U.S. patent application number 16/286002 was filed with the patent office on 2019-06-27 for bmp potentiators.
The applicant listed for this patent is NOVARTIS AG. Invention is credited to Jian DING, Marie-Helene LARRAUFIE, Deborah ROTHMAN, Nik SAVAGE, Shaowen WANG.
Application Number | 20190194227 16/286002 |
Document ID | / |
Family ID | 60569967 |
Filed Date | 2019-06-27 |
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United States Patent
Application |
20190194227 |
Kind Code |
A1 |
DING; Jian ; et al. |
June 27, 2019 |
BMP POTENTIATORS
Abstract
The disclosure provides compounds of Formula (I) or a
pharmaceutically acceptable salt thereof, wherein: ##STR00001##
Also provided are methods of making the compounds of Formula (I)
and their methods of use.
Inventors: |
DING; Jian; (Bedford,
MA) ; LARRAUFIE; Marie-Helene; (Boston, MA) ;
ROTHMAN; Deborah; (Westfield, NJ) ; SAVAGE; Nik;
(Somerville, MA) ; WANG; Shaowen; (Jamaica Plain,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Family ID: |
60569967 |
Appl. No.: |
16/286002 |
Filed: |
February 26, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15807462 |
Nov 8, 2017 |
10259827 |
|
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16286002 |
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62420535 |
Nov 10, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/453 20130101;
A61P 19/08 20180101; A61P 7/04 20180101; A61P 3/00 20180101; A61K
31/436 20130101; A61P 27/06 20180101; C07D 498/18 20130101; A61P
13/00 20180101; A61P 7/00 20180101; A61P 37/00 20180101; A61P 9/12
20180101; A61P 29/00 20180101; A61P 9/14 20180101; A61P 27/02
20180101; A61P 43/00 20180101; A61P 13/12 20180101; A61P 1/04
20180101; A61P 27/00 20180101; A61P 7/06 20180101; C07D 498/08
20130101; A61P 11/00 20180101; A61K 45/06 20130101 |
International
Class: |
C07D 498/18 20060101
C07D498/18; A61K 31/453 20060101 A61K031/453; C07D 498/08 20060101
C07D498/08; A61K 31/436 20060101 A61K031/436; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method of potentiating bone morphogenetic protein (BMP)
signaling in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof, wherein: ##STR00020## each R.sup.1 is independently
selected from the group consisting of halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
heteroC.sub.1-10 alkyl, and C.sub.1-6 haloalkyl; n is 1, 2, 3, 4,
or 5; and m is 0, 1, 2, 3, or 4.
2. The method of claim 1, wherein n is 1, 2 or 3.
3. The method of claim 1, wherein n is 1.
4. The method of claim 1, wherein R.sup.1 is selected from the
group consisting of halo and C.sub.1-6 alkyl.
5. The method of claim 1, wherein m is 0 or 1.
6. The method of claim 1, wherein m is 0.
7. The method of claim 1, wherein the compound is compound (A):
##STR00021##
8. A method of treating a disease or disorder in a subject in need
thereof selected from the group consisting of: PAH (pulmonary
arteria hypertension); HHT (hereditary hemorrhagic telangiectasia);
iron overload anemia; fracture healing; macular degeneration;
glaucoma; dry eye; colitis; IBD (inflammatory bowel disease);
juvenile polyposis syndrome; and fibrosis, the method comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof, wherein: ##STR00022## each R.sup.1 is independently
selected from the group consisting of halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
heteroC.sub.1-10 alkyl, and C.sub.1-6 haloalkyl; n is 1, 2, 3, 4,
or 5; and m is 0, 1, 2, 3, or 4.
9. The method of claim 8, wherein n is 1, 2 or 3.
10. The method of claim 8, wherein n is 1.
11. The method of claim 8, wherein R.sup.1 is selected from the
group consisting of halo and C.sub.1-6 alkyl.
12. The method of claim 8, wherein m is 0 or 1.
13. The method of claim 8, wherein m is 0.
14. The method of claim 8, wherein the compound is compound (A):
##STR00023##
15. The method of claim 8, wherein the macular degeneration is AMD
(age-related macular degeneration).
16. The method of claim 8, wherein the fibrosis is selected from
lung, liver and kidney.
Description
CLAIM OF PRIORITY
[0001] This application is a divisional of U.S. Ser. No. 15/807,462
filed Nov. 8, 2017, which claims priority from U.S. Ser. No.
62/420,535 filed Nov. 10, 2016, each of which is incorporated
herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Bone morphogenetic protein (BMP) signaling has been
implicated in several processes during embryonic development and in
adult tissue homeostasis. BMPs provide critical signals for
determining cell fate, embryonic patterning, osteogenesis,
chondrogenesis, iron homeostasis and are regulators of endothelial
cell proliferation, migration and tube formation. Genetic studies
in human and in mouse show that perturbations in BMP signaling lead
to various diseases. Mutations in BMP type II and type I receptors
have been linked to pulmonary arterial hypertension (PAH) (Long et
al. Nature Medicine 21:777-784, 2015), and hereditary hemorrhagic
telangiectasia (HHT) (Tillet et al. Front. Genet. 8(5): 456, 2015;
Wang et al. Genes & Diseases 1:87-105, 2014), also known as
Osler-Weber-Rendu disease and Osler-Weber-Rendu syndrome,
respectively. Deficiency of BMP signaling is also involved in
kidney injury, proteinuric diseases, and iron overload anemia
(Sampath et al. (2017) Bone Morphogenetic Protein-7 and Its Role in
Acute Kidney Injury and Chronic Kidney Failure; Vukicevic S.,
Sampath K. (eds) Bone Morphogenetic Proteins: Systems Biology
Regulators; Progress in Inflammation Research. Springer, Cham;
Steinbicker et al. Blood 118(15): 4224-4230).
[0003] Further, HET is an inherited autosome dominant vascular
dysplasia affecting 1:5000/8000 people worldwide. Hallmark features
include recurrent epistaxis (nosebleed) and/or chronic GI blood
loss due to telangiectasias (small dilated blood vessels) of
mucosal surfaces and arteriovenous malformations (AVM) in solid
organs. Larger AVMs occur in lungs (40-60% of affected
individuals), liver (40-70%), brain (10%) and spine (1%).
Management of HHT has largely been procedural to control the
symptoms. All mutations identified in HET patients to date affect
the BMP pathway, including Endoglin (ENG) (HHT1, .about.45%),
Acvrl1 (ALK1) (HHT2, .about.42%), and SMAD4 (Juvenile Polyposis
& HHT, .about.1-2%). These mutations result in
haploinsufficiency of functional proteins, which cause the
pathophysiology of HHT manifested as fragile vessels, capillary
overgrowth and numerous AVMs. Potentiating BMP signaling would
normalize the pathway signaling in vascular cells of HHT patients,
to prevent the formation of new lesions and support involution of
existing telangiectasias.
[0004] BMP-7 is expressed in all parts of the normal kidney
parenchyma, being highest in the epithelium of proximal tubules. It
protects kidney against acute and chronic injury, inflammation and
fibrosis. Diabetic nephropathy is the leading cause of chronic
kidney disease. Clinical data from 30 patients with diabetic
nephropathy (showing increased expression of BMP-7 at initial
stages of diabetic nephropathy with subsequent decrease at advanced
stage) highlights the role of BMP-7 in the protection of kidney
structure and function (Ivanac-Jankovic et al. Acta Clin Croat.
54(2):164-8, 2015).
[0005] FK506 is a potent BMP potentiator, as it displaces FKBP12
from BMP type I receptors, thus unblocking their phosphorylation
site (Spiekerkoetter et al. J. Clin. Invest. 123(8):3600-3613,
2013). In addition, FK506 is an immunosuppressive 23-membered
macrolide lactone natural product, and has been used clinically in
solid organ transplants. FK506 inhibits calcineurin activity by a
unique, small molecule-mediated, protein-protein interaction. FK506
binds to FKBP12, and this binary complex binds to calcineurin and
blocks dephosphorylation of pNFAT in mammals leading to
immunosuppression. (Nambu et al. Bioorganic & Medicinal
Chemistry Letters 27: 2465-2471, 2017). However, pharmacologically,
calcineurin inhibition by FK506 is not required to potentiate BMP
signaling. (Dumont et al. J. Exp. Med. 176:751-760, 1992). The
majority of clinical toxicities, including nephrotoxicity, of FK506
and FK506 analogs are associated with calcineurin inhibition.
Therefore, calcineurin-sparing FK506 analogs should have an
improved therapeutic index. As such, there remains a need for new
treatments and therapies for renal diseases, HHT and other
disorders related to BMP signaling deficiency that potentiate BMP
signaling, but are calcineurin-sparing.
SUMMARY OF THE INVENTION
[0006] The disclosure provides, inter alia, compounds,
pharmaceutically acceptable salts thereof, pharmaceutical
compositions thereof and pharmaceutical combinations thereof, which
are calcineurin-sparing BMP potentiators. The disclosure further
provides methods of treating, preventing, or ameliorating a disease
or disorder related to BMP signaling deficiency, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of a calcineurin-sparing BMP
potentiator. In an embodiment, the disease or disorder is a renal
disorder. In an embodiment, the renal disorder is selected from the
group consisting of diabetic nephropathy; AKI (acute kidney
injury); and proteinuric diseases. In an embodiment, the disease or
disorder is selected from the group consisting of PAH (pulmonary
arteria hypertension); HHT (hereditary hemorrhagic telangiectasia);
iron overload anemia; fracture healing; macular degeneration (e.g.,
AMD (age-related macular degeneration)); glaucoma; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; and
fibrosis (e.g., lung, liver and kidney).
[0007] In one aspect, provided herein are compounds of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
##STR00002##
[0008] each R.sup.1 is independently selected from the group
consisting of halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-10 alkyl, and
C.sub.1-6 haloalkyl;
[0009] n is 1, 2, 3, 4, or 5; and
[0010] m is 0, 1, 2, 3, or 4.
[0011] In an embodiment, n is 1, 2 or 3. In an embodiment, n is 1
or 2. In an embodiment, n is 1.
[0012] In an embodiment, R.sup.1 is independently selected from the
group consisting of halo and C.sub.1-6 alkyl. In an embodiment,
R.sup.1 is independently C.sub.1-6 alkyl. In an embodiment, R.sup.1
is independently heteroC.sub.1-10 alkyl.
[0013] In an embodiment, m is 0 or 1. In an embodiment, m is 0. In
an embodiment, n is 1 and m is 0.
[0014] In an embodiment, the compound is compound (A):
##STR00003##
or a pharmaceutically acceptable salt thereof.
[0015] In another aspect, provided herein are compounds of Formula
(II) or a pharmaceutically acceptable salt thereof, wherein:
##STR00004##
[0016] In an embodiment the compound is compound (B):
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0017] In an embodiment, the compound is compound (C):
##STR00006##
or a pharmaceutically acceptable salt thereof.
[0018] In another aspect, the disclosure provides a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable carriers.
[0019] In another aspect, the disclosure provides a pharmaceutical
combination comprising a therapeutically effective amount of a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof, and one
or more therapeutically active agents.
[0020] In another aspect, the disclosure provides a method of
potentiating bone morphogenetic protein (BMP) signaling in a
subject in need thereof, the method comprising administering to the
subject a therapeutically effective amount of a compound of Formula
(I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof; a pharmaceutical
composition comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof and one or more pharmaceutically acceptable carriers;
or a pharmaceutical combination comprising a compound of Formula
(I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof, and one or more
therapeutically active agents.
[0021] In another aspect, the disclosure provides a method of
treating hereditary hemorrhagic telangiectasia (HHT) in a subject
in need thereof, the method comprising administering to the subject
a therapeutically effective amount of a compound of Formula (I),
(II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents.
[0022] In another aspect, the disclosure provides a method of
treating renal disease in a subject in need thereof, the method
comprising administering to the subject a therapeutically effective
amount of a compound of Formula (I), (II), compound (A), compound
(B), or compound (C) or a pharmaceutically acceptable salt thereof
and one or more pharmaceutically acceptable carriers; or a
pharmaceutical combination comprising a compound of Formula (I),
(II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof, and one or more
therapeutically active agents.
[0023] In an embodiment, the renal disease is selected from the
group consisting of diabetic nephropathy; AKI (acute kidney
injury); and proteinuric diseases.
[0024] In another aspect, the disclosure provides a method of
treating a disease or disorder associated with deficient BMP
signaling in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and one
or more pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents.
[0025] In an embodiment, the disease or disorder is selected from
the group consisting of PAH (pulmonary arteria hypertension); HET
(hereditary hemorrhagic telangiectasia); iron overload anemia;
fracture healing; macular degeneration (e.g., AMD (age-related
macular degeneration); glaucoma; dry eye; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; and
fibrosis (e.g., lung, liver and kidney).
[0026] In another aspect, the disclosure provides a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, for
use as a medicament.
[0027] In another aspect, the disclosure provides a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, for
use in the treatment of hereditary hemorrhagic telangiectasia (HHT)
in a subject in need thereof.
[0028] In another aspect, the disclosure provides a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, for
use in the treatment of renal disease in a subject in need
thereof.
[0029] In an embodiment, the renal disease is selected from the
group consisting of diabetic nephropathy; AKI (acute kidney
injury); and proteinuric diseases.
[0030] In another aspect, the disclosure provides a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, for
use in the treatment of a disease or disorder associated with
deficient BMP signaling in a subject in need thereof.
[0031] In an embodiment, the disease or disorder is selected from
the group consisting of PAH (pulmonary arteria hypertension); HHT
(hereditary hemorrhagic telangiectasia); iron overload anemia;
fracture healing; macular degeneration (e.g., AMD (age-related
macular degeneration)); glaucoma; dry eye; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; and
fibrosis (e.g., lung, liver and kidney).
[0032] In another aspect, the disclosure provides a use of Formula
(I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, in the
manufacture of a medicament for the treatment of hereditary
hemorrhagic telangiectasia (HHT) in a subject in need thereof.
[0033] In another aspect, the disclosure provides a use of Formula
(I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, in the
manufacture of a medicament for the treatment of renal disease in a
subject in need thereof.
[0034] In an embodiment, the renal disease is selected from the
group consisting of diabetic nephropathy; AKI (acute kidney
injury); and proteinuric diseases.
[0035] In another aspect, the disclosure provides a use of Formula
(I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers; or a pharmaceutical
combination comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and one or more therapeutically active agents, in the
manufacture of a medicament for the treatment of a disease or
disorder associated with deficient BMP signaling in a subject in
need thereof.
[0036] In an embodiment, the disease or disorder is selected from
the group consisting of PAH (pulmonary arteria hypertension); HHT
(hereditary hemorrhagic telangiectasia); iron overload anemia;
fracture healing; macular degeneration (e.g., AMD (age-related
macular degeneration)); glaucoma; dry eye; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; and
fibrosis (e.g., lung, liver and kidney).
[0037] The details of one or more embodiments of the invention are
set forth herein. Other features, objects, and advantages of the
disclosure will be apparent from the Detailed Description, the
Examples, and the Claims.
DETAILED DESCRIPTION
Definitions
[0038] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0039] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, Z
and E double bond isomers, and Z and E conformational isomers.
Therefore, single stereochemical isomers as well as enantiomeric,
diastereomeric, and geometric (or conformational) mixtures of the
present compounds are within the scope of the invention. Unless
otherwise stated, all tautomeric forms of the compounds of the
invention are within the scope of the invention. Additionally,
unless otherwise stated, structures depicted herein are also meant
to include compounds that differ only in the presence of one or
more isotopically enriched atoms. For example, compounds having the
present structures including the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as
probes in biological assays, or as therapeutic agents in accordance
with the present invention.
[0040] Where a particular enantiomer is preferred, it may, in some
embodiments be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically-enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound is made up of at least about 90%
by weight of a preferred enantiomer. In other embodiments the
compound is made up of at least about 95%, 98%, or 99% by weight of
a preferred enantiomer. Preferred enantiomers may be isolated from
racemic mixtures by any method known to those skilled in the art,
including chiral high pressure liquid chromatography (HPLC) and the
formation and crystallization of chiral salts or prepared by
asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E.
L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962);
Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p.
268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972).
[0041] The term "alkyl" refers to a radical of a straight-chain or
branched saturated hydrocarbon group having from 1 to 10 carbon
atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl group has
1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some embodiments, an
alkyl group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some
embodiments, an alkyl group has 1 to 7 carbon atoms ("C.sub.1-7
alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon
atoms ("C.sub.1-6 alkyl"). In some embodiments, an alkyl group has
1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some embodiments, an
alkyl group has 1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("C.sub.1-3
alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon
atoms ("C.sub.1-2 alkyl"). In some embodiments, an alkyl group has
1 carbon atom ("C.sub.1 alkyl"). In some embodiments, an alkyl
group has 2 to 6 carbon atoms ("C.sub.2-6 alkyl"). Examples of
C.sub.1-6 alkyl groups include methyl (C.sub.1), ethyl (C.sub.2),
propyl (C.sub.3) (e.g., n-propyl, isopropyl), butyl (C.sub.4)
(e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C.sub.5)
(e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl,
tertiary amyl), and hexyl (C.sub.6) (e.g., n-hexyl). Additional
examples of alkyl groups include n-heptyl (C.sub.7), n-octyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkyl group is independently unsubstituted (an "unsubstituted
alkyl") or substituted (a "substituted alkyl") with one or more
substituents (e.g., halogen, such as F). In certain embodiments,
the alkyl group is an unsubstituted C.sub.1-10 alkyl (such as
unsubstituted C.sub.1-6 alkyl, e.g., --CH.sub.3 (Me), unsubstituted
ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl
(n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu,
e.g., unsubstituted n-butyl (n-Bu), unsubstituted tent-butyl
(tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted
isobutyl (i-Bu)). In certain embodiments, the alkyl group is a
substituted C.sub.1-10 alkyl (such as substituted C.sub.1-6 alkyl,
e.g., --CF.sub.3).
[0042] The term "haloalkyl" refers to a substituted alkyl group,
wherein one or more of the hydrogen atoms are independently
replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo and
includes alkyl moieties in which all hydrogens have been replaced
by halo (e.g., perfluoroalkyl). In some embodiments, the haloalkyl
moiety has 1 to 8 carbon atoms ("C.sub.1-8 haloalkyl"). In some
embodiments, the haloalkyl moiety has 1 to 6 carbon atoms
("C.sub.1-6 haloalkyl"). In some embodiments, the haloalkyl moiety
has 1 to 4 carbon atoms ("C.sub.1-4 haloalkyl"). In some
embodiments, the haloalkyl moiety has 1 to 3 carbon atoms
("C.sub.1-3 haloalkyl"). In some embodiments, the haloalkyl moiety
has 1 to 2 carbon atoms ("C.sub.1-2 haloalkyl"). Examples of
haloalkyl groups include --CF.sub.3, --CF.sub.2CF.sub.3,
--CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3, --CFCl.sub.2,
--CF.sub.2Cl, and the like.
[0043] The terms "alkylamino" and "dialkylamino" refer to
--NH(alkyl) and --NH(alkyl).sub.2 radicals, respectively. In some
embodiments, the alkylamino is a --NH(C.sub.1-4 alkyl). In some
embodiments, the alkylamino is methylamino, ethylamino,
propylamino, isopropylamino, n-butylamino, iso-butylamino,
sec-butylamino or tert-butylamino. In some embodiments, the
dialkylamino is --NH(C.sub.1-6 alkyl).sub.2. In some embodiments,
the dialkylamino is a dimethylamino, a methylethylamino, a
diethylamino, a methylpropylamino, a methylisopropylamino, a
methylbutylamino, a methylisobutylamino or a
methyltertbutylamino.
[0044] The term "alkoxy" or "alkoxyl" refers to an --O-alkyl
radical. In some embodiments, the alkoxy groups are methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. In some embodiments,
alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon
atoms. In some embodiments, alkoxy groups have between 1 and 4
carbon atoms.
[0045] "Hydroxyalkyl" or "hydroxylalkyl" can include alkyl
structures that are substituted with one or more hydroxyl
groups.
[0046] The term "heteroalkyl" refers to an alkyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkyl group refers to a saturated group having
from 1 to 10 carbon atoms and 1 or more heteroatoms within the
parent chain ("heteroC.sub.1-10 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 9 carbon atoms
and 1 or more heteroatoms within the parent chain ("heteroC.sub.1-9
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 8 carbon atoms and 1 or more heteroatoms within
the parent chain ("heteroC.sub.1-8 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 7 carbon atoms
and 1 or more heteroatoms within the parent chain ("heteroC.sub.1-7
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 6 carbon atoms and 1 or more heteroatoms within
the parent chain ("heteroC.sub.1-6 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 5 carbon atoms
and 1 or 2 heteroatoms within the parent chain ("heteroC.sub.1-5
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 4 carbon atoms and for 2 heteroatoms within the
parent chain ("heteroC.sub.1-4 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 3 carbon atoms
and 1 heteroatom within the parent chain ("heteroC.sub.1-3 alkyl").
In some embodiments, a heteroalkyl group is a saturated group
having 1 to 2 carbon atoms and 1 heteroatom within the parent chain
("heteroC.sub.1-2 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 carbon atom and 1 heteroatom
("heteroC.sub.1 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 2 to 6 carbon atoms and 1 or 2
heteroatoms within the parent chain ("heteroC.sub.2-6 alkyl").
Unless otherwise specified, each instance of a heteroalkyl group is
independently unsubstituted (an "unsubstituted heteroalkyl") or
substituted (a "substituted heteroalkyl") with one or more
substituents. In certain embodiments, the heteroalkyl group is an
unsubstituted heteroC.sub.1-10 alkyl. In certain embodiments, the
heteroalkyl group is a substituted heteroC.sub.1-10 alkyl.
[0047] The term "alkenyl" refers to a radical of a straight-chain
or branched hydrocarbon group having from 2 to 10 carbon atoms and
one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double
bonds). In some embodiments, an alkenyl group has 2 to 9 carbon
atoms ("C.sub.2-9 alkenyl"). In some embodiments, an alkenyl group
has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In some embodiments,
an alkenyl group has 2 to 7 carbon atoms ("C.sub.2-7 alkenyl"). In
some embodiments, an alkenyl group has 2 to 6 carbon atoms
("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2
to 5 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an
alkenyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkenyl"). In
some embodiments, an alkenyl group has 2 to 3 carbon atoms
("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group has 2
carbon atoms ("C.sub.2 alkenyl"). The one or more carbon-carbon
double bonds can be internal (such as in 2-butenyl) or terminal
(such as in 1-butenyl). Examples of C.sub.2-4 alkenyl groups
include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl
(C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkenyl groups as well as
pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and
the like. Additional examples of alkenyl include heptenyl
(C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like.
Unless otherwise specified, each instance of an alkenyl group is
independently unsubstituted (an "unsubstituted alkenyl") or
substituted (a "substituted alkenyl") with one or more
substituents. In certain embodiments, the alkenyl group is an
unsubstituted C.sub.2-10 alkenyl. In certain embodiments, the
alkenyl group is a substituted C.sub.2-10 alkenyl. In an alkenyl
group, a C.dbd.C double bond for which the stereochemistry is not
specified (e.g., --CH.dbd.CHCH.sub.3 or
##STR00007##
may be an (E)- or (Z)-double bond.
[0048] The term "alkynyl" refers to a radical of a straight-chain
or branched hydrocarbon group having from 2 to 10 carbon atoms and
one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple
bonds) ("C.sub.2-10 alkynyl"). In some embodiments, an alkynyl
group has 2 to 9 carbon atoms ("C.sub.2-9 alkynyl"). In some
embodiments, an alkynyl group has 2 to 8 carbon atoms ("C.sub.2-8
alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon
atoms ("C.sub.2-7 alkynyl"). In some embodiments, an alkynyl group
has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In some embodiments,
an alkynyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkynyl"). In
some embodiments, an alkynyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkynyl"). In some embodiments, an alkynyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkynyl"). In some embodiments, an
alkynyl group has 2 carbon atoms ("C.sub.2 alkynyl"). The one or
more carbon-carbon triple bonds can be internal (such as in
2-butynyl) or terminal (such as in 1-butynyl). Examples of
C.sub.2-4 alkynyl groups include, without limitation, ethynyl
(C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3), 1-butynyl
(C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of C.sub.2-6
alkenyl groups include the aforementioned C.sub.2-4 alkynyl groups
as well as pentynyl (C.sub.5), hexynyl (C.sub.6), and the like.
Additional examples of alkynyl include heptynyl (C.sub.7), octynyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkynyl group is independently unsubstituted (an
"unsubstituted alkynyl") or substituted (a "substituted alkynyl")
with one or more substituents. In certain embodiments, the alkynyl
group is an unsubstituted C.sub.2-10 alkynyl. In certain
embodiments, the alkynyl group is a substituted C.sub.2-10
alkynyl.
[0049] A group is optionally substituted unless expressly provided
otherwise. The term "optionally substituted" refers to being
substituted or unsubstituted. In certain embodiments, alkyl,
alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are
optionally substituted. "Optionally substituted" refers to a group
which may be substituted or unsubstituted (e.g., "substituted" or
"unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl,
"substituted" or "unsubstituted" alkynyl, "substituted" or
"unsubstituted" heteroalkyl, "substituted" or "unsubstituted"
heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl,
"substituted" or "unsubstituted" carbocyclyl, "substituted" or
"unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl
or "substituted" or "unsubstituted" heteroaryl group). In general,
the term "substituted" means that at least one hydrogen present on
a group is replaced with a permissible substituent, e.g., a
substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, and includes any of the substituents described herein
that result in the formation of a stable compound. The disclosure
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this disclosure, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety. The
disclosure is not intended to be limited in any manner by the
exemplary substituents described herein.
[0050] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(--NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3, --OSi(R.sup.aa),
--C(.dbd.S)N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa, --SC(.dbd.O)SR.sup.aa,
--OC(.dbd.O)SR.sup.aa, --SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--OP(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--OP(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--NR.sup.bbp(.dbd.O)(R.sup.aa).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.CC).sub.2,
--NR.sup.bbP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, --P(R.sup.cc).sub.2,
--P(OR.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.3.sup.+X.sup.-, --P(R.sup.cc).sub.4,
--P(OR.sup.cc).sub.4, --OP(R.sup.cc).sub.2,
--OP(R.sup.cc).sub.3.sup.+X.sup.-, --OP(OR.sup.cc).sub.2,
--OP(OR.sup.cc).sub.3.sup.+X.sup.-, --OP(R.sup.cc).sub.4,
--OP(OR.sup.cc).sub.4, --B(R.sup.AA).sub.2, --B(OR.sup.cc).sub.2,
--BR.sup.aa(OR.sup.cc), C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X.sup.- is a
counterion;
[0051] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc,
[0052] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.aa groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0053] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10alkyl, heteroC.sub.2-10alkenyl,
heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X.sup.- is a
counterion;
[0054] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.cc groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0055] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O)(OR.sup.ee).sub.2, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups,
or two geminal R.sup.dd substituents can be joined to form .dbd.O
or .dbd.S; wherein X.sup.- is a counterion;
[0056] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg
groups;
[0057] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl,
heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10
carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl and 5-10
membered heteroaryl, or two R.sup.ff groups are joined to form a
3-10 membered heterocyclyl or 5-10 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0058] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3--C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O)(OC.sub.1-6 alkyl).sub.2,
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6alkynyl, C3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, 5-10 membered heteroaryl; or two geminal
R.sup.gg substituents can be joined to form .dbd.O or .dbd.S;
wherein X.sup.- is a counterion.
[0059] The term "halo" or "halogen" refers to fluorine (fluoro,
--F), chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine
(iodo, --I).
[0060] The term "hydroxyl" or "hydroxy" refers to the group
--OH.
[0061] The term "amino" refers to the group --NH.sub.2. The term
"substituted amino," by extension, refers to a monosubstituted
amino, a disubstituted amino, or a trisubstituted amino. In certain
embodiments, the "substituted amino" is a monosubstituted amino or
a disubstituted amino group.
[0062] The term "monosubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with one hydrogen and one group other than hydrogen,
and includes groups selected from --NH(R.sup.bb),
--NHC(.dbd.O)R.sup.aa, --NHCO.sub.2R.sup.aa,
--NHC(.dbd.O)N(R.sup.bb).sub.2,
--NHC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --NHSO.sub.2R.sup.aa,
--NHP(.dbd.O)(OR.sup.cc).sub.2, and
--NHP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein R.sup.aa, R.sup.bb
and R.sup.cc are as defined herein, and wherein R.sup.bb of the
group --NH(R.sup.bb) is not hydrogen.
[0063] The term "disubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with two groups other than hydrogen, and includes
groups selected from --N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
and --NR.sup.bbP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein
R.sup.aa, R.sup.bb, and R.sup.cc are as defined herein, with the
proviso that the nitrogen atom directly attached to the parent
molecule is not substituted with hydrogen.
[0064] The term "trisubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with three groups, and includes groups selected from
--N(R.sup.bb).sub.3 and --N(R.sup.bb).sub.3.sup.+X.sup.-, wherein
R.sup.bb and X.sup.- are as defined herein.
Compounds
[0065] Described herein are compounds, pharmaceutical compositions
and pharmaceutical combinations that potentiate BMP signaling. In
an embodiment, provided is a compound of Formula (I), (II),
compound (A), compound (B), or compound (C) or a pharmaceutically
acceptable salt thereof.
[0066] In one aspect, provided herein are compounds of Formula (I)
or pharmaceutically acceptable salt thereof, wherein:
##STR00008##
[0067] each R.sup.1 is independently selected from the group
consisting of halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-10 alkyl, and
C.sub.1-6 haloalkyl;
[0068] n is 1, 2, 3, 4, or 5; and
[0069] m is 0, 1, 2, 3, or 4.
[0070] In an embodiment, n is 1, 2 or 3. In an embodiment, n is 1
or 2. In an embodiment, n is 1.
[0071] In an embodiment, R.sup.1 is independently selected from the
group consisting of halo and C.sub.1-6 alkyl. In an embodiment,
R.sup.1 is independently C.sub.1-6 alkyl. In an embodiment, R.sup.1
is independently heteroC.sub.1-10 alkyl.
[0072] In an embodiment, m is 0 or 1. In an embodiment, m is 0.
[0073] In a first embodiment, the invention is the compound (A) or
a pharmaceutically acceptable salt thereof, wherein the compound
is:
##STR00009##
[0074] In another aspect, provided herein are compounds of Formula
(II) or a pharmaceutically acceptable salt thereof, wherein:
##STR00010##
[0075] In a second embodiment, the invention is the compound (B) or
a pharmaceutically acceptable salt thereof, wherein the compound
is:
##STR00011##
[0076] In a third embodiment, the invention is a pharmaceutical
composition comprising a therapeutically effective amount of a
compound according to any one of the first or second embodiments,
or a pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable carriers.
[0077] In a fourth embodiment, the invention is a combination
comprising a therapeutically effective amount of a compound
according to any one of the first or second embodiments or a
pharmaceutically acceptable salt thereof and one or more
therapeutically active agents. In certain such embodiments, the
combination is a pharmaceutical combination.
[0078] In a fifth embodiment, the invention is a method of
potentiating BMP signaling in a subject in need thereof, wherein
the method comprises administering to the subject a therapeutically
effective amount of the compound according to any one of the first
or second embodiments or a pharmaceutically acceptable salt
thereof.
[0079] In a sixth embodiment, the invention is a method of treating
hereditary hemorrhagic telangiectasia (HHT) and related conditions
comprising administering to the subject a therapeutically effective
amount of the compound according to any one of the first or second
embodiments or a pharmaceutically acceptable salt thereof.
[0080] In a seventh embodiment, the invention is a compound
according to any one of the first or second embodiments, or a
pharmaceutically acceptable salt thereof, for use as a
medicament.
[0081] In an eighth embodiment, the invention is a compound
according to any one of the first or second embodiments, or a
pharmaceutically acceptable salt thereof, for use in the treatment
of hereditary hemorrhagic telangiectasia (HHT) and related
conditions.
[0082] In a ninth embodiment, the invention is the use of a
compound according to any one of the first or second embodiments,
or a pharmaceutically acceptable salt thereof in the manufacture of
a medicament for the treatment of hereditary hemorrhagic
telangiectasia and related conditions.
[0083] In a tenth embodiment, the invention is a method of treating
renal disease comprising administering to the subject a
therapeutically effective amount of the compound according to any
one of the first or second embodiments or a pharmaceutically
acceptable salt thereof. In an embodiment, the renal disease is
selected from the group consisting of diabetic nephropathy; AKI
(acute kidney injury); and proteinuric diseases.
[0084] In an eleventh embodiment, the invention is a compound
according to any one of the first or second embodiments, or a
pharmaceutically acceptable salt thereof, for use in the treatment
of renal disease. In an embodiment, the renal disease is selected
from the group consisting of diabetic nephropathy; AKI (acute
kidney injury); and proteinuric diseases.
[0085] In a twelfth embodiment, the invention is a use of a
compound according to any one of the first or second embodiments,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for the treatment of renal disease. In an
embodiment, the renal disease is selected from the group consisting
of diabetic nephropathy; AKI (acute kidney injury); and proteinuric
diseases.
[0086] As used herein, the terms "salt" or "salts" refer to an acid
addition or base addition salt of a compound of the invention.
"Salts" include in particular "pharmaceutical acceptable salts."
The term "pharmaceutically acceptable salts" refers to salts that
retain the biological effectiveness and properties of the compounds
disclosed herein and, which typically are not biologically or
otherwise undesirable. In many cases, the compounds disclosed
herein are capable of forming acid and/or base salts by virtue of
the presence of amino and/or carboxyl groups or groups similar
thereto.
[0087] Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids.
[0088] Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like.
[0089] Organic acids from which salts can be derived include, for
example, acetic acid, propionic acid, glycolic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic
acid, and the like.
[0090] Pharmaceutically acceptable base addition salts can be
formed with inorganic and organic bases.
[0091] Inorganic bases from which salts can be derived include, for
example, ammonium salts and metals from columns I to XII of the
periodic table. In certain embodiments, the salts are derived from
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, and copper; particularly suitable salts include ammonium,
potassium, sodium, calcium and magnesium salts.
[0092] Organic bases from which salts can be derived include, for
example, primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines, basic ion exchange resins, and the like. Certain organic
amines include isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine and
tromethamine.
[0093] In another aspect, the disclosure provides a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) in
acetate, ascorbate, adipate, aspartate, benzoate, besylate,
bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,
camphorsulfonate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, glutamate, glutarate,
glycolate, hippurate, hydroiodide/iodide, isethionate, lactate,
lactobionate, laurylsulfate, malate, maleate, malonate, mandelate,
mesylate, methylsulphate, mucate, naphthoate, napsylate,
nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate trifenatate,
trifluoroacetate or xinafoate salt form.
[0094] In an embodiment, the disclosure provides compound (A) in
acetate, ascorbate, adipate, aspartate, benzoate, besyl ate,
bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,
camphorsulfonate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, glutamate, glutarate,
glycolate, hippurate, hydroiodide/iodide, isethionate, lactate,
lactobionate, laurylsulfate, malate, maleate, malonate, mandelate,
mesylate, methylsulphate, mucate, naphthoate, napsylate,
nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate trifenatate,
trifluoroacetate or xinafoate salt form.
[0095] In an embodiment, the disclosure provides compound (B) in
acetate, ascorbate, adipate, aspartate, benzoate, besyl ate,
bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,
camphorsulfonate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate,
gluceptate, gluconate, glucuronate, glutamate, glutarate,
glycolate, hippurate, hydroiodide/iodide, isethionate, lactate,
lactobionate, laurylsulfate, malate, maleate, malonate, mandelate,
mesylate, methylsulphate, mucate, naphthoate, napsylate,
nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate trifenatate,
trifluoroacetate or xinafoate salt form.
[0096] In another aspect, the disclosure provides compound (A) and
compound (B) in sodium, potassium, ammonium, calcium, magnesium,
iron, silver, zinc, copper, isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine or
tromethamine salt form.
[0097] In an embodiment, the disclosure provides compound (A) in
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, copper, isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine or
tromethamine salt form.
[0098] In an embodiment, the disclosure provides compound (B) in
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, copper, isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine or
tromethamine salt form.
[0099] A compound of Formula (I), (II), compound (A), compound (B),
or compound (C) or a pharmaceutically acceptable salt thereof is
also intended to represent unlabeled forms as well as isotopically
labeled forms of the compounds. Isotopically labeled compounds have
structures depicted by the formulas given herein except that one or
more atoms are replaced by an atom having a selected atomic mass or
mass number. Examples of isotopes that can be incorporated into
compounds of the disclosure include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as
.sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F
.sup.31P, .sup.32P, .sup.35S, .sup.36Cl, .sup.123I, .sup.124I,
.sup.125I, respectively. The disclosure includes various
isotopically labeled compounds as defined herein, for example,
those into which radioactive isotopes, such as .sup.3H and
.sup.14C, or those into which non-radioactive isotopes, such as
.sup.2H and .sup.13C are present. Such isotopically labelled
compounds are useful in metabolic studies (with .sup.14C), reaction
kinetic studies (with, for example .sup.2H or .sup.3H), detection
or imaging techniques, such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT) including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. In particular, an .sup.18 F or labeled
compound may be particularly desirable for PET or SPECT studies.
Isotopically-labeled compounds of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof can generally be prepared by conventional techniques known
to those skilled in the art or by processes analogous to those
described in the accompanying Examples and Preparations using an
appropriate isotopically-labeled reagents in place of the
non-labeled reagent previously employed.
[0100] Further, substitution with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example,
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof. The concentration of such
a heavier isotope, specifically deuterium, may be defined by the
isotopic enrichment factor. The term "isotopic enrichment factor"
as used herein means the ratio between the isotopic abundance and
the natural abundance of a specified isotope. If a substituent in a
compound of the disclosure is denoted deuterium, such compound has
an isotopic enrichment factor for each designated deuterium atom of
at least 3500 (52.5% deuterium incorporation at each designated
deuterium atom), at least 4000 (60% deuterium incorporation), at
least 4500 (67.5% deuterium incorporation), at least 5000 (75%
deuterium incorporation), at least 5500 (82.5% deuterium
incorporation), at least 6000 (90% deuterium incorporation), at
least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%
deuterium incorporation), at least 6600 (99% deuterium
incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
[0101] Pharmaceutically acceptable solvates in accordance with the
disclosure include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0102] A compound of Formula (I), (II), compound (A), compound (B),
or compound (C) or a pharmaceutically acceptable salt thereof that
contains groups capable of acting as donors and/or acceptors for
hydrogen bonds may be capable of forming co-crystals with suitable
co-crystal formers. These co-crystals may be prepared from a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof by known
co-crystal forming procedures. Such procedures include grinding,
heating, co-subliming, co-melting, or contacting in solution a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof with the
co-crystal formed under crystallization conditions and isolating
co-crystals thereby formed. Suitable co-crystal formers include
those described in WO 2004/078163, which is incorporated herein by
reference in its entirety. Hence, the disclosure further provides
co-crystals comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof.
[0103] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, and the like and combinations thereof, as
would be known to those skilled in the art (see, for example,
Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, pp. 1289-1329). Except insofar as any conventional
carrier is incompatible with the active ingredient, its use in the
therapeutic or pharmaceutical compositions is contemplated.
[0104] The term "a therapeutically effective amount" of a compound
of Formula (I), (II), compound (A), compound (B), or compound (C)
or a pharmaceutically acceptable salt thereof refers to an amount
of the compound that will elicit the biological or medical response
of a subject, for example, reduction or inhibition of an enzyme or
a protein activity, or ameliorate symptoms, alleviate conditions,
slow or delay disease progression, or prevent a disease, etc. In
one non-limiting embodiment, the term "a therapeutically effective
amount" refers to the amount of a compound of Formula (I), (II),
compound (A), compound (B), or compound (C) or a pharmaceutically
acceptable salt thereof that, when administered to a subject, is
effective to (1) at least partially alleviate, inhibit, prevent
and/or ameliorate a condition, or a disorder or a disease (i)
mediated by BMP, or (ii) associated with BMP activity, or (iii)
characterized by activity (normal or abnormal) of BMP; or (2)
enhance or potentiate BMP signaling. In another non-limiting
embodiment, the term "a therapeutically effective amount" refers to
the amount of a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof that, when administered to a cell, or a tissue, or a
non-cellular biological material, or a medium, is effective to at
least partially enhance or potentiate BMP signaling.
[0105] The term "BMP potentiator" as used herein means an agent
that (measurably) enhances BMP signaling, by sequestering FKBP12,
to a level that is at least about 10%, at least about 15%, at least
about 20%, about 25%, about 30%, about 35% about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, about 95%, about 100%, about 120%,
about 150%, about 200%, about 250%, about 300%, about 350%, about
400%, about 450%, or about 500% more than the BMP signaling in a
sample from a subject harboring a mutation in the BMP signaling
pathway, e.g., an ENG, ALK1 or Smad4 mutation. In an embodiment,
the agent is a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof.
[0106] The phrase "enhance BMP signaling" or "potentiate BMP
signaling" as used herein refers to the ability of an agent, e.g. a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof, to
sequester FKBP12 and potentiate BMP signaling through sensitization
or de-repression. In an embodiment, BMP signaling is enhanced to a
level that is at least about 10%, at least about 15%, at least
about 20%, about 25%, about 30%, about 35% about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, about 95%, about 100%, about 120%,
about 150%, about 200%, about 250%, about 300%, about 350%, about
400%, about 450%, or about 500% more than the BMP signaling in a
sample from a subject harboring a mutation in the BMP signaling
pathway, e.g., an ENG, ALK1 or Smad4 mutation.
[0107] As used herein, the term "subject" refers to an animal.
Typically the animal is a mammal. A subject also refers to for
example, primates (e.g., humans, male or female), cows, sheep,
goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the
like. In certain embodiments, the subject is a primate. In yet
other embodiments, the subject is a human.
[0108] As used herein, the term "inhibit", "inhibition" or
"inhibiting" refers to the reduction or suppression of a given
condition, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or
process.
[0109] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment, "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the patient. In yet another embodiment, "treat",
"treating" or "treatment" refers to preventing or delaying the
onset or development or progression of the disease or disorder.
[0110] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0111] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0112] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0113] Any asymmetric atom (e.g., carbon or the like) of a compound
of Formula (I), (II), compound (A), compound (B), or compound (C)
or a pharmaceutically acceptable salt thereof can be present in
racemic or enantiomerically enriched, for example the (R)-, (S)- or
(R,S)-configuration. In certain embodiments, each asymmetric atom
has at least 50% enantiomeric excess, at least 60% enantiomeric
excess, at least 70% enantiomeric excess, at least 80% enantiomeric
excess, at least 90% enantiomeric excess, at least 95% enantiomeric
excess, or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated double
bonds may, if possible, be present in cis-(Z)- or
trans-(E)-form.
[0114] Accordingly, as used herein a compound of Formula (I), (II),
compound (A), compound (B), or compound (C) or a pharmaceutically
acceptable salt thereof can be in the form of one of the possible
isomers, rotamers, atropisomers, tautomers or mixtures thereof, for
example, as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof.
[0115] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization.
[0116] Any resulting racemates of final products or intermediates
can be resolved into the optical antipodes by known methods, e.g.,
by separation of the diastereomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. In particular, a basic moiety may thus be
employed to resolve the compounds of the present invention into
their optical antipodes, e.g., by fractional crystallization of a
salt formed with an optically active acid, e.g., tartaric acid,
dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl
tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic
acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC)
using a chiral adsorbent.
[0117] Furthermore, a compound of Formula (I), (II), compound (A),
compound (B), or compound (C), including their salts, can also be
obtained in the form of their hydrates, or include other solvents
used for their crystallization. The compound of Formula (I), (II),
compound (A), compound (B), or compound (C) or a pharmaceutically
acceptable salt thereof may inherently or by design form solvates
with pharmaceutically acceptable solvents (including water);
therefore, it is intended that the invention embrace both solvated
and unsolvated forms. The term "solvate" refers to a molecular
complex of a compound of Formula (I), (II), compound (A), compound
(B), or compound (C) or a pharmaceutically acceptable salt thereof
(including pharmaceutically acceptable salts thereof) with one or
more solvent molecules. Such solvent molecules are those commonly
used in the pharmaceutical art, which are known to be innocuous to
the recipient, e.g., water, ethanol, and the like. The term
"hydrate" refers to the complex where the solvent molecule is
water.
[0118] The compound of Formula (I), (II), compound (A), compound
(B), or compound (C), including salts, hydrates and solvates
thereof, may inherently or by design form polymorphs.
[0119] In another aspect, the disclosure provides a pharmaceutical
composition comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier. In a
further embodiment, the pharmaceutical composition comprises at
least two pharmaceutically acceptable carriers, such as those
described herein. For purposes of the disclosure, unless designated
otherwise, solvates and hydrates are generally considered
compositions. Preferably, pharmaceutically acceptable carriers are
sterile. The pharmaceutical composition can be formulated for
particular routes of administration such as oral administration,
parenteral administration, and rectal administration, etc. In
addition, the pharmaceutical compositions of the disclosure can be
made up in a solid form (including without limitation capsules,
tablets, pills, granules, powders or suppositories), or in a liquid
form (including without limitation solutions, suspensions or
emulsions). The pharmaceutical compositions can be subjected to
conventional pharmaceutical operations such as sterilization and/or
can contain conventional inert diluents, lubricating agents, or
buffering agents, as well as adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers and buffers.
[0120] Typically, the pharmaceutical compositions are tablets or
gelatin capsules comprising the active ingredient together with one
or more of:
[0121] a) diluents, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine;
[0122] b) lubricants, e.g., silica, talcum, stearic acid, its
magnesium or calcium salt and/or polyethyleneglycol; for tablets
also
[0123] c) binders, e.g., magnesium aluminum silicate, starch paste,
gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose
and/or polyvinylpyrrolidone; if desired
[0124] d) disintegrants, e.g., starches, agar, alginic acid or its
sodium salt, or effervescent mixtures; and
[0125] e) absorbents, colorants, flavors and sweeteners.
[0126] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0127] Suitable compositions for oral administration include an
effective amount of a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof in the form of tablets, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs. Compositions intended for oral
use are prepared according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions
can contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with nontoxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
are, for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets are uncoated or coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent,
for example, calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules wherein the active ingredient is mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
[0128] Certain injectable compositions are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
[0129] Suitable compositions for transdermal application include an
effective amount of a compound of the invention with a suitable
carrier. Carriers suitable for transdermal delivery include
absorbable pharmacologically acceptable solvents to assist passage
through the skin of the host. For example, transdermal devices are
in the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin through the
host at a controlled and predetermined rate over a prolonged period
of time, and means to secure the device to the skin.
[0130] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0131] As used herein a topical application may also pertain to an
inhalation or to an intranasal application. They may be
conveniently delivered in the form of a dry powder (either alone,
as a mixture, for example a dry blend with lactose, or a mixed
component particle, for example with phospholipids) from a dry
powder inhaler or an aerosol spray presentation from a pressurized
container, pump, spray, atomizer or nebulizer, with or without the
use of a suitable propellant. Dosage forms for the topical or
transdermal administration of a compound of this invention include
powders, sprays, ointments, pastes, creams, lotions, gels,
solutions, patches and inhalants. The active compound may be mixed
under sterile conditions with a pharmaceutically acceptable
carrier, and with any preservatives, buffers, or propellants that
may be desirable.
[0132] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0133] Powders and sprays can contain, in addition to a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof, excipients such as
lactose, talc, silicic acid, aluminum hydroxide, calcium silicates
and polyamide powder, or mixtures of these substances. Sprays can
additionally contain customary propellants, such as
chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,
such as butane and propane.
[0134] Transdermal patches have the added advantage of providing
controlled delivery of a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof to the body. Such dosage forms can be made by
dissolving or dispersing the compound in the proper medium.
Absorption enhancers can also be used to increase the flux of the
compound across the skin. The rate of such flux can be controlled
by either providing a rate controlling membrane or dispersing the
active compound in a polymer matrix or gel.
[0135] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0136] The compound of Formula (I), (II), compound (A), compound
(B), or compound (C) in free form or in pharmaceutically acceptable
salt form, exhibit valuable pharmacological properties, e.g. BMP
potentiating properties, e.g. as indicated in vitro and in vivo
tests as provided in the next sections, and are therefore indicated
for therapy or for use as research chemicals, e.g. as tool
compounds.
Methods of Use
[0137] A compound of Formula (I), (II), compound (A), compound (B),
or compound (C) or a pharmaceutically acceptable salt thereof may
be useful in the treatment of the diseases and disorders described
herein. In an embodiment, the disease or disorder is associated
with deficient BMP signalling and may be treated by potentiation of
BMP. In an embodiment, the disorder is renal disease. In an
embodiment, the renal disease is selected from the group consisting
of diabetic nephropathy; AKI (acute kidney injury); and proteinuric
diseases. In an embodiment, the disorder is selected from the group
consisting of PAH (pulmonary arterial hypertension); HHT
(hereditary hemorrhagic telangiectasia); iron overload anemia;
fracture healing; macular degeneration (e.g., AMD (age-related
macular degeneration)); glaucoma; dry eye; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; wound
healing; fibrosis (e.g., lung, liver and kidney); skeletal muscle
neurogenic atrophy; Alagille syndrome; and biliary atresia.
[0138] In an embodiment, the disclosure provides a method of
treatment comprising a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof. In an embodiment, the therapy is selected from a disease
which may be treated by potentiation of BMP signaling. In an
embodiment, the disorder is renal disease. In an embodiment, the
renal disease is selected from the group consisting of diabetic
nephropathy; AKI (acute kidney injury); and proteinuric diseases.
In an embodiment, the disorder is selected from the group
consisting of PAH (pulmonary arterial hypertension); HHT
(hereditary hemorrhagic telangiectasia); iron overload anemia;
fracture healing; macular degeneration (e.g., AMD (age-related
macular degeneration)); glaucoma; dry eye; colitis; IBD
(inflammatory bowel disease); juvenile polyposis syndrome; wound
healing; fibrosis (e.g., lung, liver and kidney); skeletal muscle
neurogenic atrophy; Alagille syndrome; and biliary atresia.
[0139] In an embodiment, the disease is HHT (hereditary hemorrhagic
telangiectasia).
[0140] In an embodiment, the disease is pulmonary arterial
hypertension (PAH).
[0141] In an embodiment, the disease is proteinuric kidney disease
or acute kidney injury (AKI).
[0142] In an embodiment, the disease is iron overload anemia.
[0143] In an embodiment, the disease is fracture healing.
[0144] In an embodiment, the disease is glaucoma.
[0145] In an embodiment, the disease is dry eye.
[0146] In an embodiment, the disease is juvenile polyposis
syndrome.
[0147] In an embodiment, the disease is skeletal muscle neurogenic
atrophy.
[0148] In an embodiment, the disease is lung, liver or kidney
fibrosis.
[0149] In an embodiment, the disease is Alagille syndrome.
[0150] In an embodiment, the disease is Biliary Atresia.
[0151] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
Hemorrhagic Telangiectasia (HET).
[0152] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
pulmonary arterial hypertension (PAH).
[0153] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
proteinuric kidney disease and acute kidney injury.
[0154] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
iron overload anemia.
[0155] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
fracture healing.
[0156] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
glaucoma.
[0157] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably dry
eye.
[0158] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
juvenile polyposis syndrome.
[0159] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP. In another embodiment, the disease
is selected from the afore-mentioned list, suitably skeletal muscle
neurogenic atrophy.
[0160] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP signaling. In another embodiment,
the disease is selected from the afore-mentioned list, suitably
lung, liver and kidney fibrosis.
[0161] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP. In another embodiment, the disease
is selected from the afore-mentioned list, suitably Alagille
syndrome.
[0162] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof in therapy. In a further
embodiment, the therapy is selected from a disease which may be
treated by potentiation of BMP. In another embodiment, the disease
is selected from the afore-mentioned list, suitably Biliary
Atresia.
[0163] Further, the disclosure provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof for the manufacture of a
medicament. In a further embodiment, the medicament is for
treatment of a disease which may be treated by potentiation of BMP
signaling. In another embodiment, the disease is selected from the
afore-mentioned list, suitably Hemorrhagic Telangiectasia
(HET).
[0164] The pharmaceutical composition or combination of the
disclosure can be in unit dosage of about 1-1000 mg of active
ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or
about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50
mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0165] The above-cited dosage properties are demonstrable in in
vitro and in vivo tests using advantageously mammals, e.g., mice,
rats, dogs, monkeys or isolated organs, tissues and preparations
thereof. The compounds of the present invention can be applied in
vitro in the form of solutions, e.g., aqueous solutions, and in
vivo either enterally, parenterally, advantageously intravenously,
e.g., as a suspension or in aqueous solution. The dosage in vitro
may range between about 10.sup.-3 molar and 10.sup.-9 molar
concentrations. A therapeutically effective amount in vivo may
range depending on the route of administration, between about
0.1-500 mg/kg, or between about 1-100 mg/kg.
[0166] The activity of a compound according to the disclosure can
be assessed by the following methods.
[0167] The compound of Formula (I), (II), compound (A), compound
(B), or compound (C) or a pharmaceutically acceptable salt thereof
may be administered either simultaneously with, or before or after,
one or more other therapeutic agent. The compound of Formula (I),
(II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof may be administered
separately, by the same or different route of administration, or
together in the same pharmaceutical composition as the other
agents. A therapeutic agent is, for example, a chemical compound,
peptide, antibody, antibody fragment or nucleic acid, which is
therapeutically active or enhances the therapeutic activity when
administered to a patient in combination with a compound of the
invention.
[0168] In one embodiment, the disclosure provides a product
comprising a compound of Formula (I), (II), compound (A), compound
(B), or compound (C) or a pharmaceutically acceptable salt thereof
and at least one other therapeutic agent as a combined preparation
for simultaneous, separate or sequential use in therapy. In one
embodiment, the therapy is the treatment of a disease or condition
mediated by BMP signaling. Products provided as a combined
preparation include a composition comprising the compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and the other therapeutic
agent(s) together in the same pharmaceutical composition, or the
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and the
other therapeutic agent(s) in separate form, e.g. in the form of a
kit.
[0169] In one embodiment, the disclosure provides a pharmaceutical
composition comprising a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof and another therapeutic agent(s). Optionally, the
pharmaceutical composition may comprise a pharmaceutically
acceptable carrier, as described above.
[0170] In one embodiment, the disclosure provides a kit comprising
two or more separate pharmaceutical compositions, at least one of
which contains a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof. In one embodiment, the kit comprises means for separately
retaining said compositions, such as a container, divided bottle,
or divided foil packet. An example of such a kit is a blister pack,
as typically used for the packaging of tablets, capsules and the
like.
[0171] The kit of the disclosure may be used for administering
different dosage forms, for example, oral and parenteral, for
administering the separate compositions at different dosage
intervals, or for titrating the separate compositions against one
another. To assist compliance, the kit of the disclosure typically
comprises directions for administration.
[0172] In the combination therapies of the disclosure, the compound
of Formula (I), (II), compound (A), compound (B), or compound (C)
or a pharmaceutically acceptable salt thereof and the other
therapeutic agent may be manufactured and/or formulated by the same
or different manufacturers. Moreover, the compound of Formula (I),
(II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof and the other therapeutic
may be brought together into a combination therapy: (i) prior to
release of the combination product to physicians (e.g. in the case
of a kit comprising the compound of the invention and the other
therapeutic agent); (ii) by the physician themselves (or under the
guidance of the physician) shortly before administration; (iii) in
the patient themselves, e.g. during sequential administration of
the compound of the invention and the other therapeutic agent.
[0173] Accordingly, the invention provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof for treating a disease or
condition mediated by BMP, wherein the medicament is prepared for
administration with another therapeutic agent. The disclosure also
provides the use of another therapeutic agent for treating a
disease or condition mediated by BMP, wherein the medicament is
administered with a compound of Formula (I), (II), compound (A),
compound (B), or compound (C) or a pharmaceutically acceptable salt
thereof.
[0174] The disclosure also provides a compound of Formula (I),
(II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof for use in a method of
treating a disease or condition mediated by BMP, wherein the
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof is
prepared for administration with another therapeutic agent. The
disclosure also provides another therapeutic agent for use in a
method of treating a disease or condition mediated by BMP, wherein
the other therapeutic agent is prepared for administration with a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof. The
disclosure also provides a compound of Formula (I), (II), compound
(A), compound (B), or compound (C) or a pharmaceutically acceptable
salt thereof for use in a method of treating a disease or condition
mediated by BMP, wherein the compound of Formula (I), (II),
compound (A), compound (B), or compound (C) or a pharmaceutically
acceptable salt thereof is administered with another therapeutic
agent. The disclosure also provides another therapeutic agent for
use in a method of treating a disease or condition mediated by BMP,
wherein the other therapeutic agent is administered with a compound
of Formula (I), (II), compound (A), compound (B), or compound (C)
or a pharmaceutically acceptable salt thereof.
[0175] The disclosure also provides the use of a compound of
Formula (I), (II), compound (A), compound (B), or compound (C) or a
pharmaceutically acceptable salt thereof for treating a disease or
condition mediated by BMP, wherein the patient has previously (e.g.
within 24 hours) been treated with another therapeutic agent. The
disclosure also provides the use of another therapeutic agent for
treating a disease or condition mediated by BMP, wherein the
patient has previously (e.g. within 24 hours) been treated with a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof.
[0176] In one embodiment, the other therapeutic agent is selected
from: an anti-VEGF antibody, e.g. Bevacizumab, a soy protein
isolate, an antifibrionic, e.g. tranexamic acid, a CRBN modulator,
e.g. thalidomide, bFGF induced antiangiogenic, VEGF induced
antiangiogenic, a somastatin mimic, e.g. ocreotide, a GHIH mimic,
an estrogen receptor antagonist, e.g. tamoxifen and
pomalidomide.
[0177] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and an
anti-VEGF antibody as a combined preparation for simultaneous,
separate or sequential use in therapy.
[0178] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
soy protein isolate as a combined preparation for simultaneous,
separate or sequential use in therapy.
[0179] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and an
antifibrionic as a combined preparation for simultaneous, separate
or sequential use in therapy.
[0180] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
CRBN modulator as a combined preparation for simultaneous, separate
or sequential use in therapy.
[0181] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
bFGF induced antiangiogenic as a combined preparation for
simultaneous, separate or sequential use in therapy.
[0182] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
VEGF induced antiangiogenic as a combined preparation for
simultaneous, separate or sequential use in therapy.
[0183] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
somastatin mimic as a combined preparation for simultaneous,
separate or sequential use in therapy.
[0184] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and a
GHIH mimic as a combined preparation for simultaneous, separate or
sequential use in therapy.
[0185] In one embodiment, there is provided a product comprising a
compound of Formula (I), (II), compound (A), compound (B), or
compound (C) or a pharmaceutically acceptable salt thereof and an
estrogen receptor antagonist as a combined preparation for
simultaneous, separate or sequential use in therapy.
EXAMPLES
[0186] The following examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees Celsius. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g., microanalysis
and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations
used are those conventional in the art.
[0187] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesis the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art. Further, the
compounds of the present invention can be produced by organic
synthesis methods known to one of ordinary skill in the art as
shown in the following examples.
Analytical Conditions
[0188] HRMS column: Experimental: LC-UV/ESI-MS data was recorded on
an Acquity G2 Xevo QTof-Rs(FWHM)>20000 Eluent A: Water+0.1%
Formic Acid Eluent B: Acetonitrile+0.1% Formic Acid
[0189] Macrocycle column: Waters BEH C18 2.1.times.50 mm 1.7 um 60
C: Conditions: 20-90% Acetonitrile:Methanol:Water (80:15:5) in 10
mM Ammonium formate with 0.1% Formic Acid 1 mL/min
List of Abbreviations
[0190] HGII=Hoveyda Grubbs 2.sup.nd Generation catalyst
[0191] DCE=1,2-Dichloroethane
[0192] MeOH=methanol
[0193] r.t.=room temperature
##STR00012##
(also known as FK-506 or fujimycin, trade names Prograf.RTM.,
Advagraf.RTM., Protopic.RTM.) is an immunosuppressive drug used
mainly after allogeneic organ transplant to lower the risk of organ
rejection. It achieves this by inhibiting the production of
interleukin-2, a molecule that promotes the development and
proliferation of T cells, which are vital to the body's learned (or
adaptive) immune response. Chemically it is a 23 membered macrolide
lactone that was first discovered in 1987 from the fermentation
broth of a Japanese soil sample that contained the bacterium
Streptomyces tsukatbaensis.
Example 1. Synthesis of Compound A
##STR00013##
[0195] To a solution of FK506 (50 mg, 0.062 mmol) in DCE (Volume:
622 .mu.l) in a 5 mL microwave vial was added HGII (3.90 mg, 6.22
.mu.mol) and vinyloxetan-3-ol (125 mg, 1.244 mmol). The solution
was stirred for 30 seconds and then irradiated at 150.degree. C.
for 5 minutes in a microwave, over which time the reaction turned
amber in color.
[0196] The reaction mixture was filtered and rinsed with MeOH. The
crude reaction was concentrated under reduced pressure and
resuspended in a minimal amount of MeOH. The reaction was purified
by SFC (SFC Instrument: Thar 80, Column: Princeton 2-EP
20.times.150 mm 5 .mu.m, Flow Rate: 80 g/min, Cosolvent: 12%
Methanol, Detection: 205 nm, BPR set point:125 bar (Oven 40.degree.
C.)) to afford the target compound as a cream colored solid (21 mg,
39% yield). .sup.1NMR (400 MHz, CDCl.sub.3), Diagnostic analysis
shows the disappearance of terminal olefinic peaks between 6 and 7
ppm. .sup.13C NMR shows the addition of peaks between 40-80 ppm,
corresponding to an aliphatic carbon addition. .sup.13C NMR (major
isomer in MeOD) .delta.: 10.78, 13.36, 15.96, 16.52, 20.21, 22.14,
25.37, 27.25, 28.16, 28.91, 31.83, 33.55, 35.17, 35.90, 36.17,
36.79, 40.25, 41.67, 45.54, 46.50, 47.71, 53.79, 54.47, 56.18,
56.68, 57.39, 55.70, 57.90, 70.32, 73.86, 74.63, 75.12, 76.93,
81.38, 85.21, 85.25, 99.06, 124.20, 128.51, 133.05, 133.86, 134.32,
140.23, 167.51, 170.65, 198.47, 212.39. HRMS Calcd. for
C.sub.47H.sub.74NO.sub.14 (M+H) 876.5109, found 876.5105.
Example 2. Synthesis of Compound B
##STR00014##
[0198] To a 0.03 M solution of Ascomycin (1 eq.) in anhydrous DCM,
at 0.degree. C., was added mCPBA (77% moist powder, 1.2 eq.). The
reaction mixture was stirred at 0.degree. C. for 1.5 h, then at
r.t. overnight. The reaction mixture was quenched with sat.
Na.sub.2SO.sub.3 aqueous solution and diluted with EtOAc. The
organic layer was washed with sat. NaHCO.sub.3 aqueous solution and
brine. Then the organic layer was concentrated, and the residue was
purified by silica gel chromatography, eluting with Heptane/EtOAc
(40/60 to 20/80). The collected fractions were purified a second
time by reverse phase silica gel chromatography (0.1% NH.sub.4OH in
Water/Acetonitrile, gradient 30-80% of Acetonitrile).
[0199] The collected fractions were lyophilized. The dried solid
was purified with SFC to provide compound B with >98% purity and
7-8% yield. (SFC Instrument: Thar 80, Column: Kinetex Biphenyl
30.times.150 mm 5 um, Flow Rate: 80 g/min, Cosolvent: 12% Methanol,
Detection: 205 nm, BPR set point: 125 bar (Oven 40.degree. C.)).
.sup.13C NMR (major isomer in d.sub.6-DMSO) .delta.: 10.32, 11.29,
11.54, 15.60, 15.65, 18.31, 19.76, 23.57, 23.73, 24.76, 27.75,
30.31, 31.55, 32.37, 33.79, 34.73, 35.81, 35.97, 37.99, 39.69,
46.51, 50.54, 52.63, 54.87, 55.61, 56.46, 57.05, 60.02, 62.58,
66.58, 71.24, 72.32, 72.56, 74.37, 82.94, 83.07, 97.88, 129.88,
135.17, 165.64, 168.62, 197.48, 212.43. HRMS Calcd. for
C.sub.43H.sub.69NO.sub.13 807.4769, found 807.4769.
Example 3. Synthesis of Compound C
##STR00015##
[0201] To 0.03 M solution of Ascomycin (1 eq.) in anhydrous DCM, at
0.degree. C., was added mCPBA (77% moist powder, 1.2 eq.). The
reaction mixture was stirred at 0.degree. C. for 1.5 h, then at
r.t. overnight. The reaction mixture was quenched with saturated
Na.sub.2SO.sub.3 aqueous solution and diluted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 aqueous
solution and brine. Then the organic layer was concentrated, the
residue was purified by silica gel chromatography, eluting with
Heptane/EtOAc (40/60 to 20/80). The first collected fractions were
purified with HPLC (40-70% ACN:MeOH:Water (80:15:5) in 10 mM
Ammonium formate with 0.04% Formic acid). The fractions were
lyophilized to provide compound C. HRMS Calcd. for
C.sub.43H.sub.69NO.sub.13 807.48, found 807.48. HRMS retention
time: 2.96 min. Compound B HRMS retention time: 2.75 min.
[0202] The activity of a compound according to the present
invention can be assessed by the following methods.
Example 4. BMP Activity
Reporter Cell Lines
[0203] C2C12-IDBRE-luciferase reporter line was established by
infecting C2C12 cells with lentiviruses with IDBRE-luciferase
pLenti6 plasmid with Blasticidin resistance.
Reporter Assays
[0204] C2C12-IDBRE-luciferase cells were plated to 384-well plate
at 5000 cells in 36 .mu.l DMEM plus 10% FBS at day 0. Cells were
treated with different doses of compounds at day 1. Bright-Glo.TM.
Luciferase Assay (Promega, catalog #E2650) was performed with
EnVision plate reader (PerkinElmer) 24 hours after treatment at day
2. 0% activity is equal to DMSO control. 100% activity means
Luminescence reading for a compound is 200% of luminescence reading
of DMSO control. The formula to calculate the activity is:
[0205]
100*(Luminescence_compound-Luminescence_DMSO)/Luminescence_DMSO
TABLE-US-00001 Qualified absolute Structure Name Chemical Structure
AC50 (.mu.M) FK-506 ##STR00016## 0.024 Compound C ##STR00017##
0.201 Compound B ##STR00018## 0.024 Compound A ##STR00019##
0.091
Example 5. Calcineurin Inhibition
Reporter Cell Lines
[0206] NFAT-luciferase reporter line was established by
transfecting NFAT-luciferase/pTranslucent (Panomics #LR0050) and
Puromycin-resistance plasmid together into 293T cells.
Reporter Assays
[0207] 293T-NFAT-luciferase cells were plated to 384-well plate at
10000 cells in 32 .mu.l DMEM plus 10% FBS at day 0. Cells were
treated with different doses of compounds at day 1. Half an hour
after compound treatment, 293T-NFAT-luciferase cells were
co-treated with 100 ng/ml PMA (PHORBOL 12-MYRISTATE 13-ACETAT,
Sigma, catalog #P8139-1MG) and 1 .mu.M Ionomycin (Sigma, catalog
#10634-1MG). Bright-Glo.TM. Luciferase Assay (Promega, catalog
#E2650) was performed with EnVision plate reader (PerkinElmer) 24
hours after treatment at day 2.
TABLE-US-00002 Structure Name NFAT-luc IC50 (nM) FK-506 0.05
Compound C 33 Compound B >50,000 Compound A >50,000
[0208] Having thus described several aspects of several
embodiments, it is to be appreciated various alterations,
modifications, and improvements will readily occur to those skilled
in the art. Such alterations, modifications, and improvements are
intended to be part of this disclosure, and are intended to be
within the spirit and scope of the invention. Accordingly, the
foregoing description and drawings are by way of example only.
* * * * *