U.S. patent application number 15/180018 was filed with the patent office on 2016-12-15 for ibrutinib prodrugs, pharmaceutical compositions thereof, and methods of use.
The applicant listed for this patent is Archana Gangakhedkar, Mark Quang Nguyen. Invention is credited to Archana Gangakhedkar, Mark Quang Nguyen.
Application Number | 20160361315 15/180018 |
Document ID | / |
Family ID | 56381522 |
Filed Date | 2016-12-15 |
United States Patent
Application |
20160361315 |
Kind Code |
A1 |
Nguyen; Mark Quang ; et
al. |
December 15, 2016 |
IBRUTINIB PRODRUGS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND
METHODS OF USE
Abstract
Prodrugs of ibrutinib, pharmaceutical compositions comprising
the prodrugs, and methods of using the prodrugs and pharmaceutical
compositions for treating autoimmune diseases or conditions,
heteroimmune diseases or conditions, cancer, including lymphoma,
and inflammatory diseases or conditions are disclosed.
Inventors: |
Nguyen; Mark Quang; (San
Jose, CA) ; Gangakhedkar; Archana; (San Jose,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nguyen; Mark Quang
Gangakhedkar; Archana |
San Jose
San Jose |
CA
CA |
US
US |
|
|
Family ID: |
56381522 |
Appl. No.: |
15/180018 |
Filed: |
June 11, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14738907 |
Jun 14, 2015 |
9394312 |
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15180018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 9/0053 20130101; C07D 487/04 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for treating a non-Hodgkin lymphoma, Waldenstrom
macroglobulinemia, plasma cell myeloma, chronic lymphocytic
leukemia, or chronic lymphocytic leukemia with 17p delection
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of Formula (I):
##STR00050## or a pharmaceutically acceptable solvate, hydrate, or
salt thereof, wherein: A is N; each R.sup.1a, R.sup.1b, R.sup.1d,
and R.sup.1e is H; R.sup.1c is phenoxy. R.sup.2 is H; R.sup.3 is
the following structure: ##STR00051## and Z is selected from the
following structures: ##STR00052## wherein each R.sup.11, R.sup.12,
and R.sup.13 is independently selected from H, substituted or
unsubstituted lower alkyl, substituted or unsubstituted lower
heteroalkyl, substituted or unsubstituted lower cycloalkyl,
substituted or unsubstituted lower heterocycloalkyl, and
substituted or unsubstituted lower aryl, wherein each substituent
is independently selected from --F, --Cl, --CF.sub.3, --CN,
--NO.sub.2, --OH, --OCH.sub.3, and --NH.sub.2.
2. The method of claim 1, wherein the non-Hodgkin lymphoma is
selected from the group consisting of diffuse large B cell
lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt
lymphoma.
3. (canceled)
4. (canceled)
5. (canceled)
6. The method of claim 1, wherein the compound is administered
orally.
7. A method for treating a non-Hodgkin lymphoma, Waldenstrom
macroglobulinemia, plasma cell myeloma, chronic lymphocytic
leukemia, or chronic lymphocytic leukemia with 17p delection
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of Formula (I),
wherein the compound is selected from the compounds of Formula
(I-A-1), Formula (I-A-3), Formula (I-A-5), Formula (I-A-7), and
Formula (I-B-1): ##STR00053## ##STR00054##
8. The method of claim 7, wherein the non-Hodgkin lymphoma is
selected from the group consisting of diffuse large B cell
lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt
lymphoma.
9. (canceled)
10. (canceled)
11. (canceled)
12. The method of claim 7, wherein the compound is administered
orally.
13. A method for treating a non-Hodgkin lymphoma, Waldenstrom
macroglobulinemia, plasma cell myeloma, chronic lymphocytic
leukemia, or chronic lymphocytic leukemia with 17p delection
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of Formula
(I-A-3).
14. The method of claim 13, wherein the non-Hodgkin lymphoma is
selected from the group consisting of diffuse large B cell
lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt
lymphoma.
15. (canceled)
16. (canceled)
17. (canceled)
18. The method of claim 13, wherein the compound is administered
orally.
Description
FIELD
[0001] Disclosed herein are ibrutinib prodrugs, pharmaceutical
compositions comprising ibrutinib prodrugs, and methods of using
ibrutinib prodrugs and pharmaceutical compositions thereof for
treating autoimmune diseases or conditions, heteroimmune diseases
or conditions, cancer, including lymphoma, and inflammatory
diseases or conditions.
BACKGROUND
[0002] Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is
approved in United States for the treatment of mantle cell
lymphoma, chronic lymphocytic leukemia, and lymphoplasmacytic
lymphoma (U.S. Pat. Nos. 7,514,444, 7,718,662, 8,476,284,
8,497,277, 8,703,780, and 8,735,403). The recommended dose of
ibrutinib is 420 to 560 mg orally once daily. However, the absolute
bioavailability of ibrutinib in fasted humans (n=8) was 2.9% (90%
CI=2.1-3.9) and doubled when combined with a meal (European
Medicines Agency).
[0003] The need for higher ibrutinib dosage to counter its low oral
bioavailability may be responsible for adverse side effects such as
nausea or emesis, dizziness and diarrhea. Moreover, the low oral
bioavailability may result in variable absorption and therapeutic
response.
SUMMARY
[0004] Ibrutinib prodrugs having higher oral bioavailability than
the parent compound may: reduce gastrointestinal side
effects/toxicity such as nausea or emesis, dizziness and diarrhea;
facilitate the use of lower doses; reduce food effects; reduce
interpatient treatment variability; and enhance the
efficacy/responder rate.
[0005] In a first aspect, compounds of Formula (I) are
provided:
##STR00001##
or a pharmaceutically acceptable solvate, hydrate, or salt thereof,
wherein:
[0006] A is selected from N and CR.sup.11;
[0007] each R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H, halogen, --CF.sub.3, --CN,
--NO.sub.2, OH, NH.sub.2, -L.sup.1-(substituted or unsubstituted
alkyl), -L.sup.1-(substituted or unsubstituted alkenyl),
-L.sup.1-(substituted or unsubstituted heteroaryl), or
-L.sup.1-(substituted or unsubstituted aryl), wherein L.sup.1 is a
bond, O, S, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --C(O)--,
--CH.sub.2--, --NHC(O)O--, --NHC(O)--, or --C(O)NH--;
[0008] R.sup.2 is selected from H and lower alkyl;
[0009] R.sup.3 is L.sup.2-X-L.sup.3-G, wherein, [0010] L.sup.2 is
selected from a bond, substituted or unsubstituted alkylene,
substituted or unsubstituted cycloalkylene, substituted or
unsubstituted alkenylene, and substituted or unsubstituted
alkynylene; [0011] X is selected from a bond, O, --C(.dbd.O)--, S,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --NR.sup.14,
--NHC(O)--, --C(O)NH--, --NR.sup.14C(O)--, --C(O)NR.sup.14,
--S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.14, --NR.sup.14S(.dbd.O).sub.2--,
--OC(O)NH--, --NHC(O)O--, --OC(O)NR.sup.14, --NR.sup.14C(O)O--,
--CH.dbd.NO--, --ON.dbd.CH--, --NR.sup.15C(O)NR.sup.15--,
heteroarylene, arylene, --NR.sup.15C(.dbd.NR.sup.16)NR.sup.15--,
--NR.sup.15C(.dbd.NR.sup.16)--, --C(.dbd.NR.sup.16)NR.sup.15,
--OC(.dbd.NR.sup.16)--, and --C(.dbd.NR.sup.16)O--, wherein [0012]
R.sup.14 is selected from H, substituted or unsubstituted lower
alkyl, and substituted or unsubstituted lower cycloalkyl; [0013]
each R.sup.15 is independently selected from H, substituted or
unsubstituted lower alkyl, and substituted or unsubstituted lower
cycloalkyl; and [0014] R.sup.16 is selected from H,
--S(.dbd.O).sub.2R.sup.11, --S(.dbd.O).sub.2NH.sub.2,
--C(O)R.sup.11, --CN, --NO.sub.2, heteroaryl, and heteroalkyl;
[0015] L.sup.3 is selected from a bond, substituted or
unsubstituted alkylene, substituted or unsubstituted cycloalkylene,
substituted or unsubstituted alkenylene, substituted or
unsubstituted alkynylene, substituted or unsubstituted arylene,
substituted or unsubstituted heteroarylene, and substituted or
unsubstituted heterocyclene; [0016] or L.sup.2, X and L.sup.3 taken
together form a nitrogen containing heterocyclic ring; and [0017] G
is selected from the following structures:
##STR00002##
[0017] and
[0018] Z is selected from the following structures:
##STR00003##
[0019] wherein each R.sup.11, R.sup.12, and R.sup.13 is
independently selected from H, substituted or unsubstituted lower
alkyl, substituted or unsubstituted lower heteroalkyl, substituted
or unsubstituted lower cycloalkyl, substituted or unsubstituted
lower heterocycloalkyl, and substituted or unsubstituted lower
aryl.
[0020] In a second aspect, pharmaceutical compositions are provided
comprising a compound of Formula (I) and at least one
pharmaceutically acceptable vehicle.
[0021] In a third aspect, methods of treating a disease in a
patient are provided comprising administering to a patient in need
of such treatment a pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula (I). In
certain embodiments, the disease is chosen from an autoimmune
diseases or conditions, heteroimmune diseases or conditions,
cancer, including lymphoma, and inflammatory diseases or
conditions.
DETAILED DESCRIPTION
Definitions
[0022] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs. In
the event that there are a plurality of definitions for terms
herein, those in this section prevail. Where reference is made to a
URL or other such identifier or address, it is understood that such
identifiers can change and particular information on the internet
can come and go, but equivalent information can be found by
searching the internet. Reference thereto evidences the
availability and public dissemination of such information.
[0023] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a," "an" and "the" include plural referents unless the
context clearly dictates otherwise. In this application, the use of
"or" means "and/or" unless stated otherwise. Furthermore, use of
the term "including" as well as other forms, such as "include",
"includes," and "included," is not limiting.
[0024] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, but not limited to, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0025] Definition of standard chemistry terms may be found in
reference works, including Carey and Sundberg "ADVANCED ORGANIC
CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New
York. Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the skill of
the art are employed. Unless specific definitions are provided, the
nomenclature employed in connection with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic
organic chemistry, and medicinal and pharmaceutical chemistry
described herein are those known in the art. Standard techniques
can be used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and delivery, and
treatment of patients. Standard techniques can be used for
recombinant DNA, oligonucleotide synthesis, and tissue culture and
transformation (e.g., electroporation, lipofection). Reactions and
purification techniques can be performed e.g., using kits of
manufacturer's specifications or as commonly accomplished in the
art or as described herein. The foregoing techniques and procedures
can be generally performed of conventional methods well known in
the art and as described in various general and more specific
references that are cited and discussed throughout the present
specification.
[0026] It is to be understood that the methods and compositions
described herein are not limited to the particular methodology,
protocols, cell lines, constructs, and reagents described herein
and as such may vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to limit the scope of the
methods and compositions described herein, which will be limited
only by the appended claims.
[0027] All publications and patents mentioned herein are
incorporated herein by reference in their entirety for the purpose
of describing and disclosing for example, the constructs and
methodologies that are described in the publications, which might
be used in connection with the methods, compositions and compounds
described herein. The publications discussed herein are provided
solely for their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the inventors described herein are not entitled to antedate such
disclosure by virtue of prior invention or for any other
reason.
[0028] An "alkyl" group refers to an aliphatic hydrocarbon group.
The alkyl moiety may be a "saturated alkyl" group, which means that
it does not contain any alkene or alkyne moieties. The alkyl moiety
may also be an "unsaturated alkyl" moiety, which means that it
contains at least one alkene or alkyne moiety. An "alkene" moiety
refers to a group that has at least one carbon-carbon double bond,
and an "alkyne" moiety refers to a group that has at least one
carbon-carbon triple bond. The alkyl moiety, whether saturated or
unsaturated, may be branched, straight chain, or cyclic. Depending
on the structure, an alkyl group can be a monoradical or a
diradical (i.e., an alkylene group). The alkyl group could also be
a "lower alkyl" having 1 to 6 carbon atoms.
[0029] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x.
[0030] The "alkyl" moiety may have 1 to 10 carbon atoms (whenever
it appears herein, a numerical range such as "1 to 10" refers to
each integer in the given range; e.g., "1 to 10 carbon atoms" means
that the alkyl group may have 1 carbon atom, 2 carbon atoms, 3
carbon atoms, etc., up to and including 10 carbon atoms, although
the present definition also covers the occurrence of the term
"alkyl" where no numerical range is designated). The alkyl group of
the compounds described herein may be designated as
"C.sub.1-C.sub.4 alkyl" or similar designations. By way of example
only, "C.sub.1-C.sub.4 alkyl" indicates that there are one to four
carbon atoms in the alkyl chain, i.e., the alkyl chain is selected
from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and t-butyl. Thus C.sub.1-C.sub.4 alkyl includes
C.sub.1-C.sub.2 alkyl and C.sub.1-C.sub.3 alkyl. Alkyl groups can
be substituted or unsubstituted. Typical alkyl groups include, but
are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl,
butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the
like.
[0031] As used herein, the term "non-cyclic alkyl" refers to an
alkyl that is not cyclic (i.e., a straight or branched chain
containing at least one carbon atom). Non-cyclic alkyls can be
fully saturated or can contain non-cyclic alkenes and/or alkynes.
Non-cyclic alkyls can be optionally substituted.
[0032] The term "alkenyl" refers to a type of alkyl group in which
the first two atoms of the alkyl group form a double bond that is
not part of an aromatic group. That is, an alkenyl group begins
with the atoms --C(R).dbd.C(R)--R, wherein R refers to the
remaining portions of the alkenyl group, which may be the same or
different. The alkenyl moiety may be branched, straight chain, or
cyclic (in which case, it would also be known as a "cycloalkenyl"
group). Depending on the structure, an alkenyl group can be a
monoradical or a diradical (i.e., an alkenylene group). Alkenyl
groups can be optionally substituted. Non-limiting examples of an
alkenyl group include --CH.dbd.CH.sub.2, --C(CH3).dbd.CH.sub.2,
--CH.dbd.CHCH.sub.3, --C(CH.sub.3).dbd.CHCH.sub.3. Alkenylene
groups include, but are not limited to, --CH.dbd.CH--,
--C(CH.sub.3).dbd.CH--, CH.dbd.CHCH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2-- and --C(CH.sub.3).dbd.CHCH.sub.2--.
Alkenyl groups could have 2 to 10 carbons. The alkenyl group could
also be a "lower alkenyl" having 2 to 6 carbon atoms.
[0033] The term "alkynyl" refers to a type of alkyl group in which
the first two atoms of the alkyl group form a triple bond. That is,
an alkynyl group begins with the atoms --C.dbd.C--R, wherein R
refers to the remaining portions of the alkynyl group, which may be
the same or different. The "R" portion of the alkynyl moiety may be
branched, straight chain, or cyclic. Depending on the structure, an
alkynyl group can be a monoradical or a diradical (i.e., an
alkynylene group). Alkynyl groups can be optionally substituted.
Non-limiting examples of an alkynyl group include, but are not
limited to, --C.ident.CH, --C.ident.CCH.sub.3,
--C.ident.CCH.sub.2CH.sub.3, --C.ident.C--, and
--C.ident.CCH.sub.2--. Alkynyl groups can have 2 to 10 carbons. The
alkynyl group could also be a "lower alkynyl" having 2 to 6 carbon
atoms.
[0034] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0035] "Hydroxyalkyl" refers to an alkyl radical, as defined
herein, substituted with at least one hydroxy group. Non-limiting
examples of a hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl,
1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl,
3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
[0036] "Alkoxyalkyl" refers to an alkyl radical, as defined herein,
substituted with an alkoxy group, as defined herein.
[0037] An "alkenyloxy" group refers to a (alkenyl)O-- group, where
alkenyl is as defined herein.
[0038] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x and y are selected from among x=1, y=1 and x=2, y=0.
When x=2, the alkyl groups, taken together with the N atom to which
they are attached, can optionally form a cyclic ring system.
[0039] "Alkylaminoalkyl" refers to an alkyl radical, as defined
herein, substituted with an alkylamine, as defined herein.
[0040] An "amide" is a chemical moiety with the formula --C(O)NHR
or --NHC(O)R, where R is selected from among alkyl, cycloalkyl,
aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). An amide moiety may form a linkage
between an amino acid or a peptide molecule and a compound
described herein, thereby forming a prodrug. Any amine, or carboxyl
side chain on the compounds described herein can be amidified. The
procedures and specific groups to make such amides are known to
those of skill in the art and can readily be found in reference
sources such as Greene and Wuts, Protective Groups in Organic
Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999,
which is incorporated herein by reference in its entirety.
[0041] The term "ester" refers to a chemical moiety with formula
--COOR, where R is selected from among alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). Any hydroxy, or carboxyl side chain
on the compounds described herein can be esterified. The procedures
and specific groups to make such esters are known to those of skill
in the art and can readily be found in reference sources such as
Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd
Ed., John Wiley & Sons, New York, N.Y., 1999, which is
incorporated herein by reference in its entirety.
[0042] As used herein, the term "ring" refers to any covalently
closed structure. Rings include, for example, carbocycles (e.g.,
aryls and cycloalkyls), heterocycles (e.g., heteroaryls and
non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls),
and non-aromatics (e.g., cycloalkyls and non-aromatic
heterocycles). Rings can be optionally substituted. Rings can be
monocyclic or polycyclic.
[0043] As used herein, the term "ring system" refers to one, or
more than one ring.
[0044] The term "membered ring" can embrace any cyclic structure.
The term "membered" is meant to denote the number of skeletal atoms
that constitute the ring. Thus, for example, cyclohexyl, pyridine,
pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,
furan, and thiophene are 5-membered rings.
[0045] The term "fused" refers to structures in which two or more
rings share one or more bonds.
[0046] The term "carbocyclic" or "carbocycle" refers to a ring
wherein each of the atoms forming the ring is a carbon atom.
Carbocycle includes aryl and cycloalkyl. The term thus
distinguishes carbocycle from heterocycle ("heterocyclic") in which
the ring backbone contains at least one atom which is different
from carbon (i.e a heteroatom). Heterocycle includes heteroaryl and
heterocycloalkyl. Carbocycles and heterocycles can be optionally
substituted.
[0047] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2.pi. electrons,
where n is an integer. Aromatic rings can be formed from five, six,
seven, eight, nine, or more than nine atoms. Aromatics can be
optionally substituted. The term "aromatic" includes both
carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or
"heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term
includes monocyclic or fused-ring polycyclic (i.e., rings which
share adjacent pairs of carbon atoms) groups.
[0048] As used herein, the term "aryl" refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. Aryl
rings can be formed by five, six, seven, eight, nine, or more than
nine carbon atoms. Aryl groups can be optionally substituted.
Examples of aryl groups include, but are not limited to phenyl,
naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
Depending on the structure, an aryl group can be a monoradical or a
diradical (i.e., an arylene group).
[0049] An "aryloxy" group refers to an (aryl)O-- group, where aryl
is as defined herein.
[0050] "Aralkyl" means an alkyl radical, as defined herein,
substituted with an aryl group. Non-limiting aralkyl groups
include, benzyl, phenethyl, and the like.
[0051] "Aralkenyl" means an alkenyl radical, as defined herein,
substituted with an aryl group, as defined herein.
[0052] The term "cycloalkyl" refers to a monocyclic or polycyclic
radical that contains only carbon and hydrogen, and may be
saturated, partially unsaturated, or fully unsaturated. Cycloalkyl
groups include groups having from 3 to 10 ring atoms. Illustrative
examples of cycloalkyl groups include the following moieties:
##STR00004##
and the like. Depending on the structure, a cycloalkyl group can be
a monoradical or a diradical (e.g., an cycloalkylene group). The
cycloalkyl group could also be a "lower cycloalkyl" having 3 to 8
carbon atoms.
[0053] "Cycloalkylalkyl" means an alkyl radical, as defined herein,
substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl
groups include cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, and the like.
[0054] The term "heterocycle" refers to heteroaromatic and
heteroalicyclic groups containing one to four heteroatoms each
selected from O, S and N, wherein each heterocyclic group has from
4 to 10 atoms in its ring system, and with the proviso that the
ring of said group does not contain two adjacent O or S atoms.
Herein, whenever the number of carbon atoms in a heterocycle is
indicated (e.g., C.sub.1-C.sub.6 heterocycle), at least one other
atom (the heteroatom) must be present in the ring. Designations
such as "C.sub.1-C.sub.6 heterocycle" refer only to the number of
carbon atoms in the ring and do not refer to the total number of
atoms in the ring. It is understood that the heterocylic ring can
have additional heteroatoms in the ring. Designations such as "4-6
membered heterocycle" refer to the total number of atoms that are
contained in the ring (i.e., a four, five, or six membered ring, in
which at least one atom is a carbon atom, at least one atom is a
heteroatom and the remaining two to four atoms are either carbon
atoms or heteroatoms). In heterocycles that have two or more
heteroatoms, those two or more heteroatoms can be the same or
different from one another. Heterocycles can be optionally
substituted. Binding to a heterocycle can be at a heteroatom or via
a carbon atom. Non-aromatic heterocyclic groups include groups
having only 4 atoms in their ring system, but aromatic heterocyclic
groups must have at least 5 atoms in their ring system. The
heterocyclic groups include benzo-fused ring systems. An example of
a 4-membered heterocyclic group is azetidinyl (derived from
azetidine). An example of a 5-membered heterocyclic group is
thiazolyl. An example of a 6-membered heterocyclic group is
pyridyl, and an example of a 10-membered heterocyclic group is
quinolinyl. Examples of non-aromatic heterocyclic groups are
pyrrolidinyl, tetrahydrofuranyl, dihydropyranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. Examples of aromatic heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The
foregoing groups, as derived from the groups listed above, may be
C-attached or N-attached where such is possible. For instance, a
group derived from pyrrole may be pyrrol-1-yl (N-attached) or
pyrrol-3-yl (C-attached). Further, a group derived from imidazole
may be imidazol-1-yl or imidazol-3-yl (both N-attached) or
imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The
heterocyclic groups include benzo-fused ring systems and ring
systems substituted with one or two oxo (.dbd.O) moieties such as
pyrrolidin-2-one. Depending on the structure, a heterocycle group
can be a monoradical or a diradical (i.e., a heterocyclene
group).
[0055] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aryl group that includes one or more ring heteroatoms
selected from nitrogen, oxygen and sulfur. An N-containing
"heteroaromatic" or "heteroaryl" moiety refers to an aromatic group
in which at least one of the skeletal atoms of the ring is a
nitrogen atom. Illustrative examples of heteroaryl groups include
the following moieties:
##STR00005##
and the like. Depending on the structure, a heteroaryl group can be
a monoradical or a diradical (i.e., a heteroarylene group).
[0056] As used herein, the term "non-aromatic heterocycle",
"heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic
ring wherein one or more atoms forming the ring is a heteroatom. A
"non-aromatic heterocycle" or "heterocycloalkyl" group refers to a
cycloalkyl group that includes at least one heteroatom selected
from nitrogen, oxygen and sulfur. The radicals may be fused with an
aryl or heteroaryl. Heterocycloalkyl rings can be formed by three,
four, five, six, seven, eight, nine, or more than nine atoms.
Heterocycloalkyl rings can be optionally substituted. In certain
embodiments, non-aromatic heterocycles contain one or more carbonyl
or thiocarbonyl groups such as, for example, oxo- and
thio-containing groups. Examples of heterocycloalkyls include, but
are not limited to, lactams, lactones, cyclic imides, cyclic
thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran,
tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin,
1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin,
1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,
succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, morpholine, trioxane,
hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,
pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,
1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,
isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,
thiazolidine, and 1,3-oxathiolane. Illustrative examples of
heterocycloalkyl groups, also referred to as non-aromatic
heterocycles, include:
##STR00006##
and the like. The term heteroalicyclic also includes all ring forms
of the carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides.
Depending on the structure, a heterocycloalkyl group can be a
monoradical or a diradical (i.e., a heterocycloalkylene group).
[0057] The term "halo" or, alternatively, "halogen" or "halide"
means fluoro, chloro, bromo and iodo.
[0058] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and
"haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures
in which at least one hydrogen is replaced with a halogen atom. In
certain embodiments in which two or more hydrogen atoms are
replaced with halogen atoms, the halogen atoms are all the same as
one another. In other embodiments in which two or more hydrogen
atoms are replaced with halogen atoms, the halogen atoms are not
all the same as one another.
[0059] The term "fluoroalkyl," as used herein, refers to alkyl
group in which at least one hydrogen is replaced with a fluorine
atom. Examples of fluoroalkyl groups include, but are not limited
to, --CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3 and the like.
[0060] As used herein, the terms "heteroalkyl" "heteroalkenyl" and
"heteroalkynyl" include optionally substituted alkyl, alkenyl and
alkynyl radicals in which one or more skeletal chain atoms is a
heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or
combinations thereof. The heteroatom(s) may be placed at any
interior position of the heteroalkyl group or at the position at
which the heteroalkyl group is attached to the remainder of the
molecule. Examples include, but are not limited to,
--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.3,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. In addition, up to two
heteroatoms may be consecutive, such as, by way of example,
--CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
[0061] The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically independently selected from
among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not
limited to these atoms. In embodiments in which two or more
heteroatoms are present, the two or more heteroatoms can all be the
same as one another, or some or all of the two or more heteroatoms
can each be different from the others.
[0062] The term "bond" or "single bond" refers to a chemical bond
between two atoms, or two moieties when the atoms joined by the
bond are considered to be part of larger substructure.
[0063] An "isocyanato" group refers to a --NCO group.
[0064] An "isothiocyanato" group refers to a --NCS group.
[0065] The term "moiety" refers to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0066] A "sulfonyl" group refers to a --S(.dbd.O)--R.
[0067] A "sulfonyl" group refers to a --S(.dbd.O).sub.2--R.
[0068] A "thioalkoxy" or "alkylthio" group refers to a --S-alkyl
group.
[0069] A "alkylthioalkyl" group refers to an alkyl group
substituted with a --S-alkyl group.
[0070] As used herein, the term "O-carboxy" or "acyloxy" refers to
a group of formula RC(.dbd.O)O--.
[0071] "Carboxy" means a --C(O)OH radical.
[0072] As used herein, the term "acetyl" refers to a group of
formula --C(.dbd.O)CH.sub.3.
[0073] "Acyl" refers to the group --C(O)R.
[0074] As used herein, the term "trihalomethanesulfonyl" refers to
a group of formula X.sub.3CS(.dbd.O).sub.2-- where X is a
halogen.
[0075] As used herein, the term "cyano" refers to a group of
formula --CN.
[0076] "Cyanoalkyl" means an alkyl radical, as defined herein,
substituted with at least one cyano group.
[0077] As used herein, the term "N-sulfonamido" or "sulfonylamino"
refers to a group of formula RS(.dbd.O).sub.2NH--.
[0078] As used herein, the term "O-carbamyl" refers to a group of
formula --OC(.dbd.O)NR.sup.2.
[0079] As used herein, the term "N-carbamyl" refers to a group of
formula ROC(.dbd.O)NH--.
[0080] As used herein, the term "O-thiocarbamyl" refers to a group
of formula --OC(.dbd.S)NR.sup.2.
[0081] As used herein, the term "N-thiocarbamyl" refers to a group
of formula ROC(.dbd.S)NH--.
[0082] As used herein, the term "C-amido" refers to a group of
formula --C(.dbd.O)NR.sup.2.
[0083] "Aminocarbonyl" refers to a --CONH.sub.2 radical.
[0084] As used herein, the term "N-amido" refers to a group of
formula RC(.dbd.O)NH--.
[0085] As used herein, the substituent "R" appearing by itself and
without a number designation refers to a substituent selected from
among from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and non-aromatic heterocycle (bonded through a ring
carbon).
[0086] The term "optionally substituted" or "substituted" means
that the referenced group may be substituted with one or more
additional group(s) individually and independently selected from
alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro,
haloalkyl, fluoroalkyl, amino, including mono- and di-substituted
amino groups, and the protected derivatives thereof. By way of
example an optional substituents may be LsRs, wherein each Ls is
independently selected from a bond, --O--, --C(.dbd.O)--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --NHC(O)--, --C(O)NH--,
S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2, --OC(O)NH--, --NHC(O)O--,
-(substituted or unsubstituted C.sub.1-C.sub.6 alkyl), or
-(substituted or unsubstituted C.sub.2-C.sub.6 alkenyl); and each
Rs is independently selected from H, (substituted or unsubstituted
C.sub.1-C.sub.4 alkyl), (substituted or unsubstituted
C.sub.3-C.sub.6 cycloalkyl), heteroaryl, or heteroalkyl. The
protecting groups that may form the protective derivatives of the
above substituents are known to those of skill in the art and may
be found in references such as Greene and Wuts, above.
[0087] The term "Michael acceptor moiety" refers to a functional
group that can participate in a Michael reaction, wherein a new
covalent bond is formed between a portion of the Michael acceptor
moiety and the donor moiety. The Michael acceptor moiety is an
electrophile and the "donor moiety" is a nucleophile. The "G"
groups presented in Formula (I) are non-limiting examples of
Michael acceptor moieties.
[0088] The term "nucleophile" or "nucleophilic" refers to an
electron rich compound, or moiety thereof. An example of a
nucleophile includes, but in no way is limited to, a cysteine
residue of a molecule, such as, for example Cys 481 of Btk.
[0089] The term "electrophile", or "electrophilic" refers to an
electron poor or electron deficient molecule, or moiety thereof.
Examples of electrophiles include, but in no way are limited to,
Michael acceptor moieties.
[0090] The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or ingredient, as used
herein, means having no persistent detrimental effect on the
general health of the subject being treated or does not abrogate
the biological activity or properties of the compound, and is
relatively nontoxic.
[0091] As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological activity of a protein
that is the same as the biological activity resulting from the
presence of a naturally occurring ligand for the protein, such as,
for example, Btk.
[0092] As used herein, the term "partial agonist" refers to a
compound the presence of which results in a biological activity of
a protein that is of the same type as that resulting from the
presence of a naturally occurring ligand for the protein, but of a
lower magnitude.
[0093] As used herein, the term "antagonist" refers to a compound,
the presence of which results in a decrease in the magnitude of a
biological activity of a protein. In certain embodiments, the
presence of an antagonist results in complete inhibition of a
biological activity of a protein, such as, for example, Btk. In
certain embodiments, an antagonist is an inhibitor.
[0094] As used herein, "amelioration" of the symptoms of a
particular disease, disorder or condition by administration of a
particular compound or pharmaceutical composition refers to any
lessening of severity, delay in onset, slowing of progression, or
shortening of duration, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the compound or composition.
[0095] "Bioavailability" refers to the percentage of the weight of
compounds disclosed herein, such as compounds of Formula (I), dosed
that is delivered into the general circulation of the animal or
human being studied. The total exposure (AUC(0-.infin.)) of a drug
when administered intravenously is usually defined as 100%
bioavailable (F %). "Oral bioavailability" refers to the extent to
which compounds disclosed herein, such as compounds of any of
Formula (I), are absorbed into the general circulation when the
pharmaceutical composition is taken orally as compared to
intravenous injection.
[0096] "Blood plasma concentration" refers to the concentration of
compounds disclosed herein, such as compounds of Formula (I), in
the plasma component of blood of a subject. It is understood that
the plasma concentration of compounds of Formula (I) may vary
significantly between subjects, due to variability with respect to
metabolism and/or possible interactions with other therapeutic
agents. In accordance with one embodiment disclosed herein, the
blood plasma concentration of the compounds Formula (I), may vary
from subject to subject. Likewise, values such as maximum plasma
concentration (Cmax) or time to reach maximum plasma concentration
(Tmax), or total area under the plasma concentration time curve
(AUC(0-.infin.)) may vary from subject to subject. Due to this
variability, the amount necessary to constitute "a therapeutically
effective amount" of a compound of Formula (1) may vary from
subject to subject.
[0097] The term "Bruton's tyrosine kinase," as used herein, refers
to Bruton's tyrosine kinase from Homo sapiens, as disclosed in,
e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No.
NP-000052).
[0098] The term "Bruton's tyrosine kinase homolog," as used herein,
refers to orthologs of Bruton's tyrosine kinase, e.g., the
orthologs from mouse (GenBank Accession No. AAB47246), dog (GenBank
Accession No. XP-549139), rat (GenBank Accession No. NP-001007799),
chicken (GenBank Accession No. NP-989564), or zebra fish (GenBank
Accession No. XP-698117), and fusion proteins of any of the
foregoing that exhibit kinase activity towards one or more
substrates of Bruton's tyrosine kinase (e.g. a peptide substrate
having the amino acid sequence "AVLESEEELYSSARQ").
[0099] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0100] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate "effective amount" in any
individual case may be determined using techniques, such as a dose
escalation study. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. An
"effective amount" of a compound disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effect amount" or "a therapeutically effective amount" can
vary from subject to subject, due to variation in metabolism of the
compound of Formula (I), age, weight, general condition of the
subject, the condition being treated, the severity of the condition
being treated, and the judgment of the prescribing physician. By
way of example only, therapeutically effective amounts may be
determined by routine experimentation, including but not limited to
a dose escalation clinical trial.
[0101] The terms "enhance" or "enhancing" means to increase or
prolong either in potency or duration a desired effect. By way of
example, "enhancing" the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the
effect of therapeutic agents on during treatment of a disease,
disorder or condition. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or
condition. When used in a patient, amounts effective for this use
will depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0102] The term "homologous cysteine," as used herein refers to a
cysteine residue found with in a sequence position that is
homologous to that of cysteine 481 of Bruton's tyrosine kinase, as
defined herein. For example, cysteine 482 is the homologous
cysteine of the rat ortholog of Bruton's tyrosine kinase; cysteine
479 is the homologous cysteine of the chicken ortholog; and
cysteine 481 is the homologous cysteine in the zebra fish ortholog.
In another example, the homologous cysteine of TXK, a Tec kinase
family member related to Bruton's tyrosine, is Cys 350. See also
the sequence alignments of tyrosine kinases (TK) published on the
world wide web at kinase.com/human/kinome/phylogeny.html.
[0103] The term "identical," as used herein, refers to two or more
sequences or subsequences which are the same. In addition, the term
"substantially identical," as used herein, refers to two or more
sequences which have a percentage of sequential units which are the
same when compared and aligned for maximum correspondence over a
comparison window, or designated region as measured using
comparison algorithms or by manual alignment and visual inspection.
By way of example only, two or more sequences may be "substantially
identical" if the sequential units are about 60% identical, about
65% identical, about 70% identical, about 75% identical, about 80%
identical, about 85% identical, about 90% identical, or about 95%
identical over a specified region. Such percentages to describe the
"percent identity" of two or more sequences. The identity of a
sequence can exist over a region that is at least about 75-100
sequential units in length, over a region that is about 50
sequential units in length, or, where not specified, across the
entire sequence. This definition also refers to the complement of a
test sequence. By way of example only, two or more polypeptide
sequences are identical when the amino acid residues are the same,
while two or more polypeptide sequences are "substantially
identical" if the amino acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 amino acids in length,
over a region that is about 50 amino acids in length, or, where not
specified, across the entire sequence of a polypeptide sequence. In
addition, by way of example only, two or more polynucleotide
sequences are identical when the nucleic acid residues are the
same, while two or more polynucleotide sequences are "substantially
identical" if the nucleic acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 nucleic acids in
length, over a region that is about 50 nucleic acids in length, or,
where not specified, across the entire sequence of a polynucleotide
sequence.
[0104] The terms "inhibits", "inhibiting", or "inhibitor" of a
kinase, as used herein, refer to inhibition of enzymatic
phosphotransferase activity.
[0105] The term "irreversible inhibitor," as used herein, refers to
a compound that, upon contact with a target protein (e.g., a
kinase) causes the formation of a new covalent bond with or within
the protein, whereby one or more of the target protein's biological
activities (e.g., phosphotransferase activity) is diminished or
abolished notwithstanding the subsequent presence or absence of the
irreversible inhibitor.
[0106] The term "irreversible Btk inhibitor," as used herein,
refers to an inhibitor of Btk that can form a covalent bond with an
amino acid residue of Btk. In one embodiment, the irreversible
inhibitor of Btk can form a covalent bond with a Cys residue of
Btk; in particular embodiments, the irreversible inhibitor can form
a covalent bond with a Cys 481 residue (or a homolog thereof) of
Btk or a cysteine residue in the homologous corresponding position
of another tyrosine kinase.
[0107] The term "isolated," as used herein, refers to separating
and removing a component of interest from components not of
interest. Isolated substances can be in either a dry or semi-dry
state, or in solution, including but not limited to an aqueous
solution. The isolated component can be in a homogeneous state or
the isolated component can be a part of a pharmaceutical
composition that comprises additional pharmaceutically acceptable
carriers and/or excipients. By way of example only, nucleic acids
or proteins are "isolated" when such nucleic acids or proteins are
free of at least some of the cellular components with which it is
associated in the natural state, or that the nucleic acid or
protein has been concentrated to a level greater than the
concentration of its in vivo or in vitro production. Also, by way
of example, a gene is isolated when separated from open reading
frames which flank the gene and encode a protein other than the
gene of interest.
[0108] A "metabolite" of a compound disclosed herein is a
derivative of that compound that is formed when the compound is
metabolized. The term "active metabolite" refers to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term "metabolized," as used herein, refers to the
sum of the processes (including, but not limited to, hydrolysis
reactions and reactions catalyzed by enzymes, such as, oxidation
reactions) by which a particular substance is changed by an
organism. Thus, enzymes may produce specific structural alterations
to a compound. For example, cytochrome P450 catalyzes a variety of
oxidative and reductive reactions while uridine diphosphate
glucuronyl transferases catalyze the transfer of an activated
glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,
carboxylic acids, amines and free sulfhydryl groups. Further
information on metabolism may be obtained from The Pharmacological
Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites
of the compounds disclosed herein can be identified either by
administration of compounds to a host and analysis of tissue
samples from the host, or by incubation of compounds with hepatic
cells in vitro and analysis of the resulting compounds. Both
methods are well known in the art. In some embodiments, metabolites
of a compound are formed by oxidative processes and correspond to
the corresponding hydroxy-containing compound. In some embodiments,
a compound is metabolized to pharmacologically active
metabolites.
[0109] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0110] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator can
cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in
the absence of the modulator. In certain embodiments, a modulator
is an inhibitor, which decreases the magnitude of one or more
activities of a molecule. In certain embodiments, an inhibitor
completely prevents one or more activities of a molecule. In
certain embodiments, a modulator is an activator, which increases
the magnitude of at least one activity of a molecule. In certain
embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
[0111] The term "prophylactically effective amount," as used
herein, refers that amount of a composition applied to a patient
which will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic
applications, such amounts may depend on the patient's state of
health, weight, and the like. It is considered well within the
skill of the art for one to determine such prophylactically
effective amounts by routine experimentation, including, but not
limited to, a dose escalation clinical trial.
[0112] As used herein, the term "selective binding compound" refers
to a compound that selectively binds to any portion of one or more
target proteins.
[0113] As used herein, the term "selectively binds" refers to the
ability of a selective binding compound to bind to a target
protein, such as, for example, Btk, with greater affinity than it
binds to a non-target protein. In certain embodiments, specific
binding refers to binding to a target with an affinity that is at
least 10, 50, 100, 250, 500, 1000 or more times greater than the
affinity for a non-target.
[0114] As used herein, the term "selective modulator" refers to a
compound that selectively modulates a target activity relative to a
non-target activity. In certain embodiments, specific modulator
refers to modulating a target activity at least 10, 50, 100, 250,
500, 1000 times more than a non-target activity.
[0115] The term "substantially purified," as used herein, refers to
a component of interest that may be substantially or essentially
free of other components which normally accompany or interact with
the component of interest prior to purification. By way of example
only, a component of interest may be "substantially purified" when
the preparation of the component of interest contains less than
about 30%, less than about 25%, less than about 20%, less than
about 15%, less than about 10%, less than about 5%, less than about
4%, less than about 3%, less than about 2%, or less than about 1%
(by dry weight) of contaminating components. Thus, a "substantially
purified" component of interest may have a purity level of about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, about
96%, about 97%, about 98%, about 99% or greater.
[0116] The term "subject" as used herein, refers to an animal which
is the object of treatment, observation or experiment. By way of
example only, a subject may be, but is not limited to, a mammal
including, but not limited to, a human.
[0117] As used herein, the term "target activity" refers to a
biological activity capable of being modulated by a selective
modulator. Certain exemplary target activities include, but are not
limited to, binding affinity, signal transduction, enzymatic
activity, tumor growth, inflammation or inflammation-related
processes, and amelioration of one or more symptoms associated with
a disease or condition.
[0118] As used herein, the term "target protein" refers to a
molecule or a portion of a protein capable of being bound by a
selective binding compound. In certain embodiments, a target
protein is Btk.
[0119] The terms "treat," "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition. The terms "treat," "treating" or "treatment",
include, but are not limited to, prophylactic and/or therapeutic
treatments.
[0120] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as inhibition of Btk,
in an assay that measures such response.
[0121] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
Compounds
[0122] Certain embodiments provide a compound of Formula (I):
##STR00007##
or a pharmaceutically acceptable solvate, hydrate, or salt thereof,
wherein:
[0123] A is selected from N and CR.sup.11;
[0124] each R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H, halogen, --CF.sub.3, --CN,
--NO.sub.2, OH, NH.sub.2, -L.sup.1-(substituted or unsubstituted
alkyl), -L.sup.1-(substituted or unsubstituted alkenyl),
-L.sup.1-(substituted or unsubstituted heteroaryl), or
-L.sup.1-(substituted or unsubstituted aryl), wherein L is a bond,
O, S, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --C(O)--,
--CH.sub.2--, --NHC(O)O--, --NHC(O)--, or --C(O)NH;
[0125] R.sup.2 is selected from H and lower alkyl;
[0126] R.sup.3 is L.sup.2-X-L.sup.3-G, wherein, [0127] L.sup.2 is
selected from a bond, substituted or unsubstituted alkylene,
substituted or unsubstituted cycloalkylene, substituted or
unsubstituted alkenylene, and substituted or unsubstituted
alkynylene; [0128] X is selected from a bond, O, --C(.dbd.O)--, S,
--S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--, --NR.sup.14,
--NHC(O)--, --C(O)NH--, --NR.sup.14C(O)--, --C(O)NR.sup.14--,
--S(.dbd.O).sub.2NH, --NHS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.14, --NR.sup.14S(.dbd.O).sub.2--,
--OC(O)NH--, --NHC(O)O--, --OC(O)NR.sup.14, --NR.sup.14C(O)O--,
--CH.dbd.NO--, --ON.dbd.CH--, --NR.sup.15C(O)NR.sup.15--,
heteroarylene, arylene, --NR.sup.15C(.dbd.NR.sup.16)NR.sup.15--,
--NR.sup.15C(.dbd.NR.sup.16)--, --C(.dbd.NR.sup.16)NR.sup.15,
--OC(.dbd.NR.sup.16)--, and --C(.dbd.NR.sup.16)O--, wherein [0129]
R.sup.14 is selected from H, substituted or unsubstituted lower
alkyl, and substituted or unsubstituted lower cycloalkyl; [0130]
each R.sup.15 is independently selected from H, substituted or
unsubstituted lower alkyl, and substituted or unsubstituted lower
cycloalkyl; and [0131] R.sup.16 is selected from H,
--S(.dbd.O).sub.2R.sup.11, --S(.dbd.O).sub.2NH.sub.2,
--C(O)R.sup.11, --CN, --NO.sub.2, heteroaryl, and heteroalkyl;
[0132] L.sup.3 is selected from a bond, substituted or
unsubstituted alkylene, substituted or unsubstituted cycloalkylene,
substituted or unsubstituted alkenylene, substituted or
unsubstituted alkynylene, substituted or unsubstituted arylene,
substituted or unsubstituted heteroarylene, and substituted or
unsubstituted heterocyclene; [0133] or L.sup.2, X and L.sup.3 taken
together form a nitrogen containing heterocyclic ring; and [0134] G
is selected from the following structures:
##STR00008##
[0134] and Z is selected from the following structures:
##STR00009##
[0135] wherein each R.sup.11, R.sup.12, and R.sup.13 is
independently selected from H, substituted or unsubstituted lower
alkyl, substituted or unsubstituted lower heteroalkyl, substituted
or unsubstituted lower cycloalkyl, substituted or unsubstituted
lower heterocycloalkyl, and substituted or unsubstituted lower
aryl.
[0136] In certain embodiments of a compound of Formula (I), A is
selected from N and CR.sup.11, wherein R.sup.11 is selected from H,
substituted or unsubstituted lower alkyl, substituted or
unsubstituted lower heteroalkyl, substituted or unsubstituted lower
cycloalkyl, substituted or unsubstituted lower heterocycloalkyl,
and substituted or unsubstituted lower aryl.
[0137] In certain embodiments of a compound of Formula (I), A is
N.
[0138] In certain embodiments of a compound of Formula (I), A is
CR.sup.11, wherein R.sup.11 is selected from H, methyl, ethyl,
n-propyl, cyclopentyl, cyclohexyl, phenyl, and benzyl.
[0139] In certain embodiments of a compound of Formula (I), A is
CR.sup.11, wherein R.sup.11 is H.
[0140] In certain embodiments of a compound of Formula (I), each
R.sup.1 is independently selected from H, halogen, --CF.sub.3,
--CN, --NO.sub.2, OH, and NH.sub.2.
[0141] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H, -L.sup.1-(substituted or
unsubstituted alkyl), -L.sup.1-(substituted or unsubstituted
alkenyl), -L.sup.1-(substituted or unsubstituted heteroaryl), and
-L.sup.1-(substituted or unsubstituted aryl), wherein L.sup.1 is
selected from a bond, O, S, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--NH--, --C(O)--, --CH.sub.2--, --NHC(O)O--, --NHC(O)--, and
--C(O)NH--.
[0142] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H, -L.sup.1-(substituted or
unsubstituted alkyl), -L.sup.1-(substituted or unsubstituted
alkenyl), -L.sup.1-(substituted or unsubstituted heteroaryl), and
-L.sup.1-(substituted or unsubstituted aryl), wherein L.sup.1 is
selected from a bond, O, and NH.
[0143] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H, -L.sup.1-(substituted or
unsubstituted alkyl), -L.sup.1-(substituted or unsubstituted
alkenyl), -L.sup.1-(substituted or unsubstituted heteroaryl), and
-L.sup.1-(substituted or unsubstituted aryl), wherein L.sup.1 is
O.
[0144] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d and R.sup.1e is
independently selected from H and -L.sup.1-(substituted or
unsubstituted phenyl), wherein L.sup.1 is O.
[0145] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H and --O-phenyl.
[0146] In certain embodiments of a compound of Formula (I), each
R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e is H and R.sup.1c is
--O-phenyl.
[0147] In certain embodiments of a compound of Formula (I), R.sup.2
is selected from H and lower alkyl.
[0148] In certain embodiments of a compound of Formula (I), R.sup.2
is selected from H, methyl, ethyl, n-propyl, and isopropyl.
[0149] In certain embodiments of a compound of Formula (I), R.sup.2
is selected from H and methyl.
[0150] In certain embodiments of a compound of Formula (I), R.sup.2
is H.
[0151] In certain embodiments of a compound of Formula (I), R.sup.3
is L.sup.2-X-L.sup.3-G.
[0152] In certain embodiments of a compound of Formula (I), L.sup.2
is selected from a bond, substituted or unsubstituted alkylene,
substituted or unsubstituted cycloalkylene, substituted or
unsubstituted alkenylene, and substituted or unsubstituted
alkynylene.
[0153] In certain embodiments of a compound of Formula (I), L.sup.2
is selected from a bond, methylene, ethylene, propylene, butylene,
cyclopentylene, and cyclohexylene.
[0154] In certain embodiments of a compound of Formula (I), X is
selected from a bond, O, --C(.dbd.O)--, S, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NH--, --NR.sup.14, --NHC(O)--, --C(O)NH--,
--NR.sup.14C(O), --C(O)NR.sup.14--, --S(.dbd.O).sub.2NH--,
--NHS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.14--,
--NR.sup.14S(.dbd.O).sub.2--, --OC(O)NH--, --NHC(O)O--,
--OC(O)NR.sup.14--, --NR.sup.14C(O)O--, --CH.dbd.NO--,
--ON.dbd.CH--, --NR.sup.15C(O)NR.sup.15--, heteroarylene, arylene,
--NR.sup.15C(.dbd.NR.sup.16)NR.sup.15,
--NR.sup.15C(.dbd.NR.sup.16)--, --C(.dbd.NR.sup.16)NR.sup.15,
--OC(.dbd.NR.sup.16)--, and --C(.dbd.NR.sup.16)O--, wherein
R.sup.14 is selected from H, substituted or unsubstituted lower
alkyl, and substituted or unsubstituted lower cycloalkyl; each
R.sup.15 is independently selected from H, substituted or
unsubstituted lower alkyl, and substituted or unsubstituted lower
cycloalkyl; and R.sup.16 is selected from H,
--S(.dbd.O).sub.2R.sup.11, --S(.dbd.O).sub.2NH.sub.2,
--C(O)R.sup.11, --CN, --NO.sub.2, heteroaryl, and heteroalkyl.
[0155] In certain embodiments of a compound of Formula (I), L.sup.2
is a bond.
[0156] In certain embodiments of a compound of Formula (I), X is
selected from a bond, O, --C(.dbd.O)--, S, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NH--, --NHC(O)--, --C(O)NH--, --NHC(O)--,
--C(O)NH--, --S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2--, --OC(O)NH--,
--NHC(O)O--, --OC(O)NH--, --NHC(O)O--, --CH.dbd.NO--,
--ON.dbd.CH--, --NHC(O)NH--, heteroarylene, arylene,
--NHC(.dbd.NH)NH, --NHC(.dbd.NH)--, --C(.dbd.NH)NH--,
--OC(.dbd.NH)--, and --C(.dbd.NH)O--.
[0157] In certain embodiments of a compound of Formula (I), X is
selected from a bond and --NH.
[0158] In certain embodiments of a compound of Formula (I), X is
--NH.
[0159] In certain embodiments of a compound of Formula (I), X is a
bond.
[0160] In certain embodiments of a compound of Formula (I), L.sup.2
is a bond and X is a bond.
[0161] In certain embodiments of a compound of Formula (I), L.sup.3
is selected from a bond, substituted or unsubstituted alkylene,
substituted or unsubstituted cycloalkylene, substituted or
unsubstituted alkenylene, substituted or unsubstituted alkynylene,
substituted or unsubstituted arylene, substituted or unsubstituted
heteroarylene, and substituted or unsubstituted heterocyclene.
[0162] In certain embodiments of a compound of Formula (I), L.sup.3
is selected from a bond, methylene, ethylene, propylene, butylene,
cyclopentylene, cyclohexylene, phenylene, piperidylene, and
pyrrolidinylene.
[0163] In certain embodiments of a compound of Formula (I), L.sup.3
is selected from a bond, 1,2-piperidylene, 1,3-piperidylene, and
1,4-piperidylene.
[0164] In certain embodiments of a compound of Formula (I), L.sup.3
is selected from the following structures:
##STR00010##
[0165] In certain embodiments of a compound of Formula (I), L.sup.2
is a bond, X is a bond, and L.sup.3 is selected from the following
structures:
##STR00011##
[0166] In certain embodiments of a compound of Formula (I),
L.sup.2, X and L.sup.3 taken together form a nitrogen containing
heterocyclic ring.
[0167] In certain embodiments of a compound of Formula (I),
L.sup.2, X and L.sup.3 taken together form a nitrogen containing
heterocyclic ring selected from the following structures:
##STR00012##
[0168] In certain embodiments of a compound of Formula (I), G is
selected from the following structures:
##STR00013##
wherein each R.sup.11, R.sup.12, and R.sup.13 is independently
selected from H, substituted or unsubstituted lower alkyl,
substituted or unsubstituted lower heteroalkyl, substituted or
unsubstituted lower cycloalkyl, substituted or unsubstituted lower
heterocycloalkyl, and substituted or unsubstituted lower aryl.
[0169] In certain embodiments of a compound of Formula (I), G is
selected from the following structures:
##STR00014##
wherein each R.sup.11, R.sup.12, and R.sup.13 is independently
selected from H, methyl, ethyl, n-propyl, isopropyl,
2-(dimethylamino)ethyl, (dimethylamino)methyl, methoxymethyl,
cyclohexyl, and phenyl.
[0170] In certain embodiments of a compound of Formula (I), G is
selected from the following structures:
##STR00015##
[0171] In certain embodiments of a compound of Formula (I), R.sup.3
is selected from the following structures:
##STR00016## ##STR00017##
[0172] In certain embodiments of a compound of Formula (I), R.sup.3
is selected from the following structures:
##STR00018##
[0173] In certain embodiments of a compound of Formula (I), R.sup.3
is the following structure:
##STR00019##
[0174] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00020##
wherein each R.sup.11, R.sup.12, and R.sup.13 is independently
selected from H, substituted or unsubstituted lower alkyl,
substituted or unsubstituted lower heteroalkyl, substituted or
unsubstituted lower cycloalkyl, substituted or unsubstituted lower
heterocycloalkyl, and substituted or unsubstituted lower aryl.
[0175] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00021##
wherein each R.sup.11, R.sup.12, and R.sup.13 is independently
selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl,
tert-butyl, pentyl, neopentyl, n-hexyl, cyclopentyl, cyclohexyl,
cyclohexylmethyl, phenyl, and benzyl.
[0176] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00022## ##STR00023##
[0177] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00024## ##STR00025##
[0178] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00026##
[0179] In certain embodiments of a compound of Formula (I), Z is
selected from the following structures:
##STR00027##
[0180] In certain embodiments of a compound of Formula (I), A is N;
each R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, and R.sup.1e is
independently selected from H and --O-phenyl; R.sup.2 is H;
R.sup.3 is
##STR00028##
[0181] and Z is
##STR00029##
[0183] In certain embodiments of a compound of Formula (I), A is N;
each R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e is H; R.sup.1c is
--O-phenyl; R.sup.2 is H;
R.sup.3 is
##STR00030##
[0184] and Z is
##STR00031##
[0186] In certain embodiments of a compound of Formula (I), A is N;
each R.sup.1a, R.sup.1b, R.sup.1d and R.sup.1e is H; R.sup.1c is
--O-phenyl; R.sup.2 is H;
R.sup.3 is
##STR00032##
[0187] and Z is
##STR00033##
[0189] In certain embodiments of a compound of Formula (I), the
compound is chosen from a compound of Formula (I-A-1), Formula
(I-A-2), Formula (I-A-3), Formula (I-A-4), Formula (I-A-5), Formula
(I-A-6), Formula (I-A-7), Formula (I-A-8), Formula (I-A-9), Formula
(I-A-10), Formula (I-A-11), Formula (I-A-12), Formula (I-A-13),
Formula (I-A-14), Formula (I-A-15), Formula (I-A-16), Formula
(I-A-17), Formula (I-A-18), Formula (I-A-19), and Formula
(I-A-20):
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040##
[0190] In certain embodiments of a compound of Formula (I), the
compound is chosen from a compound of Formula (I-B-1) and Formula
(I-B-2):
##STR00041##
[0191] In certain embodiments of a compound of Formula (I), the
compound is chosen from a compound of Formula (I-C-1) and Formula
(I-C-2):
##STR00042##
Synthesis
[0192] Compounds disclosed herein may be obtained via the synthetic
methods illustrated in Schemes I-A and I-B. General synthetic
methods useful in the synthesis of compounds described herein are
available in the art. Starting materials useful for preparing
compounds and intermediates thereof and/or practicing methods
described herein are commercially available or can be prepared by
well-known synthetic methods. The methods presented in the schemes
provided by the present disclosure are illustrative rather than
comprehensive. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, may be practiced
without departing from the scope of the disclosure.
[0193] Ibrutinib prodrugs of Formula (I) can be prepared according
to Schemes I-A and I-B:
##STR00043##
##STR00044##
Pharmaceutical Compositions
[0194] Pharmaceutical compositions provided by the present
disclosure may comprise a therapeutically effective amount of a
compound of Formula (I) together with a suitable amount of one or
more pharmaceutically acceptable vehicles so as to provide a
composition for proper administration to a patient. Suitable
pharmaceutical vehicles are described in the art.
[0195] In certain embodiments, a compound of Formula (I) may be
incorporated into pharmaceutical compositions to be administered
orally. Oral administration of such pharmaceutical compositions may
result in uptake of a compound of Formula (I) throughout the
intestine and entry into the systemic circulation. Such oral
compositions may be prepared in a manner known in the
pharmaceutical art and comprise a compound of Formula (I) and at
least one pharmaceutically acceptable vehicle. Oral pharmaceutical
compositions may include a therapeutically effective amount of a
compound of Formula (I) and a suitable amount of a pharmaceutically
acceptable vehicle, so as to provide an appropriate form for
administration to a patient.
[0196] Compounds of Formula (I) may be incorporated into
pharmaceutical compositions to be administered by any other
appropriate route of administration including intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, oral, sublingual, intracerebral,
intravaginal, transdermal, rectal, inhalation, or topical.
[0197] Pharmaceutical compositions comprising a compound of Formula
(I) and may be manufactured by means of conventional mixing
dissolving granulating dragee-making levigating emulsifying
encapsulating entrapping or lyophilizing processes. Pharmaceutical
compositions may be formulated in a conventional manner using one
or more physiologically acceptable carriers, diluents, excipients,
or auxiliaries, which facilitate processing of compounds of Formula
(I) or crystalline forms thereof and one or more pharmaceutically
acceptable vehicles into formulations that can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. Pharmaceutical compositions provided by the
present disclosure may take the form of solutions, suspensions,
emulsion, tablets, pills, pellets, capsules, capsules containing
liquids, powders, sustained-release formulations, suppositories,
emulsions, aerosols, sprays, suspensions, or any other form
suitable for administration to a patient.
[0198] Pharmaceutical compositions provided by the present
disclosure may be formulated in a unit dosage form. A unit dosage
form refers to a physically discrete unit suitable as a unitary
dose for patients undergoing treatment, with each unit containing a
predetermined quantity of a compound of Formula (I) calculated to
produce an intended therapeutic effect. A unit dosage form may be
for a single daily dose, for administration 2 times per day, or one
of multiple daily doses, e.g., 3 or more times per day. When
multiple daily doses are used, a unit dosage form may be the same
or different for each dose. One or more dosage forms may comprise a
dose, which may be administered to a patient at a single point in
time or during a time interval.
[0199] Pharmaceutical compositions comprising a compound of Formula
(I) may be formulated for immediate release.
[0200] In certain embodiments, an oral dosage form provided by the
present disclosure may be a controlled release dosage form.
Controlled delivery technologies can improve the absorption of a
drug in a particular region or regions of the gastrointestinal
tract. Controlled drug delivery systems may be designed to deliver
a drug in such a way that the drug level is maintained within a
therapeutically effective window and effective and safe blood
levels are maintained for a period as long as the system continues
to deliver the drug with a particular release profile in the
gastrointestinal tract. Controlled drug delivery may produce
substantially constant blood levels of a drug over a period of time
as compared to fluctuations observed with immediate release dosage
forms. For some drugs, maintaining a constant blood and tissue
concentration throughout the course of therapy is the most
desirable mode of treatment. Immediate release of drugs may cause
blood levels to peak above the level required to elicit a desired
response, which may waste the drug and may cause or exacerbate
toxic side effects. Controlled drug delivery can result in optimum
therapy, and not only can reduce the frequency of dosing, but may
also reduce the severity of side effects. Examples of controlled
release dosage forms include dissolution controlled systems,
diffusion controlled systems, ion exchange resins, osmotically
controlled systems, erodable matrix systems, pH independent
formulations, gastric retention systems, and the like.
[0201] An appropriate oral dosage form for a particular
pharmaceutical composition provided by the present disclosure may
depend, at least in part, on the gastrointestinal absorption
properties of a compound of Formula (I) the stability of a compound
of Formula (I) in the gastrointestinal tract, the pharmacokinetics
of a compound of Formula (I) and the intended therapeutic profile.
An appropriate controlled release oral dosage form may be selected
for a particular compound of Formula (I). For example, gastric
retention oral dosage forms may be appropriate for compounds
absorbed primarily from the upper gastrointestinal tract, and
sustained release oral dosage forms may be appropriate for
compounds absorbed primarily from the lower gastrointestinal tract.
Certain compounds are absorbed primarily from the small intestine.
In general, compounds traverse the length of the small intestine in
about 3 to 5 hours. For compounds that are not easily absorbed by
the small intestine or that do not dissolve readily, the window for
active agent absorption in the small intestine may be too short to
provide a desired therapeutic effect.
[0202] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may be practiced with dosage forms
adapted to provide sustained release of a compound of Formula (I)
upon oral administration. Sustained release oral dosage forms may
be used to release drugs over a prolonged time period and are
useful when it is desired that a drug or drug form be delivered to
the lower gastrointestinal tract. Sustained release oral dosage
forms include any oral dosage form that maintains therapeutic
concentrations of a drug in a biological fluid such as the plasma,
blood, cerebrospinal fluid, or in a tissue or organ for a prolonged
time period. Sustained release oral dosage forms include
diffusion-controlled systems such as reservoir devices and matrix
devices, dissolution-controlled systems, osmotic systems, and
erosion-controlled systems. Sustained release oral dosage forms and
methods of preparing the same are well known in the art.
[0203] An appropriate dose of a compound of Formula (I) or
pharmaceutical composition comprising a compound of Formula (I) may
be determined according to any one of several well-established
protocols. For example, animal studies such as studies using mice,
rats, dogs, and/or monkeys may be used to determine an appropriate
dose of a pharmaceutical compound. Results from animal studies may
be extrapolated to determine doses for use in other species, such
as for example, humans.
Uses
[0204] The methods described herein include administering to a
subject in need a composition containing a therapeutically
effective amount of one or more irreversible Btk inhibitor
compounds described herein. Without being bound by theory, the
diverse roles played by Btk signaling in various hematopoietic cell
functions, e.g., B-cell receptor activation, suggests that small
molecule Btk inhibitors are useful for reducing the risk of or
treating a variety of diseases affected by or affecting many cell
types of the hematopoetic lineage including, e.g., autoimmune
diseases, heteroimmune conditions or diseases, inflammatory
diseases, cancer (e.g., B-cell proliferative disorders), and
thromboembolic disorders. Further, the irreversible Btk inhibitor
compounds described herein can be used to inhibit a small subset of
other tyrosine kinases that share homology with Btk by having a
cysteine residue (including a Cys 481 residue) that can form a
covalent bond with the irreversible inhibitor. Thus, a subset of
tyrosine kinases other than Btk are also expected to be useful as
therapeutic targets in a number of health conditions.
[0205] In some embodiments, the methods described herein can be
used to treat an autoimmune disease, which includes, but is not
limited to, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, lupus,
diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's
thyroiditis, Graves' disease, Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
and vulvodynia.
[0206] In some embodiments, the methods described herein can be
used to treat heteroimmune conditions or diseases, which include,
but are not limited to graft versus host disease, transplantation,
transfusion, anaphylaxis, allergies (e.g., allergies to plant
pollens, latex, drugs, foods, insect poisons, animal hair, animal
dander, dust mites, or cockroach calyx), type I hypersensitivity,
allergic conjunctivitis, allergic rhinitis, and atopic
dermatitis.
[0207] In further embodiments, the methods described herein can be
used to treat an inflammatory disease, which includes, but is not
limited to asthma, inflammatory bowel disease, appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and
vulvitis.
[0208] In yet other embodiments, the methods described herein can
be used to treat a cancer, e.g., B-cell proliferative disorders,
which include, but are not limited to diffuse large B cell
lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,
chronic lymphocytic leukemia, chronic lymphocytic leukemia with 17p
delection, B-cell prolymphocytic leukemia, lymphoplamacytic
lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal
zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle
cell lymphoma, mediastinal (thymic) large B cell lymphoma,
intravascular large B cell lymphoma, primary effusion lymphoma,
burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.
[0209] In further embodiments, the methods described herein can be
used to treat thromboembolic disorders, which include, but are not
limited to myocardial infarct, angina pectoris (including unstable
angina), reocclusions or restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischemia, peripheral
arterial occlusive disorders, pulmonary embolisms, and deep venous
thromboses.
[0210] Symptoms, diagnostic tests, and prognostic tests for each of
the above-mentioned conditions are known in the art. See, e.g.,
Harrison's Principles of Internal Medicine.COPYRGT.," 16th ed.,
2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojoumal
3(24), and the "Revised European American Lymphoma" (REAL)
classification system (see, e.g., the website maintained by the
National Cancer Institute).
[0211] A number of animal models of are useful for establishing a
range of therapeutically effective doses of irreversible Btk
inhibitor compounds for treating any of the foregoing diseases.
[0212] For example, dosing of irreversible Btk inhibitor compounds
for treating an autoimmune disease can be assessed in a mouse model
of rheumatoid arthritis. In this model, arthritis is induced in
Balb/c mice by administering anti-collagen antibodies and
lipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol
163:1827-1837.
[0213] In another example, dosing of irreversible Btk inhibitors
for the treatment of B-cell proliferative disorders can be examined
in, e.g., a human-to-mouse xenograft model in which human B-cell
lymphoma cells (e.g. Ramos cells) are implanted into
immunodeficient mice (e.g., "nude" mice) as described in, e.g.,
Pagel et al. (2005), Clin Cancer Res 11(13):4857-4866.
Animal models for treatment of thromboembolic disorders are also
known.
[0214] The therapeutic efficacy of the compound for one of the
foregoing diseases can be optimized during a course of treatment.
For example, a subject being treated can undergo a diagnostic
evaluation to correlate the relief of disease symptoms or
pathologies to inhibition of in vivo Btk activity achieved by
administering a given dose of an irreversible Btk inhibitor.
Cellular assays known in the art can be used to determine in vivo
activity of Btk in the presence or absence of an irreversible Btk
inhibitor. For example, since activated Btk is phosphorylated at
tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific
immunocytochemical staining of P-Y223 or P-Y551-positive cells can
be used to detect or quantify activation of Bkt in a population of
cells (e.g., by FACS analysis of stained vs unstained cells). See,
e.g., Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA
96:2221-2226. Thus, the amount of the Btk inhibitor inhibitor
compound that is administered to a subject can be increased or
decreased as needed so as to maintain a level of Btk inhibition
optimal for treating the subject's disease state.
Administration
[0215] Compounds of Formula (I) and pharmaceutical compositions
thereof may be administered orally or by any other appropriate
route, for example, by infusion or bolus injection, by absorption
through epithelial or mucocutaneous linings (e.g., oral mucosa,
rectal, and intestinal mucosa, etc.). Other suitable routes of
administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, oral, sublingual, intracerebral,
intravaginal, transdermal, rectal, inhalation, or topical.
[0216] Administration may be systemic or local. Various delivery
systems are known, e.g., encapsulation in liposomes,
microparticles, microcapsules, capsules, etc.) that may be used to
administer a compound and/or pharmaceutical composition.
[0217] The amount of a compound of Formula (I) that will be
effective in the treatment of a disease in a patient will depend,
in part, on the nature of the condition and can be determined by
standard clinical techniques known in the art. In addition, in
vitro or in vivo assays may be employed to help identify optimal
dosage ranges. A therapeutically effective amount of a compound of
Formula (I) to be administered may also depend on, among other
factors, the subject being treated, the weight of the subject, the
severity of the disease, the manner of administration, and the
judgment of the prescribing physician.
[0218] For systemic administration, a therapeutically effective
dose may be estimated initially from in vitro assays. For example,
a dose may be formulated in animal models to achieve a beneficial
circulating composition concentration range. Initial doses may also
be estimated from in vivo data, e.g., animal models, using
techniques that are known in the art. Such information may be used
to more accurately determine useful doses in humans. One having
ordinary skill in the art may optimize administration to humans
based on animal data.
[0219] A dose may be administered in a single dosage form or in
multiple dosage forms. When multiple dosage forms are used the
amount of compound contained within each dosage form may be the
same or different. The amount of a compound of Formula (I)
contained in a dose may depend on the route of administration and
whether the disease in a patient is effectively treated by acute,
chronic, or a combination of acute and chronic administration.
[0220] In certain embodiments an administered dose is less than a
toxic dose. Toxicity of the compositions described herein may be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., by determining the LD.sub.50 (the
dose lethal to 50% of the population) or the LD.sub.100 (the dose
lethal to 100% of the population). The dose ratio between toxic and
therapeutic effect is the therapeutic index. In certain
embodiments, a compound of Formula (I) may exhibit a high
therapeutic index. The data obtained from these cell culture assays
and animal studies may be used in formulating a dosage range that
is not toxic for use in humans. A dose of a compound of Formula (I)
provided by the present disclosure may be within a range of
circulating concentrations in for example the blood, plasma, or
central nervous system, that include the effective dose and that
exhibits little or no toxicity. A dose may vary within this range
depending upon the dosage form employed and the route of
administration utilized. In certain embodiments, an escalating dose
may be administered.
Combination Therapy
[0221] The irreversible Btk inhibitor compositions described herein
can also be used in combination with other well known therapeutic
reagents that are selected for their therapeutic value for the
condition to be treated. In general, the compositions described
herein and, in embodiments where combinational therapy is employed,
other agents do not have to be administered in the same
pharmaceutical composition, and may, because of different physical
and chemical characteristics, have to be administered by different
routes. The determination of the mode of administration and the
advisability of administration, where possible, in the same
pharmaceutical composition, is well within the knowledge of the
skilled clinician. The initial administration can be made according
to established protocols known in the art, and then, based upon the
observed effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0222] In certain instances, it may be appropriate to administer at
least one irreversible Btk inhibitor compound described herein in
combination with another therapeutic agent. By way of example only,
if one of the side effects experienced by a patient upon receiving
one of the irreversible Btk inhibitor compounds described herein is
nausea, then it may be appropriate to administer an anti-nausea
agent in combination with the initial therapeutic agent. Or, by way
of example only, the therapeutic effectiveness of one of the
compounds described herein may be enhanced by administration of an
adjuvant (i.e., by itself the adjuvant may have minimal therapeutic
benefit, but in combination with another therapeutic agent, the
overall therapeutic benefit to the patient is enhanced). Or, by way
of example only, the benefit experienced by a patient may be
increased by administering one of the compounds described herein
with another therapeutic agent (which also includes a therapeutic
regimen) that also has therapeutic benefit. In any case, regardless
of the disease, disorder or condition being treated, the overall
benefit experienced by the patient may simply be additive of the
two therapeutic agents or the patient may experience a synergistic
benefit.
[0223] The particular choice of compounds used will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment protocol.
The compounds may be administered concurrently (e.g.,
simultaneously, essentially simultaneously or within the same
treatment protocol) or sequentially, depending upon the nature of
the disease, disorder, or condition, the condition of the patient,
and the actual choice of compounds used. The determination of the
order of administration, and the number of repetitions of
administration of each therapeutic agent during a treatment
protocol, is well within the knowledge of the skilled physician
after evaluation of the disease being treated and the condition of
the patient.
[0224] It is known to those of skill in the art that
therapeutically-effective dosages can vary when the drugs are used
in treatment combinations. Methods for experimentally determining
therapeutically-effective dosages of drugs and other agents for use
in combination treatment regimens are described in the literature.
For example, the use of metronomic dosing i.e., providing more
frequent, lower doses in order to minimize toxic side effects, has
been described extensively in the literature Combination treatment
further includes periodic treatments that start and stop at various
times to assist with the clinical management of the patient.
[0225] For combination therapies described herein, dosages of the
co-administered compounds will of course vary depending on the type
of co-drug employed, on the specific drug employed, on the disease
or condition being treated and so forth. In addition, when
co-administered with one or more biologically active agents, the
compound provided herein may be administered either simultaneously
with the biologically active agent(s), or sequentially. If
administered sequentially, the attending physician will decide on
the appropriate sequence of administering protein in combination
with the biologically active agent(s).
[0226] In any case, the multiple therapeutic agents (one of which
is a compound of Formula (I) described herein) may be administered
in any order or even simultaneously. If simultaneously, the
multiple therapeutic agents may be provided in a single, unified
form, or in multiple forms (by way of example only, either as a
single pill or as two separate pills). One of the therapeutic
agents may be given in multiple doses, or both may be given as
multiple doses. If not simultaneous, the timing between the
multiple doses may vary from more than zero weeks to less than four
weeks. In addition, the combination methods, compositions and
formulations are not to be limited to the use of only two agents;
the use of multiple therapeutic combinations are also
envisioned.
[0227] It is understood that the dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, can be
modified in accordance with a variety of factors. These factors
include the disorder from which the subject suffers, as well as the
age, weight, sex, diet, and medical condition of the subject. Thus,
the dosage regimen actually employed can vary widely and therefore
can deviate from the dosage regimens set forth herein.
[0228] The pharmaceutical agents which make up the combination
therapy disclosed herein may be a combined dosage form or in
separate dosage forms intended for substantially simultaneous
administration. The pharmaceutical agents that make up the
combination therapy may also be administered sequentially, with
either therapeutic compound being administered by a regimen calling
for two-step administration. The two-step administration regimen
may call for sequential administration of the active agents or
spaced-apart administration of the separate active agents. The time
period between the multiple administration steps may range from, a
few minutes to several hours, depending upon the properties of each
pharmaceutical agent, such as potency, solubility, bioavailability,
plasma half-life and kinetic profile of the pharmaceutical agent.
Circadian variation of the target molecule concentration may also
determine the optimal dose interval.
[0229] In addition, the compounds described herein also may be used
in combination with procedures that may provide additional or
synergistic benefit to the patient. By way of example only,
patients are expected to find therapeutic and/or prophylactic
benefit in the methods described herein, wherein pharmaceutical
composition of a compound disclosed herein and/or combinations with
other therapeutics are combined with genetic testing to determine
whether that individual is a carrier of a mutant gene that is known
to be correlated with certain diseases or conditions.
[0230] The compounds described herein and combination therapies can
be administered before, during or after the occurrence of a disease
or condition, and the timing of administering the composition
containing a compound can vary. Thus, for example, the compounds
can be used as a prophylactic and can be administered continuously
to subjects with a propensity to develop conditions or diseases in
order to prevent the occurrence of the disease or condition. The
compounds and compositions can be administered to a subject during
or as soon as possible after the onset of the symptoms. The
administration of the compounds can be initiated within the first
48 hours of the onset of the symptoms, within the first 6 hours of
the onset of the symptoms, or within 3 hours of the onset of the
symptoms. The initial administration can be via any route
practical, such as, for example, an intravenous injection, a bolus
injection, infusion over 5 minutes to about 5 hours, a pill, a
capsule, transdermal patch, buccal delivery, and the like, or
combination thereof. A compound should be administered as soon as
is practicable after the onset of a disease or condition is
detected or suspected, and for a length of time necessary for the
treatment of the disease, such as, for example, from about 1 month
to about 3 months. The length of treatment can vary for each
subject, and the length can be determined using the known criteria.
For example, the compound or a formulation containing the compound
can be administered for at least 2 weeks, between about 1 month to
about 5 years, or from about 1 month to about 3 years.
Exemplary Therapeutic Agents for Use in Combination with an
Irreversible Btk Inhibitor Compound
[0231] Where the subject is suffering from or at risk of suffering
from an autoimmune disease, an inflammatory disease, or an allergy
disease, an irreversible Btk inhibitor compound can be used in with
one or more of the following therapeutic agents in any combination:
immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,
methotrexate, cyclophosphamide, azathioprine, mercaptopurine,
mycophenolate, or FTY720), glucocorticoids (e.g., prednisone,
cortisone acetate, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclometasone, fludrocortisone
acetate, deoxycorticosterone acetate, aldosterone), non-steroidal
anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or
sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,
celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,
minocycline, TNF-.alpha. binding proteins (e.g., infliximab,
etanercept, or adalimumab), abatacept, anakinra, interferon-.beta.,
interferon-.gamma., interleukin-2, allergy vaccines,
antihistamines, antileukotrienes, beta-agonists, theophylline, or
anticholinergics.
[0232] Where the subject is suffering from or at risk of suffering
from a B-cell proliferative disorder (e.g., plasma cell myeloma),
the subjected can be treated with an irreversible Btk inhibitor
compound in any combination with one or more other anti-cancer
agents. In some embodiments, one or more of the anti-cancer agents
are proapoptotic agents. Examples of anti-cancer agents include,
but are not limited to, any of the following: gossyphol, genasense,
polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA),
bryostatin, tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid,
doxorubicin, vincristine, etoposide, gemcitabine, imatinib
(Gleevec.RTM.), geldanamycin,
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or
PD184352, Taxol.TM., also referred to as "paclitaxel", which is a
well-known anti-cancer drug which acts by enhancing and stabilizing
microtubule formation, and analogs of Taxol.TM., such as
Taxotere.TM.. Compounds that have the basic taxane skeleton as a
common structure feature, have also been shown to have the ability
to arrest cells in the G2-M phases due to stabilized microtubules
and may be useful for treating cancer in combination with the
compounds described herein.
[0233] Further examples of anti-cancer agents for use in
combination with an irreversible Btk inhibitor compound include
inhibitors of mitogen-activated protein kinase signaling, e.g.,
U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063,
SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors;
mTOR inhibitors; and antibodies (e.g., rituxan).
[0234] Other anti-cancer agents that can be employed in combination
with an irreversible Btk inhibitor compound include Adriamycin,
Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin;
aldesleukin; altretamine; ambomycin; ametantrone acetate;
aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; interleukin II (including
recombinant interleukin II, or rIL2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0235] Other anti-cancer agents that can be employed in combination
with an irreversible Btk inhibitor compound include: 20-epi-1, 25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflomithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perfiubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras famesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; R11 retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived 1; sense oligonucleotides; signal transduction inhibitors;
signal transduction modulators; single chain antigen-binding
protein; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0236] Yet other anticancer agents that can be employed in
combination with an irreversible Btk inhibitor compound include
alkylating agents, antimetabolites, natural products, or hormones,
e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, etc.), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin).
[0237] Examples of natural products useful in combination with an
irreversible Btk inhibitor compound include but are not limited to
vinca alkaloids (e.g., vinblastin, vincristine),
epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,
daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,
L-asparaginase), or biological response modifiers (e.g., interferon
alpha).
[0238] Examples of alkylating agents that can be employed in
combination an irreversible Btk inhibitor compound include, but are
not limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and
methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl
sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomusitne, semustine, streptozocin, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include, but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine),
purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
[0239] Examples of hormones and antagonists useful in combination
with an irreversible Btk inhibitor compound include, but are not
limited to, adrenocorticosteroids (e.g., prednisone), progestins
(e.g., hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,
leuprolide). Other agents that can be used in the methods and
compositions described herein for the treatment or prevention of
cancer include platinum coordination complexes (e.g., cisplatin,
carboblatin), anthracenedione (e.g., mitoxantrone), substituted
urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g.,
procarbazine), adrenocortical suppressant (e.g., mitotane,
aminoglutethimide).
[0240] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with an irreversible Btk inhibitor compound
include without limitation the following marketed drugs and drugs
in development: Erbulozole (also known as R-55104), Dolastatin 10
(also known as DLS-10 and NSC-376128), Mivobulin isethionate (also
known as CI-980), Vincristine, NSC-639829, Discodermolide (also
known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010),
Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C),
Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin
3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7,
Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also
known as LU-103793 and NSC-D-669356), Epothilones (such as
Epothilone A, Epothilone B, Epothilone C (also known as
desoxyepothilone A or dEpoA), Epothilone D (also referred to as
KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone
F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,
21-aminoepothilone B (also known as BMS-310705),
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also
known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
[0241] Where the subject is suffering from or at risk of suffering
from a thromboembolic disorder (e.g., stroke), the subject can be
treated with an irreversible Btk inhibitor compound in any
combination with one or more other anti-thromboembolic agents.
Examples of anti-thromboembolic agents include, but are not limited
any of the following: thrombolytic agents (e.g., alteplase
anistreplase, streptokinase, urokinase, or tissue plasminogen
activator), heparin, tinzaparin, warfarin, dabigatran (e.g.,
dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux,
draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),
ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315),
ximelagatran, or BIBR 1048.
EXAMPLES
[0242] The following examples describe in detail the synthesis of
ibrutinib prodrugs of Formula (I), properties of ibrutinib prodrugs
of Formula (I), and uses of ibrutinib prodrugs of Formula (I). It
will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced
without departing from the scope of the disclosure.
[0243] All reagents and solvents that can be purchased from
commercial suppliers may be used without further purification or
manipulation. Non-commercially available reagents may be
synthesized from commercially available starting materials, and by
adapting methods well known in the art.
[0244] Analytical LC/MS was performed on an Agilent 1100 equipped
with AB Sciex API 2000 or a Waters 2790 equipped with a Waters
Micromass QZ mass spectrometer and a Phenomenex Luna C-18
analytical column. Preparative HPLC purification was performed on
an Agilent 1100. Both analytical and preparative HPLC used
acetonitrile/water gradients containing 0.05% formic acid.
Normal-phase silica gel purification was performed on a ISCO
CombiFlash Companion purification system using either a mixture of
methanol and dichloromethane or ethyl acetate and hexanes. Chemical
names were generated with Accelrys Draw 4.1 SP1, version
MDL.Draw.Editor 4.1. 100.70 (Accelrys, Inc., San Diego,
Calif.).
Example 1
[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyr-
imidin-4-yl]carbamoyloxymethyl acetate (1)
##STR00045##
[0246] A mixture of ibrutinib (15 mg, 1.0 eq),
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq),
and NaHCO.sub.3 (3.0 eq) in 1:1 water and acetonitrile (0.5 mL) was
stirred at 20.degree. C. overnight. The reaction was then purified
by reverse-phase (C-18) liquid chromatography using water and
acetonitrile as eluents to yield compound (1). MS (ESI): m/z 557.2
(M+H)+.
[0247] Alternatively, a mixture of ibrutinib (25 mg 1.0 eq),
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq),
and triethylamine (3.0 eq) in N,N-dimethylacetamide (DMA) (1.0 mL)
was stirred at 20.degree. C. overnight. The reaction was then
purified by reverse-phase (C-18) liquid chromatography using water
and acetonitrile as eluents to yield compound (1).
Example 2
[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyr-
imidin-4-yl]carbamoyloxymethyl 2-methylpropanoate (2)
##STR00046##
[0249] Compound (2) was prepared according to the method described
in Example 1 and substituting
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate with
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-methylpropanoate.
MS (ESI): m/z 585.2 (M+H)+.
Example 3
[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyr-
imidin-4-yl]carbamoyloxymethyl cyclohexanecarboxylate (3)
##STR00047##
[0251] Compound (3) was prepared according to the method described
in Example 1 and substituting
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate with
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl
cyclohexanecarboxylate. MS (ESI): m/z 625.3 (M+H)+.
Example 4
[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyr-
imidin-4-yl]carbamoyloxymethyl benzoate (4)
##STR00048##
[0253] Compound (4) was prepared according to the method described
in Example 1 and substituting
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate with
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl benzoate. MS (ESI):
m/z 619.2 (M+H)+.
Example 5
(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl
N-[3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]-
pyrimidin-4-yl]carbamate (5)
##STR00049##
[0255] Compound (5) was prepared according to the method described
in Example 1 and substituting
(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate with
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate. MS (ESI):
m/z 597.2 (M+H)+.
* * * * *