U.S. patent application number 12/498633 was filed with the patent office on 2009-10-29 for aryl sulfonamides.
This patent application is currently assigned to CHEMOCENTRYX, INC. Invention is credited to Andrew Pennell, Solomon Ugashe, Zheng Wei, J.J. Wright.
Application Number | 20090270616 12/498633 |
Document ID | / |
Family ID | 32326578 |
Filed Date | 2009-10-29 |
United States Patent
Application |
20090270616 |
Kind Code |
A1 |
Ugashe; Solomon ; et
al. |
October 29, 2009 |
ARYL SULFONAMIDES
Abstract
Compounds are provided that act as potent antagonists of the
CCR9 receptor, and which have been further confirmed in animal
testing for inflammation, one of the hallmark disease states for
CCR9. The compounds are generally aryl sulfonamide derivatives and
are useful in pharmaceutical compositions, methods for the
treatment of CCR9-mediated diseases, and as controls in assays for
the identification of CCR9 antagonists.
Inventors: |
Ugashe; Solomon; (Fremont,
CA) ; Wei; Zheng; (Redwood City, CA) ; Wright;
J.J.; (Redwood City, CA) ; Pennell; Andrew;
(San Francisco, CA) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
CHEMOCENTRYX, INC
MOUNTAIN VIEW
CA
|
Family ID: |
32326578 |
Appl. No.: |
12/498633 |
Filed: |
July 7, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12251829 |
Oct 15, 2008 |
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12498633 |
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11046565 |
Jan 27, 2005 |
7582661 |
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12251829 |
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10716170 |
Nov 17, 2003 |
6939885 |
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11046565 |
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60427670 |
Nov 18, 2002 |
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Current U.S.
Class: |
544/131 ;
544/333; 546/271.4; 546/328 |
Current CPC
Class: |
A61P 37/00 20180101;
A61P 11/00 20180101; A61P 17/00 20180101; C07C 311/46 20130101;
A61P 17/16 20180101; A61P 35/00 20180101; A61P 29/00 20180101; C07C
311/29 20130101; C07D 213/74 20130101; A61P 37/08 20180101; A61P
11/06 20180101; A61P 43/00 20180101; C07D 213/89 20130101; A61P
1/00 20180101; A61P 37/06 20180101; C07C 311/21 20130101; A61P
19/02 20180101; C07D 241/12 20130101; C07D 213/84 20130101; A61P
1/04 20180101; C07D 213/26 20130101; A61P 17/06 20180101; C07D
213/70 20130101; A61P 37/02 20180101; C07D 213/50 20130101; A61P
35/02 20180101; C07D 413/12 20130101; C07C 317/14 20130101 |
Class at
Publication: |
544/131 ;
546/271.4; 546/328; 544/333 |
International
Class: |
C07D 413/04 20060101
C07D413/04; C07D 413/12 20060101 C07D413/12; C07D 213/50 20060101
C07D213/50 |
Claims
1. A compound of the formula (I), or a salt thereof: ##STR00258##
where X represents from 1 to 4 substituents independently selected
from the group consisting of halogen, --CN, --NO.sub.2, --OH,
--OR.sup.1, --C(O)R.sup.1, --CO.sub.2R.sup.1, --O(CO)R.sup.1,
--C(O)NR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2, --SR.sup.1,
--SOR.sup.1, --SO.sub.2R.sup.1, --SO.sub.2NR.sup.1R.sup.2,
NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O).sub.2R.sup.2, --NR.sup.1SO.sub.2R.sup.2,
--NR.sup.1(CO)NR.sup.2R.sup.3, unsubstituted or substituted
C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.3-8 cycloalkyl, unsubstituted or substituted
C.sub.6-10 aryl, unsubstituted or substituted 5- to 10-membered
heteroaryl, and unsubstituted or substituted 3- to 10-membered
heterocyclyl; R.sup.1, R.sup.2 and R.sup.3 are each independently
selected from the group consisting of hydrogen, unsubstituted or
substituted C.sub.1-6 haloalkyl, unsubstituted or substituted
C.sub.1-6 alkyl, unsubstituted or substituted C.sub.3-6 cycloalkyl,
unsubstituted or substituted C.sub.2-6 alkenyl, unsubstituted or
substituted C.sub.2-6 alkynyl, unsubstituted or substituted
C.sub.6-10 aryl, unsubstituted or substituted 5- to 10-membered
heteroaryl, unsubstituted or substituted aryl-C.sub.1-4 alkyl,
unsubstituted or substituted aryl-C.sub.1-4 alkyl, and
unsubstituted or substituted aryloxy-C.sub.1-4 alkyl; or two of
R.sup.1, R.sup.2 and R.sup.3 together with the atom(s) to which
they are attached, may form an unsubstituted or substituted 5-, 6-
or 7-membered ring; Y represents from 1 to 3 substituents, each
independently selected from the group consisting of halogen, --CN,
--NO.sub.2, --OH, --OR.sup.4, --C(O)R.sup.4, --CO.sub.2R.sup.4,
--SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4, and unsubstituted or
substituted C.sub.1-4 alkyl; R.sup.4 is selected from the group
consisting of hydrogen, unsubstituted or substituted C.sub.1-6
haloalkyl, unsubstituted or substituted C.sub.1-6 alkyl,
unsubstituted or substituted C.sub.3-6 cycloalkyl, unsubstituted or
substituted C.sub.2-6 alkenyl, and unsubstituted or substituted
C.sub.2-6 alkynyl; L is --C(O)--, --S--, --SO-- or --S(O).sub.2--;
and Z represents either unsubstituted or substituted monocyclic or
bicyclic C.sub.5-10 heteroaryl or unsubstituted or substituted
monocyclic or bicyclic C.sub.3-10 heterocyclyl, with the proviso
that when X is methyl, then Z is not 2-thiophene,
2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium).
2. The compound of claim 1, where L is --CO--.
3. The compound of claim 2, where X represents from 1 to 3
substituents independently selected from the group consisting of
halogen, --CN, --NO.sub.2, --OH, --OR.sup.1, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --O(CO)R.sup.1, --OC(O)NR.sup.1R.sup.2,
--SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O).sub.2R.sup.2,
--NR.sup.1(CO)NR.sup.1R.sup.2, unsubstituted or substituted
C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.3-8 cycloalkyl, unsubstituted or substituted
C.sub.6-10 aryl, unsubstituted or substituted 5- or 6-membered
heteroaryl, or unsubstituted or substituted 4- to 7-membered
heterocyclyl.
4. The compound of claim 3, where X represents 1 to 3 substituents
independently selected from the group consisting of --NO.sub.2,
--OR.sup.1, --C(O)R.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or
substituted phenyl, unsubstituted or substituted 5- or 6-membered
heteroaryl, or unsubstituted or substituted 5- or 6-membered
heterocyclyl.
5. The compound of claim 2, where at least one X substituent is
situated para to the sulfonamido bond as defined in formula
(I).
6. The compound of claim 2, where X is unsubstituted C.sub.1-8
alkyl, unsubstituted C.sub.3-8 cycloalkyl, unsubstituted C.sub.2-8
alkenyl, or unsubstituted C.sub.2-8 alkynyl.
7. The compound of claim 2, where X is substituted C.sub.1-8 alkyl,
substituted C.sub.3-8 cycloalkyl, substituted C.sub.2-8 alkenyl, or
substituted C.sub.2-8 alkynyl, each having from 1 to 5 substituents
independently selected from the group consisting of halogen, --OH,
--CN, --NO.sub.2, .dbd.O, --OC(O)R.sup.1, --OR.sup.1,
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1C(O)NR.sup.2R.sup.3,
--CO.sub.2R.sup.1, --NR.sup.1R.sup.2, --NR.sup.2CO.sub.2R.sup.1,
--SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1,
--SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2R.sup.2, unsubstituted
or substituted aryl, unsubstituted or substituted heteroaryl, and
unsubstituted or substituted heterocyclyl.
8. The compound of claim 7, where X is substituted C.sub.1-8 alkyl
or substituted C.sub.3-8 cycloalkyl, each having from 1 to 3
substituents independently selected from the group consisting of
halogen, --OH, --CN, .dbd.O, --OC(O)R.sup.1, --OR.sup.1,
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--CO.sub.2R.sup.1, --NR.sup.1R.sup.2, --SR.sup.1, --SOR.sup.1,
--SO.sub.2R.sup.1, --NR.sup.1SO.sub.2R.sup.2, unsubstituted or
substituted aryl, and unsubstituted or substituted heteroaryl.
9. The compound of claim 8, where X is substituted C.sub.1-8 alkyl,
having from 1 to 3 substituents independently selected from the
group consisting of halogen, --OH, --CN, .dbd.O, --OC(O)R.sup.1,
--OR.sup.1, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --CO.sub.2R.sup.1, --NR.sup.1R.sup.2,
--SO.sub.2R.sup.1, unsubstituted or substituted aryl, and
unsubstituted or substituted heteroaryl.
10. The compound of claim 2, where X is unsubstituted or
substituted C.sub.6-10 aryl, unsubstituted or substituted 5- to 1
0-membered heteroaryl, or unsubstituted or substituted 3- to 1
0-membered heterocyclyl, where when X is substituted is has from 1
to 4 substituents independently selected from the group consisting
of halogen, unsubstituted or substituted C.sub.1-8 alkyl,
unsubstituted or substituted C.sub.1-8 haloalkyl, --CN, --NO.sub.2,
--OH, --OR.sup.1, .dbd.O, --OC(O)R.sup.1, --CO.sub.2R.sup.1,
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1C(O)NR.sup.2R.sup.3,
--NR.sup.1R.sup.2, --NR.sup.2CO.sub.2R.sup.1, --SR.sup.1,
--SOR.sup.1, --SO.sub.2R.sup.1, --SO.sub.2NR.sup.1R.sup.2, and
--NR.sup.1SO.sub.2R.sup.2.
11. The compound of claim 10, where X is substituted C.sub.6-10
aryl or unsubstituted or substituted 5- to 1 0-membered heteroaryl,
where when X is substituted it has from 1 to 3 substituents
independently selected from the group consisting of halogen, --CN,
--OH, --OR.sup.1, .dbd.O, --OC(O)R.sup.1, --CO.sub.2R.sup.1,
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1R.sup.2, --SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1,
--NR.sup.1SO.sub.2R.sup.2, unsubstituted or substituted C.sub.1-8
alkyl, and C.sub.1-8 unsubstituted or substituted haloalkyl.
12. The compound of claim 11, where X is unsubstituted or
substituted phenyl or unsubstituted or substituted 5- or 6-membered
heteroaryl, where when X is substituted it has from 1 to 3
substituents independently selected from the group consisting of
halogen, --OH, --OR.sup.1, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1R.sup.2, --SO.sub.2R.sup.1,
unsubstituted or substituted C.sub.1-8 alkyl, and unsubstituted or
substituted C.sub.1-8 haloalkyl.
13. The compound of claim 10, where X is unsubstituted or
substituted 4- to 7-membered heterocyclyl, where when X is
substituted it has from 1 to 3 substituents independently selected
from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl,
--OR.sup.1, --OH, --OC(O)R.sup.1, --CO.sub.2R.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --NR.sup.1R.sup.2, --SO.sub.2R.sup.1, and
--NR.sup.1SO.sub.2R.sup.2.
14. The compound of claim 13, where X is a unsubstituted or
substituted 5- or 6-membered heterocyclyl, where when X is
substituted it has 1 to 2 substituents independently selected from
the group consisting of unsubstituted or substituted C.sub.1-8
alkyl, unsubstituted or substituted C.sub.1-8 haloalkyl,
--OR.sup.1, --OH, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.1R.sup.2, and --SO.sub.2R.sup.1.
15. The compound of claim 2, where R.sup.1, R.sup.2 and R.sup.3 are
unsubstituted.
16. The compound of claim 2, where R.sup.1, R.sup.2 and R.sup.3,
when substituted, can have from 1 to 3 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.1,
--OCOHNR.sup.1, --OCONR'.sub.2, --SH, --SR', --SO.sub.2NH.sub.2,
--CONH.sub.2, --NHC(O)NH.sub.2, NR'C(O)NH.sub.2, --CO.sub.2H, --CN,
--NO.sub.2, --NH.sub.2, --NHR' and --NR'.sub.2, --S(O)R',
--S(O).sub.2R', --CO.sub.2R', --CONR'.sub.2, --CONHR', --C(O)R',
--NR'COR', --NHCOR', --NR'CO.sub.2R', --NHCO.sub.2R', --CO.sub.2R',
--NR'C(O)NR'.sub.2, --NHC(O)NR'.sub.2, --NR'C(O)NHR', --NHC(O)NHR',
--NR'SO.sub.2R', --NHSO.sub.2R', --SO.sub.2NR'.sub.2, and
--SO.sub.2NHR', where R' is C.sub.1-6alkyl.
17. The compound of claim 2, where Y represents from 1 to 2
substituents, each independently selected from the group consisting
of halogen, --CN, --NO.sub.2, --OH, --OR.sup.4, --C(O)R.sup.4,
--CO.sub.2R.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4, and
unsubstituted or substituted C.sub.1-4 alkyl.
18. The compound of claim 2, where Y represents from 1 to 3
substituents independently selected from the group consisting of
halogen, --CN, --NO.sub.2, --OR.sup.4, --C(O)R.sup.4, --SR.sup.4,
--CF.sub.3, --SOR.sup.4, and --SO.sub.2R.sup.4.
19. The compound of claim 18, where Y represents from 1 to 3
substituents independently selected from the group consisting of
halogen, --CN, --NO.sub.2, --CF.sub.3, and --SO.sub.2R.sup.4.
20. The compound of claim 18, where Y represents 1 or 2
substituents where at least halogen is present and optionally
another substituent selected from the group consisting of halogen,
--CN, --NO.sub.2, --OH, --OR.sup.4, --C(O)R.sup.4,
--CO.sub.2R.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4 and
unsubstituted or substituted C.sub.1-4 alkyl.
21-85. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application Ser. No. 60/427,670 filed Nov. 18, 2002. The disclosure
of the priority application is incorporated by reference herein in
its entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention provides compounds, pharmaceutical
compositions containing one or more of those compounds or their
pharmaceutically acceptable salts, which are effective in
inhibiting the binding or function of various chemokines, such
TECK, to the CCR9 receptor. As antagonists or modulators for the
CCR9 receptor, the compounds and compositions have utility in
treating inflammatory and immune disorder conditions and
diseases.
[0003] Chemokines are chemotactic cytokines that are released by a
wide variety of cells and attract various types of immune system
cells, such as macrophages, T cells, eosinophils, basophils and
neutrophils, to sites of inflammation (reviewed in Schall,
Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol.,
6:865 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In
addition to stimulating chemotaxis, other changes can be
selectively induced by chemokines in responsive cells, including
changes in cell shape, transient rises in the concentration of
intracellular free calcium ions ([Ca.sup.2+]), granule exocytosis,
integrin up-regulation, formation of bioactive lipids (e.g.,
leukotrienes) and respiratory burst, associated with leukocyte
activation. Thus, the chemokines are early triggers of the
inflammatory response, causing inflammatory mediator release,
chemotaxis and extravasation to sites of infection or
inflammation.
[0004] T lymphocyte (T cell) infiltration into the small intestine
and colon has been linked to the pathogenesis of Coeliac diseases,
food allergies, rheumatoid arthritis, human inflammatory bowel
diseases (IBD) which include Crohn's disease and ulcerative
colitis. Blocking trafficking of relevant T cell populations to the
intestine can lead to an effective approach to treat human IBD.
More recently, chemokine receptor 9 (CCR9) has been noted to be
expressed on gut-homing T cells in peripheral blood, elevated in
patients with small bowel inflammation such as Crohn's disease and
celiac disease. The only CCR9 ligand identified to date, TECK
(thymus-expressed chemokine) is expressed in the small intestine
and the ligand receptor pair is now thought to play a pivotal role
in the development of IBD. In particular, this pair mediates the
migration of disease causing T cells to the intestine. See for
example, Zaballos, et al., J. Immunol., 162(10):5671-5675 (1999);
Kunkel, et al., J. Exp. Med. 192(5):761-768 (2000); Papadakis, et
al., J. Immunol., 165(9):5069-5076 (2000); Papadakis, et al.,
Gastroenterology, 121(2):246-254 (2001); Campbell, et al., J. Exp.
Med., 195(1):135-141 (2002); Wurbel, et al., Blood, 98(9):2626-2632
(2001); and Uehara, et al., J. Immunol, 168(6):2811-2819
(2002).
[0005] The identification of compounds that modulate the function
of CCR9 represents an attractive new family of therapeutic agents
for the treatment of inflammatory and other conditions and diseases
associated with CCR9 activation, such as inflammatory bowel
disease.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention is directed to compounds and
pharmaceutically acceptable salts thereof, compositions, and
methods useful in modulating CCR9 chemokine activity. The compounds
and salts thereof, compositions, and methods described herein are
useful in treating or preventing CCR9-mediated conditions or
diseases, including certain inflammatory and immunoregulatory
disorders and diseases.
[0007] In one embodiment, the inventive compounds are of the
formula (I):
##STR00001##
where X, Y and Z are as defined below. Salts of these compounds are
also within the scope of the invention.
[0008] In another aspect, the present invention provides
compositions useful in modulating CCR9 chemokine activity. In one
embodiment, a composition according to the present invention
comprises a compound according to the invention and a
pharmaceutically acceptable carrier or excipient.
[0009] In yet another aspect, the present invention provides a
method of modulating CCR9 function in a cell, comprising contacting
the cell with a therapeutically effective amount of a compound or
composition according to the invention.
[0010] In still another aspect, the present invention provides a
method for modulating CCR9 function, comprising contacting a CCR9
protein with a therapeutically effective amount of a compound or
composition according to the invention.
[0011] In still another aspect, the present invention provides a
method for treating a CCR9-mediated condition or disease,
comprising administering to a subject a safe and effective amount
of a compound or composition according to the invention.
[0012] In addition to the compounds provided herein, the present
invention further provides pharmaceutical compositions containing
one or more of these compounds, as well as methods for the use of
these compounds in therapeutic methods, primarily to treat diseases
associated with CCR9 signaling activity.
BRIEF DESCRIPTION OF THE FIGURE
[0013] FIG. 1 is a graph showing in vivo efficacy for the CCR9
antagonist tested in Example 119. Closed triangle: vehicle; Open
circle: CCR9 antagonist of the formula:
##STR00002##
DETAILED DESCRIPTION OF THE INVENTION
General
[0014] The present invention is directed to compounds and salts
thereof, compositions and methods useful in the modulation of
chemokine receptor function, particularly CCR9 function. Modulation
of chemokine receptor activity, as used herein in its various
forms, is intended to encompass antagonism, agonism, partial
antagonism, inverse agonism and/or partial agonism of the activity
associated with a particular chemokine receptor, preferably the
CCR9 receptor. Accordingly, the compounds of the present invention
are compounds which modulate at least one function or
characteristic of mammalian CCR9, for example, a human CCR9
protein. The ability of a compound to modulate the function of
CCR9, can be demonstrated in a binding assay (e.g., ligand binding
or agonist binding), a migration assay, a signaling assay (e.g.,
activation of a mammalian G protein, induction of rapid and
transient increase in the concentration of cytosolic free calcium),
and/or cellular response assay (e.g., stimulation of chemotaxis,
exocytosis or inflammatory mediator release by leukocytes).
Abbreviations and Definitions
[0015] When describing the compounds, compositions, methods and
processes of this invention, the following terms have the following
meanings, unless otherwise indicated.
[0016] When describing the compounds, compositions, methods and
processes of this invention, the following terms have the following
meanings, unless otherwise indicated.
[0017] "Alkyl" by itself or as part of another substituent refers
to a hydrocarbon group which may be linear, cyclic, or branched or
a combination thereof having the number of carbon atoms designated
(i.e., C.sub.1-8 means one to eight carbon atoms). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl,
(cyclohexyl)methyl, cyclopropylmethyl and the like.
[0018] "Cycloalkyl" refers to hydrocarbon rings having the
indicated number of ring atoms (e.g., C.sub.3-6cycloalkyl) and
being fully saturated or having no more than one double bond
between ring vertices. "Cycloalkyl" is also meant to refer to
bicyclic and polycyclic hydrocarbon rings such as, for example,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
[0019] "Alkylene" by itself or as part of another substituent means
a divalent radical derived from an alkane, as exemplified by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, alkyl (or
alkylene) groups having 8 or fewer carbon atoms are preferred in
the present invention.
[0020] "Alkenyl" refers to an unsaturated hydrocarbon group which
may be linear, cyclic or branched or a combination thereof. Alkenyl
groups with 2-8 carbon atoms are preferred. The alkenyl group may
contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl
groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl,
n-hex-3-enyl and the like.
[0021] "Alkoxy" and "alkylthio" (or thioalkoxy) are used in their
conventional sense and refer to an alkyl groups attached to the
remainder of the molecule via an oxygen atom or a sulfur atom,
respectively. Examples of alkoxy and thioalkoxy include methoxy,
ethoxy, isopropoxy, butoxy, cyclopentyloxy, thiomethoxy, and the
like.
[0022] "Alkynyl" refers to an unsaturated hydrocarbon group which
may be linear, cyclic or branched or a combination thereof. Alkynyl
groups with 2-8 carbon atoms are preferred. The alkynyl group may
contain 1, 2 or 3 carbon-carbon triple bonds. Examples of alkynyl
groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and
the like.
[0023] "Aryl" refers to a polyunsaturated, aromatic hydrocarbon
group having a single ring or multiple rings which are fused
together or linked covalently. Aryl groups with 6-10 carbon atoms
are preferred. Examples of aryl groups include phenyl and
naphthalene-1-yl, naphthalene-2-yl, biphenyl and the like.
[0024] "Halo" or "halogen", by itself or as part of a substituent
refers to a chlorine, bromine, iodine, or fluorine atom.
Additionally, "haloalkyl" refers to a monohaloalkyl or
polyhaloalkyl group, most typically substituted with from 1-3
halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl,
trifluoromethyl and the like.
[0025] "Heterocyclyl" refers to a saturated or unsaturated
non-aromatic group containing at least one heteroatom. "Heteroaryl"
refers to an aromatic group containing at least one heteroatom.
Each heterocyclyl and heteroaryl can be attached at any available
ring carbon or heteroatom. Each heterocyclyl and heteroaryl may
have one or more rings. When multiple rings are present, they can
be fused together or linked covalently. Each heterocyclyl and
heteroaryl must contain at least one heteroatom (typically 1 to 5
heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably,
these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1
oxygen atoms. Examples of saturated and unsaturated heterocyclyl
groups include pyrrolidine, imidazolidine, pyrazolidine,
piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine,
3-pyrroline and the like. Examples of unsaturated and aromatic
heterocycyl groups include pyrrole, imidazole, thiazole, oxazole,
furan, thiophene, triazole, tetrazole, oxadiazole, pyrazole,
isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine,
triazine, indole, benzofuran, benzothiophene, benzimidazole,
benzopyrazole, benzthiazole, quinoline, isoquinoline, quinazoline,
quinoxaline and the like. Heterocyclyl and heteroaryl groups can be
unsubstituted or substituted. For substituted groups, the
substitution may be on a carbon or heteroatom. For example, when
the substitution is .dbd.O, the resulting group may have either a
carbonyl (--C(O)--) or a N-oxide (--N(O)--).
[0026] Suitable substituents for substituted alkyl, substituted
alkenyl, substituted alkynyl and substituted cycloalkyl include
-halogen, --OR', --NR'R'', --SR', --SiR'R'', --OR''', --OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --CN, oxo (.dbd.O or --O--)
and --NO.sub.2 in a number ranging from zero to (2m'+1), where m'
is the total number of carbon atoms in such radical.
[0027] Suitable substituents for substituted aryl, substituted
heteroaryl and substituted heterocyclyl include -halogen,
unsubstituted or substituted alkyl, unsubstituted or substituted
alkenyl, unsubstituted or substituted alkynyl, unsubstituted or
substituted cycloalkyl, --OR', oxo (.dbd.O or --O), --OC(O)R',
--NR'R'', --SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'',
--C(O)R', --OC(O)NR'R'', --NR''C(O)R', --NR''C(O).sub.2R',
--NR'--C(O)NR''R''', --NH--C(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'' and
--N.sub.3 in a number ranging from zero to the total number of open
valences on the aromatic ring system.
[0028] As used above, R', R'' and R''' each independently refer to
a variety of groups including hydrogen, halogen, unsubstituted or
substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.3-6
cycloalkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
unsubstituted or substituted heterocyclyl. Preferably, R', R'' and
R''' independently refer to a variety of groups selected from the
group consisting of hydrogen, unsubstituted C.sub.1-8 alkyl,
unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted
with 1-3 halogens, unsubstituted C.sub.1-8alkyl, unsubstituted
C.sub.1-8 alkoxy, unsubstituted C.sub.1-8 thioalkoxy groups, or
unsubstituted aryl-C.sub.1-4 alkyl groups. When R' and R'' are
attached to the same nitrogen atom, they can be combined with the
nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for
example, --NR'R'' includes 1-pyrrolidinyl and 4-morpholinyl).
[0029] Alternatively, two of the substituents on adjacent atoms of
the aryl, heteroaryl or heterocycyl ring may optionally be replaced
with a substituent of the formula -T-C(O)--(CH.sub.2).sub.q-U-,
wherein T and U are independently --NR'--, --O--, --CH.sub.2-- or a
single bond, and q is an integer of from 0 to 2. Alternatively, two
of the substituents on adjacent atoms of the aryl or heteroaryl
ring may optionally be replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B-, wherein A and B are independently
--CH.sub.2--, --O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 3. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CH.sub.2).sub.s--X--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituent R' in --NR'-- and --S(O).sub.2NR'-- is selected from
hydrogen or unsubstituted C.sub.1-6 alkyl.
[0030] "Heteroatom" is meant to include oxygen (O), nitrogen (N),
sulfur (S) and silicon (Si).
[0031] "Pharmaceutically acceptable" carrier, diluent, or excipient
is a carrier, diluent, or excipient compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0032] "Pharmaceutically-acceptable salt" refers to a salt which is
acceptable for administration to a patient, such as a mammal (e.g.,
salts having acceptable mammalian safety for a given dosage
regime). Such salts can be derived from pharmaceutically-acceptable
inorganic or organic bases and from pharmaceutically-acceptable
inorganic or organic acids, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Salts
derived from pharmaceutically-acceptable inorganic bases include
aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic, manganous, potassium, sodium, zinc and the
like. Salts derived from pharmaceutically-acceptable organic bases
include salts of primary, secondary, tertiary and quaternary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Salts
derived from pharmaceutically-acceptable acids include acetic,
ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric,
ethanesulfonic, fumaric, gluconic, glucoronic, glutamic, hippuric,
hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic,
malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,
nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, p-toluenesulfonic and the like.
[0033] Also included are salts of amino acids such as arginate and
the like, and salts of organic acids like glucuronic or
galactunoric acids and the like (see, for example, Berge, S. M., et
al, "Pharmaceutical Salts", J. Pharmaceutical Science, 1977,
66:1-19). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0034] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0035] "Salt thereof" refers to a compound formed when the hydrogen
of an acid is replaced by a cation, such as a metal cation or an
organic cation and the like. Preferably, the salt is a
pharmaceutically-acceptable salt, although this is not required for
salts of intermediate compounds which are not intended for
administration to a patient.
[0036] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0037] "Therapeutically effective amount" refers to an amount
sufficient to effect treatment when administered to a patient in
need of treatment.
[0038] "Treating" or "treatment" as used herein refers to the
treating or treatment of a disease or medical condition (such as a
bacterial infection) in a patient, such as a mammal (particularly a
human or a companion animal) which includes:
[0039] ameliorating the disease or medical condition, i.e.,
eliminating or causing regression of the disease or medical
condition in a patient;
[0040] suppressing the disease or medical condition, i.e., slowing
or arresting the development of the disease or medical condition in
a patient; or
[0041] alleviating the symptoms of the disease or medical condition
in a patient.
[0042] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, both solvated forms and unsolvated forms are
intended to be encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms (i.e., as polymorphs). In
general, all physical forms are equivalent for the uses
contemplated by the present invention and are intended to be within
the scope of the present invention.
[0043] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers and individual isomers
(e.g., separate enantiomers) are all intended to be encompassed
within the scope of the present invention. The compounds of the
present invention may also contain unnatural proportions of atomic
isotopes at one or more of the atoms that constitute such
compounds. For example, the compounds may be radiolabeled with
radioactive isotopes, such as for example tritium (.sup.3H),
iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All isotopic
variations of the compounds of the present invention, whether
radioactive or not, are intended to be encompassed within the scope
of the present invention.
Compounds that Modulate CCR9 Activity
[0044] The present invention provides compounds that modulate CCR9
activity. Specifically, the invention provides compounds having
anti-inflammatory or immunoregulatory activity. The compounds of
the invention are thought to interfere with inappropriate T-cell
trafficking by specifically modulating or inhibiting a chemokine
receptor function. Chemokine receptors are integral membrane
proteins which interact with an extracellular ligand, such as a
chemokine, and mediate a cellular response to the ligand, e.g.,
chemotaxis, increased intracellular calcium ion concentration, etc.
Therefore, modulation of a chemokine receptor function, e.g.,
interference with a chemokine receptor ligand interaction, will
modulate a chemokine receptor mediated response, and treat or
prevent a chemokine receptor mediated condition or disease.
Modulation of a chemokine receptor function includes both
inducement and inhibition of the function. The type of modulation
accomplished will depend on the characteristics of the compound,
i.e., antagonist or full, partial or inverse agonist.
[0045] Without intending to be bound by any particular theory, it
is believed that the compounds provided herein interfere with the
interaction between a chemokine receptor and one or more cognate
ligands. In particular, it is believed that the compounds interfere
with the interaction between CCR9 and a CCR9 ligand, such as TECK.
Compounds contemplated by the invention include, but are not
limited to, the exemplary compounds provided herein and salts
thereof.
[0046] For example, compounds of this invention act as potent CCR9
antagonists, and this antagonistic activity has been further
confirmed in animal testing for inflammation, one of the hallmark
disease states for CCR9. Accordingly, the compounds provided herein
are useful in pharmaceutical compositions, methods for the
treatment of CCR9-mediated diseases, and as controls in assays for
the identification of competitive CCR9 antagonists.
CCR9 Antagonists as Treatments of Cancer
[0047] In additional to inflammatory diseases, cancers that are
caused by uncontrolled proliferation of T cells may be treated with
a CCR9 antagonist. Certain types of cancer are caused by T cells
expressing chemokine receptor CCR9. For example, thymoma and thymic
carcinoma are diseases in which cancer cells are found in the
tissues of the thymus, an organ where lymphocyte development
occurs. T cells in the thymus, called thymocytes, are known to
express functional CCR9; its ligand is highly expressed in the
thymus. Another example is the acute lymphocytic leukemia (ALL),
also called acute lymphoblastic leukemia and acute, is a common
leukemia, which can occur in children as well as adults. Recent
studies have shown that T cells in patients with ALL selectively
express high level of CCR9 (Qiuping Z et al., Cancer Res. 2003, 1;
63(19):6469-77)
[0048] Chemokine receptors have been implicated in cancer. Although
the exact mechanisms of chemokine receptors' involvements have yet
to be full understood, such receptors are known to promote the
growth of cancer cells (proliferation), facilitate the spread of
cancer cells (metastasis) or help them resist program cell death
(apoptosis). For example, CCR9 in a cancer T cell line MOLT-4
provides the cells with a survival signal, allowing them to resist
apoptosis (Youn B S, et al., Apoptosis. 2002 June; 7(3):271-6). In
the cases of thymoma, thymic carcinoma and acute lymphocytic
leukemia, it is likely that CCR9 plays a key in the survival and
proliferation these cells. Thus, blocking the signaling of CCR9
should help prevent their expansion and metastasis.
Compounds of the Invention
[0049] The compounds provided herein have the general formula
(I):
##STR00003##
X Substituents
[0050] X represents from 1 to 4 substituents independently selected
from the group consisting of halogen, --CN, --NO.sub.2, --OH,
--OR.sup.1, --C(O)R.sup.1, --CO.sub.2R.sup.1, --O(CO)R.sup.1,
--C(O)NR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2, --SR.sup.1,
--SOR.sup.1, --SO.sub.2R.sup.1, --SO.sub.2NR.sup.1R.sup.2,
--NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1C(O).sub.2R.sup.2, --NR.sup.1SO.sub.2R.sup.2,
--NR.sup.1(CO)NR.sup.1R.sup.2, unsubstituted or substituted
C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.3-8 cycloalkyl, unsubstituted or substituted
C.sub.6-10 aryl, unsubstituted or substituted 5- to 10-membered
heteroaryl, and unsubstituted or substituted 3- to 10-membered
heterocyclyl.
[0051] When X is substituted C.sub.1-8 alkyl, substituted C.sub.3-8
cycloalkyl, substituted C.sub.2-8 alkenyl, or substituted C.sub.2-8
alkynyl, it may have from 1-5 substituents independently selected
from the group consisting of halogen, --OH, --CN, --NO.sub.2,
.dbd.O, --OC(O)R.sup.1, --OR.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1C(O)NR.sup.2R.sup.3, --CO.sub.2R', --NR.sup.1R.sup.2,
--NR.sup.2CO.sub.2R.sup.1, --SR.sup.1, --SOR.sup.1, --SO.sub.2R',
--SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2R.sup.2, unsubstituted
or substituted aryl, unsubstituted or substituted heteroaryl, and
unsubstituted or substituted heterocyclyl.
[0052] When X is substituted C.sub.6-10 aryl, substituted 5- to
10-membered heteroaryl, or substituted 3- to 10-membered
heterocyclyl, it may have from 1-4 substituents independently
selected from the group consisting of halogen, unsubstituted or
substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.1-8
haloalkyl, --CN, --NO.sub.2, --OH, --OR.sup.1, .dbd.O,
--OC(O)R.sup.1, --CO.sub.2R', --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--OC(O)NR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1C(O)NR.sup.2R.sup.3, --NR.sup.1R.sup.2,
--NR.sup.2CO.sub.2R', --SR.sup.1, --SOR.sup.1, --SO.sub.2R',
--SO.sub.2NR.sup.1R.sup.2, and --NR.sup.1SO.sub.2R.sup.2. Suitable
substituted C.sub.1-8 alkyl include those defined above in
paragraph [0051].
[0053] R.sup.1, R.sup.2 and R.sup.3 are each independently selected
from the group consisting of hydrogen, C.sub.1-6 haloalkyl,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.6-10 aryl, 5- to 10-membered heteroaryl,
aryl-C.sub.1-4 alkyl, aryl-C.sub.1-4 alkyl, and aryloxy-C.sub.1-4
alkyl. Each can be unsubstituted or substituted with from 1-3
substituents independently selected from the group consisting of
halogen, --OH, --OR', --OCOHNR', --OCONR'.sub.2, --SH, --SR',
--SO.sub.2NH.sub.2, --CONH.sub.2, --NHC(O)NH.sub.2,
NR'C(O)NH.sub.2, --CO.sub.2H, --CN, --NO.sub.2, --NH.sub.2, --NHR'
and --NR'.sub.2, --S(O)R.sup.1, --S(O).sub.2R', --CO.sub.2R',
--CONR'.sub.2, --CONHR', --C(O)R', --NR'COR', --NHCOR',
--NR'CO.sub.2R', --NHCO.sub.2R', --CO.sub.2R', --NR'C(O)NR'.sub.2,
--NHC(O)NR'.sub.2, --NR'C(O)NHR', --NHC(O)NHR', --NR'SO.sub.2R',
--NHSO.sub.2R', --SO.sub.2NR'.sub.2, and --SO.sub.2NHR'.
Alternatively, two of R.sup.1, R.sup.2 and R.sup.3 together with
the atom(s) to which they are attached, may form a 5-, 6- or
7-membered ring.
Y Substituents
[0054] Y represents from 1 to 3 substituents, each independently
selected from the group consisting of halogen, --CN, --NO.sub.2,
--OH, --OR.sup.4, --C(O)R.sup.4, --CO.sub.2R.sup.4, --SR.sup.4,
--SOR.sup.4, --SO.sub.2R.sup.4, and unsubstituted or substituted
C.sub.1-4 alkyl.
[0055] When Y is a substituted C.sub.1-4 alkyl, it may have from 1
to 3 substituents independently selected from the group consisting
of halogen, --OH, --OR.sup.4, --CN, --NO.sub.2, .dbd.O,
--OC(O)R.sup.4, --CO.sub.2R.sup.4, --C(O)R.sup.4,
--CONR.sup.4R.sup.5, --OC(O)NR.sup.4R.sup.5, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)NR.sup.5R.sup.6, --NR.sup.4R.sup.5,
--NR.sup.4CO.sub.2R.sup.5, --SR.sup.4, --SOR.sup.4,
--SO.sub.2R.sup.4, --SO.sub.2NR.sup.4R.sup.5, and
--NR.sup.4SO.sub.2R.sup.5.
[0056] R.sup.4, R.sup.5 and R.sup.6 are each independently selected
from the group consisting of hydrogen, unsubstituted or substituted
C.sub.1-6 haloalkyl, unsubstituted or substituted C.sub.1-6 alkyl,
unsubstituted or substituted C.sub.3-6 cycloalkyl, unsubstituted or
substituted C.sub.2-6alkenyl, and unsubstituted or substituted
C.sub.2-6 alkynyl. Each can be unsubstituted or substituted with
from 1 to 3 substituents independently selected from the group
consisting of --OH, --OR', --SH, --SR', --CN, --NO.sub.2,
--NH.sub.2, --NHR', --NR'.sub.2, --S(O)R', --S(O).sub.2R',
--CO.sub.2R', --CONHR', --CONR'.sub.2, and --C(O)R'. Additionally,
two of R.sup.4, R.sup.5 and R.sup.6 together with the atom(s) to
which they are attached, may form a 5-, 6- or 7-membered ring.
Linkers
[0057] L is --C(O)--, --S--, --SO-- or --S(O).sub.2--.
Z Substituents
[0058] Z represents either unsubstituted or substituted monocyclic
or bicyclic C.sub.5-10 heteroaryl or unsubstituted or substituted
monocyclic or bicyclic C.sub.3-10 heterocyclyl.
[0059] When Z is a substituted heteroaryl or substituted
heterocyclyl, it may have from 1 to 5 substituents independently
selected from the group consisting of halogen, unsubstituted or
substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.1-8
cycloalkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.1-8 alkoxy, .dbd.O, --CN, --NO.sub.2, --OH,
--OR.sup.7, --OC(O)R.sup.7, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7C(O)NR.sup.8R.sup.9, --NR.sup.7R.sup.8,
--NR.sup.7CO.sub.2R.sup.8, --SR.sup.7, --SOR.sup.7,
--SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted C.sub.6-10
aryl, unsubstituted or substituted heteroaryl and unsubstituted or
substituted heterocyclyl.
[0060] Suitable substituted C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl and C.sub.1-8 alkoxy
substituents on Z may have from 1 to 5 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.7,
--CN, --NO.sub.2, .dbd.O, --CN, --NO.sub.2, --OC(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)R.sup.7, --CONR.sup.7R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7C(O)NR.sup.8R.sup.9, --NR.sup.7R.sup.8,
--NR.sup.7CO.sub.2R.sup.8, --SR.sup.7, --SOR.sup.7,
--SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- or 6-membered heteroaryl, or
unsubstituted or substituted 3- to 6-membered heterocyclyl.
[0061] Suitable substituted aryl, heteroaryl and heterocyclyl
substituents on Z may have from 1 to 5 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.7,
--CN, --NO.sub.2, .dbd.O, --CN, --NO.sub.2. --OC(O)R.sup.7,
--OC(O)R.sup.7--CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7C(O)NR.sup.8R.sup.9, --NR.sup.7R.sup.8,
--NR.sup.7CO.sub.2R.sup.8, --SR.sup.7, --SOR.sup.7,
--SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8 and unsubstituted or substituted
C.sub.3-6 heterocyclyl.
[0062] R.sup.7, R.sup.8 and R.sup.9 are each independently
hydrogen, unsubstituted or substituted C.sub.1-6 haloalkyl,
unsubstituted or substituted C.sub.1-6 alkyl, unsubstituted or
substituted C.sub.3-6 cycloalkyl, unsubstituted or substituted
C.sub.2-6 alkenyl, unsubstituted or substituted C.sub.2-6 alkynyl,
unsubstituted or substituted phenyl or unsubstituted or substituted
heteroaryl, unsubstituted or substituted aryl-C.sub.1-4 alkyl, and
unsubstituted or substituted aryloxy-C.sub.1-4 alkyl. Each can be
substituted with from 1 to 3 substituents independently selected
from the group consisting of halogen, --OH, --OR', --OCONHR',
--OCONR'.sub.2, --SH, --SR', --SO.sub.2NH.sub.2, --CONH.sub.2,
--NHC(O)NH.sub.2, NR'C(O)NH.sub.2, --CO.sub.2H, --CN, --NO.sub.2,
--NH.sub.2, --NHR' and --NR'.sub.2, --S(O)R', --S(O).sub.2R',
--CO.sub.2R', --CONR'.sub.2, --CONHR', --C(O)R', --NR'COR',
--NHCOR', --NR'CO.sub.2R', --NHCO.sub.2R', --CO.sub.2R',
--NR'C(O)NR'.sub.2, --NHC(O)NR'.sub.2, --NR'C(O)NHR', --NHC(O)NHR',
--NR'SO.sub.2R', --NHSO.sub.2R', --SO.sub.2NR'.sub.2, and
--SO.sub.2NHR'. R' is defined above. It is preferably,
unsubstituted or substituted C.sub.1-6 alkyl. Alternatively, two of
R.sup.7, R.sup.8 and R.sup.9 together with the atom(s) to which
they are attached, may form a 5-, 6- or 7-membered ring.
Known Compounds
[0063] Compounds of the formula (I) where X is methyl when Z is
2-thiophene, 2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium) are
known, but not as CCR9 antagonists.
Preferred X Substituents
[0064] X preferably represents from 1 to 3 substituents
independently selected from the group consisting of halogen, --CN,
--NO.sub.2, --OH, --OR.sup.1, --C(O)R.sup.1,
--CO.sub.2R'--O(CO)R.sup.1, --OC(O)NR.sup.1R.sup.2, --SR.sup.1,
--SOR.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O).sub.2R.sup.2,
--NR.sup.1(CO)NR.sup.1R.sup.2, unsubstituted or substituted
C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.3-8 cycloalkyl, unsubstituted or substituted
C.sub.10 aryl, unsubstituted or substituted 5- or 6-membered
heteroaryl, or unsubstituted or substituted 4- to 7-membered
heterocyclyl.
[0065] X more preferably represents 1 or 2 substituents
independently selected from the group consisting of --NO.sub.2,
--OR.sup.1, --C(O)R.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or
substituted phenyl, unsubstituted or substituted 5- or 6-membered
heteroaryl, or unsubstituted or substituted 5- or 6-membered
heterocyclyl. More preferably, at least one X substituent is
situated para to the sulfonamido bond as defined in formula
(I).
[0066] When X is substituted C.sub.1-8 alkyl or substituted
C.sub.3-8 cycloalkyl, it preferably has from 1 to 3 substituents
independently selected from the group consisting of halogen, --OH,
--CN, .dbd.O, --OC(O)R.sup.1, --OR.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1, --CO.sub.2R.sup.1,
--NR.sup.1R.sup.2, --SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1,
--NR.sup.1SO.sub.2R.sup.2, unsubstituted or substituted aryl, and
unsubstituted or substituted heteroaryl. When X is a substituted
C.sub.1-8 alkyl, it more preferably has from 1 to 3 substituents
independently selected from the group consisting of halogen, --OH,
--CN, .dbd.O, --OC(O)R.sup.1, --OR.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1, --CO.sub.2R.sup.1,
--NR.sup.1R.sup.2, --SO.sub.2R', unsubstituted or substituted aryl,
and unsubstituted or substituted heteroaryl.
[0067] When X is substituted C.sub.6-10 aryl or substituted
heteroaryl, it preferably has from 1 to 3 substituents
independently selected from the group consisting of halogen, --CN,
--OH, --OR.sup.1, .dbd.O, --OC(O)R.sup.1, --CO.sub.2R',
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1R.sup.2, --SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1,
--NR.sup.1SO.sub.2R.sup.2, unsubstituted or substituted C.sub.1-8
alkyl, and C.sub.1-8 unsubstituted or substituted haloalkyl. When X
is a substituted phenyl or substituted 5- or 6-membered heteroaryl,
it is more preferably has from 1 to 3 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.1,
--C(O)R.sup.1, --CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1R.sup.2, --SO.sub.2R', unsubstituted or substituted
C.sub.1-8 alkyl, and unsubstituted or substituted C.sub.1-8
haloalkyl.
[0068] When X is a substituted 4- to 7-membered heterocyclyl, it
preferably has from 1 to 3 substituents independently selected from
the group consisting of unsubstituted or substituted C.sub.1-8
alkyl, C.sub.1-8 haloalkyl, --OR.sup.1, --OH, --OC(O)R.sup.1,
--CO.sub.2R.sup.1, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.1, and
--NR.sup.1SO.sub.2R.sup.2. When X is a 5- or 6-membered
heterocyclyl, it more preferably has 1 to 2 substituents
independently selected from the group consisting of unsubstituted
or substituted C.sub.1-8 alkyl, unsubstituted or substituted
C.sub.1-8 haloalkyl, unsubstituted or substituted C.sub.1-8
haloalkyl, --OR.sup.1, --OH, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.1R.sup.2, and --SO.sub.2R.sup.1.
Preferred Y Substituents
[0069] Y preferably represents from 1 to 3 substituents
independently selected from the group consisting of halogen, --CN,
--NO.sub.2, --OR.sup.4, --C(O)R.sup.4, --SR.sup.4, --CF.sub.3,
--SOR.sup.4, and --SO.sub.2R.sup.4. Y more preferably represents
from 1 to 3 substituents independently selected from the group
consisting of halogen, --CN, --NO.sub.2, --CF.sub.3, and
--SO.sub.2R.sup.4. Y most preferably represents 1 or 2 substituents
where at least halogen is present and optionally another
substituent selected from the group consisting of --CN, --NO.sub.2,
--OH, --OR.sup.4, --C(O)R.sup.4, --CO.sub.2R.sup.4, --SR.sup.4,
--SOR.sup.4, --SO.sub.2R.sup.4 and unsubstituted or substituted
C.sub.1-4 alkyl. Most preferably, at least one Y substituent is
located para to the sulfonamide bond as defined in formula (I), and
one Y substituent is halogen.
[0070] When Y is substituted alkyl, it preferably has from 1 to 3
substituents independently selected from the group consisting of
halogen, --OH, --OR.sup.4, --CN, --NO.sub.2, .dbd.O,
--OC(O)R.sup.4, --CO.sub.2R.sup.4, --C(O)R.sup.4,
--CONR.sup.4R.sup.5, --NR.sup.4C(O)R.sup.5, --NR.sup.4R.sup.5,
--NR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4, and
--NR.sup.4SO.sub.2R.sup.5.
Preferred Linkers
[0071] L is preferably --C(O)--.
Preferred Z Substituents
[0072] Z preferably represents an unsubstituted or substituted 5-
or 6-membered heteroaryl.
[0073] When Z is a substituted 5- or 6-membered heteroaryl, it
preferably has from 1 to 3 substituents independently selected from
the group consisting of halogen, unsubstituted or substituted
C.sub.1-8 alkyl, unsubstituted or substituted C.sub.3-8 cycloalkyl,
unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or
substituted C.sub.2-8 alkynyl, unsubstituted or substituted
C.sub.1-8 alkoxy, .dbd.O, --CN, --NO.sub.2, --OH, --OR.sup.7,
--OC(O)R.sup.1, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8,
--SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, unsubstituted
or substituted phenyl, unsubstituted or substituted 5- or
6-membered heteroaryl, and unsubstituted or substituted 3- to
7-membered heterocyclyl. If present, one substituent is preferably
located ortho to one of the heteroatoms in the ring or is directly
connected to a ring heteroatom.
[0074] Z more preferably represents unsubstituted or substituted
6-membered heteroaryl with carbon and up to 3 nitrogen atoms and
with from 1 to 3 substituents independently selected from the group
consisting of halogen, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 alkoxy, .dbd.O,
--CN, --NO.sub.2, --OH, --OR.sup.7, --OC(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8, --SR.sup.7, --SOR.sup.7,
--SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- and 6-membered heteroaryl, and
unsubstituted or substituted 3- to 6-membered heterocyclyl. In this
embodiment, Z can be any unsubstituted or substituted chemically
allowed regioisomers of pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl and the like and their respective N-oxides. In preferred
embodiments, Z is pyridinyl with from 0 to 3 substituents;
pyrimidinyl with from 0 to 3 substituents; pyrazinyl with from 0 to
3 substituents; or pyridazinyl with from 0 to 3 substituents
(especially, where one ring nitrogen has a .dbd.O substituent).
[0075] Z most preferably represents unsubstituted or substituted
6-membered heteroaryl with carbon and 1 to 2 nitrogen atoms and
with 1 or 2 substituents independently selected from the group
consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, .dbd.O,
--CN, --NO.sub.2, --OH, --OR.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8,
--SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, 5- or
6-membered heteroaryl and a 3- to 7-membered heterocyclyl. In this
embodiment, Z can be any chemically allowed regioisomers of
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and
their respective N-oxides.
[0076] When the substituent on Z is substituted C.sub.1-8 alkyl,
substituted C.sub.3-8 cycloalkyl, substituted C.sub.2-8 alkenyl,
substituted C.sub.2-8 alkynyl or substituted C.sub.1-8alkoxy
groups, it preferably has from 1 to 3 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.7,
.dbd.O, --CO.sub.2R.sup.7, --C(O)R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8, --SR.sup.7--SOR.sup.7,
--SO.sub.2R.sup.7, --NR.sup.7SO.sub.2R.sup.8, unsubstituted or
substituted phenyl, unsubstituted or substituted 5- or 6-membered
heteroaryl, and unsubstituted or substituted 3- to 6-membered
heterocyclyl. More preferably, it has from 1 to 3 substituents
independently selected from the group consisting of halogen, --OH,
--OR.sup.7, .dbd.O, --C(O)R.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8,
--SR.sup.7--SOR.sup.7, --SO.sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, and 3- to
6-membered heterocyclyl.
[0077] When the substituent on Z is substituted phenyl or
substituted heteroaryl, it preferably has from 1 to 3 substituents
independently selected from the group consisting of halogen, --OH,
--OR.sup.7, --CN, --NO.sub.2, .dbd.O, --CN, --NO.sub.2,
--OC(O)R.sup.7, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8,
--SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted C.sub.1-8
alkyl, unsubstituted or substituted C.sub.1-8 haloalkyl,
unsubstituted or substituted C.sub.3-8 cycloalkyl, and 3- to
6-membered heterocyclyl.
[0078] When the substituent on Z is substituted heterocyclyl, it
preferably has from 1 to 2 substituents independently selected from
the group consisting of unsubstituted or substituted C.sub.1-8
alkyl, C.sub.1-8 haloalkyl, --OR.sup.7, --OH, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, and --SO.sub.2R.sup.7.
Preferred Compounds
[0079] In several preferred embodiments, the compounds are
represented by the following formulae:
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009##
[0080] In each of the above formulae, X' and X'' are each
independently selected from the group consisting of hydrogen,
halogen, --CN, --NO.sub.2, --OH, --OR.sup.1, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --O(CO)R.sup.1, --C(O)NR.sup.1R.sup.2,
--OC(O)NR.sup.1R.sup.2, --SR.sup.1, --SOR.sup.1, --SO.sub.2R',
--SO.sub.2NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O).sub.2R.sup.2,
--NR.sup.1SO.sub.2R.sup.2, --NR.sup.1(CO)NR.sup.1R.sup.2,
unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or
substituted C.sub.1-8 haloalkyl, unsubstituted or substituted
C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl,
unsubstituted or substituted C.sub.3-8 cycloalkyl, unsubstituted or
substituted C.sub.6-10 aryl, unsubstituted or substituted 5- to
10-membered heteroaryl, and unsubstituted or substituted 3 to
10-membered heterocyclyl, with the proviso that X' and X'' cannot
both be hydrogen simultaneously.
[0081] In one preferred embodiment, X' and X'' are each
independently selected from the group consisting of hydrogen,
--NO.sub.2, --OR.sup.1, --C(O)R.sup.1, --SO.sub.2R.sup.1,
--NR.sup.1R.sup.2, unsubstituted or substituted C.sub.1-8alkyl,
unsubstituted or substituted C.sub.1-8 haloalkyl, unsubstituted or
substituted C.sub.3-8 cycloalkyl, unsubstituted or substituted
C.sub.2-8 alkenyl, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- or 6-membered heteroaryl,
unsubstituted or substituted 5- or 6-membered heterocyclyl, with
the proviso that X' and X'' cannot both be hydrogen
simultaneously.
[0082] In another preferred embodiment, X' and X'' are each
independently selected from the group consisting of hydrogen,
--CF.sub.3, --CH.dbd.CH.sub.2, isoamyl, phenylacetylene, t-butyl,
ethyl (Et), i-propyl (.sup.iPr),
--C(CH.sub.3).sub.2CH.sub.2CH.sub.3, hydroxybutyl,
--C(CH.sub.3).sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CO.sub.2Me, --OCF.sub.3, --OMe, --O-.sup.iPr,
--C(O)Me, --SO.sub.2Me, phenyl (Ph), --OEt, pyrazole, oxazole, and
morpholinyl, with the proviso that X' and X'' cannot both be
hydrogen simultaneously.
[0083] In each of the above formulae, Y' and Y'' are each
independently selected from the group consisting of hydrogen,
halogen, --CN, --NO.sub.2, --OH, --OR.sup.4, --C(O)R.sup.4,
--CO.sub.2R.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4,
unsubstituted or substituted C.sub.1-4 alkyl, and unsubstituted or
substituted C.sub.1-4 haloalkyl, with the proviso that Y' and Y''
cannot both be hydrogen simultaneously.
[0084] In one preferred embodiment, Y' and Y'' are each
independently hydrogen or halogen, with the proviso that one or
both are halogen. More preferably, Y' is hydrogen and Y'' is
chloro; Y' and Y'' are both fluoro; Y' is hydrogen and Y'' is
fluoro; or Y' is hydrogen and Y'' is bromo. Most preferably, one
halogen atom is para to the sulfonamide bond in formula (I).
[0085] In each of the above formulae, Z' and Z'' are each
independently selected from the group consisting of hydrogen,
halogen, unsubstituted or substituted C.sub.1-8 alkyl,
unsubstituted or substituted C.sub.3-8 cycloalkyl, unsubstituted or
substituted C.sub.2-8 alkenyl, unsubstituted or substituted
C.sub.2-8 alkynyl, unsubstituted or substituted C.sub.1-8 alkoxy,
.dbd.O, --CN, --NO.sub.2, --OH, --OR.sup.7, --OC(O)R.sup.7,
--CO.sub.2R.sup.7, --C(O)R.sup.7, --CONR.sup.7R.sup.8,
--OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7C(O)NR.sup.8R.sup.9, --NR.sup.7R.sup.8,
--NR.sup.7CO.sub.2R.sup.8, --SR.sup.7, --SOR.sup.7,
--SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted C.sub.1-10
aryl, unsubstituted or substituted 5- or 6-membered heteroaryl and
unsubstituted or substituted 3- to 7-membered heterocyclyl.
[0086] In one preferred embodiment, Z' and Z'' are each
independently selected from the group consisting of hydrogen,
halogen, unsubstituted or substituted C.sub.1-8 alkyl,
unsubstituted or substituted C.sub.3-8 cycloalkyl, --CN, --OH,
--OR.sup.7, --C(O)R.sup.7, --CO.sub.2R.sup.7, --OC(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --NR.sup.7CO.sub.2R.sup.8,
--SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted C.sub.6-10
aryl, and unsubstituted or substituted 5- or 6-membered
heteroaryl.
[0087] In a more preferred embodiment, Z' and Z'' are each
independently hydrogen, halogen, --CN, --OR.sup.7,
--NR.sup.7R.sup.8, --SR.sup.7 (e.g., thiomethyl), --SOR.sup.7, and
--SO.sub.2R.sup.7 (e.g., methylsulfonyl), unsubstituted or
substituted C.sub.1-6 alkoxyl (e.g., methoxy), unsubstituted or
substituted C.sub.1-6 alkyl (e.g., methyl), unsubstituted or
substituted phenyl, or unsubstituted or substituted 5- or
6-membered heterocyclyl.
Compositions that Modulate CCR9 Activity
[0088] In another aspect, the present invention provides
compositions that modulate CCR9 activity. Generally, the
compositions for modulating chemokine receptor activity in humans
and animals will comprise a pharmaceutically acceptable excipient
or diluent and a compound having the formula provided above as
formula (I).
[0089] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0090] The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy. All methods include the step of
bringing the active ingredient into association with the carrier
which constitutes one or more accessory ingredients. In general,
the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or 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 effect upon
the process or condition of diseases.
[0091] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions and self emulsifications
as described in U.S. Patent Application 20020012680, 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. Such compositions may
contain one or more agents selected from sweetening agents,
flavoring agents, coloring agents and preserving agents in order to
provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in admixture with other
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for
example, inert diluents such as cellulose, silicon dioxide,
aluminum oxide, calcium carbonate, sodium carbonate, glucose,
mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example PVP, cellulose, PEG,
starch, gelatin or acacia, and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated enterically or otherwise 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. 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.
[0092] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil. Additionally, emulsions can be
prepared with a non-water miscible ingredient such as oils and
stabilized with surfactants such as mono-diglycerides, PEG esters
and the like.
[0093] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0094] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti oxidant such as ascorbic
acid.
[0095] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0096] The pharmaceutical compositions of the invention may also be
in the form of oil in water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0097] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative. and
flavoring and coloring agents. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0098] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non toxic
parenterally acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, axed 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. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0099] The compounds of the present invention may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols. Additionally, the
compounds can be administered viaocular delivery by means of
solutions or ointments. Still further, transdermal delivery of the
subject compounds can be accomplished by means of iontophoretic
patches and the like.
[0100] For topical use, creams, ointments, jellies, solutions or
suspensions containing the compounds of the present invention are
employed. As used herein, topical application is also meant to
include the use of mouth washes and gargles.
[0101] The pharmaceutical compositions and methods of the present
invention may further comprise other therapeutically active
compounds as noted herein, such as those applied in the treatment
of the above mentioned pathological conditions.
Methods of Treating CCR9-Mediated Conditions or Diseases
[0102] In yet another aspect, the present invention provides
methods of treating or preventing a CCR9-mediated condition or
disease by administering to a subject having such a condition or
disease a therapeutically effective amount of any compound of
formula (I) above. Compounds for use in the present methods include
those compounds according to formula (I), those provided above as
embodiments, those specifically exemplified in the Examples below,
and those provided with specific structures herein. The "subject"
is defined herein to include animals such as mammals, including,
but not limited to, primates (e.g., humans), cows, sheep, goats,
horses, dogs, cats, rabbits, rats, mice and the like. In preferred
embodiments, the subject is a human.
[0103] As used herein, the phrase "CCR9-mediated condition or
disease" and related phrases and terms refer to a condition or
disease characterized by inappropriate, i.e., less than or greater
than normal, CCR9 functional activity. Inappropriate CCR9
functional activity might arise as the result of CCR9 expression in
cells which normally do not express CCR9, increased CCR9 expression
(leading to, e.g., inflammatory and immunoregulatory disorders and
diseases) or decreased CCR9 expression. Inappropriate CCR9
functional activity might also arise as the result of TECK
secretion by cells which normally do not secrete TECK, increased
TECK expression (leading to, e.g., inflammatory and
immunoregulatory disorders and diseases) or decreased TECK
expression. A CCR9-mediated condition or disease may be completely
or partially mediated by inappropriate CCR9 functional activity.
However, a CCR9-mediated condition or disease is one in which
modulation of CCR9 results in some effect on the underlying
condition or disease (e.g., a CCR9 antagonist results in some
improvement in patient well being in at least some patients).
[0104] The term "therapeutically effective amount" means the amount
of the subject compound that will elicit the biological or medical
response of a cell, tissue, system, or animal, such as a human,
that is being sought by the researcher, veterinarian, medical
doctor or other treatment provider.
[0105] Diseases and conditions associated with inflammation, immune
disorders, infection and cancer can be treated or prevented with
the present compounds, compositions, and methods. In one group of
embodiments, diseases or conditions, including chronic diseases, of
humans or other species can be treated with inhibitors of CCR9
function. These diseases or conditions include: (1) allergic
diseases such as systemic anaphylaxis or hypersensitivity
responses, drug allergies, insect sting allergies and food
allergies, (2) inflammatory bowel diseases, such as Crohn's
disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis,
(4) psoriasis and inflammatory dermatoses such as dermatitis,
eczema, atopic dermatitis, allergic contact dermatitis, urticaria
and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7)
scleroderma, (8) asthma and respiratory allergic diseases such as
allergic asthma, allergic rhinitis, hypersensitivity lung diseases
and the like, (9) autoimmune diseases, such as fibromyalagia,
scleroderma, ankylosing spondylitis, juvenile RA, Still's disease,
polyarticular juvenile RA, pauciarticular juvenile RA, polymyalgia
rheumatica, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, polyarticular arthritis, multiple sclerosis,
systemic lupus erythematosus, type I diabetes, type II diabetes,
glomerulonephritis, and the like, (10) graft rejection (including
allograft rejection), (11) graft-v-host disease (including both
acute and chronic), (12) other diseases in which undesired
inflammatory responses are to be inhibited, such as
atherosclerosis, myositis, neurodegenerative diseases (e.g.,
Alzheimer's disease), encephalitis, meningitis, hepatitis,
nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis,
chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome
and gout, (13) immune mediated food allergies such as Coeliac
(Celiac) disease (14) pulmonary fibrosis and other fibrotic
diseases, and (15) irritable bowel syndrome.
[0106] In another group of embodiments, diseases or conditions can
be treated with modulators and agonists of CCR9 function. Examples
of diseases to be treated by modulating CCR9 function include
cancers, cardiovascular diseases, diseases in which angiogenesis or
neovascularization play a role (neoplastic diseases, retinopathy
and macular degeneration), infectious diseases (viral infections,
e.g., HIV infection, and bacterial infections) and
immunosuppressive diseases such as organ transplant conditions and
skin transplant conditions. The term "organ transplant conditions"
is means to include bone marrow transplant conditions and solid
organ (e.g., kidney, liver, lung, heart, pancreas or combination
thereof) transplant conditions.
[0107] Preferably, the present methods are directed to the
treatment of diseases or conditions selected from inflammatory
bowel disease including Crohn's disease and Ulcerative Colitis,
allergic diseases, psoriasis, atopic dermatitis and asthma,
autoimmune disease such as rheumatoid arthritis and immune-mediated
food allergies such as Coelaic disease.
[0108] Depending on the disease to be treated and the subject's
condition, the compounds and compositions of the present invention
may be administered by oral, parenteral (e.g., intramuscular,
intraperitoneal, intravenous, ICV, intracisternal injection or
infusion, subcutaneous injection, or implant), inhalation, nasal,
vaginal, rectal, sublingual, or topical routes of administration
and may be formulated, alone or together, in suitable dosage unit
formulations containing conventional non toxic pharmaceutically
acceptable carriers, adjuvants and vehicles appropriate for each
rouse of administration. The present invention also contemplates
administration of the compounds and compositions of the present
invention in a depot formulation.
[0109] In the treatment or prevention of conditions which require
chemokine receptor modulation an appropriate dosage level will
generally be about 0.001 to 100 mg per kg patient body weight per
day which can be administered in single or multiple doses.
Preferably, the dosage level will be about 0.01 to about 25 mg/kg
per day; more preferably about 0.05 to about 10 mg/kg per day. A
suitable dosage level may be about 0.01 to 25 mg/kg per day, about
0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within
this range the dosage may be 0.005 to 0.05, 0.05 to 0.5, 0.5 to
5.0, or 5.0 to 50 mg/kg per day. For oral administration, the
compositions are preferably provided in the form of tablets
containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day.
[0110] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, hereditary
characteristics, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
[0111] In still other embodiments, the present methods are directed
to the treatment of allergic diseases, wherein a compound or
composition of the invention is administered either alone or in
combination with a second therapeutic agent, wherein said second
therapeutic agent is an antihistamine. When used in combination,
the practitioner can administer a combination of the compound or
composition of the present invention and a second therapeutic
agent. Also, the compound or composition and the second therapeutic
agent can be administered sequentially, in any order.
[0112] In yet other embodiments, the present methods are directed
to the treatment of psoriasis wherein a compound or composition of
the invention is used alone or in combination with a second
therapeutic agent such as a corticosteroid, a lubricant, a
keratolytic agent, a vitamin D.sub.3 derivative, PUVA and
anthralin.
[0113] In other embodiments, the present methods are directed to
the treatment of atopic dermatitis using a compound or composition
of the invention either alone or in combination with a second
therapeutic agent such as a lubricant and a corticosteroid.
[0114] In further embodiments, the present methods are directed to
the treatment of asthma using a compound or composition of the
invention either alone or in combination with a second therapeutic
agent such as a .beta.2-agonist and a corticosteroid.
[0115] The compounds and compositions of the present invention can
be combined with other compounds and compositions having related
utilities to prevent and treat the condition or disease of
interest, such as inflammatory conditions and diseases, including
inflammatory bowel disease, allergic diseases, psoriasis, atopic
dermatitis and asthma, and those pathologies noted above. Selection
of the appropriate agents for use in combination therapies can be
made one of ordinary skill in the art. The combination of
therapeutic agents may act synergistically to effect the treatment
or prevention of the various disorders. Using this approach, one
may be able to achieve therapeutic efficacy with lower dosages of
each agent, thus reducing the potential for adverse side
effects.
[0116] The weight ratio of the compound of the present invention to
the second active ingredient may be varied and will depend upon the
effective dose of each ingredient. Generally, an effective dose of
each will be used. Thus, for example, when a compound of the
present invention is combined with an NSAID the weight ratio of the
compound of the present invention to the NSAID will generally range
from about 1000:1 to about 1:1000, preferably about 200:1 to about
1:200. Combinations of a compound of the present invention and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
EXAMPLES
[0117] Reagents and solvents used below can be obtained from
commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.,
USA). .sup.1H-NMR were recorded on a Varian Mercury 400 MHz NMR
spectrometer. Significant peaks are tabulated in the order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet) and number of protons. Mass spectrometry results are
reported as the ratio of mass over charge, followed by the relative
abundance of each ion (in parenthesis). In tables, a single m/e
value is reported for the M+H (or, as noted, M-H) ion containing
the most common atomic isotopes. Isotope patterns correspond to the
expected formula in all cases. Electrospray ionization (ESI) mass
spectrometry analysis was conducted on a Hewlett-Packard MSD
electrospray mass spectrometer using the HP1100 HPLC for sample
delivery. Normally the analyte was dissolved in methanol at 0.1
mg/mL and 1 microlitre was infused with the delivery solvent into
the mass spectrometer, which scanned from 100 to 1500 daltons. All
compounds could be analyzed in the positive ESI mode, using
acetonitrile/water with 1% formic acid as the delivery solvent. The
compounds provided below could also be analyzed in the negative ESI
mode, using 2 mM NH.sub.4OAc in acetonitrile/water as delivery
system.
[0118] Compounds within the scope of this invention can be
synthesized as described below, using a variety of reactions known
to the skilled artisan. A sample of useful routes to both the
benzophenone and heteroaryl derived subunits and to fully
elaborated sulfonamide molecules of formula (I) within this claim
are provided below. In the descriptions of the syntheses that
follow, some precursors were obtained from commercial sources.
These commercial sources include Aldrich Chemical Co., Acros
Organics, Ryan Scientific Incorporated, Oakwood Products
Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster
Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS
Chemicals.
[0119] Compounds of the invention can be prepared using
conventional synthetic methodology. Examples of approaches that may
be taken to synthesize these compounds are shown below.
Nonetheless, one skilled in the art will recognize that alternative
methods may be employed to synthesize the target compounds of this
invention, and that the approaches described within the body of
this document are not exhaustive, but do provide broadly applicable
and practical routes to compounds of interest.
[0120] Certain molecules claimed in this patent can exist in
different enantiomeric and diastereomeric forms and all such
variants of these compounds are within the scope of the
invention.
[0121] The detailed description of the experimental procedures used
to synthesize key compounds in this text lead to molecules that are
described by the physical data identifying them as well as by the
structural depictions associated with them.
[0122] Those skilled in the art will also recognize that during
standard work up procedures in organic chemistry, acids and bases
are frequently used. Salts of the parent compounds are sometimes
produced, if they possess the necessary intrinsic acidity or
basicity, during the experimental procedures described within this
patent.
Preparation of CCR9 Modulators
[0123] The following examples are offered to illustrate, but not to
limit, the claimed invention.
[0124] Additionally, those skilled in the art will recognize that
the molecules claimed in this patent may be synthesized using a
variety of standard organic chemistry transformations.
[0125] Certain general reaction types employed widely to synthesize
target compounds in this invention are summarized in the examples.
Specifically, generic procedures for sulfonamide formation,
pyridine N-oxide formation and 2-aminophenyl-arylmethanone
synthesis via Friedel-Crafts type approaches are given, but
numerous other standard chemistries are described within and were
employed routinely.
[0126] While not intended to be exhaustive, representative
synthetic organic transformations which can be used to prepare
compounds of the invention are included below.
[0127] These representative transformations include; standard
functional group manipulations; reduction such as nitro to amino;
oxidations of functional groups including alcohols and pyridines;
aryl substitutions via IPSO or other mechanisms for the
introduction of a variety of groups including nitrile, methyl and
halogen; protecting group introductions and removals; Grignard
formation and reaction with an electrophile; metal-mediated cross
couplings including but not limited to Buckvald, Suzuki and
Sonigashira reactions; halogenations and other electrophilic
aromatic substitution reactions; diazonium salt formations and
reactions of these species; etherifications; cyclative
condensations, dehydrations, oxidations and reductions leading to
heteroaryl groups; aryl metallations and transmetallations and
reaction of the ensuing aryl-metal species with an electrophile
such as an acid chloride or Weinreb amide; amidations;
esterifications; nucleophilic substitution reactions; alkylations;
acylations; sulfonamide formation; chlorosulfonylations; ester and
related hydrolyses, and the like.
Example 1
General Procedure for the Preparation of
N-Aryl-benzenesulfonamides
##STR00010##
[0129] To the desired aniline (0.5 mmol) dissolved in pyridine and
cooled in an ice-water bath was added a solution of an aryl
sulfonyl chloride (0.5 mmol) dissolved in cold pyridine. The
reaction mixture was then heated to 60.degree. C. with gentle
shaking for 16 h. Evaporation of the solvent with standard workup
followed by either flash chromatography or reversed phase HPLC
yielded the corresponding N-aryl-benzenesulfonamides.
Example 2
General Procedure for the Synthesis of
(2-Amino-phenyl)-pyridinyl-methanones
##STR00011##
[0131] To 12.5 mL 1 M BCl.sub.3 (12 mmol, 1.2 eq.) in methylene
chloride stirred at 0.degree. C. was added a solution of the
desired haloaniline (10 mmol, 1.0 eq.) in 15 mL of TCE drop wise
over 20 minutes. After 10 minutes the desired cyanopyridine (11
mmol, 1.1 eq.) was added followed by AlCl.sub.3 (15 mmol, 1.5 eq.).
The reaction was brought to RT, stirred for an hour then heated at
80-90.degree. C. until all of the DCM was distilled off. The
reaction mixture was then refluxed at 160.degree. C. for 4 hours,
cooled to RT and stirred overnight. 10 mL 3 M HCl were carefully
added and the mixture was refluxed at 120.degree. C. for 2-3 hours
while reaction progress was monitored by LC/MS. The crude reaction
was cooled to RT and 100 mL water were added. The crude mixture was
extracted with DCM (2.times.50 mL), the aqueous layer was set aside
and the organic layer was back extracted with 50 mL 1 M HCl (aq.).
All aqueous layers were combined, brought to pH 12 with 3 M NaOH
(aq.) and extracted with DCM (4.times.50 mL). The DCM layer was
dried on Na.sub.2SO.sub.4, filtered and concentrated by rotary
evaporation. The crude product was washed liberally with Et.sub.2O
and dried under vacuum, and further purified by conventional
techniques such as column chromatography when necessary.
Example 3
General Procedure for the Synthesis of Sulfonamide
Pyridine-N-Oxides
##STR00012##
[0133] The desired N-Aryl-benzenesulfonamide (250 .mu.mol) was
dissolved in 2 mL DCM and m-CPBA (1.0-1.5 eq) was then added. The
reaction was shaken at RT and monitored by LC-MS. Additional m-CPBA
was added as needed in aliquots until the reaction was complete. In
most cases the reaction required 15-24 h r.times.n time. Standard
workup led to the isolation of crude products, which were purified
by column chromatography.
Example 4
Synthesis of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone
##STR00013##
[0135] A solution of 4-chloroaniline (2.0 g, 16 mmol) in 30 mL of
TCE was added drop wise to a solution of BCl.sub.3 (1M in DCM) (24
ml, 24 mmol) with ice bath cooling, over a period of 15 min and the
reaction mixture stirred at that temperature for an additional 10
min. 4-Cyanopyridine (2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22
mmol) were added with ice-water cooling. The solution was allowed
to warm to room temperature and stirred for 30 min. The resulting
solution was refluxed at 160.degree. C. for 4 h and stirred at room
temperature overnight. The reaction mixture was then treated with
30 mL of 3N HCl and the mixture was refluxed at 110.degree. C. for
1.5 h. The reaction mixture was allowed to cool down to room
temperature and the solution was adjusted to pH12 with 6N NaOH and
then diluted water and DCM. The resulting two layers were separated
and the aqueous layer was extracted with DCM three times and the
organic layers combined and dried over sodium sulfate. After
removal of the solvent, the resulting solid was washed with ether
to yield (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (2.8 g,
75%).
Example 5
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)methanone
##STR00014##
[0137] To 20 mL 1M BCl.sub.3 (20 mmol, 2.3 eq.) in DCM stirred at
0.degree. C. was added a solution of 1.1 g 4-chloroaniline (8.6
mmol, 1.0 eq.) in 15 mL of TCE drop wise over five minutes. After
10 minutes 1.1 g of 2-cyano-6-methylpyridine (1.1 eq.) were added
to the reaction mixture and after 2 minutes 1.6 g AlCl.sub.3 (12
mmol, 1.4 eq.) was added. After 5 minutes the reaction was brought
to RT, stirred for an hour then heated at 160.degree. C. for 17
hours. 100 mL 3M HCl were added and the reaction is monitored by
LC/MS. After 6 hours the reaction was removed from heat, cooled to
RT and 300 mL water were added. The crude mixture was extracted
with DCM (1.times.500 mL), the aqueous layer was set aside and the
organic layer was back extracted with 300 mL 3M HCl (aq.). All
aqueous layers were combined, brought to pH 11 with 3M NaOH (aq.)
and extracted with DCM. The DCM layer was dried on
Na.sub.2SO.sub.4, filtered and concentrated by rotary evaporation.
Preparatory chromatography afforded the product as a cream colored
solid which was converted to its HCl salt before being
characterized. .sup.1H NMR: .delta. (ppm): 2.83 (s, 3H), 7.32 (d,
J=2.0 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H),
7.82-7.85 (m, 2H), 7.99 (t, J=7.6 Hz, H), 8.27 (d, J=7.6 Hz, 1H),
10.83 (s, 1H). MS: (M+H)/z=247.0.
Example 6
Synthesis of
(5-chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol
##STR00015##
[0139] A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0
eq.) in 10 mL anhyd. THF was stirred at 40.degree. C. to
-50.degree. C. After five minutes, 2.2 mL of 2.1 M .sup.iPrMgBr/THF
(4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the
reaction mixture is maintained at 40 to -50.degree. C. for 30
minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was
then added and the reaction was maintained at -50.degree. C. After
1 hour, the reaction was allowed to warm to -10.degree. C., and
quenched with 50 mL saturated brine after a further fifteen
minutes. The crude product was extracted with EtOAc, dried on
Na.sub.2SO.sub.4 and concentrated by rotary evaporation to yield
desired product. MS: (M+H)/z=298.9.
Example 7
Synthesis of
(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanone
##STR00016##
[0141] To
(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol was
added an excess (ca. 2 eq.) of PDC in DCM. The suspension was
shaken at room temperature overnight. The reaction was monitored by
LC-MS, another 1-2 eq. of PDC was added and the reaction was shaken
for another 6 hours. The crude product was filtered through Celite
and purified by flash chromatography (silica gel, DCM). .sup.1H NMR
(CDCl.sub.3): .delta. (ppm): 7.50 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.0
Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.09-8.11 (m,
1H), 8.24 (d, J=8.8 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H. MS:
(M+H)/z=296.9.
Example 8
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone
##STR00017##
[0143] 3-(5-chloro-2-nitrophenyl)-pyridinylmethanone was added to a
mixture of concentrated HCl, DMF, SnCl.sub.2 and heated at
130.degree. C. The reaction was monitored by LC/MS and removed from
heat after 2 h. The crude reaction was treated with aq.
K.sub.2CO.sub.3, extracted into DCM and concentrated by rotary
evaporation. The crude product was purified by preparatory
chromatography. MS: (M+H)/z=267.0.
Example 9
Synthesis of N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide
##STR00018##
[0145] To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL
pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the
reaction mixture stirred overnight at room temperature. The mixture
was poured into vigorously stirring 6M HCl, and the solids were
collected by vacuum filtration, washed well with H.sub.2O, and
dried in vacuo to yield the title compound. 1H NMR (CDCl3) .delta.
7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s,
9H) MS (ES) m/z=212.1.
Example 10
Synthesis of
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propiona-
mide
##STR00019##
[0147] N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2
mmol) was dissolved in 15 mL THF in a dry 100 mL flask fitted with
a rubber septa and nitrogen inlet and cooled to 0.degree. C. in ice
water bath for 25 minutes. A solution of 2.5M BuLi in hexane (17.0
mL, 42.6 mmol) was added and the mixture stirred for 45 minutes. To
the thick yellow precipitate that formed was added a solution of
pyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice
bath was removed and the mixture was allowed to stir at room
temperature for 45 minutes and the reaction was quenched with 25 mL
H.sub.2O. The mixture was transferred to a separating funnel, and
the aqueous phase was discarded. The organics were dried in vacuo
to yield product as an orange oil. 1H NMR (CDCl3) .delta. 8.85 (m,
1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50
(d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m,
1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH).sup.+.
Example 11
Synthesis of
N-[4-chloro-2-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide
##STR00020##
[0149]
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-pr-
opionamide (1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and
treated with CrO.sub.3 (0.75 g, 7.5 mmol, 2.39 eq). The mixture was
stirred under N.sub.2 at room temperature for five hours, diluted
with 20 mL 1:2 EtOAc/H.sub.2O, and filtered through Celite. The
aqueous phase was separated and discarded, then the organics dried
under vacuum yielding product (680 mg, 70%) .sup.1H NMR (CDCl3)
.delta. 11.06 (s, 1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz, 1H)
8.73 (d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz,
2.0 Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1
(MH).sup.+.
Example 12
Synthesis of (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone
##STR00021##
[0151]
N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionami-
de (0.65 g) was suspended in 5 mL of 70% H.sub.2SO.sub.4 and heated
at 95.degree. C. in oil bath overnight. After cooling to room
temperature the solution was added drop wise with stirring to 20 mL
of 40% NaOH solution placed in an ice-water bath. The fine yellow
precipitate formed was collected by vacuum filtration, washed well
with water and dried under vacuum to give 370 mg of product. 1H NMR
(CDCl3) .delta. 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77 (dd, J=4.8 Hz,
2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H) 7.35 (d,
J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H) 6.21
(s, 2H) MS (ES) m/z=233.0 (MH).sup.+.
Example 13
Synthesis of 2-methyl-isonicotinonitrile
##STR00022##
[0153] Dimethyl sulfate (18.3 mL, 192.4 mmol) was added to stirring
2-picoline-N-oxide (20 g) over a 10 minute period. The reaction was
exothermic and the material quickly became homogeneous. The mixture
was heated in a 60.degree. C. oil bath for 2 hours, then the
volatiles were removed under vacuum and the pale yellow oil was
diluted with 25 mL H.sub.2O and added drop wise over 10 minutes to
160 mL of 25% (w/v) KCN/H.sub.2O. After stirring for 3.5 hours the
yellow precipitate formed was collected by vacuum filtration and
purified by column chromatography (EtOAc/Hexane) to yield 13.0 g of
product (60%). 1H NMR (CDCl3) .delta. 8.66 (d, J=4.8 Hz, 1H) 7.37
(s, 1H) 7.31 (d, J=4.4 Hz, 1H) 2.62 (s, 3H) 2.62 (s, 3H); MS (ES)
m/z=119.0
Example 14
Synthesis of
(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone
##STR00023##
[0155] The title compound was prepared according to the general
procedure for the Synthesis of (2-Amino-phenyl)-aryl-methanones,
using 4-chloro-phenylamine (1.8 g, 14.2 mmol) and
2-methyl-isonicotinonitrile (2.0 g, 16.9 mmol). 1H NMR (CDCl3)
.delta. 8.64 (d, J=4.8 Hz, 1H) 7.28 (m, 3H) 7.20 (d, J=6.0 Hz, 1H)
6.70 (d, J=12.4 Hz, 1H) 6.28 (s, 2H) 2.66 (s, 3H) MS (ES)
m/z=247.0
Example 15
Synthesis of (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone
##STR00024##
[0157] To a solution of 2-bromopyridine (5 ml, 52 mmol) in
Et.sub.2O (60 ml) was added 40 ml of a n-butyllithium (1.6M in
hexane, 64 mmol) drop wise at -40.degree. C. over 30 min under a
nitrogen atmosphere. The resulting yellow solution was stirred for
a further 1 hr at -50.degree. C. to -30.degree. C. In a separate
flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12 mmol)
in dry THF (90 ml), under nitrogen atmosphere and with ice-cooling,
was added in one portion to the solution prepared as described
above. The reaction mixture was stirred for 2 hrs at 0.degree. C.
and then chlorotrimethylsilane (30 ml) was added at 0.degree. C.
with stirring. The reaction mixture was allowed to warm to room
temperature and 1 N HCl aq (100 ml) was added. The resulting
two-phase system was separated. The aqueous phase was adjusted to
pH12 with 6N NaOH solution and extracted with ethyl acetate
(2.times.150 ml). The combined organic extractions were dried over
Na.sub.2SO.sub.4. After removal of solvent, the residue was
purified by the flash chromatography using ethyl acetate/hexane
(1:4) as eluent. Crystallization of the product from
Et.sub.2O/hexane mixture gave 1.26 g (45%) of desired product as
yellow solid. .sup.1H-NMR (DMSO-d.sub.6, 500 MHz): .delta. 6.90
(1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53
(1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H,
m), 8.69 (1H, m). MS: (ESI.sup.+): 233.2 (M+1).
Example 16
Synthesis of
(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone
##STR00025##
[0159] To a solution of 3-picoline (50 g, 0.48 mol) in glacial
acetic acid (150 ml) was added hydrogen peroxide (25 ml) at RT. The
mixture was heated to 90.degree. C. for 3 hr. The mixture was
cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly.
The mixture was again heated to 90.degree. C. for 19 hr. The excess
peroxide was carefully decomposed using Pd--C (2.5 g) at 0.degree.
C. Pd--C was removed by filtration, and the filtrate was
concentrated and crude 3-methylpyridine-1-oxide was purified by
fractional distillation in vacuo.
[0160] A solution of 3-methylpyridine-1-oxide (10 g, 0.092 mol) in
methyl iodide (15 ml) was left at rt for 18 hr and the solid was
filtered. The filtrate was diluted with diethyl ether and extracted
with water (40 ml). The solid was re-dissolved in the aqueous
extract, 1,4-dioxane (50 ml) was added, followed by potassium
cyanide (15 g, 0.23 mol) and the mixture was stirred at RT for 3
hr. The product was extracted with chloroform. The chloroform layer
was washed with water, brine and dried over sodium sulfate. The
solvent was removed in vacuo and the crude product was purified by
fractional distillation (61-62.degree. C./0.2 mm) to yield a white
low melting solid.
[0161] BCl.sub.3 (24 ml, 1M in DCM, 0.024 mol) was added slowly to
a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of
trichloroethylene over a period of 15 min. at 0.degree. C. and
stirred at this temperature for an additional 10 min.
4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AlCl.sub.3 (3 g,
0.022 mol) were added at 0.degree. C. The solution was allowed to
warm to RT and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 hr. and the DCM was distilled off. The
resulting solution was refluxed at 115.degree. C. for 4 hr and
stirred at RT overnight. 3N HCl (20 ml) was added and the mixture
refluxed at 100.degree. C. for 2 hr. The reaction mixture was
cooled to 0.degree. C. and adjusted to pH-12 with 6N NaOH. The
reaction mixture was extracted with DCM, and the DCM layer washed
with water, brine and dried over Na.sub.2SO.sub.4. The solvent was
removed, and the crude was purified by column chromatography over
silica gel to yield a yellow solid.
Example 17
Synthesis of
(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone
##STR00026##
[0163] Iron powder (28.1 g, 0.502 mol) was added as small portions
to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200
ml) and heated to 60.degree. C. Ammonium chloride (48.4 g, 0.91
mol) in water (100 ml) was added drop wise and the reaction mixture
refluxed for 5 hr. The reaction mixture was filtered over Celite
and washed with methanol. Methanol was removed, and the aqueous
layer was extracted with ethylacetate, washed with brine, dried
over sodium sulphate and concentrated to yield
1,2-difluoro-4-aminobenzene (7 g, 43%).
[0164] BCl.sub.3 (6.2 ml, 1M in DCM) was added drop wise to
1,2-difluoro-4aminobenzene (0.5 g, 0.004 mol) in trichloroethylene
(6.5 ml) at 0.degree. C. and this mixture stirred for 15 min.
4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was
warmed to RT and stirred for 30 min. The solution was then heated
at 80-90.degree. C. for 1 h. The resulting solution was refluxed at
160.degree. C. for 4 hr and stirred at RT over night. 3N HCl was
added to the reaction mixture and refluxed at 110.degree. C. for
1.5 h. The reaction mixture was cooled to RT and made basic (pH=12)
with 6N NaOH. The reaction mixture was diluted with water and DCM.
The resulting two layers were separated and the aqueous layer was
extracted with DCM, dried over sodium sulphate and concentrated.
The compound was purified by column chromatography using silica gel
to yield title compound (0.25 g, 27%).
Example 18
Synthesis of
(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone
##STR00027##
[0166] To 3,4-Difluoroaniline (2.0 g, 0.0153 mol) and triethylamine
(3.1 g, 0.0307 mol) in dry benzene (100 ml) was added
trimethylacetylchloride (2.3 g, 0.0184 mol) slowly at 0.degree. C.
and the reaction mixture stirred at RT overnight. The reaction
mixture was then quenched with water and extracted with ethyl
acetate. The organic layer was washed with water, brine, dried over
sodium sulfate and concentrated. Compound was recrystallized from
petroleum ether yielding 3.2 g, 98%.
[0167] This protected 3,4-difluoroaniline (2.7 g, 0.0126 mol) was
taken in dry THF (25 ml) and under nitrogen t-butyllithium (2.02 g,
0.032 mol) was added drop wise at -78.degree. C. Stirring was
continued at -78.degree. C. for 2 h. 4-Pyridine carboxaldehyde
(3.55 g, 0.033 mol) dissolved in dry THF (10 ml) was added slowly.
The reaction mixture was warmed to room temperature and stirred
over night. The reaction mixture was then quenched with water and
extracted with ether. The organic layer was washed with brine,
dried over sodium sulfate and concentrated. Compound was purified
by column chromatography to yield carbinol (2.6 g, 65%).
[0168] To carbinol (2.6 g, 0.0031 mol) in 17.3 ml of pyridine was
added a suspension of chromium trioxide (0.705 g, 0.007 mol) in
pyridine (6.0 ml) under a nitrogen atmosphere. The resulting
mixture was allowed to stir at RT over night. The reaction mixture
was poured into water and extracted with ether. The ether extract
was washed with brine, dried over sodium sulfate and concentrated.
The compound was purified by column chromatography to yield the
protected precursor to the title compound (1.7 g, 65.8%).
[0169] To this pivaloyl protected amino ketone (1.7 g, 0.0053 mol)
was added 70% sulfuric acid (14.6 ml) and the reaction mixture
heated to 95-100.degree. C. overnight. The reaction mixture was
basified by using 10% sodium hydroxide and extracted with
dichloromethane. The organic layer was washed with water, brine,
dried over sodium sulfate and concentrated. The product obtained
was purified by column chromatography to yield title compound (0.58
g, 46.4%).
Example 19
Synthesis of
(2-Amino-5-chloro-4-methoxy-phenyl)-pyridin-4-yl-methanone
##STR00028##
[0171] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric
acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g,
0.304 mol) in water (50 ml) was added slowly at 0.degree. C. After
15 mins, this solution was added slowly to dilute sulfuric acid
(50%, 250 ml) at 110.degree. C. Stirring was continued for 15 min.
The reaction mixture was cooled to RT, ice water was added,
extracted with ethylacetate, washed with water, brine and dried
over Na.sub.2SO.sub.4. The phenol product obtained upon
concentration was purified by column chromatography. Yield 12.0 g,
24.0%.
[0172] K.sub.2CO.sub.3 (23.84 g, 0.172 mol) was added to
2-chloro-5-nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml)
at RT. After cooling to 0.degree. C., methyl iodide (19.6 g, 0.138
mol) was added slowly and the reaction mixture stirred at RT
overnight Water (100 ml) was added and the aqueous layer extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. The product obtained upon
concentration was purified by column chromatography to yield the
anisole (6.0 g, 55.55%).
[0173] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml)
was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc.
HCl (110 ml) at 40.degree. C. and the temperature was slowly raised
to 50.degree. C. Stirring was continued for 2 h. After cooling to
RT, the reaction mixture was basified with 50% NaOH solution,
extracted by ethyl acetate, washed with water, then brine and dried
over Na.sub.2SO.sub.4. 3-Methoxy-4-chloroaniline was obtained upon
concentration and was purified further by column chromatography.
Yield: 4.0 g, 79.36%.
[0174] To 3-Methoxy-4-chloroaniline (2.0 g, 0.0126 mol) in
trichloroethylene (30 ml) was added BCl.sub.3 (2.18 g, 1 M solution
in DCM, 0.0188 mol) at 0.degree. C. After stirring for 10 min,
4-cyanopyridine (1.6 g, 0.0153 mol) and AlCl.sub.3 (2.35 g, 0.018
mol) were added and the temperature was raised to RT, with further
stirring for 30 min. The temperature was raised further to
85.degree. C. and maintained at the same temperature for 1 h. DCM
was distilled off and the solution was stirred at 115.degree. C.
for 4 h and then at RT over night. 3N HCl was added at RT and the
reaction mixture refluxed for 1.5 h. The reaction mixture was
allowed to cool and made basic using NaOH (6 N), diluted with water
and extracted with DCM, washed with water, brine and dried over
Na.sub.2SO.sub.4. The crude title compound was obtained upon
concentration and was purified by column chromatography. Yield:
0.50 g, 15%.
Example 20
Synthesis of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone
##STR00029##
[0176] To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55
ml) was added selenium dioxide (8.82 g, 0.079 mol) at RT with
stirring. The reaction mixture was stirred at 55.degree. C. for 2 h
and at 80.degree. C. for 3.5 hr. After cooling to RT and stirring
over night, the reaction mixture was filtered and the residue was
washed with pyridine. The combined pyridine solution was
concentrated and the carboxylic acid obtained was washed with water
to remove traces of selenium dioxide. Yield: 5.3 g, 80.5%.
[0177] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in
methanol (170 ml) was added conc. HCl (2 ml) at RT. After refluxing
overnight, the reaction mixture was cooled to RT and neutralized
with 10% sodium bicarbonate solution and concentrated. The ester
was extracted with diethyl ether, dried over Na.sub.2SO.sub.4 and
concentrated to get the methyl ester as a yellow solid, yield: 3.3
g, 57.55%.
[0178] Trimethyl acetylchloride (11.30 g, 0.093 mol) was added to a
benzene (500 ml) solution of triethylamine (15.75 g, 0.155 mol) and
4-chloroaniline (10.0 g, 0.078 mol) at 0.degree. C. The reaction
mixture was warmed to RT and stirred for 3 h. The reaction mixture
was then quenched with water, extracted with ethyl acetate, washed
with water, brine solution and dried over Na.sub.2SO.sub.4. The
solid product obtained was crystallized from pet ether. Yield: 14.0
g, 84.43%.
[0179] To N-(4-chlorophenyl)-2,2-dimethyl propanamide (3.5 g,
0.0165 mol) in THF (50 ml) at 0.degree. C. was added n-butyl
lithium in hexane (2.64 g, 1.2 M, 0.041 mol). Stirring was
continued at 0.degree. C. for 2 h, the reaction then cooled to
-70.degree. C., pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol)
in THF (25 ml) was then added slowly and the solution was warmed to
RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml)
were added and the organic layer was separated. The aqueous layer
was further extracted with ether. The combined ether layers were
washed with water, brine and dried over Na.sub.2SO.sub.4 The
product obtained upon concentration was purified by column
chromatography. Yield: 1.7 g, 32.69%.
[0180] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric
acid (10 ml, 70%) was heated at 95.degree. C. over night. The
reaction mixture was cooled to RT and basified with 10% NaOH,
extracted with DCM, washed with water, brine and dried over
Na.sub.2SO.sub.4. The product obtained upon concentration was
purified by column chromatography using basic alumina to yield
title compound (0.20 g, 16%).
Example 21
Synthesis of
(6-Amino-3-chloro-2-methoxy-phenyl)-pyridin-4-yl-methanone
##STR00030##
[0182] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric
acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g,
0.304 mol) in water (50 ml) was added slowly at 0.degree. C. and
maintained at this temperature for 15 min. This diazotized solution
was added slowly to dilute sulfuric acid (50%, 250 ml) at
110.degree. C. Stirring was continued for 15 min. After cooling to
RT, ice water was added, the mixture extracted with ethylacetate,
washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield 12.0 g, 24.0%.
[0183] To K.sub.2CO.sub.3 (23.84 g, 0.172 mol) and
2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in acetonitrile (100
ml) was added methyl iodide (19.60 g, 0.138 mol) at 0.degree. C.
The reaction mixture was warmed to RT and stirred overnight. Water
was added and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield: 6.0 g, 55.55%.
[0184] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml)
was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc.
HCl (110 ml) at 40.degree. C. and the temperature was slowly raised
to 50.degree. C. Stirring was continued for 2 h, the reaction
cooled to RT, basified with 50% NaOH solution and extracted by
ethyl acetate. The organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4. The product obtained upon
concentration was purified by column chromatography. Yield: 4.0 g,
79.36%.
[0185] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4-chloro
aniline (3.0 g, 0.0190 mol) in benzene (50 ml) was added
trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0.degree. C.
The temperature was raised to RT and stirred overnight. The
reaction mixture was added to ice and extracted with ethyl acetate.
The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated. Yield: 3.7 g, 80.43%.
[0186] To N-pivaloyl-3-methoxy-4-chloroaniline (1.50 g, 0.0062 mol)
in THF (30 ml) was added n-butyl lithium (1.0 g, 0.0156 mol) at
0.degree. C. and the reaction stirred for 2 hr. After cooling to
-70.degree. C., methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12
ml) was added slowly. The reaction was warmed to rt and stirred
overnight and then quenched with water and extracted with ether.
The water layer was further extracted and the combined ether layers
were washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield 0.50 g, 23.25%.
[0187] The protected ketone from step 5 (0.500 g, 0.0014 mol) was
suspended in concentrated HCl (5 ml) at RT, then the temperature
was raised to 95.degree. C. and the mixture stirred over night. The
mixture was cooled to RT, basified with 20% NaOH solution and
extracted with DCM. The combined organic layer was washed with
water, brine and dried over Na.sub.2SO.sub.4. The product obtained
upon concentration was purified by column chromatography using
basic alumina to yield title compound (0.140 g, 37.33%).
Example 22
Synthesis of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone
##STR00031##
[0189] To a solution of 2-picoline (50 g, 0.48 mol) in glacial
acetic acid (150 ml) was added hydrogen peroxide (25 ml) at RT. The
mixture was heated to 90.degree. C. for 3 hr. The mixture was
cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly.
The mixture was again heated to 90.degree. C. for 19 hr. The excess
peroxide was cautiously decomposed using Pd--C (2.5 g) at 0.degree.
C. Pd--C was filtered, the filtrate was concentrated and the crude
2-methylpyridine-1-oxide was purified by fractional distillation
under vacuum. Yield: 40 g, 69%.
[0190] A solution of 2-methylpyridine-1-oxide (10 g, 0.092 mol) in
methyl iodide (15 ml) was stirred at RT for 18 hr. The solid was
filtered. The filtrate was diluted with diethyl ether, extracted
with water (40 ml). The solid was re-dissolved in the aqueous
layer, 1,4-dioxane (50 ml) was added, followed by potassium cyanide
(15 g, 0.23 mol). The mixture was stirred at RT for 3 hr. The
product was extracted with chloroform. The chloroform layer was
washed with water, brine and dried over sodium sulfate. The solvent
was removed under vacuo and the crude material was purified by
fractional distillation (61-62.degree. C./0.2 mm) to yield a white
low melting solid (6 g, 35%).
[0191] BCl.sub.3 (24 ml, 1M in DCM, 0.024 mol) was added slowly to
a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of
trichloroethylene over a period of 15 min. at 0.degree. C. and
stirred at this temperature for an additional 10 min.
4-Cyano-2-methylpyridine (2.2 g, 0.019 mol) and AlCl.sub.3 (3 g,
0.022 mol) were added at 0.degree. C. The solution was warmed to RT
and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 h and the DCM was distilled off. The
resulting solution was refluxed at 115.degree. C. for 4 hr and
stirred at RT over night. 3N HCl (20 ml) was added to the mixture
and refluxed at 100.degree. C. for 2 hr. The reaction mixture was
cooled to 0.degree. C. and was made basic (pH-12) with 6N NaOH and
the reaction mixture was extracted with DCM. The DCM layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
solvent was removed, the crude was purified by column
chromatography (silica gel) to yield title compound as yellow solid
(1.55 g, 40%).
Example 23
Synthesis of (2-Amino-4-chloro-phenyl)-pyridin-4-yl-methanone
##STR00032##
[0193] To BCl.sub.3 (1M in DCM) (24 mL, 24 mmol), cooled to
0.degree. C., a solution of 3-chloroaniline (2.0 g, 16 mmol) in 30
mL of TCE was added drop wise over a period of 15 min and the
mixture stirred at that temperature for an additional 10 min.
4-cyanopyridine (2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22 mmol)
was added under ice-water cooling. The solution was allowed to warm
to rt and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 h and the DCM distilled off. The resulting
solution was refluxed at 160.degree. C. for 4 h and stirred at rt
overnight. 3N HCl (20 ml approx.) was added to the reaction mixture
and then refluxed at 110.degree. C. for 1.5 hr. The reaction
mixture was cooled to rt and the solution was made basic (pH 12)
with 6N NaOH. The reaction mixture was diluted with water and DCM.
The resulting two layers were separated and the aqueous layer was
extracted with DCM (3.times.150 mL), and dried (Na.sub.2SO.sub.4).
After removal of solvent, the solid was washed with Et.sub.2O to
give 650 mg (24%) of desired product.
Example 24
Synthesis of (2-Amino-3-chloro-phenyl)-pyridin-4-yl-methanone
##STR00033##
[0195] To a solution of BCl.sub.3(1M in DCM) (24 mL, 24 mmol),
cooled to 0.degree. C., was added a solution of 2-chloroaniline
(2.0 g, 16 mmol) in 30 mL of TCE drop wise over a period of 15 min
and the reaction stirred for an additional 10 min. 4-cyanopyridine
(2.0 g, 19 mmol) and AlCl, (3.0 g, 22 mmol) were added under
ice-water cooling. The solution was allowed to warm to rt and
stirred for 30 min. The solution was then heated at 80-90.degree.
C. for 1 h and the DCM distilled off. The resulting solution was
refluxed at 160.degree. C. for 4 h and stirred at rt overnight. 3N
HCl (20 ml approx.) was added to the reaction mixture and refluxed
at 110.degree. C. for 1.5 hr. The reaction mixture was cooled to rt
and the solution was made basic (pH 12) with 6N NaOH. The reaction
mixture was diluted with water and DCM. The resulting layers were
separated and the aqueous layer was extracted with DCM (3.times.150
mL), and the combined organic layers dried (Na.sub.2SO.sub.4).
After removal of solvent, the solid was washed with Et.sub.2O to
give 600 mg (21%) of desired product.
Example 25
Synthesis of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone
##STR00034##
[0197] To a solution of BCl.sub.3 (1M in DCM) (18 mL, 18 mmol),
cooled to 0.degree. C., was added drop wise over a period of 15 min
a solution of 4-bromoaniline (2 g, 11.6 mmol) in 30 mL of TCE and
the mixture stirred for an additional 10 min. 4-cyanopyridine (2.0
g, 19 mmol) and AlCl.sub.3 (3.0 g, 22 mmol) were added under
ice-water cooling. The solution was warmed to rt and stirred for 30
min. The solution was then heated at 80-90.degree. C. for 1 h and
the DCM distilled off. The resulting solution was refluxed at
160.degree. C. for 4 h and stirred at rt overnight. 3N HCl (20 ml
approx.) was added to the reaction mixture and refluxed at
110.degree. C. for 1.5 hr. The reaction mixture was allowed to cool
down and the solution was made basic (pH 12) with 6N NaOH. The
reaction mixture was diluted with water and DCM. The resulting two
layers were separated and the aqueous layer was extracted with DCM
(3.times.150 mL), and the combined organic layers dried
(Na.sub.2SO.sub.4). After removal of solvent, the solid was washed
with Et.sub.2O to give 1.050 g of desired product.
Example 26
Synthesis of (2-amino-5-fluoro-phenyl)-pyridin-4-yl-methanone
##STR00035##
[0199] To a solution of BCl.sub.3 (1M in DCM) (27 mL, 27 mmol),
cooled to 0.degree. C., was added drop wise over a period of 15 min
a solution of 4-fluoroaniline (2.0 g, 18 mmol) in 30 mL of TCE and
the mixture stirred at that temperature for an additional 10 min.
4-cyanopyridine (2.6 g, 25 mmol) and AlCl.sub.3 (3.0 g, 22 mmol)
were added under ice-water cooling. The solution was allowed to
warm to rt and then stirred for 30 min. The solution was then
heated at 80-90.degree. C. for 1 h and the DCM distilled off. The
resulting solution was refluxed at 160.degree. C. for 4 h and
stirred at rt overnight. 3N HCl (20 ml approx.) was added to the
reaction mixture and refluxed at 110.degree. C. for 1.5 hr. The
reaction mixture was allowed to cool down and the solution was made
basic (pH 12) with 6N NaOH. The reaction mixture was diluted with
water and DCM. The resulting two layers were separated and the
aqueous layer was extracted with DCM (3.times.150 mL), and the
combined organic layers dried (Na.sub.2SO.sub.4). After removal of
solvent, the solid was washed with Et.sub.2O to give 1.05 g (27%)
of desired product.
Example 27
Synthesis of
(2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone
##STR00036##
[0201] To a solution of .sup.nBuLi (0.0730 mol) in hexane was added
N-methyl imidazole (0.0608 mol) drop wise at -40.degree. C. over 30
min under a nitrogen atmosphere. The resulting yellow solution was
stirred for a further 3 hr at rt, and then refluxed for 1 h.
2-amino-5-chlorobenzoic acid (1.74 g, 0.01014 mole) in dry ether
(60 ml) was then added to the reaction mixture. The reaction
mixture was stirred overnight at rt. To the reaction mixture was
added saturated NH.sub.4Cl solution and the resulting mixture
extracted with ethyl acetate (2.times.150 ml). The combined organic
layers were dried over Na.sub.2SO.sub.4. After removal of solvent,
the residue was purified by the flash chromatography using ethyl
acetate/hexane (1:4) as eluent. Crystallization of the product from
Et.sub.2O/hexane mixture gave 300 mg (13.7%) of product as yellow
solid.
Example 28
Synthesis of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl
methanone
##STR00037##
[0203] Trimethylacetyl chloride (35 g) was added drop wise to a
solution of 4-chloroaniline (31.9 g) in dry pyridine and the
reaction was stirred under nitrogen overnight. About half of the
pyridine was removed by rotary evaporation, then the mixture was
treated with 6M hydrochloric acid and extracted with ethyl acetate.
The extracts were washed with saturated aqueous NaHCO.sub.3 and
with water, then were dried (MgSO.sub.4), filtered and concentrated
by rotary evaporation. The resulting crystalline product was vacuum
filtered and dried at high vacuum to constant weight, resulting in
a good yield of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide as
fine needles. EDC (10 g) and 2-methyl-nicotinic acid (7.15 g) were
magnetically stirred in acetonitrile-THF with
N,O-dimethylhydroxylamine hydrochloride (9.75 g) and triethylamine
(25 mL). After stirring overnight at ambient temperature, the
resulting white suspension was added to ice water and extracted
with ethyl acetate (3.times.100 mL). The extracts were dried,
filtered, and concentrated to give a light amber oil.
[0204] To a magnetically stirred solution of
N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (3.16 g, 14.9 mmol)
in dry THF was added 2.5M n-butyllithium in hexane at -40.degree.
C. and the mixture was stirred at 0.degree. C. for 2 h and a
suspension of white solid resulted. A solution of the Weinreb amide
(1.80 g, 10.0 mmol) in dry THF was added drop wise and the reaction
was stirred at ambient temp overnight. The mixture was diluted with
water and extracted with ethyl acetate and the organic layer was
dried (MgSO4), filtered and concentrated. Chromatography on silica
gel (20-30% EtOAc/Hexane) provided the desired
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propion-
amide as a waxy bright yellow solid (2.28 g, 6.89 mmol): .sup.1H
NMR (CDCl3) .delta. 11.71 (s, 1H, NH), 8.82 (d, 1H, J=9.2 Hz), 8.67
(dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.55 (m, 2H), 7.28 (d, 1H, J=2.5 Hz),
7.25 (m, 1H), 2.54 (s, 3H), 1.39 (s, 9H).
[0205] The
N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimeth-
yl-propionamide intermediate (2.28 g, 6.89 mmol) was magnetically
stirred with 70% sulfuric acid and heated at 75.degree. C. and
progress of the solvolysis was monitored by LC/MS. The reaction was
allowed to cool to ambient temperature, and was washed with
ether-hexane to remove oily by-products. The acidic aqueous layer
was cooled in an ice bath and aqueous NaOH was added drop wise to
basify the mixture. The product was extracted with ethyl acetate
and the extracts were washed with saturated aqueous NaHCO3
(2.times.100 mL), with saturated aqueous sodium chloride, dried
(MgSO4), filtered and concentrated. The bright yellow product
crystallized on standing: .sup.1H NMR (CDCl3) .delta. 8.54 (dd, 1H,
J=5.2 Hz, J=1.6 Hz), 7.45 (dd, 1H, J=7.6 Hz, J=1.5 Hz), 7.15 (m,
2H), 7.00 (d, 1H, J=2.6 Hz), 6.61 (d, 1H, J=9.1 Hz), 6.39 (br s,
2H), 2.42 (s, 3H).
Example 29
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone
##STR00038##
[0207] The title compound was prepared using procedures described
above for the synthesis of
2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone.
Example 30
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonam-
ide
##STR00039##
[0209] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116-mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg
4-oxazol-5-yl-benzenesulfonyl chloride. Purification by
purification by reversed phase HPLC gave pure product. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 7.21 (dd, H, J=1.5, 4.4 Hz), 7.30
(d, 1H, J=2.5 Hz), 7.42 (s, 1H), 7.54 (dd, 1H, J=2.5, 8.8 Hz), 7.61
(d, 2H, J=8.4 Hz), 7.77 (s, 1H), 7.78 (d, 2H, J=8.4 Hz), 7.95 (s,
1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z 440.9
(M.sup.++1).
Example 31
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00040##
[0211] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (s, 9H), 7.02 (d, 1H, J=8.4 Hz). 7.44 (m,
3H), 7.66 (d, 2H, J=8.4), 7.79 (d, 1H, J=2.4 Hz), 8.11 (d, 2H,
J=6.4), 8.88 d, 2H, J=6.0 Hz), 10.51 (s, 1H). MS: m/z 429.9
(M.sup.++1).
Example 32
Synthesis of 4-tert-Butyl-N-[4-chloro-2-(1
oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00041##
[0213]
4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesul-
fonamide (107 mg, 0.25 mmol) was dissolved in 4 mL DCM and
m-chloroperoxybenzoic (0.26 mmol) was added. The mixture was
stirred at room temperature for 16 h. The solvent was evaporated on
a rotary evaporator and the product was purified by reversed phase
HPLC to yield title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.24 (s, 9H), 7.32-7.4 (m, 5H), 7.52 (dd, 1H, J=8.8, Hz,
2.4 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.74 (d, 1H, J=8.8 Hz), 8.18 (d,
2H, J=7.6 Hz), 9.60 (s, 1H). MS: m/z 445.9 (M.sup.++1).
Example 33
Synthesis of
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00042##
[0215] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.75 (s, 3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63
(m, 2H), 7.71 (d, 1H, J=8.8 Hz), 7.78 (m, 1H), 7.88 (m, 2H), 8.64
(m, 1H), 10.24 (s, 1H). MS: m/z 403.9 (M.sup.++1).
Example 34
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00043##
[0217] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.74 (s, 3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m,
2H), 7.27 (d, 1H, J=2 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63
(m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.76 (d, 2H, J=5.6 Hz), 9.88 (s,
1H). MS: m/z 403.9 (M.sup.++1).
Example 35
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00044##
[0219] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.69 (s, 3H), 6.68 (d, 2H, J=8.8 Hz),
7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H), 9.65 (s, 1H). MS: m/z
448.3 (M.sup.++1).
Example 36
Synthesis of
4-tert-Butyl-N-[4-fluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00045##
[0221] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 108 mg of
(2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz),
7.30-7.38 (m, 3H), 7.43 (m, 2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2
Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz), 9.82 (s, 1H). MS: m/z 413.5
(M.sup.++1).
Example 37
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-tert-butyl-benzenesulfonamid-
e
##STR00046##
[0223] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.27 (3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H), 8.85 (d, 2H, J=6 Hz), 10.19 (s,
1H). MS: m/z 473.9 (M.sup.++1).
Example 38
Synthesis of
4-tert-Butyl-N-[5-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00047##
[0225] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-aminoA-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.30 (s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d,
1H, J=8.4 Hz), 7.45-7.52 (m, 4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz),
7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz), 7.78 (m, 2H), 7.84 (d, 1.6 Hz),
8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H). MS: m/z 429.0
(M.sup.++1).
Example 39
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulf-
onamide
##STR00048##
[0227] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of
4-trifluoromethoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.21 (d, 2H, J=8.8 Hz), 7.35 (m, 2H), 7.45 (s,
1H), 7.70 (m, 2H), 7.83 (m, 2H), 8.82 (dd, 2H, J=4.8 Hz, 1.6 Hz),
10.21 (s, 1H). MS: m/z 502.3 (M.sup.++1).
Example 40
Synthesis of
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00049##
[0229] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of
4-bromo-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.21 (d, 1H, J=2.4 Hz), 7.49-7.61 (m, 5H),
7.73 (d, 1H, J=8.8 Hz), 8.86 (dd, 2H, J=4.4 Hz, 1.2 Hz), 10.00 (s,
1H). MS: m/z 451.9 (M.sup.++1).
Example 41
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-cyano-benzenesulfonamide
##STR00050##
[0231] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of
3-cyano-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.36 (d, 1H, J=2.4 Hz), 7.57-7.62 (m, 4H),
7.68 (d, 1H, J=8.8 Hz), 7.80 (m, 1H), 8.04 (m, 2H), 8.90 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z 398.8 (M.sup.++1).
Example 42
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulf-
onamide
##STR00051##
[0233] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of
4-methanesulfonyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m,
2H), 7.58 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 10.29 (b, 1H). MS: m/z 451.9 (M.sup.++1).
Example 43
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-benzenesulfona-
mide
##STR00052##
[0235] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51
(dd, 1H, J=8.8 Hz, 2 Hz), 7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8
Hz), 9.33 (d, 1.2 Hz), 10.91 (b, 1H). MS: m/z 434.0
(M.sup.++1).
Example 44
Synthesis of Biphenyl-4-sulfonic acid
[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-amide
##STR00053##
[0237] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg of
biphenyl-4-sulfonyl chloride. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 7.24 (m, 1H), 7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H),
7.77-7.84 (m, 3H), 8.73 (d, 2H, J=4.4 Hz), 10.01 (s, 1H). MS: m/z
449.0 (M.sup.++1).
Example 45
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(3-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00054##
[0239] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116
mg of 4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.32 (s, 9H), 2.19 (s, 3H), 7.04 (d, 1H, J=1.4
Hz), 7.21 (d, 1H, J=5.2 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H,
J=8.8 Hz, 2.4 Hz), 7.77-7.83 (m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71
(s, 1H), 10.75 (s, 1H). MS: m/z 443.0 (M.sup.++1).
Example 46
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulf-
onamide
##STR00055##
[0241] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of
4-Trifluoromethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H),
7.54-7.59 (m, 2H), 7.73 (d, 1H, J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz),
7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H), 8.82 (dd, 2H, J=6.0 Hz, 1.2
Hz), 10.16 (s, 1H). MS: m/z 441.8 (M.sup.++1).
Example 47
Synthesis of
4-tert-Butyl-N-[4,5-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00056##
[0243] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.28 (s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d,
2H, J=8.4 Hz), 7.54 (d, 2H, J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8
Hz), 7.72 (d, 2H, J=8.4 Hz), 8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H).
MS: m/z 431.1 (M.sup.++1).
Example 48
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-morpholin-4-yl-pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00057##
[0245] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 158 mg of
(2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone
and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 1.22 (s, 3H), 3.76 (t, 4H, J=4.6
Hz), 3.857 (t, 4H, J=4.6H), 8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H),
7.34 (m, 1H), 7.46 (m, 1H), 7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2
Hz), 8.16 (v, 1H), 9.29 (s, 1H). MS: m/z 515.1 (M.sup.++1).
Example 49
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00058##
[0247] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56
(m, 3H), 7.67-7.3 (m, 3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b,
1H), 9.45 (s, 1H). MS: m/z 454.1 (M.sup.++1).
Example 50
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methylsulfanyl-pyridine-4-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00059##
[0249]
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-b-
enzenesulfonamide (475 mg, 1.0 mmol) was dissolved in 10 mL dry THF
and treated with solid sodium thiomethoxide (355 mg, 5 mmol) and
the mixture heated at 70.degree. C. for 16 h. The solvent was
concentrated to about 2 mL and added to 5 mL cold 1M HCl. The light
yellow solid precipitate was collected by filtration and product
was purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H),
7.28 (d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd, 1H, J=8.8
Hz, 2.4 Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H,
J=5.2 Hz), 10.13 (s, 1H). MS: m/z 476.1 (M.sup.++1).
Example 51
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00060##
[0251] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.78 (s, 3H), 7.29 (d, 1H, J=2.8 Hz), 7.45 (m,
2H), 7.48 (s, 1H), 7.55 (dd, 1H, J=9.2 Hz, 2.8 Hz)), 7.67 (m, 3H),
7.83 (d, 2H, J=8.4 Hz), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10
(s, 1H). MS: m/z 454.9 (M.sup.++1).
Example 52
Synthesis of N-[4-Chloro-2-(1
oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethylethyl)-benzenes-
ulfonamide
##STR00061##
[0253] To a suspension of NaBH.sub.4 (0.70 g, 18.3 mmol) in dry THF
(20 mL) was added BF.sub.3.Et.sub.2O (0.25 mL, 20.1 mmol) drop wise
at 0.degree. C. over 5 min and the mixture was stirred for 30 min.
A solution of 2-methyl-2-phenyl-propionic acid (1.0 g, 6.1 mmol) in
dry THF (10 mL) was added drop wise at 0.degree. C. over 30 min,
and the mixture was stirred at room temperature for 4 h. Methanol
was slowly added to the reaction mixture until hydrogen evolution
stopped. The mixture was diluted with 10% HCl and extracted twice
with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and
then under vacuum to yield colorless oil.
[0254] This material was dissolved in DCM (25 mL), pyridine (1.2
mL, 15.3 mmol) and acetyl chloride (2.2 mL, 30.5 mmol) added, and
the reaction mixture left to stir at room temperature overnight.
The reaction mixture was washed with 10% HCl and the organic layer
was dried over MgSO.sub.4.
[0255] The material was then dissolved in DCM (25 mL) and cooled to
0.degree. C. Chlorosulfonic acid (1.2 mL, 18 mmol) was added drop
wise over 15 minutes and the mixture was stirred at the same
temperature for 3H. The volatiles were evaporated and SOCl.sub.2
(10 mL) was added and the mixture stirred at room temperature for 3
h. The excess SOCl.sub.2 was evaporated and the residue was treated
with ice-water and extracted with ether. The organic layer was
washed with water and brine, dried over MgSO.sub.4 and concentrated
in vacuo to afford the aryl sulfonyl chloride as a yellowish
oil.
[0256] This oil was treated with a solution of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (1.2 g, 5 mmol) in
10 mL pyridine and heated at 60 C for 4 h. The solvent was
evaporated and the residue suspended in 3M HCl (10 mL) and stirred
at room temperature for 16 h. The reaction mixture was put in an
ice bath and neutralized with concentrated NaOH solution. The white
precipitate formed was collected by filtration, washed with water
and dried in vacuo and purified by flash chromatography to yield
320 mg of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-eth-
yl)-benzenesulfonamide.
[0257] Oxidation of this intermediate with mCPBA according to the
general procedure gave
N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimeth-
yl-ethyl)-benzenesulfonamide. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.24 (s, 6H), 3.58 (s, 2H), 7.29 (d, 1H, J=2.4 Hz), 7.37
(m, 4H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, 1H, J=8.8 Hz), 8.23
(d, 2H, J=6.8 Hz), 9.51 (s, 1H). MS: m/z 461.1 (M.sup.++1).
Example 53
Synthesis of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide
##STR00062##
[0259] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of
4-ethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 0.94 (t, 3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2
Hz, 7.6 Hz), 6.94 (d, 2H, J=6.8 Hz), 7.16 (m, 2H), 7.23 (m, 1H),
7.30 (m, 4H), 8.60 (b, 2H), 9.73 (b, 1H). MS: m/z 401.1
(M.sup.++1).
Example 54
Synthesis of
N-[4-Chloro-2-(pyrimidine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfon-
amide
##STR00063##
[0261] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.43 (s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55
(m, 1H), 7.64 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97
(s, 1H), 8.86 (d, 2H), 10.63 (s, 1H). MS: m/z 441.9
(M.sup.++1).
Example 55
Synthesis of
N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfon-
amide
##STR00064##
[0263] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.43 (s, 1H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz),
7.62 (m, 2H), 7.75 (m, 2H), 7.80 (m, 3H), 7.98 (s, 1H), 8.99 (d,
1H, J=5.2 Hz), 9.25 (b, 1H), 10.29 (b, 1H). MS: m/z 441.9
(M.sup.++1).
Example 56
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonam-
ide
##STR00065##
[0265] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.23 (m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m,
3H), 7.71 (dt, 1H, J=7.6 Hz, 2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H),
8.58 (bd, 1H, J=3.6 Hz), 9.67 (s, 1H). MS: m/z 458.1
(M.sup.++1).
Example 57
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00066##
[0267] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.24 (s, 9H), 7.34-7.38 (m, 2H), 7.47 (dd, 1H,
J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H,
J=8 Hz), 8.00 (td, 1H, J=7.6 Hz, 2 Hz), 8.71 (bd, 1H, J=4.8 Hz).
MS: m/z 429.9 (M.sup.++1).
Example 58
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1,1-dimethyl-propyl)-benze-
nesulfonamide
##STR00067##
[0269] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of
4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H),
1.61 (q, 2H, J=7.2 Hz), 7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53
(m, 3H), 7.67-7.74 (m, 3H), 8.84 (m, 2H), 10.14 (s, 1H). MS: m/z
443.9 (M.sup.++1).
Example 59
Synthesis of
4-tert-butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00068##
[0271] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 133 mg of
(2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116
mg of 4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25
(m, 1H), 7.32 (m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd, 1H, J=9.2
Hz, 2.4 Hz), 7.67 (m, 2H), 7.77 (d, 1H, J-8.8 Hz), 8.55 (d, 1H,
J=5.2 Hz), 10.09 (s, 1H). MS: m/z 463.0 (M.sup.++1).
Example 60
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00069##
[0273] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m,
4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0
(M.sup.++1).
Example 61
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00070##
[0275] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 116
mg of 4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8
Hz), 7.45-7.55 (m, 3H), 7.67 (m, 2H), 7.83 (m, 2H), 8.03 (s, 1H),
8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 443.9
(M.sup.++1).
Example 62
Synthesis
4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)--
phenyl]-benzenesulfonamide
##STR00071##
[0277] The title compound was prepared according to the general
procedure by mCPBA oxidation of
4-tert-butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.26 (s,
9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8 Hz), 7.50-7.57 (m, 3H), 7.67
(m, 2H), 7.87 (m, 2H), 8.24 (s, 1H), 8.89 (d, 1H, J=5.6 Hz), 10.31
(s, 1H). MS: m/z 459.0 (M.sup.++1).
Example 63
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00072##
[0279]
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-b-
enzenesulfonamide (231 mg, 0.5 mmol) was dissolved in dry THF (5
mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and
the mixture was heated at 70.degree. C. for 4 h. The solvent was
evaporated and the residue suspended in water (5 mL) and the
product was precipitated by the drop wise addition of 3M HCl and
purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.19
(s, 9H), 2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54
(m, 3H), 7.65 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz),
8.19 (m, 1H), 9.62 (s, 1H). MS: m/z 476.0 (M.sup.++1).
Example 64
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methanesulfonyl-pyridine-3-carbonyl)-phenyl-
]-benzenesulfonamide
##STR00073##
[0281]
4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-p-
henyl]-benzenesulfonamide (48 mg, 0.1 mmol) and mCPBA (35 mg, 0.2
mmol) were dissolved in DCM (4 mL) and the mixture stirred at room
temperature overnight. The solvent was evaporated and product was
purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.25
(s, 9H), 3.30 (s, 3H), 7.27 (m, 1H), 7.38 (m, 2H), 7.56 (dd, 1H,
J=8.8 Hz, 2.8 Hz), 7.66 (m, 2H), 7.80 (d, 1H, J=8.8 Hz), 8.04 (dd,
1H, J=8 Hz, 2 Hz), 8.18 (d, 1H, J=8.0 Hz), 8.61 (m, 1H), 10.00 (s,
1H). MS: m/z 508.0 (M.sup.++1).
Example 65
Synthesis of
4-tert-Butyl-N-[3,4-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00074##
[0283] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.22 (s, 9H), 7.31 (d, 2H, J=8.4 Hz),
7.40-7.47 (m, 3H), 7.55 (d, 2H, J=8.4 Hz), 7.59 (m, 1H), 8.69 (b,
1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z 431.0 (M.sup.++1).
Example 66
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyrazine-2-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00075##
[0285] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.24 (s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50
(dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70 (m, 2H), 7.76 (m, 1H), 7.80 (m,
1H), 8.62 (m, 1H), 8.77 (m, 1H), 9.06 (m, 1H), 10.37 (s, 1H). MS:
m/z 430.0 (M.sup.++1).
Example 67
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonami-
de
##STR00076##
[0287] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of
4-Isopropoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.01 (d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d,
2H, J=8.8 Hz), 6.87 (d, 1H, J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d,
2H, J=6.0 Hz), 8.64 (d, 2H, J=6 Hz), 9.60 (s, 1H). MS: m/z 431.9
(M.sup.++1).
Example 68
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamid-
e
##STR00077##
[0289] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of
4-Isopropoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.1.31 (d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz),
6.73 (d, 2H, J=6.8 Hz), 7.39 (m, 3H), 7.63-7.70 (m, 4H), 8.82 (d,
2H, J=6.0 Hz), 9.99 (s, 1H). MS: m/z 476.0 (M.sup.++1).
Example 69
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide
##STR00078##
[0291] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of
4-ethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.19 (t, 3H, J=7.6 Hz), 2.62 (q, 2H, J=7.6
Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m, 3H), 7.65-7.72 (m, 4H), 8.81
(d, 2H, 6.4 Hz), 10.06 (s, 1H). MS: m/z 446.0 (M.sup.++1).
Example 70
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulf-
onamide
##STR00079##
[0293] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of
4-Trifluoromethoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.23 (d, 2H, J=8.0 Hz), 7.45 (m, 3H), 7.71 (m,
2H), 7.85 (d, 2H, J=8.8 Hz), 8.85 (d, 2H, J=6.4 Hz), 10.23 (s, 1H).
MS: m/z 502.9 (M.sup.++1).
Example 71
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-cyano-pyridine-4-carbonyl)-phenyl]-benzenes-
ulfonamide
##STR00080##
[0295] Dimethyl sulfate (126 mg, 1 mmol) and
4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesul-
fonamide (445 mg, 1 mmol) were dissolved in dry THF (5 mL). The
reaction mixture was stirred at room temperature for 1 hour and at
60.degree. C. for two hours. After cooling to room temperature, to
the solution was added 25% (w/v) aqueous KCN solution (5 mL) and
the mixture stirred for 16 h. The solvent was evaporated in vacuo
and the product was purified by HPLC. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.27 (s, 9H), 7.22 (d, 1H, J=2.0 Hz),
7.41-7.47 (m, 3H), 7.56 (dd, 1H, J=2.4 Hz), 7.69 (m, 3H), 7.79 (d,
1H, J=9.2 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.06 (s, 1H). MS: m/z 454.0
(M.sup.++1).
Example 72
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methanesulfonyl-pyridine-4-carbonyl)-phenyl-
]-benzenesulfonamide
##STR00081##
[0297]
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-b-
enzenesulfonamide (232 mg, 0.5 mmol) was dissolved in dry THF (5
mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and
the mixture was heated at 70.degree. C. for 16 h. The solvent was
evaporated and the residue suspended in water (5 mL) and the
product was precipitated by the drop wise addition of 3M HCl. The
precipitate was collected by filtration, dissolved in DCM (10 mL)
and treated with mCPBA (172 mg, 1 mmol). After stirring at room
temperature for 16 h, the DCM solution was washed with saturated
NaHCO.sub.3 solution (10 mL). The organic layer was washed with
water, dried and the solvent was evaporated. The product was
purified by HPLC to give white powder after lyophilization.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.28 (s, 9H), 3.30 (s,
3H), 7.24 (d, 1H, J=2.4 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.48 (m, 1H),
7.54 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.74 (d, 2H, J=8.0 Hz), 7.78 (d,
1H, J=8.8 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.23 (s, 1H). MS: m/z 507.0
(M.sup.++1).
Example 73
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfo-
namide
##STR00082##
[0299] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-phenyl-methanone and 127 mg of
4-Methanesulfonyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.07 (s, 3H), 7.45 (d, 1H, J=2.0 Hz), 7.49 (d,
2H, J=6.0 Hz), 7.15 (m, 3H), 8.00 (s, 4H), 8.89 (d, 2H, J=6.0 Hz),
10.32 (b, 1H). MS: m/z 496.9.0 (M.sup.++1).
Example 74
Synthesis of
4-Acetyl-N-[4-bromo-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00083##
[0301] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-phenyl-methanone and 109 mg of
4-acetyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.59 (s, 3H), 7.44 (d, 1H, J=2.0 Hz), 7.56 (d,
2H, J=6.4 Hz, 7.64-7.71 (m, 2H), 7.90 (d, 2H, J=8.8 Hz), 7.97 (d,
2H, J=8.8 Hz), 8.88 (d, 2H, J=6.4 Hz), 10.24 (b, 1H). MS: m/z 459.8
(M.sup.++1).
Example 75
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00084##
[0303] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and
4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR: .delta. 1.29 (s, 9H), 2.94 (s, 3H), 7.42-7.46 (m, 3H), 7.51
(d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H),
7.66 (d, J=6.8 Hz, 1 H), 7.74 (d, J=8.0 Hz, 1H), 8.1 (bs, 1H). MS:
M/z 443.1 (M.sup.++1).
Example 76
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00085##
[0305] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chlorophenyl)-(6-chloro-pyridin-3-yl)-methanone and
4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR: .delta. 1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6
Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8
Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.79 (m, 3H), 8.27 (d, J=2.0 Hz,
1H), 9.73 (s, 1H). MS: M/z 463.0 (M.sup.++1).
Example 77
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesul-
fonamide
##STR00086##
[0307] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR: .delta. 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz,
2H), 7.58-7.61 (m, 3H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H),
8.74 (d, J=1.6 Hz, 1H), 8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H),
9.73 (s, 1H). MS: M/z 456.9 (M.sup.++1).
Example 78
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulf-
onamide
##STR00087##
[0309] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl.sub.3): .delta. 3.01 (s, 3H), 7.36-7.37 (d, J=2.4
Hz, 1H), 7.43 (m, 1H), 7.54 & 7.57 (dd, J=8.8 Hz, 2.4 Hz, 1H),
7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.90 (m, 4H), 8.59 (d,
J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz, 1.6 Hz, 1H), 9.98 (s,
1H). MS: M/z 450.9 (M.sup.++1).
Example 79
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesul-
fonamide
##STR00088##
[0311] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and
4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (DMSO-d6): .delta. 6.90 (d, J=8.4 Hz, 1H), 7.50 (d,
J=8.8 Hz, 2H), 7.49-7.61 (m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d,
J=4.8 Hz, 2H), 10.26 (s, 1H). MS: M/z 456.9 (M.sup.++1).
Example 80
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonami-
de
##STR00089##
[0313] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3): .delta. 1.19 (s, 3H), 1.20 (s, 3H), 4.35-4.38 (m,
1H), 6.63 (d, J=9.2 Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43
(d, J=2.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H),
7.70-7.73 (m, 1H), 8.51 (bs, 1H), 8.68 (bs, 1H), MS: M/z=431.0
(M.sup.++1).
Example 81
Synthesis of
4-Acetyl-N-[4-chloro-2,1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonam-
ide
##STR00090##
[0315] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
according to the general procedure.
Example 82
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benze-
nesulfonamide
##STR00091##
[0317] The title compound was prepared by the mCPBA oxidation of
4-methanesulfonyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H NMR (DMSO-d6):
.delta. 3.27 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.47 & 7.49 (dd,
J=8.0 Hz, 1.2 Hz, 1H), 7.51-7.55 (m, 1H), 7.56 & 7.58 (dd,
J=8.0 Hz, 2.4 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz,
2H), 8.05 (d, J=8.8 Hz, 2H), 8.19 (d, J=2.0 Hz, 1H), 8.41 &
8.42 (dd, J=6.8 Hz, 1.2 Hz, 1H), 10.46 (s, 1H). MS: M/z 467.0
(M.sup.++1).
Example 83
Synthesis of
4-Chloro-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00092##
[0319] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and
4-chloro-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl.sub.3): .delta. 7.20 (dd, 2H, J=4.4 Hz, 2.0), 7.31 (m, 2H),
7.5.3 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8
Hz), 8.79 (dd, 2H, J=4.4 Hz, 1.6 Hz), 10.00 (s, 1H). MS: m/z 407.1
(M.sup.++1).
Example 84
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00093##
[0321] To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg,
0.64 mmol) dissolved in 750 uL pyridine was added
4-tert-butylbenzenesulfonyl chloride (225 mg, 0.97 mmol) and the
mixture stirred at 60.degree. C. overnight. The reaction mixture
was diluted with 1.0 mL H.sub.2O and the precipitate formed was
collected by vacuum filtration. The crude product was
recrystallized from EtOAc/hexane yielding 190 mg of pure title
compound. .sup.1H NMR (CDCl3) .delta. 9.87 (s, 1H), 8.79 (d, J=4.8
Hz, 1H), 8.52 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz,
2H), 7.52 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz,
1H), 7.33-7.31 (m, 3H), 1.22 (s, 9H). MS: m/z=429.0
(M.sup.++1).
Example 85
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesul-
fonamide
##STR00094##
[0323] The title compound was prepared by the mCPBA oxidation of
4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonami-
de according to the general procedure and purified by HPLC. 1H NMR
(CDCl3) .delta. 9.71 (s, 1H) 8.56 (d, J=7.6 Hz, 1H) 8.43 (s, 1H)
7.71-7.66 (m, 4H) 7.61-7.53 (m, 2H) 7.44-7.38 (m, 3H) 1.28 (s, 9H).
MS (ES) m/z=445.0 (M.sup.++1).
Example 86
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00095##
[0325] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
1H NMR (CDCl3) .delta. 10.17 (s, 1H) 8.63 (d, J=4 Hz, 1H) 7.78 (m,
3H) 7.51 (s, 1H) 7.30 (s, 1H) 7.17 (s, 1H) 7.09 (s, 1H) 6.97 (d,
J=4 Hz, 2H) 2.64 (s, 3H). MS (ES) m/z=471.0 (M.sup.++1).
Example 87
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00096##
[0327] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR
(CDCl3) .delta. 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8,
1H) 7.61 (d, J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d,
J=2.4 Hz, 1H) 7.07 (s, 1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz,
2H) 4.47 (m, 1H) 2.63 (s, 3H) 1.27 (s, 6H). MS (ES) m/z=445.0
(M.sup.++1).
Example 88
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00097##
[0329] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR
(CDCl3) .delta. 8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85
(m, 4H) 2.52 (s, 3H) 2.45 (s, 3H). MS: (ES) m/z=429.0
(M.sup.++1).
Example 89
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00098##
[0331] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H
NMR (CDCl3) .delta. 10.38 (s, 1H) 8.64 (s, 1H) 7.95 (s, 4H) 7.72
(s, 1H) 7.51 (s, 1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04
(s, 3H) 2.64 (s, 3H). MS: (ES) m/z=464.9 (M.sup.++1).
Example 90
Synthesis of
3-{4-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester
##STR00099##
[0333] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. 1H NMR (CDCl3) .delta. 10.13 (s, 1H) 8.62 (d,
J=4.8 Hz, 1H) 7.73 (d, J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49
(dd, J=8.8 Hz, 2.4 Hz, 1H) 7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz,
2H) 7.13 (s, 1H) 6.95 (d, J=4.8 Hz, 1H) 3.62 (s, 3H) 2.90 (t, J=8
Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz, 2H). MS: m/z=473.0
(M.sup.++1).
Example 91
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00100##
[0335] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure and purified
by HPLC. 1H NMR (CDCl3) .delta. 9.66 (s, 1H) 8.26 (d, J=6.8 Hz, 1H)
7.89 (d, 2H, J=8.4 Hz) 7.85 (s, 1H) 7.81 (d, 2H, J=8.4 Hz) 7.73 (d,
1H, J=8.8 Hz) 7.54 (dd, 1H, J=12 Hz, 2 Hz) 7.36 (t, 1H, J=5.6 Hz,
3.2 Hz) 7.24-7.19 (m, 1H) 2.55 (s, 3H). MS (ES) m/z=486.9
(M.sup.++1).
Example 92
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00101##
[0337] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure and purified by
HPLC. 1H NMR (CDCl3) .delta. 9.39 (s, 1H) 8.32 (d, J=6.8 Hz, 1H)
7.75 (d, J=11.2, 1H) 7.57-7.52 (m, 3H) 7.36 (d, J=2.4 Hz, 1H) 7.30
(d, J=2.4 Hz, 1H) 7.21 (dd, J=7.2 Hz, 2.8 Hz, 1H) 6.71 (d, J=7.2
Hz, 2H) 4.46 (p, J=6.0 Hz, 1H) 2.57 (s, 3H) 1.29 (d, J=5.6 Hz, 6H).
MS (ES) m/z=461.0 (M++1).
Example 93
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-iodo-benzenesulfonamide
##STR00102##
[0339] To a magnetically stirred mixture of precursor amino-ketone
(2.32 g, 10.0 mmol) in dry pyridine (20 mL) was added a solution of
pipsyl chloride (4.78 g, 15.8 mmol) in toluene (20 mL) under dry
nitrogen. The addition was performed over a 2 h period. The
reaction was stirred overnight at 50.degree. C., then additional
pipsyl chloride (850 mg), as a solution in toluene, was added.
After 6 h, the reaction was concentrated and the residue was taken
up in ethyl acetate. The organic layer was washed with water, then
the mixture was filtered. The layers were separated and the organic
layer was dried (MgSO.sub.4), filtered and concentrated to provide
crystalline material. .sup.1H-NMR (CDCl3) .delta. 9.95 (br s, 1H,
NH), 8.82 (dm, 2H, J=5.2 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dm, 1H,
J=8.8 Hz, J=2.6 Hz), 7.41 (dm, 2H, J=8.8 Hz), 7.30 (d, 1H, J=2.6
Hz), 7.30 (d, 1H, J=2.6 Hz), 7.19 (dm, 2H, J=5.2 Hz). MS: m/z 499
(M+1).
Example 94
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2,4-dimethyl-oxazol-5-yl)--
benzenesulfonamide
##STR00103##
[0341] Trifluoromethanesulfonic acid (4.5 mmol) was added to a
stirred solution of iodobenzene diacetate (0.39 g, 1.2 mmol) in
acetonitrile (10 mL) and stirred at ambient temperature for 20
minutes. To this reaction propiophenone (1.0 mmol) was added and
the reaction was refluxed for 2.5 h. After completion of the
reaction, as judged by TLC, excess acetonitrile was evaporated and
the crude product was extracted into dichloromethane (3.times.40
mL). The combined organic extracts were then washed with saturated
aqueous sodium bicarbonate (2.times.50 mL), dried (MgSO4), filtered
and concentrated to give a dark amber waxy solid. The product was
purified by column chromatography on silica gel using ethyl
acetate-hexane (5:95, 10:90) to furnish a crystalline solid.
[0342] 2,4-dimethyl-5-phenyloxazole (53 mg, 0.31 mmol) was treated
with chlorosulfonic acid (3.0 equivalents) in dry dichloromethane
(8 mL) at 0.degree. C. The solution was allowed to slowly warm to
room temperature and monitored by LC/MS for complete reaction, then
the reaction was washed with cold water. The organic layer was
dried over magnesium sulfate, filtered and concentrated.
[0343] The residue was treated with thionyl chloride (2
equivalents) in dry dichloromethane (5 mL). The desired product was
isolated by concentration of the reaction mixture to give
4-(2,4-dimethyl-oxazol-5-yl)benzenesulfonyl chloride, which was
used immediately in the next step: mass spectrum m/z 272 (M+1);
[0344] To a magnetically stirred solution of the aminoketone (1.62
g, 7.0 mmol) in dry pyridine (30 mL) was added drop wise a solution
of the sulfonyl chloride in 1.0 mL of dichloromethane and the
slightly turbid reaction was stirred at ambient temperature. After
5 h, the reaction was diluted with ethyl acetate (25 mL) and washed
with cold 3M HCl, followed by washing with aqueous NaHCO.sub.3,
then washed with water. The organic layer was dried (MgSO4),
filtered and concentrated to give a pale yellow waxy solid. The
product was purified by preparative hplc and pure material
lyophilized to give the desired product. .sup.1H NMR (CDCl3)
.delta. 8.84 (br s, 2H), 7.69 (dm, 2H, J=8.4 Hz), 7.65 (d, 1H,
J=8.8 Hz), 7.46 (dm, 1H, J=2.2 Hz), 7.43 (dm, 2H, J=8.4 Hz), 7.36
(ddd, 1H, J=8.8 Hz, J=2.6 Hz, J=0.7 Hz), 7.24 (2H, obscured), 7.15
(br s, 1H), 3.19 (s, 3H), 3.13 (s, 3H). MS: m/z 468 (M+1).
Example 95
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00104##
[0346] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243
mg, 1.0 mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg,
1.0 mmol) and purified by HPLC. .sup.1H NMR (CDCl3) .delta. 10.71
(br s, 1H, NH), 8.63 (dd, 1H, J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H,
J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz), 7.49 (dd, 1H, J=8.8 Hz, J=2.6
Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=9.5 Hz, J=1.8 Hz),
7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H, J=2.6 Hz), 2.29 (s,
3H), 1.29 (s, 9H). MS: m/z 443 (M+1).
Example 96
Synthesis of 4-tert-Butyl-N-[4-chloro-2-(2-methyl-1
oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
##STR00105##
[0348] The title compound was prepared by the mCPBA oxidation of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 10.71 (br s, 1H, NH), 8.62 (dm, 1H, J=5.9 Hz),
7.81 (d, 1H, J=9.1 Hz), 7.78 (dm, 2H, J=8.4 Hz), 7.54 (dd, 1H,
J=8.8 Hz, J=2.6 Hz), 7.48 (dm, 2H, J=8.4 Hz), 7.44 (m, 2H), 7.18
(d, 1H, J=2.6 Hz), 2.32 (s, 3H), 1.32 (s, 9H). MS: m/z 459
(M+1).
Example 97
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00106##
[0350] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 10.63 (br s, 1H, NH), 8.63 (dd, 1H, J=4.8
Hz, J=1.8 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.48
(dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.27 (dd, 1H, J=7.7 Hz, J=1.8 Hz),
7.19 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.14 (d, 1H, J=2.2 Hz), 4.55
(septet, 1H, J=6 Hz), 2.35 (s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z
445 (M+1).
Example 98
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00107##
[0352] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2 amino
5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-trifluoromethoxy-benzenesulfonyl chloride and purified by
HPLC.
[0353] .sup.1H NMR (CDCl3) .delta. 10.76 (br s, 1H, NH), 8.65 (dd,
1H, J=4.8 Hz, J=2.0 Hz), 7.88 (dm, 2H, J=8.8 Hz), 7.80 (d, H1,
J=9.2 Hz), 7.52 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.1-7.3 (m, 4H), 7.18
(d, 1H, J=2.6 Hz), 2.35 (s, 3H). MS: m/z 471 (M+1).
Example 99
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00108##
[0355] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl.sub.3) .delta. 10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz,
J=1.8 Hz), 7.98 (d, 2H, J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d,
1H, J=9.2 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H,
J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS:
m/z 429 (M+1).
Example 100
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00109##
[0357] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl3) .delta. 10.86 (br s, 1, NH), 8.65 (dd, 1H,
J=4.8 Hz, J=1.8 Hz), 8.02 (m, 4H), 7.78 (d, 1H, J=8.8 Hz), 7.53
(dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.1-7.3 (m, 3H), 3.07 (s, 3H), 2.41
(s, 3H). MS: m/z 465 (M+1).
Example 101
Synthesis of
3-(4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl)--
propionic acid methyl ester
##STR00110##
[0359] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. .sup.1H-NMR (CDCl3) .delta. 10.75 (br s, 1H, NH),
8.64 (dm, 1H, J=4.8 Hz), 7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75
(d, 2H, J=7.3 Hz), 7.49 (dm, 1H, J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65
(s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.35 (s,
3H). MS: m/z 473 (M+1).
Example 102
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00111##
[0361] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl3) .delta. 10.68 (br s, 1H, NH), 8.54 (dm, 1H, J=6.6 Hz), 7.92
(dm, 2H, J=8.8 Hz), 7.78 (d, 1, J=8.8 Hz), 7.56 (dd, 1, J=8.8 Hz,
J=2.2 Hz), 7.45-7.15 (m, 4), 7.18 (d, 1, J=2.6 Hz), 2.33 (s, 3H).
MS: m/z 487 (M+1).
Example 103
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00112##
[0363] The title compound was prepared by the mCPBA oxidation of
N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure. .sup.1H NMR (CDCl3)
.delta. 10.56 (br s, 1H, NH), 8.56 (dm, 1H, J=6.6 Hz), 7.79 (d, 1H,
J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6
Hz), 7.39 (t, 1H, J=7.2 Hz), 7.21 (d, 1H, J=8.0 Hz), 7.17 (d, 1H,
J=2.6 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.58 (septet, 1H, J=6 Hz), 2.32
(s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z 461 (M+1).
Example 104
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benze-
nesulfonamide
##STR00113##
[0365] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H NMR (CDCl3)
.delta. 10.7 (br s, 1H, NH), 8.54 (d, 1H, J=6.6 Hz), 8.02 (d, 2H,
J=8.4 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54
(dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.38 (m, 1H), 7.22 (d, 1H, J=2.6 Hz),
7.16 (dm, 1H, J=7.7 Hz), 2.62 (s, 3H), 2.33 (s, 3H). MS: m/z 445
(M+1).
Example 105
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfo-
nyl-benzenesulfonamide
##STR00114##
[0367] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 10.78 (br s, 1H, NH), 8.38 (dm, 1H, J=6.6 Hz),
8.05 (s, 4H), 7.76 (d, 1H, J=8.8 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2
Hz), 7.25 (m, 1H), 7.22 (d, 1H, J=2.2 Hz), 6.76 (dm, 1H, J=7.7 Hz),
3.09 (s, 3H), 2.32 (s, 3H). MS: m/z 481 (M+1).
Example 106
Synthesis of
3-{4-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-ph-
enyl}-propionic acid methyl ester
##STR00115##
[0369] The title compound was prepared by the mCPBA oxidation of
3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester according to the general procedure.
.sup.1H NMR (CDCl3) .delta. 10.66 (br s, 1H, NH), 8.54 (dm, 1H,
J=6.2 Hz), 7.78 (m, 3H), 7.52 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.39
(t, 1H, J=7.2 Hz), 7.31 (d, 2H, J=8.0 Hz), 7.18 (m, 2H), 3.65 (s,
3H), 2.99 (t, 2H, J=7.6 Hz), 2.64 (t, 2H, J=7.6 Hz), 2.31 (s, 3H).
MS: m/z 489 (M+1).
Example 107
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00116##
[0371] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8
Hz), 7.77 (dm, 1H, J=8.6 Hz), 7.71 (dd, 1H, J=8.1 Hz, J=2.2 Hz),
7.58 (dm, 2H, J=8.6 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32
(d, 1H, J=2.2 Hz), 7.29 (dm, 2H, J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz),
2.63 (s, 3H), 1.20 (s, 9H). MS: m/z 443 (M+1).
Example 108
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-b-
enzenesulfonamide
##STR00117##
[0373] The title compound was prepared by the mCPBA oxidation of
4-tert-butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 9.64 (br s, 1H, NH), 8.47 (m, 1H), 7.68 (d,
1H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.64 (m, 1H), 7.53 (m, 2H),
7.41 (d, 1H, J=2.2 Hz), 7.40 (d, 2H, J=8.8 Hz), 2.69 (s, 3H), 1.26
(s, 9H). MS: m/z 459 (M+1).
Example 109
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00118##
[0375] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-trifluoromethyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H-NMR (CDCl3) .delta. 9.76 (br s, 1, NH), 8.50 (d, 1H, J=2.2
Hz), 7.76 (d, 1H, J=8.8), 7.73 (d, 2H, J=9.2), 7.66 (dd, 1H, J=8.0,
J=2.2), 7.54 (ddm, 1H, J=8.8 Hz, J=2.6 Hz), 7.37 (d, 1H, J=2.6),
7.24 (d, 1H, J=6 Hz), 7.10 (d, 2H, J=8.8 Hz), 2.35 (s, 3). MS: m/z
471 (M+1).
Example 110
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00119##
[0377] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8
Hz), 7.75 (d, 1H, J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz),
7.55 (d, 2H, J=9.0 Hz), 7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d,
1H, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43
(septet, 1H, J=6 Hz), 2.65 (s, 3H), 1.28 (d, 3H, J=6 Hz). MS: m/z
445 (M+1).
Example 111
Synthesis of
4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00120##
[0379] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl.sub.3) .delta. 9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2,
J=8.8 Hz), 7.71 (d, 2, J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8
Hz, J=2.2 Hz), 7.33 (d, 1, J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1,
J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3). MS: m/z 429 (M+1).
Example 112
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00121##
[0381] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl.sub.3) .delta. 9.77 (br s, 1H, NH), 8.44 (dm, 1H,
J=2.2 Hz), 7.87 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d,
1H, J=8.8 Hz), 7.60 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H,
J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H, J=2.2), 7.26 (d, 1H, J=8.0 Hz),
3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465 (M+1).
Example 113
Synthesis of
3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester
##STR00122##
[0383] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. .sup.1H NMR (CDCl3) .delta. 9.66 (br s, 1H, NH),
8.34 (d, 1H, J=2.2 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0
Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz,
J=2.2 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d,
2H, J=8.4 Hz), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.66 (s, 3H),
2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).
Example 114
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00123##
[0385] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 9.60 (br s, 1, NH), 8.42 (m, 1H), 7.78 (dm,
2H, J=8.4 Hz), 7.70 (dm, 1H, J=8.8 Hz), 7.56 (dd, 1H, J=8.0 Hz,
J=2.2 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.2 Hz), 7.38
(dm, 1H, J=8.0 Hz), 7.20 (dm, 2H, J=8.4 Hz), 2.65 (s, 3H). MS: m/z
487 (M+1).
Example 115
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00124##
[0387] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure. .sup.1H-NMR
(CDCl.sub.3) .delta. 9.53 (br s, 1H, NH), 8.25 (dm, 1H, J=1.5 Hz),
7.74 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H, J=8.8 Hz), 7.52 (dd, 1H,
J=8.8 Hz, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.33 (d, 1H, J=2.6
Hz), 7.20 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 6.75 (dm, 2H, J=8.8 Hz),
4.51 (septet, 1H, J=6 Hz), 2.59 (s, 3H), 1.30 (d, 3H, J=6 Hz). MS:
m/z 461 (M+1).
Example 116
Synthesis of
4-Acetyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benze-
nesulfonamide
##STR00125##
[0389] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H-NMR (CDCl3)
.delta. 9.16 (br s, 1H, NH), 8.15 (dm, 1H, J=2.0 Hz), 7.83 (d, 2H,
J=8.1 Hz), 7.71 (d, 2H, J=8.1 Hz), 7.71-7.67 (m, 2H), 7.58 (dd, 1H,
J=8.8 Hz, J=2.2 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.37 (d, 1H, J=2.2
Hz), 2.66 (s, 3H), 2.60 (s, 3H). MS: m/z 445 (M+1).
Example 117
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfo-
nyl-benzenesulfonamide
##STR00126##
[0391] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide according to the general procedure. .sup.1H-NMR
(CDCl3) .delta. 9.39 (br s, 1H, NH), 8.61 (m, 1H), 7.88 (m, 4H),
7.68 (d, 1H, J=8.8 Hz), 7.60 (m, 2H), 7.40 (m, 2H), 3.03 (s, 3H),
2.69 (s, 3H). m/z 481 (M+1).
Example 118
Synthesis of
3-{4-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-ph-
enyl}-propionic acid methyl ester
##STR00127##
[0393] The title compound was prepared by the mCPBA oxidation of
3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester according to the general procedure.
.sup.1H-NMR (CDCl3) .delta. 9.47 (br s, 1H, NH), 8.26 (m, 1H), 7.69
(d, 1H, J=8.8 Hz), 7.59 (dm, 2H, J=8.4 Hz), 7.53 (dd, 1H, J=8.8 Hz,
J=2.6 Hz), 7.48 (m, 2H), 7.35 (d, 1H, J=2.6 Hz), 7.18 (dm, 2H,
J=8.4 Hz), 3.64 (s, 3H), 2.88 (t, 2H, J=7.6 Hz), 2.67 (s, 3H), 2.51
(t, 2H, J=7.6 Hz). MS: m/z 489 (M+1).
Measuring Efficacy of CCR9 Modulators
In Vitro Assays
[0394] A variety of assays can be used to evaluate the compounds
provided herein, including signaling assays, migration assays, and
other assays of cellular response. CCR9 receptor signaling assays
can be used to measure the ability of a compound, such as a
potential CCR9 antagonist, to block CCR9 ligand- (e.g.
TECK)-induced signaling. A migration assay can be used to measure
the ability of a compound of interest, such as a possible CCR9
antagonist, to block CCR9-mediated cell migration in vitro. The
latter is believed to resemble chemokine-induced cell migration in
vivo.
[0395] In a suitable assay, a CCR9 protein (whether isolated or
recombinant) is used which has at least one property, activity, or
functional characteristic of a mammalian CCR9 protein. The property
can be a binding property (to, for example, a ligand or inhibitor),
a signaling activity (e.g., activation of a mammalian G protein,
induction of rapid and transient increase in the concentration of
cytosolic free calcium [Ca.sup.++]), cellular response function
(e.g., stimulation of chemotaxis or inflammatory mediator release
by leukocytes), and the like.
[0396] The assay can be a cell based assay that utilizes cells
stably or transiently transfected with a vector or expression
cassette having a nucleic acid sequence which encodes the CCR9
receptor. The cells are maintained under conditions appropriate for
expression of the receptor and are contacted with a putative agent
under conditions appropriate for binding to occur. Binding can be
detected using standard techniques. For example, the extent of
binding can be determined relative to a suitable control (for
example, relative to background in the absence of a putative agent,
or relative to a known ligand). Optionally, a cellular fraction,
such as a membrane fraction, containing the receptor can be used in
lieu of whole cells.
[0397] Detection of binding or complex formation can be detected
directly or indirectly. For example, the putative agent can be
labeled with a suitable label (e.g., fluorescent label,
chemiluminescent label, isotope label, enzyme label, and the like)
and binding can be determined by detection of the label. Specific
and/or competitive binding can be assessed by competition or
displacement studies, using unlabeled agent or a ligand (e.g.,
TECK) as a competitor.
[0398] Binding inhibition assays can be used to evaluate the
present compounds. In these assays, the compounds are evaluated as
inhibitors of ligand binding using, for example, TECK. In this
embodiment, the CCR9 receptor is contacted with a ligand such as
TECK and a measure of ligand binding is made. The receptor is then
contacted with a test agent in the presence of a ligand (e.g.,
TECK) and a second measurement of binding is made. A reduction in
the extent of ligand binding is indicative of inhibition of binding
by the test agent. The binding inhibition assays can be carried out
using whole cells which express CCR9, or a membrane fraction from
cells which express CCR9.
[0399] The binding of a G protein coupled receptor by, for example,
an agonist, can result in a signaling event by the receptor.
[0400] Accordingly, signaling assays can also be used to evaluate
the compounds of the present invention and induction of signaling
function by an agent can be monitored using any suitable method.
For example, G protein activity, such as hydrolysis of GTP to GDP,
or later signaling events triggered by receptor binding can be
assayed by known methods (see, for example, PCT/US97/15915; Neote,
et al., Cell, 72:415425 (1993); Van Riper, et al., J. Exp. Med.,
177:851-856 (1993) and Dahinden, et al., J. Exp. Med., 179:751-756
(1994)).
[0401] Chemotaxis assays can also be used to assess receptor
function and evaluate the compounds provided herein. These assays
are based on the functional migration of cells in vitro or in vivo
induced by an agent, and can be used to assess the binding and/or
effect on chemotaxis of ligands, inhibitors, or agonists. A variety
of chemotaxis assays are known in the art, and any suitable assay
can be used to evaluate the compounds of the present invention.
Examples of suitable assays include those described in
PCT/US97/15915; Springer, et al., WO 94/20142; Berman et al.,
Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.
Immunol., 146:4149-4156 (1991)).
[0402] Calcium signaling assays measure calcium concentration over
time, preferably before and after receptor binding. These assays
can be used to quantify the generation of a receptor signaling
mediator, Ca.sup.++, following receptor binding (or absence
thereof). These assays are useful in determining the ability of a
compound, such as those of the present invention, to generate the
receptor signaling mediator by binding to a receptor of interest.
Also, these assays are useful in determining the ability of a
compound, such as those of the present invention, to inhibit
generation of the receptor signaling mediator by interfering with
binding between a receptor of interest and a ligand.
[0403] In calcium signaling assays used to determine the ability of
a compound to interfere with binding between CCR9 and a known CCR9
ligand, CCR9-expressing cells (such as a T cell line MOLT-4 cells)
are first incubated with a compound of interest, such as a
potential CCR9 antagonist, at increasing concentrations. The cell
number can be from 10.sup.5 to 5.times.10.sup.5 cells per well in a
96-well microtiter plate. The concentration of the compound being
tested may range from 0 to 100 uM. After a period of incubation
(which can range from 5 to 60 minutes), the treated cells are
placed in a Fluorometric Imaging Plate Reader (FLIPR.RTM.)
(available from Molecular Devices Corp., Sunnyvale, Calif.)
according to the manufacturer's instruction. The FLIPR system is
well known to those skilled in the art as a standard method of
performing assays. The cells are then stimulated with an
appropriate amount of the CCR9 ligand TECK (e.g. 5-100 nM final
concentration) and the signal of intracellular calcium increase
(also called calcium flux) is recorded. The efficacy of a compound
as an inhibitor of binding between CCR9 and the ligand can be
calculated as an IC50 (the concentration needed to cause 50%
inhibition in signaling) or IC90 at 90% inhibition).
[0404] In vitro cell migration assays can be performed (but are not
limited to this format) using the 96-well microchamber (called
ChemoTX.TM.). The ChemoTX system is well known to those skilled in
the art as a type of chemotactic/cell migration instrument. In this
assay, CCR9-expressing cells (such as MOLT-4) are first incubated
with a compound of interest, such as a possible CCR9 antagonist, at
increasing concentrations. Typically, fifty thousand cells per well
are used, but the amount can range from 10.sup.3-10.sup.6 cells per
well. CCR9 ligand TECK, typically at 50 nM (but can range from
5-100 nM), is placed at the lower chamber and the migration
apparatus is assembled. Twenty microliters of test compound-treated
cells are then placed onto the membrane. Migration is allowed to
take place at 37 C for a period of time, typically 2.5 hours. At
the end of the incubation, the number of cells that migrated across
the membrane into the lower chamber is then quantified. The
efficacy of a compound as an inhibitor of CCR9-mediated cell
migration is calculated as an IC50 (the concentration needed to
reduce cell migration by 50%) or IC90 (for 90% inhibition).
In Vivo Efficacy Models for Human IBD
[0405] T cell infiltration into the small intestine and colon have
been linked to the pathogenesis of human inflammatory bowel
diseases which include Coeliac disease, Crohn's disease and
ulcerative colitis. Blocking trafficking of relevant T cell
populations to the intestine is believed to be an effective
approach to treat human IBD. CCR9 is expressed on gut-homing T
cells in peripheral blood, elevated in patients with small bowel
inflammation such as Crohn's disease and Coeliac disease. CCR9
ligand TECK is expressed in the small intestine. It is thus
believed that this ligand-receptor pair plays a role in IBD
development by mediating migration of T cells to the intestine.
Several animal models exist and can be used for evaluating
compounds of interest, such as potential CCR9 antagonists, for an
ability to affect such T cell migration and/or condition or
disease, which might allow efficacy predictions of antagonists in
humans.
Animal Models with Pathology Similar to Human Ulcerative
Colitis
[0406] A murine model described by Panwala and coworkers (Panwala,
et al., J. Immunol., 161(10):5733-44 (1998)) involves genetic
deletion of the murine multi-drug resistant gene (MDR). MDR
knockout mice (MDR-/-) are susceptible to developing a severe,
spontaneous intestinal inflammation when maintained under specific
pathogen-free facility conditions. The intestinal inflammation seen
in MDR-/- mice has a pathology similar to that of human
inflammatory bowel disease (IBD) and is defined by Th1 type T cells
infiltration into the lamina propria of the large intestine.
[0407] Another murine model was described by Davidson et al., J Exp
Med., 184(1):241-51(1986). In this model, the murine IL-10 gene was
deleted and mice rendered deficient in the production of
interleukin 10 (IL-10-/-). These mice develop a chronic
inflammatory bowel disease (IBD) that predominates in the colon and
shares histopathological features with human IBD.
[0408] Another murine model for IBD has been described by Powrie et
al., Int Immunol., 5(11):1461-71 (1993), in which a subset of CD4+
T cells (called CD45RB(high)) from immunocompetent mice are
purified and adoptively transferred into immunodeficient mice (such
as C.B-17 scid mice). The animal restored with the CD45RBhighCD4+ T
cell population developed a lethal wasting disease with severe
mononuclear cell infiltrates in the colon, pathologically similar
with human IBD.
Murine Models with Pathology Similar to Human Crohn's Disease
[0409] The TNF ARE(-/-) model. The role of TNF in Crohn's disease
in human has been demonstrated more recently by success of
treatment using anti-TNF alpha antibody by Targan et al., N Engl J
Med., 337(15):1029-35 (1997). Mice with aberrant production of
TNF-alpha due to genetic alteration in the TNF gene (ARE-/-)
develop Crohn's-like inflammatory bowel diseases (see Kontoyiannis
et al., Immunity, 10(3):387-98 (1999)).
[0410] The SAMP/yit model. This is model described by Kosiewicz et
al., J Clin Invest., 107(6):695-702 (2001). The mouse strain,
SAMP/Yit, spontaneously develops a chronic inflammation localized
to the terminal ileum. The resulting ileitis is characterized by
massive infiltration of activated T lymphocytes into the lamina
propria, and bears a remarkable resemblance to human Crohn's
disease.
Example 119
[0411] This example illustrates the activity associated with
representative compounds of the invention.
Materials and Methods (In Vitro Assays)
[0412] Reagents and Cells
[0413] MOLT-4 cells were obtained from the American Type Culture
Collection (Manassas, Va.) and cultured in RPMI tissue culture
medium supplemented with 10% fetal calf serum (FCS) in a humidified
5% CO.sub.2 incubator at 37.degree. C. Recombinant human chemokine
protein TECK was obtained from R&D Systems (Minneapolis,
Minn.). ChemoTX.RTM. chemotaxis microchambers were purchased from
Neuro Probe (Gaithersburg, Md.). CyQUANT.RTM. cell proliferation
kits were purchased from Molecular Probes (Eugene, Oreg.). Calcium
indicator dye Fluo-4 AM was purchased from Molecular Devices
(Mountain View, Calif.).
Conventional Migration Assay
[0414] Conventional migration assay was used to determine the
efficacy of potential receptor antagonists in blocking migration
mediated through CCR9. This assay was routinely performed using the
ChemoTX.RTM. microchamber system with a 5-.mu.m pore-sized
polycarbonate membrane. To begin such an assay, MOLT-4 cells were
harvested by centrifugation of cell suspension at 1000 PRM on a
GS-6R Beckman centrifuge. The cell pellet was resuspended in
chemotaxis buffer (HBSS with 0.1% BSA) at 5.times.10.sup.6
cells/mL. Test compounds at desired concentrations were prepared
from 10 mM stock solutions by serial dilutions in chemotaxis
buffer. An equal volume of cells and compounds were mixed and
incubated at room temperature for 15 minutes. Afterwards, 20 .mu.L
of the mixture was transferred onto the porous membrane of a
migration microchamber, with 29 .mu.L of 50 nM chemokine TECK
protein placed at the lower chamber. Following a 150-minute
incubation at 37.degree. C., during which cells migrated against
the chemokine gradient, the assay was terminated by removing the
cell drops from atop the filter. To quantify cells migrated across
the membrane, 5 .mu.L of 7.times. CyQUANT.RTM. solution was added
to each well in the lower chamber, and the fluorescence signal
measured on Spectrafluor Plus fluorescence plate reader (TECAN,
Durham, N.C.). The degree of inhibition was determined by comparing
migration signals between compound-treated and untreated cells.
IC50 calculation was further performed by non-linear squares
regression analysis using Graphpad Prism (Graphpad Software, San
Diego, Calif.).
RAM Assay
[0415] The primary screen to identify CCR9 antagonists was carried
out using RAM assay (WO 02101350), which detects potential hits by
their ability to activate cell migration under inhibitory TECK
concentration. To begin such an assay, MOLT-4 cells were harvested
by centrifugation of cell suspension at 1000 RPM on a GS-6R Beckman
centrifuge. The cell pellet was resuspended in chemotaxis buffer
(HBSS/0.1% BSA) at 5.times.10.sup.6 cells/mL. Twenty-five
microliters of cells was mixed with an equal volume of a test
compound diluted to 20 .mu.M in the same buffer. Twenty microliters
of the mixture was transferred onto the filter in the upper
chemotaxis chamber, with 29 .mu.L of 500 nM chemokine protein TECK
placed in the lower chamber. Following a 150-minute incubation at
37.degree. C., the assay was terminated by removing the cell drops
from atop the filter. To quantify cells migrated across the
membrane, 5 .mu.L of 7.times. CyQUANT.RTM. solution was added to
each well in the lower chamber, and the fluorescence signal
measured on a Spectrafluor Plus fluorescence plate reader (TECAN,
Durham, N.C.).
[0416] For selection of potential hits, the level of migration
activation was calculated as a RAM index--the ratio between the
signal of a particular well and the median signal of the whole
plate. Compounds with a RAM index of greater than 1.8 were regarded
as RAM positive, and were selected for IC.sub.50 determinations in
conventional functional assays.
Calcium Flux Assay
[0417] Calcium flux assay measures an increase in intracellular
calcium following ligand-induced receptor activation. In the screen
of CCR9 antagonists, it was used as a secondary assay carried out
on a FLIPR.RTM. machine (Molecular Devices, Mountain View, Calif.).
To begin an assay, MOLT-4 cells were harvested by centrifugation of
cell suspension, and resuspended to 1.5.times.10.sup.6 cells/mL in
HBSS (with 1% fetal calf serum). Cells were then labeled with a
calcium indicator dye Fluo-4 AM for 45 minutes at 37.degree. C.
with gentle shaking. Following incubation, cells were pelleted,
washed once with HBSS and resuspended in the same buffer at a
density of 1.6.times.10.sup.6 cells/mL. One hundred microliters of
labeled cells were mixed with 10 .mu.L of test compound at the
appropriate concentrations on an assay plate. Chemokine protein
TECK was added at a final concentration of 25 nM to activate the
receptor. The degree of inhibition was determined by comparing
calcium signals between compound-treated and untreated cells. IC50
calculations were further performed by non-linear squares
regression analysis using Graphpad Prism (Graphpad Software, San
Diego, Calif.).
Discovery of CCR9 Antagonists
[0418] The discovery of CCR9 antagonists was carried out in two
steps: First, RAM assay was used to screen a compound library in a
high-throughput manner. The assay detected compounds by their
ability to cause a positive migration signal under RAM condition.
Secondly, RAM positive compounds were tested to determine their
IC.sub.50s using the conventional migration and calcium flux
assays.
[0419] For instance, in a screen of approximately 100,000
compounds, 2000 individual wells representing approximately 2% of
total compounds showed a RAM index greater than 1.8. These
compounds were cheery-picked and retested in duplicate wells by RAM
assay. A total of 270 compounds, or 0.27% of the library, were
confirmed RAM positives.
[0420] Since a RAM positive signal indicates only the presence of a
receptor antagonist and not how strongly it blocks receptor
functions, the RAM positive compounds were further tested for
potency in calcium flux assay using MOLT-4 cells. IC.sub.50
determinations on this subset discovered several compounds with
IC.sub.50's less than 1 .mu.M and that did not inhibit other
chemokine receptors examined at significant levels.
In Vivo Efficacy Studies
[0421] The MDR1a-knockout mice, which lack the P-glycoprotein gene,
spontaneously develop colitis under specific pathogen-free
condition. The pathology in these animals has been characterized as
Th1-type T cell-mediated inflammation similar to ulcerative colitis
in humans. Disease normally begins to develop at around 8-10 weeks
after birth. However the ages at which disease emerges and the
ultimate penetrance level often vary considerably among different
animal facilities.
[0422] In a study using the MDR1a-knockout mice, the CCR9
antagonist shown below
##STR00128##
was evaluated by prophylactic administration for its ability to
delay disease onset. Female mice (n=34) were dosed with 50 mg/kg
twice a day by subcutaneous injections for 14 consecutive weeks
starting at age 10 weeks. The study showed that the compound
prevented IBD-associated growth retardation. Moreover, the number
of mice developing diarrhea was also lower among compound-treated
mice (17%), compared to mice receiving vehicle alone (24% (FIG.
1).
[0423] In the table below, structures and activity are provided for
representative compounds described herein. Activity is provided as
follows for either or both of the chemotaxis assay and/or calcium
mobilization assays, described above: +1000 nM<IC.sub.50<1000
nM; ++, 100 nM<IC.sub.50<1000 nM; and +++, IC.sub.50<100
nM.
TABLE-US-00001 TABLE 1 Compounds with activity in either or both of
the chemotaxis assay and calcium mobilization assays, with
IC.sub.50 < 100 nM (+++) ##STR00129## ##STR00130## ##STR00131##
##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136##
##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141##
##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##
##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161##
##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166##
##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171##
##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176##
##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181##
##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186##
##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191##
##STR00192## ##STR00193## ##STR00194## ##STR00195##
TABLE-US-00002 TABLE 2 Compounds with activity in either or both of
the chemotaxis assay and calcium mobilization assays, with 100 nM
< IC.sub.50 < 1000 nM (++) ##STR00196## ##STR00197##
##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202##
##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207##
##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##
##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217##
##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227##
##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232##
##STR00233##
TABLE-US-00003 TABLE 3 Compounds with activity in either or both of
the chemotaxis assay and calcium mobilization assays, with 1000 nM
< IC.sub.50 < 10000 nM (+): ##STR00234## ##STR00235##
##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240##
##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245##
##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250##
##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255##
##STR00256## ##STR00257##
[0424] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purposes.
* * * * *