U.S. patent application number 13/103811 was filed with the patent office on 2011-09-01 for pyrazole derivatives as kinase inhibitors.
This patent application is currently assigned to BURNHAM INSTITUTE FOR MEDICAL RESEARCH. Invention is credited to Elisa Barile, Surya De, Maurizio Pellecchia.
Application Number | 20110212961 13/103811 |
Document ID | / |
Family ID | 40591466 |
Filed Date | 2011-09-01 |
United States Patent
Application |
20110212961 |
Kind Code |
A1 |
Pellecchia; Maurizio ; et
al. |
September 1, 2011 |
Pyrazole Derivatives as Kinase Inhibitors
Abstract
The present invention provides compounds having the general
structure I, or a pharmaceutically acceptable salt thereof:
##STR00001## wherein X is a six-member ring selected from phenyl,
pyridine, or pyrimidine; Y is H, an alkenyl, a substituted alkenyl,
or alkynyl, and R is H or alkyl. Pharmaceutical compositions for
treating various disorders such as cancers, the compositions
including compound I are also provided.
Inventors: |
Pellecchia; Maurizio; (La
Jolla, CA) ; De; Surya; (San Diego, CA) ;
Barile; Elisa; (San Diego, CA) |
Assignee: |
BURNHAM INSTITUTE FOR MEDICAL
RESEARCH
|
Family ID: |
40591466 |
Appl. No.: |
13/103811 |
Filed: |
May 9, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12261584 |
Oct 30, 2008 |
7951832 |
|
|
13103811 |
|
|
|
|
60984302 |
Oct 31, 2007 |
|
|
|
Current U.S.
Class: |
514/234.5 ;
514/303; 514/341; 514/406; 544/139; 546/119; 546/275.7;
548/361.1 |
Current CPC
Class: |
C07D 403/14 20130101;
C07D 401/06 20130101; C07D 401/04 20130101; C07D 405/14 20130101;
C07D 403/06 20130101; A61P 35/00 20180101; C07D 231/54 20130101;
C07D 401/14 20130101; C07D 409/14 20130101; C07D 409/06
20130101 |
Class at
Publication: |
514/234.5 ;
548/361.1; 514/406; 546/275.7; 514/341; 546/119; 514/303;
544/139 |
International
Class: |
A61K 31/416 20060101
A61K031/416; C07D 231/56 20060101 C07D231/56; C07D 403/06 20060101
C07D403/06; C07D 401/06 20060101 C07D401/06; A61K 31/4439 20060101
A61K031/4439; C07D 401/14 20060101 C07D401/14; C07D 409/14 20060101
C07D409/14; C07D 405/14 20060101 C07D405/14; C07D 471/04 20060101
C07D471/04; A61K 31/444 20060101 A61K031/444; C07D 413/14 20060101
C07D413/14; A61K 31/5377 20060101 A61K031/5377; A61P 35/00 20060101
A61P035/00 |
Claims
1. A compound having the general structure I or a pharmaceutically
acceptable salt thereof: ##STR00050## wherein: X is a six-member
ring selected from the group consisting of an unsubstituted phenyl,
a substituted phenyl, an unsubstituted pyridine, a substituted
pyridine, an unsubstituted pyrimidine and a substituted pyrimidine;
Y is selected from the group consisting of H, an unsubstituted
alkenyl, a substituted alkenyl, an unsubstituted alkynyl and a
substituted alkynyl; and R is selected from the group consisting of
H, an unsubstituted alkyl and a substituted alkyl.
2. A pharmaceutical composition comprising a compound claim 1 and a
pharmaceutically acceptable carrier therefor.
3. A method of treatment of a disorder, disease, or pathology,
comprising administering a pharmacologically effective dose of a
pharmaceutical composition of claim 2 to a subject in need thereof,
thereby treating the disorder, disease, or pathology.
4. The method of claim 3, wherein the disorder, disease, or
pathology is cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 12/261,584 filed Oct. 30, 2008, now pending;
which claims the benefit under 35 USC .sctn.119(e) to U.S.
Application Ser. No. 60/984,302 filed Oct. 31, 2007, now expired.
The disclosure of each of the prior applications is considered part
of and is incorporated by reference in the disclosure of this
application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates generally to compounds useful for the
inhibition of kinases, and more specifically, to new pyrazole
derivatives, including those comprising pyridine or pyrimidine
moieties, that are useful as kinase inhibitors.
[0004] 2. Background Information
[0005] Inhibiting kinases, such as PI3K and mTOR, is one method of
treating various diseases, disorders and pathologies. Previously,
some compounds that can be useful as inhibitors of certain kinases
have been identified and synthesized. However, no compounds have
been reported that are capable of targeting and inhibiting kinases
PI3 K-AKT-mTOR signaling pathway.
SUMMARY OF THE INVENTION
[0006] Currently, there is a need for novel, potent, and selective
agents for the treatment of various diseases, disorders and
pathologies, such as tumors, as well as for the pharmaceutical
compositions including such agents. Such agents can be based on
inhibitors of kinases PI3 K-AKT-mTOR signaling pathway.
[0007] According to embodiments of the present invention, there are
provided compounds having the general structure I, or
pharmaceutically acceptable salts thereof:
##STR00002##
wherein X is a six-member ring selected from the group consisting
of an unsubstituted phenyl, a substituted phenyl, an unsubstituted
pyridine, a substituted pyridine, an unsubstituted pyrimidine and a
substituted pyrimidine; Y is selected from the group consisting of
H, an unsubstituted alkenyl, a substituted alkenyl, an
unsubstituted alkynyl and a substituted alkynyl; and R is selected
from the group consisting of H, an unsubstituted alkyl and a
substituted alkyl.
[0008] According to one embodiment of the present invention,
compounds are provided having the general structure II:
##STR00003##
wherein R.sub.1 is selected from a group consisting of a
substituted alkenyl and a substituted alkynyl, wherein the
substitutent(s) in each of the substituted alkenyl and the
substituted alkynyl is(are) selected from the group consisting of
an aryl, a substituted aryl, a heteroaryl, and a substituted
heteroaryl; R.sub.2 is selected from a group consisting of a
halogen, an unsubstituted aryl, a substituted aryl, an
unsubstituted heteroaryl, a substituted heteroaryl, an
unsubstituted alkyl, a substituted alkyl, and
(CH.sub.2).sub.nOR.sub.6; R.sub.3 is selected from a group
consisting of H, an unsubstituted aryl, a substituted aryl, an
unsubstituted heteroaryl, a substituted heteroaryl, an
unsubstituted alkyl, and a substituted alkyl; R.sub.4 is selected
from a group consisting of OH and OR.sub.7; each of R.sub.5,
R.sub.6 and R.sub.7 is independently selected from a group
consisting of an unsubstituted alkyl and a substituted alkyl; and n
is an integer having the value of 1, 2, or 3.
[0009] According to embodiments of the present invention, compounds
are provided having the general structure IIIA or IIIB:
##STR00004##
wherein R.sub.8 is selected from a group consisting of an
unsubstituted aryl and a substituted aryl; each of R.sub.9,
R.sub.10, R.sub.11, and R.sub.12 is selected from a group
consisting of an unsubstituted alkyl, a substituted alkyl, an acyl,
an unsubstituted aryl, a substituted aryl, and a halogen; and Z is
selected from a group consisting of C, O, and N.
[0010] According to other embodiments of the present invention,
pharmaceutical compositions are provided for the treatment of
various disorders, diseases, and pathologies, such as cancer, the
compositions comprising a compound having the general structure II,
IIIA or IIIB, and a pharmaceutically acceptable carrier.
[0011] According to other embodiments of the present invention,
methods for the treatment of various disorders, diseases, and
pathologies, such as cancer, are provided, the methods comprising
administering to a subject in need thereof a pharmacologically
effective dose of a pharmaceutical composition comprising a
compound having the general structure II, IIIA or IIIB.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows the data on inhibition of PC3 cell
proliferation by some compounds of the present invention, according
to one embodiment of the present invention.
[0013] FIG. 2 shows the data on inhibition of U87 spheroid cell
growth by some compounds of the present invention, according to one
embodiment of the present invention.
[0014] FIG. 3 shows the data on inhibition of target kinase
activities in U87 spheroid cell by some compounds of the present
invention, according to one embodiment of the present
invention.
[0015] FIG. 4 shows the data on inhibition of PC3 cell
proliferation by some compounds of the present invention, according
to another embodiment of the present invention.
[0016] FIG. 5 shows the data on inhibition of U87 spheroid cell
growth by some compounds of the present invention, according to
another embodiment of the present invention.
[0017] FIG. 6 shows the data on inhibition of target kinase
activities in U87 spheroid cell by some compounds of the present
invention, according to another embodiment of the present
invention.
[0018] FIG. 7 shows the PI3K assay data, including compound 1 of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The following definitions are used, unless otherwise
described.
[0020] The terms "alkyl" and "substituted alkyl" refer to
substituted and unsubstituted C.sub.1-C.sub.10 straight chain
saturated aliphatic hydrocarbon groups, substituted and
unsubstituted C.sub.2-C.sub.10 straight chain unsaturated aliphatic
hydrocarbon groups, substituted and unsubstituted C.sub.4-C.sub.10
branched saturated aliphatic hydrocarbon groups, substituted and
unsubstituted C.sub.4-C.sub.10 branched unsaturated aliphatic
hydrocarbon groups, substituted and unsubstituted C.sub.3-C.sub.8
cyclic saturated aliphatic hydrocarbon groups, substituted and
unsubstituted C.sub.5-C.sub.8 cyclic unsaturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, the definition of "alkyl" shall include but is not limited
to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl,
hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl,
butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,
undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu),
sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl,
ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbornyl and the
like. Alkyl substituents are independently selected from a group
consisting of halogen, --OH, --SH, --NH.sub.2, --CN, --NO.sub.2,
.dbd.O, .dbd.CH.sub.2, trihalomethyl, carbamoyl,
arylC.sub.0-10alkyl, heteroarylC.sub.0-10alkyl, C.sub.1-10alkyloxy,
arylC.sub.0-10alkyloxy, arylC.sub.1-10alkylthio,
arylC.sub.0-10alkylthio, C.sub.1-10alkylamino,
arylC.sub.0-10alkylamino, N-aryl-N--C.sub.0-10alkylamino,
C.sub.1-10alkylcarbonyl, arylC.sub.0-10alkylcarbonyl,
C.sub.1-10alkylcarboxy, arylC.sub.0-10alkylcarboxy,
C.sub.1-10alkylcarbonylamino, arylC.sub.0-10alkylcarbonylamino,
tetrahydrofuryl, morpholinyl, piperazinyl, hydroxypyronyl,
--C.sub.0-10alkylCOOR.sub.a and --C.sub.0-10alkylCONR.sub.bR.sub.c,
wherein R.sub.a, R.sub.b and R.sub.c are independently selected
from hydrogen, alkyl, aryl, or R.sub.b and R.sub.c are taken
together with the nitrogen to which they are attached forming a
saturated cyclic or unsaturated cyclic system containing 3 to 8
carbon atoms, with at least one substituent.
[0021] The term "alkenyl" refers to straight-chained or branched
hydrocarbyl groups having at least one carbon-carbon double bond,
and having between about 2 and about 12 carbon atoms, and the term
"substituted alkenyl" refers to alkenyl groups further bearing one
or more substitutents described above. The term "alkynyl" refers to
straight-chained or branched hydrocarbyl groups having at least one
carbon-carbon triple bond, and having between about 2 and about 12
carbon atoms, and the term "substituted alkynyl" refers to alkynyl
groups further bearing one or more substitutents described
above.
[0022] The term "aryl" refers to an unsubstituted, monosubstituted,
disubstituted or trisubstituted monocyclic, polycyclic, biaryl
aromatic groups covalently attached at any ring position capable of
forming a stable covalent bond, certain preferred points of
attachment being apparent to those skilled in the art (e.g.,
3-phenyl, 4-naphtyl and the like). The aryl substituents are
independently selected from a group consisting of halogen, --OH,
--SH, --CN, --NO.sub.2, trihalomethyl, hydroxypyronyl,
C.sub.1-10alkyl, arylC.sub.0-10alkyl,
C.sub.0-10alkyloxyC.sub.0-10alkyl,
arylC.sub.0-10alkyloxyC.sub.0-10alkyl,
C.sub.0-10alkylthioC.sub.0-10alkyl,
arylC.sub.0-10alkylthioC.sub.0-10alkyl,
C.sub.0-10alkylaminoC.sub.0-10alkyl,
arylC.sub.0-10alkylaminoC.sub.0-10alkyl,
N-aryl-N--C.sub.0-10alkylaminoC.sub.0-10alkyl,
C.sub.1-10alkylcarbonylC.sub.0-10alkyl,
arylC.sub.0-10alkylcarbonylC.sub.0-10alkyl,
C.sub.1-10alkylcarboxyC.sub.0-10alkyl,
arylC.sub.0-10alkylcarboxyC.sub.0-10alkyl,
C.sub.1-10alkylcarbonylaminoC.sub.0-10alkyl,
arylC.sub.0-10alkylcarbonylaminoC.sub.0-10alkyl,
--C.sub.0-10alkylCOOR.sub.a, and
--C.sub.0-10alkylCONR.sub.bR.sub.c, wherein R.sub.a, R.sub.b and
R.sub.c, are independently selected from hydrogen, alkyl, aryl or
R.sub.b and R.sub.c, are taken together with the nitrogen to which
they are attached forming a saturated cyclic or unsaturated cyclic
system containing 3 to 8 carbon atoms with at least one
substituent.
[0023] The definition of "aryl" includes, but is not limited to,
such specific groups as phenyl, biphenyl, naphthyl,
dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl,
anthryl, phenanthryl, fluorenyl, pyrenyl and the like.
[0024] The terms "heteroaryl", "heterocycle" or "heterocyclic"
refer to a monovalent unsaturated group having a single ring or
multiple condensed (also known as "fused") rings, from 1 to 8
carbon atoms and from 1 to 4 hetero atoms selected from nitrogen,
sulfur or oxygen within the ring. The heteroaryl groups in this
invention can be optionally substituted with 1 to 3 substituents
selected from a group consisting of: halogen, --OH, --SH, --CN,
--NO.sub.2, trihalomethyl, hydroxypyronyl, C.sub.1-10alkyl,
arylC.sub.0-10alkyl, C.sub.0-10alkyloxyC.sub.0-10alkyl,
arylC.sub.0-10alkyloxyC.sub.0-10alkyl,
C.sub.0-10alkylthioC.sub.0-10alkyl,
arylC.sub.0-10alkylaminoC.sub.0-10alkyl,
C.sub.0-10alkylaminoC.sub.0-10alkyl,
arylC.sub.0-10alkylaminoC.sub.0-10alkyl,
N-aryl-N--C.sub.0-10alkylaminoC.sub.1-10alkyl,
C.sub.1-10alkylcarbonylC.sub.0-10alkyl,
arylC.sub.0-10alkylcarbonylC.sub.0-10alkyl,
C.sub.1-10alkylcarboxyC.sub.0-10alkyl,
arylC.sub.0-10alkylcarboxyC.sub.0-10alkyl,
C.sub.1-10alkylcarbonylaminoC.sub.0-10alkyl,
aryl-C.sub.0-10alkylcarbonylaminoC.sub.0-10alkyl,
--C.sub.0-10alkylCOOR.sub.a, and --C.sub.0-10alkylCONR.sub.bR.sub.c
wherein R.sub.a, R.sub.b and R.sub.c, are independently selected
from hydrogen, alkyl, aryl, or R.sub.b and R.sub.c, are taken
together with the nitrogen to which they are attached forming a
saturated cyclic or unsaturated cyclic system containing 3 to 8
carbon atoms with at least one substituent.
[0025] The definition of "heteroaryl" includes, but is not limited
to, such specific groups as thienyl, benzothienyl, isobenzothienyl,
2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl,
isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,
pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl,
indolinyl, indolizinyl, indazolyl, phthalimidyl (or
isoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl,
pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl,
isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl,
tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl,
isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl,
pyrrolidinyl-2,5-dione, imidazolidinyl-2,4-dione,
2-thioxo-imidazolidinyl-4-one, imidazolidinyl-2,4-dithione,
thiazolidinyl-2,4-dione, 4-thioxo-thiazolidinyl-2-one,
piperazinyl-2,5-dione, tetrahydro-pyridazinyl-3,6-dione,
1,2-dihydro-[1,2,4,5]tetrazinyl-3,6-dione,
[1,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl-2,4-dione,
pyrimidinyl-2,4,6-trione and the like.
[0026] The term "acyl" refers to a radical --R--C(.dbd.O)--, i.e.,
to a radical derived from an organic acid by the removal of the
carboxylic hydroxyl group. Typical examples of acyl groups include
acetyl and benzoyl moieties.
[0027] The terms "halogen", "halide" or "halo" refer to fluorine,
chlorine, bromine, and iodine.
[0028] The term "kinase" refers to any enzyme that catalyzes the
addition of phosphate groups to a protein residue; for example,
serine and threonine kinases catalyze the addition of phosphate
groups to serine and threonine residues.
[0029] The term "effective amount" of a compound refers a non-toxic
but sufficient amount of the compound that provides a desired
effect. This amount may vary from subject to subject, depending on
the species, age, and physical condition of the subject, the
severity of the disease that is being treated, the particular
compound used, its mode of administration, and the like. Therefore,
it is difficult to generalize an exact "effective amount," yet, a
suitable effective amount may be determined by one of ordinary
skill in the art.
[0030] The term "pharmaceutically acceptable" refers to a compound,
additive or composition that is not biologically or otherwise
undesirable. For example, the additive or composition may be
administered to a subject along with a compound of the invention
without causing any undesirable biological effects or interacting
in an undesirable manner with any of the other components of the
pharmaceutical composition in which it is contained.
[0031] The term "pharmaceutically acceptable salts" includes
hydrochloric salt, hydrobromic salt, hydroiodic salt, hydrofluoric
salt, sulfuric salt, citric salt, maleic salt, acetic salt, lactic
salt, nicotinic salt, succinic salt, oxalic salt, phosphoric salt,
malonic salt, salicylic salt, phenylacetic salt, stearic salt,
pyridine salt, ammonium salt, piperazine salt, diethylamine salt,
nicotinamide salt, formic salt, urea salt, sodium salt, potassium
salt, calcium salt, magnesium salt, zinc salt, lithium salt,
cinnamic salt, methylamino salt, methanesulfonic salt, picric salt,
tartaric salt, triethylamino salt, dimethylamino salt,
tris(hydroxymethyl)aminomethane salt and the like. Additional
pharmaceutically acceptable salts are known to those of skill in
the art.
[0032] As used herein, the term "patient" refers to organisms to be
treated by the methods of the present invention. Such organisms
include, but are not limited to, humans. In the context of the
invention, the term "subject" generally refers to an individual who
will receive or who has received treatment for the treatment of a
disease, disorder or pathology.
[0033] According to embodiments of the present invention, there are
provided compounds having the general structure I, or
pharmaceutically acceptable salts thereof:
##STR00005##
[0034] In the general structure I, X is a six-member ring selected
from the group consisting of an unsubstituted phenyl, a substituted
phenyl, an unsubstituted pyridine, a substituted pyridine, an
unsubstituted pyrimidine and a substituted pyrimidine; Y is
selected from the group consisting of H, an unsubstituted alkenyl,
a substituted alkenyl, an unsubstituted alkynyl and a substituted
alkynyl; and R is selected from the group consisting of H, an
unsubstituted alkyl and a substituted alkyl.
[0035] In some embodiments, the compounds of the general structure
I may be derivatives of indazole, which are described in more
detail below. For these embodiments, accordingly, in the general
structure I, X may be an unsubstituted or substituted phenyl having
at least one substitutent independently selected from the group
consisting of an amino group, a substituted amido group, nitro
group, an ester group, carboxyl group, and morpholino group.
[0036] In other embodiments, the compounds of the general structure
I may be derivatives of pyrazolopyridine, which are described in
more detail below. For these embodiments, accordingly, in the
general structure I, X may be an unsubstituted or substituted
pyridine. In yet other embodiments, the compounds of the general
structure I may be derivatives of pyrazolopyrimidine, which are
described in more detail below. For these embodiments, accordingly,
in the general structure I, X may be a substituted pyrimidine
having at least one substitutent independently selected from the
group consisting of a substituted amino group, morpholino group,
piperazino group, and piperidino group.
[0037] Examples of some sub-genera that are within the purview of
the present invention and are described by the general structure I
include the structures where X is a moiety derived from substituted
pyridine, such as compounds having the general structure II:
##STR00006##
[0038] In the general structure II, R.sub.1 is selected from a
group consisting of a substituted alkenyl and a substituted
alkynyl, wherein the substitutent(s) in each of the substituted
alkenyl and the substituted alkynyl is(are) selected from the group
consisting of an aryl, a substituted aryl, a heteroaryl, and a
substituted heteroaryl; R.sub.2 is selected from a group consisting
of a halogen, an unsubstituted aryl, a substituted aryl, an
unsubstituted heteroaryl, a substituted heteroaryl, an
unsubstituted alkyl, a substituted alkyl, and
(CH.sub.2).sub.nOR.sub.6; R.sub.3 is selected from a group
consisting of H, an unsubstituted aryl, a substituted aryl, an
unsubstituted heteroaryl, a substituted heteroaryl, an
unsubstituted alkyl, and a substituted alkyl; R.sub.4 is selected
from a group consisting of OH and OR.sub.7; each of R.sub.5,
R.sub.6 and R.sub.7 is independently selected from a group
consisting of an unsubstituted alkyl and a substituted alkyl; and n
is an integer having the value of 1, 2, or 3.
[0039] Examples of some other sub-genera that are within the
purview of the present invention and are described by the general
structure I include the structures, where X is a moiety derived
from substituted pyrimidine, such as compounds having the general
IIIA or IIIB:
##STR00007##
[0040] In the general structures IIIA and IIIB, R.sub.8 is selected
from a group consisting of an unsubstituted aryl and a substituted
aryl; each of R.sub.9, R.sub.10, R.sub.11, and R.sub.12 is selected
from a group consisting of an unsubstituted alkyl, a substituted
alkyl, an acyl, an unsubstituted aryl, a substituted aryl, and a
halogen; and Z is selected from a group consisting of C, O, and
N.
[0041] Non-limiting examples of some specific compounds that are
within the purview of the present invention include the compounds
1-37:
##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017##
[0042] The compounds of the present invention are capable of
inhibiting kinase, for example, by selectively targeting at the
kinases PI3 K-AKT-mTOR signal transduction pathway, for the
treatment of various disorders, diseases, and pathologies, such as
cancer. Accordingly, the compounds having the structure I,
including sub-genera II, IIIA and IIIB, or pharmaceutically
acceptable salts thereof can be used for preparing pharmaceutical
compositions, e.g., by combining these compounds and
pharmaceutically acceptable carriers. The pharmaceutical
compositions can then be used in pharmacologically effective doses
for the treatment of various disorders, diseases, and pathologies,
such as cancer.
[0043] Various synthetic schemes can be designed for manufacturing
the products having the structure I, including the sub-genera II,
IIIA and IIIB. Two such schemes, as applicable to compounds of the
sub-genera II and IIIA are shown below as reaction schemes A and B,
respectively.
##STR00018##
[0044] Pharmaceutically acceptable salts of the compounds of the
present invention may be obtained using standard procedures well
known in the art, for example by reacting a sufficiently basic
compound such as an amine with a suitable acid affording a
physiologically acceptable anion. Alkali metal (for example,
sodium, potassium or lithium) or alkaline earth metal (for example
calcium) salts of carboxylic acids can also be made.
[0045] The above-described compounds I, including the sub-genera
II, IIIA and IIIB can be formulated as pharmaceutical compositions
and administered to a mammalian host, such as a human patient in a
variety of forms adapted to the chosen route of administration,
i.e., orally or parenterally, by intravenous, intramuscular,
topical or subcutaneous routes.
[0046] Thus, the present compounds may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations should contain at
least 0.1% of active compound. The percentage of the compositions
and preparations may, of course, be varied and may conveniently be
between about 2 to about 60% of the weight of a given unit dosage
form. The amount of active compound in such therapeutically useful
compositions is such that an effective dosage level will be
obtained.
[0047] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0048] The active compound may also be administered intravenously
or intraperitoneally by infusion or injection. Solutions of the
active compound or its salts can be prepared in water, optionally
mixed with a nontoxic surfactant. Dispersions can also be prepared
in glycerol, liquid polyethylene glycols, triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of
microorganisms.
[0049] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form should be
sterile, fluid and stable under the conditions of manufacture and
storage. The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol, a polyol
(for example, glycerol, propylene glycol, liquid polyethylene
glycols, and the like), vegetable oils, nontoxic glyceryl esters,
and suitable mixtures thereof. The proper fluidity can be
maintained, for example, by the formation of liposomes, by the
maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0050] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile
powders, for the preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and the freeze
drying techniques, which yield a powder of the active ingredient
plus any additional desired ingredient present in the previously
sterile-filtered solutions.
[0051] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid or a
liquid.
[0052] Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0053] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts and esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0054] Useful dosages of the compounds I, including the sub-genera
II, IIIA and IIIB can be determined by comparing their in vitro
activity, and in vivo activity in animal models. Methods for the
extrapolation of effective dosages in mice, and other animals, to
humans are known to those having ordinary skill in the art who can,
for example, be guided by the procedures described in U.S. Pat. No.
4,938,949.
[0055] Generally, the concentration of the compound(s) I, including
the sub-genera II, IIIA and IIIB in a liquid composition, such as a
lotion, can be between about 0.1 and 25 mass %, such as between
about 0.5 and 10 mass %. The concentration in a semi-solid or solid
composition such as a gel or a powder can be between about 0.1 and
25 mass %, such as between about 0.5 and 2.5 mass %.
[0056] The amount of the compound(s) I, including the sub-genera
II, IIIA and IIIB, or an active salt or derivative thereof,
required for use in treatment will vary not only with the
particular salt selected but also with the route of administration,
the nature of the condition being treated and the age and condition
of the patient and will be ultimately at the discretion of the
attendant physician or clinician.
[0057] In general, however, a suitable dose can be in the range of
between about 0.5 and 100 mg/kg, e.g., between about 10 and 75
mg/kg of body weight per day, such as between about 15 and 60
mg/kg/day. The compound(s) I, including the sub-genera II, IIIA and
IIIB can be conveniently administered in unit dosage form; for
example, containing 5 to 1000 mg, such as 10 to 750 mg, for
example, 50 to 500 mg of active ingredient per unit dosage form.
The desired dose may conveniently be presented in a single dose or
as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations.
[0058] FIGS. 1-7 further exemplify embodiments of the present
invention, which are intended to further illustrate but not limit
the invention. FIG. 1 illustrates inhibition of PC3 cell
proliferation by pyrazolopyridines (the above shown compounds of
the sub-genera II). FIG. 4 illustrates inhibition of PC3 cell
proliferation by amininopyrimidines (the above shown compounds of
the sub-genera IIIA). As can be seen from FIGS. 1 and 4, a
substantial degree of inhibition has been achieved.
[0059] FIG. 2 illustrates inhibition of U87 spheroid cell growth by
pyrazolopyridines (the above shown compounds of the sub-genera II).
FIG. 5 illustrates inhibition of U87 spheroid cell growth by
amininopyrimidines (the above shown compounds of the sub-genera
IIIA).
[0060] Finally, FIG. 3 shows the data on inhibition of target
kinase activities in U87 spheroid cell by pyrazolopyridines (the
above shown compounds of the sub-genera II), while FIG. 6 shows the
same for amininopyrimidines (the above shown compounds of the
sub-genera IIIA). These figures provide additional information as
to the effectiveness of inhibition using compounds of the present
invention.
[0061] Table 1 below provides shows the data on inhibition of PI3K
and mTOR kinases by some compounds of the invention.
TABLE-US-00001 TABLE 1 Assay results on Inhibition PI3K and mTOR by
Compounds of the Invention PI3 K (% at 25 .mu.M, mTOR or
(Inhibition IC.sub.50), % at 50 P110.alpha., .mu.M, or Structure
.mu.M IC.sub.50) ##STR00019## 0.083 9% ##STR00020## 6% ##STR00021##
6% ##STR00022## 0.075 34% ##STR00023## 0.299 30% (IC.sub.50 >
100 uM) ##STR00024## 0.062 46% (IC.sub.50 > 100 uM) ##STR00025##
-1% ##STR00026## 5% ##STR00027## -3% ##STR00028## 7% ##STR00029##
13% ##STR00030## 4% ##STR00031## 24% ##STR00032## 1% ##STR00033##
0.058 9% ##STR00034## 3% ##STR00035## 2% ##STR00036## 5%
##STR00037## 0.082 ##STR00038## 3% ##STR00039## -7% ##STR00040##
-27% ##STR00041## -14% ##STR00042## -5% ##STR00043## -11%
##STR00044## -17% ##STR00045## 31 .mu.M ##STR00046## -6%
##STR00047## 3% ##STR00048## 15% ##STR00049## 7%
[0062] Although the invention has been described with reference to
the above example, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention. Accordingly, the invention is limited only by the
following claims.
* * * * *