Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMPOUNDS AND COMPOSITIONS FOR TREATING CANCER
Claim of Priority
This application claims priority to United States Provisional Application
Serial
No.61/275,754, filed September 2, 2009 and entitled "COMPOUNDS AND
COMPOSITIONS FOR TREATING CANCER" which is incorporated by reference in its
entirety."
Field of the Invention
The invention relates to compounds and composition for the treatment and
prevention of cancer. The invention also covers all diseases that may be
treated by
selective modulation of levels of reactive oxygen species in diseased cells
versus normal
cells. Methods for the preparation and administration of such compositions are
also
disclosed.
Background of the Invention
The present invention relates to compounds and compositions for the treatment
and prevention of cancer, or decreasing the intensity or duration of cancer.
The invention
also covers all diseases that may be treated by selective modulation of levels
of reactive
oxygen species in diseased cells versus normal cells.
All living aerobic cells are normally exposed to some reactive oxygen species
(ROS) but if ROS levels rise, oxidative stress (OS) occurs, which results in
oxygen and
oxygen-derived oxidants, and in turn increases the rates of cellular damage.
Cells are
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exposed to both endogenous and exogenous sources of ROS. At high levels, ROS
can
lead to impaired physiological function through cellular damage of DNA,
proteins, lipids,
and other macromolecules, which can lead to certain human pathologies
including
cancers, neurodegenerative disorders, and cardiovascular disease, as well as
aging.
Moreover, ROS are important in mediating apoptosis.
Selectively increasing levels of ROS in cancer cells and not normal cell may
be a
safe and effective method for treating cancer.
x~Eea-
Me4i
ANIQ
....................................................................::.........
.................................................
.....::::::::::................
Z ti
z
Reducing ROS leads to treatment of neurodegenerative diseases, inflammation
and for the treatment of a broad range of disorders including,
neurodegenerative diseases,
chronic inflammatory diseases, inflammatory bowel disease, rheumatoid
arthritis,
psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's
disease,
congestive heart failure and skin disease.
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There remains a need for compounds which can increase ROS in cancer cells
while reducing or maintaining ROS levels in normal cells..
Summary of the Invention
Compounds and compositions that are useful for the treatment and prevention of
cancer are provided. The present invention encompasses compounds having the
following formula IA, or salts, derivatives, or mixtures thereof:
15 Ri
R2 A
B--C
R3
IA
or a pharmaceutically acceptable salt or pharmaceutically acceptable
derivative thereof,
wherein:
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Ring A is selected from the group consisting of one or more monocyclic aryl,
one or
more heteroaryl, a 3-7 membered saturated or partially unsaturated carbocyclic
ring, an 8-
membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6
membered
5 monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected
from
nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated
heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen,
oxygen,
or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated
heterocyclic ring
having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur,
or an 8-
10 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur;
each R1, R2, and R3 is independently selected from the group consisting of
hydrogen,
halogen, deuterium, CF3, CN, OR, SR, NRR, NRCOR, NRCONRR, NRCO2R, COR,
CO2R, NOR, NO2, CONRR, OC(O)NRR, SO2R, SO2NRR, NRSO2R, NRSO2NRR,
C(O)C(O)R, or C(O)CH2C(O)R, alkyl, aryl, heteroaryl and morpholino,
wherein either R1 and R2, or R2 and R3 are optionally taken together to form a
4-8
membered saturated, partially unsaturated, or fully unsaturated ring having 0-
3
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and z is 0, 1 or 2;
each R is independently selected from hydrogen or an optionally substituted C1-
C4
aliphatic moiety, wherein:
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or alternately, two R moieties bound to the same nitrogen atom are optionally
taken
together with the nitrogen atom to form a 3-7 membered saturated, partially
unsaturated,
or fully unsaturated ring having 1-2 additional heteroatoms independently
selected from
nitrogen, oxygen, or sulfur;
B is selected from:
X R4 X
R4 X
R5 R5
R6 X R6 X
VW \V
R7 R7
wherein
R4, R5, R6 and R7 are independently selected from a substituted or
unsubstituted Ci to
C12 alkyl, a substituted or unsubstituted Ci to C12 alkenyl or a substituted
or unsubstituted
CI to C12 alkynyl;
X is 0, S; and
C is a saturated or unsaturated heteroaryl or a saturated or unsaturated Cl to
C7
heterocyclic containing one or more hetero atoms wherein the heteroatoms are
independently selected from N, 0 or S;
or C a fused ring; and
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wherein any one or more H is optionally replaced by a deuterium.
The compounds of the present invention may be produced using piperlongumine
as a starting material yet offer numerous advantages over piperlongumine. In
the course
of the experimental investigations, it was found that more than 0.25 mg/ml of
piperlongumine in DMS 0 was precipitated out when diluted 1:10 inphosphate
buffered
saline or water. It was also found that piperlongumine is soluble in water at
0.1 mg/mL.
The compounds of the instant invention are highly soluble in water at
concentration of at
least 25mg/mL facilitating pharmaceutical preparation and delivery. Many
chemotherapeutic agents transiently increase ROS levels in both cancer cells
and normal
cells.In contrast, the compounds of the instant invention have a large
therapeutic window
and do not increase ROS or cause DNA damage in normal cells. Compared to
current
standards such as etoposide, 5-fluorouracil, cisplatin and taxol, the drug is
comparable in
its effect on net cancer cell growth (melanoma, ovarian, renal, glioblastoma,
drug-
resistant non-small cell lung cancer cell lines) as a percent of control.
Brief Description of the Drawings
FIG. 1 shows the effect of compounds on pancreatic cells
FIG. 2 shows viability of normal breast epithelium in the presence of
compounds
of the invention.
FIG. 3 shows the effect of compounds on EJ Bladder Carcinoma cells
FIG. 4 shows the effect of compounds on pancreatic cells
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FIG. 5 shows the effect of SP2007 and SP83 on bladder tumor xenograft-bearing
mice
Description of the Preferred Embodiments
Definitions
The term "about" or "approximately" means within an acceptable error range for
the particular value as determined by one of ordinary skill in the art, which
will depend in
part on how the value is measured or determined, i.e., the limitations of the
measurement
system. For example, "about" can mean within 1 or more than 1 standard
deviations, per
practice in the art. Alternatively, "about" with respect to the formulations
can mean a
range of up to 10%, preferably up to 5%.
The terms "alkyl", "alkenyl", "alkoxy", "alkylene", "alkenylene", "alkenyl",
"alkyl(arylene)", "alkynyl", and "aryl(alkylene)" include, but are not limited
to, linear and
branched alkyl, alkenyl, alkoxy, alkylene, alkenylene, alkyl(arylene), and
aryl(alkylene)
groups, respectively.
The phrase "pharmaceutically acceptable" refers to compounds or compositions
that are physiologically tolerable and do not typically produce an allergic or
similar
untoward reaction, such as gastric upset, dizziness and the like, when
administered to a
mammal.
An "effective amount of compound" means the amount of compound, salt or salts,
or (including its solvates, active metabolites, prodrugs, or racemates or
enantiomers
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thereof (assuming the salt has a chiral center)) that, when administered to a
mammal for
treating or preventing a state, disorder or condition is sufficient to effect
such treatment
or prevention. The "effective amount" will vary depending on the active
ingredient, the
state, disorder, or condition to be treated and its severity, and the age,
weight, physical
condition and responsiveness of the mammal to be treated. According to one
embodiment
of the present invention, a therapeutically effective amount of a compound is
an amount
effective to treat any one of the above mentioned disorders. The compound or
its salt or
salts may be augmented with a second medication (such as a chemotherapeutic
agent, or
adjunctive chemotherapeutic agent to treat any of the aforementioned
disorders, such as
malignancies).
An "effective amount of the pharmaceutical formulation" is an amount of the
pharmaceutical formulation described which is effective to treat or prevent a
condition in
a subject to whom it is administered over some period of time, e.g., provides
a
therapeutic effect during a desired dosing interval. Generally, an effective
amount of the
pharmaceutical formulation includes amounts of compound its salt or salts to
treat or
prevent the desired condition over a desired period of time.
As used herein, the term "treat" includes one or more of the following:
(a) arresting, delaying the onset (i.e., the period prior to clinical
manifestation of a disorder) and/or reducing the risk of developing or
worsening a disorder;
(b) relieving or alleviating at least one symptom of a disorder in a
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mammal, including for example, cancer; or
(c) relieving or alleviating the intensity and/or duration of a manifestation
of a disorder experienced by a mammal including, but not limited to, those
which are in response to a given stimulus (e.g., pressure, tissue injury or
cold temperature).
The term "treat" also includes prophylactically preventing, curing, healing,
alleviating, relieving, altering, remedying, ameliorating, improving, or
affecting a
condition (e.g., a disease), the symptoms of the condition, or the
predisposition toward
the condition.
The term "sustained release" as used herein refers to the release of an active
ingredient over an extended period of time leading to lower peak plasma
concentrations
and a prolonged Tmax as compared to "immediate release" formulations of the
same active
ingredient.
The term "bioavailability" refers to the rate and extent to which the active
ingredient (compound its salt or salts) or active moiety is absorbed from a
drug product
and becomes systematically available.
The term "polymorph" refers to crystallographically distinct forms of a
substance.
The term "hydrate" as used herein includes, but is not limited to, (i) a
substance
containing water combined in the molecular form and (ii) a crystalline
substance
containing one or more molecules of water of crystallization or a crystalline
material
containing free water.
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The term "solvate" as used herein includes, but is not limited to, a molecular
or
ionic complex of molecules or ions of a solvent with molecules or ions of a
compound or
its salt or salts.
The term "adjunctive chemotherapeutic agent" includes agents which treat,
alleviate, relieve, or amelliorate the side effects of chemotherapeutic
agents. Such agents
include those which modify blood cell growth and maturation. Examples of
adjunctive
chemotherapeutic agents include, but are not limited to, filgrastim and
erythropoietin.
The term "salt" includes compound salt or salts, complexes and active
metabolites, prodrugs, racemates, enantiomers, and hydrates thereof.
The term "chemotherapeutic agent" includes any agent which treats, prevents,
cures, heals, alleviates, relieves, alters, remedies, ameliorates, improves,
or affects
malignancies and their metastasis. Examples of such agents (also known as
"antineoplastic agents") include, but are not limited to, prednisone,
fluorouracil (e.g., 5-
fluorouracil (5-FU)), anastrozole, bicalutamide, carboplatin, cisplatin,
chlorambucil,
docetaxel, doxorubicin, flutamide, interferon-alpha, letrozole, leuprolide,
megestrol,
mitomycin, paclitaxel, plicamycin (Mithracin.TM.), tamoxifen, thiotepa,
topotecan,
valrubicin, vinvlastin, vincristine, and any combination of any of the
foregoing. Further
examples are provided herein.
The term `Hydrogen" or "H" includes any form of hydrogen, including
deuterium.
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Compounds
The present invention provides compounds and compositions which treat and
prevent
cancer. Compounds of the present invention include those having the following
formula
I:
RI
BC
R2
R3
I
or a pharmaceutically acceptable salt or pharmaceutically acceptable
derivative thereof,
wherein:
Ring A is selected from the group consisting of one or more monocyclic aryl,
one or
more heteroaryl, a 3-7 membered saturated or partially unsaturated carbocyclic
ring, an 8-
10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6
membered
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monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated
heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen,
oxygen,
or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated
heterocyclic ring
having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur,
or an 8-
membered bicyclic heteroaryl ring having 1-5 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur;
each R1, R2, and R3 is independently selected from the group consisting of
hydrogen,
10 halogen, deuterium, CF3, CN, OR, SR, NRR, NRCOR, NRCONRR, NRCO2R, COR,
CO2R, NOR, NO2, CONRR, OC(O)NRR, SO2R, SO2NRR, NRSO2R, NRSO2NRR,
C(O)C(O)R, or C(O)CH2C(O)R, alkyl, aryl, heteroaryl and morpholino,
wherein either R1 and R2, or R2 and R3 are optionally taken together to form a
4-8
membered saturated, partially unsaturated, or fully unsaturated ring having 0-
3
heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently selected from hydrogen or an optionally substituted C1-
C4
aliphatic moiety (i.e. alkyl, alkenyl, or alkynyl), wherein:
or alternately, two R moieties bound to the same nitrogen atom are optionally
taken
together with the nitrogen atom to form a 3-7 membered saturated, partially
unsaturated,
or fully unsaturated ring having 1-2 additional heteroatoms independently
selected from
nitrogen, oxygen, or sulfur;
B is selected from:
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R4 X X R4 X R6 X
R5 R5 R7
R6;-, X
R7
wherein
R4, R5, R6 and R7 are independently selected from a substituted or
unsubstituted Ci to
C12 alkyl, a substituted or unsubstituted Ci to C12 alkenyl or a substituted
or unsubstituted
C1 to C12 alkynyl;
X is 0, S; and
C is a saturated or unsaturated heteroaryl or a saturated or unsaturated Cl to
C7
heterocyclic containing one or more hetero atoms wherein the heteroatoms are
independently selected from N, 0 or S;
or C is a fused ring; and
wherein any one or more H is optionally replaced by a deuterium.
In another embodiment, the compounds of the invention are compounds of Formula
I
above wherein ring A is selected from:
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Y I YY YY
Y
wherein the ring carries R1, R2 and R3 as defined above;
wherein Y is N, 0 or S; and
C is selected from:
X 1 X /111
R10 I I ~ \
R11 R10 R11
X
N
wherein the ring is optionally substituted with one or more R10 and R11,
wherein Rio and
R11 are independently selected from a substituted or unsubstituted Ci to C12
alkyl, a
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substituted or unsubstituted Ci to C12 alkenyl or a substituted or
unsubstituted Ci to C12
alkynyl, an ether, a thioether, aryl,
n is 1, 2 or 3;
X1is0orS;
In a preferred embodiment, the compound of formula I is represented by the
following
compounds:
O O
MeO
\ N
O
OMe
CN)
O
O O
MeO
N
O
OMe
N
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0 0
MeO
N
O
OMe
/NH
O O
MeO
N
O
OMe
NH
2 and
0 0
MeO
N
O
J OMe
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In one embodiment, the compounds of the present invention interact with
proteins
to increase ROS in cancer cells but not in normal cells. In one embodiment,
the
compounds of the present invention increase phosphor-JNK levels. In one
embodiment,
the compounds of the present invention increase p53 activity. In one
embodiment, the
compounds of the present invention increase p21 activity. In one embodiment,
the
compounds of the present invention decrease pro-survival gene activity. In one
embodiment, the compounds of the present invention induce apoptosis in cancer
cell
lines.
In another embodiment, the one or more compounds of the instant invention are
used to treat cancer. Another embodiment includes a method for increasing
apoptosis by
administering a compound of the instant invention. Another embodiment includes
a
method for increasing p53 activity by administering one or more compounds of
the
instant invention. Another embodiment includes a method for increasing p21
activity by
administering one or more compounds of the instant invention. Another
embodiment
includes a method of preferentially inducing DNA damage in cancer cells by
administering one or more compounds of the instant invention. Another
embodiment is a
method of suppressing DNA damage in normal cells by administering one or more
compounds of the instant invention.
In another embodiment, the invention provides a method for improving the
expression of proteins associated with normal cell survival. In another
embodiment, the
invention provides for a method of sparing normal cells while killing cancer
cells.
In another embodiment, the invention provides a method of administering a
compound of the instant invention at a dose of about 100mg/kg to about
3000mg/kg. In
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another embodiment the invention provides a method of administering a compound
of the
instant invention at a dose of about 2.5 mg/kg to about 10mg/kg. In some
embodiments, a
therapeutically effective amount is less than 50 mg/kg, such as less than 45
mg/kg, less
than 40 mg/kg, less than 35 mg/kg, less than 30 mg/kg, less than 25 mg/kg,
less than 20
mg/kg or less than 15 mg/kg. In some embodiments, a therapeutically effective
amount is
less than 10 mg/kg, such as less than 9 mg/kg, less than 8 mg/kg, less than 7
mg/kg, less
than 6 mg/kg, less than 5 mg/kg, less than 4 mg/kg, less than 3 mg/kg or less
than 2
mg/kg. In some embodiments, a therapeutically effective amount is less than
1.5 mg/kg,
such as less than 1.4 mg/kg, less than 1.3 mg/kg, less than 1.2 mg/kg, less
than 1.1
mg/kg, less than 1 mg/kg, less than 0.9 mg/kg, less than 0.8 mg/kg, less than
0.7 mg/kg,
less than 0.6 mg/kg, less than 0.5 mg/kg, less than 0.4 mg/kg, less than 0.3
mg/kg, less
than 0.2mg/kg or less than 0.1 mg/kg.
In another aspect, the invention provides a method for inhibiting cell
proliferation.
In some embodiments, the method for inhibiting cell proliferation comprises
contacting a
cell with an effective amount of a composition comprising a compound of the
invention
to inhibit the proliferation of the cell. In some embodiments, the method
further
comprises contacting the cells with a compound of the invention and a
chemotherapeutic
agent. In another aspect, the invention provides a method for increasing
apoptosis of a
cell or in a population of cells. In some embodiments, the method for
increasing
apoptosis of a cell or in a population of cells, the method comprises
contacting the cell or
population of cells with an effective amount of a composition comprising a
compound of
the invention to increase apoptosis in the cell or population of cells. In
some
embodiments, the number of apoptotic cells in a population of cells is
increased by at
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least two-fold. In some embodiments, the number of apoptotic cells in a
population of
cells is increased by at least five-fold. In some embodiments, the number of
apoptotic
cells in a population of cells is increased by at least ten-fold. In some
embodiments, the
method further comprises contacting the cells with a compound of the invention
and a
chemotherapeutic agent.
In another embodiment one or more compounds of the instant invention are
administered with one or more chemotherapeutic agent. In another embodiment,
one or
more compounds of the instant invention are administered prior to one or more
chemotherapeutic agents. In another embodiment, one or more compounds of the
instant
invention are administered following one or more chemotherapeutic agents.
Chemotherapeutic agents include, but are not limited to an agent which is
administered to a subject for the purpose of treating a cancer.
Chemotherapeutic agents
include, but are not limited to antiproliferative compounds, anti-neoplastic
compounds,
anti-cancer supplementary potentiating agents and radioactive agents. One of
ordinary
skill in the art is familiar with a variety of chemotherapeutic agents, or can
find those
agents in the routine art, which are used in the medical arts to treat cancer.
Chemotherapeutic agents include, but are not limited to, the following sub-
classes
of compounds: Antineoplastic agents such as: Acivicin; Aclarubicin; Acodazole
Hydrochloride; Acronine; Adozelesin; Adriamycin; Aldesleukin; Altretamine;
Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole;
Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin;
Batimastat;
Buniodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate;
Bizelesin;
Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin;
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Calusterone; Caracemide; Carbetimer; Carboplatin;Carmustine; Carubicin
Hydrochloride; Carzelesin; Cedefingol; Chlorombucil; Cirolemycin; Cisplatin;
Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine;
DACA
(N-[2- (Dimethyl-amino)ethyl]acridine-4-carboxamide); Dactinomycin;
Daunorubicin
Hydrochloride; Daunomycin; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine
Ifesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride;
Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin;
Edatrexate;
Eflornithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine;
Epirubicin 30 Hydrochloride; Erbulozole; Esorubicin Hydrochloride;
Estramustine;
Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil 1131; Etoposide;
Etoposide
Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide;
Floxuridine;
Fludarabine Phosphate; Fluorouracil; 5-FdUMP; Flurocitabine; Fosquidone;
Fostriecin
Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold An 198; Hydroxyurea;
Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;
Interferon Alfa-2b;
Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta-la; Interferon Gamma-
lb;
Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole;
Leuprolide Acetate;
Liarozole Hydrochloride; 5 Lometrexol Sodium; Lomustine; Losoxantrone
Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride;
Megestrol
Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine;
Methotrexate;
Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin;
Mitocromin;
Mitogillin; Mitomalcin; Mitomycin,. Mitosper; Mitotane; Mitoxantrone
Hydrochloride;
Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel
Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide;
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Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
Porfimer
Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;
Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol;
Safingol
Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin;
Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;
Streptozocin;
Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan
Sodium;
Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone;
Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thymitaq; Tiazofurin;
Tirapazamine;
Tomudex; TOP-53; Topotecan Hydrochloride; Toremifene Citrate; Trestolone
Acetate;
Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;
Tubulozole
Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine;
Vinblastine Sulfate; Vincristine; Vincristine Sulfate, Vindesine; Vindesine
Sulfate;
Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine
Tartrate;
Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin;
Zorubicin
Hydrochloride;2-Chlorodeoxyadenosine; 2'-Deoxyformycin; 9-aminocamptothecin;
raltitrexed; N-propargyl-5, 8-dideazafolic acid, 2-chloro-2'-arabino-fluoro-2'-
deoxyadenosine; 2-chloro-2'-deoxyadenosine; anisomycin; trichostatin A; hPRL-
G129R;
CEP-75 1; linomide; Piritrexim Isethionate; Sitogluside; Tamsulosin
Hydrochloride and
Pentomone. Anti-neoplastic compounds include, but are not limited to 20-epi-
1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene;
adecypenol;
adozelesin; aldesleukin; ALL-TK antogonists; altretamine; ambamustine; amidox;
amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;
anastrozole;
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andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;
antarelix; anti-
dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma;
antiestrogen;
antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis
gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine
deaminase;
asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin
3; azasetron;
azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives;
beta-alethine;
betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;
bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate;
bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin
derivatives
(e.g., 10-hydroxy-camptothecin); canarypox IL-2; capecitabine; carboxamide-
amino-
triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor;
carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B;
cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; 15 cis-porphyrin;
cladribine;
clomifene analogues; clotrimazole; collismycin A; collismycin 13;
combretastatin A4;
combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin
8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam;
cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab;
decitabine; dehydrodidemnin 10 deslorelin; dexifosfamide; dexrazoxane;
dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;
dihydrotaxol;
dioxamycin; diphenyl spiromustine; discodermolide; docosanol; dolasetron;
doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;
edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;
epothilones;
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epithilones; epristeride; estramustine analogue; estrogen agonists; estrogen
antagonists;
etanidazole; etoposide; etoposide 4'-phosphate (etopofos); exemestane;
fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;
fluasterone;
fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase
inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin;
hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone;
ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like
growth
factor-1 receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane;
iododoxorubicin; ipomeanol; irinotecan; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N
triacetate;
lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin;
letrozole; leukemia
inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen +
progesterone;
leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic
disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin;
lombricine;
lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan;
lutetium
texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;
marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors;
menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor;
mifepristone; miltefosine; mirimostim; mismatched double stranded RNA;
mithracin;
mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast
growth
factor-saporin; mitoxantrone;mofarotene; molgramostim; monoclonal antibody,
human
chorionic gonadotrophin;monophosphoryl lipid A + myobacterium cell wall sk;
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mopidamol; multiple drug resistancegene inhibitor, multiple tumor suppressor 1-
based
therapy; mustard anticancer agent;15 mycaperoxide B; mycobacterial cell wall
extract;
myriaporone; N-acetyldinaline;N-substituted benzamides; nafarelin; nagrestip;
naloxone
+ pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin;
neridronic
acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators;
nitroxide
antioxidant; nitrullyn; 06-benzylguanine;octreotide; okicenone;
oligonucleotides;
onapristone; ondansetron; oracin; oral cytokine inducer; ormaplatin;
osaterone;
oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives;
palauamine;
palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin;
pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;
phosphatase
inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim;
placetin A;
placetin B; plasminogen activator inhibitor; platinum complex; platinum
compounds;
platinum-triamine complex; podophyllotoxin; porfimer sodium; porfiromycin;
propyl bis-
acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune
modulator;
protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein
tyrosine
phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists;
raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras
inhibitors; ras-GAP
inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII
retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1;
ruboxyl;
safingol; saintopin; SarCNU; sarcophytol A; Sargramostim; Sdi 1 mimetics;
semustine;
senescence derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors;
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signal transduction modulators; single chain antigen binding protein;
sizofiran;
sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin
binding
protein; sonermin; 5 sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide;
stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide
antagonist;
suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium;
telomerase inhibitors; temoporfin; temozolomide; teniposide;
tetrachlorodecaoxide;
tetrazomine; thaliblastine; thalidomide; thiocoraline; thrombopoietin;
thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid
stimulating
hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride;
topotecan;
topsentin; toremifene; totipotent stem cell factor; translation inhibitors;
tretinoin;
triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine
kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex urogenital sinus-
derived growth
inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B;
vector system,
erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;
vinorelbine;
vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin
stimalamer.
Anti-cancer supplementary potentiating agents include, but are not limited to,
Tricyclic
anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline,
clomipramine,
trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and
maprotiline); non-
tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram);
Ca2+
antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine);
Calmodulin
inhibitor (e.g. prenylamine, trifluoroperazine and clomipramine); Amphotericin
B;
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Triparanol analogues (e.g. tamoxifen); antiarrhythmic drugs (e.g., quinidine);
antihypertensive drugs (e.g. reserpine); Thiol depleters (e.g., buthionine and
sulfoximine)
and Multiple Drug Resistance reducing agents such as Cremaphor EL. The
compounds of
the invention also can be administered with cytokines such as granulocyte
colony
stimulating factor.
Radioactive agents include but are not limited to Fibrinogen 1125;
Fludeoxyglucose F18; Fluorodopa F 18; Insulin 1125; Insulin 1131; lobenguane
1123;
lodipamide Sodium 113 1; lodoantipyrine 113 1; lodocholesterol 113 1;
lodohippurate
Sodium 1123; lodohippurate - 23 -Sodium 1125; lodohippurate Sodium 113 1;
lodopyracet 1125; lodopyracet 113 1; lofetamine Hydrochloride 1123; lomethin
1125;
lomethin 1131; lothalamate Sodium 1125; lothalamate Sodium 1131; lotyrosine
1131;
Liothyronine 1125; Liothyronine 113 1; Merisoprol Acetate Hg 197; Merisoprol
Acetate-
Hg 203; Merisoprol Hg 197; Selenomethionine Se 75; Technetium Tc 99m Atimony
Trisulfide Colloid; Technetium Tc 99m Bicisate; Technetium Tc 99m Disofenin;
Technetium Tc 99m Etidronate; Technetium Tc 99m Exametazime; Technetium Tc 99m
Furifosmin; Technetium Tc 99m Gluceptate; Technetium 99m Lidofenin; Technetium
Tc
99mm Mebrofenin; Technetium Tc 99m Medronate; TechnetiumTc 99m Medronate
Disodium; Technetium Tc 99m Mertiatide; Technetium Tc 99m Oxidronate;
Technetium
Tc 99m Pentetate; Technetium Ic 99m Pentetate Calcium Trisodium; Technetium Tc
99m
Sestamibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m Succimer;
Technetium
Tc 99m Sulfur Colloid; Technetium Tc 99m Teboroxime; Technetium Tc 99m
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Tetrofosmin; Technetium Tc 99m Tiatide; Thyroxine 1125: Thyroxine 113 1;
Tolpovidone 113 1; Triolein 1125; Triolein 113 1.
The compounds of the instant invention are efficacious in the treatment and/or
prevention of a broad range of cancers. Such cancers include but are not
limited to lung
cancer, bladder cancer, melanoma, bladder carcinoma, pancreatic cancer, breast
cancer.
In one aspect, the invention provides methods for the treatment of cancer.
"Cancer" as used herein refers to an uncontrolled growth of cells which
interferes with
the normal functioning of the bodily organs and systems. Cancers which migrate
from
their original location and seed vital organs can eventually lead to the death
of the subject
through the functional deterioration of the affected organs. Carcinomas are
malignant
cancers that arise from epithelial cells and include adenocarcinoma and
squamous cell
carcinoma. Sarcomas are cancer of the connective or supportive tissue and
include
osteosarcoma, chondrosarcoma and gastrointestinal stromal tumor. Hematopoietic
cancers, such as leukemia, are able to outcompete the normal hematopoietic
compartments in a subject, thereby leading to hematopoietic failure (in the
form of
anemia, thrombocytopenia and neutropenia) ultimately causing death. A person
of
ordinary skill in the art can classify a cancer as a sarcoma, carcinoma or
hematopoietic
cancer. Cancer, as used herein, includes the following types of cancer, breast
cancer,
biliary tract cancer; bladder cancer; brain cancer including glioblastomas and
medulloblastomas; cervical cancer; choriocarcinoma; colon cancer; endometrial
cancer;
esophageal cancer; gastric cancer; hematological neoplasms including acute
lymphocytic
and myelogenous leukemia; T-cell acute lymphoblastic leukemia/lymphoma; hairy
cell
leukemia; chromic myelogenous leukemia, multiple myeloma; AIDS-associated
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leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms
including
Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas
including
Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer
including
squamous cell carcinoma; ovarian cancer including those arising from
epithelial cells,
stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate
cancer;
rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma,
liposarcoma,
fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Kaposi's
sarcoma,
basocellular cancer, and squamous cell cancer; testicular cancer including
germinal
tumors such as seminoma, non-seminoma (teratomas, choriocarcinomas), stromal
tumors,
and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and
medullar
carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. Other
cancers
will be known to one of ordinary skill in the art.
The compounds may be in the form of the carboxylic acid and/or their salts.
Salts
include but are not limited to organic and inorganic salts, for example alkali-
metal salts,
such as sodium, potassium and lithium; alkaline-earth metal salts, such as
magnesium,
calcium or barium; ammonium salts; basic amino acids such as lysine or
arginine; and
organic amines, such as dimethylamine or pyridine. Preferably, the salts are
tartrate and
will be hydrochloride salts. The salts may be mono- or multi-valent salts,
such as
monosodium salts and di-sodium salts. The salts may also be solvates including
ethanol
solvates.
The compounds described herein can be readily prepared synthetically by
methods described herein. For example, the compounds may be prepared as in
Example
1. Other methods of preparation are known to those skilled in the art and are
found, for
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WO 2011/028860 PCT/US2010/047615
example in Synthesis of diverse analogues of Oenostacin and their
antibacterial activities
(Vandana, Bioorganic & Medicinal Chemistry 15 (2007) 518-525); A Simple
Regioselective Demethylation of p-Aryl Methyl Ethers Using Aluminum Chloride-
Dichloromethane System (Negi, Synthetic Communications, 35: 15-21, 2005);
Antiplatelet Activities of Newly Synthesized Derivatives of Piperlongumine
(Park,
Phytother, Res. 22, 1195-1199 (2008)); On the structure of Pipertine and a
synthesis of
dihydropiplartine (Joshi, Tetrahedron Letters No.20, pp. 2395-2420, 1968);
Synthesis and
Molecular Structure of Piplartine (Boll, Tetrahedron Letters No.40, pp. 171-
175, 1984);
Isolation, Synthesis and Evolutionary Ecology of Piper Amides: June 2004
(Dyer);
Inter- and Intraspecific Compararisons of Antiherbivore Defenses in Three
Species of
Rainforest Understory Shrubs (Fincher, J Chem Ecol (2008) 34: 558-557). The
contents
of these references and these methods are incorporated by reference in their
entirety.
Salts of the present compound may be made by methods known in the art. For
example, sodium salts may be made by dissolving the compound in ethanol and
adding
aqueous sodium hydroxide. Hydrochloride and Tartrate salts are prepared as
described in
Examples 1 and 2.
Scheme I represents the preparation of Compound 1 and its tartaric acid salt.
(N^,_i0H
O O O O J O O
0
I \ N
meo I \ N I AIC13 meo I \ N I DEAD,PPh3 O meo
meo DCM HO O
OMe OMe OMe
BPS-02083-01 BPS-02083-00
O O
ON Meo L-Tartaric Acid O I / N
OMe L-Tartaric Acid
BPS-02083-00-L-Tartaric Acid
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WO 2011/028860 PCT/US2010/047615
Scheme I
Another embodiment is a method of preparation of the compounds of the instant
invention. In yet another embodiment, the preparation of the representative
compounds
of the instant invention is represented by Scheme II:
\--/H-\-CI MolecidarWe!giht:46052 0
BPS-02083-00
0 0 P,"ieG \ \, n
n
iN~OH Mein" HCI,MeOH,r.t
0 0 0 0 BPS-02084-00 ! i ~0
11 ~ Mde-c Me0 N BPS-020801 blecular 4rg: 295
e.33
DCK25TJ2min H
'N~
0
OMe OMe Bac OH , 0 MeO V V
r) C
SM-00 BPS-02084-01 H N, j HCI,MeOH,r.t. H2N
i
EtOH
BPS-02087-00'IJ 0 de-Boc 0
04e
tubecuIai We!ght:281.3
Molecuar'P'el;ht:44 49
BPS-02086-01
Scheme II-Preparation of representative compounds of the invention.
Mechanism
Without being bound to any particular theory, the compounds of the present
invention exert their therapeutic effect by reducing oxidative stress and
thereby reducing
damage to DNA in normal cells while increasing ROS levels in cancer cells. The
resulting effect of exposure to Reactive oxygen species (ROS) is often changes
in cell
differentiation and finally, over a prolonged period, apoptosis. Under non-
stressed
conditions, GSTP1 inhibits JNK phosphorylation by sequestering the JNK-c-JUN
complex. Stressor triggers oligomeraization of GSTP1 and results in
dissociation of the
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JNK-c-JUN complex. JNK can then become phosphorylated and activate downstream
kinase and transcription factors.
Reactive oxygen species (ROS) have been shown to be increased in, for example,
EJ Bladder Carcinoma cells, Breast Carcinoma cells, and removal of GSTJI has
been
shown to block the increase in ROS. SP2007 has been shown to increase ROS in
cancer
cells and causes apoptosis. Other compounds of this invention have been shown
to be
efficacious in vivo against pancreatic cancer cells, breast epithelium and EJ
Bladder
cancer cells.
Furthermore, compounds of the instant invention are superior to the
traditional
Piper longum parent molecule in that the compounds are highly soluble. For
example
whereas the parent Piper longum can dissolve only in quantities of 0.1 mg/ml
in water,
much larger quantities of compounds of the present invention are soluble in
water. For
example, the tartrate salt of compound one of the present invention is soluble
at
100mg/ml of water.
Pharmaceutical Forms
The administration compositions may alternately be in the form of a solid,
such as
a tablet, capsule or particle, such as a powder or sachet. Solid dosage forms
may be
prepared by mixing the solid form of the compound with the solid form of the
active
agent. Alternately, a solid may be obtained from a solution of compound and
active agent
by methods known in the art, such as freeze drying, precipitation,
crystallization and solid
dispersion.
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The amount of compound used in an administration composition of the present
invention is an amount effective to accomplish the purpose of the particular
compound.
However, the amount can be less than that amount when the composition is used
in a
dosage unit form because the dosage unit form may contain a plurality of
compound
compositions or may contain a divided pharmacologically, biologically,
therapeutically,
or chemically effective amount. The total effective amount can then be
administered in
cumulative units containing, in total, an effective amount of the active
agent.
The total amount of compound to be used can be determined by methods known
to those skilled in the art.
The presently disclosed compounds may be in any dosage form known to those
skilled in the art, particularly suitable for oral, intranasal, sublingual,
intraduodenal,
subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary,
transdermal,
intradermal, parenteral, intravenous, intramuscular, intrathecal,
intraperitoneal and ocular
administrations, as well as traversing the blood-brain barrier. The compounds
may also
be prepared for injections, either by infusion into a vein or artery or
injected into the
peritoneum, bladder, or directly into tumors. Topical preparations such as
creams,
ointments, gels, lotions or transdermal patches are contemplated dosage forms.
Dosage unit forms can also include any one or combination of excipients,
diluents, disintegrants, lubricants, plasticizers, colorants, flavorants,
taste-masking agents,
sugars, sweeteners, salts, and dosing vehicles, including, but not limited to,
water, 1,2-
propane diol, ethanol, olive oil, or any combination thereof.
The compounds and compositions of the subject invention are useful for
administering biologically or chemically active agents to any animals,
including but not
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WO 2011/028860 PCT/US2010/047615
limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs,
cats,
primates, and particularly humans; and insects.
The compounds of the invention can be administered to animal and man, directly
or together with a vehicle commonly used. The dose form is not particularly
limited, and
is selected appropriately as needed on use, including oral drugs such as
tablets, capsules,
granules, grains and powder, or non-oral drugs such as injection and
suppository.
The oral drugs are prepared by ordinary methods, using starch, lactose,
sucrose,
mannitol, carboxymethylcellulose, corn starch, or inorganic salts.
In the drugs of this type, use can be made of a binder, a disintegrator, a
surfactant,
a lubricant, a fluidity-promoting agent, a flavor, a tinction, a perfume and
the like, in
addition to the vehicle mentioned above. Non-limiting examples of some of
these
substances are presented below:
Binder: Starch, dextrin, powdered acasia, gelatin, hydroxypropylstarch,
methylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose,
crystalline
cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.
Disintegrator: Starch, hydroxypropylstarch, carboxymethylcellulose sodium,
carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted
hydroxyprop ylcellulo se.
Surfactant: Sodium laurylsulfate, soybean lecithin, succharose fatty acid
ester, and
polysorbate 80.
Lubricant: Talc, waxes, hydrogenated vegetable oil, succharose fatty acid
ester,
magnesium stearate, calcium stearate, aluminum stearate, and polyethylene
glycol.
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Fluidity-Promoting Agent: Light anhydrous silicic acid, dry aluminum hydroxide
gel, synthetic aluminum silicate, and magnesium silicate.
The compounds of the present invention can also be administered in the form of
suspension, emulsion, syrup or elixir. These forms of drugs may also contain
flavor,
perfume and tinction.
The non-oral drugs can be prepared by ordinary methods, and use may be made of
an attenuant such as distilled water for injection, physiological saline,
aqueous solution of
glucose, vegetable oil for injection, sesame oil, peanut oil, soybean oil,
corn oil,
propylene glycol, or polyethylene glycol. If necessary, germicide,
preservative, and
stabilizer may be added. The non-oral drugs can be filled in a vial or the
like and frozen,
and then be removed of water by the ordinary freeze-dry technique. A liquid
drug can be
reformulated from the freeze-dried drug immediately before administration.
Further, an
isotonic, a stabilizer, a preservative, an antiseptic, a sedative, and the
like may be added.
The compositions comprising the compounds have utility in the treatment of
cancer.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate the invention without limitation. All parts
are
given by weight unless otherwise indicated.
EXAMPLE 1
Compound Preparation
la. Preparation of Compound 1 and its Tartaric Acid Salt.
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Scheme I represents the preparation of Compound 1 and its tartaric acid salt.
(N^,_iOH
O O O O J O O
0
Me0 I \ N I AIC13 Me0 I \ N I DEAD,PPh3 O Me0 I \ N
Meo DCM HO O
OMe OMe OMe
BPS-02083-01 BPS-02083-00
O O
ON Meo
L-Tartaric Acid O I / N
OMe L-Tartaric Acid
BPS-02083-00-L-Tartaric Acid
Scheme I
Preparation of BPS-02083-01
To a stirred solution of Piperlongumine (5.60 g, 17.6 mmol) in anhydrous DCM
was
added A1C13 (23.3 g, 174 mmol) at 28 T. A1C13 cannot be completely dissolved
in the
solution and the red suspension became a yellow suspension while stirred at
28oC for 15
min. Saturated NaHCO31 was added and the mixture was extracted with
dichloromethane
(150 mL*2). The combined organic layers were washed with brine (50 mL*3),
dried over
anhydrous Na2SO4, concentrated in vacuo and washed with
dichloromethane/petroleum
ether(v/v=2:3) to give BPS-02083-01 (3.5 g, 11.6 mmol, 66%) as a yellow solid.
MS
(ESI/FT-MS): 304 [M+H]+; expected 304.
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WO 2011/028860 PCT/US2010/047615
Preparation of Compound I
To a stirred solution of BPS-02083-01 intermediate (1.94 g, 6.4 mmol), 2-
morpholinoethanol (1.0 g, 7.7 mmol) and PPh3 (2.52 g, 9.6 mmol) in anhydrous
dichloromethane (80 mL) was added slowly a solution of DEAD (1.67 g, 9.6 mmol)
in
dichloromethane (20 mL) under N2 at 0 C. The mixture was slowly warmed to room
temperature and stirred overnight. The solvent was removed in vacuo and
purified by
chromatography on silica gel (petroleum ether/ethyl acetate=1:1 to 2:1) to
give BPS-
02083-00 (1.4 g, 3.37 mmol, 53%) as a pale yellow oil. MS (ESUFT-MS): 417
[M+H]';
expected 417.
Compound 1-L-tartaric acid salt.
To a solution of BPS-02083-00 [Compound 1] (4.16 g, 10.0 mmol) in
dichloromethane (25 mL) was added a solution of L-tartaric acid (1.50 g, 10.0
mmol) in
dichloromethane/methanol (10 mL). The solvent was removed in vacuo to give the
L-
tartaric acid salt of BPS-02083-00 (5.66 g, 10.0 mmol, 100%) as a colorless
solid. MS
(ESUFT-MS): 417 [M+H]+; expected 417, same as the free base.
EXAMPLE 2
Attempted preparation of Compound I HCL Salt
5 gram free base of Compound I (thick oil) (-97% by HPLC). BPS-02083-00
(100mg) was dissolved in ether (2.0 mL) and cooled to -10 C. HC1 in ether
(saturated)
was added and stirred for 10 min. The solvent was removed (<25 C) to give a
colorless
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solid (BPS-02083-00-HC1). The spectra indicated that it is not the HC1 salt of
BPS-
02083-00. The structure is B (HC1 addition to double bond).
0 N H
x t Mass: 452.17
B
EXAMPLE 3
Preparation of representative compounds of the Invention
The Intermediate was prepared as in Example 1 and the procedure for the de-boc
step to form the by product is as follows. To a solution of BPS-02085 (about
35 mg) in
menthol (5.Oml) was bubled HC1(g) for 15 minutes at room temperature (20 Q.
The
solvent was removed in vacuo and the residue was purified by TLC
(DCM:MA:NH3H2O=70:4:1) to give by-product (confirmed by 1NMR and LCMS).
Non-limiting example of compounds which may be prepared by the ad-boc method
described in Example 3 are represented below.
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0 0 0 0
N N
OMe OMe 0
N N v, OMe
0
BPS-02083-00 ,
BPS-02084-00 ;~'~ -' ~ ~='. .._ . - _. BPS-02087-00
0--/NCI
BPS-02083-00
0 0 Me0 0 0 ~i OH BPS-02084-00
Me0 I\ \ N AICI3 N I Boc'N`~OH de-Boc
DCM, 25 C,12 min HO H
Me0
OMe Boc'N\/\OH de-Boc
OMe
--------
BPS-02084-01 SM-00 68%yield EtOH
BPS-02087-00
Example 4
Report of Representative Compounds
SM Quantity Product Quantity HPLC HNMR LCMS[M+H]+
SM-00 190mg BPS- 124mg+32mg >95% Passed 304
02084-01 SM-00
SM-00 9.3mg Passed 304
SM-00 13mg BPS- 254mg+84mg 304
>95%
SM-00 176mg 02084-01 SM-00 304
SM-00 190mg 304
BPS- 56mg BPS- 7.1mg 95.0% Passed 417
02084- 02083-00
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01
BPS- 56mg BPS- 22mg 96.1 % Passed 375
02084- 02084-00
01
BPS- 96mg BPS- 30-40mg >90% Passed
02084- 02085-01
01
BPS- 30-40mg BPS- 0mg
02085- 02085-00
01
BPS- 65mg+36mg BPS- 25-30mg >90% Passed
02084- 02086-01
01
BPS- 25-30mg BPS- 0mg
02086- 02085-00
01
BPS- 56mg BPS- 42mg 97.1 % Passed 332
02084- 02087-00
01
EXAMPLE 5
Effect of Compound on Pro-survival Gene Suppression
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Additional studies will demonstrate that compounds of the instant invention
have
a large therapeutic window by sparing normal cells, such as fibroblasts and
keratocytes,
but killing tumors cells, such as EJ cells and HCT116 cells. Studies will also
demonstrate
that DNA in normal cells remains unaffected by compounds of the instant
invention and
that there is no increase in ROS in normal cells.
Figures 1-4 show in-vivo efficacy of the compounds against pancreatic
cancers cells, breast epithelium and EJ Bladder Cancer Cells.
EXAMPLE 6
Antitumor Effect of SP2007 and SP83 On Bladder Tumor Xenograft-Bearing Mice
We tested the anti-tumor effect SP2007 and SP83 in bladder tumor xenograft-
bearing mice.
Four nude/nude mice weighing approximately 0.02 Kg were fasted overnight and
anestatized with Avertin (2,2,2, Tribromoethanol), 250mg/kg, body weight; IP
injection.
A total 2 x 106 EJ cells (acquired from Japanese cellbank) were implanted
subcutaneously on opposite site flanks in each of four nude/nude mice in each
treatment
group. Mice were fed and given water ad lib. When tumor masses grew to
approximately
2 to 5 mm in diameter, control vehicle, SP2007 or SP83 were administered
intraperitoneally (total 2 mg/kg) every 24 hours for 25 days. Anti-tumor
effects were
observed in SP2007 and SP83 administered tumor mice, as compared to control
DMSO-
administered tumor mice. Results are shown in Figure 5.
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Although this invention has been described with a certain degree of
particularity,
it is to be understood that the present disclosure has been made only by way
of
illustration and that numerous changes in the details of construction and
arrangement of
parts may be resorted to without departing from the spirit and the scope of
the invention.
Many variations of the present invention will suggest themselves to those
skilled in the
art in light of the above detailed description. All such obvious variations
are within the
fully intended scope of the appended claims.
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