U.S. patent application number 13/437463 was filed with the patent office on 2012-07-26 for selective sphingosine-1-phosphate receptor antagonists.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Ken Chow, Michael E. Garst, Todd M. Heidelbaugh, Phong X. Nguyen.
Application Number | 20120190694 13/437463 |
Document ID | / |
Family ID | 42732196 |
Filed Date | 2012-07-26 |
United States Patent
Application |
20120190694 |
Kind Code |
A1 |
Nguyen; Phong X. ; et
al. |
July 26, 2012 |
SELECTIVE SPHINGOSINE-1-PHOSPHATE RECEPTOR ANTAGONISTS
Abstract
Described herein are compounds useful as antagonists of
sphingosine-1-phosphate receptors. Further described herein is the
use of these compounds and related pharmaceutical compositions to
treat disorders associated with sphingosine-1-phosphate-3 (S1P3)
receptor modulation.
Inventors: |
Nguyen; Phong X.;
(Placentia, CA) ; Heidelbaugh; Todd M.; (Fountain
Valley, CA) ; Chow; Ken; (Newport Coast, CA) ;
Garst; Michael E.; (Newport Beach, CA) |
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
42732196 |
Appl. No.: |
13/437463 |
Filed: |
April 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12852768 |
Aug 9, 2010 |
8168795 |
|
|
13437463 |
|
|
|
|
61232997 |
Aug 11, 2009 |
|
|
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Current U.S.
Class: |
514/256 ;
544/322 |
Current CPC
Class: |
C07D 405/12 20130101;
A61P 9/04 20180101; A61P 9/00 20180101; C07D 213/81 20130101; A61P
11/06 20180101; A61P 27/02 20180101; A61P 19/02 20180101; C07D
409/12 20130101; A61P 9/06 20180101; A61P 25/04 20180101; A61P
25/02 20180101 |
Class at
Publication: |
514/256 ;
544/322 |
International
Class: |
A61K 31/501 20060101
A61K031/501; A61P 27/02 20060101 A61P027/02; C07D 401/12 20060101
C07D401/12 |
Claims
1. A compound having a structure ##STR00047## wherein R.sup.1 and
R.sup.2 are each independently selected from H, C.sub.1-C.sub.4
alkyl; C is a heteroaryl, having a structure ##STR00048## and p is
1 and Z.sup.1-Z.sup.6 are each independently selected from C and N;
R.sup.3 and R.sup.8 are each independently selected from H,
C.sub.1-C.sub.6 straight or branched chain alkyl, alkenyl, or
alkynyl, alkoxy (such as O(C.sub.1-C.sub.6)), --OH, halogen,
--NR.sup.4.sub.2, --CN, --CO.sub.2R.sup.4, --C(O)NR.sup.4R.sup.5,
--CH.sub.2OH, --CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --NO.sub.2,
alkylamino, and alkylcarboxyl; m is 0-5; n is 0-5; R.sup.4 and
R.sup.5 are each independently selected from H, C.sub.1-C.sub.6,
branched or unbranched alkyl, alkenyl, or alkynyl, C.sub.3-C.sub.6
saturated or unsaturated cyclic hydrocarbon, aryl, heteroaryl,
haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl,
oxycarbonyl, carboxyl, alkyl carboxylate, alkylamide, alkylamino
aminocarbonyl, or amino; A is CR.sup.6.sub.3, CXR.sup.6.sub.2,
CX.sub.2R.sup.6, CX.sub.3, COQ.sup.1, SOQ.sup.1, SO.sub.2Q.sup.1,
CSQ.sup.1, amide, sulfonyl, sulfone, sulfonamide, sulfoxide, ester,
thiocarbonyl, phenyl, substituted phenyl, heterocyclic,
heteroaromatic, cycloalkyl, and cycloalkenyl; X is a halogen;
R.sup.6 is H, C.sub.1-C.sub.6 straight or branched chain alkyl,
alkenyl, or alkynyl, haloalkyl, perfluorinated alkyl, partially
fluorinated alkyl, perhalogenated alkyl, partially halogenated
alkyl. Q.sup.1 is an aryl or heteroaryl variably substituted with
(R.sup.3).sub.n, a phenyl, heteroaromatic or cycloalkyl,
cycloalkenyl, or partially saturated or saturated heterocyclic ring
a bicyclic compound, NR.sup.4R.sup.5; R.sup.7 is H, C.sub.1-C.sub.6
branched or unbranched alkyl, alkenyl, or alkynyl, haloalkyl, aryl,
herteoaryl, perfluorinated alkyl and partially fluorinated alkyl,
perhalogenated alkyl, partially perhalogenated alkyl, phenyl,
cyano, ketyl, CF.sub.3, substituted aryl or heteroaryl and
spirocyclic compounds; and B is heteroaromatic.
2. The compound according to claim 1 wherein R.sup.1 and R.sup.2
are H; C is heteroaryl having the structure ##STR00049## wherein p
is 1, and Z.sup.1-Z.sup.6 are each independently selected from C
and N; R.sup.3 and R.sup.8 are H, halogen; m is 0-2; n is 0-2; A is
CR.sup.6.sub.3, CXR.sup.6.sub.2, CX.sub.2R.sup.6, CX.sub.3; X is a
halogen; R.sup.6 is H, C.sub.1-C.sub.6 straight or branched chain
alkyl, haloalkyl, perfluorinated alkyl, partially fluorinated
alkyl, perhalogenated alkyl, partially halogenated alkyl; R.sup.7
is H, C.sub.1-C.sub.6 branched or unbranched alkyl, haloalkyl,
perfluorinated alkyl and partially fluorinated alkyl,
perhalogenated alkyl, partially perhalogenated alkyl; and B is
heteroaromatic.
3. The compound according to claim 2 wherein C is pyridyl; A is
CX.sub.2R.sup.6 or CR.sup.6.sub.3; R.sup.6 is H, perfluorinated
alkyl, partially fluorinated alkyl, partially halogenated alkyl;
R.sup.7 is H, perfluorinated alkyl and partially fluorinated alkyl,
perhalogenated alkyl, partially perhalogenated alkyl.
4. The compound according to claim 3 wherein A is CX.sub.2R.sup.6;
R.sup.6 is perfluorinated alkyl, partially fluorinated alkyl,
partially halogenated alkyl; R.sup.7 is H.
5. The compound of claim 2 having a structure ##STR00050##
6. The compound of claim 2 having a structure ##STR00051##
7. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are H; C is heteroaryl having the structure ##STR00052## wherein p
is 1, and Z.sup.1-Z.sup.6 are each independently selected from C
and N; R.sup.3 and R.sup.8 are halogen; m is 0-2; n is 0-2; A is
CR.sup.6.sub.3, CX.sub.2R.sup.6; X is a halogen; R.sup.6 is H,
C.sub.1-C.sub.6 straight or branched chain alkyl, haloalkyl,
perfluorinated alkyl, partially fluorinated alkyl, perhalogenated
alkyl, partially halogenated alkyl; R.sup.7 is H; and B is
heteroaromatic.
8. The compound according to claim 7, wherein m is 1 or 2; n is 1
or 2; A is CX.sub.2R.sup.6; and R.sup.6 is perfluorinated alkyl or
partially fluorinated alkyl.
9. The compound according to claim 7, wherein R.sup.3 is bromine
and R.sup.8 is chlorine.
10. The compound according to claim 1 having a structure selected
from ##STR00053##
11. An ophthalmic composition comprising as active ingredient a
therapeutically effective amount of a compound according to claim 1
and a pharmaceutically acceptable adjuvant, diluents or
carrier.
12. An ophthalmic composition according to claim 11 wherein the
compound is selected from: ##STR00054##
Description
CROSS-REFERENCE
[0001] This application is a Divisional of U.S. patent application
Ser. No. 12/852,768, filed Aug. 9, 2010, which the benefit of U.S.
Provisional Patent Application Ser. No. 61/232,997, filed on Aug.
11, 2009, each of which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] Described herein are compounds useful as antagonists of
sphingosine-1-phosphate receptors. Use of these compounds and
pharmaceutical compositions including these compounds in treating
disorders associated with sphingosine-1-phosphate 3 (S1P3) receptor
modulations are described.
BACKGROUND
[0003] A sphingolipid is a lipid having important roles within a
living body. Various sphingolipids, having sphingosine as a
constituent, are widely distributed within a living body, including
within the nervous system on the surface cell membranes.
Sphingosine is a compound having the chemical structure
##STR00001##
wherein Y is hydrogen. Sphingolipids present on cell membranes
function to regulate cell growth; participate in the development
and differentiation of cells; function in nerves; are involved in
the infection and malignancy of cells; and the like.
[0004] Many of the physiological roles of sphingolipids remain to
be solved. However, it is known that lipidosis, for example, is
caused by accumulation of a particular sphingolipid in the body.
Further, it has recently been discovered that ceramide, a
derivative of sphingosine, potentially has an important role in the
mechanism of cell signal transduction, and studies about its effect
on apoptosis and cell cycle have been reported.
[0005] Sphingosine-1-phosphate, for example, is an important
cellular metabolite, derived from ceramide that is synthesized de
novo or as part of the sphingomyeline cycle (in animal cells).
Sphingosine-1-phosphate has also been found in insects, yeasts and
plants.
[0006] The enzyme, ceramidase, acts upon ceramides to release
sphingosine, which is phosphorylated by sphingosine kinase, a
ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form
sphingosine-1-phosphate. The reverse reaction can also occur by the
action of sphingosine phosphatases, and the enzymes act in concert
to control the cellular concentrations of sphingosine-1-phosphate.
In plasma, sphingosine-1-phosphate concentrations can reach 0.2 to
0.9 .mu.M, and is found in association with the lipoproteins,
especially high density lipoproteins (HDL). It should also be noted
that sphingosine-1-phosphate formation is an essential step in the
catabolism of sphingoid bases.
[0007] Like its precursors, sphingosine-1-phosphate is a potent
messenger molecule that perhaps uniquely operates both intra- and
inter-cellularly, but with very different functions from ceramides
and sphingosine. The balance between these various sphingolipid
metabolites may be important for health. For example, within the
cell, sphingosine-1-phosphate promotes cellular division (mitosis)
as opposed to cell death (apoptosis), which it inhibits.
Intracellularly, sphingosine-1-phosphate also functions to regulate
calcium mobilization and cell growth in response to a variety of
extracellular stimuli. It is suggested that the balance between
sphingosine-1-phosphate and ceramide and/or sphingosine levels in
cells is critical for their viability. In common with the
lysophospholipids, especially lysophosphatidic acid, with which it
has some structural similarities, sphingosine-1-phosphate exerts
many of its extra-cellular effects through interaction with five
specific G protein-coupled receptors on cell surfaces. These are
important for the growth of new blood vessels, vascular maturation,
cardiac development, cardiac immunity, and for directed cell
movement.
[0008] Sphingosine-1 phosphate is stored in relatively high
concentrations in human platelets, which lack the enzymes
responsible for its catabolism. Sphingosine-1 phosphate is released
into the blood stream upon activation of physiological stimuli,
such as growth factors, cytokines, and receptor agonists and
antigens. It might also play a critical role in platelet
aggregation and thrombosis, and could aggravate cardiovascular
disease. Alternatively, the relatively high concentration of the
sphingosine-1 phosphate in HDL may have beneficial implications for
atherogenesis. For example, there are recent suggestions that
sphingosine-1-phosphate, together with other lysolipids such as
sphingosylphosphorylcholine and lysosulfatide, are responsible for
beneficial clinical effects of HDL by stimulating the production of
the potent antiatherogenic signaling molecule nitric oxide by the
vascular endothelium. In addition, similar to lysophosphatidic
acid, sphingosine-1 phosphate is a marker for certain types of
cancer, and there is evidence that sphingosine-1 phosphate's role
in cell division and proliferation may have an influence on the
development of cancers. These are currently topics that are
attracting great interest amongst medical researchers, and the
potential for therapeutic intervention in sphingosine-1-phosphate
metabolism is under active investigation.
[0009] Further, fungi and plants have sphingolipids and the major
sphingosine contained in these organisms has the formula
##STR00002##
These lipids have important roles in the cell growth of fungi and
plants, but details of the roles remain to be solved.
[0010] Derivatives of sphingolipids and their related compounds
exhibit a variety of biological activities through inhibition or
stimulation of metabolic pathways. These compounds include
inhibitors of protein kinase C, inducers of apoptosis,
immuno-suppressive compounds, antifungal compounds, and the like.
Substances having these biological activities can be useful
compounds for treating various diseases.
[0011] Derivatives of sphingosine have been prepared in various
patents. For example, see U.S. Pat. Nos. 4,952,683; 5,110,987;
6,235,912 and 6,239,297. Also, compounds which are similar to some
sphingosine derivatives, but which are not reported as being
ligands for the sphingosine receptors, are reported in various
patents and published patent applications. See for example, U.S.
Pat. Nos. 5,294,722; 5,102,901; 5,403,851 and 5,580,878, and U.S.
Patent Application Publication No. U.S. 2003/0125371.
SUMMARY
[0012] Described herein are compounds that are useful as
sphingosine-1-phosphate (S1P) antagonists. These compounds are
useful in treating a wide variety of disorders associated with
modulation of S1P receptors. These compounds are useful for the
treatment of humans with diseases and conditions that are
alleviated by S1P modulation, such as S1P2 and S1P3 receptor
modulations, and in particular, use as S1P3 antagonists. The
compounds described herein can be, in one example embodiment,
substituted picolinamines and substituted benzamides. Further,
pharmaceutically acceptable salts, hydrates, solvates, crystal
forms and individual isomers, enantiomers, and diastereomers
thereof of the compounds described herein can be utilized.
[0013] In one embodiment described herein, compounds are described
having the structure
##STR00003##
wherein R.sup.1 and R.sup.2 are each independently selected from H
and C.sub.1-C.sub.4 alkyl; C is a phenyl, aryl or heteroaryl having
the structure
##STR00004##
wherein the dashed line represents the presence or absence of a
bond, and wherein p is 0-1, and Z.sup.1-Z.sup.6 are each
independently selected from C, N, O or S;
[0014] R.sup.3 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6 straight or branched chain alkyl, alkenyl, or
alkynl, alkoxy (such as O(C.sub.1-C.sub.6)), --OH, halogen,
--NR.sup.4.sub.2, --CN, --CO.sub.2R.sup.4, --C(O)NR.sup.4R.sup.5,
--CH.sub.2OH, --CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --NO.sub.2,
alkylamino, or alkylcarboxyl;
[0015] m is 0-5;
[0016] n is 0-5;
[0017] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6, branched or unbranched alkyl, alkenyl, or alkynl,
C.sub.3-C.sub.6 saturated or unsaturated cyclic hydrocarbon, aryl,
heteroaryl, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl,
alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate,
alkylamide, alkylamino aminocarbonyl, or amino;
[0018] A is CR.sup.6.sub.3, CXR.sup.6.sub.2, CX.sub.2R.sup.6,
CX.sub.3, COQ.sup.1, SOQ.sup.1, SO.sub.2Q.sup.1, CSQ.sup.1, phenyl,
substituted phenyl, heterocylic, heteroaromatic, cycloalkyl,
cycloalkenyl sulfonyl, sulfone, sulfonamide, sulfoxide, ester, or
thiocarbonyl;
[0019] X is a halogen;
[0020] R.sup.6 is H, C.sub.1-C.sub.6 straight or branched chain
alkyl, alkenyl, or alkynyl, haloalkyl, perfluorinated alkyl,
partially fluorinated alkyl, perhalogenated alkyl, partially
halogenated alkyl, phenyl, substituted phenyl, heteroaryl, cyano,
ketyl, and the like;
[0021] Q.sup.1 is an aryl or heteroaryl variably substituted with
(R.sup.3).sub.n, a phenyl, heteroaromatic or cycloalkyl,
cycloalkenyl, or partially saturated or saturated heterocyclic ring
a bicyclic compound, NR.sup.4R.sup.5;
[0022] R.sup.7 is H, C.sub.1-C.sub.6 branched or unbranched alkyl,
alkenyl, or alkynl, haloalkyl, aryl, heteroaryl, perfluorinated
alkyl and partially fluorinated alkyl, phenyl, cyano, ketyl,
CF.sub.3, substituted aryl or heteroaryl or spirocyclic compounds;
and
[0023] B is phenyl, aryl, heteroaromatic or cycloalkyl,
cycloalkenyl, or partially saturated or saturated heterocyclic
ring, or a bicyclic compound, with the proviso that when A is
CX.sub.3, B is not phenyl.
[0024] In one example embodiment, R.sup.1 and R.sup.2 are H; C is
aryl or heteroaryl having the structure
##STR00005##
wherein p is 0 or 1, and Z.sup.1-Z.sup.6 are each independently
selected from C, N, O and S; R.sup.3 and R.sup.8 are halogen; m is
0-2; n is 0-2; A is COQ.sup.1, SOQ.sup.1, SO.sub.2Q.sup.1,
CSQ.sup.1, amide, sulfonyl, sulfone, sulfonamide, sulfoxide, ester,
or thiocarbonyl; Q.sup.1 is an aryl or heteroaryl variably
substituted with (R.sup.3).sub.n, a phenyl, heteroaromatic or
cycloalkyl, cycloalkenyl, or partially saturated or saturated
heterocyclic ring a bicyclic compound, NR.sup.4R.sup.5; R.sup.7 is
H; and B is phenyl, heteroaromatic or cycloalkyl, cycloalkenyl, or
partially saturated or saturated heterocyclic ring, or a bicyclic
compound.
[0025] In another example embodiment, C is pyridyl; A is COQ.sup.1;
Q.sup.1 is an aryl or heteroaryl variably substituted with
(R.sup.3).sub.n; and B is phenyl.
[0026] In yet another example embodiment, the compound has a
structure selected from:
##STR00006##
[0027] In one example embodiment described herein, a compound is
described wherein R.sup.1 and R.sup.2 are H; C is aryl or
heteroaryl having the structure
##STR00007##
wherein p is 0 or 1, and Z.sup.1-Z.sup.6 are each independently
selected from C, N, O and S; R.sup.3 and R.sup.8 are halogen; m is
0-2; n is 0-2; A is CR.sup.6.sub.3, CXR.sup.6.sub.2,
CX.sub.2R.sup.6, CX.sub.3; X is a halogen; R.sup.6 is H,
C.sub.1-C.sub.6 straight or branched chain alkyl, alkenyl, or
alkynl, haloalkyl, perfluorinated alkyl, partially fluorinated
alkyl, phenyl, substituted phenyl, heteroaryl, cyano, ketyl, and
the like; R.sup.7 is H; and B is phenyl, aryl, heteroaromatic or
cycloalkyl, cycloalkenyl, or partially saturated or saturated
heterocyclic ring, or a bicyclic compound, with the proviso that
when A is CX.sub.3, B is not phenyl.
[0028] In another example embodiment, m is 0-2; n is 0-2; A is
CR.sup.6.sub.3, CXR.sup.6.sub.2, CX.sub.2R.sup.6; X is a halogen;
R.sup.6 is perfluorinated alkyl or partially fluorinated alkyl,
perhalogenated alky or partially halogenated alkyl; and B is
phenyl, aryl, or heteroaromatic.
[0029] In yet another example embodiment, R.sup.3 is bromine and
R.sup.8 is halogen or methyl.
[0030] In yet another example embodiment, the compound has a
structure selected from:
##STR00008##
[0031] In one example embodiment, wherein R.sup.1 and R.sup.2 are
each independently selected from H and C.sub.1-C.sub.4 alkyl;
C is a phenyl, aryl or heteroaryl having the structure
##STR00009##
p is 0-1, and Z.sup.1-Z.sup.6 are each independently selected from
C, N, O or S;
[0032] R.sup.3 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6 straight or branched chain alkyl, alkenyl, or
alkynl, alkoxy (such as O(C.sub.1-C.sub.6)), --OH, halogen,
--NR.sup.4.sub.2, --CN, --CO.sub.2R.sup.4, --C(O)NR.sup.4R.sup.5,
--CH.sub.2OH, --CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --NO.sub.2,
alkylamino, or alkylcarboxyl;
[0033] m is 0-2;
[0034] n is 0-2;
[0035] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6, branched or unbranched alkyl, alkenyl, or alkynl,
C.sub.3-C.sub.6 saturated or unsaturated cyclic hydrocarbon, aryl,
heteroaryl, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl,
alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate,
alkylamide, alkylamino aminocarbonyl, or amino;
[0036] A is phenyl, substituted phenyl, heterocylic,
heteroaromatic, cycloalkyl, or cycloalkenyl;
[0037] R.sup.7 is H, C.sub.1-C.sub.6 branched or unbranched alkyl,
alkenyl, or alkynl, haloalkyl, aryl, heteroaryl, perfluorinated
alkyl and partially fluorinated alkyl, phenyl, cyano, ketyl,
CF.sub.3, substituted aryl or heteroaryl; and
[0038] B is phenyl, aryl, heteroaromatic or cycloalkyl,
cycloalkenyl, or partially saturated or saturated heterocyclic
ring, or a bicyclic compound.
[0039] In another example embodiment, the compound has a structure
selected from
##STR00010##
[0040] Further described herein in one embodiment is a compound
having a structure selected from
##STR00011## ##STR00012##
[0041] Also described herein are compositions comprising a
pharmaceutically acceptable amount of a compound as described
herein.
DEFINITION OF TERMS
[0042] Certain terms as used in the specification are intended to
refer to the following definitions, as detailed below. Where the
definition of terms departs from the commonly used meaning of the
term, applicant intends to utilize the definitions provided below,
unless specifically indicated.
[0043] As used herein, "alkyl" refers to straight, branched chain
or cyclic hydrocarbyl groups having from 1 to about 100 carbon
atoms. Whenever it appears herein, a numerical range, such as "1 to
100" or "C.sub.1-C.sub.100", refers to each integer in the given
range; e.g., "C.sub.1-C.sub.100 alkyl" means that an alkyl group
may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 100 carbon atoms, although the term
"alkyl" also includes instances where no numerical range of carbon
atoms is designated. As used herein, "substituted alkyl" refers to
alkyl moieties bearing substituents typically selected from alkyl,
alkenyl, alkynyl, hydroxy, alkoxy, heterocyclic, aryl, heteroaryl,
aryloxy, halogen, haloalkyl, cyano, nitro, amino, lower alkylamino,
lower dialkylamino, amido, azido, acyl (--C(O)R.sup.9),
alkoxymethyl, mercapto (--S--R.sup.9), sulfoxy (--S(O)--R.sup.9),
sulfonyl (--S(O).sub.2--R.sup.9), sulfonamide
(--S(O).sub.2N(R.sup.9).sub.2), carbonate (--OC(O)--O--R.sup.9),
oxyacyl (--OC(O)--R.sup.9), carboxyl (--C(O)ON), ester
(--C(O)OR.sup.9), carbamate (--OC(O)--N(R.sup.9).sub.2), wherein
R.sup.9 is H or lower alkyl, lower alkenyl, lower alkynyl, aryl,
heteroaryl, heterocycle, and the like. As used herein, "lower
alkyl" refers to alkyl moieties having from 1 to about 6 carbon
atoms.
[0044] As used herein, "alkenyl" refers to straight, branched chain
or cyclic hydrocarbyl groups having at least one carbon-carbon
double bond, and having in the range of about 2 up to about 100
carbon atoms, and "substituted alkenyl" refers to alkenyl groups
further bearing one or more substituents as set forth above. As
used herein, "lower alkenyl" refers to alkenyl moieties having from
1 to about 6 carbon atoms.
[0045] As used herein, "alkylacyl" refers to an alkyl ketone such
as ethanone, propanone, and the like.
[0046] As used herein, "alkynyl" refers to straight or branched
chain hydrocarbyl groups having at least one carbon-carbon triple
bond, and having in the range of about 2 up to about 100 carbon
atoms, and "substituted alkynyl" refers to alkynyl groups further
bearing one or more substituents as set forth above. As used
herein, "lower alkynyl" refers to alkynyl moieties having from 2 to
about 6 carbon atoms.
[0047] As used herein, "aryl" refers to aromatic groups having in
the range of 6 up to 14 carbon atoms and "substituted aryl" refers
to aryl groups further bearing one or more substituents as set
forth above.
[0048] As used herein, "cycloalkyl" refers to cyclic (i.e.,
ring-containing) alkyl moieties typically containing in the range
of about 3 up to about 8 carbon atoms, and "substituted cycloalkyl"
refers to cycloalkyl groups further bearing one or more
substituents as set forth above.
[0049] As used herein, "halogen" or "halide" refers to fluoride,
chloride, bromide or iodide. The terms "fluoro", "chloro", "bromo",
and "iodo" may also be used when referring to halogenated
substituents, for example, "trifluoromethyl."
[0050] As used herein, "heteroaryl" refers to aromatic moieties
containing one or more heteroatoms (e.g., N, O, S, or the like) as
part of the ring structure and having in the range of 5 up to 14
total atoms in the ring structure (i.e., carbon atoms and
heteroatoms). "Substituted heteroaryl" refers to heteroaryl groups
further bearing one or more substituents as set forth above.
[0051] As used herein, "heterocyclic" or "heterocycle" refers to
non-aromatic cyclic (i.e., ring-containing) groups containing one
or more heteroatoms (e.g., N, O, S, or the like) as part of the
ring structure, and having in the range of 3 up to 14 carbon atoms
and "substituted heterocyclic" or "substituted heterocycle" refers
to heterocyclic groups or heterocycles further bearing one or more
substituents as set forth above.
[0052] As used herein, "hydroxyalkyl" refers to alkyl-OH, such as
hydroxymethyl, hydroxyethyl, and the like.
[0053] As used herein, "pharmaceutically acceptable salt" refers to
any salt that retains the activity of the parent compound and does
not impart any additional deleterious or untoward effects on the
subject to which it is administered and in the context in which it
is administered compared to the parent compound. A pharmaceutically
acceptable salt also refers to any salt which may form in vivo as a
result of administration of an acid, another salt, or a prodrug
which is converted into an acid or salt. Further, pharmaceutically
acceptable salt refers to those salts which retain the biological
effectiveness and properties of the free bases and which are
obtained by reaction with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid and the like.
[0054] Pharmaceutically acceptable salts of acidic functional
groups may be derived from organic or inorganic bases. The salt may
comprise a mono or polyvalent ion. Of particular interest are the
inorganic ions, lithium, sodium, potassium, calcium, and magnesium.
Organic salts may be made with amines, particularly ammonium salts
such as mono-, di- and trialkyl amines or ethanol amines. Salts may
also be formed with caffeine, tromethamine and similar molecules.
Hydrochloric acid or some other pharmaceutically acceptable acid
may form a salt with a compound that includes a basic group, such
as an amine or a pyridine ring.
[0055] As used herein "prodrug" refers to a compound which is
converted to a therapeutically active compound after
administration, and the term should be interpreted as broadly
herein as is generally understood in the art. While not intending
to limit the scope of the present description, conversion may occur
by hydrolysis of an ester group or some other biologically labile
group. Generally, but not necessarily, a prodrug is inactive or
less active than the therapeutically active compound to which it is
converted. Ester prodrugs of the compounds disclosed herein are
contemplated. An ester may be derived from a carboxylic acid of
C.sub.1 (i.e. the terminal carboxylic acid of a natural
prostaglandin), or an ester may be derived from a carboxylic acid
functional group on another part of the molecule, such as on a
phenyl ring. While not intending to be limiting, an ester may be an
alkyl ester, an aryl ester, or a heteroaryl ester.
[0056] As used herein, "tautomer" refers to the migration of
protons between adjacent single and double bonds. The
tautomerization process is reversible. Compounds described herein
can undergo any possible tautomerization that is within the
physical characteristics of the compound. The following is an
example tautomerization that can occur in compounds described
herein:
##STR00013##
[0057] As used herein, the term "therapeutically effective amount"
means the amount of the pharmaceutical composition that will elicit
the biological or medical response of a subject in need thereof
that is being sought by the researcher, veterinarian, medical
doctor or other clinician. In some embodiments, the subject in need
thereof is a mammal. In some embodiments, the mammal is human.
DETAILED DESCRIPTION OF THE INVENTION
[0058] Described herein are compounds that are useful as
sphingosine-1-phosphate (S1P) antagonists, and therefore, are
useful in treating a wide variety of disorders associated with
modulation of S1P receptors or are useful for the treatment of
humans with diseases and conditions that are alleviated by S1P
modulation, and in particular use as S1P3 antagonists. The
compounds described herein can be, in one example embodiment,
substituted picolinamines and substituted benzamides.
[0059] In one example embodiment described herein, compounds are
described having the structure
##STR00014##
wherein R.sup.1 and R.sup.2 are each independently selected from H,
C.sub.1-C.sub.4 alkyl; C is a phenyl, aryl or heteroaryl having the
structure
##STR00015##
wherein a dashed line represents the presence or absence of a bond
and wherein p is 0-1, and Z.sup.1-Z.sup.6 are each independently
selected from C, N, O or S;
[0060] R.sup.3 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6 straight or branched chain alkyl, alkenyl, or
alkynl, alkoxy (such as O(C.sub.1-C.sub.6)), --OH, halogen,
--NR.sup.4.sub.2, --CN, --CO.sub.2R.sup.4, --C(O)NR.sup.4R.sup.5,
--CH.sub.2OH, --CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --NO.sub.2,
alkylamino, or alkylcarboxyl;
[0061] m is 0-5;
[0062] n is 0-5;
[0063] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6, branched or unbranched alkyl, alkenyl, or alkynl,
C.sub.3-C.sub.6 saturated or unsaturated cyclic hydrocarbon, aryl,
heteroaryl, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl,
alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate,
alkylamide, alkylamino aminocarbonyl, or amino;
[0064] A is CR.sup.6.sub.3, CXR.sup.6.sub.2, CX.sub.2R.sup.6,
CX.sub.3, COQ.sup.1, SOQ.sup.1, SO.sub.2Q.sup.1, CSQ.sup.1, amide,
sulfonyl, sulfone, sulfonamide, sulfoxide, ester, thiocarbonyl,
phenyl, substituted phenyl, heterocylic, heteroaromatic,
cycloalkyl, or cycloalkenyl;
[0065] X is a halogen;
[0066] R.sup.6 is H, C.sub.1-C.sub.6 straight or branched chain
alkyl, alkenyl, or alkynl, haloalkyl, perfluorinated alkyl,
partially fluorinated alkyl, perhalogenated alkyl, phenyl,
substituted phenyl, heteroaryl, cyano, ketyl, or the like;
[0067] Q.sup.1 is an aryl or heteroaryl variably substituted with
(R.sup.3).sub.n, a phenyl, heteroaromatic or cycloalkyl,
cycloalkenyl, or partially saturated or saturated heterocyclic ring
a bicyclic compound, NR.sup.4R.sup.5;
[0068] R.sup.7 is H, C.sub.1-C.sub.6 branched or unbranched alkyl,
alkenyl, or alkynl, haloalkyl, aryl, herteoaryl, perfluorinated
alkyl and partially fluorinated alkyl, phenyl, cyano, ketyl,
CF.sub.3, substituted aryl or heteroaryl or spirocyclic compounds;
and
[0069] B is a variably substituted phenyl, heteroaromatic or
cycloalkyl, cycloalkenyl, or partially saturated or saturated
heterocyclic ring, or a bicyclic compound.
[0070] Further, pharmaceutically acceptable salts, hydrates,
solvates, crystal forms and individual isomers, enantiomers, or
diastereomers thereof of the above compounds are contemplated.
[0071] In one example embodiment, when A is CX.sub.3, for example
in the structure
##STR00016##
then B is not phenyl.
[0072] Another example embodiment includes the following
structure
##STR00017##
wherein Q.sup.2=C(O)Q.sup.1 where Q.sup.1 is primarily the carbon
ring.
[0073] Some example compounds include:
##STR00018## ##STR00019## ##STR00020##
Further example compounds include:
##STR00021## ##STR00022##
Further example compounds include
##STR00023## ##STR00024##
[0074] The compounds and pharmaceutical compositions described
herein are useful as medicaments in mammals, including humans, for
treatment of diseases and or alleviations of conditions which are
responsive to treatment by antagonists of sphingosine-1-phosphate
receptors. Thus, in further example embodiments, there are provided
methods for treating a disorder associated with modulation of
sphingosine-1-phosphate receptors. Such methods can be performed,
for example, by administering to a subject in need thereof a
pharmaceutical composition containing a therapeutically effective
amount of at least one invention compound. The compounds described
herein are useful for the treatment of mammals, including humans,
with a range of conditions and diseases that are alleviated by S1P
modulation such as the following conditions: [0075] Allergies and
other inflammatory diseases: Urticaria, bronchial asthma, and other
airway inflammations including pulmonary emphysema and chronic
obstructive pulmonary diseases; [0076] Cardiac functions:
bradycardia, congestional heart failure, cardiac arrhythmia,
prevention and treatment of atherosclerosis, and
ischemia/reperfusion injury; [0077] Anti-fibrosis: ocular, cardiac,
hepatic and pulmonary fibrosis, proliferative vitreoretinopathy,
cicatricial pemphigoid, surgically induced fibrosis in cornea,
conjunctiva and tenon; and [0078] Pains and Inflammatory diseases:
Acute pain, flare-up of chronic pain, musculo-skeletal pains,
visceral pain, pain associated with diabetic neuropathy, rheumatoid
arthritis, chronic knee and joint pain, tendonitis, osteoarthritis,
bursitis, neuropathic pains.
[0079] The compounds described herein may be administered at
pharmaceutically effective dosages. Such dosages are normally the
minimum dose necessary to achieve the desired therapeutic effect;
in the treatment of chromic pain, this amount would be roughly that
necessary to reduce the discomfort caused by the pain to tolerable
levels. Generally, such doses will be in the range 1-1000 mg/day;
more preferably in the range 10 to 500 mg/day. In another example
embodiment, the compound or compounds may be present in a
composition in a range of about 0.5 or about 1 to about 100
mg/kg/day. However, the actual amount of the compound to be
administered in any given case will be determined by a physician
taking into account the relevant circumstances, such as the
severity of the pain, the age and weight of the patient, the
patient's general physical condition, the cause of the pain, and
the route of administration.
[0080] The compounds are useful in the treatment of pain in a
mammal; particularly a human being. Both acute pain and chronic
pain may be treated by administration of the compounds and
compositions described herein. By "acute pain" is meant immediate,
usually high threshold, pain brought about by injury such as a cut,
crush, burn, or by chemical stimulation such as that experienced
upon exposure to capsaicin, the active ingredient in chili peppers.
By "chronic pain" is meant pain other than acute pain, such as,
without limitation, neuropathic pain, visceral pain (including that
brought about by Crohn's disease and irritable bowel syndrome
(IBS)), and referred pain.
[0081] Preferably, the patient will be administered a compound
orally in any acceptable form, such as a tablet, liquid, capsule,
powder and the like. However, other routes may be desirable or
necessary, particularly if the patient suffers from nausea. Such
other routes may include, without exception, transdermal,
parenteral, subcutaneous, intranasal, intrathecal, intramuscular,
intravenous, and intrarectal modes of delivery. Additionally,
formulations may be designed to delay release of the active
compound over a given period of time, or to carefully control the
amount of drug released at a given time during the course of
therapy.
[0082] In another embodiment, provided are pharmaceutical
compositions including at least one compound in a pharmaceutically
acceptable carrier. The phrase "pharmaceutically acceptable" means
the carrier, dilutent or excipient must be compatible with the
other ingredients of the formulation and not deleterious to the
recipient thereof.
[0083] Pharmaceutical compositions can be used in the form of a
solid, a solution, an emulsion, a dispersion, a micelle, a
liposome, and the like, wherein the resulting composition contains
one or more compounds described herein, as an active ingredient, in
admixture with an organic or inorganic carrier or excipient
suitable for enteral or parenteral applications. One or more
compounds may be combined, for example, with the usual non-toxic,
pharmaceutically acceptable carriers for tablets, pellets,
capsules, suppositories, solutions, emulsions, suspensions, and any
other form suitable for use. The carriers which can be used include
glucose, lactose, gum acacia, gelatin, mannitol, starch paste,
magnesium trisilicate, talc, corn starch, keratin, colloidal
silica, potato starch, urea, medium chain length triglycerides,
dextrans, and other carriers suitable for use in manufacturing
preparations, in solid, semisolid, or liquid form. In addition
auxiliary, stabilizing, thickening and coloring agents and perfumes
may be used. Compounds described herein are included in
pharmaceutical compositions in an amount sufficient to produce the
desired effect upon the process or disease condition.
[0084] Pharmaceutical compositions may be in a form suitable for
oral use, for example, as tablets, troches, lozenges, aqueous or
oily suspensions, dispersible powders or granules, emulsions, hard
or soft capsules, or syrups or elixirs. Compositions intended for
oral use may 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 a sweetening agent such as sucrose, lactose, or
saccharin, flavoring agents such as peppermint, oil of wintergreen
or cherry, coloring agents and preserving agents in order to
provide pharmaceutically elegant and palatable preparations.
Tablets containing compounds described herein in admixture with
non-toxic pharmaceutically acceptable excipients may also be
manufactured by known methods.
[0085] The excipients used may be, for example, (1) inert diluents
such as calcium carbonate, lactose, calcium phosphate or sodium
phosphate; (2) granulating and disintegrating agents such as corn
starch, potato starch or alginic acid; (3) binding agents such as
gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating
agents such as magnesium stearate, stearic acid or talc. The
tablets may be uncoated or they may 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 may be employed.
[0086] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the compounds are mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin. They may also be in the form of soft gelatin
capsules wherein the invention compounds are mixed with water or an
oil medium, for example, peanut oil, liquid paraffin, or olive
oil.
[0087] The pharmaceutical compositions may also be in the form of a
sterile injectable suspension. Suspensions may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparations
may also be sterile injectable solutions or suspensions in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0088] Compounds described herein may also be administered in the
form of suppositories for rectal administration. These compositions
may be prepared by mixing the compounds with a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters of polyethylene glycols, which are solid at ordinary
temperatures, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0089] The compounds described herein can also be administered as
an ophthalmically acceptable formulation or composition. A liquid
which is ophthalmically acceptable is formulated such that it can
be administered topically to the eye. The comfort should be
maximized as much as possible, although sometimes formulation
considerations (e.g. drug stability) may necessitate less than
optimal comfort. In the case that comfort cannot be maximized, the
liquid should be formulated such that the liquid is tolerable to
the patient for topical ophthalmic use. Additionally, an
ophthalmically acceptable liquid should either be packaged for
single use, or contain a preservative to prevent contamination over
multiple uses.
[0090] For ophthalmic application, solutions or medicaments are
often prepared using a physiological saline solution as a major
vehicle. Ophthalmic solutions should preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0091] Preservatives that may be used in ophthalmic compositions
described herein include, but are not limited to, benzalkonium
chloride, chlorobutanol, thimerosal, phenylmercuric acetate and
phenylmercuric nitrate. A useful surfactant is, for example, Tween
80. Likewise, various useful vehicles may be used in the ophthalmic
preparations of the present invention. These vehicles include, but
are not limited to, polyvinyl alcohol, povidone, hydroxypropyl
methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl
cellulose and purified water.
[0092] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0093] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
[0094] In one example embodiment, an ophthalmic composition as
described herein may have ingredients used in the following amounts
listed in Table 1.
TABLE-US-00001 TABLE 1 Ingredient Amount (% w/v) active ingredient
about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor
1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as
needed surfactant as needed purified water as needed to make
100%
[0095] Since individual subjects may present a wide variation in
severity of symptoms and each composition has its unique
therapeutic characteristics, the precise mode of administration and
dosage employed for each subject is left to the discretion of the
practitioner.
Example 1
General Synthesis A
##STR00025##
[0097] Scheme A depicts example methods for preparation of
compounds described herein. Substituted (halogenated) picolinamides
101 are reacted with substituted 2,2-dihydroxy-1-arylethanones 102
to form intermediates such as 103. Activation of 103 with a reagent
such as PCl.sub.5 precedes reaction with various anilines, such as
4-haloaniline 104, to form Product 1.
Example 2
General Synthesis B
##STR00026##
[0099] Scheme B depicts example methods for preparation of
compounds described herein. Aldehydes such as substituted aryl
aldehydes or heteroaryl aldehydes 104 are condensed with
substituted analines to form intermediates such as arylimine 105.
Benzamines (Z.dbd.CH) or picolinamides (Z.dbd.N) 106 are treated
with a base such as sodium hydride and reacted with the arylimines
105, to form Product 2.
Example 3
General Synthesis C
##STR00027##
[0101] Scheme C depicts example methods for preparation of a
variety of compounds described herein. Substituted benzamines or
picolinamines 107 are reacted with an aldehyde in the presence of
an acid (HCl or pTsOH) to form intermediate material 108. The
intermediate material 108 can be activated with an appropriate
leaving group such as a halogen or a benzotraizole. This activated
moiety of 108 is reacted with substituted anilines (in the presence
of a base) to form Product 3.
Example 4
General Synthesis D
##STR00028##
[0103] Scheme D depicts another example method for the preparation
of compounds described herein. Materials such as
4-substituted-furan-2-carboxamide 109 are reacted with chloral to
produce materials such as intermediate 110. Intermediate 110 is
reacted with isocyanide compounds to form Product 4.
Example 5
Preparation of
5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-1-O-2-oxoethyl)picolinam-
ide (Compound 1)
##STR00029##
[0105] A mixture of 5-bromopicolinamide 111 (0.588 g, 2.92 mmol)
and 2,2-dihydroxy-1-(naphthalen-1-yl)ethanone 112 (1.20 g, 5.67
mmol) in dioxane (20 mL) were heated at 100.degree. C. for 18
hours. The dioxane was removed under vacuum and the residue was
dissolved in chloroform and methanol and concentrated onto silica
gel. The material was purified by auto flash system
(CH.sub.2Cl.sub.2 to 1% MeOH: CH.sub.2Cl.sub.2) to give
5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide
113 as a tan solid (0.74 g, 66%).
[0106]
5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide
113 (0.74 g, 1.93 mmol) in chloroform (20 mL) was reacted with
PCl.sub.5 (0.43 g, 1.96 mmol). The mixture was heated to 50.degree.
C. for 30 minutes and cooled to 0.degree. C. 4-Chloroaniline 114
(0.512 g, 4.01 mmol) in THF (10 mL) was added and allowed to react
for 1 hour. The reaction was quenched with water and the product
was extracted with ethyl acetate. The organic solution was dried
over MgSO.sub.4, filtered and concentrated onto silica gel. The
product was purified by auto flash column chromatography (30 to 50%
CH.sub.2Cl.sub.2: hexane) followed by titration with diethyl ether
to give
5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-1-yl)-2-oxoethyl)picolin-
amide (Compound 1, 352 mg, 37%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.83 (d, J=8.7 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.46 (d,
J=9.6 Hz, 1H), 8.39 (dd, J=1.2, 7.2 Hz, 1H), 8.07-8.03 (m, 2H),
7.93 (dd, J=2.4, 8.7 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68-7.63 (m,
1H), 7.56 (t, J=7.8 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.09-7.03 (m,
1H), 6.82 (d, J=9.0 Hz, 2H) 5.41 (d, J=8.1 Hz, 1H).
Example 5A-2
[0107] Use of 2,2-dihydroxy-1-(naphthalen-2-yl)ethanone in the
procedure for Example A-1 produced
5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-2-yl)-2-oxoethyl)picolin-
amide (Compound 2): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.87
(d, J=1.5 Hz, 1H), 8.50 (d, J=0.6, 2.4 Hz, 1H), 8.42 (d, J=9.9 Hz,
1H), 8.17 (dd, J=1.8, 8.4 Hz, 1H), 8.10 (dd, J=0.6, 8.4 Hz, 1H),
8.03 (d, J=7.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.86 (d, J=8.1 Hz, 1H),
7.65-7.53 (m, 2H), 7.19-7.12 (m, 3H), 6.85 (d, J=8.7 Hz, 2H), 5.50
(brs, 1H).
Example 5A-3
[0108] Use of 2,2-dihydroxy-1-(3-methoxyphenyl)ethanone in the
procedure for Example A-1 produced
5-bromo-N-(1-(4-chlorophenylamino)-2-(3-methoxyphenyl)-2-oxoethyl)picolin-
amide (Compound 3): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.51
(dd, J=0.9, 2.4 Hz, 1H), 8.35 (d, J=10.2 Hz, 1H), 8.09 (dd, J=0.9,
8.4 Hz, 1H), 7.96 (dd, J=2.1, 8.1 Hz, 1H), 7.84-7.81 (m, 1H),
7.74-7.73 (m, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H),
6.96 (dd, J=8.1, 10.2 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 5.40 (d,
J=8.1 Hz, 1H).
Example 5A-4
[0109] Use of 2,2-dihydroxy-1-phenylethanone in the procedure for
Example A-1 produced
5-bromo-N-(1-(4-chlorophenylamino)-2-oxo-2-phenylethyl)picolinamide
(Compound 4): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.52 (dd,
J=0.9, 2.1 Hz, 1H), 8.36 (d, J=9.9 Hz, 1H), 8.24-8.20 (m, 2H), 8.10
(dd, J=0.9, 8.4 Hz, 1H), 7.97 (dd, J=2.4, 8.4 Hz, 1H), 7.65-7.59
(m, 1H), 7.54-7.59 (m, 1H), 7.54-7.48 (m, 2H), 7.16 (d, J=9.0, 2H),
7.01-6.95 (m, 1H), 6.81 (d, J=9.0 Hz, 2H), 5.38 (d, J=8.1 Hz,
1H).
Example 5A-5
[0110] Use of 1-(biphenyl-4-yl)-2,2-dihydroxyethanone in the
procedure for Example A-1 produced
N-(2-(biphenyl-4-yl)-1-(4-chlorophenylamino)-2-oxoethyl)-5-bromopicolinam-
ide (Compound 5): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.52
(dd, J=0.6, 2.1 Hz, 1H), 8.39 (d, J=9.9 Hz, 1H), 8.29 (d, J=9.0 Hz,
2H), 8.11 (dd, J=0.6, 8.1 Hz, 1H), 7.96 (dd, J=2.4, 8.4 hz, 1H),
7.72 (d, J=8.4 Hz, 2H), 7.62-7.59 (m, 2H), 7.49-7.40 (m, 3H), 7.16
(d, J=8.7 Hz, 2H), 7.01 (dd, J=8.4, 9.9 Hz, 1H), 6.83 (d, J=8.7 Hz,
2H).
Example 6
Preparation of
4-bromo-N-((4-chlorophenylamino)(2,6-difluorophenyl)methyl)benzamide
(Compound 6)
##STR00030##
[0112] A mixture of 4-chloroaniline (1.84 g, 14.1 mmol) and
2,6-difluorobenzaldehyde 115 (1.55 mL, 14.1 mmol) in methanol
(MeOH, 30 mL) was allowed to react for 18 hours at room
temperature. The mixture was evaporated giving
4-chloro-N-(2,6-difluorobenzylidene)aniline 116 as a yellow
solid.
[0113] 4-Bromobenzamide 117 (0.94 g, 4.56 mmol) and 18-crown-6 (1.2
g, 4.54 mmol) in DMF (6 mL) was treated with sodium hydride (0.37
g, 9.25 mmol) for 5 minutes at room temperature.
4-Chloro-N-(2,6-difluorobenzylidene)aniline 116 (0.936 g, 3.72
mmol) in DMF (4 mL) was added and the mixture was heated to
50.degree. C. for 5 minutes. The reaction mixture was quenched with
crushed ice and the product was isolated by a typical aqueous
workup and extraction with ethyl acetate. Chromatographic
purification (9:1 hexanes:ethyl acetate) followed by trituration
(ethanol) of the material gave
4-bromo-N-((4-chlorophenylamino)(2,6-difluorophenyl)methyl)benzamide
(Compound 6) as a white solid (292 mg, 17%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=7.62-7.52 (series m, 4H), 7.38-7.28 (m, 1H),
7.19-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.02-6.96 (m, 2H), 6.88-6.85
(m, 1H), 6.76-6.72 (m, 2H).
Example 6A-1
[0114]
5-Bromo-N-((4-chlorophenyl)(4-chlorophenylamino)methyl)picolinamide
(Compound 7): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.57 (dd,
J=2.1, 0.6 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.08 (dd, J=8.1, 0.6
Hz, 1H), 7.99 dd, J=8.4, 2.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.40-7.36
(m, 2H), 7.15-7.11 (m, 2H), 6.69-6.65 (m, 2H), 6.57 (t, J=7.5 Hz,
1H), 4.35 (d, J=7.2 Hz, 1H).
Example 6A-2
[0115]
4-Bromo-N-((4-chlorophenylamino)(quinolin-7-yl)methyl)benzamide
(Compound 8): .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta.=9.35 (t,
J=3.6 Hz, 1H), 8.90 (dd, J=4.2, 1.8 Hz, 1H), 8.36 (d, J=8.1 Hz,
1H), 8.20 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H),
7.78 (dd, J=8.4, 1.5 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.52 (dd,
J=8.1, 4.2 Hz, 1H), 7.14 (d, J=9.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H),
6.65 (d, J=3.6 Hz, 2H).
Example 6A-3
[0116]
5-Bromo-N-((4-chlorophenylamino)(quinolin-7-yl)methyl)picoinamide
(Compound 9): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.87 (dd,
J=4.5, 1.8 Hz, 1H), 8.59 (d, J=8.7 Hz, 1H), 8.50 (dd, J=2.1, 0.6
Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=4.2 Hz, 1H), 8.04 (dd, J=8.4, 0.5
Hz, 1H), 7.93 (dd, J=8.4, 2.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68
(dd, J=8.7, 1.8 Hz, 1H), 7.38 (dd, J=8.7, 2H), 6.82 (t, J=8.4 Hz,
1H), 6.72 (d, J=9.3 Hz, 2H), 4.77 (d, J=7.5 Hz, 1H).
Example 6A-4
[0117]
N-(benzofuran-2-yl(4-chlorophenylamino)methyl)-5-bromopicolinamide
(Compound 10): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.59 (dd,
J=0.9, 2.1 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.11 (dd, J=0.6, 8.4
Hz, 1H), 7.99 (dd, J=2.4, 8.1 Hz, 1H), 7.57-7.48 (m, 2H), 7.34-7.24
(m, 2H), 7.18-7.15 (m, 2H), 6.85-6.76 (m, 4H), 4.77 (d, J=8.4 Hz,
1H).
Example 6A-5
[0118]
N-(benzo[b]thiophen-2-yl(4-chlorophenylamino)methyl)-5-bromopicolin-
amide (Compound 11): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.59 (dd, J=0.9, 2.1 Hz, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.11
(dd, J=0.6, 8.4 Hz, 1H), 7.98 (dd, J=1.8, 8.1 Hz, 1H), 7.82-7.78
(m, 1H), 7.73-7.70 (m, 1H), 7.39-7.31 (m, 3H), 7.15 (d, J=8.7 Hz,
2H), 6.98-6.92 (m, 1H), 6.76 (d, J=9.0 Hz, 2H), 4.70 (d, J=8.1 Hz,
1H).
Example 6A-6
[0119]
5-bromo-N-((4-chlorophenylamino)(pyridin-3-yl)methyl)picolinamide
(Compound 12): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.81 (d,
J=2.4 Hz, 1H), 8.60 (dd, J=1.8, 5.1 Hz, 1H), 8.56 (dd, J=0.9, 2.4
Hz, 1H), 8.44 (d, J=8.7 Hz, 1H), 8.07 (dd, J=0.9, 8.7 Hz, 1H), 7.98
(dd, J=1.8, 8.1 Hz, 1H), 7.87-7.83 (m, 1H), 7.34-7.30 (m, 1H), 7.13
(d, J=9.0 Hz, 2H), 6.71-6.63 (m, 3H), 4.51 (d, J=7.5 Hz, 1H).
Example 6A-7
[0120]
5-bromo-N-((4-chlorophenylamino)(pyridin-4-yl)methyl)picolinamide
(Compound 13): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.65 (dd,
J=1.8, 4.8 Hz, 2H), 8.58 (dd, J=0.6, 2.1 Hz, 1H), 8.42 (d, J=8.4
Hz, 1H), 8.08 (dd, J=0.9, 8.4 Hz, 1H), 8.00 (dd, J=2.1, 8.1 Hz,
1H), 7.47-7.45 (m, 2H), 7.14 (d, J=9.0 Hz, 2H), 6.69 (t, J=8.7 Hz,
2H), 6.62 (t, J=8.4 Hz, 1H), 4.48 (d, J=7.8 Hz, 1H).
Example 6A-8
[0121]
5-bromo-N-((4-chlorophenylamino)(pyridin-2-yl)methyl)picolinamide
(Compound 14): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.62-8.60
(m, 1H), 8.52 (dd, J=0.6, 2.4 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.10
(dd, J=0.6, 8.4 Hz, 1H), 7.96 (dd, J=2.4, 8.4 Hz, 1H), 7.75-7.69
(m, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.13 (d, J=9.0
Hz, 2H), 6.77 (d, J=8.7 Hz, 2H), 6.69 (dd, J=7.5, 9.0 Hz, 1H), 5.78
(d, J=7.5 Hz, 1H).
Example 7
Preparation of
4-bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)benmide
(Compound 15)
##STR00031##
[0123] 4-Bromobenzamide 118 (1.0 g, 4.85 mmol), 2,2-dichlorobutanal
(2 mL) and HCl (3 drops) in dioxane (4 mL) were heated to
120.degree. C. (bath temperature) for 18 hours. The mixture was
concentrated, and absorbed onto silica gel. Chromatography
(CH.sub.2Cl.sub.2) produced an off-white solid as
4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g,
51%).
[0124] A solution of
4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g, 2.48
mmol) in chloroform (15 mL) was reacted with PCl.sub.5 (0.54 g,
2.46 mmol) at 50.degree. C. for 30 minutes. The mixture was cooled
to room temperature and quenched with ice. The aqueous layer was
extracted with ether. The organic solution was dried over
MgSO.sub.4, filtered, and reacted with 4-chloroaniline (0.66 g,
5.17 mmol). The mixture was stirred for 18 hours at room
temperature. An acidic, (HCl) aqueous workup and ether extraction
preceded chromatographic purification on silica gel (7:3
hexane:CH.sub.2Cl.sub.2).
4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)benzamide
(Compound 15) was obtained as a white solid (701 mg, 62%). .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=7.64-7.56 (m, 4H), 7.16 (d,
J=9.0 Hz, 2H), 6.73 (d, J=8.7 Hz, 2H), 6.48 (d, J=9.6 Hz, 1H), 6.01
(d, J=9.0 Hz, 1H), 2.50-2.27 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
[0125] The following compounds were prepared according to
procedures outlined in Example B.
Example 7B-1
[0126]
4-Bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,3-pentafluoropropyl)benz-
amide (Compound 16): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=7.71 (d, J=5.4 Hz, 2H), 7.64 (d, J=5.4 Hz, 2H), 7.15 (d,
J=5.4 Hz, 2H), 6.33 (dd, J=9.3, 5.1 Hz, 1H).
Example 7B-2
[0127]
4-Bromo-N-(2-chloro-1-(4-chlorophenylamino)-2,2-difluoroethyl)benza-
mid (Compound 17): .sup.1H NMR (500 MHz, CD.sub.3OD): .delta.=7.72
(d, J=5.1 Hz, 2H), 7.63 (d, J=5.4 Hz, 2H), 6.78 (d, J=5.4 Hz, 2H),
6.22 (dd, J=5.4, 4.2 Hz, 1H).
Example 7B-3
[0128]
4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)ethyl)benzamide
(Compound 18): .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.=7.71 (d,
J=8.8 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 6.77
(d, J=9.3 Hz, 2H), 6.30 (d, J=3.9 Hz, 1H), 5.93 (d, J=3.9 Hz,
1H).
Example 7B-4
[0129]
4-bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,4,4,5,5,6,6,7,7-dodecafl-
uoroheptyl)benzamide (Compound 19): .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=8.53 (dd, J=2.4, 0.9 Hz, 1H), 8.24 (d, J=10.2,
1H), 8.03 (dd, J=8.4, 0.9 Hz, 1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H),
7.10 (d, J=9.0 Hz, 2H), 6.68 (d, J=8.7 Hz, 2H), 6.33-6.26 (m, 1H),
--CF.sub.2H 5.97 (tt, J=51.9, 5.1 Hz, 1H), 4.26 (d, J=11.1 Hz,
1H).
Example 7B-5
[0130]
4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)ethyl)benzamide
(Compound 20): .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.=7.71 (d,
J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 6.79
(d, J=9.0 Hz, 2H), 6.02 (d, J=10.2 Hz, 1H), 5.47 (d, J=10.2 Hz,
1H), 2.39-2.33 (m, 2H), 1.90-1.70 (m, 2H), 0.99 (t, J=7.2 Hz,
3H).
Example 7B-6
[0131]
4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)hexyl)benzamide
(Compound 21): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.62 (d,
J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 6.74
(d, J=9.0 Hz, 2H), 6.50 (d, J=9.6 Hz, 1H), 6.01 (d, J=9.0 Hz, 1H),
2.44-2.24 (m, 2H), 1.83-1.62 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t,
J=7.2 Hz, 3H).
Example 7B-7
[0132]
4-Bromo-N-(2,2-dichloro-1-(4-chloro-3-fluorophenylamino)hexyl)benza-
mide (Compound 22): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=7.63-7.53 (m, 4H), 7.16 (t, 8.7 Hz, 1H), 6.65-6.51 (m, 3H),
5.98 (d, J=9.0 Hz, 1H), 4.64 (brs, 1H), 2.42-2.22 (m, 2H),
1.82-1.60 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
Example 7B-8
[0133]
4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)propyl)benzamide
(Compound 23): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.63 (d,
J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 6.71
(d, J=9.0 Hz, 2H), 6.43 (d, J=9.0 Hz, 1H), 5.97 (d, J=9.0 Hz, 1H),
2.29 (s, 3H).
Example 7B-9
[0134]
5-Bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,4,4,4-heptafluorobutyl)p-
icolinamide (Compound 24): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.58 (d, J=2.1 Hz, 1H), 8.32 (d, J=9.9 Hz, 1H), 8.09 (d,
J=8.4 Hz, 1H), 8.00 (dd, J=8.4, 2.4 Hz, 1H), 7.16 (d, J=8.7 Hz,
2H), 6.74 (d, J=8.7 Hz, 2H), 6.42-6.28 (m, 1H), 4.35 (d, J=10.8 Hz,
1H).
Example 7B-10
[0135]
5-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)hexyl)picolinamide
(Compound 25): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.60 (dd,
J=2.4, 0.9 Hz, 1H), 8.39 (d, J=9.9 Hz, 1H), 8.10 (dd, J=8.4, 0.6
Hz, 1H), 8.00 (dd, J=8.1, 2.1 Hz, 1H), 7.14 (d, J=9.3 Hz, 2H), 6.74
(d, J=9.0 Hz, 2H).
Example 7B-11
[0136]
5-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)phenyl)picolinamide
(Compound 26): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.60 (dd,
J=2.1, 0.6 Hz, 1H), 8.39 (d, J=9.9 Hz, 1H), 8.10 (dd, J=8.7, 0.9
Hz, 1H), 8.00 (dd, J=8.4, 2.4 Hz, 1H), 7.14 (d, J=9.0 Hz, 2H), 5.97
(t, J=9.9 Hz, 1H), 4.57 (d, J=10.2 Hz, 1H), 2.41-2.22 (m, 2H),
1.89-1.69 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).
Example 7B-12
[0137]
5-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)picolinamide
(Compound 27): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.60 (dd,
J=2.1, 0.6 Hz, 1H), 8.39 (d, J=9.6 Hz, 1H), 8.10 (dd, J=8.4, 0.6
Hz, 1H), 8.00 (dd, J=8.4, 2.1 Hz, 1H), 7.14 (d, J=9.0 Hz, 2H), 6.74
(d, J=8.7 Hz, 2H), 5.98 (t, J=9.9 Hz, 1H), 4.59 (d, J=9.9 Hz, 1H),
2.48-2.28 (m, 2H), 1.27 (t, J=7.5 Hz, 3H).
Example 7B-13
[0138]
5-Bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,3-pentafluoropropyl)pico-
linamide (Compound 28): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.57 (dd, J=2.4, 0.9 Hz, 1H), 8.31 (d, J=10.2 Hz, 1H), 8.00
(dd, J=8.4, 2.4 Hz, 1H), 7.16 (dd J=8.7 Hz, 2H), 6.74 (d, J=8.7 Hz,
2H), 6.36-6.229 (m, 1H), 4.38 (d, J=10.8 Hz, 1H).
Example 7B-14
[0139]
5-Bromo-N-(1-(4-chlorophenylamnio)-2,2,3,3,4,4,5,5,5-nonafluoroprop-
yl)picolinamide (Compound 29): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.59 (dd, J=2.4, 0.9 Hz, 1H), 8.32 (d, J=9.6, 1H), 8.10
(dd, J=8.4, 0.9 Hz, 1H), 8.01 (dd, J=8.7, 2.4 Hz, 1H), 7.17 (d,
J=8.7 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.45-6.30 (m, 1H), 4.35 (d,
J=10.8 Hz, 1H).
Example 7B-15
[0140]
5-Bromo-N-(1-(4-chloro-3-fluorophenylamino)-2,2,3,3,4,4,5,5,5-nonaf-
luoropentyl)picolinamide (Compound 30): .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=8.60 (dd, J=2.1, 0.6 Hz, 1H), 8.35 (d, J=10.2
Hz, 1H), 8.10 (dd, J=8.4, 0.9 Hz, 1H), 8.02 (dd, J=8.4, 2.1 Hz,
1H), 7.20 (t, J=8.4 Hz, 1H), 6.64 (dd, J=10.5, 2.7 Hz, 1H),
6.57-6.53 (m, 1H), 6.40-6.26 (m, 1H), 4.44 (d, J=10.8 Hz, 1H).
Example 7B-16
[0141]
5-Bromo-N-(1-(cycloheptylamino)-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-
picolinamide (Compound 31): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.27 (dd, J=2.1, 0.9 Hz, 1H), 8.12-7.99 (m, 3H), 5.70 (brs,
1H), 2.85 (brs, 1H), 1.90-1.30 (series of m, 13H).
Example 7B-17, and 7B-18
[0142]
5-Bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,3-pentafluoropropyl)pico-
linamide (Compound 28) was separated by chiral HPLC: Chiralcell
OJ-H 20% IPA(0.1% DEA)/CO.sub.2, 100 bar; 80 mL/min, 220 nm. First
eluting enantiomer
(-)-5-bromo-N-(1-(4-chlorophenylamino)-2,2,3,3,3-pentafluoropropyl)picoli-
namide (Compound 32) [.alpha.]-119 (c=0.728 CHCl.sub.3) (active
enantiomer); second eluting enantiomer (+)-enantiomer (Compound
33): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=same as for the
racemate Compound 28, Example B-13.
Example 7B-19
[0143]
5-Bromo-N-(1-(4-chloro-3-fluorophenylamino)-2,2,3,3,3-pentafluoropr-
opyl)picolinamide (Compound 34) .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.=8.56 (dd, J=0.6, 2.1, 1H), 8.37 (d, J=9.6 Hz, 1H), 8.09
(dd, J=0.6, 8.1 Hz, 1H), 8.00 (dd, J=2.1, 8.1 Hz, 1H), 7.17 (t,
J=8.7 Hz, 1H), 6.63 (dd, J=2.4, 10.8 Hz, 1H), 6.56-6.52 (m, 1H),
6.33-6.19 9m, 1H), 4.55 (d, J=10.5 Hz, 1H).
Example 7B-20
[0144]
5-Bromo-N-(1-(2-chloropyrimidin-5-ylamino)-2,2,3,3,3-pentafluoropro-
pyl)picolinamide (Compound 35) .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.=8.61 (dd, J=0.9, 2.4 Hz), 8.43 (d, J=9.9 Hz, 1H), 8.27 (s,
2H), 8.09 (dd, J=2.1, 8.1 Hz, 1H), 6.35-6.20 (m, 1H), 4.52 (d,
J=10.8 Hz, 1H).
Example 7B-21
[0145]
5-Bromo-N-(1-(2,6-dichloropyridin-4-ylamino)-2,2,3,3,4,4,4-heptaflu-
orobutyl)picolinamide (Compound 36) .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.=8.62 (dd, J=0.6, 2.1 Hz, 1H), 8.49 (d, J=9.9
Hz, 1H), 8.13 (dd, J=0.9, 8.1 Hz, 1H), 8.05 (dd, J=2.1, 8.1 Hz,
1H), 6.72 (s, 2H), 6.44-6.30 (m, 1H), 5.14 (d, J=9.9 Hz, 1H).
Example 7B-22
[0146]
5-Bromo-N-(1-(2-chloropyrimidin-5-ylamino)-2,2,3,3,4,4,5,5,6,6,7,7--
dodecafluoroheptyl)picolinamide (Compound 37) .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.=8.62 (dd, J=0.9, 2.1 Hz, 1H), 8.45 (d, J=8.3
Hz, 1H), 8.27 (s, 2H), 8.09 (dd, J=0.9, 8.4 Hz, 1H), 8.04 (dd,
J=2.1, 8.1 Hz, 1H), 6.42-6.28 (m, 1H), 6.23-5.85 (m, 1H), 4.48 (d,
J=10.8 Hz, 1H).
Example 8
Preparation of
4-bromo-N-(1-(4-chlorophenylamino)-2,2-dimethylpropyl)benzamide
(Compound 38)
##STR00032##
[0148] A mixture of 4-bromobenzamide 118 (0.73 g, 3.54 mmol),
benzotriazole (0.42 g, 3.52 mmol), pivaldehyde (0.8 mL, 7.27 mmol)
and pTSA-HOH (about 60 mg) was heated at reflux for 5 hours in a
Dean-Stark apparatus. The mixture was concentrated onto silica gel
and purified by chromatography (8:2 CH.sub.2Cl.sub.2:hexanes to
CH.sub.2Cl.sub.2) to give
N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-2,2-dimethylpropyl)-4-bromobenzamid-
e 120 as a white solid.
[0149] A mixture of
N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-2,2-dimethylpropyl)-4-bromobenzamid-
e 120 as a white solid (2.38 mmol), 4-chloroaniline (0.64 g, 5.0
mmol), and K.sub.2CO.sub.3 (1 g, 7.23 mmol) in methanol (20 mL) and
THF (2 mL) was stirred for 18 h at room temperature. The reaction
was quenched with 2M HCl and extracted with ether. The organic
solution was concentrated onto silica gel and chromatography (9:1
hexanes:ethyl acetate) and gave
4-bromo-N-(1-methoxy-2,2-dimethylpropyl)benzamide and the title
product. The product was titrated with ether to give pure
4-bromo-N-(1-(4-chlorophenylamino)-2,2-dimethylpropyl)benzamide
(Compound 38) (104 mg, 11%). .sup.1H NMR (300 MHz, d.sup.6-DMSO):
.delta.=8.34 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (d,
J=8.4 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.71 (J=8.7 Hz, 2H), 5.81
(d, J=6.6 Hz, 1H), 5.19 (t, J=3.9 Hz, 1H), 1.03 (s, 9H).
Example 8C-1
[0150] 4-Bromo-N-((4-chlorophenylamino)(phenyl)methyl)benzamide
(Compound 39): .sup.1H NMR (300 MHz, d.sup.6-acetone): .delta.=8.44
(d, J=8.1 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.65-7.62 (m, 4H),
7.43-7.28 (m, 3H), 7.14 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H),
6.85 (d, J=9.0 Hz, 2H), 6.70-6.64 (9m, 2H).
Example 8C-2
[0151]
4-Bromo-N-((4-chloro-3-fluorophenylamino)(cyclohexyl)methyl)benzami-
de (Compound 40): .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta.=8.55
(d, J=8.4 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H),
7.15 (t, J=8.7 Hz, 1H), 6.61 (dd, J=12.9, 2.7 Hz, 1H), 6.51 (dd,
J=8.7, 2.1 Hz, 1H), 6.43 (brs, 1H), 5.10-5.00 (m, 1H), 1.95 (d,
J=12.6 Hz, 1H), 1.80-1.56 9m, 5H), 1.23-1.00 (m, 5H).
Example 8C-3
[0152] 4-Bromo-N-((4-chlorophenylamino)(cyclohexyl)methyl)benzamide
(Compound 41): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.59-7.51
(m, 4H), 7.10 (d, J=9.0 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.05 (d,
J=8.4 Hz, 1H), 5.37 (dd, J=8.4, 6.3 Hz, 1H), 1.96-1.66 (m, 6H),
1.33-1.13 (m, 6H).
Example 9
Preparation of
4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide
(Compound 42)
##STR00033##
[0154] A mixture of 4-bromoaniline 118 (5.0 g, 24.2 mmol) and
chloral (4.7 mL, 48.2 mmol) in THF (4 mL) was heated for 30
minutes. Solvent was removed under vacuum.
4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide 121 (1.26 g,
3.62 mmol) in chloroform (15 mL) and PCl.sub.5 (0.8 g, 3.65 mmol)
was heated at 50.degree. C. for 30 minutes. The product was
isolated from a standard aqueous work-up and extraction to produce
4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide.
4-Bromo-N-(1,2,2,2-tetrachloroethyl)benzamide (1.21 mmol) in ether
(50 mL) was reacted with 6-chloropyridin-3-amine (0.32 g, 2.44
mmol) at room temperature for 18 hours. The mixture was subjected
to a standard aqueous work-up and extraction. Chromatography on
silica gel (7:3 hexanes:CH.sub.2Cl.sub.2) gave
4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide
(Compound 42, 0.36 g, 65%). .sup.1H NMR (300 MHz,
d.sup.4-methanol): .delta.=7.99 (dd, J=3.0, 0.6 Hz, 1H), 7.74 (d,
J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.36 (dd, J=9.0, 3.3 Hz,
1H), 7.26 (dd, J=8.7, 0.6 Hz, 1H), 6.36 (s, 1H).
Example 9D-1
[0155]
4-Bromo-N-(2,2,2-trichloro-1-(5-chloropyrimidin-2-ylamino)ethyl)ben-
zamide (Compound 43): .sup.1H NMR (300 MHz, d.sup.4-methanol):
.delta.=8.40 (s, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.67 (d, J=9.0 Hz,
2H), 7.23 (s, 1H).
Example 9D-2
[0156]
4-Bromo-N-(2,2,2-trichloro-1-(5-chloropyrazin-2-ylamino)ethyl)benza-
mide (Compound 44): .sup.1H NMR (300 MHz, d.sup.4-methanol):
.delta.=8.20 (d, J=1.5 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.74 (d,
J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.17 (s, 1H).
Example 9D-3
[0157]
4-Bromo-N-(2,2,2-tribromo-1-(cyclohex-3-enylamino)ethyl)benzamide
(Compound 45): 2.sup.nd eluting diastereomer .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta.=7.67-7.55 (series of m, 4H), 6.58-6.54 (m,
1H), 5.97 (d, J=2.4 Hz, 1H), 5.66-5.55 (m, 1H), 5.28-5.23 (m, 1H),
3.03-2.94 (m, 1H), 2.46-1.42 (series of m, 7H).
Example 10
Preparation of
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcycloheylamino)ethyl)picolinamide
(Compound 46) and
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcyclohexylamino)ethyl)picolinamide
(Compound 47)
##STR00034##
[0159] 5-Bromopicolinamide 112 (1.29 g, 6.4 mmol) and chloral (1.25
mL) in dioxane (10 mL) were heated to 100.degree. C. The mixture
was concentrated to give
5-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)picolinamide 122
(99%).
[0160] A solution of
5-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)picolinamide 122 (0.83 g,
2.39 mmol) in chloroform (20 mL) was reacted with PCl.sub.5 (0.51
g, 2.33 mmol) at 50.degree. C. for 30 minutes. The mixture was
cooled to -78.degree. C. and 4-ethylcyclohexanamine was added (1 g,
7.5 mmol). After 1 hour, the mixture was warmed to room
temperature. The reaction mixture was subjected to an aqueous
work-up and the product extracted with chloroform. The organic
solution was concentrated onto silica gel and the product was
eluted (flash: 97:3 hexane:ether then prep-HPLC: Phenomenex Luna
column (SiO.sub.2), 10 micron, 250.times.50 mm, 150 mL/minute; 3:7
hexanes:dichloromethane) to give first eluting fraction:
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcyclohexylamino)ethyl)picolinamide
(Compound 46, 106 mg) .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.64 (dd, J=2.1, 0.6 Hz, 1H), 8.26 (d, J=9.9 Hz, 1H), 8.11
(dd, J=8.4, 0.6 Hz, 1H), 8.01 (dd, J=8.4, 2.4 Hz, 1H), 5.56 (t,
J=9.3 Hz, 1H), 2.96 (brs, 1H), 1.80-1.71 (m, 2H), 1.59-1.21 (m,
10H), 0.85 (t, J=7.2 Hz, 3H), and second eluting fraction:
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcyclohexylamino)ethyl)picolinamide
(Compound 47, 166 mg) .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=8.64 (dd, J=2.1, 0.6 Hz, 1H), 8.30 (d, J=9.9 Hz, 1H), 8.11
(dd, J=8.4, 0.9 Hz, 1H), 8.01 (dd, J=8.4, 2.1 Hz, 1H), 5.50 (t,
J=8.7 Hz, 1H), 2.68-2.58 (m, 1H), 2.16-2.07 (m, 1H), 1.86-1.70 (m,
4H), 1.27-1.01 (m, 6H), 0.96-0.087 (m, 1H) 0.83 (t, J=7.5 Hz,
3H).
Example 10E-1
[0161] MPLC separation with 9:1 hexanes:ether and 8:2 then 7:3
hexanes:dichloromethane. Single diastereomer: first eluting
fraction:
5-bromo-N-(2,2,2-trichloro-1-(4-methylcyclohexylamino)ethyl)picolinamide
(Compound 48): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.65-8.64
(m, 1H), 8.27 (d, J=9.9 Hz, 1H), 8.12-8.09 (m, 1H), 8.02-7.99 (m,
1H), 5.56 (t, J=9.3 Hz, 1H), 2.94 (brs, 1H), 1.81-1.71 (m, 2H),
1.60-1.25 (m, 8H), 0.89 (d, J=6.0 Hz, 3H).
Example 10E-2
[0162] MPLC separation with 3 to 6% ether in hexanes gave products.
First eluting diastereomer: "cis" compound,
4-bromo-N-(2,2,2-trichloro-1-(4-methylcyclohexylamino)ethyl)benzamide
(Compound 49): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.67 (d,
J=8.7 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H), 6.51 (d, J=9.3 Hz, 1H), 5.61
(d, J=9.3 Hz, 1H), 2.98-2.95 (m, 1H), 1.80-1.74 (m, 2H), 1.59-1.26
(m, 8H), 0.90 (d, J=6.0 Hz, 3H). Second eluting diastereomer:
"trans" compound,
4-bromo-N-(2,2,2-trichloro-1-(4-methylcyclohexylamino)ethyl)benzamide
(Compound 50): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.68 (d,
J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 6.61 (d, J=9.3 Hz, 1H), 5.66
(d, J=9.0 Hz, 1H), 2.67-2.58 (m, 1H), 2.12-2.05 (m, 1H), 1.90-1.60
(m, 4H), 1.37-0.90 (m, 8H), 0.86 (d, J=6.3 Hz, 3H).
Example 11
Preparation of
4-bromo-N-(2,2,2-trichloro-1-(cyclooctylamino)ethyl)furan-2-carboxamide
(Compound 51)
##STR00035##
[0164] A mixture of 4-bromofuran-2-carbaldehyde 123 (1.75 g, 10
mmol) in ethanol (15 mL) and AgNO.sub.3 (3.06 g, 20 mmol) in water
(5 mL) was treated (drop-wise addition) with sodium hydroxide (1.2
g in 5 mL HOH) at room temperature for 20 minutes. The mixture was
subjected to an aqueous, acidic (HCl) work-up and extraction with
ether. The solvents were removed under vacuum.
4-Bromofuran-2-carboxylic acid (1.9 g) in CH.sub.2Cl.sub.2 was
treated with oxalyl chloride (6.5 mL, 2M in CH.sub.2Cl.sub.2) and
DMF (a few drops) for a couple hours. The solvents were removed
under vacuum and replaced with benzene. The organic layer was
decanted and solvent removed under reduced pressure.
4-Bromofuran-2carbonyl chloride was dissolved in CH.sub.2Cl.sub.2
and cooled to -70.degree. C. before addition of NH.sub.3 (3 mL,
.about.7M solution in methanol). 4-Bromofuran-2-carboxamide 124 was
recrystallized from hexanes-ethyl acetate.
[0165] A mixture of 4-bromofuran-2-carboxamide 124 (0.85 g, 4.47
mmol) and chloral (0.78 mL) in xylene was heated at 95.degree. C.
for 1.5 hours. The mixture was concentrated to give
4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125
as a tan solid that was used without further purification.
[0166]
4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125
(0.16 g, 0.47 mmol) and isocyanatocyclooctane (0.08 mL, 0.51 mmol)
in benzene (2 mL) with triethyl amine (2 drops) was heated to
95.degree. C. for 1.5 hours. The mixture was concentrated onto
silica gel and purified by chromatography (7:3 to 6:4
hexane:CH.sub.2Cl.sub.2) to give
4-bromo-N-(2,2,2-trichloro-1-(cyclooctylamino)ethyl)furan-2-carboxamide
(Compound 51) (142 mg, 67%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=7.50 (d, J=0.9 Hz, 1H), 7.21 (d, J=0.9 Hz, 1H), 6.59 (d,
J=9.6 Hz, 1H), 5.55 (t, J=9.3 Hz, 1H), 2.96-2.85 (m, 1H), 1.79-1.42
(m, 15H).
Example 11F-1
[0167]
4-Bromo-N-(2,2,2-trichloro-1-(cycloheptylamino)ethyl)furan-2-carbox-
amide (Compound-52): .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.=7.50 (d, J=0.9 Hz, 1H), 7.22 (d, J=0.9 Hz, 1H), 6.59 (d,
J=9.6 Hz, 1H), 5.55 (t, J=8.7 Hz, 1H), 2.92-2.89 (m, 1H), 1.91-1.77
(m, 2H), 1.71-1.63 (m, 3H) 1.60-1.39 (m, 8H).
Example 11F-2
[0168]
4-Bromo-N-(2,2,2-trichloro-1-(cyclohexylamino)ethyl)furan-2-carboxa-
mide (Compound 53): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.50
(d, J=0.9 Hz, 1H), 7.22 (d, J=0.6 Hz, 1H), 6.61 (d, J=9.6 Hz, 1H),
5.62-5.57 (m, 1H), 2.69 (brs, 1H), 2.02-1.99 (m, 1H), 1.82-1.69 (m,
4H), 1.62-1.52 (m, 1H), 1.30-1.13 (m, 5H).
Example 12
In Vitro Activity
[0169] A Novel compounds with this structure were synthesized and
tested for S1P3 activity using the Flipr assay. These compounds may
be assessed for their ability to activate or block activation of
the human S1P3 receptor in T24 cells stably expressing the human
S1P3 receptor.
[0170] Ten thousand cells/wells are plated into 384-well
poly-D-lysine coated plates one day prior to use. The growth media
for the S1P3 receptor expressing cell line is McCoy's 5A medium
supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1%
antibiotic-antimycotic and 400 .mu.g/ml geneticin. On the day of
the experiment, the cells are washed twice with Hank's Balanced
Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer).
The cells are then dye loaded with 2 .mu.M Fluo-4 diluted in the
HBSS/Hepes buffer with 1.25 mM Probenecid and incubated at
37.degree. C. for 40 minutes. Extracellular dye is removed by
washing the cell plates four times prior to placing the plates in
the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices).
Ligands are diluted in HBSS/Hepes buffer and prepared in 384-well
microplates. The positive control, Sphingosine-1-phosphate (S1P),
is diluted in HBSS/Hepes buffer with 4 mg/ml fatty acid free bovine
serum albumin. The FLIPR transfers 12.5 .mu.l from the ligand
microplate to the cell plate and takes fluorescent measurements for
75 seconds, taking readings every second, and then for 2.5 minutes,
taking readings every 10 seconds. Drugs are tested over the
concentration range of 0.61 nM to 10,000 nM. Data for Ca.sup.2+
responses are obtained in arbitrary fluorescence units and not
translated into Ca.sup.2+ concentrations. IC.sub.50 values are
determined through a linear regression analysis using the Levenburg
Marquardt algorithm.
[0171] B. Novel compounds were synthesized and tested for S1P3
activity using the GTP .gamma..sup.35S binding assay. GTP
.gamma..sup.35S binding was measured in the medium containing (mM)
HEPES 25, pH 7.4, MgCl.sub.2 10, NaCl 100, dithiothreitol 0.5,
digitonin 0.003%, 0.2 nM GTP .gamma..sup.35S, and 5 .mu.g membrane
protein in a volume of 150 .mu.l. Test compounds were included in
the concentration range from 0.08 to 5,000 nM unless indicated
otherwise. Membranes were incubated with 100 .mu.M
5'-adenylylimmidodiphosphate for 30 min, and subsequently with 10
.mu.M GDP for 10 min on ice. Drug solutions and membrane were
mixed, and then reactions were initiated by adding GTP
.gamma..sup.35S and continued for 30 min at 25.degree. C. Reaction
mixtures were filtered over Whatman GF/B filters under vacuum, and
washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4,
MgCl.sub.2 10 and NaCl 100). Filters were dried and mixed with
scintillant, and counted for .sup.35S activity using a
.beta.-counter. Agonist-induced GTP .gamma..sup.35S binding was
obtained by subtracting that in the absence of agonist. Binding
data were analyzed using a non-linear regression method. In case of
antagonist assay, the reaction mixture contained 10 nM S1P in the
presence of test antagonist at concentrations ranging from 0.08 to
5000 nM.
[0172] Resulting Data is Shown in Table 2
TABLE-US-00002 TABLE 2 Activity potency at S1P3 receptor: assay GTP
.sub.Y.sup.35S, IC.sub.50 nM. S1P3 Compound GTP.sub.Y.sup.35S
Number Structure IC50 nM Compound-1 ##STR00036## 10 Compound-2
##STR00037## 31 Compound-3 ##STR00038## 5.2 Compound-29
##STR00039## 5.5 Compound-32 ##STR00040## 1.3 Compound-7
##STR00041## 115 Compound-27 ##STR00042## 56 Compound-49
##STR00043## 671 Compound-10 ##STR00044## 4.7 Compound-37
##STR00045## 59 Compound-35 ##STR00046## 2
Example 13
Treating Pain
[0173] I. A patient exhibits moderate pain after a bowel surgery. A
tablet including
5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-1-yl)-2-oxoeth-
yl)picolinamide is delivered taken by the patient twice daily as
needed for the pain. The patient reports a reduction of pain when
taking the tablet.
[0174] II. A patient exhibits moderate pain after a bowel surgery.
A tablet including
4-bromo-N-((4-chlorophenylamino)(2,6-difluorophenyl)methyl)benzamide
is delivered taken by the patient twice daily as needed for the
pain. The patient reports a reduction of pain when taking the
tablet.
[0175] III. A patient exhibits moderate pain after a bowel surgery.
A tablet including
4-bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)benmide is
delivered taken by the patient twice daily as needed for the pain.
The patient reports a reduction of pain when taking the tablet.
[0176] IV. A patient exhibits moderate pain after a bowel surgery.
A tablet including
4-bromo-N-(1-(4-chlorophenylamino)-2,2-dimethylpropyl)benzamide is
delivered taken by the patient twice daily as needed for the pain.
The patient reports a reduction of pain when taking the tablet.
[0177] V. A patient exhibits moderate pain after a bowel surgery. A
tablet including
4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)b-
enzamide is delivered taken by the patient twice daily as needed
for the pain. The patient reports a reduction of pain when taking
the tablet.
[0178] VI. A patient exhibits moderate pain after a bowel surgery.
A tablet including
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcycloheylamino)ethyl)picolinamide
is delivered taken by the patient twice daily as needed for the
pain. The patient reports a reduction of pain when taking the
tablet.
[0179] VII. A patient exhibits moderate pain after a bowel surgery.
A tablet including
5-bromo-N-(2,2,2-trichloro-1-(4-ethylcyclohexylamino)ethyl)picolinamide
is delivered taken by the patient twice daily as needed for the
pain. The patient reports a reduction of pain when taking the
tablet.
[0180] Unless specific definitions are provided, the nomenclatures
utilized in connection with, and the laboratory procedures and
techniques of analytical chemistry, synthetic organic and inorganic
chemistry described herein are those known in the art. Standard
chemical symbols are used interchangeably with the full names
represented by such symbols. Thus, for example, the terms
"hydrogen" and "H" are understood to have identical meaning.
Standard techniques may be used for chemical syntheses, chemical
analyses, and formulation.
[0181] The structures depicted and described herein are intended to
include every possible stereoisomer, both pure or in any possible
mixture.
[0182] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary
rounding techniques. Notwithstanding that the numerical ranges and
parameters setting forth the broad scope of the invention are
approximations, the numerical values set forth in the specific
examples are reported as precisely as possible. Any numerical
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements.
[0183] Specific embodiments disclosed herein may be further limited
in the claims using consisting of or and consisting essentially of
language. When used in the claims, whether as filed or added per
amendment, the transition term "consisting of" excludes any
element, step, or ingredient not specified in the claims. The
transition term "consisting essentially of" limits the scope of a
claim to the specified materials or steps and those that do not
materially affect the basic and novel characteristic(s).
Embodiments of the invention so claimed are inherently or expressly
described and enabled herein.
[0184] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0185] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0186] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0187] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
[0188] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *