U.S. patent application number 17/558445 was filed with the patent office on 2022-06-16 for compounds, compositions, and methods for the treatment of cancers.
The applicant listed for this patent is XLINK Therapeutics, Inc.. Invention is credited to Mark T. BILODEAU, Beno t MOREAU.
Application Number | 20220185836 17/558445 |
Document ID | / |
Family ID | 1000006168288 |
Filed Date | 2022-06-16 |
United States Patent
Application |
20220185836 |
Kind Code |
A1 |
BILODEAU; Mark T. ; et
al. |
June 16, 2022 |
COMPOUNDS, COMPOSITIONS, AND METHODS FOR THE TREATMENT OF
CANCERS
Abstract
The present teachings relate to compounds and compositions for
treatment of cancers. In some embodiments, the composition
comprises a platinum (IV) complex having at least one polar moiety
as a ligand.
Inventors: |
BILODEAU; Mark T.; (Waltham,
MA) ; MOREAU; Beno t; (Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XLINK Therapeutics, Inc. |
Dover |
MA |
US |
|
|
Family ID: |
1000006168288 |
Appl. No.: |
17/558445 |
Filed: |
December 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16364400 |
Mar 26, 2019 |
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17558445 |
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15652563 |
Jul 18, 2017 |
10287308 |
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16364400 |
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15108547 |
Jun 27, 2016 |
9738672 |
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PCT/US2014/071160 |
Dec 18, 2014 |
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15652563 |
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61922272 |
Dec 31, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 15/0093
20130101 |
International
Class: |
C07F 15/00 20060101
C07F015/00 |
Claims
1-24. (canceled)
25. A compound of Formula I: ##STR00013## or a
pharmaceutically-acceptable salt thereof, wherein: two of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are each independently a halide or a
carboxylate; the remaining two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are each independently ammonia; (i) X is NR.sup.5 and Y is
absent, C(R.sup.6).sub.2, or NR.sup.6; or (ii) X is absent,
C(R.sup.5).sub.2, or NR.sup.5 and Y is NR.sup.6; and R.sup.5 and
R.sup.6 are each independently hydrogen, alkyl, alkenyl, alkynyl,
ether, amine, or carboxylate, wherein each of the alkyl, alkenyl,
alkynyl, ether, and amine is unsubstituted or substituted with one
or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of
the ether, alkoxy, or amine is unsubstituted or substituted;
provided that when X and Y are each NH, each R.sup.5 and R.sup.6
are independently hydrogen, linear alkyl, alkenyl, alkynyl, ether,
amine, or carboxylate, wherein each of the linear alkyl, alkenyl,
alkynyl, ether, and amine is unsubstituted or substituted with one
or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of
the ether, alkoxy, or amine is unsubstituted or substituted.
26. The compound of claim 25, wherein the compound has Formula Ia:
##STR00014##
27. The compound of claim 25, wherein: when X is NR.sup.5, Y is
absent or C(R.sup.6).sub.2, and when Y is NR.sup.6, X is absent or
C(R.sup.5).sub.2.
28. The compound of claim 25, wherein X and Y are different.
29. The compound of claim 25, wherein each of R.sup.1 and R.sup.2
is ammonia.
30. The compound of claim 25, wherein each of R.sup.3 and R.sup.4
is Cl.
31. The compound of claim 25, wherein R.sup.3 and R.sup.4 are
joined together to form oxalate.
32. The compound of claim 25, wherein one of R.sup.5 and R.sup.6 is
methyl.
33. The compound of claim 25, wherein X or Y is absent.
34. The compound of claim 25, wherein X or Y is NH.
35. The compound of claim 25, wherein one of R.sup.5 and R.sup.6 is
an alkyl that is unsubstituted or substituted with an amine,
wherein the amine is unsubstituted or substituted.
36. The compound of claim 25, wherein the compound has a log P of
less than about 2.0, wherein the log P is determined by (i)
measuring a retention time of the compound on a reverse phase HPLC
column by applying a mobile phase, wherein the mobile phase
comprises: (A) 95/5 mixture of water/acetonitrile with 0.1%
trifluoroacetic acid; and (B) 95/5 mixture of acetonitrile/water
with 0.1% trifluoroacetic acid; at a gradient of 90% (A) :10% (B)
to 0% (A) :100% (B) over 8 minutes, at a flow rate of 1.5 ml/min;
and (ii) comparing the retention time of the compound to a
reference sample.
37. The compound of claim 36, wherein the compound has a log P of
less than about 1.7.
38. The compound of claim 36, wherein the compound has a log P of
less than about 1.3.
39. The compound of claim 36, wherein the compound has a log P of
less than about 1.1.
40. The compound of claim 25, wherein the compound has the formula:
##STR00015##
41. A pharmaceutical composition comprising in unit dosage form a
compound having the formula I, and a pharmaceutically acceptable
carrier ##STR00016## or a pharmaceutically-acceptable salt thereof,
wherein: two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each
independently a halide or a carboxylate; the remaining two of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently
ammonia; (i) X is NR.sup.5 and Y is absent, C(R.sup.6).sub.2, or
NR.sup.6; or (ii) X is absent, C(R.sup.5).sub.2, or NR.sup.5 and Y
is NR.sup.6; and R.sup.5 and R.sup.6 are each independently
hydrogen, alkyl, alkenyl, alkynyl, ether, amine, or carboxylate,
wherein each of the alkyl, alkenyl, alkynyl, ether, and amine is
unsubstituted or substituted with one or more halogen, hydroxyl,
ether, alkoxy, or amine; wherein each of the ether, alkoxy, or
amine is unsubstituted or substituted; provided that when X and Y
are each NH, each R.sup.5 and R.sup.6 are independently hydrogen,
linear alkyl, alkenyl, alkynyl, ether, amine, or carboxylate,
wherein each of the linear alkyl, alkenyl, alkynyl, ether, and
amine is unsubstituted or substituted with one or more halogen,
hydroxyl, ether, alkoxy, or amine; wherein each of the ether,
alkoxy, or amine is unsubstituted or substitute.
42. The pharmaceutical composition of claim 41, in a form suitable
for intravenous administration.
43. The pharmaceutical composition of claim 41, wherein the
pharmaceutical composition comprises a buffering agent.
44. The pharmaceutical composition of claim 41, wherein the
pharmaceutical composition comprises a sugar.
45. A method of treating cancer, comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of formula I or a pharmaceutical composition comprising a
compound of formula I ##STR00017## or a pharmaceutically-acceptable
salt thereof, wherein: two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are each independently a halide or a carboxylate; the
remaining two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each
independently ammonia; (i) X is NR.sup.5 and Y is absent,
C(R.sup.6).sub.2, or NR.sup.6; or (ii) X is absent,
C(R.sup.5).sub.2, or NR.sup.5 and Y is NR.sup.6; and R.sup.5 and
R.sup.6 are each independently hydrogen, alkyl, alkenyl, alkynyl,
ether, amine, or carboxylate, wherein each of the alkyl, alkenyl,
alkynyl, ether, and amine is unsubstituted or substituted with one
or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of
the ether, alkoxy, or amine is unsubstituted or substituted;
provided that when X and Y are each NH, each R.sup.5 and R.sup.6
are independently hydrogen, linear alkyl, alkenyl, alkynyl, ether,
amine, or carboxylate, wherein each of the linear alkyl, alkenyl,
alkynyl, ether, and amine is unsubstituted or substituted with one
or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of
the ether, alkoxy, or amine is unsubstituted or substitute.
46. The method of claim 45, wherein the cancer is lung cancer.
47. The method of claim 45, wherein the cancer is ovarian
cancer.
48. The method of claim 45, wherein the cancer is breast
cancer.
49. The method of claim 45, wherein the cancer is prostate cancer
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 16/364,400, filed Mar. 26, 2019, which is a
continuation application of U.S. application Ser. No. 15/652,563,
filed Jul. 18, 2017, now U.S. Pat. No. 10,287,308, which is a
divisional application of U.S. application Ser. No. 15/108,547,
filed Jun. 27, 2016, now U.S. Pat. No. 9,738,672, which is a
National Stage Entry of U.S. Application No. PCT/US2014/071160,
filed Dec. 18, 2014, which claims priority to U.S. provisional
application No. 61/922,272, filed Dec. 31, 2013, each of which is
incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to platinum based compounds,
compositions, and methods of using thereof.
BACKGROUND
[0003] Platinum-based drugs are among the most active and widely
used anticancer agents and cisplatin represents one of the three
FDA-approved, platinum-based cancer chemotherapeutics. Although
cisplatin is effective against a number of solid tumors, especially
testicular and ovarian cancer, its clinical use has been limited
because of its toxic effects as well as the intrinsic and acquired
resistance of some tumors to this drug.
[0004] To overcome these limitations, platinum analogs with lower
toxicity and greater activity in cisplatin-resistant tumors have
been developed and tested, resulting in the approval of carboplatin
and oxaliplatin in the United States. For example, carboplatin has
the advantage of being less nephrotoxic, but its cross-resistance
with cisplatin has limited its application in otherwise
cisplatin-treatable diseases.
[0005] Oxaliplatin, however, exhibits a different anticancer
spectrum from that of cisplatin. It has been approved as the first
or second line therapy in combination with
5-fluorouracil/leucovorin for advanced colorectal cancer, for which
cisplatin and carboplatin are essentially inactive. These platinum
drugs have platinum in the 2+ oxidative state (Pt(II)) and are not
orally active.
[0006] Platinum complexes in the 4+ oxidative state (Pt(IV)
complexes) provide several advantages. The two additional
coordination sites (the axial sites) can be modified to change the
pharmacokinetic properties of the complexes. For example, the two
axial sites, as well as the four equatorial sites, can include
ligands that have polar moieties. Not wishing to be bound by any
theory, the polarity increase of the Pt(IV) complexes of the
present teachings may increase the Pt concentration in tumor cells.
In certain instances, Pt(IV) complexes of the present teachings can
be orally active and/or have a reduced long-term toxicity.
SUMMARY
[0007] The present teachings relate to compositions, for example,
for reducing, disrupting, or inhibiting the growth of a cancer cell
or inducing the death of a cancer cell.
[0008] The composition can include a platinum (IV) compound. In
various embodiments, the platinum (IV) compound includes a polar
moiety. For example, the polar moiety can be hydrophilic. In some
embodiments, the present teachings provide a compound of Formula
I:
##STR00001## [0009] or a pharmaceutically acceptable salt thereof,
[0010] wherein: [0011] two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 each independently is a halide or a carboxylate; the
remaining two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each
independently is an amine; and
[0012] X is absent, C(R.sup.5).sub.2, or NR.sup.5,
[0013] Y is absent, C(R.sup.6).sub.2, or NR.sup.6, [0014] R.sup.5
and R.sup.6 independently at each occurrence is selected from
hydrogen, alkyl, alkenyl, alkynyl, ether, amine, and carboxylate,
wherein each of the alkyl, the alkenyl, the alkynyl, the ether, and
the amine groups optionally is substituted with one or more groups,
each independently selected from halogen, hydroxyl, ether, alkoxy,
and amine, wherein each of the ether, the alkoxy, or the amine is
optionally substituted with one or more suitable substituents; and
at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 comprises a polar moiety.
[0015] The present teachings also provide compositions including a
compound as described herein and methods of using a compound or a
composition as described herein. In various embodiments, the
methods of the present teachings are useful for the prevention or
treatment of diseases that benefit from increased cell death or
decreased cell proliferation. For example, the method of the
present teachings can be used to increase cancer cell death or
decrease cancer cell proliferation. The increased cancer cell death
or decreased cancer proliferation can occur, for example, outside
the body (in vitro) or inside the body (in vivo).
[0016] Certain embodiments of the present teachings also provide
for use of a compound as described herein as a medicament for
treating or preventing a disease and/or in the manufacture of such
a medicament, e.g., for use in the treatment of a disease. Some
embodiments provide the use of a compound as described herein for
use as a medicament. In certain embodiments, the teachings provide
a compound or composition as described herein for the treatment of
disease, e.g. for the treatment of a cancer.
BRIEF DESCRIPTION OF DRAWINGS
[0017] FIG. 1 shows exemplary growth curves of Calu-6 tumor in nude
mice xenograft when the mice were dosed with control vehicle or an
exemplary compound of the present teachings.
[0018] FIG. 2 shows exemplary platinum levels in tumor when
platinum (IV) was dosed in the form of three exemplary compounds of
the present teachings and two comparison compounds to tumor-bearing
nude mice via intravenous administration.
DETAILED DESCRIPTION
[0019] For convenience, before further description of the present
teachings, certain terms employed in the specification, examples,
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and as understood
by a person of ordinary skill in the art. Unless defined otherwise,
all technical and scientific terms used herein have the same
meaning as commonly understood by a person of ordinary skill in the
art.
[0020] The articles "a" and "an," as used herein, should be
understood to mean "at least one," unless clearly indicated to the
contrary.
[0021] The phrase "and/or," as used herein, should be understood to
mean "either or both" of the elements so conjoined, i.e., elements
that are conjunctively present in some cases and disjunctively
present in other cases. Other elements may optionally be present
other than the elements specifically identified by the "and/or"
clause, whether related or unrelated to those elements specifically
identified unless clearly indicated to the contrary. Thus, as a
non-limiting example, a reference to "A and/or B," when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A without B (optionally including
elements other than B); in another embodiment, to B without A
(optionally including elements other than A); in yet another
embodiment, to both A and B (optionally including other
elements).
[0022] As used herein, "or" should be understood to have the same
meaning as "and/or" as defined above. For example, when separating
items in a list, "or" or "and/or" shall be interpreted as being
inclusive, i.e., the inclusion of at least one, but also including
more than one, of a number or list of elements, and, optionally,
additional unlisted items. Only terms clearly indicated to the
contrary, such as "only one of" or "exactly one of," or, when used
in the claims, "consisting of," will refer to the inclusion of
exactly one element of a number or list of elements.
[0023] In general, the term "or" as used herein shall only be
interpreted as indicating exclusive alternatives (i.e. "one or the
other but not both") when preceded by terms of exclusivity, such as
"either," "one of," "only one of," or "exactly one of." "Consisting
essentially of," when used in the claims, shall have its ordinary
meaning as used in the field of patent law.
[0024] As used herein, the phrase "at least one" in reference to a
list of one or more elements should be understood to mean at least
one element selected from any one or more of the elements in the
list of elements, but not necessarily including at least one of
each and every element specifically listed within the list of
elements and not excluding any combinations of elements in the list
of elements. This definition also allows that elements may
optionally be present other than the elements specifically
identified within the list of elements to which the phrase "at
least one" refers, whether related or unrelated to those elements
specifically identified.
[0025] Thus, as a non-limiting example, "at least one of A and B"
(or, equivalently, "at least one of A or B," or, equivalently "at
least one of A and/or B") can refer, in one embodiment, to at least
one, optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0026] As used herein, all transitional phrases such as
"comprising," "including," "carrying," "having," "containing,"
"involving," "holding," and the like are to be understood to be
open-ended, i.e., to mean including but not limited to.
[0027] Only the transitional phrases "consisting of" and
"consisting essentially of" shall be closed or semi-closed
transitional phrases, respectively, as set forth in the United
States Patent Office Manual of Patent Examining Procedures.
[0028] As used herein, a "subject" or a "patient" refers to any
mammal (e.g., a human), such as a mammal that may be susceptible to
a disease or disorder, for example, tumorigenesis or cancer.
Examples include a human, a non-human primate, a cow, a horse, a
pig, a sheep, a goat, a dog, a cat, or a rodent such as a mouse, a
rat, a hamster, or a guinea pig. In various embodiments, a subject
refers to one that has been or will be the object of treatment,
observation, or experiment. For example, a subject can be a subject
diagnosed with cancer or otherwise known to have cancer or one
selected for treatment, observation, or experiment on the basis of
a known cancer in the subject.
[0029] As used herein, "treatment" or "treating" refers to an
amelioration of a disease or disorder, or at least one discernible
symptom thereof. In another embodiment, "treatment" or "treating"
refers to an amelioration of at least one measurable physical
parameter, not necessarily discernible by the patient. In yet
another embodiment, "treatment" or "treating" refers to reducing
the progression of a disease or disorder, either physically, e.g.,
stabilization of a discernible symptom, physiologically, e.g.,
stabilization of a physical parameter, or both. In yet another
embodiment, "treatment" or "treating" refers to delaying the onset
of a disease or disorder.
[0030] As used herein, "prevention" or "preventing" refers to a
reduction of the risk of acquiring a given disease or disorder.
[0031] The phrase "therapeutically effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present teachings which is effective
for producing some desired therapeutic effect. Accordingly, a
therapeutically effective amount treats or prevents a disease or a
disorder. In various embodiments, the disease or disorder is a
cancer.
[0032] A dash ("--") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom (C).
[0033] By "optional" or "optionally," it is meant that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where the event or
circumstance occurs and instances in which it does not. For
example, "optionally substituted aryl" encompasses both "aryl" and
"substituted aryl" as defined herein. It will be understood by
those ordinarily skilled in the art, with respect to any group
containing one or more substituents, that such groups are not
intended to introduce any substitution or substitution patterns
that are sterically impractical, synthetically non-feasible, and/or
inherently unstable.
[0034] The term "alkyl" as used herein refers to a saturated
straight or branched hydrocarbon, such as a straight or branched
group of 1-22, 1-8, 1-6, or 1-4 carbon atoms, referred to herein as
(C.sub.1-C.sub.22)alkyl, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.4)alkyl, respectively.
Exemplary alkyl groups include, but are not limited to, methyl,
ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,
2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,
2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, and octyl.
[0035] The term "alkenyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
double bond (shown, for example, as "="), such as a straight or
branched group of 2-22, 2-8, 2-6, or 2-4 carbon atoms, referred to
herein as (C.sub.2-C.sub.22)alkenyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.4)alkenyl,
respectively. Exemplary alkenyl groups include, but are not limited
to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and
4-(2-methyl-3-butene)-pentenyl.
[0036] The term "alkynyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
triple bond (shown, for example, as ".ident."), such as a straight
or branched group of 2-22, 2-8, 2-6, 2-4 carbon atoms, referred to
herein as (C.sub.2-C.sub.22)alkynyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.2-C.sub.6)alkynyl, and (C.sub.2-C.sub.4)alkynyl,
respectively. Exemplary alkynyl groups include, but are not limited
to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
[0037] The term "cycloalkyl" as used herein refers to a saturated
or unsaturated monocyclic, bicyclic, other multicyclic, or bridged
cyclic hydrocarbon group. A cyclocalkyl group can have 3-22, 3-12,
or 3-8 ring carbons, referred to herein as
(C.sub.3-C.sub.22)cycloalkyl, (C.sub.3-C.sub.12)cycloalkyl, or
(C.sub.3-C.sub.8)cycloalkyl, respectively. A cycloalkyl group can
also have one or more carbon-carbon double bond or carbon-carbon
triple bond.
[0038] Exemplary monocyclic cycloalkyl groups include, but are not
limited to, cyclopentanes (cyclopentyls), cyclopentenes
(cyclopentenyls), cyclohexanes (cyclohexyls), cyclohexenes
(cyclopexenyls), cycloheptanes (cycloheptyls), cycloheptenes
(cycloheptenyls), cyclooctanes (cyclooctyls), cyclooctenes
(cyclooctenyls), cyclononanes (cyclononyls), cyclononenes
(cyclononenyls), cyclodecanes (cyclodecyls), cyclodecenes
(cyclodecenyls), cycloundecanes (cycloundecyls), cycloundecenes
(cycloundecenyls), cyclododecanes (cyclododecyls), and
cyclododecenes (cyclododecenyls). Other exemplary cycloalkyl
groups, including bicyclic, multicyclic, and bridged cyclic groups,
include, but are not limited to, bicyclobutanes (bicyclobutyls),
bicyclopentanes (bicyclopentyls), bicyclohexanes (bicyclohexyls),
bicycleheptanes (bicycloheptyls, including bicyclo[2,2,1]heptanes
(bicycle[2,2,1]heptyls) and bicycle[3,2,0]heptanes
(bicycle[3,2,0]heptyls)), bicyclooctanes (bicyclooctyls, including
octahydropentalene (octahydropentalenyl), bicycle[3,2,1]octane
(bicycle[3,2,1]octyl), and bicylo[2,2,2]octane
(bicycle[2,2,2]octyl)), and adamantanes (adamantyls). Cycloalkyl
groups can be fused to other cycloalkyl saturated or unsaturated,
aryl, or heterocyclyl groups.
[0039] The term "aryl" as used herein refers to a mono-, bi-, or
other multi-carbocyclic aromatic ring system. The aryl can have
6-22, 6-18, 6-14, or 6-10 carbons, referred to herein as
(C.sub.6-C.sub.22)aryl, (C.sub.6-C.sub.18)aryl,
(C.sub.6-C.sub.14)aryl, or (C.sub.6-C.sub.1o)aryl, respectively.
The aryl group can optionally be fused to one or more rings
selected from aryls, cycloalkyls, and heterocyclyls. The term
"bicyclic aryl" as used herein refers to an aryl group fused to
another aromatic or non-aromatic carbocylic or heterocyclic ring.
Exemplary aryl groups include, but are not limited to, phenyl,
tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but
are not limited to a monocyclic aromatic ring system, wherein the
ring comprises 6 carbon atoms, referred to herein as
"(C.sub.6)aryl" or phenyl. The phenyl group can also be fused to a
cyclohexane or cyclopentane ring to form another aryl.
[0040] The term "arylalkyl" as used herein refers to an alkyl group
having at least one aryl substituent (e.g., -aryl-alkyl-).
Exemplary arylalkyl groups include, but are not limited to,
arylalkyls having a monocyclic aromatic ring system, wherein the
ring comprises 6 carbon atoms, referred to herein as
"(C.sub.6)arylalkyl." The term "benzyl" as used herein refers to
the group --CH.sub.2-phenyl.
[0041] The term "heteroalkyl" refers to an alkyl group as described
herein in which one or more carbon atoms is replaced by a
heteroatom. Suitable heteroatoms include oxygen, sulfur, nitrogen,
phosphorus, and the like. Examples of heteroalkyl groups include,
but are not limited to, alkoxy, amino, thioester, and the like.
[0042] The terms "heteroalkenyl" and "heteroalkynyl" refer to
unsaturated aliphatic groups analogous in length and possible
substitution to the heteroalkyls described above, but that contain
at least one double or triple bond, respectively.
[0043] The term "heterocycle" refers to cyclic groups containing at
least one heteroatom as a ring atom, in some cases, 1 to 3
heteroatoms as ring atoms, with the remainder of the ring atoms
being carbon atoms. Suitable heteroatoms include oxygen, sulfur,
nitrogen, phosphorus, and the like. In some cases, the heterocycle
may be 3- to 10-membered ring structures or 3- to 7-membered rings,
whose ring structures include one to four heteroatoms. The term
"heterocycle" may include heteroaryl groups, saturated heterocycles
(e.g., cycloheteroalkyl) groups, or combinations thereof. The
heterocycle may be a saturated molecule, or may comprise one or
more double bonds. In some case, the heterocycle is a nitrogen
heterocycle, wherein at least one ring comprises at least one
nitrogen ring atom. The heterocycles may be fused to other rings to
form a polycylic heterocycle. Thus, heterocycles also include
bicyclic, tricyclic, and tetracyclic groups in which any of the
above heterocyclic rings is fused to one or two rings independently
selected from aryls, cycloalkyls, and heterocycles. The heterocycle
may also be fused to a spirocyclic group.
[0044] Heterocycles include, for example, thiophene,
benzothiophene, thianthrene, furan, tetrahydrofuran, pyran,
isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole,
dihydropyrrole, pyrrolidine, imidazole, pyrazole, pyrazine,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline, triazole,
tetrazole, oxazole, isoxazole, thiazole, isothiazole,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane, thiolane, oxazole, oxazine, piperidine, homopiperidine
(hexamethyleneimine), piperazine (e.g., N-methyl piperazine),
morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, sultones, other saturated and/or
unsaturated derivatives thereof, and the like.
[0045] In some cases, the heterocycle may be bonded to a compound
via a heteroatom ring atom (e.g., nitrogen). In some cases, the
heterocycle may be bonded to a compound via a carbon ring atom. In
some cases, the heterocycle is pyridine, imidazole, pyrazine,
pyrimidine, pyridazine, acridine, acridin-9-amine, bipyridine,
naphthyridine, quinoline, isoquinoline, benzoquinoline,
benzoisoquinoline, phenanthridine-1,9-diamine, or the like.
[0046] The term "heteroaromatic" or "heteroaryl" as used herein
refers to a mono-, bi-, or multi-cyclic aromatic ring system
containing one or more heteroatoms, for example 1-3 heteroatoms,
such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused
to non-aromatic rings. In various embodiments, the term
"heteroaromatic" or "heteroaryl," as used herein except where
noted, represents a stable 5- to 7-membered monocyclic, stable 9-
to 10-membered fused bicyclic, or stable 12- to 14-membered fused
tricyclic heterocyclic ring system which contains an aromatic ring
that contains at least one heteroatom selected from the group
consisting of N, O, and S. In some embodiments, at least one
nitrogen is in the aromatic ring.
[0047] Heteroaromatics or heteroaryls can include, but are not
limited to, a monocyclic aromatic ring, wherein the ring comprises
2-5 carbon atoms and 1-3 heteroatoms, referred to herein as
"(C.sub.2-C.sub.5)heteroaryl." Illustrative examples of monocyclic
heteroaromatic (or heteroaryl) include, but are not limited to,
pyridine (pyridinyl), pyridazine (pyridazinyl), pyrimidine
(pyrimidyl), pyrazine (pyrazyl), triazine (triazinyl), pyrrole
(pyrrolyl), pyrazole (pyrazolyl), imidazole (imidazolyl), (1,2,3)-
and (1,2,4)-triazole ((1,2,3)- and (1,2,4)-triazolyl), pyrazine
(pyrazinyl), pyrimidine (pyrimidinyl), tetrazole (tetrazolyl),
furan (furyl), thiophene (thienyl), isoxazole (isoxazolyl),
thiazole (thiazolyl), isoxazole (isoxazolyl), and oxazole
(oxazolyl).
[0048] The term "bicyclic heteroaromatic" or "bicyclic heteroaryl"
as used herein refers to a heteroaryl group fused to another
aromatic or non-aromatic carbocylic or heterocyclic ring. Exemplary
bicyclic heteroaromatics or heteroaryls include, but are not
limited to 5,6- or 6,6-fused systems, wherein one or both rings
contain heteroatoms. The term "bicyclic heteroaromatic" or
"bicyclic heteroaryl" also encompasses reduced or partly reduced
forms of fused aromatic system wherein one or both rings contain
ring heteroatoms. The ring system may contain up to three
heteroatoms, independently selected from oxygen, nitrogen, and
sulfur.
[0049] Exemplary bicyclic heteroaromatics (or heteroaryls) include,
but are not limited to, quinazoline (quinazolinyl), benzoxazole
(benzoxazolyl), benzothiophene (benzothiophenyl), benzoxazole
(benzoxazolyl), benzisoxazole (benzisoxazolyl), benzimidazole
(benzimidazolyl), benzothiazole (benzothiazolyl), benzofurane
(benzofuranyl), benzisothiazole (benzisothiazolyl), indole
(indolyl), indazole (indazolyl), indolizine (indolizinyl),
quinoline (quinolinyl), isoquinoline (isoquinolinyl), naphthyridine
(naphthyridyl), phthalazine (phthalazinyl), phthalazine
(phthalazinyl), pteridine (pteridinyl), purine (purinyl),
benzotriazole (benzotriazolyl), and benzofurane (benzofuranyl). In
some embodiments, the bicyclic heteroaromatic (or bicyclic
heteroaryl) is selected from quinazoline (quinazolinyl),
benzimidazole (benzimidazolyl), benzothiazole (benzothiazolyl),
indole (indolyl), quinoline (quinolinyl), isoquinoline
(isoquinolinyl), and phthalazine (phthalazinyl). In certain
embodiments, the bicyclic heteroaromatic (or bicyclic heteroaryl)
is quinoline (quinolinyl) or isoquinoline (isoquinolinyl).
[0050] The term "tricyclic heteroaromatic" or "tricyclic
heteroaryl" as used herein refers to a bicyclic heteroaryl group
fused to another aromatic or non-aromatic carbocylic or
heterocyclic ring. The term "tricyclic heteroaromatic" or
"tricyclic heteroaryl" also encompasses reduced or partly reduced
forms of fused aromatic system wherein one or both rings contain
ring heteroatoms. Each of the ring in the tricyclic heteroaromatic
(tricyclic heteroaryl) may contain up to three heteroatoms,
independently selected from oxygen, nitrogen, and sulfur.
[0051] Exemplary tricyclic heteroaromatics (or heteroaryls)
include, but are not limited to, acridine (acridinyl),
9H-pyrido[3,4-b]indole (9H-pyrido[3,4-b]indolyl), phenanthridine
(phenanthridinyl), pyrido[1,2-a]benzimidazole
(pyrido[1,2-a]benzimidazolyl), and pyrido[1,2-b]indazole
(pyrido[1,2-b]indazolyl).
[0052] The term "alkoxy" as used herein refers to an alkyl group
attached to an oxygen (--O-alkyl-). "Alkoxy" groups also include an
alkenyl group attached to an oxygen ("alkenyloxy") or an alkynyl
group attached to an oxygen ("alkynyloxy") groups. Exemplary alkoxy
groups include, but are not limited to, groups with an alkyl,
alkenyl or alkynyl group of 1-22, 1-8, or 1-6 carbon atoms,
referred to herein as (C.sub.1-C.sub.22)alkoxy,
(C.sub.1-C.sub.8)alkoxy, or (C.sub.1-C.sub.6)alkoxy, respectively.
Exemplary alkoxy groups include, but are not limited to methoxy and
ethoxy.
[0053] The term "cycloalkoxy" as used herein refers to a cycloalkyl
group attached to an oxygen.
[0054] The term "aryloxy" or "aroxy" as used herein refers to an
aryl group attached to an oxygen atom. Exemplary aryloxy groups
include, but are not limited to, aryloxys having a monocyclic
aromatic ring system, wherein the ring comprises 6 carbon atoms,
referred to herein as "(C.sub.6)aryloxy." The term "arylalkoxy" as
used herein refers to an arylalkyl group attached to an oxygen
atom. An exemplary aryalkyl group is benzyloxy group.
[0055] The term "amine" or "amino" as used herein refers to both
unsubstituted and substituted amines, e.g.,
NR.sub.aR.sub.bR.sub.b', where R.sub.a, R.sub.b, and R.sub.b' are
independently selected from alkyl, alkenyl, alkynyl, aryl,
arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl,
heterocyclyl, and hydrogen, and at least one of the R.sub.a,
R.sub.b, and R.sub.b' is not hydrogen. The amine or amino can be
attached to the parent molecular group through the nitrogen. The
amine or amino also may be cyclic, for example any two of R.sub.a,
R.sub.b, and R.sub.b' may be joined together and/or with the N to
form a 3- to 12-membered ring (e.g., morpholino or piperidinyl).
The term amino also includes the corresponding quaternary ammonium
salt of any amino group. Exemplary amines include alkylamine,
wherein at least one of R.sub.a, R.sub.b, and R.sub.b' is an alkyl
group, or cycloalkylamine, wherein at least one of R.sub.a,
R.sub.b, and R.sub.b' is a cycloalkyl group.
[0056] The term "ammonia" as used herein refers to NH.sub.3.
[0057] The term "aldehyde" or "formyl" as used herein refers to
--CHO.
[0058] The term "acyl" term as used herein refers to a carbonyl
radical attached to an alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycyl, aryl, or heteroaryl. Exemplary acyl groups include,
but are not limited to, acetyl, formyl, propionyl, benzoyl, and the
like.
[0059] The term "amide" as used herein refers to the form
--NR.sub.cC(O)(R.sub.d)-- or --C(O)NR.sub.cR.sub.e, wherein
R.sub.c, R.sub.d, and R.sub.e are each independently selected from
alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,
heteroaryl, heterocyclyl, and hydrogen. The amide can be attached
to another group through the carbon, the nitrogen, R.sub.c,
R.sub.d, or R.sub.e. The amide also may be cyclic, for example
R.sub.c and R.sub.e, may be joined to form a 3- to 12-membered
ring, such as a 3- to 10-membered ring or a 5- or 6-membered ring.
The term "amide" encompasses groups such as sulfonamide, urea,
ureido, carbamate, carbamic acid, and cyclic versions thereof. The
term "amide" also encompasses an amide group attached to a carboxy
group, e.g., -amide-COON or salts such as -amide-COONa.
[0060] The term "arylthio" as used herein refers to an aryl group
attached to an sulfur atom. Exemplary arylthio groups include, but
are not limited to, arylthios having a monocyclic aromatic ring
system, wherein the ring comprises 6 carbon atoms, referred to
herein as "(C.sub.6)arylthio."
[0061] The term "arylsulfonyl" as used herein refers to an aryl
group attached to a sulfonyl group, e.g., --S(O).sub.2-aryl-.
Exemplary arylsulfonyl groups include, but are not limited to,
arylsulfonyls having a monocyclic aromatic ring system, wherein the
ring comprises 6 carbon atoms, referred to herein as
"(C.sub.6)arylsulfonyl."
[0062] The term "carbamate" as used herein refers to the form
--R.sub.fOC(O)N(R.sub.g)--, --R.sub.fOC(O)N(R.sub.g)R.sub.h--, or
--OC(O)NR.sub.gR.sub.h, wherein R.sub.f, R.sub.g, and R.sub.h are
each independently selected from alkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and
hydrogen. Exemplary carbamates include, but are not limited to,
arylcarbamates or heteroaryl carbamates (e.g., wherein at least one
of R.sub.f, R.sub.g and R.sub.h are independently selected from
aryl or heteroaryl, such as pyridinyl, pyridazinyl, pyrimidinyl,
and pyrazinyl).
[0063] The term "carbonyl" as used herein refers to --C(O)--.
[0064] The term "carboxy" or "carboxylate" as used herein refers to
R.sub.j--COON or its corresponding carboxylate salts (e.g.,
R.sub.j--COONa), where R.sub.j can independently be selected from
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,
arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and
heterocyclyl. Exemplary carboxys include, but are not limited to,
alkyl carboxy wherein R.sub.j is alkyl, such as --O--C(O)-alkyl.
Exemplary carboxy also include aryl or heteoraryl carboxy, e.g.
wherein R.sub.j is an aryl, such as phenyl and tolyl, or heteroaryl
group such as pyridine, pyridazine, pyrmidine and pyrazine. The
term carboxy also includes "carboxycarbonyl," e.g. a carboxy group
attached to a carbonyl group, e.g., --C(O)--COON or salts, such as
--C(O)--COONa.
[0065] The term "dicarboxylic acid" as used herein refers to a
group containing at least two carboxylic acid groups such as
saturated and unsaturated hydrocarbon dicarboxylic acids and salts
thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic
acids. Dicarboxylic acids include, but are not limited to succinic
acid, glutaric acid, adipic acid, suberic acid, sebacic acid,
azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic
acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-)
tartaric acid, isophthalic acid, and terephthalic acid.
Dicarboxylic acids further include carboxylic acid derivatives
thereof, such as anhydrides, imides, hydrazides (for example,
succinic anhydride and succinimide).
[0066] The term "cyano" as used herein refers to --CN.
[0067] The term "ester" refers to the structure --C(O)O--,
--C(O)O--R--, --R.sub.jC(O)O--R--, or --R.sub.jC(O)O--, where O is
not bound to hydrogen, and R.sub.i and R.sub.j can independently be
selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,
amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl,
and heterocyclyl. R.sub.i can be a hydrogen, but R.sub.j cannot be
hydrogen. The ester may be cyclic, for example the carbon atom and
R.sub.j the oxygen atom and R.sub.i, or R.sub.i and R.sub.j may be
joined to form a 3- to 12-membered ring. Exemplary esters include,
but are not limited to, alkyl esters wherein at least one of
R.sub.i or R.sub.j is alkyl, such as --O--C(O)-alkyl,
--C(O)--O-alkyl-, and -alkyl-C(O)--O-alkyl-. Exemplary esters also
include aryl or heteroaryl esters, e.g. wherein at least one of
R.sub.i or R.sub.j is an aryl group, such as phenyl or tolyl, or a
heteroaryl group, such as pyridine, pyridazine, pyrimidine or
pyrazine, such as a nicotinate ester. Exemplary esters also include
reverse esters having the structure --RC(O)O--, where the oxygen is
bound to the parent molecule. Exemplary reverse esters include
succinate, D-argininate, L-argininate, L-lysinate and D-lysinate.
Esters also include carboxylic acid anhydrides and acid
halides.
[0068] The term "ether" refers to the structure
--R.sub.kO--R.sub.l--, where R.sub.k and R.sub.l can independently
be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and
ether. The ether can be attached to the parent molecular group
through R.sub.k or R.sub.l. Exemplary ethers include, but are not
limited to, alkoxyalkyl and alkoxyaryl groups. Ethers also includes
polyethers, e.g., where one or both of R.sub.k and R.sub.l are
ethers.
[0069] The terms "halo" or "halogen" or "hal" or "halide" as used
herein refer to F, Cl, Br, or I.
[0070] The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms. "Haloalkyls" also
encompass alkenyl or alkynyl groups substituted with one or more
halogen atoms.
[0071] The terms "hydroxy" and "hydroxyl" as used herein refers to
--OH.
[0072] The term "hydroxyalkyl" as used herein refers to a hydroxy
attached to an alkyl group.
[0073] The term "hydroxyaryl" as used herein refers to a hydroxy
attached to an aryl group.
[0074] The term "ketone" as used herein refers to the structure
--C(O)--R.sub.m (such as acetyl, --C(O)CH.sub.3) or
--R.sub.m--C(O)--R.sub.n--. The ketone can be attached to another
group through R.sub.m or R.sub.n. R.sub.m or R.sub.n can be alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R.sub.m or
R.sub.n can be joined to form, for example, a 3- to 12-membered
ring.
[0075] The term "monoester" as used herein refers to an analogue of
a dicarboxylic acid wherein one of the carboxylic acids is
functionalized as an ester and the other carboxylic acid is a free
carboxylic acid or salt of a carboxylic acid. Examples of
monoesters include, but are not limited to, to monoesters of
succinic acid, glutaric acid, adipic acid, suberic acid, sebacic
acid, azelaic acid, oxalic and maleic acid.
[0076] The term "nitro" as used herein refers to --NO.sub.2.
[0077] The term "nitrate" as used herein refers to
NO.sub.3.sup.-.
[0078] The term "perfluoroalkyl" as used herein refers to an alkyl
group in which all of the hydrogen atoms have been replaced by
fluorine atoms. Exemplary perfluoroalkyl groups include, but are
not limited to, C.sub.1-C.sub.5 perfluoroalkyl, such as
trifluoromethyl.
[0079] The term "perfluorocycloalkyl" as used herein refers to a
cycloalkyl group in which all of the hydrogen atoms have been
replaced by fluorine atoms.
[0080] The term "perfluoroalkoxy" as used herein refers to an
alkoxy group in which all of the hydrogen atoms have been replaced
by fluorine atoms.
[0081] The term "phosphate" as used herein refers to the structure
--OP(O)O.sub.2.sup.2-, --R.sub.oOP(O)O.sub.2.sup.2-,
--OP(O)(OR.sub.q)O.sup.-, or --R.sub.oOP(O)(OR.sub.p)O.sup.-,
wherein R.sub.o, R.sub.p and R.sub.q each independently can be
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, or
hydrogen.
[0082] The term "sulfide" as used herein refers to the structure
--R.sub.qS--, where R.sub.q can be alkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl. The
sulfide may be cyclic, for example, forming a 3 to 12-membered
ring. The term "alkylsulfide" as used herein refers to an alkyl
group attached to a sulfur atom.
[0083] The term "sulfinyl" as used herein refers to the structure
--S(O)O--, --R.sub.rS(O)O--, --R.sub.rS(O)OR.sub.s--, or
--S(O)OR.sub.s--, wherein R.sub.r and R.sub.s can be alkyl,
alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,
heterocyclyl, hydroxyl. Exemplary sulfinyl groups include, but are
not limited to, alkylsulfinyls wherein at least one of R.sub.r or
R.sub.s is alkyl, alkenyl, or alkynyl.
[0084] The term "sulfonamide" as used herein refers to the
structure --(R.sub.t)--N--S(O).sub.2--R.sub.v-- or
--R.sub.t(R.sub.u)N--S(O).sub.2--R.sub.v, where R.sub.t, R.sub.u,
and R.sub.v can be, for example, hydrogen, alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides include
alkylsulfonamides (e.g., where R.sub.v is alkyl), arylsulfonamides
(e.g., where R.sub.v is aryl), cycloalkyl sulfonamides (e.g., where
R.sub.v is cycloalkyl), and heterocyclyl sulfonamides (e.g., where
R.sub.v is heterocyclyl).
[0085] The term "sulfonate" as used herein refers to a salt or
ester of a sulfonic acid. The term "sulfonic acid" refers to
R.sub.wSO.sub.3H, where R.sub.w is alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, or heterocyclyl (e.g., alkylsulfonyl). The term
"sulfonyl" as used herein refers to the structure
R.sub.xSO.sub.2--, where R.sub.x can be alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, and heterocyclyl (e.g., alkylsulfonyl). The term
"alkylsulfonyl" as used herein refers to an alkyl group attached to
a sulfonyl group. "Alkylsulfonyl" groups can optionally contain
alkenyl or alkynyl groups.
[0086] The term "sulfonate" as used herein refers
R.sub.wSO.sub.3--, where R.sub.w is alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heterocyclyl, hydroxyl, alkoxy, aroxy, or
aralkoxy, where each of the alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, heteroaryl, alkoxy, aroxy, or aralkoxy optionally is
substituted. Non-limiting examples include triflate (also known as
trifluoromethanesulfonate, CF.sub.3SO.sub.3.sup.-),
benzenesulfonate, tosylate (also known as toluenesulfonate), and
the like.
[0087] The term "thioketone" refers to the structure
--Ry--C(S)--R.sub.z--. The ketone can be attached to another group
through R.sub.y or R.sub.z. R.sub.y or R.sub.z can be alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R.sub.y or
R.sub.z can be joined to form a ring, for example, a 3- to
12-membered ring.
[0088] Each of the above groups may be optionally substituted. As
used herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds, "permissible" being
in the context of the chemical rules of valence known to those of
ordinary skill in the art. It will be understood that "substituted"
also includes that the substitution results in a stable compound,
e.g., which does not spontaneously undergo transformation such as
by rearrangement, cyclization, elimination, etc. In some cases,
"substituted" may generally refer to replacement of a hydrogen with
a substituent as described herein. However, "substituted," as used
herein, does not encompass replacement and/or alteration of a
functional group by which a molecule is identified, e.g., such that
the "substituted" functional group becomes, through substitution, a
different functional group. For example, a "substituted phenyl
group" must still comprise the phenyl moiety and cannot be modified
by substitution, in this definition, to become, e.g., a pyridine
ring.
[0089] In a broad aspect, the permissible substituents include
acyclic and cyclic, branched and unbranched, carbocyclic and
heterocyclic, aromatic and nonaromatic substituents of organic
compounds. Illustrative substituents include, for example, those
described herein. The permissible substituents can be one or more
and the same or different for appropriate organic compounds. For
purposes of the present teachings, the heteroatoms such as nitrogen
may have hydrogen substituents and/or any permissible substituents
of organic compounds described herein which satisfy the valencies
of the heteroatoms.
[0090] In various embodiments, the substituent is selected from
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,
arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic
acid, sulfonamide, and thioketone, each of which optionally is
substituted with one or more suitable substituents. In some
embodiments, the substituent is selected from alkoxy, aryloxy,
alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,
carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl,
heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl,
sulfonic acid, sulfonamide, and thioketone, wherein each of the
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,
arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl,
haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide,
sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can
be further substituted with one or more suitable substituents.
[0091] Examples of substituents include, but are not limited to,
halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone,
ester, heterocyclyl, --CN, aryl, aryloxy, perhaloalkoxy, aralkoxy,
heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido,
alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy,
aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,
arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl,
carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy,
aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl,
arylalkyloxyalkyl, and the like. In some embodiments, the
substituent is selected from cyano, halogen, hydroxyl, and
nitro.
[0092] As a non-limiting example, in various embodiments when one
of the R.sub.a, R.sub.b, and R.sub.b' in NR.sub.aR.sub.bR.sub.b',
referred to herein as an amine or amino, is selected from alkyl,
alkenyl, alkynyl, cycloalkyl, and heterocyclyl, each of the alkyl,
alkenyl, alkynyl, cycloalkyl, and heterocyclyl independently can be
optionally substituted with one or more substituents each
independently selected from alkoxy, aryloxy, alkyl, alkenyl,
alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy,
cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl,
heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl,
sulfonic acid, sulfonamide, and thioketone, wherein each of the
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,
arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl,
haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide,
sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can
be further substituted with one or more suitable substituents. In
some embodiments when the amine is an alkyl amine or a
cycloalkylamine, the alkyl or the cycloalkyl can be substituted
with one or more substituents each independently selected from
alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,
arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic
acid, sulfonamide, and thioketone. In certain embodiments when the
amine is an alkyl amine or a cycloalkylamine, the alkyl or the
cycloalkyl can be substituted with one or more substituents each
independently selected from amino, carboxy, cyano, and hydroxyl.
For example, the alkyl or the cycloalkyl in the alkyl amine or the
cycloalkylamine is substituted with an amino group, forming a
diamine.
[0093] As used herein, a "suitable substituent" refers to a group
that does not nullify the synthetic or pharmaceutical utility of
the compounds of the invention or the intermediates useful for
preparing them. Examples of suitable substituents include, but are
not limited to: (C.sub.1-C.sub.22), (C.sub.1-C.sub.8),
(C.sub.1-C.sub.6), or (C.sub.1-C.sub.4) alkyl, alkenyl or alkynyl;
(C.sub.6-C.sub.22), (C.sub.6-C.sub.18), (C.sub.6-C.sub.14), or
(C.sub.6-C.sub.10) aryl; (C.sub.2-C.sub.21), (C.sub.2-C.sub.17),
(C.sub.2-C.sub.13), or (C.sub.2-C.sub.9) heteroaryl;
(C.sub.3-C.sub.22), (C.sub.3-C.sub.12), or (C.sub.3-C.sub.8)
cycloalkyl; (C.sub.1-C.sub.22), (C.sub.1-C.sub.8),
(C.sub.1-C.sub.6), or (C.sub.1-C.sub.4) alkoxy; (C.sub.6-C.sub.22),
(C.sub.6-C.sub.18), (C.sub.6-C.sub.14), or (C.sub.6-C.sub.10)
aryloxy; --CN; --OH; oxo; halo; carboxy; amino, such as
--NH((C.sub.1-C.sub.22), (C.sub.1-C.sub.8), (C.sub.1-C.sub.6), or
(C.sub.1-C.sub.4) alkyl), --N((C.sub.1-C.sub.22),
(C.sub.1-C.sub.8), (C.sub.1-C.sub.6), or (C.sub.1-C.sub.4)
alkyl).sub.2, --NH((C.sub.6)aryl), or --N((C.sub.6-C.sub.10)
aryl).sub.2; formyl; ketones, such as --CO((C.sub.1-C.sub.22),
(C.sub.1-C.sub.8), (C.sub.1-C.sub.6), or (C.sub.1-C.sub.4) alkyl),
--CO(((C.sub.6-C.sub.10) aryl) esters, such as
--CO.sub.2((C.sub.1-C.sub.22), (C.sub.1-C.sub.8),
(C.sub.1-C.sub.6), or (C.sub.1-C.sub.4) alkyl) and
--CO.sub.2((C.sub.6-C.sub.10) aryl). One of skill in art can
readily choose a suitable substituent based on the stability and
pharmacological and synthetic activity of the compound of the
invention.
[0094] The term "pharmaceutically acceptable counter ion" refers to
a pharmaceutically acceptable anion or cation. In various
embodiments, the pharmaceutically acceptable counter ion is a
pharmaceutically acceptable ion. For example, the pharmaceutically
acceptable counter ion is selected from citrate, matate, acetate,
oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate,
phosphate, acid phosphate, isonicotinate, acetate, lactate,
salicylate, tartrate, oleate, tannate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). In some embodiments,
the pharmaceutically acceptable counter ion is selected from
chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate,
acid phosphate, citrate, matate, acetate, oxalate, acetate, and
lactate. In particular embodiments, the pharmaceutically acceptable
counter ion is selected from chloride, bromide, iodide, nitrate,
sulfate, bisulfate, and phosphate.
[0095] The term "pharmaceutically acceptable salt(s)" refers to
salts of acidic or basic groups that may be present in compounds
used in the present teachings. Compounds included in the present
teachings that are basic in nature are capable of forming a wide
variety of salts with various inorganic and organic acids. The
acids that may be used to prepare pharmaceutically acceptable acid
addition salts of such basic compounds are those that form
non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including but not limited to
sulfate, citrate, matate, acetate, oxalate, chloride, bromide,
iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, tartrate,
oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,
maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,
formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present teachings that include an amino moiety may
form pharmaceutically acceptable salts with various amino acids, in
addition to the acids mentioned above. Compounds included in the
present teachings, that are acidic in nature are capable of forming
base salts with various pharmacologically acceptable cations.
Examples of such salts include alkali metal or alkaline earth metal
salts and, particularly, calcium, magnesium, sodium, lithium, zinc,
potassium, and iron salts.
[0096] In addition, if the compounds described herein are obtained
as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the product
is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free
base in a suitable organic solvent and treating the solution with
an acid, in accordance with conventional procedures for preparing
acid addition salts from base compounds. Those skilled in the art
will recognize various synthetic methodologies that may be used to
prepare non-toxic pharmaceutically acceptable addition salts.
[0097] A pharmaceutically acceptable salt can be derived from an
acid selected from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid,
4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic
acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic
acid, camphoric acid, camphor-10-sulfonic acid, capric acid
(decanoic acid), caproic acid (hexanoic acid), caprylic acid
(octanoic acid), carbonic acid, cinnamic acid, citric acid,
cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,
ethanesulfonic acid, formic acid, fumaric acid, galactaric acid,
gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid,
glutamic acid, glutaric acid, glycerophosphoric acid, glycolic
acid, hippuric acid, hydrobromic acid, hydrochloric acid,
isethionic, isobutyric acid, lactic acid, lactobionic acid, lauric
acid, maleic acid, malic acid, malonic acid, mandelic acid,
methanesulfonic acid, mucic, naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic
acid, oxalic acid, palmitic acid, pamoic acid, pantothenic,
phosphoric acid, proprionic acid, pyroglutamic acid, salicylic
acid, sebacic acid, stearic acid, succinic acid, sulfuric acid,
tartaric acid, thiocyanic acid, toluenesulfonic acid,
trifluoroacetic, and undecylenic acid.
[0098] Unless otherwise specified, the chemical groups include
their corresponding monovalent, divalent, trivalent, and
tetravalent groups. For example, methyl includes monovalent methyl
(--CH.sub.3), divalent methyl (--CH.sub.2--, methylyl), trivalent
methyl
##STR00002##
and tetravalent methyl
##STR00003##
[0099] Unless otherwise specified, all numbers expressing
quantities of ingredients, reaction conditions, and other
properties or parameters used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless otherwise indicated, it should be
understood that the numerical parameters set forth in the following
specification and attached claims are approximations. At the very
least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, numerical
parameters should be read in light of the number of reported
significant digits and the application of ordinary rounding
techniques. For example, the term "about" can encompass variations
of .+-.10%, .+-.5%, .+-.2%, .+-.1%, .+-.0.5%, or .+-.0.1% of the
numerical value of the number which the term "about" modifies. In
various embodiments, the term "about" encompasses variations of
.+-.5%, .+-.2%, .+-.1%, or .+-.0.5% of the numerical value of the
number. In some embodiments, the term "about" encompasses
variations of .+-.5%, .+-.2%, or .+-.1% of the numerical value of
the number. In certain embodiments, the term "about" encompasses
variations of .+-.5% of the numerical value of the number. In
certain embodiments, the term "about" encompasses variations of
.+-.2% of the numerical value of the number. In certain
embodiments, the term "about" encompasses variations of .+-.1% of
the numerical value of the number.
[0100] All numerical ranges herein include all numerical values and
ranges of all numerical values within the recited range of
numerical values. As a non-limiting example, (C.sub.1-C.sub.6)
alkyls also include any one of C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, C.sub.6, (C.sub.1-C.sub.2), (C.sub.1-C.sub.3),
(C.sub.1-C.sub.4), (C.sub.1-C.sub.5), (C.sub.2-C.sub.3),
(C.sub.2-C.sub.4), (C.sub.2-C.sub.5), (C.sub.2-C.sub.6),
(C.sub.3-C.sub.4), (C.sub.3-C.sub.5), (C.sub.3-C.sub.6),
(C.sub.4-C.sub.5), (C.sub.4-C.sub.6), and (C.sub.5-C.sub.6)
alkyls.
[0101] Further, while the numerical ranges and parameters setting
forth the broad scope of the disclosure are approximations as
discussed above, the numerical values set forth in the Examples
section are reported as precisely as possible. It should be
understood, however, that such numerical values inherently contain
certain errors resulting from the measurement equipment and/or
measurement technique.
[0102] The term "hydrophilic," as used herein, generally describes
the property of attracting water and the term "hydrophobic," as
used herein, generally describes the property of repelling water.
Thus, a hydrophilic compound (e.g., small molecule or polymer) is
one generally that attracts water and a hydrophobic compound (e.g.,
small molecule or polymer) is one that generally repels water. A
hydrophilic or a hydrophobic compound can be identified, for
example, by preparing a sample of the compound and measuring its
contact angle with water. In some cases, the hydrophilicity of two
or more compounds may be measured relative to each other, i.e., a
first compound may be more hydrophilic than a second compound.
Compounds
[0103] The present teachings generally provide compounds,
compositions, and methods of using the compounds or
compositions.
[0104] In various embodiments, each of the compounds of the present
teachings has Formula I:
##STR00004## [0105] or a pharmaceutically acceptable salt thereof,
[0106] wherein: [0107] two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 each independently is a halide or a carboxylate; [0108] the
remaining two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each
independently is an amine; and
[0109] X is absent, C(R.sup.5).sub.2, or NR.sup.5,
[0110] Y is absent, C(R.sup.6).sub.2, or NR.sup.6,
[0111] R.sup.5 and R.sup.6 independently at each occurrence is
selected from hydrogen, alkyl, alkenyl, alkynyl, ether, amine, and
carboxylate, wherein each of the alkyl, the alkenyl, the alkynyl,
the ether, and the amine groups optionally is substituted with one
or more groups, each independently selected from halogen, hydroxyl,
ether, alkoxy, and amine, wherein each of the ether, the alkoxy, or
the amine is optionally substituted with one or more suitable
substituents; and [0112] at least one of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 comprises a polar moiety.
[0113] In some embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each comprises a polar
moiety. In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 each comprise a polar moiety. For example, two of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4, joined together, can
comprise a polar moiety. In certain embodiments, at least one of
R.sup.5 and R.sup.6 comprises a polar moiety. For example, each of
R.sup.5 and R.sup.6 can comprise a polar moiety. A polar moiety in
various embodiments can be ether, amino, or carboxylate, each of
which is optionally substituted with one or more suitable
substituents. In some embodiments, the polar moiety is a
dicarboxylic acid, a carboxylate, a polyether, an amine, or a
diamine, each of which optionally is substituted with a suitable
substituent. In certain embodiments, the polar moiety is a
dicarboxylic acid, a carboxylate, a polyether, or a diamine. In
particular embodiments, the polar moiety is a dicarboxylic acid. In
particular embodiments, the polar moiety is a carboxylate. In
particular embodiments, the polar moiety is a polyether.
[0114] In various embodiments, at least one of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 is a halide. For example, at least one of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is Cl. In some embodiments,
two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is a halide. In
some embodiments, two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
each is Cl.
[0115] In various embodiments, at least one of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 is --O(C.dbd.O)R.sup.a, and R.sup.a is
hydrogen, alkyl, aryl, arylalkyl, or cycloalkyl, wherein each of
the alkyl, aryl, arylalkyl, and cycloalkyl is optionally
substituted with one or more suitable substituents. In some
embodiments, two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is
--O(C.dbd.O)R.sup.a, and R.sup.a is as defined herein. In some
embodiments, two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 form a
bidentate ligand as described herein.
[0116] In various embodiments, at least one of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 is an amine. In some embodiments, two of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is an amine. In some
embodiments, two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 form a
bidentate ligand as described herein.
[0117] Some embodiments comprise compounds having two ligands
(e.g., R.sup.1, R.sup.2, R.sup.3, and R.sup.4) positioned in a cis
configuration, i.e., the compound may be a cis isomer. However, it
should be understood that compounds of the present teachings may
also have two ligands (e.g., R.sup.1, R.sup.2, R.sup.3, and
R.sup.4) positioned in a trans configuration, i.e., the compound
may be a trans isomer. Those of ordinary skill in the art would
understand the meaning of these terms.
[0118] A "polar moiety", as used herein, refers to any chemical
group in which the distribution of electrons is uneven enabling it
to take part in electrostatic interactions. For example, a chemical
group comprising electronegative atoms may give rise to unequal
sharing of electrons in the bonds and thereby rendering the
chemical group a polar moiety. Examples of polar moieties include,
but not limited to, ether groups, amine groups, halide groups,
carboxic acid groups, carboxylate groups, ester groups, thiol
groups, and so on.
[0119] In some embodiments, the compounds of the present invention
are polar. In some embodiments, the compounds of the present
teachings have a logarithm of partition-coefficient value (logP)
less than about 2. In some embodiments, the compouds of the present
teachings have a logP less than about 1.7. In some embodiments, the
compounds of the present teachings have a logP less than about 1.3.
In some embodiments, the compoudns of the present teachings have a
logP less than about 1.1. As used herein, partition coefficient P
measures the tendency of the compound to partition between
lipophilic organic phase (immisciple with water) and polar aqueous
phase. LogP may be measured using any known method. As a
non-limiting example, logP may be measured using a "shake-flask"
method, wherein the compound is incubated in two-phase system under
shaking, and samples collected from both phases after equilibration
are analyzed with using analytical methods such as HPLC, LC/MS, or
by spectrophotometer. As another non-limiting example, logP may be
measured based on chromatographic retention times, e.g., measured
using an HPLC retention time method, under validated conditions
using reference compounds with reported logP. In some embodiments,
the compounds of the present invention are charged. In some
embodiments, the compounds of the present invention are not
charged.
[0120] In various embodiments, the compounds of the present
teachings each has Formula Ia:
##STR00005## [0121] wherein X, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are as defined herein.
[0122] In some embodiments, at least one of R.sup.3 and R.sup.4 is
a halide. In certain embodiments, both R.sup.3 and R.sup.4 are
Cl.
[0123] In some embodiments, at least one of R.sup.3 and R.sup.4 is
--O(C.dbd.O)R.sup.a, and R.sup.a is hydrogen, alkyl, aryl,
arylalkyl, or cycloalkyl, wherein each of the alkyl, the aryl, the
arylalkyl, and the cycloalkyl is optionally substituted with one or
more suitable substituents. In some embodiments, both R.sup.3 and
R.sup.4 are --O(C.dbd.O)R.sup.a, and R.sup.a is hydrogen, alkyl,
aryl, arylalkyl, or cycloalkyl, wherein each of the alkyl, the
aryl, the arylalkyl, and the cycloalkyl is optionally substituted
with one or more suitable substituents. In certain embodiments,
R.sup.3 and R.sup.4, joined together, form a bidentate ligand as
described herein.
[0124] In some embodiments, at least one of R.sup.1 and R.sup.2 is
an amine. For example, at least one of R.sup.1 and R.sup.2 is an
alkylamine, alkenylamine, alkynylamine, arylamine, arylalkylamine,
cycloalkylamine, heterocycloalkylamine, or heteroarylamine. In
certain embodiments, R.sup.1 and R.sup.2, joined together, form a
bidentate ligand as described herein.
[0125] In some embodiments, two ligands may be joined together to
form a bidentate ligand. As will be known to those of ordinary
skill in the art, a bidentate ligand, as used herein, when bound to
a metal center, forms a metallacycle structure with the metal
center, also known as a chelate ring. Bidentate ligands include
species that have at least two sites capable of binding to a metal
center. For example, a bidentate ligand may comprise at least two
heteroatoms that coordinate the metal center, or a heteroatom and
an anionic carbon atom that coordinate the metal center.
[0126] Examples of bidentate ligands suitable for use in the
present teachings include diamines, including ethylenediamine,
cyclohexyldiamine, cyclobutanediyldimethanamine, and the like, or
dicarboxylic acids. In some embodiments, R.sup.1 and R.sup.2 are
joined together to form ethylenediamine,
cyclobutane-1,2-diyldimethanamine, cyclohexane-1,2-diamine, or the
like. In certain embodiments, R.sup.1 and R.sup.2 are joined
together to form cyclobutane-1,2-diyldimethanamine or
cyclohexane-1,2-diamine. In certain embodiments, R.sup.1 and
R.sup.2 are joined together to form cyclohexane-1,2-diamine.
[0127] In various embodiments, the compounds of the present
teachings each has Formula II:
##STR00006## [0128] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, and R.sup.6 are as defined herein and [0129] at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6
comprises a polar moiety.
[0130] In various embodiments, the compounds of the present
teachings each has Formula IIIa:
##STR00007## [0131] wherein R.sup.5 and R.sup.6 are as defined
herein and [0132] at least one of R.sup.5 and R.sup.6 comprises a
polar moiety.
[0133] In some embodiments, R.sup.3 and R.sup.4 are joined together
to form a dicarboxylic acid. For example, the dicarboxylic acid can
be oxalic acid, malonic acid, succinic acid, glutaric acid, adipic
acid, pimelic acid, cyclobutane dicarboxylic acid, cyclopentane
dicarboxylic acid, cyclohexane dicarboxylic acid, cycloheptane
dicarboxylic acid, or the like. In certain embodiments, R.sup.3 and
R.sup.4 are joined together to form oxalic acid.
[0134] In various embodiments, the compounds of the present
teachings each has Formula IIIb:
##STR00008## [0135] wherein R.sup.5 and R.sup.6 are as defined
herein and [0136] at least one of R.sup.5 and R.sup.6 comprises a
polar moiety.
[0137] In various embodiments, X or Y is absent.
[0138] In various embodiments, X is C(R.sup.5).sub.2, wherein each
R.sup.5 independently is defined herein. In various embodiments, X
is NR.sup.5, where R.sup.5 is as defined herein.
[0139] In various embodiments, Y is C(R.sup.6).sub.2, wherein each
R.sup.6 independently is defined herein. In various embodiments, Y
is NR.sup.6, where R.sup.6 is as defined herein.
[0140] In various embodiments, R.sup.5 and R.sup.6 at each
occurrence is hydrogen or alkyl, optionally substituted with one or
more groups, each independently selected from halogen, hydroxyl,
ether, alkoxy, and amine, wherein each of the ether, the alkoxy, or
the amine is optionally substituted with one or more suitable
substituents. In some embodiments, R.sup.5 or R.sup.6 at least at
one occurrence is hydrogen or CH.sub.3.
[0141] In particular embodiments, X is CH.sub.2 or C(CH3).sub.2. In
particular embodiments, X is NH.
[0142] In particular embodiments, Y is CH.sub.2 or C(CH3).sub.2. In
particular embodiments, Y is NH.
[0143] In various embodiments, X, Y, R.sup.5 and R.sup.6 are
different. For example, the compound of the present teachings
is:
##STR00009##
[0144] In various embodiments, R.sup.5 and R.sup.6 can be the same.
For example, the compound of the present teachings can be selected
from:
##STR00010## ##STR00011##
[0145] As described herein, some compounds of the present teachings
may be provided as a salt comprising a charged platinum complex and
a counter ion, including a pharmaceutically acceptable counter ion.
The counter ion may be a weak or non-nucleophilic stabilizing ion,
having a charge of (-1), (-2), (-3), (+1), (+2), (+3), etc. In some
embodiments, the counter ion has a charge of (-1). In other
embodiments, the counter ion has a charge of (-2). In some
embodiments, the counter ion has a charge of (+1). In other
embodiments, the counter ion has a charge of (+2).
Formulation, Delivery, Administration, and Dosing
[0146] The present teachings further comprise compositions
(including pharmaceutical compositions) each comprising one or more
of the compounds as described herein, and at least one
pharmaceutically acceptable excipient.
[0147] In some embodiments, compositions are administered to
humans, human patients or subjects. For the purposes of the present
disclosure, the phrase "active ingredient" generally refers to the
compounds to be delivered as described herein.
[0148] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to any other animal,
e.g., to non-human animals, e.g. non-human mammals. Modification of
pharmaceutical compositions suitable for administration to humans
in order to render the compositions suitable for administration to
various animals is well understood, and the ordinarily skilled
veterinary pharmacologist can design and/or perform such
modification with merely ordinary, if any, experimentation.
Subjects to which administration of the pharmaceutical compositions
is contemplated include, but are not limited to, humans and/or
other primates; mammals, including commercially relevant mammals
such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats;
and/or birds, including commercially relevant birds such as
poultry, chickens, ducks, geese, and/or turkeys.
[0149] Formulations of the pharmaceutical compositions described
herein may be prepared by any method known or hereafter developed
in the art of pharmacology. In general, such preparatory methods
include the step of bringing the active ingredient into association
with an excipient and/or one or more other accessory ingredients,
and then, if necessary and/or desirable, dividing, shaping and/or
packaging the product into a desired single- or multi-dose
unit.
[0150] A pharmaceutical composition in accordance with the
invention may be prepared, packaged, and/or sold in bulk, as a
single unit dose, and/or as a plurality of single unit doses. As
used herein, a "unit dose" is discrete amount of the pharmaceutical
composition comprising a predetermined amount of the active
ingredient. The amount of the active ingredient is generally equal
to the dosage of the active ingredient which would be administered
to a subject and/or a convenient fraction of such a dosage such as,
for example, one-half or one-third of such a dosage.
[0151] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition in accordance with the
invention will vary, depending upon the identity, size, and/or
condition of the subject treated and further depending upon the
route by which the composition is to be administered. By way of
example, the composition may comprise between 0.1% and 100%, e.g.,
between 0.5 and 50%, between 1-30%, between 5-80%, at least 80%
(w/w) active ingredient.
[0152] The compounds of the present invention can be formulated
using one or more excipients to: (1) increase stability; (2) permit
the sustained or delayed release (e.g., from a depot formulation of
the compounds of the present invention); (3) alter the
biodistribution (e.g., target the compounds of the present
invention to specific tissues or cell types); (4) alter the release
profile of the compounds of the invention in vivo. Non-limiting
examples of the excipients include any and all solvents, dispersion
media, diluents, or other liquid vehicles, dispersion or suspension
aids, surface active agents, isotonic agents, thickening or
emulsifying agents, and preservatives. Excipients of the present
invention may also include, without limitation, lipidoids,
liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell
nanoparticles, peptides, proteins, hyaluronidase, nanoparticle
mimics and combinations thereof. Accordingly, the formulations of
the invention may include one or more excipients, each in an amount
that together increases the stability of the compounds of the
present invention.
[0153] Excipients
[0154] Pharmaceutical formulations may additionally comprise a
pharmaceutically acceptable excipient, which, as used herein,
includes any and all solvents, dispersion media, diluents, or other
liquid vehicles, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's The Science and
Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott,
Williams & Wilkins, Baltimore, Md., 2006; incorporated herein
by reference in its entirety) discloses various excipients used in
formulating pharmaceutical compositions and known techniques for
the preparation thereof. Except insofar as any conventional
excipient medium is incompatible with a substance or its
derivatives, such as by producing any undesirable biological effect
or otherwise interacting in a deleterious manner with any other
component(s) of the pharmaceutical composition, its use is
contemplated to be within the scope of this invention.
[0155] In some embodiments, a pharmaceutically acceptable excipient
is at least 95%, at least 96%, at least 97%, at least 98%, at least
99%, or 100% pure. In some embodiments, an excipient is approved
for use in humans and for veterinary use. In some embodiments, an
excipient is approved by United States Food and Drug
Administration. In some embodiments, an excipient is pharmaceutical
grade. In some embodiments, an excipient meets the standards of the
United States Pharmacopoeia (USP), the European Pharmacopoeia (EP),
the British Pharmacopoeia, and/or the International
Pharmacopoeia.
[0156] Pharmaceutically acceptable excipients used in the
manufacture of pharmaceutical compositions include, but are not
limited to, inert diluents, dispersing and/or granulating agents,
surface active agents and/or emulsifiers, disintegrating agents,
binding agents, preservatives, buffering agents, lubricating
agents, and/or oils. Such excipients may optionally be included in
pharmaceutical compositions.
[0157] Exemplary diluents include, but are not limited to, calcium
carbonate, sodium carbonate, calcium phosphate, dicalcium
phosphate, calcium sulfate, calcium hydrogen phosphate, sodium
phosphate lactose, sucrose, cellulose, microcrystalline cellulose,
kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch,
cornstarch, powdered sugar, etc., and/or combinations thereof.
[0158] Exemplary granulating and/or dispersing agents include, but
are not limited to, potato starch, corn starch, tapioca starch,
sodium starch glycolate, clays, alginic acid, guar gum, citrus
pulp, agar, bentonite, cellulose and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(VEEGUM.RTM.), sodium lauryl sulfate, quaternary ammonium
compounds, etc., and/or combinations thereof.
[0159] Exemplary surface active agents and/or emulsifiers include,
but are not limited to, natural emulsifiers (e.g. acacia, agar,
alginic acid, sodium alginate, tragacanth, chondrux, cholesterol,
xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol,
wax, and lecithin), colloidal clays (e.g. bentonite [aluminum
silicate] and VEEGUM.RTM. [magnesium aluminum silicate]), long
chain amino acid derivatives, high molecular weight alcohols (e.g.
stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin
monostearate, ethylene glycol distearate, glyceryl monostearate,
and propylene glycol monostearate, polyvinyl alcohol), carbomers
(e.g. carboxy polymethylene, polyacrylic acid, acrylic acid
polymer, and carboxyvinyl polymer), carrageenan, cellulosic
derivatives (e.g. carboxymethylcellulose sodium, powdered
cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty
acid esters (e.g. polyoxyethylene sorbitan monolaurate
[TWEEN.RTM.20], polyoxyethylene sorbitan [TWEENn.RTM.60],
polyoxyethylene sorbitan monooleate [TWEEN.RTM.80], sorbitan
monopalmitate [SPAN.RTM.40], sorbitan monostearate [SPAN.RTM.60],
sorbitan tristearate [SPAN.RTM.65], glyceryl monooleate, sorbitan
monooleate [SPAN.RTM.80]), polyoxyethylene esters (e.g.
polyoxyethylene monostearate [MYRJ.RTM.45], polyoxyethylene
hydrogenated castor oil, polyethoxylated castor oil,
polyoxymethylene stearate, and SOLUTOL.RTM.), sucrose fatty acid
esters, polyethylene glycol fatty acid esters (e.g.
CREMOPHOR.RTM.), polyoxyethylene ethers, (e.g. polyoxyethylene
lauryl ether [BRIJ.RTM.30]), poly(vinyl-pyrrolidone), diethylene
glycol monolaurate, triethanolamine oleate, sodium oleate,
potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium
lauryl sulfate, PLUORINC.RTM.F 68, POLOXAMER.RTM.188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, etc. and/or combinations thereof.
[0160] Exemplary binding agents include, but are not limited to,
starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g.
sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol,
mannitol,); natural and synthetic gums (e.g. acacia, sodium
alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage
of isapol husks, carboxymethylcellulose, methylcellulose,
ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, microcrystalline cellulose,
cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum
silicate (Veegum.RTM.), and larch arabogalactan); alginates;
polyethylene oxide; polyethylene glycol; inorganic calcium salts;
silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and
combinations thereof.
[0161] Exemplary preservatives may include, but are not limited to,
antioxidants, chelating agents, antimicrobial preservatives,
antifungal preservatives, alcohol preservatives, acidic
preservatives, and/or other preservatives. Exemplary antioxidants
include, but are not limited to, alpha tocopherol, ascorbic acid,
acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and/or sodium sulfite. Exemplary chelating
agents include ethylenediaminetetraacetic acid (EDTA), citric acid
monohydrate, disodium edetate, dipotassium edetate, edetic acid,
fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric
acid, and/or trisodium edetate. Exemplary antimicrobial
preservatives include, but are not limited to, benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and/or thimerosal.
Exemplary antifungal preservatives include, but are not limited to,
butyl paraben, methyl paraben, ethyl paraben, propyl paraben,
benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium
sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
Exemplary alcohol preservatives include, but are not limited to,
ethanol, polyethylene glycol, phenol, phenolic compounds,
bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl
alcohol. Exemplary acidic preservatives include, but are not
limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric
acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid,
and/or phytic acid. Other preservatives include, but are not
limited to, tocopherol, tocopherol acetate, deteroxime mesylate,
cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened
(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl
ether sulfate (SLES), sodium bisulfite, sodium metabisulfite,
potassium sulfite, potassium metabisulfite, GLYDANT PLUS.RTM.,
PHENONIP.RTM., methylparaben, GERMALL.RTM.115, GERMABEN.RTM.II,
NEOLONE.TM., KATHON.TM., and/or EUXYL.RTM..
[0162] Exemplary buffering agents include, but are not limited to,
citrate buffer solutions, acetate buffer solutions, phosphate
buffer solutions, ammonium chloride, calcium carbonate, calcium
chloride, calcium citrate, calcium glubionate, calcium gluceptate,
calcium gluconate, D-gluconic acid, calcium glycerophosphate,
calcium lactate, propanoic acid, calcium levulinate, pentanoic
acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium
phosphate, calcium hydroxide phosphate, potassium acetate,
potassium chloride, potassium gluconate, potassium mixtures,
dibasic potassium phosphate, monobasic potassium phosphate,
potassium phosphate mixtures, sodium acetate, sodium bicarbonate,
sodium chloride, sodium citrate, sodium lactate, dibasic sodium
phosphate, monobasic sodium phosphate, sodium phosphate mixtures,
tromethamine, magnesium hydroxide, aluminum hydroxide, alginic
acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl
alcohol, etc., and/or combinations thereof.
[0163] Exemplary lubricating agents include, but are not limited
to, magnesium stearate, calcium stearate, stearic acid, silica,
talc, malt, glyceryl behanate, hydrogenated vegetable oils,
polyethylene glycol, sodium benzoate, sodium acetate, sodium
chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate,
etc., and combinations thereof.
[0164] Exemplary oils include, but are not limited to, almond,
apricot kernel, avocado, babassu, bergamot, black current seed,
borage, cade, camomile, canola, caraway, carnauba, castor,
cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton
seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol,
gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba,
kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary oils include, but are not limited
to, butyl stearate, caprylic triglyceride, capric triglyceride,
cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl
myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone
oil, and/or combinations thereof.
[0165] Excipients such as cocoa butter and suppository waxes,
coloring agents, coating agents, sweetening, flavoring, and/or
perfuming agents can be present in the composition, according to
the judgment of the formulator.
Administration
[0166] The compounds of the present invention may be administered
by any route which results in a therapeutically effective outcome.
These include, but are not limited to enteral, gastroenteral,
epidural, oral, transdermal, epidural (peridural), intracerebral
(into the cerebrum), intracerebroventricular (into the cerebral
ventricles), epicutaneous (application onto the skin), intradermal,
(into the skin itself), subcutaneous (under the skin), nasal
administration (through the nose), intravenous (into a vein),
intraarterial (into an artery), intramuscular (into a muscle),
intracardiac (into the heart), intraosseous infusion (into the bone
marrow), intrathecal (into the spinal canal), intraperitoneal,
(infusion or injection into the peritoneum), intravesical infusion,
intravitreal, (through the eye), intracavernous injection, (into
the base of the penis), intravaginal administration, intrauterine,
extra-amniotic administration, transdermal (diffusion through the
intact skin for systemic distribution), transmucosal (diffusion
through a mucous membrane), insufflation (snorting), sublingual,
sublabial, enema, eye drops (onto the conjunctiva), or in ear
drops. In specific embodiments, compositions may be administered in
a way which allows them cross the blood-brain barrier, vascular
barrier, or other epithelial barrier.
Dosing
[0167] The present invention provides methods comprising
administering the compounds of the present invention to a subject
in need thereof. Compunds as described herein may be administered
to a subject using any amount and any route of administration
effective for preventing or treating or imaging a disease,
disorder, and/or condition (e.g., a disease, disorder, and/or
condition relating to working memory deficits). The exact amount
required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the disease, the particular composition, its mode of
administration, its mode of activity, and the like.
[0168] Compositions in accordance with the invention are typically
formulated in dosage unit form for ease of administration and
uniformity of dosage. It will be understood, however, that the
total daily usage of the compositions of the present invention may
be decided by the attending physician within the scope of sound
medical judgment. The specific therapeutically effective,
prophylactically effective, or appropriate imaging dose level for
any particular patient will depend upon a variety of factors
including the disorder being treated and the severity of the
disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed;
and like factors well known in the medical arts.
[0169] In some embodiments, compositions in accordance with the
present invention may be administered at dosage levels sufficient
to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about
0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about
0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about
0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50
mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg
to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from
about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about
25 mg/kg, of subject body weight per day, one or more times a day,
to obtain the desired therapeutic, diagnostic, prophylactic, or
imaging effect. The desired dosage may be delivered three times a
day, two times a day, once a day, every other day, every third day,
every week, every two weeks, every three weeks, or every four
weeks. In some embodiments, the desired dosage may be delivered
using multiple administrations (e.g., two, three, four, five, six,
seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or
more administrations). When multiple administrations are employed,
split dosing regimens such as those described herein may be
used.
[0170] As used herein, a "split dose" is the division of single
unit dose or total daily dose into two or more doses, e.g, two or
more administrations of the single unit dose. As used herein, a
"single unit dose" is a dose of any therapeutic administed in one
dose/at one time/single route/single point of contact, i.e., single
administration event. As used herein, a "total daily dose" is an
amount given or prescribed in 24 hr period. It may be administered
as a single unit dose. In one embodiment, the compounds of the
present invention are administed to a subject in split doses. The
compounds may be formulated in buffer only or in a formulation
described herein.
[0171] Dosage Forms
[0172] A pharmaceutical composition described herein can be
formulated into a dosage form described herein, such as a topical,
intranasal, intratracheal, or injectable (e.g., intravenous,
intraocular, intravitreal, intramuscular, intracardiac,
intraperitoneal, subcutaneous).
[0173] Liquid Dosage Forms
[0174] Liquid dosage forms for parenteral administration include,
but are not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups, and/or elixirs. In
addition to active ingredients, liquid dosage forms may comprise
inert diluents commonly used in the art including, but not limited
to, water or other solvents, solubilizing agents and emulsifiers
such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene glycol, dimethylformamide, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and
fatty acid esters of sorbitan, and mixtures thereof. In certain
embodiments for parenteral administration, compositions may be
mixed with solubilizing agents such as CREMOPHOR.RTM., alcohols,
oils, modified oils, glycols, polysorbates, cyclodextrins,
polymers, and/or combinations thereof.
[0175] Injectable
[0176] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art and may include suitable dispersing agents, wetting
agents, and/or suspending agents. Sterile injectable preparations
may be sterile injectable solutions, suspensions, and/or emulsions
in nontoxic parenterally acceptable diluents and/or solvents, for
example, a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed include, but are not
limited to, water, Ringer's solution, U.S.P., and isotonic sodium
chloride solution. Sterile, fixed oils are conventionally employed
as a solvent or suspending medium. For this purpose any bland fixed
oil can be employed including synthetic mono- or diglycerides.
Fatty acids such as oleic acid can be used in the preparation of
injectables.
[0177] Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, and/or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0178] In order to prolong the effect of an active ingredient, it
may be desirable to slow the absorption of the active ingredient
from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compounds then depends upon its rate of
dissolution which, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound may be accomplished by
dissolving or suspending the compounds in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices
of the compunds of the present invention in biodegradable polymers
such as polylactide-polyglycolide. Depending upon the ratio of the
compounds of the present invention to polymer and the nature of the
particular polymer employed, the rate of compound release can be
controlled. Examples of other biodegradable polymers include, but
are not limited to, poly(orthoesters) and poly(anhydrides). Depot
injectable formulations may be prepared by entrapping the compounds
of the present invention in liposomes or microemulsions which are
compatible with body tissues.
[0179] Pulmonary
[0180] Formulations described herein as being useful for pulmonary
delivery may also be used for intranasal delivery of a
pharmaceutical composition. Another formulation suitable for
intranasal administration may be a coarse powder comprising the
active ingredient and having an average particle from about 0.2 um
to 500 um. Such a formulation may be administered in the manner in
which snuff is taken, i.e. by rapid inhalation through the nasal
passage from a container of the powder held close to the nose.
[0181] Formulations suitable for nasal administration may, for
example, comprise from about as little as 0.1% (w/w) and as much as
100% (w/w) of active ingredient, and may comprise one or more of
the additional ingredients described herein. A pharmaceutical
composition may be prepared, packaged, and/or sold in a formulation
suitable for buccal administration. Such formulations may, for
example, be in the form of tablets and/or lozenges made using
conventional methods, and may, for example, contain about 0.1% to
20% (w/w) active ingredient, where the balance may comprise an
orally dissolvable and/or degradable composition and, optionally,
one or more of the additional ingredients described herein.
Alternately, formulations suitable for buccal administration may
comprise a powder and/or an aerosolized and/or atomized solution
and/or suspension comprising active ingredient. Such powdered,
aerosolized, and/or aerosolized formulations, when dispersed, may
have an average particle and/or droplet size in the range from
about 0.1 nm to about 200 nm, and may further comprise one or more
of any additional ingredients described herein.
[0182] General considerations in the formulation and/or manufacture
of pharmaceutical agents may be found, for example, in Remington:
The Science and Practice of Pharmacy 21st ed., Lippincott Williams
& Wilkins, 2005 (incorporated herein by reference in its
entirety).
[0183] Coatings or Shells
[0184] Solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally comprise opacifying agents and
can be of a composition that they release the active ingredient(s)
only, or preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
which can be used include polymeric substances and waxes. Solid
compositions of a similar type may be employed as fillers in soft
and hard-filled gelatin capsules using such excipients as lactose
or milk sugar as well as high molecular weight polyethylene glycols
and the like.
Methods of Using The Compounds and Compositions
[0185] These and other embodiments of the present teachings may
also involve promotion of the treatment of cancer or tumor
according to any of the techniques and compositions and
combinations of compositions described herein.
[0186] In various embodiments, methods for treating a subject
having a cancer are provided, wherein the method comprises
administering a therapeutically-effective amount of a compound, as
described herein, to a subject having a cancer, suspected of having
cancer, or having a predisposition to a cancer. According to the
present invention, cancer embraces any disease or malady
characterized by uncontrolled cell proliferation, e.g.,
hyperproliferation. Cancers may be characterized by tumors, e.g.,
solid tumors or any neoplasm. In some embodiments, the subject may
be otherwise free of indications for treatment with said compound.
In some embodiments, methods include use of cancer cells, including
but not limited to mammalian cancer cells. In some instances, the
mammalian cancer cells are human cancer cells.
[0187] In some embodiments, the compounds of the present teachings
can inhibit growth of a cancer and/or tumor. They may also reduce
cell proliferation, invasiveness, and/or metastasis, thereby
rendering them useful for treating a cancer.
[0188] In some embodiments, the compounds of the present teachings
may be used to prevent the growth of a tumor or cancer, and/or to
prevent the metastasis of a tumor or cancer. In some embodiments,
compositions of the present teachings may be used to shrink or
destroy a cancer.
[0189] In some embodiments, a compound provided herein is useful
for inhibiting proliferation of a cancer cell. In some embodiments
a compound provided herein is useful for inducing cell death of a
cancer cell or both inhibiting proliferation or inducing cell death
of a cancer cell.
[0190] The cancers treatable by methods of the present teachings
generally occur in mammals. Mammals include, for example, humans
and non-human primates, as well as pet or companion animals, such
as dogs and cats, laboratory animals, such as rats, mice and
rabbits, and farm animals, such as horses, pigs, sheep, and cattle.
In various embodiments, the cancer is lung cancer, breast cancer,
colorectal cancer, ovarian cancer, bladder cancer, prostate cancer,
cervical cancer, renal cancer, leukemia, central nervous system
cancers, myeloma, and melanoma. In some embodiments, the cancer is
lung cancer. In certain embodiments, the cancer is human lung
carcinoma and/or normal lung fibroblast.
[0191] In some embodiments, the compounds of the present invention
are effective for inhibiting tumor growth, whether measured as a
net value of size (weight, surface area or volume) or as a rate
over time, in multiple types of tumors.
[0192] In some embodiments, the size of a tumor is reduced by 60%or
more. In some embodiments, the size of a tumor is reduced by at
least 20%, at least 30%, at least 40%, at least 50%, at least 60%,
at least 70%, at least 80%, at least 90%, at least 95%, at least
96%, at least 97%, at least 98%, at least 99%, at least 100%, by a
measure of weigth, and/or area and/or volume.
[0193] In some embodiments, the RECIST (Response Evaluation
Criteria In Solid Tumors) criteria are used to characterize the
effects of the compounds of the invention on solid tumors. The
guidelines for gauging tumors were updated and published in the
European Journal of Cancer (EJC) in January 2009 (Eisenhauer, et
al., European Journal of Cancer: 45 (2009) 228-247), the contents
of which are incorporated herein by reference in their entirety.
Any of the RECIST metrics may be used to characterize the effects
of the compounds of the invention on tumors including but not
limited to response, assessment and measurement criteria.
[0194] The following examples are intended to illustrate certain
embodiments of the present teachings, but do not necessarily
exemplify the full scope of the present teachings and therefore
should not be construed to limit the scope of the present
teachings.
EXAMPLES
Example 1
[0195] General procedure for synthesizing a compound of the present
teachings: Dihydroxy cisplatin,
oxalato[(1R,2R)-1,2-cyclohexanediamine-KN,KN']dihydroxyplatinum or
dichloro[(1R,2R)-1,2-cyclohexanediamine-KN,KN']dihydroxyplatinum
was suspended in N,N-dimethylformamide and 1-3 equivalents of the
appropriate anhydride or isocyanate was added. The solution was
stirred at 25-40 .degree. C. for 1-5 days. The solution was
centrifuged and then decanted. Unreacted starting material was
recovered from decanted solid. The solvent from the filtrate was
removed under vacuum and the crude residue was purified on silica
gel chromatography to afford pure products.
[0196] The following analogs were prepared according to the above
general procedure by using the appropriate isocyanate or
anhydride:
[0197] 1: LCMS (Mobile Phase: A: water (0.01% formic acid) B: ACN
(0.01% formic acid); Gradient: 5%-40% B in 5.0 minutes (min); Flow
Rate: 1.5 ml/min, 6.0 min run; Column: CORTECS C18+,4.6*50 mm,2.7
um; Oven Temperature: 30.degree. C.) Rt: 0.67; MH.sup.+: 446, 447,
448, 449, 450.
[0198] 2: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.436; MH.sup.+: 662.8, 663.8, 664.8.
[0199] 3: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.684; MH.sup.+: 555.7, 556.7, 557.7.
[0200] 4: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.2 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.270; MH.sup.+: 575.1, 576.1, 577.1.
[0201] 5: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.4 min; Flow Rate: 2.3 ml/min, 3.2 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
50.degree. C.) Rt: 2.062; MH.sup.+: 741.4, 742.4, 743.3.
[0202] 6: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5min; Flow Rate: 1.8 ml/min, 3.0 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.450; MH.sup.+: 572.8, 573.8, 574.87: LCMS
(Mobile Phase: A: water (0.01% TFA) B: ACN (0.01% TFA); Gradient:
5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min run; Column:
SunFire C18,4.6*50 mm,3.5 um; Oven Temperature: 45.degree. C.) Rt:
1.639; MH.sup.+: 732.8, 733.8, 734.8, 735.8, 736.8
[0203] 8: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.590; MH.sup.+: 644.8, 645.8, 646.8, 647.8,
648.8.
[0204] 9: LCMS (Mobile Phase: A: water (0.01% TFA) B: ACN (0.01%
TFA); Gradient: 5%-95% B in 1.5 min; Flow Rate: 1.8 ml/min, 3.0 min
run; Column: SunFire C18,4.6*50 mm,3.5 um; Oven Temperature:
45.degree. C.) Rt: 1.661; MH.sup.+: 750.8, 751.8, 752.8.
Example 2
[0205] To test the effect of a compound described herein on cancer
cells, human cancer cell lines were plated in 96 well plates
(Costar) and 24 hours later were treated with a compound for 48-72
hours. Specifically, H460 cells (ATCC) were plated at a
concentration of 1,500 cells per well and incubated for 48 hours.
Compound starting dose was 20 .mu.M and three fold serial dilutions
were done for a total of ten samples. Inhibition of proliferation
was measured using Cell Titer-Glo.RTM. reagent using the standard
protocol (Promega) and a GloMax.RTM. multi+detection system
(Promega). Percent proliferation inhibition was calculated using
the following formula: %
inhibition=(control-treatment)/control*100. Control is defined as
vehicle alone. IC50 curves were generated using nonlinear
regression analysis (four parameter) with GraphPad Prism 6.
[0206] Compounds of the present teachings each has an IC.sub.50
between 0.0001 .mu.M and 50 .mu.M. For example, as shown below,
some examples of the present teachings each has an IC.sub.50 value
between 0.01 .mu.M and 30 .mu.M. In some embodiments, the compounds
have the following IC.sub.50.
TABLE-US-00001 Compound IC.sub.50/.mu.M No. (H460) 3 0.94 6 21.7 8
1.08 2 13.6
[0207] These data demonstrate that compounds described herein are
efficacious for inducing cell death in a cancer cell.
Example 3
[0208] To assess the activity of the compounds in vivo, the effect
of compound 5 on the growth of human Calu-6 NSCLC xenografts was
tested. All mice were treated in accordance with the OLAW Public
Health Service Policy on Human Care and Use of Laboratory Animals
and the ILAR Guide for the Care and Use of Laboratory Animals, and
were conducted at Charles River Laboratories (Morrisville, N.C.).
All in vivo studies were conducted following the protocols approved
by the Charles River Institutional Animal Care and Use Committee.
For the Calu-6 in vivo studies, 10 week old female NCR nude mice
were inoculated subcutaneously into the right flank with 10 million
cells in 1:1 RPMI 1640 (Invitrogen, Carlsbad, Calif.)/Matrigel (BD
Biosciences, San Jose, Calif.). Tumor measurements were taken twice
weekly, using vernier calipers. Tumor volume was calculated using
the formula: V=0.5.times.width.times.width.times.length.
[0209] When tumors approached a volume of 100 mm.sup.3, mice were
randomized into two groups of ten animals. Mice were treated with
vehicle control (10% Solutol.RTM. HS15 in saline) or 30 mg/kg 5 by
intravenous injection. Mice were dosed twice weekly for the
duration of the study. Twenty-four hours after the final dose tumor
volumes were measured again for calculation of tumor growth
inhibition. All statistical analysis was done using GraphPad
PRISM..RTM.. Version 6.00. Final tumor volumes were analyzed using
with a one-way analysis of variance and Tukey multiple comparison
test. Efficacy data for 5 is shown in FIG. 1. Similar experiments
were also conducted to access the activity of the compounds in
other xenograft models.
Example 4
Mouse PK/PD Studies
[0210] To examine the ability of compounds to accumulate in tumors,
a murine cancer model was used. Animals were inoculated with
5.times.10.sup.5 H460 small cell lung cancer cells via subcutaneous
injection to the flank. Tumors were allowed to reach an approximate
volume of .about.500 mm.sup.3. Animals were then randomized into
treatment groups of 3 animals per time point and were dosed at the
maximum tolerated dose (MTD). The 24 hour time point was used as a
benchmark across compounds
TABLE-US-00002 Compound Dose No. (mg/kg) 10 8 2 40 5 30 6 50
[0211] Tumor platinum levels were determined by inductively coupled
plasma mass spectrometry (ICP-MS). Tumors were excised from animals
and dissolved in fuming nitric acid (60% w/w) by adding four parts
nitric acid to 1 part tumor w/w and heating overnight at 60 degrees
Centigrade. The resulting digest was diluted 1:10 in ICP-MS
analysis buffer (1% nitric acid, 2% Triton.RTM. x-100), and
directly introduced into the ICP-MS unit by peristaltic pump. The
end dilution factor for the samples as introduced to the ICP-MS was
50.times..
[0212] FIG. 2 shows the platinum levels in the tumor for three
exemplary compounds (Compound 2; Compound 5; and Compound 6 in FIG.
2) of the present teachings, respectively, in which each of the
compounds was dosed as a free drug. Compound 10 is
##STR00012##
[0213] The figure shows higher platinum levels in the tumors for
the exemplary compounds 2, 5 and 6. On the contrary, compound 10, a
less poloar compound, has a lower platinum level than compound 2, 5
and 6.
Example 5
[0214] The logP of the compounds was measured using a
chromatographic method and by comparison of the retention time with
a calibration curve generated from known compounds. The following
reverse phase HPLC method was used: mobile phase: A 95% water/5%
ACN/0.1% TFA (Trifluoroacetic acid); B: 95% CAN/water/5% water/0.1%
TFA; Gradient 10%-100% B in 8 minutes (min),\; Flow rate 1.5
ml/min, 12 min run; Column: Zorbax Eclipse XDB C8, 4.6.times.100
mm,3.5 mm; Column temperature: 30.degree. C.
TABLE-US-00003 Compound Rt Measured No. (mins) LogP 1 No <1
retention 2 1.59 1.00 3 2.588 1.29 4 No <1 retention 5 No <1
retention 6 1.854 1.07 7 2.827 1.38 8 2.551 1.27 9 3.553 1.66
oxaliplatin 0.879 0.83 10 7.618 4.79 Reference Literature compounds
logP Aniline 0.922 0.9 Benzyl alcohol 2.602 1.1 Benzoic acid 3.305
1.9 Nitrobenzene 4.545 1.9 Toluene 5.838 2.7 Naphthalene 6.32 3.6
Triphenylamine 8.219 5.7
Equivalents and Scope
[0215] While several embodiments of the present teachings have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present teachings. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present teachings
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the present teachings
described herein. It is, therefore, to be understood that the
foregoing embodiments are presented by way of example only and
that, within the scope of the appended claims and equivalents
thereto, the present teachings may be practiced otherwise than as
specifically described and claimed. The present teachings are
directed to each individual feature and/or method described herein.
In addition, any combination of two or more such features and/or
methods, if such features and/or methods are not mutually
inconsistent, is included within the scope of the present
teachings.
[0216] The scope of the present invention is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims.
[0217] In the claims, articles such as "a," "an," and "the" may
mean one or more than one unless indicated to the contrary or
otherwise evident from the context. Claims or descriptions that
include "or" between one or more members of a group are considered
satisfied if one, more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process unless indicated to the contrary or otherwise evident
from the context. The invention includes embodiments in which
exactly one member of the group is present in, employed in, or
otherwise relevant to a given product or process. The invention
includes embodiments in which more than one, or all of the group
members are present in, employed in, or otherwise relevant to a
given product or process.
[0218] It is also noted that the term "comprising" is intended to
be open and permits but does not require the inclusion of
additional elements or steps. When the term "comprising" is used
herein, the term "consisting of" is thus also encompassed and
disclosed.
[0219] Where ranges are given, endpoints are included. Furthermore,
it is to be understood that unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or subrange within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0220] In addition, it is to be understood that any particular
embodiment of the present invention that falls within the prior art
may be explicitly excluded from any one or more of the claims.
Since such embodiments are deemed to be known to one of ordinary
skill in the art, they may be excluded even if the exclusion is not
set forth explicitly herein. Any particular embodiment of the
compositions of the invention can be excluded from any one or more
claims, for any reason, whether or not related to the existence of
prior art.
[0221] All cited sources, for example, references, publications,
databases, database entries, and art cited herein, are incorporated
into this application by reference, even if not expressly stated in
the citation. In case of conflicting statements of a cited source
and the instant application, the statement in the instant
application shall control.
[0222] Section and table headings are not intended to be
limiting.
* * * * *