COMPOUNDS, COMPOSITIONS AND METHODS COMPRISING
PYRIDAZINE SULFONAMIDE DERIVATIVES
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional
Serial No. 61/326,179, filed April 20, 2010, the contents of which is incorporated by
reference in its entirety into the current disclosure.
FIELD OF THE INVENTION
[0002] This application and invention disclose pyridazine sulfonamide-containing
compounds that inhibit the transport of ions (e.g., chloride ions) across cell membranes
containing chloride channels such as, calcium activated chloride channel (CaCC) and/or
volume regulated anion channel (or volume regulated anion conductance or swellingactivated
chloride conductance or volume activated chloride channel, VRAC). The structures
of the compounds and derivatives thereof, as well as pharmaceutical formulations and
methods of use are described in more detail below.
BACKGROUND
[0003] Ion channels are not only essential for normal cellular functions but also play a critical
role in numerous diseased states. For example, cystic fibrosis results when ion transport in
epithelial cells of individuals is altered due to a genetic defect of the cystic fibrosis
transmembrane conductance regulator (CFTR; Knowles et al, (1983) J. Clin. Invest.
71:1410-1417). Although serious airway pathology may usually be the primary cause of
mortality in young adults with CF, intestinal epithelial alterations may also be observed. The
severity of tissue lesions may not correlate exclusively with the expression of CFTR in
humans or mice, suggesting the involvement of cell-specific channels in addition to CFTR.
Further support for the involvement of other channel protein molecules in CF comes from
observations that airway CaCCs are found to be up-regulated in cystic fibrosis, providing an
alternative chloride conductance to compensate for missing or defective CFTR.
[0004] Calcium-activated chloride channels (CaCCs) are an addition to the family of chloride
conductance proteins. CaCCs possess multifunctional capability and have been shown not
only to be anion channels but also to mediate cell adhesion (Abdel-Ghany et al. (2001) J. Biol
Chem 276:25438-25446). In particular, the human isoform, hCLCA2, when expressed in the
lung, is believed to play a role in modulating the severity of cystic fibrosis (Gruber et al.
(1999) Am J Physiol Cell Physiol 276:0261-1270). It is also a key molecule in the adhesion
of tumor cells to lung endothelia (Abdel-Ghany et al. 2001, supra) and in the tumorigenicity
of human breast cancer (Gruber and Pauli, (1999) Cancer Res 59:5488-5491).
[0005] CaCCs regulate sensory transduction, epithelial secretion, neuronal excitability,
smooth muscle contraction and vascular tone (Hartzell et al. (2005) Annu. Rev. Physiol.
67:719-58). CaCCs have been implicated in a wide range of important physiological
functions including the high-gain, low-noise amplification in olfactory transduction, taste
adaptation, control of action potential waveform in neurons, membrane potential stabilization
in photoreceptors, modulation of fluid secretion from glands and airway epithelia, and
positive feedback regulation of smooth muscle contraction induced by G protein-coupled
receptors (GPCRs). Notwithstanding the multitude of CaCC types reported, CaCCs are
found in many different cell types including Xenopus oocytes, secretory epithelial cells,
hepatocytes, pulmonary artery endothelial cells, and vascular, airway and gut smooth
muscles.
[0006] Volume-regulated anion channels (VRAC) are ubiquitous ion channels that are
typically nonconducting, but may be opened upon cell swelling. An increase in a cell volume
activates, in most mammalian cells, a CI current. Activation of ion channels may be the
primary event during the regulatory volume decrease (RVD) that occurs upon a sudden
increase in cell volume. Currents carried by these channels play a role in the mechanism of
cell volume regulation such that the outward flow of CI results in the subsequent
depolarization and activation of K+ channels resulting in water efflux which ultimately allows
the cell to recover its volume following exposure to a hypotonic challenge. Coactivation of
K+ and CI channels shift the resting potential of the cell to a value intermediate between the
equilibrium potential of these ions and thereby, allow a net efflux of KC1. VRAC are present
in diverse tissues, from neuronal and muscle cells to non-excitable cells, such as, epithelial
cells, osteoclasts, glia cells and endothelium. See Nilius et al. (1996) Gen. Pharmac.
27(7):1 131-1 140.
[0007] Despite the fact that CaCC and VRAC are so broadly expressed in cells and play such
important functions, understanding these channels has been limited by the absence of specific
blockers. Thus, a need exists for methods that block the ion transport through the chloride
channels and are useful for the treatment of diseases responsive to such blockage.
SUMMARY OF THE INVENTION
[0008] This invention is directed to one or more of compounds, compositions and methods
which are useful in treating diseases that are responsive to the blocking of a chloride channel.
In some embodiments, the chloride channel is calcium activated chloride channel (CaCC)
and/or volume regulated anion channel (or volume regulated anion conductance or swellingactivated
chloride conductance or volume activated chloride channel, VRAC). Also provided
are methods for inhibiting or blocking a transport of halide ion across these chloride
channels.
[0009] In one aspect, this invention provides a method of treating a disease in an animal,
which disease is responsive to blocking of a chloride channel, comprising or alternatively
consisting essentially of, or alternatively consisting of, administering to an animal in need
thereof an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0010] In another aspect, this invention provides a method for blocking a transport of a halide
ion across a calcium activated chloride channel (CaCC), comprising or alternatively
consisting essentially of, or alternatively consisting of, contacting the CaCC with an effective
amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0011] In another aspect, this invention provides a method for blocking a transport of an ion
across a volume regulated anion channel (VRAC), comprising contacting the VRAC with an
effective amount of a compound of formula I :
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0012] In another aspect, this invention provides an in vitro method for blocking a transport
of a halide ion across a calcium activated chloride channel (CaCC), comprising contacting the
CaCC with an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0013] In another aspect, this invention provides an in vitro method for blocking a transport
of an ion across a volume regulated anion channel (VRAC), comprising contacting the
VRAC with an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0014] Specific aspects of the methods described above comprise use of one or more of the
compounds set forth in Tables 1-3 or encompassed by formulas I-III, or compositions
comprising these compounds.
BRIEF DESCRIPTION OF THE FIGURES
[0015] Figure 1 demonstrates that compound 2 blocks CaCC and that the block is voltage
dependent.
[0016] Figure 2 demonstrates that compound 2 blocks VRAC significantly and that the block
is voltage dependent.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The invention provides methods of using pyridazine sulfonamide-containing
compounds to inhibit or block one or more of chloride channels such as, CaCC or VRAC.
The compounds and derivatives thereof, as well as compositions, pharmaceutical
formulations, and methods of use, are further provided by the invention.
[0018] Throughout this application, the various embodiments are only exemplary and should
not be construed as descriptions of alternative species. Rather it should be noted that the
descriptions of various embodiments provided herein may be of overlapping scope. The
embodiments discussed herein are merely illustrative and are not meant to limit the scope of
the present invention.
[0019] Also throughout this disclosure, various publications, patents and published patent
specifications are referenced by an identifying citation. The disclosures of these publications,
patents and published patent specifications are hereby incorporated by reference into the
present disclosure in their entirety to more fully describe the state of the art to which this
invention pertains .
A. Definitions
[0020] The practice of the present invention will employ, unless otherwise indicated,
conventional techniques of organic chemistry, pharmacology, immunology, molecular
biology, microbiology, cell biology and recombinant DNA, which are within the skill of the
art. See, e.g., Sambrook, Fritsch and Maniatis, MOLECULAR CLONING: A
LABORATORY MANUAL, 2nd edition (1989); CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY (F. M. Ausubel, et al. eds., (1987)); the series METHODS IN
ENZYMOLOGY (Academic Press, Inc.): PCR 2 : A PRACTICAL APPROACH (M.J.
MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988)
ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R.I.
Freshney, ed. (1987)).
[0021] As used in the specification and claims, the singular form "a," "an" and "the" includes
plural references unless the context clearly dictates otherwise. For example, the term "a cell"
includes a plurality of cells, including mixtures thereof.
[0022] "Animal" of diagnosis or treatment refers to an animal such as a mammal, or a
human, ovine, bovine, feline etc. Non-human animals subject to diagnosis or treatment
include, for example, simians, murine, such as, rat, mice, canine, leporid, livestock, sport
animals, and pets.
[0023] The term "blocking" refers to a decrease or an inhibition of the activity of the
chloride channel by at least about 10%, or alternatively at least about 20%, or alternatively at
least about 25%, or alternatively at least about 30%, or alternatively at least about 35%, or
alternatively at least about 40%, or alternatively at least about 45%, or alternatively at least
about 50%, or alternatively at least about 55%, or alternatively at least about 60%, or
alternatively at least about 65%, or alternatively at least about 70%, or alternatively at least
about 80%, or alternatively at least about 90%, or alternatively at least about 99%, or
alternatively at least about 100%, compared to the activity of the chloride channel in the
absence of the compounds, described herein.
[0024] The term "chloride channel" refers to channels that regulate the flow of ions across
the membrane in all cells. The "ions" are as described herein.
[0025] The term "calcium activated chloride channel" refers to the chloride channel whose
conductance is activated by calcium. In some embodiments, for the in vitro methods provided
herein the chloride channel is activated with calcium prior to contact with the compound.
[0026] The term "volume regulated anion channel" refers to ubiquitous ion channels that
open upon cell swelling. They may also be called volume sensitive anion channel or volume
regulated anion conductance or swelling activated chloride conductance or volume activated
chloride channel, etc.
[0027] As used herein, the term "comprising" is intended to mean that the compositions and
methods include the recited elements, but not excluding others. "Consisting essentially of
when used to define compositions and methods, shall mean excluding other elements of any
essential significance to the combination. Thus, a composition consisting essentially of the
elements as defined herein would not exclude trace contaminants from the isolation and
purification method and pharmaceutically acceptable carriers, such as phosphate buffered
saline, preservatives, and the like. "Consisting of shall mean excluding more than trace
elements of other ingredients. Embodiments defined by each of these transition terms are
within the scope of this invention.
[0028] All numerical designations, e.g., pH, temperature, time, concentration, and molecular
weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of
0.1. It is to be understood, although not always explicitly stated that all numerical
designations are preceded by the term "about." It also is to be understood, although not
always explicitly stated, that the reagents described herein are merely exemplary and that
equivalents of such are known in the art.
[0029] The terms "polypeptide" and "protein" are synonymously used in their broadest sense
to refer to a compound of two or more subunit amino acids, amino acid analogs, or
peptidomimetics. The subunits may be linked by peptide bonds. In another embodiment, the
subunit may be linked by other bonds, e.g., ester, ether, etc. As used herein the term "amino
acid" refers to either natural and/or unnatural or synthetic amino acids, including glycine and
both the D or L optical isomers, and amino acid analogs and peptidomimetics. A peptide of
three or more amino acids is commonly called an oligopeptide if the peptide chain is short. If
the peptide chain is long, the peptide is commonly called a polypeptide or a protein.
[0030] "Hybridization" refers to a reaction in which one or more polynucleotides react to
form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide
residues. The hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein
binding, or in any other sequence-specific manner. The complex may comprise two strands
forming a duplex structure, three or more strands forming a multi-stranded complex, a single
self-hybridizing strand, or any combination of these. A hybridization reaction may constitute
a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic
cleavage of a polynucleotide by a ribozyme.
[0031] Hybridization reactions can be performed under conditions of different "stringency."
In general, a low stringency hybridization reaction is carried out at about 40 °C in 10 x SSC
or a solution of equivalent ionic strength/temperature. A moderate stringency hybridization
is typically performed at about 50 °C in 6 x SSC, and a high stringency hybridization reaction
is generally performed at about 60 °C in 1 x SSC.
[0032] When hybridization occurs in an antiparallel configuration between two
single-stranded polynucleotides, the reaction is called "annealing" and those polynucleotides
are described as "complementary." A double-stranded polynucleotide can be
"complementary" or "homologous" to another polynucleotide, if hybridization can occur
between one of the strands of the first polynucleotide and the second. "Complementarity" or
"homology" (the degree that one polynucleotide is complementary with another) is
quantifiable in terms of the proportion of bases in opposing strands that are expected to form
hydrogen bonding with each other, according to generally accepted base-pairing rules.
[0033] A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region)
has a certain percentage (for example, 80%, 85%, 90%, or 95%) of "sequence identity" to
another sequence when aligned, that percentage of bases (or amino acids) are the same in
comparing the two sequences. This alignment and the percent homology or sequence identity
can be determined using software programs known in the art, for example those described in
CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F.M. Ausubel et al., eds., 1987) Supplement
30, section 7.7.18, Table 7.7.1. Preferably, default parameters are used for alignment. A
preferred alignment program is BLAST, using default parameters. In particular, preferred
programs are BLASTN and BLASTP, using the following default parameters: Genetic code =
standard; filter = none; strand = both; cutoff = 60; expect = 10; Matrix = BLOSUM62;
Descriptions = 50 sequences; sort by = HIGH SCORE; Databases = non-redundant, GenBank
+ EMBL + DDBJ + PDB + GenBank CDS translations + SwissProtein + SPupdate + PIR.
Details of these programs can be found at the following Internet address:
http://www.ncbi.nlm.nih.gov/cgi-bin/BLAST.
[0034] A variety of sequence alignment software programs are available in the art.
Non-limiting examples of these programs are BLAST family programs including BLASTN,
BLASTP, BLASTX, TBLASTN, and TBLASTX (BLAST is available from the worldwide
web at ncbi.nlm.nih.gov/BLAST/), FastA, Compare, DotPlot, BestFit, GAP, FrameAlign,
ClustalW, and Pileup. These programs are obtained commercially available in a
comprehensive package of sequence analysis software such as GCG Inc.'s Wisconsin
Package. Other similar analysis and alignment programs can be purchased from various
providers such as DNA Star's MegAlign, or the alignment programs in GeneJockey.
Alternatively, sequence analysis and alignment programs can be accessed through the world
wide web at sites such as the CMS Molecular Biology Resource at
sdsc.edu/ResTools/cmshp.html. Any sequence database that contains DNA or
protein sequences corresponding to a gene or a segment thereof can be used for sequence
analysis. Commonly employed databases include but are not limited to GenBank, EMBL,
DDBJ, PDB, SWISS-PROT, EST, STS, GSS, and HTGS.
[0035] Parameters for determining the extent of homology set forth by one or more of the
aforementioned alignment programs are known. They include but are not limited to p value,
percent sequence identity and the percent sequence similarity. P value is the probability that
the alignment is produced by chance. For a single alignment, the p value can be calculated
according to Karlin et al. (1990) PNAS 87:2246. For multiple alignments, the p value can be
calculated using a heuristic approach such as the one programmed in BLAST. Percent
sequence identify is defined by the ratio of the number of nucleotide or amino acid matches
between the query sequence and the known sequence when the two are optimally aligned.
The percent sequence similarity is calculated in the same way as percent identity except one
scores amino acids that are different but similar as positive when calculating the percent
similarity. Thus, conservative changes that occur frequently without altering function, such
as a change from one basic amino acid to another or a change from one hydrophobic amino
acid to another are scored as if they were identical.
[0036] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to
10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example,
linear and branched hydrocarbyl groups such as methyl (CH -), ethyl (CH CH2-), n-propyl
(CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl
((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl
(CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[0037] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6
carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1
to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by
vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or
mixtures of these isomers.
[0038] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from
2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably
from 1 to 2 sites of acetylenic (-Cº C-) unsaturation. Examples of such alkynyl groups
include acetylenyl (-Cº CH), and propargyl (-CH2Cº CH).
[0039] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or
more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted
sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein
said substituents are as defined herein.
[0040] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and
preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted
sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein
said substituents are as defined herein and with the proviso that any hydroxyl or thiol
substitution is not attached to a vinyl (unsaturated) carbon atom.
[0041] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and
preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted
sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein
said substituents are as defined herein and with the proviso that any hydroxyl or thiol
substitution is not attached to an acetylenic carbon atom.
[0042] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy
includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
sec-butoxy, and n-pentoxy.
[0043] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted
alkyl is defined herein.
[0044] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-,
alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-,
cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted
cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted
heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
herein. Acyl includes the "acetyl" group CH3C(0)-.
[0045] "Acylamino" refers to the groups -NR4 C(0)alkyl, -NR4 C(0)substituted alkyl,
-NR4 C(0)cycloalkyl, -NR4 C(0)substituted cycloalkyl, -NR4 C(0)cycloalkenyl,
-NR C(0)substituted cycloalkenyl, -NR C(0)alkenyl, -NR C(0)substituted alkenyl,
-NR4 C(0)alkynyl, -NR4 C(0)substituted alkynyl, -NR4 C(0)aryl, -NR4 C(0)substituted
aryl, -NR4 C(0)heteroaryl, -NR4 C(0)substituted heteroaryl, -NR4 C(0)heterocyclic, and
-NR4 C(0)substituted heterocyclic wherein R47 is hydrogen or alkyl and wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
herein.
[0046] "Acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-,
alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-,
aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-,
cycloalkenyl-C(0)0-, substituted cycloalkenyl-C(0)0-, heteroaryl-C(0)0-, substituted
heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
herein.
[0047] "Amino" refers to the group -NH2.
[0048] "Substituted amino" refers to the group -NR4 R49 where R48 and R49 are
independently selected from the group consisting of hydrogen, acyl, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, substituted heterocyclic, -S0 -alkyl, -S0 -substituted alkyl,
-S0 -alkenyl, -S0 -substituted alkenyl, -S0 -cycloalkyl, -S0 -substituted cylcoalkyl,
-S0 2-cycloalkenyl, -S0 2-substituted cylcoalkenyl,-S0 2-aryl, -S0 2-substituted aryl,
-S0 2-heteroaryl, -S0 2-substituted heteroaryl, -S0 2-heterocyclic, and -S0 2-substituted
heterocyclic and wherein R48 and R49 are optionally joined, together with the nitrogen bound
thereto to form a heterocyclic or substituted heterocyclic group, provided that R48 and R49 are
both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein. When R48 is hydrogen and R49 is alkyl, the substituted
amino group is sometimes referred to herein as alkylamino. When R48 and R49 are alkyl, the
substituted amino group is sometimes referred to herein as dialkylamino. When referring to a
monosubstituted amino, it is meant that either R48 or R49 is hydrogen but not both. When
referring to a disubstituted amino, it is meant that neither R nor R49 are hydrogen.
[0049] "Aminocarbonyl" refers to the group -C(O)NR50R5 1 where R50 and R5 1 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, substituted heterocyclic, sulfonyl, and substituted sulfonyl and
where R50 and R5 1 are optionally joined together with the nitrogen bound thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0050] "Aminothiocarbonyl" refers to the group -C(S)NR50R5 1 where R50 and R5 1 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R50 and R5 1 are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0051] "Aminocarbonylamino" refers to the group -NR4 C(O)NR50R5 1 where R4 is
hydrogen or alkyl and R50 and R5 1 are independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,
and where R50 and R5 1 are optionally joined together with the nitrogen bound thereto to form
a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0052] "Aminothiocarbonylamino" refers to the group -NR4 C(S)NR50R5 1 where R is
hydrogen or alkyl and R50 and R5 1 are independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and
where R50 and R5 1 are optionally joined together with the nitrogen bound thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0053] "Aminocarbonyloxy" refers to the group -O-C(O)NR50R5 1 where R50 and R5 1 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R50 and R5 1 are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0054] "Aminosulfonyl" refers to the group -SO2NR50R5 1 where R50 and R5 1 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R50 and R5 1 are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0055] "Aminosulfonyloxy" refers to the group -O-SO2NR50R5 1 where R50 and R5 1 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R50 and R5 1 are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0056] "Aminosulfonylamino" refers to the group -NR4 SO2NR50R5 1 where R4 is hydrogen
or alkyl and R50 and R5 1 are independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R50
and R5 1 are optionally joined together with the nitrogen bound thereto to form a heterocyclic
or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted heterocyclic are as defined herein.
[0057] "Amidino" refers to the group -C(=NR5 )NR50R5 1 where R50, R5 1, and R52 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R50 and R5 1 are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0058] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14
carbon atoms having a single ring (e.g. , phenyl) or multiple condensed rings (e.g. , naphthyl or
anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone,
2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at
an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
[0059] "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1
to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio,
substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted
sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein
said substituents are as defined herein.
[0060] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes,
by way of example, phenoxy and naphthoxy.
[0061] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl
is as defined herein.
[0062] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.
[0063] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl
is as defined herein.
[0064] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=0)-.
[0065] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.
[0066] "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl,
-C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl,
-C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl,
-C(0)0-substituted cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted cycloalkenyl,
-C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-heterocyclic, and
-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic are as defined herein.
[0067] "(Carboxyl ester)amino" refers to the group -NR4 C(0)0-alkyl,
-NR4 C(0)0-substituted alkyl, -NR4 C(0)0-alkenyl, -NR4 C(0)0-substituted alkenyl,
-NR4 C(0)0-alkynyl, -NR4 C(0)0-substituted alkynyl, -NR4 C(0)0-aryl,
-NR4 C(0)0-substituted aryl, -NR4 C(0)0-cycloalkyl, -NR4 C(0)0-substituted cycloalkyl,
-NR4 C(0)0-cycloalkenyl, -NR4 C(0)0-substituted cycloalkenyl, -NR4 C(0)0-heteroaryl,
-NR4 C(0)0-substituted heteroaryl, -NR4 C(0)0-heterocyclic, and -NR4 C(0)0-substituted
heterocyclic wherein R47 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0068] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted
alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl,
-0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl,
-0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-cycloalkenyl,
-0-C(0)0-substituted cycloalkenyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl,
-0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0069] "Cyano" refers to the group -CN.
[0070] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single
or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of
suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclooctyl.
[0071] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon
atoms having single or multiple cyclic rings and having at least one >C=C< ring unsaturation
and preferably from 1 to 2 sites of >C=C< ring unsaturation.
[0072] "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or
cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the
group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted
amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted
cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted
cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted
cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted
heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol,
alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.
[0073] "Cycloalkyloxy" refers to -O-cycloalkyl.
[0074] "Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
[0075] "Cycloalkylthio" refers to -S-cycloalkyl.
[0076] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[0077] "Cycloalkenyloxy" refers to -O-cycloalkenyl.
[0078] "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).
[0079] "Cycloalkenylthio" refers to -S-cycloalkenyl.
[0080] "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
[0081] "Guanidino" refers to the group -NHC(=NH)NH2.
[0082] "Substituted guanidino" refers to -NR5 C(=NR5 )N(R5 )2 where each R53 is
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
heterocyclic, and substituted heterocyclic and two R53 groups attached to a common
guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to
form a heterocyclic or substituted heterocyclic group, provided that at least one R53 is not
hydrogen, and wherein said substituents are as defined herein.
[0083] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
[0084] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0085] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4
heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the
ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple
condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may
not be aromatic and/or contain a heteroatom provided that the point of attachment is through
an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur
ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide
(N®0), sulfmyl, or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl,
indolyl, thiophenyl, and furanyl.
[0086] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to
5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting
of the same group of substituents defined for substituted aryl.
[0087] "Heteroaryloxy" refers to -O-heteroaryl.
[0088] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryl).
[0089] "Heteroarylthio" refers to the group -S-heteroaryl.
[0090] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).
[0091] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a
saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon
atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur,
or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including
fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be
cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic
ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are
optionally oxidized to provide for the N-oxide, sulfmyl, or sulfonyl moieties.
[0092] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted
heterocyclyl" refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably
1 to 3 of the same substituents as defined for substituted cycloalkyl.
[0093] "Heterocyclyloxy" refers to the group -O-heterocycyl.
[0094] "Substituted heterocyclyloxy" refers to the group -0-(substituted heterocycyl).
[0095] "Heterocyclylthio" refers to the group -S-heterocycyl.
[0096] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl).
[0097] Examples of heterocycle and heteroaryls include, but are not limited to, azetidine,
pyrrole, imidazole, oxadiazole, pyridine, pyrazine, pyrimidine, isoxazole, indolizine,
isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline,
phthalimide, 1,2,3,4-tetrahydroisoquino line, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole,
thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as
thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
[0098] "Nitro" refers to the group -N0 2.
[0099] "Oxo" refers to the atom (=0) or (-0 ) .
[0100] "Spirocycloalkyl" and "spiro ring systems" refers to divalent cyclic groups from 3 to
10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union
formed by a single atom which is the only common member of the rings) as exemplified by
the following structure:
[0101] "Sulfonyl" refers to the divalent group -S(0) 2-
[0102] "Substituted sulfonyl" refers to the group -S0 2-alkyl, -S0 2-substituted alkyl,
-S0 -alkenyl, -S0 -substituted alkenyl, -S0 -cycloalkyl, -S0 -substituted cylcoalkyl,
-S0 -cycloalkenyl, -S0 -substituted cylcoalkenyl, -S0 -aryl, -S0 -substituted aryl,
-S0 -heteroaryl, -S0 -substituted heteroaryl, -S0 -heterocyclic, -S0 -substituted
heterocyclic, -S0 2-amino, and -S0 2-substituted amino, wherein alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted
sulfonyl includes groups such as methyl-S0 2-, phenyl-S0 2-, and 4-methylphenyl-S0 2- .
[0103] "Substituted sulfonyloxy" refers to the group -OS0 -alkyl, -OS0 -substituted alkyl,
-OS0 -alkenyl, -OS0 -substituted alkenyl, -OS0 -cycloalkyl, -OS0 -substituted cylcoalkyl,
-OS0 2-cycloalkenyl, -OS0 2-substituted cylcoalkenyl,-OS0 2-aryl, -OS0 2-substituted aryl,
-OS0 2-heteroaryl, -OS0 2-substituted heteroaryl, -OS0 2-heterocyclic, -OS0 2-substituted
heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as defined herein.
[0104] "Sulfonylamino" refers to the group -NR 50SO2R5 1, wherein R50 and R5 1
independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted
heteroaryl, heterocyclic, substituted heterocyclic, amino, and substituted amino, and where
R50 and R5 1 are optionally joined together with the atoms bound thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0105] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-,
alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-,
cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted
cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted
heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
herein.
[0106] "Thiol" refers to the group -SH.
[0107] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
[0108] "Thioxo" refers to the atom (=S).
[0109] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.
[0110] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted
alkyl is as defined herein.
[0111] An "ion" or "ions" refers to an ion present in the chloride channel. Examples of such
ions include, but are not limited to, halide ion such as, CI , Br , or G, HCO 3 , SCN , NO3 ,
water, amino acid, or organic osmolyte.
[0112] "Isomer" refers to tautomerism, conformational isomerism, geometric isomerism,
stereoisomerism and/or optical isomerism. For example, the compounds and prodrugs of the
invention may include one or more chiral centers and/or double bonds and as a consequence
may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers),
enantiomers, diasteromers, and mixtures thereof, such as racemic mixtures. As another
example, the compounds and prodrugs of the invention may exist in several tautomeric
forms, including the enol form, the keto form, and mixtures thereof.
[0113] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of
one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0114] "Tautomer" refer to alternate forms of a compound that differ in the position of a
proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl
groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety
such as oxadiazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0115] "Prodrug" refers to art recognized modifications to one or more functional groups
which functional groups are metabolized in vivo to provide a compound of this invention or
an active metabolite thereof. Such functional groups are well known in the art including acyl
or thioacyl groups for hydroxyl and/or amino substitution, conversion of one or more
hydroxyl groups to the mono-, di- and tri-phosphate wherein optionally one or more of the
pendent hydroxyl groups of the mono-, di- and tri-phosphate have been converted to an
alkoxy, a substituted alkoxy, an aryloxy or a substituted aryloxy group, and the like.
[0116] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a
compound, which salts are derived from a variety of organic and inorganic counter ions well
known in the art and include, by way of example only, sodium, potassium, calcium,
magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic
functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide,
tartrate, mesylate, acetate, maleate, and oxalate (see Stahl and Wermuth, eds., "HANDBOOK
OF PHARMACEUTICALLY ACCEPTABLE SALTS," (2002), Verlag Helvetica Chimica
Acta, Zurich, Switzerland), for an extensive discussion of pharmaceutical salts, their
selection, preparation, and use.
[0117] Generally, pharmaceutically acceptable salts are those salts that retain substantially
one or more of the desired pharmacological activities of the parent compound and which are
suitable for administration to humans. Pharmaceutically acceptable salts include acid
addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for
forming pharmaceutically acceptable acid addition salts include, by way of example and not
limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid,
etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
[0118] Organic acids suitable for forming pharmaceutically acceptable acid addition salts
include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic
acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid,
lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid,
citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,
mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-
ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g.,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-
toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene-lcarboxylic
acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid,
salicylic acid, stearic acid, muconic acid, and the like.
[0119] Pharmaceutically acceptable salts also include salts formed when an acidic proton
present in the parent compound is either replaced by a metal ion (e.g. , an alkali metal ion, an
alkaline earth metal ion, or an aluminum ion) or coordinates with an organic base (e.g.,
ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine,
dimethylamine, diethylamine, triethylamine, and ammonia).
[0120] Unless indicated otherwise, the nomenclature of substituents that are not explicitly
defined herein are arrived at by naming the terminal portion of the functionality followed by
the adjacent functionality toward the point of attachment. For example, the substituent
"arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-.
[0121] It is understood that in all substituted groups defined above, polymers or other
compounds arrived at by defining substituents with further substituents to themselves (e.g.,
substituted aryl having a substituted aryl group or another group as a substituent which is
itself substituted with a substituted aryl group or another group, which is further substituted
by a substituted aryl group or another group etc.) are not intended for inclusion herein. In
such cases, the maximum number of such substitutions is four. For example, serial
substitutions of substituted aryl groups with two other substituted aryl groups are limited to
-substituted aryl-(substituted aryl)-substituted aryl-(substituted aryl).
[0122] Similarly, it is understood that the above definitions are not intended to include
impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such
impermissible substitution patterns are well known to the skilled artisan.
[0123] An "effective amount" is an amount sufficient to effect beneficial or desired results.
An effective amount can be administered in one or more administrations, applications or
dosages. Such delivery is dependent on a number of variables including the time period for
which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the
route of administration, etc. It is understood, however, that specific dose levels of the
therapeutic agents of the present invention for any particular subject depends upon a variety
of factors including the activity of the specific compound employed, bioavailability of the
compound, the route of administration, the age of the animal and its body weight, general
health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug
combination, and the severity of the particular disorder being treated and form of
administration. Treatment dosages generally may be titrated to optimize safety and efficacy.
Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide
useful guidance on the proper doses for patient administration. Studies in animal models
generally may be used for guidance regarding effective dosages for treatment of diseases
such as diarrhea and PKD. In general, one will desire to administer an amount of the
compound that is effective to achieve a serum level commensurate with the concentrations
found to be effective in vitro. Thus, where a compound is found to demonstrate in vitro
activity, for example as noted in the Tables discussed below one can extrapolate to an
effective dosage for administration in vivo. These considerations, as well as effective
formulations and administration procedures are well known in the art and are described in
standard textbooks. Consistent with this definition and as used herein, the term
"therapeutically effective amount" is an amount sufficient to treat a specified disorder or
disease or alternatively to obtain a pharmacological response such as inhibiting or blocking
the activity of chloride channel, CaCC and/or VRAC.
[0124] As used herein, "treating" or "treatment" of a disease in a patient refers to (1)
preventing the symptoms or disease from occurring in an animal that is predisposed or does
not yet display symptoms of the disease; (2) inhibiting the disease or arresting its
development; or (3) ameliorating or causing regression of the disease or the symptoms of the
disease. As understood in the art, "treatment" is an approach for obtaining beneficial or
desired results, including clinical results. For the purposes of this invention, beneficial or
desired results can include one or more, but are not limited to, alleviation or amelioration of
one or more symptoms, diminishment of extent of a condition (including a disease),
stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of
condition (including disease), progression, amelioration or palliation of the condition
(including disease), states and remission (whether partial or total), whether detectable or
undetectable. Preferred are compounds that are potent and can be administered locally at
very low doses, thus minimizing systemic adverse effects.
B. Methods of the invention
[0125] The methods disclosed herein are useful in the treatment of a condition, disorder or
disease or symptom of such condition, disorder, or disease, where the condition, disorder or
disease is responsive to blocking of a chloride channel. In some embodiments, the chloride
channel is CaCC or VRAC. In one aspect, the methods of the invention treat the diseases by
inhibiting or blocking ion transport, e.g. HCO3 or halide ion, e.g., chloride ion, transport by
the chloride channel or CaCC or VRAC. In some embodiments, the halide ion is at least one
of G , C , or Br . In some embodiments, the halide ion is Cl . In some embodiments, the
channels are present in animal cell membranes. In some embodiments, the channels are
present in mammalian cell membranes. In some embodiments, the animal cell or the
mammalian cell includes, but is not limited to, epithelial cell, bipolar cell, smooth muscle
cell, acinar and duct cell of lachrymal, parotid, submandibular, and/or sublingual gland,
endothelial cell, or kidney cell.
[0126] In one aspect, there is provided a method of treating a disease in an animal, which
disease is responsive to blocking of a chloride channel in the animal, by administering to the
animal in need thereof an effective amount of a compound, as described herein. In one
aspect, there is provided a method of treating a disease in an animal, which disease is
responsive to blocking of a calcium activated chloride channel (CaCC) in the animal, by
administering to the animal in need thereof an effective amount of a compound, as described
herein. In one aspect, there is provided a method of treating a disease in an animal, which
disease is responsive to blocking of a volume regulated anion channel (VRAC) in the animal,
by administering to the animal in need thereof an effective amount of a compound, as
described herein. In one aspect, the channel has been activated prior to contacting the
channel with the compound provided herein. The channel may be activated by several
_|
_ factors including, but are not limited to, voltage, Ca , extracellular ligands, and pH.
[0127] In another aspect, there is provided a method for blocking a transport of a halide ion
across a calcium activated chloride channel (CaCC), by contacting the CaCC with an
effective amount of a compound, as described herein. In another aspect, there is provided a
method for blocking a transport of a halide ion across a volume regulated anion channel
(VRAC), by contacting the VRAC with an effective amount of a compound, as described
herein.
[0128] In another aspect, there is provided a method for blocking a transport of an ion across
a volume regulated anion channel (VRAC), by contacting the VRAC with an effective
amount of a compound, as described herein. In some embodiments, the ion is selected from
the group consisting of halide ion, HCO 3 , SCN , NO3 , water, amino acids, and organic
osmolytes. Small organic molecules that serve as intracellular osmotic effectors are termed
as organic osmolytes. Examples of organic osmolytes include, but are not limited to, polyols
(such as sorbitol, myo-inositol), amino acids and their derivatives (such as taurine, proline,
alanine) and methylamines (such as betaine, glycerophosphoryicholine).
[0129] In some embodiments, the methods of the invention are practiced in vitro, in vivo, or
ex vivo.
Calcium-activated chloride channel (CaCC)
[0130] CaCC plays a significant role in cellular physiology, including epithelial secretion of
electrolytes and water, sensory transduction, regulation of neuronal and cardiac excitability,
and regulation of vascular tone. See Hartzell et al. supra.; Kotlikoff and Wang, Am J Respir
Crit Care Med 158:S 109-S 114 (1998); and Connon et al. J of Histochem. And Cytochem.
52(3):415-418 (2004).
[0131] Vertebrate olfactory receptor neurons express CaCCs that play a role in transduction
of olfactory stimuli. Odorants may bind to and activate G protein-coupled receptors in the
ciliary membrane of olfactory receptor neurons. These receptors may activate adenylyl
cyclase, which may produce cAMP and turn on cyclic-nucleotide-gated channels that are
permeable to both Na and Ca . This may lead to a membrane depolarization and an
_|
_ _ elevation of [Ca ] in the cilium, which may activate CaCCs. The CI efflux (inward current)
may depolarize the membrane further. Thus, in olfactory receptor neurons, the CI efflux
through CaCCs may serve as an amplification system of the odorant-activated current. The
physiological role of the amplification could serve to increase the signal-to-noise ratio and
hence to increase sensitivity to odorants. Further, CaCCs are present in both mammalian and
amphibian taste receptors. Taste stimuli produce a depolarizing current in taste receptor cells
that may result in a discharge of action potentials. The action potentials in the taste receptors
are followed by an outward current that is mediated by CaCCs, which open in response to
_|
_ Ca influx during the action potentials. Therefore, CaC s play a role in olfactory and taste
disorders.
[0132] The inner segments of rods and cones in the retina may express CaCCs. In addition,
CaCCs may also be present in the synaptic terminal of bipolar cells. CaCCs are expressed in
a variety of different neurons, including dorsal root ganglion (DRG) neurons, spinal cord
neurons, and autonomic neurons. About 45-90% of the somatosensory neurons from the
DRG that sense skin temperature, touch, muscle tension, and pain, may express CaCCs.
[0133] CaCCs also play a role in repolarization of the cardiac action potential.
[0134] Airway epithelia use ion transport mechanisms to control the level of airway surface
liquid, which may be important for mucous hydration and protection against infection.
Secretion of fluid into the airway is accomplished by basally located transporters that
accumulate CI in the cell against the CI electrochemical gradient and by apical CI channels
that permit CI to flow into the extracellular space down its electrochemical gradient. Airway
epithelial cells as well as intestinal epithelia express CaCCs in their membrane.
[0135] In some embodiments of the methods of the invention, CaCC is CLCAl, CLCA2, or
CLCA4, or homologs thereof. The calcium-activated chloride channel CLCAl, the calciumactivated
chloride channel CLCA2, the calcium-activated chloride channel CLCA4, and lungendothelial
cell adhesion molecule- 1 (Lu-ECAM-1) are members of a family of proteins that
may mediate a calcium-activated chloride conductance in a variety of tissues. These proteins
may share high degrees of homology in size, sequence (75 to 89% identity), and predicted
structure, but may differ significantly in their tissue distributions. In some embodiments, the
calcium activated chloride channel is human CLCAl and/or CLCA2 and/or CLCA4.
[0136] CLCAl is a protein that in humans is encoded by the CLCAl gene. All members of
this gene family may map to the same region on chromosome Ip31-p22 and may share a high
degree of homology in size, sequence, and predicted structure, but may differ significantly in
their tissue distributions. The encoded protein may be expressed as a precursor protein that
may be processed into two cell-surface-associated subunits. The encoded protein may be
involved in mediating calcium-activated chloride conductance in the intestine.
[0137] CLCA2 is a protein that in humans is encoded by the CLCA2 gene. All members of
this gene family may also map to the same site on chromosome Ip31-p22 and may share high
degree of homology in size, sequence and predicted structure, but may differ significantly in
their tissue distributions. Since this protein is expressed predominantly in trachea and lung, it
may play a role in the complex pathogenesis of cystic fibrosis. It may serve as adhesion
molecule for lung metastatic cancer cells, mediating vascular arrest and colonization, and
may also act as a tumor suppressor gene for breast cancer. For example, target CLCA2
proteins are hCLCA2 and homologs thereof, particularly functional homologs or fragment
thereof, e.g., mCLCA4, etc. By functional homolog thereof is meant that the homolog has
substantially the same mucin secretion modulatory activity, particularly respiratory system
cell mucin secretion modulatory activity, as hCLCA2.
[0138] In many embodiments, the subject homologs are proteins whose amino acid sequence
is at least about 55%, usually at least about 75% and more usually at least about 90%
identical and/or at least about 60% similar, usually at least about 75% and more usually at
least about 90% similar over at least a substantial portion of its length, e.g., at least about
50%, usually at least about 75% and more usually at least about 90%, and often at least about
95% and higher, with the amino acid sequence of hCLCA2, and in many embodiments with
the sequence of hCLCA2 as reported in Genbank Accession Nos. AX054697, AF043977,
AB026833, AF127980 and Z24653.
[0139] CLCA4 is another protein which is encoded by humans CLCA4 gene.
Volume regulated anion channel (VRAC)
[0140] The volume regulated anion channel, VRAC, plays a significant role in cell volume
regulation. This channel is permeable for a wide variety of ions such as, but are not limited
to, water, anions, amino acids, and organic osmolytes, including taurine. A few functional
roles of VRAC include, but are not limited to, contribution to regulatory volume decrease
(RVD) and changes in membrane potential.
[0141] Cell swelling initiates a cascade of events, including the activation of chloride
channels. Their opening may result in an efflux of osmolytes and a concomitant decrease in
cell volume. Block of Ici,voi (Cl current in most mammalian cells activated by increase in cell
volume) may decrease and delay RVD. Pronounced alterations in osmolarity may not occur
in a normal cell environment, except for changes in osmolarity in the renal medulla and in
intestinal epithelium during nonosmotic intake. The cell volume may, however, change
significantly during metabolic activity, proteolysis, or glycolysis during the cell cycle, as an
integrated part of the function of certain hormones (insuline, glucagon) during events such as
secretion, reabsorption and muscle activity. Under pathophysiologic conditions, the cell
volume changes following ischemic stroke, hypoxic and ischemic insults, diabetic neuropathy
and retinopathy, intracellular acidosis, sickle-cell disease, neurectomia, etc. (See Nilius et al.
supra). Cell swelling and volume regulation may also be involved in inflammation due to
allergies.
[0142] Another functional role of VRAC may be related to changes in membrane potential.
During cell swelling, the resting membrane potential may shift to a potential between the
reversal potentials of the coactivated ionic channels, in general between that of K+ and CI .
_|
_ This may change the driving force for Ca ions, and might be of interest for the modulation
of Ca2 release-activated Ca2 entry (CRAC), which is also activated by cell swelling.
Depolarisation due to activation of the volume-sensitive CI conductance may also trigger
_|
_ exocytosis in cells that possess L-type Ca channels (e.g, chromaffin cells, Pcells, etc.). In
other cell types {e.g., cardiac cells), Ici,voi may be involved in the repolarisation process,
rhythmic modulation of cardiac electrical activity and, under pathological condition, in the
genesis of arrhythmias.
[0143] Outwardly rectifying VRAC may not only provide a volume-regulatory pathway for
CI efflux, but they may also be the pathway for the loss of organic anions and osmolytes
from the cell. Small organic molecules, such as, but are not limited to, polyols (sorbitol,
myo-inositol), amino acids and their derivatives (aspartate, glutamate, alanine, proline,
taurine), and methylamines (betaine, glycerylphosphorylcholine), which may be present at
millimolar concentrations in the cytoplasm, may permeate through a volume-sensitive,
nonsaturable, Na -independent pathway. This transport route may be identical to VRAC.
Negatively charged molecules, such as, but are not limited to, gluconate, amino acids,
aspartate and glutamate, may all permeate through VRAC. The VRAC may also mediate the
efflux of taurine and may be permeable for metabolic intermediates {e.g. pyruvate, acetate, b-
hydroxybutyrate). The VRAC have also been termed VSOAC (volume-sensitive organic
osmolyte anion channels).
[0144] Ici,voi may affect cell proliferation since block of VRAC in endothelium may suppresse
cell growth and serum-induced proliferation of myeloblastic leukemia cells. Therefore,
VRAC may play a modulatory role in cell proliferation.
[0145] Examples of VRAC include, but are not limited to, CIC-2, P-glycoprotein (Pgp), plcln
and phospholemman. CIC-2 is a chloride channel that belongs to the CIC family which
comprises plasma membrane-located chloride channels that share a conserved primary
structure. A common topological model with 12 hydrophobic membrane-spanning regions
and intracellularly located N- and C-termini is a proposed model for the CIC family. CIC
channels may be functionally discriminated by their voltage-sensitivity, kinetics and anion
selectivity. In addition, individual CIC channels may display tissue-specific and/or
developmentally-regulated expression patterns. For example, CIC-2 channels may be found
in brain, kidney, and intestine. Pgp is encoded by the MDR1 gene belonging to the family of
ABC transporters and may be located in the plasma membrane. It contains two hydrophobic
domains, each consisting of 6 membrane spanning regions and two cytosolic domains that
bind and hydrolyse ATP. plcl is a protein of 235 to 241 amino acids, depending on the
species. Phospholemman is a 72 amino acid intrinsic membrane protein that is the major
proteine kinase A substrate in cardiac muscle sarcolemma.
Therapeutic Use of the Compounds and Compositions
[0146] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate diseases or disorders that are responsive to blocking of a chloride channel or CaCC
and/or VRAC or their activity. Examples of such diseases, as in the methods of the present
invention, are as described below.
[0147] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate an olfactory disease including, but not limited to, smell and taste disorder such as,
anosmia - inability to detect odors; hyposmia - decreased ability to detect odors; dysosmia -
distorted identification of smell; parosmia - altered perception of smell in the presence of an
odor, usually unpleasant; phantosmia - perception of smell without an odor present; agnosia -
inability to classify or contrast odors, although able to detect odors; ageusia - inability to
taste; hypogeusia - decreased ability to taste; and dysgeusia - distorted ability to taste.
[0148] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate an ophthalmic angiogenesis related disease, such as, but are not limited to, exudative
macular degeneration, age-related macular degeneration (AMD), retinopathy, diabetic
retinopathy, proliferative diabetic retinopathy, diabetic macular edema (DME), ischemic
retinopathy (e.g. retinal vain or artery occlusion), retinopathy of prematurity, neovascular
glaucoma, and corneal neovascularization.
[0149] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate neuronal disorders that include, but are not limited to, myotonia congenital,
myotonia dystrophy, epilepsy, cerebrovascular accident (stroke), Parkinson's disease,
multiple sclerosis, myasthenia gravis, Huntington's disease (Huntington's chorea),
Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, black widow spider, blepharospasm,
complex repetitive discharges, Crisponi syndrome, dystonia variants, fasciculations,
geniospasm, hemifacial spasm, Isaac's Syndrome, motor neuron disorders, motor
neuropathies, myokymia, neuromyotonia, palmaris brevis spasm, polyneuropathy, vascular
disease of spinal chord, startle syndrome (hyperekplexia), strychnine, Stiffman Syndrome,
superior oblique myokymia, tetanus, tetany, tremor, and Whipple's.
[0150] In some embodiments, the compounds of the invention are used to treat, prevent or
alleviate a cardiovascular disease, such as, but not limited to, atherosclerosis, ischemia,
reperfusion injury, hypertension, restenosis, arterial inflammation, myocardial ischaemia and
ischaemic heart disease.
[0151] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate asthma.
[0152] In some embodiments, the methods of the invention are used to treat stroke. The
stroke includes stroke caused by ischemia. Increased activation of excitatory amino acid
(EAA) receptors may be a cause of neuronal damage in ischemia and large increases in EAA
concentrations in the extracellular space may occur during ischemia. The compounds
provided herein that block the chloride channel may lead to reduced EAA release in vitro and
in vivo.
[0153] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate an obstructive or inflammatory airway disease, such as, but is not limited to, airway
hyperreactivity, pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,
siderosis, silicosis, tabacosis, byssinosis, sarcoidosis, berylliosis, pulmonary emphysema,
acute respiratory distress syndrome (ARDS), acute lung injury (ALI), acute or chronic
infectious pulmonary disease, chronic obstructive pulmonary disease (COPD), bronchitis,
chronic bronchitis, wheezy bronchitis, excerbation of airways hyperreactivity or cystic
fibrosis, or cough including chronic cough, excerbation of airways hyperreactivity,
pulmonary fibrosis, pulmonary hypertension, inflammatory lung diseases, and acute or
chronic respiratory infectious diseases.
[0154] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate diarrhea and/or urinary incontinence.
[0155] As used herein, "diarrhea" intends a medical syndrome which is characterized by the
primary symptom of diarrhea (or scours in animals) and secondary clinical symptoms that
may result from a secretory imbalance and without regard to the underlying cause and
therefore includes exudative (inflammatory), decreased absorption (osmotic, anatomic
derangement, and motility disorders) and secretory. All forms of diarrhea have a secretory
component. Symptoms include, but are not limited to impaired colonic absorption, ulcerative
colitis, shigellosis, and amebiasis. Osmotic diarrhea can occur as a result of digestive
abnormalities such as lactose intolerance. Anatomic derangement results in a decreased
absorption surface caused by such procedures as subtotal colectomy and gastrocolic fistula.
Motility disorders result from decreased contact time resulting from such diseases as
hyperthyroidism and irritable bowel syndrome. Secretory diarrhea is characterized by the
hypersecretion of fluid and electrolytes from the cells of the intestinal wall. In classical form,
the hypersecretion is due to changes which are independent of the permeability, absorptive
capacity and exogenously generated osmotic gradients within the intestine. However, all
forms of diarrhea can manifest a secretory component.
[0156] Diarrhea may be caused by infection by a variety of bacteria, parasites and viruses
and may be a threat to regions lacking potable water. Preventing exposure to the pathogens
responsible for diarrhea may be the only way to avert infection. This may require massive
improvement in both sanitation and nutritional status in developing countries, which may be
unlikely to occur in the short term. Thus, it is a continuing threat to the third world and
especially the health of children who may lack a robust immune response. Many who do
survive may have lasting health problems due to the effects of recurrent infections and
malnutrition. Diarrheal diseases may also be the major cause of childhood hospitalization,
primarily for dehydration.
[0157] Diarrhea amenable to treatment using the compounds of the invention can result from
exposure to a variety of pathogens or agents including, without limitation, cholera toxin
{Vibrio cholera), E. coli (particularly enterotoxigenic (ETEC)), Salmonella,
e.g.Cryptosporidiosis, diarrheal viruses (e.g., rotavirus)), food poisoning, or toxin exposure
that results in increased intestinal secretion mediated by CaCC.
[0158] Other diarrheas that can be treated by the methods of the invention include diarrhea
associated with AIDS {e.g., AIDS-related diarrhea), diarrheas caused by anti-AIDS
medications such as protease inhibitors and inflammatory gastrointestinal disorders, such as
ulcerative colitis, inflammatory bowel disease (IBD), Crohn's disease, chemotherapy, and the
like. It has been reported that intestinal inflammation modulates the expression of three
major mediators of intestinal salt transport and may contribute to diarrhea in ulcerative colitis
both by increasing transepithelial CI secretion and by inhibiting the epithelial NaCl
absorption. See, e.g., Lohi et al. (2002) Am. J . Physiol. Gastrointest. Liver Physiol
283(3 ):G567-75.
[0159] Diarrheal episodes can be either acute or persistent (lasting two weeks or more).
Diarrheal diseases may have other effects, such as reduced growth, reduced appetite, altered
feeding patterns, decreased absorption of nutrients, reduced fitness, reduced cognitive
function, and reduced school performance. The primary cause of death from diarrhea may be
dehydration. As dehydration worsens, symptoms may progress from thirst, restlessness,
decreased skin turgor and sunken eyes to diminished consciousness, rapid and feeble pulse
and low or undetectable blood pressure. Diarrhea also may arise as a result of coinfection
with other diseases such as malaria and HIV and may be a comorbidity factor associated with
deaths due to these diseases.
[0160] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate a kidney disease. Examples of kidney diseases include, but are not limited to, renal
tubular disorders such as, but are not limited to, hypercalciuric nephrolithiasis, x-linked
recessive nephrolithiasis, dent disease; nephrogenic diabetes insipidus; and Bartter syndrome
(hypokalemic alkalosis with hypercalciuria).
[0161] The methods of the invention can also treat polycystic kidney disease (PKD) and
associated diseases or disorders such as autosomal dominant polycystic kidney disease
(ADPKD), autosomal recessive polycystic kidney disease and aquired cystic kidney disease.
The manifestation of PKD may be the progressive cystic dilation of renal tubules which
ultimately may lead to renal failure in half of affected individuals. PKD-associated renal
cysts may enlarge to contain several liters of fluid and the kidneys may enlarge progressively
causing pain. Other abnormalities such as hematuria, renal and urinary infection, renal
tumors, salt and water imbalance and hypertension may frequently result from the renal
defect. Cystic abnormalities in other organs, including the liver, pancreas, spleen and ovaries
may be found in PKD. Massive liver enlargement may cause portal hypertension and hepatic
failure.
[0162] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate a bone metabolic disease, such as an osteoclast related bone disease, such as
osteoporosis, postmenopausal osteoporosis, secondary osteoporosis, osteolytic breast cancer
bone metastasis, osteolytic cancer invation, or Paget's disease of bone.
[0163] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate diseases that are responsive to inhibition of angiogenesis, such as diseases that
involve the proliferation of tumor cells, such as, but are not limited to, cancer, metastatic
cancer, prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer,
gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and
lymphoma.
[0164] In some embodiments, the methods of the invention are used to treat, prevent or
alleviate disease, disorder or condition that is responsive to reduction of intraocular pressure,
such as ocular hypertension, open-angle glaucoma, chronic open-angle glaucoma, angleclosure
glaucoma and ciliary injection caused by angle-closure glaucoma, rheumatoid
arthritis, and sickle-cell anaemia.
[0165] In one aspect, the compounds and compositions in the methods of the invention are
administered or delivered to treat the diseases as provided herein and/or associated symptoms
in an animal in need of such treatment. The term "animal" is used broadly to include
mammals such as a human patient or other farm animals in need of such treatment. In one
aspect, the animal is an infant (i.e., less than 2 years old, or alternatively, less than one year
old, or alternatively, less than 6 months old, or alternatively, less than 3 months old, or
alternatively, less than 2 months old, or alternatively, less than 1 one month old, or
alternatively, less than 2 weeks old), a newborn (e.g., less than one week old, or alternatively,
less than one day old), a pediatric patient (e.g., less than 18 years old or alternatively less than
16 years old) or yet further, a geriatric patient (e.g., greater than 65 years old).
[0166] In one aspect, the methods of the invention are used in the treatment of the conditions
as described above by administering an effective amount of the compound defined herein
(including those compounds set forth in Tables 1-3 or encompassed by compounds of
formulas I-III) or compositions thereof.
[0167] In one embodiment, this invention provides use of a compound of formula I, II, or III,
or compounds set forth in Tables 1-3 or a composition comprising a compound of formula I,
II, or III, or compounds set forth in Tables 1-3 for treating a disease in an animal, which
disease is responsive to blocking of a chloride channel or CaCC or VRAC in the animal,
comprising administering to an animal in need thereof an effective amount of a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, or a composition comprising a
compound of formula I, II, or III, or compounds set forth in Tables 1-3, thereby treating the
disease.
[0168] In another embodiment, this invention provides use of a compound of formula I, II, or
III, or compounds set forth in Tables 1-3, or a composition comprising a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, for blocking a transport of a halide
ion across a chloride channel or CaCC or VRAC, comprising contacting the channel with an
effective amount of a compound of formula I, II, or III, or compounds set forth in Tables 1-3,
or a composition comprising a compound of formula I, II, or III, or compounds set forth in
Tables 1-3.
[0169] In another embodiment, this invention provides use of a compound of formula I, II, or
III, or compounds set forth in Tables 1-3, or a composition comprising a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, for blocking a transport of an ion
across a chloride channel or CaCC or VRAC, comprising contacting the channel with an
effective amount of a compound of formula I, II, or III, or compounds set forth in Tables 1-3,
or a composition comprising a compound of formula I, II, or III, or compounds set forth in
Tables 1-3.
[0170] In another embodiment, this invention provides use of a compound of formula I, II, or
III, or compounds set forth in Tables 1-3, or a composition comprising a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, in the manufacture of a
medicament for treating a disease responsive to blocking of a chloride channel or CaCC or
VRAC.
[0171] In another embodiment, this invention provides use of a compound of formula I, II, or
III, or compounds set forth in Tables 1-3, or a composition comprising a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, in the manufacture of a
medicament for blocking a transport of a halide ion across a chloride channel or CaCC or
VRAC.
[0172] In another embodiment, this invention provides use of a compound of formula I, II, or
III, or compounds set forth in Tables 1-3, or a composition comprising a compound of
formula I, II, or III, or compounds set forth in Tables 1-3, in the manufacture of a
medicament for blocking a transport of an ion across a chloride channel or CaCC or VRAC.
[0173] The compounds and compositions can be administered alone or combined with other
suitable therapy such as Oral Rehydration Therapy (ORT), supportive renal therapy,
administration of an antiviral, vaccine, or other compound to treat the underlying infection or
by administering an effective amount of an oral glucose-electrolyte solution to the animal. In
another aspect, the compounds or compositions are co-administered with micronutrients, e.g.,
zinc, iron, and vitamin A. The therapies may be administered simultaneously or
concurrently. Administration is by any appropriate route and varies with the disease or
disorder to be treated and the age and general health of the animal or human patient.
[0174] The compounds described herein can be administered on a mucosal surface of the
gastrointestinal tract (e.g., by an enteral route, such as oral, intraintestinal, intraluminally,
rectal as a suppository, and the like) or to a mucosal surface of the oral or nasal cavities (e.g. ,
intranasal, buccal, sublingual, and the like) or to lungs. In one embodiment, the compounds
disclosed herein are administered in a pharmaceutical formulation suitable for oral
administration, intraluminally or intraperitoneal administration, or via inhalation therapy. In
another embodiment, the compounds disclosed herein are administered in a pharmaceutical
formulation suitable for sustained release.
[0175] In some embodiments of the methods of the invention, the composition is
administered by a parenteral route. In some embodiments, the parenteral route includes, but
is not limited to, intravenous, intramuscular, intraperitoneal and subcutaneous administration.
In some embodiments of the methods of the invention, the composition is administered by an
oral route. In some embodiments, the composition is formulated for oral administration in a
formulation including, but not limited to, capsules, tablets, elixirs, suspensions and syrups. In
some embodiments of the methods of the invention, the composition is formulated as a
controlled release formulation. In some embodiments of the methods of the invention, the
composition is administered in combination with a second agent for the treatment of the
disease. In some embodiments, the second agent includes, but is not limited to, expectorants,
mucolytics, antibiotics, anti-histamines, steroids, anti-inflammatory agents, and
decongestants.
[0176] In one aspect, the compound is administered in a sustained release formulation which
comprises the compound and an effective amount of a pharmaceutically-acceptable polymer.
Such sustained release formulations provide a composition having a modified
pharmacokinetic profile that is suitable for treatment as described herein. In one aspect of the
invention, the sustained release formulation provides decreased Cmax and increased Tmax
without altering bioavailability of the drug.
[0177] In one aspect, the compound is admixed with about 0.2 % to about 5.0 % w/v solution
of a pharmaceutically-acceptable polymer. In other embodiments, the amount of
pharmaceutically-acceptable polymer is between about 0.25% and about 5.0 %; between
about 1% and about 4.5%; between about 2.0% and about 4.0 %; between about 2.5% and
about 3.5%; or alternatively about 0.2%; about 0.25%; about 0.3%; about 0.35%; about 0.4%;
about 0.45%; about 0.5%, about 1.0%, about 2.0%, about 3.0%, or about 4.0%, of the
polymer.
[0178] The therapeutic and prophylactic methods of this invention are useful to treat human
patients in need of such treatment. However, the methods are not to be limited only to human
patient but rather can be practiced and are intended to treat any animal in need thereof. Such
animals will include, but not be limited to farm animals and pets such as simians, cows, pigs
and horses, sheep, goats, cats and dogs. Diarrhea, also known as scours, is a cause of death in
these animals. Infections with rotavirus and coronavirus are common in newborn calves and
pigs. Rotavirus infection often occurs within 12 hours of birth. Symptoms of rotaviral
infection include excretion of watery feces, dehydration and weakness. Coronavirus which
causes a more severe illness in the newborn animals, has a higher mortality rate than rotaviral
infection. Often, however, a young animal may be infected with more than one virus or with
a combination of viral and bacterial microorganisms at one time. This may increase the
severity of the disease.
[0179] The methods can be practiced in vivo in an acceptable animal model to confirm in
vitro efficacy or to treat the disease or condition as described above.
[0180] When used to treat or prevent the diseases responsive to blocking of chloride channel
or CaCC or VRAC, the compounds of the present invention can be administered singly, as
mixtures of one or more compounds of the invention, or in mixture or combination with other
agents useful for treating such diseases and/or the symptoms associated with such diseases.
The compounds of the present invention may also be administered in mixture or in
combination with agents useful to treat other disorders or maladies, such as steroids,
membrane stabilizers, 5-lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptor
inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG
synthesis, b-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitors,
methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and
antihistamines, to name a few. The compounds of the invention can be administered per se in
the form of prodrugs or as pharmaceutical compositions, comprising an active compound or
prodrug.
[0181] The method can be practiced in vitro or in vivo. When practiced in vitro, the method
can be used to screen for compounds, compositions and methods that possess the same or
similar activity using the methods provided in the accompanying examples. Activity is
determined using the methods described herein or others known to those of skill in the art.
C. Compounds of the invention
[0182] Provided herein are methods using pyridazine sulfonamide-containing compounds
which are blockers or inhibitors of chloride channel. In one aspect, the methods relate to a
compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or Pv 1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof;
wherein said compound exhibits at least one of the following:
a) an IC50 of less than 30 mM in the T84 assay;
b) a greater than 30% inhibition at 20 mM in the FRT assay; or
c) a greater than 35% inhibition at 50 mM in a T84 assay, provided that
the compound does not have an IC50 greater than 30 mM.
[0183] In some embodiments, R is hydrogen, hydroxyl, bromo, chloro, methoxy, amino,-
NH-S(0) 2-R2, or -C(0)NH-S(0) 2-R2 where R2 is selected from the group consisting of alkyl,
substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, and
substituted amino.
[0184] In some embodiments, R is -NH-S(0) 2 2 2-R , where R is selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
amino, and substituted amino. In some embodiments, substituted aryl is substituted wth a
substituent selected from the group consisting of halo, alkyl, alkoxy, halo, cyano, amino,
substituted amino, heterocycle, and substituted heterocycle. In some embodiments,
substituted alkyl is substituted wth a halo or aryl.
[0185] In some embodiments, R is -C(0)NH-S(0) -R2, where R2 is selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
amino, and substituted amino. In some embodiments, substituted aryl is substituted wth a
group selected from the group consisting of alkyl, alkoxy, halo, cyano, amino, substituted
amino, heterocycle, and substituted heterocycle. In some embodiments, substituted alkyl is
substituted wth a halo or aryl.
[0186] In some embodiments, R1 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
[0187] In some embodiments, R1 and L are taken together with the atom to which they are
bonded to form a heterocycle or substituted heterocycle.
[0188] In some embodiments, R1 is substituted alkyl substituted with aryl or substituted aryl.
[0189] In some embodiments, R1 is substituted alkyl substituted with phenyl or halo
substituted phenyl.
[0190] In some embodiments, R1 is substituted alkyl substituted with a substitutent selected
from the group consisting of phenyl, 4-chlorophenyl, 4-phenoxyphenyl, 4-
trifluoromethylphenyl, 3,4-dichlorophenyl, and 3-trifluoromethylphenyl.
[0191] In some embodiments, L is selected from the group consisting of alkylene, substituted
alkylene, -0-, -NR3-, -S-, -NR C(0)-, and -C(OH)R3- ; where
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and R3 are taken together with the atom to which they are bonded to
form a heterocycle or substituted heterocycle.
[0192] In some embodiments, L is selected from the group consisting of -0-, -NR -, and -
NR3C(O)-, where R3 is selected from the group consisting of hydrogen, methyl, and ethyl.
[0193] In some embodiments, L is -O- or -N(CH 2CH3)-.
[0194] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n
is 3.
[0195] In one aspect, the method comprises a compound of formula II:
II
wherein
L is -0-, -NR3-, and -NR 3C(O)- where R3 is selected from the group consisting of
hydrogen, methyl, and ethyl;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
R4 is sulfonylamino or aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0196] Some embodiments of the above noted aspect are as provided below. It is to be
understood that any combination of the below noted embodiments is within the scope of the
invention.
[0197] In some embodiments of the above noted aspect, L is -O- or -NR3- where R3 is
selected from the group consisting of hydrogen, methyl, and ethyl.
[0198] In some embodiments, R1 is substituted alkyl substituted with phenyl or halo
substituted phenyl.
[0199] In some embodiments, R4 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2 is
selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, amino, and substituted amino.
[0200] In some embodiments, the method comprises a compound of formula II wherein L is
-O- or -NR3- where R3 is selected from the group consisting of hydrogen, methyl, and ethyl;
R1 is substituted alkyl substituted with phenyl or halo substituted phenyl; and R4 is -NH-
S(0) -R2 or -C(0)NH-S(0) -R2 where R2 is selected from the group consisting of alkyl,
substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, and
substituted amino.
[0201] In some embodiments, the method comprises a compound of formula II wherein L is
-O- or -NR3- where R3 is selected from the group consisting of hydrogen, methyl, and ethyl;
R1 is substituted alkyl substituted with phenyl or halo substituted phenyl; and R4 is -NH-
S(0) 2 2 2 2-R or -C(0)NH-S(0) -R where R is selected from the group consisting of alkyl;
substituted alkyl substituted with halo or aryl; aryl; substituted aryl substituted with halo,
alkyl, alkoxy, cyano, or acylamino; heteroaryl; substituted heteroaryl substituted with
heterocycle; amino; and substituted amino substituted with alkyl.
[0202] In another aspect, the method comprises a compound of formula III:
N-N =
R -L— y— — r 5
III
wherein
L is -0-, -NR3-, and -NR 3C(O)- where R3 is selected from the group consisting of
hydrogen, methyl, and ethyl;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
R5 is sulfonylamino or aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0203] Some embodiments of the above noted aspect are as provided below. It is to be
understood that any combination of the below noted embodiments is within the scope of the
invention.
[0204] In some embodiments, L is -O- or -NR3- where R3 is selected from the group
consisting of hydrogen, methyl, and ethyl.
[0205] In some embodiments, R1 is substituted alkyl substituted with phenyl or halo
substituted phenyl.
[0206] In some embodiments, R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2 is
selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, amino, and substituted amino.
[0207] In some embodiments, L is -O- or -NR3- where R3 is selected from the group
consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with phenyl or
halo substituted phenyl; and R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2 is selected
from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl.
[0208] In some embodiments, L is -O- or -NR3- where R3 is selected from the group
consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with phenyl or
halo substituted phenyl; and R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2 is selected
from the group consisting of alkyl; substituted alkyl substituted with halo; aryl; substituted
aryl substituted with halo or alkyl.
[0209] In some embodiments, the method comprises a compound selected from the group
consisting of:
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)methanesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-4-cyanobenzenesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-6-morpholinopyridine-3-
sulfonamide;
N-(4-(N-(3-(6-(4-chlorophenethoxy)pyridazin-3-
yl)phenyl)sulfamoyl)phenyl)acetamide;
4-(6-(4-chlorophenethoxy)pyridazin-3-yl)-2-methoxyphenol;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)dimethylaminosulfonam
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)methanesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)-4-methylbenzenesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)-3-bromobenzenesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(4-methoxyphenylsulfonyl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(4-fluorophenylsulfonyl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(ethylsulfonyl)benzamide;
N-(4-tert-butylphenylsulfonyl)-3-(6-(4-chlorophenethoxy)pyridazin-3-yl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(3,4-difluorophenylsulfonyl)benzamide;
N-(3-(6-(benzylamino)pyridazin-3-yl)phenyl)-4-methylbenzenesulfonamide;
N-(benzylsulfonyl)-3-(6-(4-chlorophenethoxy)pyridazin-3-yl)benzamide;
4-tert-butyl-N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)benzenesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(3,4-difluorophenylsulfonyl)benzamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-2,2,2-
trifluoroethanesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(2,4-difluorophenylsulfonyl)benzamide;
N-(4-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
4-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-tosylbenzamide;
Benzyl- {6-[3-(l ,1-dioxo-isothiazolidin-2-yl)-phenyl]-pyridazin-3-yl} -ethylamine; and
N-(4-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-2-methylpropane-lsulfonamide;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
[0210] It will be appreciated by one of skill in the art that the embodiments summarized
above may be used together in any suitable combination to generate additional embodiments
not expressly recited above, and that such embodiments are considered to be part of the
present invention.
[0211] Those of skill in the art will appreciate that the compounds described herein may
include functional groups that can be masked with progroups to create prodrugs. Such
prodrugs are usually, but need not be, pharmacologically inactive until converted into their
active drug form. The compounds described in this invention may include promoieties that
are hydrolyzable or otherwise cleavable under conditions of use. For example, ester groups
commonly undergo acid-catalyzed hydrolysis to yield the parent hydroxyl group when
exposed to the acidic conditions of the stomach or base-catalyzed hydrolysis when exposed to
the basic conditions of the intestine or blood. Thus, when administered to a subject orally,
compounds that include ester moieties can be considered prodrugs of their corresponding
hydroxyl, regardless of whether the ester form is pharmacologically active.
[0212] Prodrugs designed to cleave chemically in the stomach to the active compounds can
employ progroups including such esters. Alternatively, the progroups can be designed to
metabolize in the presence of enzymes such as esterases, amidases, lipolases, and
phosphatases, including ATPases and kinase, etc. Progroups including linkages capable of
metabolizing in vivo are well known and include, by way of example and not limitation,
ethers, thioethers, silylethers, silylthioethers, esters, thioesters, carbonates, thiocarbonates,
carbamates, thiocarbamates, ureas, thioureas, and carboxamides.
[0213] In the prodrugs, any available functional moiety can be masked with a progroup to
yield a prodrug. Functional groups within the compounds of the invention that can be
masked with progroups include, but are not limited to, amines (primary and secondary),
hydroxyls, sulfanyls (thiols), and carboxyls. A wide variety of progroups suitable for
masking functional groups in active compounds to yield prodrugs are well-known in the art.
For example, a hydroxyl functional group can be masked as a sulfonate, ester, or carbonate
promoiety, which can be hydrolyzed in vivo to provide the hydroxyl group. An amino
functional group can be masked as an amide, carbamate, imine, urea, phosphenyl,
phosphoryl, or sulfenyl promoiety, which can be hydrolyzed in vivo to provide the amino
group. A carboxyl group can be masked as an ester (including silyl esters and thioesters),
amide, or oxadiazolepromoiety, which can be hydrolyzed in vivo to provide the carboxyl
group. Other specific examples of suitable progroups and their respective promoieties will be
apparent to those of skill in the art. All of these progroups, alone or in combinations, can be
included in the prodrugs.
[0214] As noted above, the identity of the progroup is not critical, provided that it can be
metabolized under the desired conditions of use, for example, under the acidic conditions
found in the stomach and/or by enzymes found in vivo, to yield a biologically active group,
e.g., the compounds as described herein. Thus, skilled artisans will appreciate that the
progroup can comprise virtually any known or later-discovered hydroxyl, amine or thiol
protecting group. Non- limiting examples of suitable protecting groups can be found, for
example, in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Greene & Wuts, 2nd Ed.,
John Wiley & Sons, New York, 1991 .
[0215] Additionally, the identity of the progroup(s) can also be selected so as to impart the
prodrug with desirable characteristics. For example, lipophilic groups can be used to
decrease water solubility and hydrophilic groups can be used to increase water solubility. In
this way, prodrugs specifically tailored for selected modes of administration can be obtained.
The progroup can also be designed to impart the prodrug with other properties, such as, for
example, improved passive intestinal absorption, improved transport-mediated intestinal
absorption, protection against fast metabolism (slow-release prodrugs), tissue-selective
delivery, passive enrichment in target tissues, and targeting-specific transporters. Groups
capable of imparting prodrugs with these characteristics are well-known and are described,
for example, in Ettmayer et al. (2004), J . Med. Chem. 47(10 ):2393-2404. All of the various
groups described in these references can be utilized in the prodrugs described herein.
[0216] As noted above, progroup(s) may also be selected to increase the water solubility of
the prodrug as compared to the active drug. Thus, the progroup(s) may include or can be a
group(s) suitable for imparting drug molecules with improved water solubility. Such groups
are well-known and include, by way of example and not limitation, hydrophilic groups such
as alkyl, aryl, and arylalkyl, or cycloheteroalkyl groups substituted with one or more of an
amine, alcohol, a carboxylic acid, a phosphorous acid, a sulfoxide, a sugar, an amino acid, a
thiol, a polyol, an ether, a thioether, and a quaternary amine salt. Numerous references teach
the use and synthesis of prodrugs, including, for example, Ettmayer et a , supra and
Bungaard et al. (1989) J . Med. Chem. 32(12): 2503-2507.
[0217] One of ordinary skill in the art will appreciate that many of the compounds of the
invention and prodrugs thereof, may exhibit the phenomena of tautomerism, conformational
isomerism, geometric isomerism, and/or optical isomerism. For example, the compounds and
prodrugs of the invention may include one or more chiral centers and/or double bonds and as
a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers, diasteromers, and mixtures thereof, such as racemic mixtures. As
another example, the compounds and prodrugs of the invention may exist in several
tautomeric forms, including the enol form, the keto form, and mixtures thereof. As the
various compound names, formulae and compound drawings within the specification and
claims can represent only one of the possible tautomeric, conformational isomeric, optical
isomeric, or geometric isomeric forms, it should be understood that the invention
encompasses any tautomeric, conformational isomeric, optical isomeric, and/or geometric
isomeric forms of the compounds or prodrugs having one or more of the utilities described
herein, as well as mixtures of these various different isomeric forms.
[0218] Depending upon the nature of the various substituents, the compounds and prodrugs
of the invention can be in the form of salts. Such salts include pharmaceutically acceptable
salts, salts suitable for veterinary uses, etc. Such salts can be derived from acids or bases, as
is well-known in the art. In one embodiment, the salt is a pharmaceutically acceptable salt.
[0219] In one embodiment, this invention provides a compound, isomer, tautomer, prodrug,
or pharmaceutically acceptable salt thereof, selected from Table 1.
Table 1
II
Table 2
III
Table 3

D. Pharmaceutical formulations and administration
[0220] The compounds or isomers, prodrug, tautomer, or pharmaceutically acceptable salts
thereof, of the present invention can be formulated in the pharmaceutical compositions per
se, or in the form of a hydrate, solvate, N-oxide, or pharmaceutically acceptable salt, as
described herein. Typically, such salts are more soluble in aqueous solutions than the
corresponding free acids and bases, but salts having lower solubility than the corresponding
free acids and bases may also be formed. The present invention includes within its scope
solvates of the compounds and salts thereof, for example, hydrates. The compounds may
have one or more asymmetric centers and may accordingly exist both as enantiomers and as
diastereoisomers. It is to be understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention.
[0221] In one embodiment, this invention provides a pharmaceutical composition comprising
a compound provided herein and a pharmaceutically acceptable carrier. In another
embodiment, this invention provides a pharmaceutical composition comprising a
therapeutically effective amount of a compound provided herein and a pharmaceutically
acceptable carrier. In one embodiment, this invention provides a pharmaceutical formulation
comprising a compound selected from the compounds of the invention or isomers, hydrates,
tautomer, or pharmaceutically acceptable salts thereof and at least one pharmaceutically
acceptable excipient, diluent, preservative, stabilizer, or mixture thereof.
[0222] In one embodiment, the methods can be practiced as a therapeutic approach towards
the treatment of the conditions described herein. Thus, in a specific embodiment, the
compounds of the invention can be used to treat the conditions described herein in animal
subjects, including humans. The methods generally comprise administering to the subject an
amount of a compound of the invention, or a salt, prodrug, hydrate, or N-oxide thereof,
effective to treat the condition.
[0223] In some embodiments, the subject is a non-human mammal, including, but not limited
to, bovine, horse, feline, canine, rodent, or primate. In another embodiment, the subject is a
human.
[0224] The compounds of the invention can be provided in a variety of formulations and
dosages. It is to be understood that reference to the compound of the invention, or "active" in
discussions of formulations is also intended to include, where appropriate as known to those
of skill in the art, formulation of the prodrugs of the compounds.
[0225] In one embodiment, the compounds are provided as non-toxic pharmaceutically
acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this
invention include acid addition salts such as those formed with hydrochloric acid, fumaric
acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,
carbonic acid, or phosphoric acid. Salts of amine groups may also comprise quaternary
ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an
alkyl, alkenyl, alkynyl, or substituted alkyl moiety. Furthermore, where the compounds of
the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may
include metal salts such as alkali metal salts, e.g., sodium or potassium salts; and alkaline
earth metal salts, e.g., calcium or magnesium salts.
[0226] The pharmaceutically acceptable salts of the present invention can be formed by
conventional means, such as by reacting the free base form of the product with one or more
equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in
a solvent such as water which is removed in vacuo, by freeze drying, or by exchanging the
anions of an existing salt for another anion on a suitable ion exchange resin.
[0227] Pharmaceutical compositions comprising the compounds described herein (or
prodrugs thereof) can be manufactured by means of conventional mixing, dissolving,
granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or
lyophilization processes. The compositions can be formulated in conventional manner using
one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries which
facilitate processing of the active compounds into preparations which can be used
pharmaceutically.
[0228] The compounds of the invention can be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion,
subcutaneous injection, or implant), by inhalation spray nasal, vaginal, rectal, sublingual,
urethral (e.g., urethral suppository) or topical routes of administration (e.g., gel, ointment,
cream, aerosol, etc.) and can be formulated, alone or together, in suitable dosage unit
formulations containing conventional non-toxic pharmaceutically acceptable carriers,
adjuvants, excipients, and vehicles appropriate for each route of administration.
[0229] The pharmaceutical compositions for the administration of the compounds can be
conveniently presented in dosage unit form and can be prepared by any of the methods well
known in the art of pharmacy. The pharmaceutical compositions can be, for example,
prepared by uniformly and intimately bringing the active ingredient into association with a
liquid carrier, a finely divided solid carrier or both, and then, if necessary, shaping the
product into the desired formulation. In the pharmaceutical composition the active object
compound is included in an amount sufficient to produce the desired therapeutic effect. For
example, pharmaceutical compositions of the invention may take a form suitable for virtually
any mode of administration, including, for example, topical, ocular, oral, buccal, systemic,
nasal, injection, transdermal, rectal, and vaginal, or a form suitable for administration by
inhalation or insufflation.
[0230] For topical administration, the compound(s) or prodrug(s) can be formulated as
solutions, gels, ointments, creams, suspensions, etc., as is well-known in the art.
[0231] Systemic formulations include those designed for administration by injection (e.g.,
subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection) as well as
those designed for transdermal, transmucosal, oral, or pulmonary administration.
[0232] Useful injectable preparations include sterile suspensions, solutions, or emulsions of
the active compound(s) in aqueous or oily vehicles. The compositions may also contain
formulating agents, such as suspending, stabilizing, and/or dispersing agents. The
formulations for injection can be presented in unit dosage form, e.g., in ampules or in
multidose containers, and may contain added preservatives.
[0233] Alternatively, the injectable formulation can be provided in powder form for
reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water,
buffer, and dextrose solution, before use. To this end, the active compound(s) can be dried by
any art-known technique, such as lyophilization, and reconstituted prior to use.
[0234] For transmucosal administration, penetrants appropriate to the barrier to be permeated
are used in the formulation. Such penetrants are known in the art.
[0235] For oral administration, the pharmaceutical compositions may take the form of, for
example, lozenges, tablets, or capsules prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize
starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose,
microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium
stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known
in the art with, for example, sugars, films, or enteric coatings. Additionally, the
pharmaceutical compositions containing the 2,4-substituted pyrmidinediamine as active
ingredient or prodrug thereof in a form suitable for oral use may also include, for example,
troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions,
hard or soft capsules, or syrups or elixirs.
[0236] Compositions intended for oral use can be prepared according to any method known
to the art for the manufacture of pharmaceutical compositions, and such compositions may
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 contain the active ingredient (including drug
and/or prodrug) in admixture with non-toxic pharmaceutically acceptable excipients which
are suitable for the manufacture of tablets. These excipients can be for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents (e.g., corn starch or alginic acid); binding
agents (e.g. starch, gelatin, or acacia); and lubricating agents (e.g., magnesium stearate,
stearic acid, or talc). The tablets can be left uncoated or they can be 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. They may also be coated by
the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form
osmotic therapeutic tablets for control release. The pharmaceutical compositions of the
invention may also be in the form of oil-in-water emulsions.
[0237] Liquid preparations for oral administration may take the form of, for example, elixirs,
solutions, syrups, or suspensions, or they can be presented as a dry product for constitution
with water or other suitable vehicle before use. Such liquid preparations can be prepared by
conventional means with pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents
(e.g., lecithin, or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol,
cremophore™, or fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts,
preservatives, flavoring, coloring, and sweetening agents as appropriate.
[0238] Preparations for oral administration can be suitably formulated to give controlled
release or sustained release of the active compound, as is well known. The sustained release
formulations of this invention are preferably in the form of a compressed tablet comprising an
intimate mixture of compound of the invention and a partially neutralized pH-dependent
binder that controls the rate of compound dissolution in aqueous media across the range of
pH in the stomach (typically approximately 2) and in the intestine (typically approximately
about 5.5).
[0239] To provide for a sustained release of compounds of the invention, one or more pHdependent
binders can be chosen to control the dissolution profile of the sustained release
formulation so that the formulation releases compound slowly and continuously as the
formulation is passed through the stomach and gastrointestinal tract. Accordingly, the pHdependent
binders suitable for use in this invention are those which inhibit rapid release of
drug from a tablet during its residence in the stomach (where the pH is-below about 4.5), and
which promotes the release of a therapeutic amount of the compound of the invention from
the dosage form in the lower gastrointestinal tract (where the pH is generally greater than
about 4.5). Many materials known in the pharmaceutical art as enteric binders and coating
agents have a desired pH dissolution properties. The examples include phthalic acid
derivatives such as the phthalic acid derivatives of vinyl polymers and copolymers,
hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates,
cellulose ethers, alkylcellulose acetates, and the partial esters thereof, and polymers and
copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters
thereof. One or more pH-dependent binders present in the sustained release formulation of
the invention are in an amount ranging from about

WHAT IS CLAIMED IS:
1. A method of treating a disease in an animal, which disease is responsive to blocking
of a chloride channel, comprising administering to an animal in need thereof an effective
amount of a compound of formula I :
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
2. A method for blocking a transport of a halide ion across a calcium activated chloride
channel (CaCC), comprising contacting the CaCC with an effective amount of a compound of
formula I :
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
3. A method for blocking a transport of an ion across a volume regulated anion channel
(VRAC), comprising contacting the VRAC with an effective amount of a compound of
formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
4. An in vitro method for blocking a transport of an ion across a calcium activated
chloride channel (CaCC), comprising contacting the CaCC with an effective amount of a
compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
5. An in vitro method for blocking a transport of an ion across a volume regulated anion
channel (VRAC), comprising contacting the VRAC with an effective amount of a compound
of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
6. The method of claim 1, wherein the chloride channel is a calcium activated chloride
channel (CaCC).
7. The method of claim 1, wherein the chloride channel is a volume regulated anion
channel (VRAC).
8. The method of any of the preceding claims, wherein the compound inhibits halide ion
transport by CaCC or VRAC.
9. The method of claim 1, wherein the disease is selected from the group consisting of
chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, stroke, and an
acute or chronic infectious disease.
10. The method of claim 1, wherein the disease is selected from the group consisting of
asthma, bronchitis, cystic fibrosis, emphysema, gastrointestinal malabsorption syndrome,
steatorrhea, secretory diarrhea, inflammatory diarrhea, allergic inflammation, airway
inflammation, inflammatory bowel disease, infectious diarrhea, polycystic kidney disease
(PKD), cardiac arrhythmia, male infertility and disorders associated with neovascularization.
11. The method of claim 1, wherein the disease is selected from the group consisting of
olfactory and taste disorders; ophthalmic angiogenesis related disease; neuronal disorders;
cardiovascular disease; obstructive or inflammatory airway disease; diarrhea and/or urinary
incontinence; kidney disease; bone metabolic disease; diseases that are responsive to
inhibition of angiogenesis; and diseases that is responsive to reduction of intraocular
pressure.
12. The method of claim 1, wherein the disease is a cardiovascular disease selected from
the group consisting of atherosclerosis, ischemia, reperfusion injury, hypertension, restenosis,
arterial inflammation, and ischaemic heart disease.
13. The method of claim 1, 2, or 3, wherein the compound is administered by a parenteral
or transdermal route.
14. The method of claim 13, wherein the parenteral route is selected from the group
consisting of intravenous, intramuscular, intraperitoneal and subcutaneous administration.
15. The method of claim 1, 2, or 3, wherein the compound is administered by an oral
route or by inhalation.
16. The method of claim 1, 2, or 3, wherein the compound is formulated for oral
administration in a formulation selected from the group consisting of capsules, tablets, elixirs,
suspensions and syrups.
17. The method of claim 1, 2, or 3, wherein the compound is formulated as a controlled
release formulation.
18. The method of claim 1, 2, or 3, wherein the compound is administered in combination
with a second agent for the treatment of the disease.
19. The method of claim 18, wherein the second agent is selected from the group
consisting of expectorants, mucolytics, antibiotics, anti-histamines, steroids, antiinflammatory
agents, and decongestants.
20. The method of any of the preceding claims, wherein R is hydrogen, hydroxyl, bromo,
chloro, methoxy, amino, -NH-S(0) 2-R2, or -C(0)NH-S(0) 2-R2 where R2 is selected from the
group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, amino, and substituted amino.
21. The method of any of the preceding claims, wherein R is -NH-S(0) -R2, where R2 is
selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, amino, and substituted amino.
22. The method of claim 21, wherein substituted aryl is substituted wth a substituent
selected from the group consisting of halo, alkyl, alkoxy, halo, cyano, amino, substituted
amino, heterocycle, and substituted heterocycle.
23. The method of claim 21, wherein substituted alkyl is substituted wth a halo or aryl.
24. The method of any of the preceding claims, wherein R is -C(0)NH-S(0) 2-R , where
R is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, amino, and substituted amino.
25. The method of claim 24, wherein substituted aryl is substituted wth a group selected
from the group consisting of alkyl, alkoxy, halo, cyano, amino, substituted amino,
heterocycle, and substituted heterocycle.
26. The method of claim 24, wherein substituted alkyl is substituted wth a halo or aryl.
27. The method of any of the preceding claims, wherein R is selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and
substituted heteroaryl.
28. The method of any of claims 1-5, wherein R1 and L are taken together with the atom
to which they are bonded to form a heterocycle or substituted heterocycle.
29. The method of any of the preceding claims, wherein R1 is substituted alkyl substituted
with aryl or substituted aryl.
30. The method of claim 29, wherein R1 is substituted alkyl substituted with phenyl or
halo substituted phenyl.
31. The method of any of the preceding claims, wherein R1 is substituted alkyl substituted
with a substitutent selected from the group consisting of phenyl, 4-chlorophenyl, 4-
phenoxyphenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, and 3-trifluoromethylphenyl.
32. The method of any of the preceding claims, wherein L is selected from the group
consisting of alkylene, substituted alkylene, -0-, -NR3-, -S-, -NR C(0)-, and -C(OH)R3- ;
where
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and R3 are taken together with the atom to which they are bonded to
form a heterocycle or substituted heterocycle.
33. The method of any of the preceding claims, wherein L is selected from the group
consisting of -0-, -NR3-, and -NR 3C(O)-, where R3 is selected from the group consisting of
hydrogen, methyl, and ethyl.
34. The method of any of the preceding claims, wherein L is -O- or -N(CH 2CH3)-.
35. The method of any of the preceding claims, wherein n is 1 or 2.
The method of any of the preceding claims, wherein the compound is of formula II
II
wherein
L is -0-, -NR3-, and -NR 3C(O)- where R3 is selected from the group consisting of
hydrogen, methyl, and ethyl;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
R4 is sulfonylamino or aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
3 3 37. The method of claim 36, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl.
38. The method of claim 36 or 37, wherein R1 is substituted alkyl substituted with phenyl
or halo substituted phenyl.
39. The method of any of claims 36-38, wherein R4 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-
R2 where R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, amino, and substituted amino.
3 3 40. The method of claim 39, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with
phenyl or halo substituted phenyl; and R4 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2
is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, amino, and substituted amino.
3 3 41. The method of claim 39, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with
phenyl or halo substituted phenyl; and R4 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2
is selected from the group consisting of alkyl; substituted alkyl substituted with halo or aryl;
aryl; substituted aryl substituted with halo, alkyl, alkoxy, cyano, or acylamino; heteroaryl;
substituted heteroaryl substituted with heterocycle; amino; and substituted amino substituted
with alkyl.
42. The method of any of claims 1-5, wherein the compound is of formula III:
III
wherein
L is -0-, -NR3-, and -NR 3C(O)- where R3 is selected from the group consisting of
hydrogen, methyl, and ethyl;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
R5 is sulfonylamino or aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
3 3 43. The method of claim 42, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl.
44. The method of claim 42 or 43, wherein R1 is substituted alkyl substituted with phenyl
or halo substituted phenyl.
45. The method of any of claims 42-44, wherein R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-
R2 where R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, amino, and substituted amino.
3 3 46. The method of claim 42, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with
phenyl or halo substituted phenyl; and R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2
is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl.
3 3 47. The method of claim 42, wherein L is -O- or -NR - where R is selected from the
group consisting of hydrogen, methyl, and ethyl; R1 is substituted alkyl substituted with
phenyl or halo substituted phenyl; and R5 is -NH-S(0) 2-R2 or -C(0)NH-S(0) 2-R2 where R2
is selected from the group consisting of alkyl; substituted alkyl substituted with halo; aryl;
substituted aryl substituted with halo or alkyl.
48. The method of any of claims 1-5, wherein the compound is selected from the group
consisting of:
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)methanesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-4-cyanobenzenesulfonamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-6-morpholinopyridine-3-
sulfonamide;
N-(4-(N-(3-(6-(4-chlorophenethoxy)pyridazin-3-
yl)phenyl)sulfamoyl)phenyl)acetamide;
4-(6-(4-chlorophenethoxy)pyridazin-3-yl)-2-methoxyphenol;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)dimethylaminosulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)methanesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)-4-methylbenzenesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)-3-bromobenzenesulfonamide;
N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(4-methoxyphenylsulfonyl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(4-fluorophenylsulfonyl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(ethylsulfonyl)benzamide;
N-(4-tert-butylphenylsulfonyl)-3-(6-(4-chlorophenethoxy)pyridazin-3-yl)benzamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(3,4-difluorophenylsulfonyl)benzamide;
N-(3-(6-(benzylamino)pyridazin-3-yl)phenyl)-4-methylbenzenesulfonamide;
N-(benzylsulfonyl)-3-(6-(4-chlorophenethoxy)pyridazin-3-yl)benzamide;
4-tert-butyl-N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)benzenesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(3,4-difluorophenylsulfonyl)benzamide;
N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-2,2,2-
trifluoroethanesulfonamide;
3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(2,4-difluorophenylsulfonyl)benzamide;
N-(4-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)- 1,1,1-
trifluoromethanesulfonamide;
4-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-tosylbenzamide;
Benzyl- {6-[3-(l ,1-dioxo-isothiazolidin-2-yl)-phenyl]-pyridazin-3-yl} -ethylamine; and
N-(4-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-2-methylpropane-lsulfonamide;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
49. The method of any of claims 1-5, wherein the compound is in a composition which
further comprises a pharmaceutically acceptable carrier.
50. The method of any of claims 3 or 5, wherein the ion is selected from the group
consisting of halide ion, HCO 3 , SCN , NO3 , water, amino acids, and organic osmolytes.
51. The method of any of claims 2 or 4, wherein the halide ion is CI .
52. The method of any of claims 2-3, wherein the method is in vitro, in vivo, or ex vivo.
53. The method of any of claims 2-5, wherein the channel is present in an animal cell
selected from the group consisting of epithelial cell, bipolar cell, smooth muscle cell, acinar
and duct cell of lachrymal, parotid, submandibular, and/or sublingual gland, endothelial cell,
and kidney cell.
54. The method of any of claims 2-5, wherein the channel is present in a mammalian cell
selected from the group consisting of an intestinal epithelial cell and a colon epithelial cell.
55. Use of a compound of formula I for treating a disease in an animal, which disease is
responsive to blocking of a chloride channel, comprising administering to an animal in need
thereof an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
56. Use of a compound of formula I in a manufacture of a medicament for treating a
disease in an animal, which disease is responsive to blocking of a chloride channel,
comprising administering to an animal in need thereof an effective amount of a compound of
formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
57. Use of a compound of formula I for blocking a transport of a halide ion across a
calcium activated chloride channel (CaCC), comprising contacting the CaCC with an
effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
58. Use of a compound of formula I in a manufacture of a medicament for blocking a
transport of a halide ion across a calcium activated chloride channel (CaCC), comprising
contacting the CaCC with an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
59. Use of a compound of formula I for blocking a transport of an ion across a volume
regulated anion channel (VRAC), comprising contacting the VRAC with an effective amount
of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.
60. Use of a compound of formula I in a manufacture of a medicament for blocking a
transport of an ion across a volume regulated anion channel (VRAC), comprising contacting
the VRAC with an effective amount of a compound of formula I :
I
wherein
n is 1, 2, 3, 4, or 5;
L is a bond or a linker of 1 to 6 linear or branched covalently linked atoms;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl,
substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy, aryloxy and substituted aryloxy;
or R1 and L are taken together with the atom to which they are bonded to form
a heterocycle or substituted heterocycle; and
each R is independently selected from the group consisting of hydrogen, hydroxyl,
alkyl, substituted alkyl, halo, amino, sulfonylamino, aminocarbonyl, alkoxy
and substituted alkoxy, provided that at least one R is sulfonylamino or
aminocarbonyl;
or a pharmaceutically acceptable salt, isomer, or tautomer thereof.