratios
of reactants,
solvents, pressures, etc.) are given, other suitable process conditions can
also be used
unless otherwise stated, as determined by one skilled in the art by routine
procedures.
[0081] The processes described herein can be monitored according to any
suitable
method known in the art. For example, product formation can be monitored by
spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,'H
or13C
NMR), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible), or
mass
spectrometry, or by chromatography such as high performance liquid
chromatograpy (HPLC)
or thin layer chromatography.
[0082] Preparation of compounds can involve the protection and deprotection of
various
chemical groups. The need for protection and deprotection, and the selection
of appropriate
protecting groups can be readily determined by one skilled in the art. The
chemistry of
protecting groups can be found, for example, in Greene, T.W. and Wuts, P.G.M.
Protective
Groups in Organic Synthesis, 2nd Ed.; Wiley & Sons, 1991, which is
incorporated herein by
reference in its entirety.
[0083] The reactions of the processes described herein can be carried out in
suitable
solvents which can be readily selected by one of skill in the art of organic
synthesis. Suitable
solvents can be substantially nonreactive with the starting materials
(reactants), the
intermediates, or products at the temperatures at which the reactions are
carried out, i.e.,
temperatures which can range from the solvent's freezing temperature to the
solvent's
boiling temperature. A given reaction can be carried out in one solvent or a
mixture of more
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than one solvent. Depending on the particular reaction step, suitable solvents
for a
particular reaction step can be selected.
[0084] The compounds can be prepared, for example, using the reaction pathways
and
techniques as described below.
[0085] As shown in Scheme 1, a series of novel bazedoxifene di-phosphorates
(compounds of formulas 1-4 and 1-5) are synthesized starting from 1-[4-(2-
azepan-1-yl-
ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1 H-indol-5-ol (bazedoxifene
free base,
compound 1-1). Compound 1-1 is reacted with 2 or more molar equivalents of
phosphoramidite 1-2, wherein
R' and R2 are each independently selected from a protecting group, C,-,o
alkyl, C1-1o
haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of
the Cl-lo alkyl, C1-10
haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally
substituted by 1, 2, 3, 4
or 5 R5;
each R5 is independently halo, Cl-6 alkyl, Cl-6 haloalkyl, aryl, cycloalkyl,
heteroaryl,
heterocycloalkyl, CN, NO2, ORa, SRa, C(=O)Rb, C(=O)NR Rd, C(=O)ORa, OC(=O)Rb,
OC(=O)NR Rd, NR Rd, NR C(=O)Rb, NR C(=O)ORa, NR S(=O)2Rb, S(=O)Rb, S(=O)NR Rd,
S(=0)2Rb, or S(=0)2NR Rd;
R6 and R' are each independently selected from Cl-lo alkyl, Cl-6 haloalkyl, C2-
6
alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, each optionally substituted by 1,
2, 3, 4 or 5 R5;
or R6 and R' together with the N atom to which they are attached form a 4-, 5-
, 6- or
7-membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5
R5;
each Ra is independently selected from H, Cl-6 alkyl, Cl-6 haloalkyl, C2-6
alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein each of said C1-6 alkyl, Cl-6 haloalkyl, C2-
6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl is optionally substituted by OH, Cl-6 alkoxy, Cl-6
haloalkoxy, amino,
halo, Cl-6 alkyl, Cl-6 haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl or
heterocycloalkyl;
each Rb is independently selected from H, C,-6 alkyl, C,-6 haloalkyl, C2-6
alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl, wherein each of said Cl-6 alkyl, Cl-6 haloalkyl, C2-
6 alkenyl, C2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl
and heterocycloalkylalkyl is optionally substituted by OH, Cl-6 alkoxy, Cl-6
haloalkoxy, amino,
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halo, Cl_6 alkyl, Cl_6 haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl or
heterocycloalkyl; and
R and Rd are each, independently, selected from H, Cl_lo alkyl, Cl_6
haloalkyl, C2_6
alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Cl_lo alkyl,
Cl_6 haloalkyl, C2_6
alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl,
cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH,
Cl_6 alkoxy, Cl_6
haloalkoxy, amino, halo, C1_6 alkyl, C,_6 haloalkyl, C,_6 haloalkyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R and Rd together with the N atom to which they are attached form a 4-, 5-
, 6- or
7-membered heterocycloalkyl group,
in the presence of a base (e.g., tetrazole) to form a bis-(phosphorous acid
tri-ester)
intermediate 1-3. In certain embodiments, R' and R2 are each independently
selected from
a protecting group, Cl_lo alkyl and cycloalkyl. In some embodiments, R6 and R'
are each
independently selected from Cl_lo alkyl and cycloalkyl, or R6 and R' together
with the N atom
to which they are attached form a hetercycloalkyl optionally substituted by
one or more Cl_6
alkyl substituents, e.g., methyl or ethyl, or Cl_6 alkoxy substituents.
Suitable protecting
groups include those for hydroxyl groups, examples of which can be found, for
example, in
Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd Ed.;
Wiley &
Sons, 1991, which is incorporated herein by reference in its entirety.
[0086] The bis-(phosphorous acid tri-ester) intermediate 1-3 is oxidized to
the
corresponding bis-(phosphoric acid tri-ester) 1-4 by an oxidizing reagent
(e.g., hydrogen
peroxide). In some embodiments, excess oxidizing reagent is used to ensure
both
phosphorus atoms in the intermediate 1-3 are oxidized to form the P=O bonds in
the bis-
(phosphoric acid tri-ester) 1-4. The excess oxidizing reagents are removed by
suitable
methods such as using a reducing reagent (e.g., sodium metabisulfate) during
the work-up
procedure (e.g., when isolating and/or purifying the product). The bis-
(phosphoric acid tri-
ester) 1-4 is (partially) hydrolyzed under appropriate conditions, such as
under acidic
conditions (e.g., in the presence of an inorganic acid such as HCI), to afford
the bis-
(phosphoric acid mono-ester) 1-5.
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Scheme 1
CH3
HO I~\N \/ OH R'O,,P ORZ R'OINI CH3 - ~ R'
P-O
\
>=2 eq. N R ~ / \ ~ ~ O-P
R6 ~R~ N \ORZ
No 1-2 &\/: 11 O /~
base Nv)
1-1
1-3
0
11 CH3 0
C,Ha
R'O-P-O \ - ~ HO-P-O \ - ~
OH
~~ O- i-OH
ORZ ~/ N \~ O- i-OR OH I/ N
oxidation OR2 OH
-~ 6-/- hydrolysis
O~~ No 0"-~ No
1-4 1-5
[0087] Alternatively, as shown in Scheme 2, 1-[4-(2-azepan-1-yl-ethoxy)-
benzyl]-2-(4-
hydroxy-phenyl)-3-methyl-1 H-indol-5-ol (bazedoxifene free base; compound 2-1)
is reacted
with phosphoramidite 2-2a and phosphoramidite 2-2b concurrently or
sequentially in the
presence of a base such as a tertiary amine (e.g., tetrazole), to afford a
mixed bis-
(phosphorous acid tri-ester) intermediate 2-3 (wherein the phosphoramidite 2-
2a is the same
as or different from phosphoramidite 2-2b; R', R2, R3 and R4 are each
independently defined
as for R' and R2 in Scheme 1; and R6, R', R 8 and R9 are each independently
defined as for
R6 and R' in Scheme 1). The bis-(phosphorous acid tri-ester) intermediate 2-3
[wherein R"
and R12 are each independently selected from -P(OR3)(OR4) and -P(OR')(OR2)]
undergoes
similar transformations to those described in Scheme 1 hereinabove to form the
corresponding bis-(phosphoric acid tri-ester) 2-4 [wherein R13 and R14 are
each
independently selected from -P(=O)(OR3)(OR4) and-P(=O)(OR1)(OR2)] and the bis-
(phosphoric acid mono-ester) 2-5.
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Scheme 2
R3O~ /OR
P CH3
CH3 a) ~N R11-O
HO ~ \ R$ R9 N / O-R12
~ / N OH 2-2a
~
\ / R10~PORz ONo
N~
O~~\
b) RsiN%, R7 2-3
2-1
2-2b
R3 j P~ R1 % P~
R11, R12 : or
R O RZO
CH3
13
R O _
C/ 0-R14 HO-OP-O CH3 O
OH N ~/ O-I~i-OH
oxidation ~ / OH
O,-,--~ No partial hydrolysis O ~~
No
2-4
2-5
O O 11 R13, R14 ~ R30-P~ R1 ~~
O-P-~
OR or OR 2
[0088] Alternatively, as shown in Scheme 3, the bazedoxifene di-phosphorate 3-
5 is
synthesized starting from 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-
phenyl)-3-
methyl-1 H-indol-5-ol (bazedoxifene free base, compound 3-1). Compound 3-1 is
reacted
with 2 or more molar equivalents of phosphorous oxytrihalide 3-2 (wherein each
X' is
independently halo, such as chloro or bromo) in the presence of a suitable
organic base
(such as pyridine) and a suitable inorganic base (such as alkali metal
carbonate, e.g.,
Na2CO3) to form a mixed ester-halide intermediate 3-3. In some embodiments,
the
phosphorous oxytrihalide 3-2 [having the formula of P(=O)(X')3] is P(=O)C13.
In some
embodiments, the amount of phosphorous oxytrihalide 3-2 used is about 2 to
about 4, about
2 to about 3, about 2.0 to about 2.5, or about 2.5 to about 3.0 molar
equivalents to that of
compound 3-1. In some embodiments, the organic base is selected from tertiary
amines
such as trialkylamines [e.g., triethylamine ("TEA"), diisopropylethylamine
("DIPEA")], cyclic
amines [e.g., 1,4-diazabicyclo[2.2.2]octane ("DABCO"),
diaza(1,3)bicyclo[5.4.0]undecane
("DBU")], aromatic amines (e.g., triphenylamine), dimethylaminopyridine (DMAP)
and
heteroaromatic amines (e.g., pyridine and lutidine). In some embodiments, the
organic base
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includes pyridine. In some embodiments, the amount of the organic base used is
greater
than about 4, about 5, about 7, about 9, about 11, or about 13 molar
equivalents to that of
compound 3-1. In some embodiments, the amount of the organic base used is at a
value of
between about 9 and about 13 molar equivalents, or between about 10 and about
12 molar
equivalents to that of compound 3-1. In some embodiments, the inorganic base
includes
alkali metal carbonate (e.g., sodium carbonate, or potassium carbonate, or
cesium
carbonate). In some embodiments, the amount of the inorganic base used is
greater than
about 4, about 5, about 6, about 7, about 8, or about 9 molar equivalents to
that of
compound 3-1. In some embodiments, the amount of the inorganic base (such as
sodium
carbonate) used is at a value of between about 4 and about 6 molar
equivalents, or of
between about 4 and about 5 molar equivalents to that of compound 3-1. In some
embodiments, the amount of the inorganic base used is about 4 molar
equivalents to that of
compound 3-1. Although not wishing to be bound by any particular theory, it is
believed that
the presence of both the organic base and inorganic base is advantageous in
improving the
yield of the intermediate 3-3.
[0089] The reaction to form the intermediate 3-3 is carried out in a suitable
organic
solvent system which includes one or more organic solvents. A wide variety of
suitable
organic solvents can be employed for the solvent system, including polar
organic solvents,
such as polar aprotic organic solvents - i.e., organic solvents that are not
readily
deprotonated in the presence of a strongly basic reactant or reagent. Suitable
aprotic
solvents can include, by way of example and without limitation, ethers,
halogenated
hydrocarbons (e.g., a chlorinated hydrocarbon such as methylene chloride, and
chloroform),
propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone,
ethyl methyl
ketone, ethyl acetate, sulfolane, nitromethane, nitrobenzene, Also included
within the term
aprotic solvent are esters, alkylnitriles (such as acetonitrile), and many
ether solvents
including, without limitation, dimethoxymethane, tetrahydrofuran (THF), 2-
methyl-
tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,
tetrahydropyran, diisopropyl
ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl
ether, diethylene
glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol
dimethyl ether,
anisole, and t-butyl methyl ether. In some embodiments, the solvent system
includes a
halogenated hydrocarbon (e.g., methylene chloride). In some embodiments, the
solvent
system includes an ether (e.g., THF).
[0090] The mixed ester-halide intermediate 3-3 is hydrolyzed under appropriate
conditions, such as under basic conditions (e.g., in the presence of an
inorganic base such
as an alkali metal hydroxide, for example, an aqueous solution of NaOH), to
afford the bis-
(phosphoric acid mono-ester) salt 3-4 (the sodium salt when NaOH is used). In
some
embodiments, an aqueous solution of NaOH (for example, a 3N solution) is added
to
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facilitate the hydrolysis by adjusting the pH of the reaction mixture to a
value of greater than
7 (such as adjusting the pH to about 8 to about 9). In some embodiments, an
inorganic acid
(such as aqueous HCI solution) is added after the addition of a base (such as
aqueous
NaOH) so that the pH of the reaction mixture is adjusted to a value of about 8
to about 9.
[0091] The aqueous layer of the reaction mixture (containing salt 3-4) is
separated from the
organic layer (containing the organic solvent), for example, by using a
separatory funnel.
Then the bis-(phosphoric acid mono-ester) 3-5 is isolated/separated by
acidifying the
aqueous solution of salt 3-4 (for example, adjusting the pH of the aqueous
mixture to about 2
or about 1) using a suitable inorganic acid such as aqueous HCI solution, and
thus
precipitating the bis-(phosphoric acid mono-ester) 3-5. The precipitate is
isolated, e.g., by
filtration. In some embodiments, further purification of the bis-(phosphoric
acid mono-ester)
3-5 is achieved, for example, by preparative high-performance liquid
chromatography
(HPLC). In some embodiments, the entire process of making the bis-(phosphoric
acid
mono-ester) 3-5 from compound 3-1 (as shown in Scheme 3) is carried out in one
reaction
vessel (one-pot process).
Scheme 3
CHg
HO \ ~ - P(=O) (xl)2 CH3
~ OH O
/~N ~ ~
+ P(=O) (xl)s N P(=O) (xl)2
3-2 an organic base, ~
0 ~
~ an inorganic base, O /
solvent
N
0
v
3-1 3-3
O.P'O CH3 HO. 0
0 \ - HO'OP, CH3
hydrolysis I/ N 0 POO_ O OH
under basic O acidification, N
condition P-OH
precipitation 0
e.g., NaOH/Hz0 0 \ /
O
N/
N
3-4 3-5
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[0092] It should be noted that in the schemes described herein, if there are
functional
(reactive) groups present on a substituent group such as R1, R2, etc., further
modification
can be made if appropriate and/or desired. For example, a CN group can be
hydrolyzed to
afford an amide group; a carboxylic acid can be converted to an amide; a
carboxylic acid can
be converted to a ester, which in turn can be reduced to an alcohol, which in
turn can be
further modified. In another example, an OH group can be converted into a
better leaving
group such as mesylate, which in turn is suitable for nucleophilic
substitution, such as by
CN. One skilled in the art will recognize further such modifications. Thus, a
compound of
Formula I (such as compound 1-4 of Scheme 1) having a substituent which
contains a
functional group can be converted to another compound of Formula I having a
different
substituent group.
Methods
[0093] As described in U.S. Pat. No. 5,998,402, which is incorporated herein
by
reference in its entirety, bazedoxifene and salts thereof are selective
estrogen agonists with
affinity for the estrogen receptor. Unlike other types of estrogen agonists,
bazedoxifene and
salts thereof are antiestrogenic in the uterus and can antagonize the trophic
effects of
estrogen agonists in uterine tissues. Phosphorates (phosphoric acid esters) of
bazedoxifene
can serve as prodrugs of bazedoxifene (see Example 5 below). During metabolism
(e.g., in
the presence of alkaline phosphatase), the P-OR bond of a compound having the
formula
P(=O)(OH)20R is cleaved to yield the active drug (HOR). Accordingly, the
bazedoxifene bis-
phosphorates described herein, and compositions containing the same, can find
many uses
related to treating or preventing a disease, condition or disorder associated
with an estrogen
deficiency or an excess of estrogen. They may also be used in methods of
treatment for a
disease, condition or disorder which results from proliferation or abnormal
development,
actions or growth of endometrial or endometrial-like tissues.
[0094] The bis-phosphoric acid esters of bazedoxifene of this disclosure, and
compositions thereof have improved properties relating, for example, to
solubility and
bioavailability. For example, the bazedoxifene bis-phosphorate of Formula II
shows
improved solubility (about 4.0 mg/mL; see Example 4 below) compared with other
forms of
bazedoxifene (for example, the solubility of bazedoxifene ascorbate was
determined to be
1.66 mg/mL; see, e.g., U.S. Pat. Pub. No. 2005/0227964), which can result in
increased
bioavailability and lower dosages.
[0095] The bazedoxifene bis-phosphorates described herein have the ability to
behave
like estrogen agonists by lowering cholesterol and preventing bone loss.
Accordingly, the
bazedoxifene bis-phosphorates are useful for treating many diseases,
conditions or
disorders which result from estrogen effects and estrogen excess or deficiency
including
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osteoporosis, prostatic hypertrophy, male pattern baldness, vaginal and skin
atrophy, acne,
dysfunctional uterine bleeding, endometrial polyps, benign breast disease,
uterine
leiomyomas, adenomyosis, ovarian cancer, infertility, breast cancer,
endometriosis,
endometrial cancer, polycystic ovary syndrome, cardiovascular disease,
contraception,
Alzheimer's disease, cognitive decline and other CNS disorders, as well as
certain cancers
including melanoma, prostrate cancer, cancers of the colon, CNS cancers, among
others.
Additionally, the bazedoxifene bis-phosphorates can be used for contraception
in pre-
menopausal women, as well as hormone replacement therapy in post-menopausal
women
(such as for treating vasomotor disturbances such as hot flush) or in other
estrogen
deficiency states where estrogen supplementation would be beneficial. They can
also be
used in disease states where amenorrhea is advantageous, such as leukemia,
endometrial
ablations, chronic renal or hepatic disease or coagulation diseases or
disorders.
[0096] The bazedoxifene bis-phosphorates can be used in methods of treatment
for and
prevention of bone loss, which can result from an imbalance in a individual's
formation of
new bone tissues and the resorption of older tissues, leading to a net loss of
bone. Such
bone depletion results in a range of individuals, particularly in post-
menopausal women,
women who have undergone bilateral oophorectomy, those receiving or who have
received
extended corticosteroid therapies, those experiencing gonadal dysgenesis, and
those
suffering from Cushing's syndrome. Special needs for bone, including teeth and
oral bone,
replacement can also be addressed using the bazedoxifene bis-phosphorates in
individuals
with bone fractures, defective bone structures, and those receiving bone-
related surgeries
and/or the implantation of prosthesis. In addition to the problems described
above, the
bazedoxifene bis-phosphorates can be used in treatments for osteoarthritis,
hypocalcemia,
hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple
myeloma and
other forms of cancer having deleterious effects on bone tissues.
[0097] Methods of treating the diseases, conditions and disorders listed
herein are
understood to involve administering to an individual in need of such treatment
a
therapeutically effective amount of a bazedoxifene bis-phosphorate as
described herein or a
salt or solvate (e.g., hydrate) form thereof, or a solid dispersion or
composition containing
the same. In some embodiments, the bazedoxifene bis-phosphorates are
administered in
the form of a solid dispersion. As used herein, the term "treating" in
reference to a disease
includes preventing, inhibiting and/or ameliorating the disease.
[0098] As used herein, "individual" or "patient," used interchangeably, refers
to any
animal, including mammals, such as mice, rats, other rodents, rabbits, dogs,
cats, swine,
cattle, sheep, horses, primates, or humans.
[0099] As used herein, "therapeutically effective amount" refers to an amount
of active
compound or pharmaceutical agent that elicits a biological or medicinal
response in a tissue,
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system, animal, or human that is being sought by a researcher, veterinarian,
medical doctor
or other clinician, which includes one or more of the following:
(1) preventing the disease; for example, preventing a disease, condition or
disorder
in an individual that may be predisposed to the disease, condition or disorder
but does not
yet experience or display the pathology or symptomatology of the disease;
(2) inhibiting the disease; for example, inhibiting a disease, condition or
disorder in an
individual that is experiencing or displaying the pathology or symptomatology
of the disease,
condition or disorder (i.e., arresting or slowing further development of the
pathology and/or
symptomatology); and
(3) ameliorating the disease; for example, ameliorating a disease, condition
or
disorder in an individual that is experiencing or displaying the pathology or
symptomatology
of the disease, condition or disorder (i.e., reversing the pathology and/or
symptomatology).
Dosage and Formulation
[0100] The bazedoxifene bis-phosphorates described herein can be formulated
for
administration to a patient in any of a variety of ways. In some embodiments,
the
bazedoxifene bis-phosphorates are administered alone, i.e., without the
addition of
excipients or other additives. For example, solid dosage forms or dispersions
(e.g., tablets
or capsules) containing greater than about 95%, greater than about 98%, or
greater than
about 99% (by weight) of a bazedoxifene bis-phosphorate described herein are
directly
administered to a patient.
[0101] In some embodiments, a bazedoxifene bis-phosphorate described herein is
combined with one or more pharmaceutically acceptable carriers (excipients) to
form a
pharmaceutical composition for administration to a patient. The composition
can contain any
therapeutically effective amount of the bazedoxifene bis-phosphorate. In some
embodiments, the composition contains about 1 to about 99% by weight of the
bazedoxifene
bis-phosphorate. In further embodiments, the composition contains about 1 to
about 50% by
weight of the bazedoxifene bis-phosphorate. In yet further embodiments, the
composition
contains about 1 to about 30% by weight of the bazedoxifene bis-phosphorate.
In yet further
embodiments, the composition contains about 1 to about 20% by weight of the
bazedoxifene
bis-phosphorate. In yet further embodiments, the composition contains about 1
to about
10% by weight of the bazedoxifene bis-phosphorate.
[0102] Formulations containing the bazedoxifene bis-phosphorates can be
administered
in daily doses ranging from about 0.1 mg to about 1000 mg of a the
bazedoxifene bis-
phosphorate to a person in need. Exemplary dose ranges include from about 10
mg/day to
about 600 mg/day, or from about 10 mg/day to about 60 mg/day. The dosing can
be either
in a single dose or two or more divided doses per day. Such doses can be
administered in
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any manner that facilitates the compound's entry into the bloodstream
including orally, via
implants, parenterally, vaginally, rectally, and transdermally.
[0103] Transdermal administrations include all administrations across the
surface of the
body and the inner linings of body passages including epithelial and mucosal
tissues. Such
administration may be, e.g., in the form of a lotion, cream, colloid, foam,
patch, or
suspension.
[0104] Oral formulations containing the bazedoxifene bis-phosphorates
described herein
include any conventionally used oral forms, including without limitation
tablets, capsules,
buccal forms, troches, lozenges, oral liquids, and suspensions. In certain
embodiments, oral
forms containing the bazedoxifene bis-phosphorates described herein include
mixtures of
other active compounds and/or inert fillers and diluents such as the
pharmaceutically
acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial
sweetening
agents, powdered celluloses, such as crystalline and microcrystalline
celluloses, flours,
gelatins, and gums.
[0105] Tablet formulations can be made by conventional compression, wet
granulation,
or dry granulation methods and utilize pharmaceutically acceptable diluents
(fillers), binding
agents, lubricants, disintegrants, suspending or stabilizing agents,
including, but not limited
to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate,
microcrystalline cellulose,
carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid,
acacia gum,
xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine,
dextrin, sucrose,
sorbitol, dicalcium phosphorate, calcium sulfate, lactose, kaolin, mannitol,
sodium chloride,
talc, dry starches and powdered sugar. Oral formulations used herein may
utilize standard
delay or time release formulations or spansules. Suppository formulations may
be made
from traditional materials, including cocoa butter, with or without the
addition of waxes to
alter the suppositories melting point, and glycerin. Water soluble suppository
bases, such as
polyethylene glycols of various molecular weights, may also be used.
[0106] Film coatings useful with the present formulations are known in the art
and
generally consist of a polymer (usually a cellulose polymer), a colorant and a
plasticizer.
Additional ingredients such as wetting agents, sugars, flavors, oils and
lubricants can be
included in film coating formulations. The compositions and formulations
herein may also be
combined and processed as a solid, then placed in a capsule form, such as a
gelatin
capsule.
[0107] The filler or diluent can be any substance known in the art that is
useful for the
preparation of solid oral formulations. Non-limiting examples of
pharmaceutically acceptable
fillers are lactose, microcrystalline cellulose, sucrose, mannitol, calcium
phosphorate,
calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, and
xylitol.
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[0108] The present formulations can also include disintegrant agents. These
disintegrants can be selected from those known in the art, including
pregelatinized starch
and sodium starch glycolate. Other non-limiting examples of useful
disintegrants are
croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate,
clays (e.g.,
veegum or xanthan gum), cellulose floc, ion exchange resins, or effervescent
systems, such
as those utilizing food acids (such as citric acid, tartaric acid, malic acid,
fumaric acid, lactic
acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic
acid, and succinic
acid) and an alkaline carbonate component (such as sodium bicarbonate, calcium
carbonate, magnesium carbonate, potassium carbonate, and ammonium carbonate).
In
certain embodiments, disintegrant(s) useful herein can comprise from about 4%
to about
40% of the composition by weight, e.g., from about 15% to about 35%, e.g.,
from about 20%
to about 35%.
[0109] Some components can have multiple functions in the formulations; a
component
can act, for example, as both a filler and a disintegrant. Function of a
component in a
specific formulation may be singular even though its properties may allow
multiple
functionality.
[0110] The pharmaceutical formulations and excipient systems herein can also
contain
an antioxidant or a mixture of antioxidants, such as ascorbic acid. Other
antioxidants which
can be used include sodium ascorbate and ascorbyl palmitate, optionally in
conjunction with
an amount of ascorbic acid. An exemplary range for the amount of
antioxidant(s) in the
formulationis from about 0.05% to about 15% by weight, from about 0.5% to
about 15% by
weight, or from about 0.5% to about 5% by weight of the formulation. In some
embodiments,
the pharmaceutical formulations contain substantially no antioxidant.
[0111] Pharmaceutical compositions containing the bazedoxifene bis-
phosphorates
described herein can also be formulated with steroidal estrogens, such as
conjugated
estrogens, USP. The amount of the present bazedoxifene bis-phosphorates used
in the
formulation can be adjusted according to the particular formulation used, the
amount and
type of steroidal estrogen in the formulation, as well as the particular
therapeutic indication
being considered. In some embodiments, the bazedoxifene bis-phosphorates
described
herein are used in an amount sufficient to antagonize the effect of the
particular estrogen to
the level desired. The dose range of conjugated estrogens can be from about
0.3 mg to
about 2.5 mg, about 0.3 mg to about 1.25 mg, or about 0.3 mg to about 0.625
mg. An
exemplary range for the amount of a bazedoxifene bis-phosphorate described
herein in a
combination formulation is about 10 mg to about 40 mg. For the steroidal
estrogen
mestranol, a daily dosage can be from about 1 pG to about 150 pG, and for
ethinyl estradiol
a daily dosage of from about 1 pG to 300 pG can be used. In some embodiments,
the daily
dose is between about 2 pG and about 150 pG.
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[0112] An exemplary oral formulation contains a bazedoxifene bis-phosphorate
described herein and the following excipient systems:
a) a filler and disintegrant together forming from about 1% to about 99% by
weight (wt) of the total formulation, for example between about 20% and about
85% of the
formulation, of which from about 4% to about 45% by weight of the total
formulation is the
disintegrant; and
b) a lubricant forming from about 0.2% to about 15% of the composition (wt).
In
some embodiments the lubricant is magnesium stearate or another metallic
stearate (e.g.,
calcium stearate or zinc stearate), a fatty acid ester (e.g., sodium stearyl
fumarate), fatty acid
(e.g., stearic acid), fatty alcohol, glyceryl behenate, mineral oil, paraffin,
hydrogenated
vegetable oil, leucine, polyethylene glycol, metallic lauryl sulfate or sodium
chloride.
[0113] The percentages listed above for the filler, disintegrant, lubricant
and antioxidant
in the exemplary formulation are based on final pharmaceutical composition.
The remainder
of the final composition is made up of a bazedoxifene bis-phosphorate and, for
example,
additional active compounds and/or a pharmaceutically acceptable surface
covering, such
as a coating or capsule, as described herein. In some embodiments, the
bazedoxifene bis-
phosphorate comprises from about 1% to about 99%, about 10 to about 95%, or
about 20 to
about 90% by weight, of the final composition; and a coating or capsule
comprises up to
about 8%, by weight, of the formulation.
[0114] Additional excipients and dosage forms that are suitable for use in
connection
with the bazedoxifene bis-phosphorates are known in the art and described in,
for example,
Remington, J.P., Remington's Pharmaceutical Sciences, 17 th Ed., Mack
Publishing
Company, Easton, PA, 1985, which is incorporated herein by reference in its
entirety.
[0115] The following examples are offered for illustrative purposes, and are
not intended
to be limiting. Those of skill in the art will readily recognize a variety of
parameters which can
be changed or modified to yield the same or similar results.
EXAMPLES
Example 1: Preparation of Bazedoxifene Bis-phosphorates 4-2 and 4-3
[0116] As shown in Scheme 4, bazedoxifene free base (compound 4-1, 941 mg, 2
mmol) and tetrazole (840 mg, 12 mmol) were dissolved in 50 mL 1:1 mixture of
dry
tetrahydrofuran and methylene chloride. Under nitrogen and with stirring, di-
tert-butyl
diisopropyl-phosphoramidite (3.3 g, 12 mmol) was added and reaction mixture
was stirred
overnight at room temperature. Then 30% hydrogen peroxide (1.2 mL) was added
and
reaction mixture was stirred for 1 hour. Then the excess hydrogen peroxide was
reduced by
25 mL of saturated sodium metabisulfite aqueous solution in the presence of an
ice bath
over a period of 30 minutes. The reaction mixture was extracted with 50 mL of
ethyl acetate
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and washed with 2x50 mL of sodium metabisulfite. The organic layer was dried
over
anhydrous sodium sulfate and the organic solvent was removed by rotary
evaporation
(rotavap). The oil material (3 g) was obtained by preparative HPLC (Luna C18
column,
50x250 mm, flow=100 mL/min using 75% acetonitrile (ACN) and 25% 20 mM ammonium
acetate buffer pH=4.5). Retention time of the bazedoxifene bis-phosphorate 4-2
(C46H68N209P2) is 10 minutes. The acetonitrile was first removed from the
collected fraction
by rotavap and then extracted by CH2C12. The organic solvent was removed by
rotavap.
About 3 mL of the yellow oil material (the bazedoxifene bis-phosphorate 4-2)
was obtained
(measured accurate mass [M+H]+ 855.45; calculated 855.44) and then it was
dissolved into
4 mL of ethanol and 1 mL of 36% HCI. The reaction mixture was stirred at room
temp for 3
hours and then the pH of the mixture was adjusted by ammonium hydroxide to
about 5-7.
The pure final product (the bazedoxifene bis-phosphorate 4-3) was isolated by
preparative
HPLC (the same Luna column, flow=100mL/min, A=0.1 % trifluoroacetic acid
(TFA)/H20,
B=100% ACN; 0-2 min 15% B, 2-25 min from 15% B to 40% B). The product at the
major
peak at 15 minutes was collected and lyophilized. A total 237 mg of white
solid was
obtained. The structure of the bazedoxifene bis-phosphorate 4-3 (i.e., the
bazedoxifene bis-
phosphorate of Formula II) was characterized by high-resolution mass
spectrometry (HRMS)
(measured accurate mass [M+H]+ 631.20; calculated 631.19).
Scheme 4
O
HO ~ O-PO ~
I OH 0 I O-P-O~
~ N 1.Tetrazole, Di-t-butyl-diisopropyl 0; N 0
phosphoramidite, 1:1 THF and CHZCIZ I
2. 30% HzOz /~
O~\No 3. Sodium metabisulfate No
4-1 4-2
C H N O C46H68N209P2
so 3a z 3 Exact Mass: 854.44
Exact Mass: 470.26
Mol. Wt.: 470.60 O Mol. Wt.: 854.99
11
HO-P-O ~ O
OH ~ / O-P-OH
N OH
HC1 &-,,'
O,_,,-\ No
4-3
C30H36N209P2
Exact Mass: 630.19
Mol. Wt.: 630.56
Example 2: Characterization of the Bazedoxifene Bis-phosphorate 4-2
Proton and Carbon Nuclear Magnetic Resonance ('H-NMR and13C-NMR)
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[0117] The proton and carbon NMR spectra of the bazedoxifene bis-phosphorate 4-
2
prepared according to Example 1 in deuterated dimethyl sulfoxide (DMSO-d6) was
consistent with its structure. DMSO-d6 was used as internal reference for both
proton
(6=2.50 ppm) and carbon (6=39.5 ppm). Table 1 summarizes the chemical shift
assignment
of bazedoxifene bis-phosphorate 4-2.
O
11 4\9 \2 b 0
(Me)3C0-P O - II
I a d O-P-OC(Me)3
OC(Me)3 6 7/8 N 1 \/ OC(Me)s
12 10
~ 11 16
13
/
O 14 15
18 ? 17
b o e'
c' d'
Bazedoxifene bis-phosphorate 4-2
Table 1. Chemical shift assignment of bazedoxifene bis-phosphorate 4-2
Carbon S C S H
numbers
2 137.76
3 108.40
4 109.56, d, 7.31, t, J=1.81
J=4.32
5 144.65, d,
J=7.29
6 114.64, J=4.98 6.94, dd, J=8.87;
1.88
7 111.10 7.36, d, J=8.87
8 133.28
9 128.30
46.15 5.23, s
11 130.63
12,16 127.40 6.75, d, J=9.03
13,15 114.52 6.78, d, J=9.03
14 156.83
17 63.5, br 4.17, t like, br
18 55.10 3.25, s, br
a 127.40
b,f 131.65 7.41, d, J=8.50
c,e 120.02, d, 7.29, d, J=8.50
J=5.08
d 150.80, d,
J=6.92
a',f' 54.40 3.08, s, br
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WO 2008/106600 PCT/US2008/055326
Carbon S C S H
numbers
b',e' 24.16 1.56, s, br.
c',d' 24.06, br. 1.72, s, br.
3-Me 9.17 2.16
-C(Me)3 83.44, d, J=7.43
82.62, d, J=7.43
-C(Me)3 29.48, d, J=4.37 1.45
29.41, d, J=4.37
Example 3: Characterization of the Bazedoxifene Bis-phosphorate 4-3
Proton and Carbon Nuclear Magnetic Resonance ('H-NMR and13C-NMR)
[0118] The proton and carbon NMR spectra of the bazedoxifene bis-phosphorate 4-
3
prepared according to Example 1 in deuterated dimethyl sulfoxide (DMSO-d6) was
consistent with its structure. DMSO-d6 was used as internal reference for both
proton
(6=2.50 ppm) and carbon (6=39.5 ppm). Table 2 summarizes the chemical shift
assignment
of bazedoxifene bis-phosphorate 4-3.
O
HO-PI-O ~9 3 2 b- ~ II
S I \ O-P-OH
OH 7 OH
/8 N 1 a\ / d
12 10
~ 11
13 \
/ 16
O 14 15
18 17
b~ )e'
\dJd/'
Bazedoxifene bis-phosphorate 4-3
Table 2. Chemical shift assignment of bazedoxifene bis-phosphorate 4-3
Carbon S13C S'H
numbers
2 137.79
3 108.02
4 108.99, d, J=4.4 7.28, s, br.
145.4, d, J=6.7
6 115.2, d, J=4.4 6.92, dd, J=8.79;
1.44
7 110.62 7.22, m overla
8 132.91
9 128.42
46.08 5.16s
11 131.05*
12,16 127.36 6.75, m
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WO 2008/106600 PCT/US2008/055326
Carbon S C S H
numbers
13,15 114.55 6.75, m
14 156.44
17 62.27 4.18, t like, br.
18 54.83 3.41, t like, br
a 126.02
b,f 131.10* 7.22, m (overlap)
c,e 119.97, d, 7.22, m (overlap)
J=5.39
d 152.1, d, J=6.5
a',f' 54.21 3.31 (eq), s, br.
3.17, (ax), s, br.
b',e' 25.94 1.55, s, br.
c',d' 22.59 1..74, s, br.
3-Me 9.19 2.04,s
OH 9.99
Example 4: Solubility of Bazedoxifene Bis-phosphorate 4-3 at 37 C
[0119] Samples of bazedoxifene bis-phosphorate 4-3 of Example 1 (ca. 20 mg
each)
were placed in vials to which 1 mL of water was added. The mixture was shaken
by hand
for 10 seconds and then placed in a water bath of 37 C at 50 rotations/minute
for 18 hours.
The samples were then filtered through syringe disc filters (13 mm of 0.2 pm
nylon
(Whatman)). The filtrate was analyzed by HPLC. The solubility of bazedoxifene
bis-
phosphorate 4-3 was determined to be 4 mg/mL.
Example 5: Conversion of Bazedoxifene Bis-phosphorate 4-3 to Bazedoxifene
[0120] The conversion of bazedoxifene bis-phosphorate 4-3 (5 pg/mL in 20 mM
Tris
buffer, pH 7.4) to bazedoxifene was observed in vitro with alkaline
phosphatase.
Concentration of alkaline phosphatase was -7 units. Table 3 summarizes the in
vitro
conversion profile of bazedoxifene bis-phosphorate 4-3 to bazedoxifene in the
presence of
alkaline phosphatase.
Table 3
ime (min) 0.0 1.0 2.0 3.0 5.0 10.0 20.0 30.0
% bazedoxifene bis-phosphorate 4-3 100.0 2.2 0.0 0.0 0.0 0.0 0.0 0.0
% intermediate bazedoxifene mono- 0.0 82.7 53.5 46.8 19.0 11.5 1.0 1.8
hos horate
% bazedoxifene 0.0 15.2 46.5 53.2 81.0 88.5 99.0 98.2
Example 6: Three-day Immature Rat Uterine Assay
[0121] The in vivo effect of bazedoxifene bis-phosphorate 4-3 on uterine
weight was
observed as shown in Table 4. Immature Sprague Dawley rats were treated once
daily for
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WO 2008/106600 PCT/US2008/055326
three days (see, e.g., Komm et al. Endocrinology, 2005, 146(9), 3999-4008,
which is
incorporated herein by reference in its entirety). Each group (N=6) was dosed
orally with
ethinyl estradiol (EE), EE + 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-
phenyl)-3-
methyl-1 H-indol-5-ol (bazedoxifene/BZA), or EE + 4-3. The vehicle was 2%
Tween 80/ 0.5%
methylcellulose. Approximately 24 hours after the last dose, the animals were
euthanized
and uteri were removed and weighed after trimming associated fat and
expressing any
internal fluid.
Table 4
Mean Uterine Standard Standard
Treatment Weight (mg) Deviation Erro
ehicle 28.33 4.13 1.68
EE (0.5 g/rat) 99.57 16.8 6.86
EE (0.5 g/rat) + BZA (15 pg/rat) 52.27 3.93 1.61
EE (0.5 g/rat) + BZA (5 pg/rat) 70.95 5.69 2.32
EE (0.5 g/rat) + 4-3 (500 pg/rat) 29.58 5.96 2.43
EE (0.5 g/rat) + 4-3 (167 pg/rat) 34.40 5.16 2.11
EE (0.5 g/rat) + 4-3 (55.6 pg/rat) 38.88 3.07 1.25
EE (0.5 g/rat) + 4-3 (18.5 pg/rat) 54.02 6.04 2.47
EE (0.5 g/rat) + 4-3 (6.2 pg/rat) 63.98 8.04 3.28
EE (0.5 g/rat) + 4-3 (2.1 pg/rat) 81.93 11.1 4.53
EE (0.5 g/rat) + 4-3 (0.69 pg/rat) 94.33 6.59 2.69
Example 7: Preparation of Bazedoxifene Bis-phosphorate 5-5
[0122] As shown in Scheme 5, 1-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-2-(4-hydroxy-
phenyl)-3-methyl-lH-indol-5-ol (bazedoxifene free base; compound 5-1, 3.88 g,
8.08 mmol)
and pyridine (7.0 mL, 86.4 mmol, 11 molar equivalents) were dissolved in
dichloromethane
(70 mL). To this solution was added sodium carbonate (3.4 g) and phosphorous
oxychloride
(compound 5-2, 2.00 mL, 21.8 mmol, 2.7 equivalents) with stirring. The
stirring was
continued under nitrogen and the reaction was monitored by mass spectroscopy.
Upon
completion of phosphorylation (formation of compound 5-3), a cold NaOH
solution (3N, 20
mL) and water (300 mL) was added. Afterward, the pH of the aqueous portion of
the mixture
was adjusted to 8-9 by addition of proper amount of aqueous HCI solution.
Dichloromethane
(100 mL) then was added. After the mixture was mixed thoroughly, the aqueous
layer was
separated and was acidified by addition of concentrated HCI aqueous solution
(the pH value
of the aqueous layer was adjusted to about 1) . The solid precipitated was
then collected by
filtration to give an off-white solid (compound 5-5, 3.10 g, phosphoric acid
mono-[1-[4-(2-
33
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WO 2008/106600 PCT/US2008/055326
azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-(4-phosphonooxy-phenyl)-1 H-indol-5-yl]
ester). The
solid 5-5 was further purified using preparative HPLC.
Scheme 5
CH3
HO ~ \ - P(=O)CIz CHa
~ OH O
/~N ~ ~
+ P(=OCIa N (=0)CI2
5-2 pyridine ~
~ /
NazCO3, CHzCIz O
N
N
5-1 5-3
O-P ~ CH3 HO O
O HO'P" CH3
O O- O
O OH
hydrolysis N OP-O acidification (pH -1), N OP
O -OH
~ precipitation a
\ / pH = $-9 l O
(N
N
5-4 5-5
[0123] Various modifications of this disclosure, in addition to those
described herein, will
be apparent to those skilled in the art from the foregoing description. Such
modifications are
also intended to fall within the scope of the appended claims.
34
