U.S. patent application number 11/601025 was filed with the patent office on 2007-03-22 for ccr9 inhibitors and methods of use thereof.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Shaowu Chen, Paul Fleming, Geraldine C.B. Harriman, Zhan Shi.
Application Number | 20070066823 11/601025 |
Document ID | / |
Family ID | 29584585 |
Filed Date | 2007-03-22 |
United States Patent
Application |
20070066823 |
Kind Code |
A1 |
Fleming; Paul ; et
al. |
March 22, 2007 |
CCR9 inhibitors and methods of use thereof
Abstract
The invention relates to compounds represented by Structural
Formula I, which can bind to CCR9 receptors and block the binding
of a ligand (e.g., TECK) to the receptors. The invention also
relates to a method of inhibiting a function of CCR9, and to the
use compounds represented by Structural Formula I in research,
therapeutic, prophylactic and diagnostic methods.
Inventors: |
Fleming; Paul; (Wellesley,
MA) ; Harriman; Geraldine C.B.; (Charlestown, RI)
; Shi; Zhan; (Concord, MA) ; Chen; Shaowu;
(Sudbury, MA) |
Correspondence
Address: |
MILLENNIUM PHARMACEUTICALS, INC.
40 Landsdowne Street
CAMBRIDGE
MA
02139
US
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
|
Family ID: |
29584585 |
Appl. No.: |
11/601025 |
Filed: |
November 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10443155 |
May 21, 2003 |
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11601025 |
Nov 17, 2006 |
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60383573 |
May 24, 2002 |
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Current U.S.
Class: |
544/224 ;
544/334; 546/262; 548/236; 548/364.1; 549/76; 564/86 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 401/06 20130101; A61P 1/00 20180101; C07D 213/46 20130101;
C07D 239/42 20130101; C07D 333/34 20130101; A61P 21/04 20180101;
C07D 413/14 20130101; C07D 213/89 20130101; A61P 7/00 20180101;
A61P 1/18 20180101; A61P 9/10 20180101; C07D 213/80 20130101; C07D
409/06 20130101; A61P 43/00 20180101; C07C 311/21 20130101; A61P
17/00 20180101; A61P 11/02 20180101; A61P 1/04 20180101; C07D
213/76 20130101; A61P 37/00 20180101; C07C 311/46 20130101; A61P
37/08 20180101; C07D 237/08 20130101; C07D 213/65 20130101; C07C
317/34 20130101; A61P 19/02 20180101; C07D 213/71 20130101; A61P
15/14 20180101; A61P 25/00 20180101; C07D 413/04 20130101; A61P
37/06 20180101; A61P 17/04 20180101; C07D 333/62 20130101; C07D
409/04 20130101; A61P 25/28 20180101; C07D 405/06 20130101; C07D
239/26 20130101; A61P 3/10 20180101; A61P 11/00 20180101; C07C
311/44 20130101; C07D 213/50 20130101; A61P 17/06 20180101; C07D
213/70 20130101; A61P 5/14 20180101; C07C 323/49 20130101; A61P
11/06 20180101; A61P 1/16 20180101; C07C 311/29 20130101; A61P
15/00 20180101; A61P 21/00 20180101; C07D 513/04 20130101; A61P
13/12 20180101; A61P 9/00 20180101; C07D 213/75 20130101 |
Class at
Publication: |
544/224 ;
544/334; 546/262; 548/364.1; 548/236; 564/086; 549/076 |
International
Class: |
C07D 333/22 20060101
C07D333/22; C07D 263/34 20060101 C07D263/34; C07D 213/44 20060101
C07D213/44; C07D 401/02 20060101 C07D401/02 |
Claims
1. A compound represented by the following structural formula:
##STR76## or pharmaceutically acceptable salts, solvates or
hydrates thereof, wherein: Y is C(O), O, S, S(O), or S(O).sub.2;
X.sub.1, X.sub.2, and X.sub.3 are each, independently, N or CR,
provided that at least one of X.sub.1, X.sub.2, or X.sub.3 is CR; R
for each occurrence and R.sub.1 are each, independently, H or a
substituent; R.sub.6 is H, an aliphatic carbonyl group, or an
aliphatic ester; ring A is substituted or unsubstituted; and
Ar.sub.1 and Ar.sub.2 are each, independently, a substituted or
unsubstituted aryl or a substituted or unsubstituted
heteroaryl.
2. The compound of claim 1, wherein Ar.sub.2 is phenyl, naphthyl,
thienyl, or thianaphthenyl, each group being substituted or
unsubstituted.
3. The compound of claim 1, wherein Ar.sub.1 is phenyl, pyridyl,
pyrimidinyl, or pyrazinyl, each group being substituted or
unsubstituted.
4. The compound of claim 1, which is represented by the following
structural formula: ##STR77## or a pharmaceutically acceptable
salts, solvates, or hydrates thereof, wherein: Y is S, O, S(O), or
S(O).sub.2; R.sub.19 and R.sub.20 are each, independently, H or a
substituent.
5. The compound of claim 1, which is represented by the following
structural formula: ##STR78## or pharmaceutically acceptable salts,
solvates, or hydrates thereof, wherein: R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, and each R are, independently, H, an aliphatic
group, haloalkyl, halo, COOH, NO.sub.2, alkoxy, or haloalkoxy; and
X.sub.4 is CR, N or N.sup.+--O.sup.-.
6. The compound of claim 1 which is represented by the following
structural formula: ##STR79## or pharmaceutically acceptable salts,
solvates, or hydrates thereof, wherein: X.sub.4 is CR, N or
N.sup.+--O.sup.-; R.sub.8 is H or an electron withdrawing group; m
and n are each, independently, 0 or an integer from 1 to 3; each
R.sub.9 is, independently, aliphatic group, haloalkyl, aryl,
arylalkyl, alkoxy, cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy,
alkylthio, halo, nitro, cyano, hydroxy, NR.sub.11CO.sub.2R.sub.12,
C(O)N(R.sub.11).sub.2, C(O)R.sub.12, CO.sub.2R.sub.12,
OC(O)N(R.sub.11).sub.2, OC(O)R.sub.12, N(R.sub.11).sub.2, or
NR.sub.11C(O)R.sub.12; or two adjacent R.sub.9 groups taken
together with the atoms to which they are attached form a fused,
saturated, unsaturated or partially unsaturated 5 to 7 membered
ring having 0, 1 or 2 heteroatoms selected from the group
consisting of N, O, and S; each R.sub.10 is, independently, halo,
an aliphatic group, alkoxy, or haloalkyl; or two adjacent R.sub.10
groups taken together with the atoms to which they are attached
form a fused, saturated, unsaturated or partially unsaturated 5 to
7 membered ring having 0, 1 or 2 heteroatoms selected from the
group consisting of N, O, and S; each R.sub.11, is, independently,
H or an aliphatic group; and R.sub.12 is an aliphatic group.
7. The compound of claim 1 wherein the compound is represented by
the following structural formula: ##STR80## or pharmaceutically
acceptable salts, solvates, or hydrates thereof, wherein: ring B is
substituted or unsubstituted; p is 0 or an integer from 1-3; and
each R.sub.13 is, independently, a halo or a substituted or
unsubstituted heteroaryl.
8. A compound selected from the group consisting of: TABLE-US-00010
N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
Thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-chloro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-propyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-isopropyl-benzenesulfonamide
4-Ethyl-N-[4-nitro-2-(3-trifluoromethyl-benzoyl)-phenyl]-benzenesulfonamid-
e
N-[4-Chloro-2-(3-methyl-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-chloro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-propoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-butoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-benzyloxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-phenoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesulfonamide
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-ethoxy-benzenesulfonam-
ide
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-isopropoxy-benzenesulf-
onamide
N-(3-Benzoyl-5-trifluoromethyl-pyridin-2-yl)-4-isopropoxy-benzenesulfonami-
de N-(2-Benzoyl-4-nitro-phenyl)-4-chloro-benzenesulfonamide
5-Benzoyl-6-(4-isopropoxy-benzenesulfonylamino)-nicotinic acid
N-(2-Benzoyl-4-chloro-phenyl)-2-nitro-benzenesulfonamide
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
N-(5-Benzoyl-pyrimidin-4-yl)-4-isopropoxy-benzenesulfonamide
N-(3-Benzoyl-5-trifluoromethoxy-pyridin-2-yl)-4-isopropoxy-benzenesulfonam-
ide
N-(5-Benzoyl-2-trifluoromethyl-pyrimidin-4-yl)-4-isopropoxy-benzenesulfona-
mide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclobutyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-tert-butoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopentyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylsulfanyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylamino-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclohexyl-benzenesulfonamide
N-(3-Benzenesulfinyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamid-
e
N-(3-Benzenesulfonyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamid-
e
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonam-
ide
N-[4-Chloro-2-(pyridazine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonam-
ide
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropoxy-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-trifluoromethoxy-benzenesulfonamide
5-Oxazol-5-yl-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-methoxy-benzenesulfonamide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethylamino-benzenesulfonamide
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic
acid (2-benzoyl- 4-chloro-phenyl)-amide
N-(2-Benzoyl-4-iodo-phenyl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(3-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-nitro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-diethylamino-benzenesulfonamide
N-(2-Benzoyl-4-fluoro-phenyl)-4-methoxy-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-methyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-dimethylamino-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-fluoro-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-benzenesulfonamide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
Thiophene-3-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
5-Bromo-thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
5-Chloro-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-benzenesulfonamide
N-[4-(2-Benzoyl-4-chloro-phenylsulfamoyl)-phenyl]-acetamide
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-cyano-benzenesulfonamide
4,5-Dibromo-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(pyridine-3-sulfonyl)-phenyl]-4-nitro-benzenesulfonamide
Naphthalene-2-sulfonic acid
[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-amide
N-(2-Benzoyl-4-chloro-phenyl)-3-bromo-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-methyl-3-nitro-benzenesulfonamide
N-[4-Chloro-2-(2-methoxy-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-2-trifluoromethyl-benzenesulfonamide
5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)- amide
N-(2-Benzoyl-phenyl)-4-nitro-benzenesulfonamide
5-Isoxazol-3-yl-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-(2-Benzoyl-phenyl)-4-methyl-benzenesulfonamide
Benzo[b]thiophene-3-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
N-(4-Chloro-2-phenylsulfanyl-phenyl)-4-isopropoxy-benzenesulfonamide
N-(2-Benzenesulfonyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamid-
e
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulf-
onamide
4-Isopropoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-
benzenesulfonamide
4-Ethoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-benzenesulfo-
namide
N-[5-Chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]-4-isopropyl-benzenesulfonam-
ide
N-[5-Chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-benzenesulfona-
mide
N-[5-Chloro-3-(thiophene-2-carbonyl)-pyridin-2-yl]-4-isopropoxy-benzenesul-
fonamide 5-Oxazol-5-yl-thiophene-2-sulfonic acid
[5-chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]- amide
N-[3-(Benzofuran-2-carbonyl)-5-chloro-pyridin-2-yl]-4-isopropoxy-
benzenesulfonamide
N-(2-Benzoyl-4-trifluoromethyl-phenyl)-4-isopropoxy-benzenesulfonamide
N-(3-Benzoyl-pyridin-4-yl)-4-isopropoxy-benzenes
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropyl-benzenesulfonamide
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
5-Oxazol-5-yl-thiophene-2-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropylamino-benzenesulfonamide
N-(4-Benzoyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide
N-(4-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide
N-[3-(3-Fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropoxy-benzenesulfonamide
4-Isopropoxy-N-[3-(pyridine-4-carbonyl)-pyridin-4-yl]-benzenesulfonamide
6-Isopropoxy-pyridine-3-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide
6-Isopropoxy-pyridine-3-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(pyridin-2-ylsulfanyl)-phenyl]-4-isopropyl-benzenesulfonamid-
e N-(2-Benzoyl-phenyl)-4-isopropoxy-benzenesulfonamide; and
pharmaceutically acceptable salts, solvates, and hydrates
thereof.
9. A pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and the compound of claim 1.
10. A method of inhibiting a CCR9 receptor function in a subject in
need thereof, comprising the step of administering to the subject
an effective amount of a compound represented by the following
structural formula: ##STR81## or pharmaceutically acceptable salts,
solvates or hydrates thereof, wherein: Y is C(O), S, O, S(O) or
S(O).sub.2; X.sub.1, X.sub.2, and X.sub.3 are each, independently,
N or CR, provided that at least one of X.sub.1, X.sub.2, or X.sub.3
is CR; R, for each occurrence, and R.sub.1 are each, independently,
H or a substituent; R.sub.6 is H, an aliphatic carbonyl group, or
an aliphatic ester; and ring A is substituted or unsubstituted;
Ar.sub.1 and Ar.sub.2 are each, independently, a substituted or
unsubstituted aryl group or a substituted or unsubstituted
heteroaryl group.
11. The method of claim 10, wherein the compound is represented by
a structural formula selected from the group consisting of A, B, C,
and D: A. ##STR82## or pharmaceutically acceptable salts, solvates
or hydrates thereof, wherein: R.sub.19 and R.sub.20 are each,
independently, H or a substituent; ##STR83## B. or pharmaceutically
acceptable salts, solvates or hydrates thereof, wherein: R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, and each R are, independently,
H, an aliphatic group, haloalkyl, a halo, COOH, NO.sub.2, alkoxy,
or haloalkoxy; and X.sub.4 is CR, N or N.sup.+--O.sup.-; C.
##STR84## or pharmaceutically acceptable salts, solvates or
hydrates thereof, wherein: X.sub.4 is CR, N or N'-O--; R.sub.8 is H
or an electron withdrawing group; m and n are each, independently,
0 or an integer from 1 to 3; each R.sub.9 is, independently, an
aliphatic group, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy,
haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano,
hydroxy, NR.sub.11CO.sub.2R.sub.12, C(O)N(R.sub.11).sub.2,
C(O)R.sub.12, CO.sub.2R.sub.12, OC(O)N(R.sub.11).sub.2,
OC(O)R.sub.12, N(R.sub.11).sub.2, or NR.sub.11C(O)R.sub.12; or two
adjacent R.sub.9 groups taken together with the atoms to which they
are attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.10
is, independently, halo, aliphatic group, alkoxy, or haloalkyl; or
two adjacent R.sub.10 groups taken together with the atoms to which
they are attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.11
is, independently, H or an aliphatic group; and R.sub.12 is an
aliphatic group; and D. ##STR85## or pharmaceutically acceptable
salts, solvates or hydrates thereof, wherein: R.sub.8 is halo,
nitro, alkylcarbonyl or trihaloalkyl; p is 0 or an integer from 1
to 3; and each R.sub.13 is, independently, a halo, a substituted or
unsubstituted heterocycle, or a substituted or unsubstituted
heteroaryl.
12. The method of claim 10 wherein the subject is being treated for
an inflammatory disease or condition.
13. A method of treating or preventing an inflammatory disease or
condition in a subject in need thereof, comprising administering to
the subject an effective amount of a compound represented by the
following structural formula: ##STR86## or pharmaceutically
acceptable salts, solvates or hydrates thereof, wherein: Y is C(O),
S, O, S(O) or S(O).sub.2; X.sub.1, X.sub.2, and X.sub.3 are each,
independently, N or CR, provided that at least one of X.sub.1,
X.sub.2, or X.sub.3 is CR; R, for each occurrence, and R.sub.1 are
each, independently, H or a substituent; and ring A is substituted
or unsubstituted; R.sub.6 is H, an aliphatic group, an aryl group
or an aliphatic carbonyl group; and Ar.sub.1 and Ar.sub.2 are each,
independently, a substituted or unsubstituted aryl group or a
substituted or unsubstituted heteroaryl group.
14. The method of claim 13, wherein the compound is represented by
a structural formula selected from the group consisting of A, B, C,
and D: A. ##STR87## or pharmaceutically acceptable salts, solvates
or hydrates thereof, wherein: R.sub.19 and R.sub.20 are each,
independently, H or a substituent. B. ##STR88## or pharmaceutically
acceptable salts, solvates or hydrates thereof, wherein: R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, and each R are, independently,
H. an aliphatic group, haloalkyl, halo, COOH, NO.sub.2, alkoxy, or
haloalkoxy; and X.sub.4 is CR, N or N.sup.+--O.sup.-; C. ##STR89##
or pharmaceutically acceptable salts, solvates or hydrates thereof,
wherein: X.sub.4 is CR, N or N'-O--; R.sub.8 is H or an electron
withdrawing group; m and n are each, independently, 0 or an integer
from 1 to 3; each R.sub.9 is, independently, aliphatic group,
haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy,
aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy,
NR.sub.11CO.sub.2R.sub.12, C(O)N(R.sub.11).sub.2, C(O)R.sub.12,
CO.sub.2R.sub.12, OC(O)N(R.sub.11).sub.2, OC(O)R.sub.12,
N(R.sub.11).sub.2, or NR.sub.11C(O)R.sub.12; or two adjacent
R.sub.9 groups taken together with the atoms to which they are
attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.10
is, independently, halo, aliphatic group, alkoxy, or haloalkyl; or
two adjacent R.sub.10 groups taken together with the atoms to which
they are attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.11,
is, independently, H or an aliphatic group; and R.sub.12 is an
aliphatic group; and D. ##STR90## or pharmaceutically acceptable
salts, solvates or hydrates thereof, wherein: R.sub.8 is a halo,
nitro, alkylcarbonyl or trihaloalkyl; p is 0 or an integer from 1
to 3; and each R.sub.13 is, independently, a halo, a substituted or
unsubstituted heterocycle, or a substituted or unsubstituted
heteroaryl.
15. The method of claim 13, wherein the compound is selected from
the group consisting of: TABLE-US-00011
N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
Thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-chloro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-propyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-isopropyl-benzenesulfonamide
4-Ethyl-N-[4-nitro-2-(3-trifluoromethyl-benzoyl)-phenyl]-benzenesulfonamid-
e
N-[4-Chloro-2-(3-methyl-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-chloro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-propoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-butoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-benzyloxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-phenoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesulfonamide
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-ethoxy-benzenesulfonam-
ide
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-isopropoxy-benzenesulf-
onamide
N-(3-Benzoyl-5-trifluoromethyl-pyridin-2-yl)-4-isopropoxy-benzenesulfonami-
de N-(2-Benzoyl-4-nitro-phenyl)-4-chloro-benzenesulfonamide
5-Benzoyl-6-(4-isopropoxy-benzenesulfonylamino)-nicotinic acid
N-(2-Benzoyl-4-chloro-phenyl)-2-nitro-benzenesulfonamide
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
N-(5-Benzoyl-pyrimidin-4-yl)-4-isopropoxy-benzenesulfonamide
N-(3-Benzoyl-5-trifluoromethoxy-pyridin-2-yl)-4-isopropoxy-benzenesulfonam-
ide
N-(5-Benzoyl-2-trifluoromethyl-pyrimidin-4-yl)-4-isopropoxy-benzenesulfona-
mide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclobutyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-tert-butoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopentyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylsulfanyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylamino-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropyl-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclohexyl-benzenesulfonamide
N-(3-Benzenesulfinyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamid-
e
N-(3-Benzenesulfonyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamid-
e
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonam-
ide
N-[4-Chloro-2-(pyridazine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonam-
ide
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-isopropo-
xy- benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropoxy-benzenesulfonamide
N-(2-Benzoyl-4-nitro-phenyl)-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-trifluoromethoxy-benzenesulfonamide
5-Oxazol-5-yl-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-methoxy-benzenesulfonamide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-ethylamino-benzenesulfonamide
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic
acid (2-benzoyl- 4-chloro-phenyl)-amide
N-(2-Benzoyl-4-iodo-phenyl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(3-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-nitro-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-diethylamino-benzenesulfonamide
N-(2-Benzoyl-4-fluoro-phenyl)-4-methoxy-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
N-(2-Benzoyl-4-bromo-phenyl)-4-methyl-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-dimethylamino-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-4-fluoro-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-benzenesulfonamide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
Thiophene-3-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
5-Bromo-thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
5-Chloro-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
4-Chloro-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide
N-(2-Benzoyl-4-chloro-phenyl)-benzenesulfonamide
N-[4-(2-Benzoyl-4-chloro-phenylsulfamoyl)-phenyl]-acetamide
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
N-(3-Benzoyl-pyridin-4-yl)-4-isopropoxy-benzenesulfonamide
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropyl-benzenesulfonamide
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
5-Oxazol-5-yl-thiophene-2-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropylamino-benzenesulfonamide
N-(4-Benzoyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide
N-(4-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropyl-benzenesulfonamide
N-(2-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide
N-[3-(3-Fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-benzenesulfonamide
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropoxy-benzenesulfonamide
4-Isopropoxy-N-[3-(pyridine-4-carbonyl)-pyridin-4-yl]-benzenesulfonamide
6-Isopropoxy-pyridine-3-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide
6-Isopropoxy-pyridine-3-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide
N-[4-Chloro-2-(pyridin-2-ylsulfanyl)-phenyl]-4-isopropyl-benzenesulfonamid-
e N-(2-Benzoyl-phenyl)-4-isopropoxy-benzenesulfonamide; and
pharmaceutically acceptable salts, solvates, and hydrates
thereof.
16. The method of claim 13, wherein the inflammatory disease or
condition is Crohn's disease or colitis.
17. The method of claim 13, wherein the inflammatory disease or
condition is Celiac's disease.
18. The method of claim 13, wherein the compound inhibits the
binding of a ligand to CCR9.
19. The method of claim 18, wherein the ligand is TECK.
20. A method of inhibiting CCR9-mediated homing of leukocytes in a
subject in need of such treatment comprising administering to the
subject an effective amount of at least one compound represented by
the following structural formula: ##STR91## or pharmaceutically
acceptable salts, solvates or hydrates thereof, wherein: Y is C(O),
S, S(O) or S(O).sub.2; X.sub.1, X.sub.2, and X.sub.3 are each,
independently, N or CR, provided that at least one of X.sub.1,
X.sub.2, or X.sub.3 is CR; R, for each occurrence, and R.sub.1 are
each, independently, H or a substituent; R.sub.6 is H, an aliphatic
group, an aryl group or an aliphatic carbonyl group; ring A is
substituted or unsubstituted; and Ar.sub.1 and Ar.sub.2 are each,
independently, a substituted or unsubstituted aryl group or a
substituted or unsubstituted heteroaryl group.
21. The method of claim 20, wherein the compound is represented by
a structural formula selected from the group consisting of A, B, C,
and D: A. ##STR92## or pharmaceutically acceptable salts, solvates
or hydrates thereof, wherein: R.sub.19 and R.sub.20 are each,
independently, H or a substituent. B. ##STR93## or pharmaceutically
acceptable salts, solvates or hydrates thereof, wherein: R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, and each R are, independently,
H, an aliphatic group, haloalkyl, halo, COOH, NO.sub.2, alkoxy, or
haloalkoxy; and X.sub.4 is CR, N or N.sup.+--O.sup.-; C. ##STR94##
or pharmaceutically acceptable salts, solvates or hydrates thereof,
wherein: X.sub.4 is CR, N or N'-O--; R.sub.8 is H or an electron
withdrawing group; m and n are each, independently, 0 or an integer
from 1 to 3; each R.sub.9 is, independently, an aliphatic group,
haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy,
aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, hydroxy,
NR.sub.11CO.sub.2R.sub.12, C(O)N(R.sub.11).sub.2, C(O)R.sub.12,
CO.sub.2R.sub.12, OC(O)N(R.sub.11).sub.2, OC(O)R.sub.12,
N(R.sub.11).sub.2, or NR.sub.11C(O)R.sub.12; or two adjacent
R.sub.9 groups taken together with the atoms to which they are
attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.10
is, independently, halo, aliphatic group, alkoxy, or haloalkyl; or
two adjacent R.sub.10 groups taken together with the atoms to which
they are attached form a fused, saturated, unsaturated or partially
unsaturated 5 to 7 membered ring having 0, 1 or 2 heteroatoms
selected from the group consisting of N, O, and S; each R.sub.11
is, independently, H or an aliphatic group; and R.sub.12 is an
aliphatic group; and D. ##STR95## or pharmaceutically acceptable
salts, solvates or hydrates thereof, wherein: R.sub.8 is a halo,
nitro, alkylcarbonyl or trihaloalkyl; p is 0 or an integer from 1
to 3; and each R.sub.13 is, independently, a halo, a substituted or
unsubstituted heterocycle, or a substituted or unsubstituted
heteroaryl.
22. A method of inhibiting homing of leukocytes to mucosal tissue
in a subject in need of such treatment, comprising administering to
the subject an effective amount of at least one compound
represented by the following structural formula: ##STR96## or
pharmaceutically acceptable salts, solvates or hydrates thereof,
wherein: Y is C(O), S, S(O) or S(O).sub.2; X.sub.1, X.sub.2, and
X.sub.3 are each, independently, N or CR, provided that at least
one of X.sub.1, X.sub.2, or X.sub.3 is CR; R, for each occurrence,
and R.sub.1 are each, independently, H or a substituent; R.sub.6 is
H, an aliphatic group, an aryl group or an aliphatic carbonyl
group; ring A is substituted or unsubstituted; and Ar.sub.1 and
Ar.sub.2 are each, independently, a substituted or unsubstituted
aryl group or a substituted or unsubstituted heteroaryl group.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/443,155, filed May 21, 2003, which claims the benefit of
U.S. Provisional Application No. 60/383,573, filed May 24, 2002,
the contents of which are incorporated herein by this
reference.
BACKGROUND OF THE INVENTION
[0002] Chemokines are a large and growing family of nearly forty
6-14 kD (non-glycosylated) heparin binding proteins that mediate a
wide range of biological functions (Taub, D. D. and Openheim, J.
J., Ther. Immunol., 1:229-246 (1994)). The chemokines can be
divided into families based on the position of four cysteine
residues that form two disulfide bonds (Kelner, G. S. et al.,
Science, 266:12395-1399 (1994); Bazan, J., Nature, 385:640-644
(1997); Pin, Y., et al., Nature, 385:611-617 (1997)). Chemokine
receptors can also be divided into families based on the type of
chemokine they bind, although, no clear structural differences have
been identified that distinguish the receptor sub-families (Mackay,
C. R., J. Exp. Med., 184:799-802 (1996)).
[0003] Chemokines play a vital role in leukocyte adhesion and
extravasation. For example, in various in vitro assays, chemokines
can induce the chemotaxis or transendothelial migration of
leukocytes (Taub, D. D. and Openheim, J. J., Ther. Immunol.,
1:229-246 (1994)), while in vivo injection (Taub, D., J. Clin.
Invest., 97:1931-1941 (1996)) or over-expression of chemokines
(Fuentes, M., J. Immunol., 155:5769-5776 (1995)) can result in
leukocyte accumulation at the site of chemokine injection or
expression. Antagonists of chemokines can prevent leukocyte
trafficking (Bargatze, R. F. and Butcher, E. C., J. Exp. Med.,
178:367-372 (1993)) and may have beneficial effects on acute and
chronic inflammation (Sekido, N., et al., Nature, 365:654-657
(1993); Karpus, W., J. Immunol., 155:5003-5010 (1995)). Chemokines
have also been reported to modulate angiogenesis (Gupta, S. K., et
al., Proc. Natl. Acad. Sci. USA, 92:7799-7803 (1995)),
hematopoiesis (Taub, D. D. and Openheim, J. J., Ther. Immunol.,
1:229-246 (1994)) as well as T lymphocyte activation (Zhou, Z., et
al., J. Immunol. 151:4333-4341 (1993); Taub, D. D., et al., J.
Immunol., 156:2095-2103 (1996)). In addition, several chemokine
receptors act as co-receptors, along with CD4, for entry of M
tropic and T tropic HIV-1 (Choe, H., et al., Cell, 85:1135-1148
(1996); Feng, Y., et al., Science, 272:872-877 (1996)).
[0004] Several subsets of CD4 lymphocytes can be defined based on
their expression of various adhesion molecules that are known to
effect trafficking to different physiologic sites (Mackay, C. R.,
Curr. Opin. Immunol., 5:423-427 (1993)). For example, CLA.sup.+ve
memory CD4 lymphocytes traffic to the skin (Berg, E. L., et al.,
Nature, 174(6):1461-1466 (1991)), while
CLA.sup.-ve.alpha.4.beta.7.sup.+ve memory CD4 lymphocytes traffic
to mucosal sites (Hamman, A., et al., J. Immunol., 152:3282-3292
(1994)). Leukocyte adhesion to endothelium is thought to involve
several overlapping steps including rolling, activation and arrest.
Rolling leukocytes are exposed to factors expressed at the adhesion
site resulting in activation of the leukocyte and up-regulation of
integrin-mediated adhesion. As a consequence of such
integrin-mediated interactions, leukocytes arrest on the
endothelium (Bargatze, R. F. and Butcher, E. C., J. Exp. Med.,
178:367-372 (1993); Bargatze, R. F., et al., Immunity, 3:99-108
(1995)). Leukocyte activation and up-regulation of integrin
molecules occurs via a pertussis toxin sensitive mechanism that is
thought to involve chemokine receptors (Bargatze, R. F. and
Butcher, E. C., J. Exp. Med., 178:367-372 (1993); Campbell, J. J.,
et al., Science, 279:381-383 (1998)).
[0005] Memory CD4.sup.+ lymphocytes can be grouped based upon the
expression of certain chemokine receptors. For example, CXCR3, CCR2
and CCR5 (Qin, S., et al., Eur. J. Immunol., 26:640-647 (1996);
Qin, S., et al., J. Clin. Invest., 101:746-754 (1998); Liao, F., et
al., J. Immunol., 162:186-194 (1999)) are all expressed on subsets
of memory CD4 lymphocytes, and certain chemokines act selectively
on naive T cells (Adema, G. J., et al., Nature, 387:713-717
(1997)). Furthermore, several chemokines which are ligands for such
receptors have been shown to be expressed in inflammatory sites
(Gonzalo, J. A., et al., J. Clin. Invest., 98:2332-2345 (1996)) and
in some cases in lymph nodes draining a challenged site (Tedla, N.,
et al., J. Immunol., 161:5663-5672 (1998)). In vitro derived
T.sub.H1/T.sub.H2 lymphocyte lines have also been shown to
differentially express chemokine receptors. Specifically, T.sub.H1
lymphocytes have been shown to selectively express CXCR3 and CCR5,
while T.sub.H2 lymphocytes selectively express CCR4, CCR8 and CCR3
(Bonecchi, R. G., et al., J. Exp. Med., 187:129-134 (1998);
Sallusto, F. D., et al., J. Exp. Med., 187:875-883 (1998);
Sallusto, F., Science, 277:2005-2007 (1997); Andrew, D. P., et al.,
J. Immunol 161:5027-5038 (1998); Zingoni, A., et al., J. Immunol.,
161:547-555 (1998)). Interestingly, in some cases the chemokines
for these respective chemokine receptors, such as MDC for CCR4 and
IP-10 for CXCR3, are induced by cytokines associated with a
T.sub.H1/T.sub.H2 environment (Andrew, D. P., et al., J. Immunol
161:5027-5038(1998); Luster, A. D., et al., Nature, 315:672-676
(1985)).
SUMMARY OF THE INVENTION
[0006] The present invention relates to compounds represented by
Structural Formula I, and pharmaceutically acceptable salts,
solvates, and hydrates of such compounds: ##STR1##
[0007] In Structural Formula I, Y is C(O), O, S, S(O) or
S(O).sub.2; X.sub.1, X.sub.2, and X.sub.3 are each, independently,
N or CR, provided that at least one of X.sub.1, X.sub.2, or X.sub.3
is CR; R, for each occurrence, and R.sub.1 are each, independently,
H or a substituent. In preferred embodiments, the substituents at
positions R and R.sub.1 are each, independently, an aliphatic
group, haloalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, haloalkoxy,
aryloxy, arylalkoxy, alkylthio, halo, nitro, cyano, sulonamido,
sulfone, sulfoxide, hydroxy, NR.sub.11CO.sub.2R.sub.12,
C(O)N(R.sub.11).sub.2, C(O)R.sub.12, CO.sub.2R.sub.12,
OC(O)N(R.sub.11).sub.2, OC(O)R.sub.12, N(R.sub.11).sub.2, or
NR.sub.11C(O)R.sub.12. R.sub.11 and R.sub.12 are defined further
herein; R.sub.6 is H, an aliphatic carbonyl group, or an aliphatic
ester; and Ar.sub.1 and Ar.sub.2 are each, independently, a
substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group. Preferably, Ar.sub.1 is a
substituted or unsubstituted phenyl, a substituted or unsubstituted
pyridyl, a substituted or unsubstituted pyrimidinyl, or a
substituted or unsubstituted pyrazinyl. Preferably, Ar.sub.2 is a
substituted or unsubstituted phenyl, or a substituted or
unsubstituted pyridyl. More preferably, Ar.sub.1 is a substituted
phenyl and Ar.sub.2 is substituted pyridyl. Ring A is substituted
or unsubstituted.
[0008] In a preferred embodiment, compounds of the invention are
represented by Structural Formula II: ##STR2##
[0009] In Structural Formula II, X.sup.4 is N, N.sup.+--O.sup.-, or
CR; and ring A, ring B, and ring C are each, independently,
substituted or unsubstituted. R is H or a substituent. Examples of
substituents for R are defined as in Structural Formula I.
[0010] In a more preferred embodiment, compounds of the invention
are represented by Structural Formula III: ##STR3##
[0011] In Structural Formula III, X.sub.4 is N, N.sup.+--O.sup.- or
CR; ring A, ring B, and ring C are each, independently, substituted
or unsubstituted, and R is H or a substituent. Examples of
substituents for R are defined as in Structural Formula I; and
R.sub.8 is H or an electron withdrawing group. Preferably, R.sub.8
is a halo, nitro, alkylcarbonyl or trihaloalkyl. More preferably,
R.sub.8 is Cl, Br or NO.sub.2.
[0012] In another preferred embodiment, compounds of the invention
are represented by Structural Formula IV. ##STR4##
[0013] In Structural Formula IV, Ar.sub.1, Ar.sub.2, R.sub.1 and
R.sub.6 are defined as in Structural Formula I; and R.sub.19 and
R.sub.20 are each, independently, H or a substituent. Examples of
substituents in the R.sub.19 and R.sub.20 positions include an
aliphatic group, a haloalkyl group, an ester, an amide,
alkylcarbonyl, a halogen, COOH, NO.sub.2, alkoxy, haloalkoxy, CN,
amino, and aminoalkyl.
[0014] In another preferred embodiment, compounds of the invention
are represented by Structural Formula V. ##STR5##
[0015] In Structural Formula V, X.sub.4 is CR, N or
N.sup.+--O.sup.-; X.sub.1, X.sub.2, X.sub.3, R, and Ar.sub.2 are
defined as in Structural Formula I; R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, are, independently, H, an aliphatic group, a
haloalkyl group, a halo, COOH, NO.sub.2, or an alkoxy, a
haloalkoxy.
[0016] In a more preferred embodiment, compounds of the invention
are represented by Structural Formula VI. ##STR6##
[0017] In Structural Formula VI, X.sub.1 is defined as in
Structural Formula I; X.sub.4 is defined as in Structural Formula
V; R.sub.8 is H or an electron withdrawing group; m and n are each,
independently, 0 or an integer from 1 to 3; each R.sub.9 is,
independently, aliphatic group, haloalkyl, aryl, arylalkyl, alkoxy,
cycloalkoxy, haloalkoxy, aryloxy, arylalkoxy, alkylthio, halo,
nitro, cyano, hydroxy, NR.sub.11CO.sub.2R.sub.12,
C(O)N(R.sub.11).sub.2, C(O)R.sub.12, CO.sub.2R.sub.12,
OC(O)N(R.sub.11).sub.2, OC(O)R.sub.12, N(R.sub.11).sub.2, or
NR.sub.11C(O)R.sub.12; or two adjacent R.sub.9 groups taken
together with the atoms to which they are attached form a fused,
saturated, unsaturated or partially unsaturated 5 to 7 membered
ring having 0, 1, or 2 heteroatoms selected from N, O, and S; each
R.sub.10 is, independently, halo, aliphatic group, alkoxy, or
haloalkyl; or two adjacent R.sub.10 groups taken together with the
atoms to which they are attached form a fused, saturated,
unsaturated or partially unsaturated 5 to 7 membered ring having 0,
1 or 2 heteroatoms selected from N, O, and S; each R.sub.1 is,
independently, selected from H or an aliphatic group; and R.sub.12
is an aliphatic group.
[0018] In another preferred embodiment, compounds of the invention
are represented by Structural Formula VII. ##STR7##
[0019] In Structural Formula VII, ring B is substituted or
unsubstituted; X.sub.1 is defined as in Structural Formula I;
R.sub.8 is defined as in Structural Formula VI; p is 0 or an
integer from 1-3; and each R.sub.13 is, independently, a halo or a
substituted or unsubstituted heteroaryl.
[0020] In another preferred embodiment, compounds of the invention
are represented by Structural Formula VIII. ##STR8##
[0021] In Structural Formula VIII, ring A, Ar.sub.1, Ar.sub.2,
X.sub.1, R.sub.1, R.sub.6 are defined as in Structural Formula I;
R.sub.19 and R.sub.20 are defined as in Structural Formula IV; and
Y.sub.1 is S, O, S(O), or S(O).sub.2.
[0022] The present invention provides a method of inhibiting a CCR9
receptor by contacting the receptor with an effective amount of a
compound of the present invention, and/or pharmaceutically
acceptable salts, solvates and hydrates thereof.
[0023] In one embodiment, the invention provides a method of
inhibiting CCR9-mediated homing of leukocytes in a subject by
administering to the subject an effective amount of a compound of
the present invention, and/or pharmaceutically acceptable salts,
solvates and hydrates thereof. In a preferred embodiment, the
method inhibits homing of leukocytes to mucosal tissue.
[0024] In another embodiment, the invention provides a method of
treating a subject having a disease that is mediated by a CCR9
receptor, such as an inflammatory disease, for example Celiac's
disease or an inflammatory bowel disease, by administering to the
subject an effective amount of a compound of the present invention,
and/or pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0025] The present invention provides a pharmaceutical composition
having a pharmaceutically acceptable carrier and at least one
compound of the present invention.
[0026] Chemokines and their associated receptors (e.g., TECK and
CCR9, respectively) are proinflammatory mediators that promote
recruitment and activation of multiple lineages of leukocytes and
lymphocytes. Continuous release of chemokines at sites of
inflammation mediates the ongoing migration of effector cells in
chronic inflammation. CCR9 and its associated chemokine TECK, have
been implicated in chronic inflammatory diseases, such as
inflammatory bowel diseases. Small molecule inhibitors of the
interaction between CCR9 and its ligands (e.g., TECK), such as the
compounds of the invention, are useful for inhibiting harmful
inflammatory processes triggered by receptor-ligand interactions
and thus are useful for treating diseases mediated by CCR9, such as
chronic inflammatory diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The term "aliphatic" as used herein means straight-chain,
branched or cyclic C.sub.1-C.sub.12 hydrocarbons which are
completely saturated or which contain one or more units of
unsaturation but which are not aromatic. For example, suitable
aliphatic groups include substituted or unsubstituted linear,
branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", and "alkylthio",
used alone or as part of a larger moiety includes both straight and
branched chains containing one to twelve carbon atoms. The terms
"alkenyl" and alkynyl" used alone or as part of a larger moiety
shall include both straight and branched chains containing two to
twelve carbon atoms. The term "cycloalkyl" used alone or as part of
a larger moiety shall include cyclic C.sub.3-C.sub.12 hydrocarbons
which are completely saturated or which contain one or more units
of unsaturation, but which are not aromatic.
[0028] As used herein, aryl groups are carbocyclic aromatic ring
systems (e.g. phenyl), fused polycyclic aromatic ring systems (e.g.
naphthyl and anthracenyl) and aromatic ring systems fused to
carbocyclic non-aromatic ring systems (e.g.,
1,2,3,4-tetrahydronaphthyl) having six to about fourteen carbon
atoms.
[0029] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means
alkyl, alkenyl or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br or I.
[0030] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic
ring groups having five to fourteen members, such as phenyl,
benzyl, phenethyl, 1-napthyl, 2-naphthyl, 1-anthracyl and
2-anthracyl. The term "aryl" also refers to rings that are
optionally substituted. The term "aryl" may be used interchangeably
with the term "aryl ring". "Aryl" also includes fused polycyclic
aromatic ring systems in which an aromatic ring is fused to one or
more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl
and 2-anthracyl. Also included within the scope of the term "aryl",
as it is used herein, is a group in which an aromatic ring is fused
to one or more non-aromatic rings, such as in an indanyl,
phenantriidinyl, or tetrahydronaphthyl, where the radical or point
of attachment is on the aromatic ring.
[0031] The term "heteroatom" means nitrogen, oxygen, or sulfur and
includes any oxidized form of nitrogen and sulfur, and the
quaternized form of any basic nitrogen. Also the term "nitrogen"
includes a substitutable nitrogen of a heterocyclic ring. As an
example, in a saturated or partially unsaturated ring having 0-3
heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen
may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl)
or NR.sub.18 (as in N-substituted pyrrolidinyl).
[0032] The term "heterocycle", as used herein includes non-aromatic
ring systems having five to fourteen members, preferably five to
ten, in which one or more ring carbons, preferably one to four, are
each replaced by a heteroatom such as N, O, or S. Examples of
heterocyclic rings include 3-1H-benzimidazol-2-one,
3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,
4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,
[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,
2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,
3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl,
2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
4-thiazolidinyl, diazolonyl, N-substituted diazolonyl,
1-pthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl,
benzoxolanyl, benzothiolanyl, and benzothianyl. Also included
within the scope of the term "heterocycle", as it is used herein,
is a group in which a non-aromatic heteroatom-containing ring is
fused to one or more aromatic or non-aromatic rings, such as in an
indolinyl, chromanyl, phenantrhidinyl, or tetrahydroquinolinyl,
where the radical or point of attachment is on the non-aromatic
heteroatom-containing ring. The term "heterocycle", whether
saturated or partially unsaturated, also refers to rings that are
optionally substituted.
[0033] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
heteroaromatic ring groups having five to fourteen members.
Examples of heteroaryl rings include 2-furanyl, 3-furanyl,
N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,
5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,
3-thienyl, thianaphthenyl, carbazolyl, benzimidazolyl,
benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl,
benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl,
indolyl, isoindolyl, acridinyl, or benzoisazolyl. Also included
within the scope of the term "heteroaryl", as it is used herein, is
a group in which a heteroatomic ring is fused to one or more
aromatic or nonaromatic rings where the radical or point of
attachment is on the heteroaromatic ring. Examples include
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3,4-d]
pyrimidinyl. The term "heteroaryl" also refers to rings that are
optionally substituted. Preferred heteroaryl groups are thienyl,
benzo(b)thienyl, pyrrolyl, indolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, furanyl, and benzo(b)furanyl. More
preferred heteroaryl groups are pyridyl and thienyl.
[0034] An arylalkyl group, as used herein, is an aryl substituent
that is linked to a compound by an alkyl group having from one to
twelve carbon atoms.
[0035] An alkoxy group, as used herein, is a C.sub.1-C.sub.12 alkyl
group that is connected to a compound via an oxygen atom. Examples
of alkoxy groups include but are not limited to methoxy, ethoxy,
propoxy, isopropoxy, and t-butoxy.
[0036] A cycloalkoxy group, as used herein, is a cyclic
C.sub.3-C.sub.12 hydrocarbon which is attached to a compound via an
oxygen. Cycloalkoxy groups include but are not limited to
cyclopropoxy and cyclobutoxy.
[0037] A haloalkoxy, as used herein, is a haloalkyl group that is
attached to a compound via an oxygen. A preferred haloalkoxy is
trifluoromethoxy.
[0038] An aryloxy, as used herein, is an aryl group that is
attached to a compound via an oxygen. A preferred aryloxy is
phenoxy.
[0039] A arylalkoxy group, as used herein, is a arylalkyl group
that is attached to a compound via an oxygen on the
C.sub.1-C.sub.12 alkyl portion of the arylalkyl. A preferred
arylalkoxy is phenylmethoxy.
[0040] An alklythio group, as used herein, is a C.sub.1-C.sub.12
alkyl group that is connected to a compound via a sulfur atom.
[0041] A aliphatic carbonyl group, as used herein, is an aliphatic
group that is connected to a compound via a carbonyl group. A
preferred aliphatic carbonyl is acetyl.
[0042] A aliphatic ester group, as used herein, an aliphatic group
that is connected to a compound via an ester linkage (i.e.,
--C(O)O-aliphatic group).
[0043] An electron withdrawing group is a group which causes a
dipole moment in the direction of the group. Suitable electron
withdrawing groups include but are not limited to halo (preferably
chloro), haloalkyl (preferably trifluoromethyl), nitro, cyano,
sulfonamido, sulfone, and sulfoxide.
[0044] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) may contain one or more substituents. Examples of
suitable substituents include aliphatic groups, aryl groups,
haloalkoxy groups, heteroaryl groups, halo, hydroxy, OR.sub.14,
COR.sub.14, COOR.sub.14, NHCOR.sub.14, OCOR.sub.14, benzyl,
haloalkyl (e.g., trifluoromethyl and trichloromethyl), cyano,
nitro, S(O),S(O).sub.2, SO.sub.3.sup.-, SH, SR.sub.14, NH.sub.2,
NHR.sub.14, NR.sub.14R.sub.15, NR.sub.6S(O).sub.2--R.sub.7, and
COOH, wherein R.sub.14 and R.sub.15 are each, independently, an
aliphatic group, a cycloalkyl, an aryl group, or an arylalky group.
Other substituents for an aryl or heteroaryl group include
--R.sub.16, --OR.sub.16, --SR.sub.16, 1,2-methylene-dioxy,
1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph),
substituted Ph, --O(Ph), substituted --O(Ph), --CH.sub.2(Ph),
substituted --CH.sub.2CH.sub.2(Ph), substituted
--CH.sub.2CH.sub.2(Ph), --N(R.sub.16).sub.2,
--NR.sub.16CO.sub.2R.sub.16, --NR.sub.16NR.sub.16C(O)R.sub.16,
--NR.sub.16R.sub.16C(O)N(R.sub.16).sub.2,
--NR.sub.16NR.sub.16CO.sub.2R.sub.16, --C(O)C(O)R.sub.16,
--C(O)CH.sub.2C(O)R.sub.16, --CO.sub.2R.sub.16, --C(O)R.sub.16,
--C(O)N(R.sub.16).sub.2, --OC(O)N(R.sub.16).sub.2,
--S(O).sub.2R.sub.16, --SO.sub.2N(R.sub.16).sub.2, --S(O)R.sub.16,
--NR.sub.16SO.sub.2N(R.sub.16).sub.2, --NR.sub.16SO.sub.2R.sub.16,
--C(.dbd.S)N(R.sub.16).sub.2, --C(.dbd.NH)--N(R.sub.16).sub.2,
--(CH.sub.2).sub.yNHC(O)R.sub.16,
--(CH.sub.2).sub.yNHC(O)CH(V--R.sub.16)(R.sub.16); wherein R.sub.16
is hydrogen, a substituted or unsubstituted heteroaryl or
heterocyclic ring, phenyl (Ph), substituted Ph, --O(Ph),
substituted --O(Ph), --CH.sub.2 (Ph), or substituted --CH.sub.2
(Ph); y is 0-6; and V is a linker group. Preferred substituents on
the aryl or heteroaryl group include halo, haloalkyl, sulfone,
sulfoxide, nitro, cyano, alkyl group, alkoxy group, and alkylamino
group. Examples of substituents on the aliphatic group or the
phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl,
halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro,
cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy,
or haloalkyl. Substituents for an aryl or a heteroaryl group
include aryl groups (including a carbocyclic aryl group or a
heteroaryl group), aliphatic groups, cycloalkyl groups, haloalkoxy
groups, heteroaryl groups, hydroxy, OR.sub.14, aldehyde,
COR.sub.14, COOR.sub.14, NHCOR.sub.14, OCOR.sub.14, benzyl,
haloalkyl (e.g., trifluoromethyl and trichloromethyl), halo, cyano,
nitro, SO.sub.3--, SH, SR.sub.14, NH.sub.2, NHR.sub.14,
NR.sub.14R.sub.15, NR.sub.6S(O).sub.2--R.sub.7, or COOH, wherein
R.sub.14 and R.sub.15 are each, independently, an aliphatic group,
a cycloalkyl, an aryl group, or an arylalky group.
[0045] An aliphatic group or a heterocycle may contain one or more
substituents. Examples of suitable substituents on the saturated
carbon of an aliphatic group of a heterocycle include those listed
above for an aryl or heteroaryl group and the following: .dbd.o,
.dbd.S, .dbd.NNHR.sub.17, .dbd.NN(R.sub.17).sub.2,
.dbd.NNHC(O)R.sub.17, .dbd.NNHCO.sub.2(alkyl),
.dbd.NNHSO.sub.2(alkyl), or .dbd.NR.sub.17, where each R.sub.17 is
independently selected from hydrogen, an unsubstituted aliphatic
group or a substituted aliphatic group. Examples of substituents on
the aliphatic group include amino, alkylamino, dialkylamino,
aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxy, thioalkyl, nitro, cyano, carboxy,
alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or
haloalkyl.
[0046] Suitable substitutents on the nitrogen of a non-aromatic
heterocycle or on an unsaturated nitrogen of a heteroaryl include
--R.sub.18, --N(R.sub.18).sub.2, --C(O)R.sub.18,
--CO.sub.2R.sub.18, --C(O)C(O)R.sub.18, --C(O)CH.sub.2C(O)R.sub.18,
--SO.sub.2R.sub.18, --SO.sub.2N(R.sub.8).sub.2,
--C(.dbd.S)N(R.sub.18).sub.2, --C(.dbd.NH)--N(R.sub.18).sub.2, and
--NR.sub.18SO.sub.2R.sub.18; wherein R.sub.18 is hydrogen, an
aliphatic group, a substituted aliphatic group, phenyl (Ph),
substituted Ph, --O(Ph), substituted --O(Ph), --CH.sub.2(Ph), or an
unsubstituted heteroaryl or heterocyclic ring. Examples of
substituents on the aliphatic group or the phenyl ring include
amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,
alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,
carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or
haloalkyl.
[0047] The term "linker group" or "linker" means an organic moiety
that connects two parts of a compound. Linkers are typically
comprised of an atom, such as oxygen or sulfur, a unit, such as
--NH--, --CH.sub.2--, --C(O)--, or --C(O)NH--, or a chain of atoms,
such as an alkylene chain. The molecular mass of a linker is
typically in the range of about 14 to 200, preferably in the range
of 14 to 96 with a length of up to about six atoms. Examples of
linkers include a saturated or unsaturated C.sub.1-C.sub.6 alkylene
chain which is substituted or unsubstituted, and wherein one or two
saturated carbons of the chain are optionally replaced by --C(O)--,
--C(O)C(O)--, --CONH--, --CONHNH--, --CO.sub.2--, --OC(O)--,
--NHCO.sub.2--, --O--, --NHCONH--, --OC(O)NH--, --NHNH--, --NHCO--,
--S--, --SO--, --SO.sub.2--, --NH--, --SO.sub.2NH--, or
--NHSO.sub.2--.
[0048] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention. Unless otherwise stated, structures depicted herein are
also meant to include all stereochemical forms of the structure;
i.e., the R and S configurations for each asymmetric center.
Therefore, single stereochemical isomers as well as enantiomeric
and diastereomeric mixtures of the present compounds are within the
scope of the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which differ
only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structure except for the
replacement of a hydrogen by a deuterium or tritium, or the
replacement of a carbon by a .sup.13C- or .sup.14C-enriched carbon
are within the scope of this invention.
[0049] The compounds of the present invention have IC50s of less
than 1 .mu.m; less than 750 nm; preferably less than 500 nm; more
preferably less than 250 nm; even more preferably less than 100 nm,
most preferably less than 50 nm; and the most preferable less than
10 nm, e.g., less than 5 nm.
[0050] As used herein "mammalian CCR9" refers to naturally
occurring or endogenous mammalian CCR9 proteins and to proteins
having an amino acid sequence which is the same as that of a
naturally occurring or endogenous corresponding mammalian CCR9
protein (e.g., recombinant proteins, synthetic proteins (i.e.,
produced using the methods of synthetic organic chemistry)).
Accordingly, as defined herein, the term includes mature receptor
protein, polymorphic or allelic variants, and other isoforms of a
mammalian CCR9 (e.g., produced by alternative splicing or other
cellular processes), and modified or unmodified forms of the
foregoing (e.g., lipidated, glycosylated, unglycosylated).
Naturally occurring or endogenous mammalian CCR9 proteins (see
e.g., GenBank Accession Numbers NM.sub.--031200 and U45982 and Yu
et al. (2000) J. Immunol. 164:1293-1305 which describe various
forms of naturally occurring mammalian CCR9) include wild type
proteins such as mature CCR9, polymorphic or allelic variants and
other isoforms which occur naturally in mammals (e.g., humans,
non-human primates). Such proteins can be recovered or isolated
from a source which naturally produces mammalian CCR9, for example.
Polymorphic, allelic, splice and other naturally occurring variants
of mammalian CCR9 can be expressed in particular organs, tissues or
cells and have altered properties (e.g., altered affinity for
ligand (e.g. TECK)) and specialized biological function (e.g., T
cell development, T cell recruitment). Naturally occurring or
endogenous mammalian CCR9 proteins and proteins having the same
amino acid sequence as a naturally occurring or endogenous
corresponding mammalian CCR9, are referred to by the name of the
corresponding mammal. For example, where the corresponding mammal
is a human, the protein is designated as a human CCR9 protein
(e.g., a recombinant human CCR9 produced in a suitable host
cell).
[0051] As used herein "mammalian TECK" refers to naturally
occurring or endogenous mammalian TECK proteins and to proteins
having an amino acid sequence which is the same as that of a
naturally occurring or endogenous corresponding mammalian TECK
protein (e.g., recombinant proteins, synthetic proteins (i.e.,
produced using the methods of synthetic organic chemistry)).
Accordingly, as defined herein, the term includes mature receptor
protein, polymorphic or allelic variants, and other isoforms of a
mammalian TECK (e.g., produced by alternative splicing or other
cellular processes), and modified or unmodified forms of the
foregoing (e.g., lipidated, glycosylated, unglycosylated).
Naturally occurring or endogenous mammalian TECK proteins (see
e.g., GenBank Accession Number U86358 and Vicari et al. (1997)
Immunity 7:291-301 which describe naturally occurring mammalian
TECK) include wild type proteins such as mature TECK, polymorphic
or allelic variants and other isoforms which occur naturally in
mammals (e.g., humans, non-human primates). Such proteins can be
recovered or isolated from a source which naturally produces
mammalian TECK, for example.
[0052] The term "pharmaceutically acceptable" means that the
carrier, diluent, excipients and salt must be compatible with the
other ingredients of the formulation, and not deleterious to the
recipient thereof. Pharmaceutical formulations of the present
invention are prepared by procedures known in the art using well
known and readily available ingredients.
[0053] "Preventing" refers to reducing the likelihood that the
recipient will incur or develop any of the pathological conditions
described herein, for example inhibiting the onset of these
symptoms.
[0054] "Treating" refers to eliminating or reducing the severity of
a pathological condition described herein and/or eliminating,
alleviating and/or reducing the symptoms of a pathological
condition described herein.
[0055] Compounds of the invention can be used to treat a subject
having an inflammatory disease. In one embodiment, the method is a
method of inhibiting a CCR9 function in a subject. In particular
embodiments, the method is a method of treating a subject having an
inflammatory disease associated with mucosal tissue, such as
Crohn's disease, colitis, or Celiac disease. In another embodiment,
the method is a method of inhibiting CCR9-mediated homing of
leukocytes in a subject. See Papadakis, et al., Gastroenterology
(2001), 121:246-254 for a discussion of the relationship of CCR9
receptors to the above diseases or conditions.
[0056] In one embodiment, the compounds of the invention are
represented by any one of Structural Formulas IX-XXIV: ##STR9##
##STR10## ##STR11##
[0057] In Structural Formulas IX-XXV, Ar.sub.2 and Y are defined as
in Structural Formula I; and rings A and B are substituted or
unsubstituted.
[0058] In another embodiment of the invention, compounds used in
the method of the invention and in pharmaceutical compositions of
the invention are represented by Structural Formula XXVI or XXVII:
##STR12##
[0059] In Structural Formulas XXVI and XXVII, R.sub.8 is defined as
in Structural Formula V, and R.sub.13 and p are defined as in
Structural Formula VII.
[0060] In a first preferred embodiment of the invention, Y in
Structural Formula I, or IX-XXIV is C.dbd.O.
[0061] In a second preferred embodiment, ring C in Structural
Formula II or III or Ar.sub.2 in Structural Formula I, IV, V or in
any one of Structural Formulas IX-XXV is unsubstituted or
substituted with one or more substituents selected from aliphatic
group (including substituted aliphatic groups such as haloalkyl)
aryl, arylalkyl, alkoxy (including cycloalkoxy and substituted
alkoxy groups such as haloalkoxy), aryloxy, arylalkoxy, alkylthio,
halo, nitro, cyano, S(O)-(aliphatic), S(O).sub.2-(aliphatic),
NR.sub.11S(O).sub.2-(aliphatic), C(O)N(R.sub.11).sub.2,
C(O)R.sub.12, N(R.sub.11).sub.2, NR.sub.11C(O).sub.2R.sub.12 and
NR.sub.11C(O)R.sub.12, wherein R.sub.11, for each occurrence is,
independently, H or an aliphatic group, and R.sub.12 is an
aliphatic group. More preferred substitutents for ring C or R.sub.7
are selected from an aliphatic group, an alkoxy, and a
haloalkoxy.
[0062] In a third preferred embodiment, ring A in Structural
Formula I or IV, or one or both rings A and B in Structural Formula
II or III or in any one of Structural Formulas IX-XXV are,
independently, substituted with a stubstituent selected from halo,
aliphatic group, alkoxy, and haloalkyl.
[0063] In a fourth preferred embodiment, ring A in Structural
Formula I, II, III, IV, V, VI, VII, VIII, or in any one of
Structural Formulas IX-XXV is substituted with an electron
withdrawing substituent para to the sulfonamide group.
[0064] In a fifth preferred embodiment of the invention, X.sub.3 in
Structural Formula V is CR.sub.21, wherein R.sub.21 is an electron
withdrawing group. More preferably, R.sub.21 is halo, nitro,
aliphatic carbonyl, or trihalomethyl. Most preferably, R.sub.21 is
Cl, Br, or nitro.
[0065] In a sixth preferred embodiment of the invention, Ar.sub.2
in Structural Formula I, IV, V, VIII or in any one of Structural
Formulas IX-XXV is a substituted or unsubstituted phenyl, a
substituted or unsubstituted naphthyl, a substituted or
unsubstituted thienyl, or a substituted or unsubstituted
thianaphthenyl. More preferably, Ar.sub.2 is a substituted or
unsubstituted phenyl or a substituted or unsubstituted thienyl.
[0066] In a seventh preferred embodiment of the invention, R.sub.9
for each occurrence in Structural Formula VI is, independently, an
aliphatic group, an alkoxy, or a haloalkoxy.
[0067] In an eighth preferred embodiment of the invention, R.sub.8
in Structural Formula I, VI, VII, VII, XXV and XXVI is a halo,
nitro, alkylcarbonyl or trihaloalkyl. More preferably, R.sub.8 is
Cl, Br or NO.sub.2.
[0068] In an ninth preferred embodiment of the invention, Y and
Ar.sub.2 in Structural Formula I and VIII or in any one of
Structural Formulas IX-XXV are defined as in the first and the
sixth preferred embodiments, respectively.
[0069] In a tenth preferred embodiment of the invention, Ar.sub.2
Structural Formula V is defined as in the sixth preferred
embodiments, and X.sub.3 is defined as in the fifth preferred
embodiment.
[0070] In an eleventh preferred embodiment, X.sub.4 in Structural
Formulas V or VI is an nitrogen oxide (N.sup.+--O.sup.-).
[0071] In a twelfth preferred embodiment, n is one in Structural
Formula VI and R.sub.9 is para to the sulfonamide substituent. More
preferably, R.sub.9 is as defined in seventh preferred
embodiment.
[0072] In a thirteen preferred embodiment, m is one in Structural
Formula VI and R.sub.10 is meta to the carbonyl substituent.
[0073] In a fourteenth preferred embodiment, R.sub.6 in Structural
Formula I, IV, or VIII is H.
[0074] Specific examples of compounds used in the method of the
invention and in pharmaceutical compositions of the invention
include but are not limited to the compounds listed in Table 1.
Pharmaceutically acceptable salts, solvates and hydrates of the
compounds listed in Table 1 are also useful in the method of the
invention and in pharmaceutical compositions of the invention.
TABLE-US-00001 TABLE 1 Specific compounds of the invention Example
Compound Name 7
N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
8 Thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide 9
N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide 10
N-(2-Benzoyl-4-chloro-phenyl)-4-chloro-benzenesulfonamide 11
N-(2-Benzoyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide 12
N-(2-Benzoyl-4-chloro-phenyl)-4-propyl-benzenesulfonamide 13
N-(2-Benzoyl-4-chloro-phenyl)-4-ethyl-benzenesulfonamide 14
N-(2-Benzoyl-4-nitro-phenyl)-4-ethyl-benzenesulfonamide 15
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropyl-benzenesulfonamide 16
N-(2-Benzoyl-4-bromo-phenyl)-4-ethyl-benzenesulfonamide 17
N-(2-Benzoyl-4-bromo-phenyl)-4-methoxy-benzenesulfonamide 18
N-(2-Benzoyl-4-bromo-phenyl)-4-isopropyl-benzenesulfonamide 19
4-Ethyl-N-[4-nitro-2-(3-trifluoromethyl-benzoyl)-phenyl]-
benzenesulfonamide 20
N-[4-Chloro-2-(3-methyl-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
21 N-(2-Benzoyl-4-bromo-phenyl)-4-chloro-benzenesulfonamide 22
N-(2-Benzoyl-4-chloro-phenyl)-4-ethoxy-benzenesulfonamide 23
N-(2-Benzoyl-4-chloro-phenyl)-4-propoxy-benzenesulfonamide 24
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide 25
N-(2-Benzoyl-4-chloro-phenyl)-4-butoxy-benzenesulfonamide 26
N-(2-Benzoyl-4-chloro-phenyl)-4-benzyloxy-benzenesulfonamide 27
N-(2-Benzoyl-4-chloro-phenyl)-4-phenoxy-benzenesulfonamide 31
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
32
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfonamide
33 N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-
bezenesulfonamide 34
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesulfonami-
de 35 N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-ethoxy-
benzenesulfonamide 36
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-isopropoxy-
benzenesulfonamide 45
N-(3-Benzoyl-5-trifluoromethyl-pyridin-2-yl)-4-isopropoxy-
benzenesulfonamide 46
N-(2-Benzoyl-4-nitro-phenyl)-4-chloro-benzenesulfonamide 47
5-Benzoyl-6-(4-isopropoxy-benzenesulfonylamino)-nicotinic acid 48
N-(2-Benzoyl-4-chloro-phenyl)-2-nitro-benzenesulfonamide 49
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
50 N-(5-Benzoyl-pyrimidin-4-yl)-4-isopropoxy-benzenesulfonamide 51
N-(3-Benzoyl-5-trifluoromethoxy-pyridin-2-yl)-4-isopropoxy-
benzenesulfonamide 52
N-(5-Benzoyl-2-trifluoromethyl-pyrimidin-4-yl)-4-isopropoxy-
benzenesulfonamide 53
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropoxy-benzenesulfonamide
54
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclobutyl-benzenesulfonamide
55
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-tert-butoxy-benzenesulfonamide
56
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopentyl-benzenesulfonamide
57 N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylsulfanyl-
benzenesulfonamide 58
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropylamino-benzenesulfonamide
59
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclopropyl-benzenesulfonamide
60
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-cyclohexyl-benzenesulfonamide
61 N-(3-Benzenesulfinyl-5-chloro-pyridin-2-yl)-4-isopropoxy-
benzenesulfonamide 62
N-(3-Benzenesulfonyl-5-chloro-pyridin-2-yl)-4-isopropoxy-
benzenesulfonamide 63
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-
benzenesulfonamide 64
N-[4-Chloro-2-(pyridazine-4-carbonyl)-phenyl]-4-isopropoxy-
benzenesulfonamide 65
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-
isopropoxy-benzenesulfonamide 66
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-
isopropoxy-benzenesulfonamide 67
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-
isopropoxy-benzenesulfonamide 68
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4-
isopropoxy-benzenesulfonamide 69
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropyl-benzenesulfonamide 70
N-(2-Benzoyl-4-nitro-phenyl)-4-isopropoxy-benzenesulfonamide 71
N-(2-Benzoyl-4-nitro-phenyl)-4-methoxy-benzenesulfonamide 72
N-(2-Benzoyl-4-chloro-phenyl)-4-trifluoromethoxy-benzenesulfonamide
73 5-Oxazol-5-yl-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide 74
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
75 N-(2-Benzoyl-4-chloro-phenyl)-4-methoxy-benzenesulfonamide 76
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
77 N-(2-Benzoyl-4-chloro-phenyl)-4-ethylamino-benzenesulfonamide 78
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic
acid (2- benzoyl-4-chloro-phenyl)-amide 79
N-(2-Benzoyl-4-iodo-phenyl)-4-isopropoxy-benzenesulfonamide 80
N-[4-Chloro-2-(3-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
81
N-[4-Chloro-2-(3-chloro-benzoyl)-phenyl]-4-isopropyl-benzenesulfonamide
82 N-(2-Benzoyl-4-chloro-phenyl)-4-nitro-benzenesulfonamide 83
N-(2-Benzoyl-4-chloro-phenyl)-4-diethylamino-benzenesulfonamide 84
N-(2-Benzoyl-4-fluoro-phenyl)-4-methoxy-benzenesulfonamide 85
4-Chloro-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
86 N-(2-Benzoyl-4-bromo-phenyl)-4-methyl-benzenesulfonamide 87
N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide 88
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamid-
e 89
N-(2-Benzoyl-4-chloro-phenyl)-4-dimethylamino-benzenesulfonamide 90
N-(2-Benzoyl-4-chloro-phenyl)-4-fluoro-benzenesulfonamide 91
4-Chloro-N-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-benzenesulfonamide
92
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methoxy-benzenesulfonamide
93 Thiophene-3-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide 94
5-Bromo-thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
95 5-Chloro-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide 96
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
97
N-[4-Chloro-2-(2-fluoro-benzoyl)-phenyl]-4-methyl-benzenesulfonamide
98
4-Chloro-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide
99 N-(2-Benzoyl-4-chloro-phenyl)-benzenesulfonamide 100
N-[4-(2-Benzoyl-4-chloro-phenylsulfamoyl)-phenyl]-acetamide 101
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonami-
de 102
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methyl-benzenesulfonamid-
e 103 N-(2-Benzoyl-4-chloro-phenyl)-4-cyano-benzenesulfonamide 104
4,5-Dibromo-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide 105
N-[4-Chloro-2-(pyridine-3-sulfonyl)-phenyl]-4-nitro-benzenesulfonamide
106 Naphthalene-2-sulfonic acid
[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-amide 107
N-(2-Benzoyl-4-chloro-phenyl)-3-bromo-benzenesulfonamide 108
N-(2-Benzoyl-4-chloro-phenyl)-4-methyl-3-nitro-benzenesulfonamide
109
N-[4-Chloro-2-(2-methoxy-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
110
N-(2-Benzoyl-4-chloro-phenyl)-2-trifluoromethyl-benzenesulfonamide
111 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid
(2-benzoyl-4-chloro- phenyl)-amide 112
N-(2-Benzoyl-phenyl)-4-nitro-benzenesulfonamide 113
5-Isoxazol-3-yl-thiophene-2-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide 114
N-(2-Benzoyl-phenyl)-4-methyl-benzenesulfonamide 115
Benzo[b]thiophene-3-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
116
N-(4-Chloro-2-phenylsulfanyl-phenyl)-4-isopropoxy-benzenesulfonamide
117
N-(2-Benzenesulfonyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
118 N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-
benzenesulfonamide 119
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-
benzenesulfonamide 120
4-Isopropoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-
benzenesulfonamide 121
4-Ethoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-
benzenesulfonamide 122
N-[5-Chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]-4-isopropyl-
benzenesulfonamide 123
N-[5-Chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-
benzenesulfonamide 124
N-[5-Chloro-3-(thiophene-2-carbonyl)-pyridin-2-yl]-4-isopropoxy-
benzenesulfonamide 125 5-Oxazol-5-yl-thiophene-2-sulfonic acid
[5-chloro-3-(3-fluoro-benzoyl)- pyridin-2-yl]-amide 126
N-[3-(Benzofuran-2-carbonyl)-5-chloro-pyridin-2-yl]-4-isopropoxy-
benzenesulfonamide 127
N-(2-Benzoyl-4-trifluoromethyl-phenyl)-4-isopropoxy-benzenesulfonamide
128 N-(3-Benzoyl-pyridin-4-yl)-4-isopropoxy-benzenesulfonamide 129
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropyl-benzenesulfonamide
130
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
131 5-Oxazol-5-yl-thiophene-2-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)- amide 132
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropylamino-benzenesulfonamide
133 N-(4-Benzoyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide 134
N-(4-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide 135
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropyl-benzenesulfonamide
136 N-(2-Benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide 137
N-[3-(3-Fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-benzenesulfonamide
138
N-[4-Chloro-2-(pyridin-3-yloxy)-phenyl]-4-isopropoxy-benzenesulfonamid-
e 139
4-Isopropoxy-N-[3-(pyridine-4-carbonyl)-pyridin-4-yl]-benzenesulfonami-
de 140 6-Isopropoxy-pyridine-3-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)- amide 141
6-Isopropoxy-pyridine-3-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide 142
N-[4-Chloro-2-(pyridin-2-ylsulfanyl)-phenyl]-4-isopropyl-
benzenesulfonamide 143
N-(2-Benzoyl-phenyl)-4-isopropoxy-benzenesulfonamide
[0075] The structural formulas of Examples 7-27, 31-36, and 116-119
of Table 1 are shown the Examples section. Examples 45-143
(Examples 116-119 are also included below) of Table 1 have the
following structural formulas: ##STR13## ##STR14## ##STR15##
##STR16## ##STR17## ##STR18## ##STR19## ##STR20## ##STR21##
##STR22## ##STR23## ##STR24## ##STR25## ##STR26## ##STR27##
##STR28##
[0076] The following compounds are preferred compounds for use in
the method of the invention: [0077]
N-(2-Benzoyl-4-chlorophenyl)-4-ethyl-benzenesulfonamide; [0078]
N-(2-Benzoyl-4-nitrophenyl)-4-ethyl-benzenesulfonamide; [0079]
N-(2-Benzoyl-4-bromophenyl)-4-isopropyl-benzenesulfonamide; [0080]
N-(2-Benzoyl-4-chlorophenyl)-4-ethoxy-benzenesulfonamide; [0081]
N-(2-Benzoyl-4-chlorophenyl)-4-isopropoxy-benzenesulfonamide;
[0082]
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide;
[0083]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfo-
namide; [0084]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamid-
e; [0085]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesulfonamide-
; [0086]
N-(3-Benzoyl-5-nitro-pyridin-2-yl)-4-isopropoxy-benzenesulfonam-
ide; [0087]
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-benzenesulfona-
mide; [0088]
N-(2-Benzoyl-4-nitrophenyl)-4-isopropyl-benzenesulfonamide; [0089]
N-(2-Benzoyl-4-nitrophenyl)-4-isopropoxy-benzenesulfonamide; [0090]
N-(4-Chloro-2-phenylsulfanyl-phenyl)-4-isopropoxy-benzenesulfonam-
ide; [0091]
N-(2-Benzenesulfonyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide;
[0092]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenes-
ulfonamide; [0093]
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesul-
fonamide; [0094]
4-Ethoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-benzenesulf-
onamide; [0095]
N-[5-Chloro-3-(3-fluoro-benzoyl)-pyridin-2-yl]-4-isopropoxy-benzenesulfon-
amide; [0096]
N-(2-Benzoyl-4-trifluoromethyl-phenyl)-4-isopropoxy-benzenesulfonamide;
[0097] N-(3-Benzoyl-pyridin-4-yl)-4-isopropoxy-benzenesulfonamide;
[0098]
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropyl-benzenesulfonamid-
e; [0099] 5-Oxazol-5-yl-thiophene-2-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide; [0100]
6-Isopropoxy-pyridine-3-sulfonic acid
(3-benzoyl-5-chloro-pyridin-2-yl)-amide; [0101]
6-Isopropoxy-pyridine-3-sulfonic acid
(2-benzoyl-4-chloro-phenyl)-amide; [0102]
N-[4-Chloro-2-(pyridin-2-ylsulfanyl)-phenyl]-4-isopropyl-benzenes-
ulfonamide; and pharmaceutically acceptable salts, solvates, or
hydrates thereof. Models of Inflammation
[0103] In vivo models of inflammation are available which can be
used to assess the efficacy of compounds of the invention. For
example, leukocyte infiltration upon intradermal injection of a
chemokine and compound of the invention into a suitable animal,
such as rabbit, mouse, rat, guinea pig or primate (e.g., rhesus
macaque) can be monitored (see e.g., Van Damme, J. et al., J. Exp.
Med., 176: 59-65 (1992); Zachariae, C. O. C. et al., J. Exp. Med.
171: 2177-2182 (1990); Jose, P. J. et al., J. Exp. Med. 179:
881-887 (1994)). In one embodiment, skin biopsies are assessed
histologically for infiltration of leukocytes (e.g., CCR9.sup.+T
cells). In another embodiment, labeled cells (e.g., stably
transfected cells expressing a mammalian CCR9, labeled with
.sup.111In for example) capable of chemotaxis and extravasation are
administered to the animal. For example, compound of the invention
to be assessed which binds a mammalian CCR9 can be administered,
either before, simultaneously with or after a CCR9 ligand or
agonist (e.g., TECK) is administered to the test animal. A decrease
of the extent of infiltration in the presence of the compound of
the invention as compared with the extent of infiltration in the
absence of said compound is indicative of inhibition.
[0104] As described herein, CCR9 is selectively expressed on memory
lymphocytes which home to mucosal sites (e.g., CLA.sup.-ve
.alpha.4.beta.7.sup.hi CD4.sup.+ lymphocytes). Thus, animal models
of inflammatory diseases of the mucosa (e.g., respiratory tract,
urogenital tract, alimentary canal and associated organs and
tissues (e.g., pancreas, liver, gall bladder)) can be used to
assess the therapeutic efficacy of CCR9 inhibiting compounds. For
example, the therapeutic efficacy of a compound of the invention
can be studied in the cotton-top tamarin model of inflammatory
bowel disease (Podolsky, D. K., et al., J. Clin. Invest. 92:372-380
(1993)). The CD45RB.sup.Hi/SCID model provides a mouse model with
similarity to both Crohn's disease and ulcerative colitis (Powrie,
F. et al., Immunity, 1: 553-562 (1994)). Therapeutic efficacy in
this model can be assessed, for example, by using parameters such
as inhibition of recruitment of .sup.111In-labeled cells to the
colon and reduction in the number of CD4.sup.+ T lymphocytes in the
lamina propria of the large intestine after administration (e.g.,
intravenous (i.v.), intraperitoneally (i.p.) and per oral (p.o.))
of a compound.
Methods of Therapy
[0105] Inhibition of at least one function characteristic of a
mammalian CCR9 protein according to the present invention provides
an effective and selective way of inhibiting receptor-mediated
functions. Once lymphocytes are recruited to a site, other
leukocyte types, such as monocytes, may be recruited by secondary
signals. Thus, compounds which can inhibit CCR9 function (e.g.,
compounds of the invention) can be used to inhibit leukocyte
function (e.g., leukocyte infiltration including recruitment and/or
accumulation).
[0106] In one aspect, the present invention provides a method of
inhibiting an inflammatory response in a subject, comprising
administering an effective amount of a compound of the invention
which inhibits mammalian CCR9 function to a subject in need of such
therapy. In one embodiment, an effective amount of a compound which
inhibits one or more functions of a mammalian CCR9 protein (e.g., a
human CCR9) is administered to a subject to inhibit (i.e., reduce
or prevent) inflammation. Preferred compounds of the invention,
inhibit an inflammatory response in a subject by inhibiting (i.e.,
reduce or prevent) binding of ligand (e.g. TECK) to CCR9. As a
result, one or more inflammatory processes, such as leukocyte
emigration, chemotaxis, exocytosis (e.g., of enzymes) or
inflammatory mediator release, is inhibited. For example,
leukocytic infiltration of inflammatory sites (e.g., in a inflamed
mucus membrane (e.g., colon, small intestine)) can be inhibited
according to the present method. In another embodiment, an
effective amount of a compound of the invention which inhibits one
or more functions of a mammalian CCR9 protein (e.g., a human CCR9)
is administered to a subject to inhibit (i.e., reduce or prevent)
CCR9-mediated homing of leukocytes. In particular embodiments, an
effective amount of a compound which binds to human CCR9 and/or an
effective amount of a compound which binds to human TECK is
administered to a subject in need thereof.
[0107] Thus, the invention relates to a method of treating a
subject having an inflammatory disease, comprising administering an
effective amount of a compound of the invention that antagonizes
CCR9 function. In a particular embodiment, the subject has an
inflammatory bowel disease, such as Crohn's disease or colitis.
Treatment includes therapeutic or prophylactic treatment.
Treatment, in accordance with the method, can prevent disease or
reduce the severity of disease in whole or in part.
[0108] The invention also relates to a method of inhibiting
CCR9-mediated homing of leukocytes in a subject, comprising
administering an effective amount of a compound of the invention
that antagonizes CCR9 function, for example, the homing of
leukocytes to mucosal sites can be inhibited. Immigration of
circulating leukocytes into organs or tissue (e.g., intestine)
and/or local recruitment of lymphocytes within an organ or tissue
(e.g., IEL, LPL) can be inhibited in accordance with the
method.
[0109] The term "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, guinea pigs, rats,
mice or other bovine, ovine, equine, canine, feline, rodent or
murine species. A "subject in need of treatment to inhibit CCR9
function" is a subject in whom a beneficial therapeutic or
prophylactic effect can be achieved by inhibiting CCR9 function.
Examples include subjects with one of the diseases or conditions
described herein.
[0110] Diseases and conditions associated with inflammation and/or
infection can be treated using the methods described herein. In a
preferred embodiment, the disease or condition is one in which the
actions of lymphocytes, particularly lymphocytes which home to
mucosal tissues, are to be inhibited or promoted for therapeutic
(including prophylactic) purposes. In a particularly preferred
embodiment, the inflammatory disease or condition is a T
cell-mediated disease or condition.
[0111] Examples of inflammatory diseases associated with mucosal
tissues which can be treated according to the present method
include mastitis (mammary gland), vaginitis, cholecystitis,
cholangitis or pericholangitis (bile duct and surrounding tissue of
the liver), chronic bronchitis, chronic sinusitis, asthma, and
graft versus host disease (e.g., in the gastrointestinal tract). As
seen in Crohn's disease, inflammation often extends beyond the
mucosal surface, accordingly chronic inflammatory diseases of the
lung which result in interstitial fibrosis, such as interstitial
lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD
associated with rheumatoid arthritis, or other autoimmune
conditions), hypersensitivity pneumonitis, collagen diseases,
sarcoidosis, and other idiopathic conditions can be amenable to
treatment. Pancreatitis and insulin-dependent diabetes mellitus are
other diseases which can be treated using the present method.
[0112] In a particularly preferred embodiment, diseases which can
be treated accordingly include inflammatory bowel disease (IBD),
such as ulcerative colitis, Crohn's disease, ileitis, Celiac
disease, nontropical Sprue, enteritis, enteropathy associated with
seronegative arthropathies, microscopic or collagenous colitis,
eosinophilic gastroenteritis, or pouchitis resulting after
proctocolectomy, and ileoanal anastomosis.
[0113] Additional diseases or conditions, including chronic
diseases, of humans or other species which can be treated with
compounds of the invention that inhibit of CCR9 function, include,
but are not limited to: [0114] inflammatory or allergic diseases
and conditions, including systemic anaphylaxis or hypersensitivity
responses, drug allergies (e.g., to penicillin, cephalosporins),
insect sting allergies; psoriasis and inflammatory dermatoses such
as dermatitis, eczema, atopic dermatitis, allergic contact
dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous,
and hypersensitivity vasculitis); spondyloarthropathies;
scleroderma; respiratory allergic diseases such as asthma, allergic
rhinitis; [0115] autoimmune diseases, such as arthritis (e.g.,
rheumatoid arthritis, psoriatic arthritis), multiple sclerosis,
systemic lupus erythematosus, myasthenia gravis, juvenile onset
diabetes, glomerulonephritis and other nephritides, autoimmune
thyroiditis, Behcet's disease; [0116] graft rejection (e.g., in
transplantation), including allograft rejection or
graft-versus-host disease; [0117] other diseases or conditions in
which undesirable inflammatory responses are to be inhibited can be
treated, including, but not limited to, atherosclerosis,
restenosis, myositis (including polymyositis, dermatomyositis).
Modes of Administration
[0118] The compound can be administered as a neutral compound or as
a salt. Salts of compounds containing an amine or other basic group
can be obtained, for example, by contacting the compound with a
suitable organic or inorganic acid, such as hydrogen chloride,
hydrogen bromide, acetic acid, perchloric acid and the like.
Compounds with a quaternary ammonium group also contain a
counteranion such as chloride, bromide, iodide, acetate,
perchlorate and the like. Other examples of such salts include
hydrochlorides, hydrobromides, sulfates, methanesulfonates,
nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g.
(+)-tartrates, (-)-tartrates or mixtures thereof including racemic
mixtures], succinates, benzoates and salts with amino acids such as
glutamic acid.
[0119] Salts of compounds containing a carboxylic acid or other
acidic functional group can be prepared by reacting with a suitable
base. Such a pharmaceutically acceptable salt may be made with a
base which affords a pharmaceutically acceptable cation, which
includes alkali metal salts (especially sodium and potassium),
alkaline earth metal salts (especially calcium and magnesium),
aluminum salts and ammonium salts, as well as salts made from
physiologically acceptable organic bases such as trimethylamine,
triethylamine, morpholine, pyridine, piperidine, picoline,
dicyclohexylamine, N,N'-dibenzylethylenediamine,
2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,
tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine,
collidine, quinine, quinoline, and basic amino acid such as lysine
and arginine. These salts may be prepared by methods known to those
skilled in the art.
[0120] Salts of acidic functional groups contain a countercation
such as sodium, potassium and the like.
[0121] Certain compounds described herein and their salts may also
exist in the form of solvates, for example hydrates, and the
present invention includes each solvate and mixtures thereof.
[0122] Certain compounds described herein may exist in different
stable conformational forms which may be separable. Torsional
asymmetry due to restricted rotation about an asymmetric single
bond, for example because of steric hindrance or ring strain, may
permit separation of different conformers. The present invention
includes each conformational isomer of these compounds and mixtures
thereof.
[0123] Certain compounds described herein may exist in zwitterionic
form. The present invention includes each zwitterionic form of
these compounds and mixtures thereof.
[0124] Certain compounds described herein and their salts may exist
in more than one crystal form. Polymorphs of these compounds form
part of this invention and may be prepared by crystallization of
the compound under different conditions, for example, by using
different solvents or different solvent mixtures for
recrystallization; by crystallization at different temperatures; or
by various modes of cooling, ranging from very fast to very slow
cooling during crystallization. Polymorphs may also be obtained by
heating or melting the compound followed by gradual or fast
cooling. The presence of polymorphs may be determined by solid
probe nmr spectroscopy, ir spectroscopy, differential scanning
calorimetry, powder X-ray diffraction or such other techniques.
[0125] The language an "effective amount" or "pharmaceutically
effective amount" is intended to include an amount which is
sufficient to ameliorate a disease or condition and prevent its
further progression or ameliorate the symptoms associated with the
disease or condition. Such an amount can be administered
prophylactically to a patient thought to be susceptible to
development of a disease or condition. Such amount when
administered prophylactically to a patient can also be effective to
prevent or lessen the severity of the mediated condition. Such an
amount is intended to include an amount which is sufficient to
modulate a CCR9 receptor-mediated disease or condition. Conditions
mediated by CCR9 receptors include all of the diseases or
conditions described herein. Although the amount to be administered
to a subject will, of course, be determined by a physician, in the
light of all the relevant circumstances, an "effective amount"
typically ranges between about 0.01 mg/kg/day to about 100
mg/kg/day, preferably between about 0.5 mg/kg/day to about 50
mg/kg/day.
[0126] The compounds described herein, and the pharmaceutically
acceptable salts, solvates and hydrates thereof, have valuable
pharmacological properties and can be used in pharmaceutical
preparations containing the compound or pharmaceutically acceptable
salts thereof, in combination with a pharmaceutically acceptable
carrier or diluent. They are useful as therapeutic substances in
preventing or treating diseases mediated by CCR9 receptors, such as
inflammatory diseases, in human or non-human animals. Suitable
pharmaceutically acceptable carriers include inert solid fillers or
diluents and sterile aqueous or organic solutions. The active
compound will be present in such pharmaceutical compositions in
amounts sufficient to provide the desired dosage amount in the
range described herein. Techniques for formulation and
administration of the compounds of the instant invention can be
found in Remington: the Science and Practice of Pharmacy, 19.sup.th
edition, Mack Publishing Co., Easton, Pa. (1995).
[0127] For oral administration, the compound or salts thereof can
be combined with a suitable solid or liquid carrier or diluent to
form capsules, tablets, pills, powders, syrups, solutions,
suspensions and the like.
[0128] The tablets, pills, capsules, and the like may also contain
a binder such as gum tragacanth, acacias, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid, a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0129] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0130] The active compounds can also be administered intranasally
as, for example, liquid drops or spray. For oral or nasal
inhalation, the compounds for use according to the present
invention are conveniently delivered in the form of a dry powder
inhaler, or an aerosol spray presentation from pressurized packs or
a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of gelatin for use in an inhaler or insufflator may be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0131] For parental administration the compounds of the present
invention, or salts thereof can be combined with sterile aqueous or
organic media to form injectable solutions or suspensions. For
example, solutions in sesame or peanut oil, aqueous propylene
glycol and the like can be used, as well as aqueous solutions of
water-soluble pharmaceutically-acceptable salts of the compounds.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to
prevent the growth of microorganisms.
[0132] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that each syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against any contamination. The carrier can be solvent or
dispersion medium containing, for example, water, ethanol, polyol
(e.g. glycerol, propylene glycol and liquid polyethylene glycol),
propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oils. The injectable solutions prepared in
this manner can then be administered intravenously,
intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular administration being preferred in humans.
[0133] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0134] In addition, to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation, for
example, subcutaneously or intramuscularly or by intramuscular
injection. Thus, for example, as an emulsion in an acceptable oil,
or ion exchange resins, or as sparingly soluble derivatives, for
example, as sparingly soluble salts.
[0135] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated.
[0136] The compositions are formulated and administered in the same
general manner as detailed herein. The compounds of the instant
invention may be used effectively alone or in combination with one
or more additional active agents depending on the desired target
therapy. Combination therapy includes administration of a single
pharmaceutical dosage formulation which contains a compound
described herein and one or more additional active agents, as well
as administration of the compound and each active agent in its own
separate pharmaceutical dosage formulation. For example, a compound
described herein or salt thereof can be administered to the patient
together in a single oral dosage composition such as a tablet or
capsule, or each agent administered in separate oral dosage
formulations. Where separate dosage formulations are used, a
compound of the invention and one or more additional active agents
can be administered at essentially the same time, i.e.,
concurrently, or at separately staggered times, i.e., sequentially;
combination therapy is understood to include all these
regimens.
[0137] An effective amount of the compounds described herein can be
used for the preparation of a medicament useful for treating a
disease mediated by CCR9 receptors, such as an inflammatory
disease, and for treating, preventing or reducing the risk of
developing a disease mediated by CCR9 receptors, such as an
inflammatory disease, in mammals, particularly in humans.
[0138] Preferably compounds of the invention or pharmaceutical
formulations containing these compounds are in unit dosage form for
administration to a mammal. The unit dosage form can be any unit
dosage form known in the art including, for example, a capsule, an
IV bag, a tablet, or a vial. The quantity of active ingredient
(viz., a compound of Structural Formula I or salts thereof) in a
unit dose of composition is an effective amount and may be varied
according to the particular treatment involved. It may be
appreciated that it may be necessary to make routine variations to
the dosage depending on the age and condition of the patient. The
dosage will also depend on the route of administration which may be
by a variety of routes including oral, aerosol, rectal,
transdermal, subcutaneous, intravenous, intramuscular,
intraperitoneal and intranasal.
[0139] Pharmaceutical formulations of the invention are prepared by
combining (e.g., mixing) an effective amount of a compound of the
invention together with a pharmaceutically acceptable carrier or
diluent. The present pharmaceutical formulations are prepared by
known procedures using well known and readily available
ingredients.
[0140] In making the compositions of the present invention, the
active ingredient will usually be admixed with a carrier, or
diluted by a carrier, or enclosed within a carrier which may be in
the form of a capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, lyophilized solid
or paste, semi-solid, or liquid material which acts as a vehicle,
or can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), or ointment, containing, for example,
up to 10% by weight of the active compound. The compounds of the
present invention are preferably formulated prior to
administration.
[0141] For the pharmaceutical formulations any suitable carrier
known in the art can be used. In such a formulation, the carrier
may be a solid, liquid, or mixture of a solid and a liquid.
[0142] Advantageously, compositions containing the compounds of the
invention or the salts thereof may be provided in dosage unit form,
each dosage unit containing from about 5% to about 95%, preferably
about 20% to about 80%, of a compound of the invention, although it
will, of course, readily be understood that the amount of the
compound or compounds actually to be administered will be
determined by a physician, in the light of all the relevant
circumstances.
[0143] Powders and tablets preferably contain from about 1 to about
99 weight percent of the active ingredient which is the novel
compound of this invention. Suitable solid carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, low melting waxes, and cocoa butter.
[0144] The following pharmaceutical formulations 1 through 8 are
illustrative only and are not intended to limit the scope of the
invention in any way. "Active Ingredient", refers to a compound
according to Structural Formula I or salts thereof. TABLE-US-00002
Formulation 1 Hard gelatin capsules are prepared using the
following ingredients: Quantity (mg/capsule) Active Ingredient 250
Starch, dried 200 Magnesium stearate 10 Total 460 mg
[0145] TABLE-US-00003 Formulation 2 A tablet is prepared using the
ingredients below: Quantity (mg/tablet) Active Ingredient 250
Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic
acid 5 Total 665 mg
[0146] The components are blended and compressed to form tablets
each weighing 665 mg TABLE-US-00004 Formulation 3 An aerosol
solution is prepared containing the following components: Weight
Active Ingredient 0.25 Ethanol 25.75 Propellant 22
(Chlorodifluoromethane) 74.00 Total 100.00
[0147] The Active Ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30.degree. C.
and transferred to a filling device. The required amount is then
fed to a stainless steel container and diluted with the remainder
of the propellant. The valve units are then fitted to the
container. TABLE-US-00005 Formulation 4 Tablets, each containing 60
mg of Active ingredient, are made as follows: Active Ingredient 60
mg Starch 45 mg Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium
carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg
Total 150 mg
[0148] The Active Ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous
solution containing polyvinylpyrrolidone is mixed with the
resultant powder, and the mixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 150 mg. TABLE-US-00006 Formulation 5
Capsules, each containing 80 mg of Active Ingredient, are made as
follows: Active Ingredient 80 mg Starch 59 mg Microcrystalline
cellulose 59 mg Magnesium stearate 2 mg Total 200 mg
[0149] The Active Ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 mesh U.S. sieve, and
filled into hard gelatin capsules in 200 mg quantities.
TABLE-US-00007 Formulation 6 Suppositories, each containing 225 mg
of Active Ingredient, are made as follows: Active Ingredient 225 mg
Saturated fatty acid glycerides 2,000 mg Total 2,225 mg
[0150] The Active Ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool. TABLE-US-00008 Formulation 7 Suspensions, each
containing 50 mg of Active Ingredient per 5 mL dose, are made as
follows: Active Ingredient 50 mg Sodium carboxymethyl cellulose 50
mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavor q.v. Color
q.v. Purified water to total 5 mL
[0151] The Active Ingredient is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethyl cellulose and syrup
to form a smooth paste. The benzoic acid solution, flavor and color
are diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
TABLE-US-00009 Formulation 8 An intravenous formulation may be
prepared as follows: Active Ingredient 100 mg Isotonic saline 1,000
mL
[0152] The solution of the above materials generally is
administered intravenously to a subject at a rate of 1 mL per
minute.
EXAMPLES
[0153] ##STR29##
[0154] The sulfonamides of the invention can be synthesized by
treating a protected aromatic amine (XXVI) or a protected
heteroaromatic amine (XXVI), such as an aminobenzene, an
aminopyridine, an aminopyrimidine, an aminopyridazine, an
aminopyrazine, an aminotriazine or an aminotetrazine, with an alkyl
lithium. Typically, the amino group of the aromatic amine or
heteroaromatic amine is protected with protecting group which is
stable under basic condition, such as a tert-butoxycarbonyl (BOC)
group. The aromatic amine or heteroaromatic amine is dissolved in
an aprotic solvent, preferably an ether. The solution is then
cooled to about -50.degree. C. to about -100.degree. C. and about 1
equ. to about 2.5 equ. of alkyl lithium (e.g., n-butyl lithium,
s-butyl lithium or t-butyl lithium) is added slowly to the reaction
mixture. The temperature of the reaction mixture is allowed to
increase to about -25.degree. C. to about 25.degree. C. After about
5 min. to about 45 min., about 1 equ. to about 1.5 equ. of a
Weinreb amide (XXVII), such as a N-methoxy-N-methyl-benzamide or a
N-methoxy-N-methyl-isonicotinamide, dissolved in an aprotic solvent
is added to the reaction mixture. The reaction is allowed to
continue stirring until the protected aromatic amine (XXVI) or
protected heteroaromatic amine (XXVI) is consumed (typically, for
about 0.5 hr to about 3 hr at about 15.degree. C. to about
35.degree. C.). The reaction is monitored by thin layer
chromatography (tlc) to determine when the aromatic amine (XXVI) or
heteroaromatic amine (XXVI) has been consumed. When the reaction is
complete, it is quenched with an acidic aqueous solution to yield
compound XXVIII.
[0155] After the amino group of compound XXVIII has been
deprotected to yield compound XXIX, compound XXIX is converted to a
sulfonamide by using one of two alternative methods. In method 1,
compound XXIX is dissolved in an aprotic solvent and the solution
is cooled to about -25.degree. C. to about 10.degree. C. and about
1 equ. to about 1.5 equ. of NaH is added to the mixture. After
about 1 min. to about 15 min., about 1 equ. to about 1.5 equ. of
sulfonyl chloride (XXX) dissolved in an aprotic solvent is added to
the reaction mixture. An additional, amount of up to about 0.5 equ.
NaH may be added to the reaction mixture. The reaction is stirred
at about 15.degree. C. to about 30.degree. C. until the reaction is
complete as indicated by tlc (typically, about 1 hr to about 3 hr).
The reaction is quench by addition of water to yield sulfonamide
(XXXI).
[0156] In the second method of forming sulfonamide (XXXI), compound
XXIX is dissolved in an aprotic solvent and the mixture is cooled
to about -10.degree. C. to about 10.degree. C. An excess amount of
sodium bis(trimethylsilyl)amide (typically, about 1.5 equ. to about
3 equ.) in an aprotic solvent is added to the solution, and the
reaction is allowed to stir for about 10 min. to about 45 min. A
solution of about 1 equ. to about 2 equ. of sulfonyl chloride (XXX)
in an aprotic solvent is added to the reaction mixture and the
reaction is allowed to warm up to about 15.degree. C. to about
30.degree. C. and is stirred for about 6 hr to about 24 hr. The
reaction is quenched with an acidic water solution to yield
sulfamide (XXXI). II. General Synthesis of
N-(2-Benzoyl-Phenyl)-Arylsulfonamides and
N-(2-Benzoyl-Phenyl)-Heteroarylsulfonamides ##STR30## Procedure A
(Synthesis of Weinreb amides):
[0157] A substituted anthranilic acid (24 mmol) was dissolved in
acetonitrile (200 mL). 1.05 equivalents of N,O
dimethylhydroxylamine hydrochloride, 1.05 equivalents of EDC, 0.05
equivalents of dimethylaminopyridine, and 1.0 equivalent of
triethylamine were added and the reaction was stirred at room
temperature overnight. The acetonitrile was removed by rotary
evaporation and the residue was partitioned between ethyl acetate
and water. The organic layer was washed with brine then
concentrated to a residue. The residue was chromatographed on
silica gel (ethyl acetate as eluent) to give the product. Typical
yields are 70-90%.
The following compounds were prepared using Procedure A:
Example 1
2-Amino-5-bromo-N-methoxy-N-methyl-benzamide
[0158] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 259 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 7.5 (s, 1H) .delta. 7.23 (d, 1H) .delta. 6.58 (d, 1H)
.delta. 4.68 (br s, 2H) .delta. 3.55 (s, 3H) .delta. 3.41 (s,
3H).
Example 2
2-Amino-N-methoxy-N-methyl-5-nitro-benzamide
[0159] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 226 (M+H.sup.+). .sup.1H NMR (CDCl.sub.3, shifts
relative to the solvent peak at 7.24 ppm) .delta. 8.5 (s, 1H),
.delta. 8.1 (d, 1H) .delta. 6.7 (d, 1H) .delta. 3.6 (s, 3H) .delta.
3.4 (s, 3H).
Example 3
2-Amino-5-chloro-N-methoxy-N-methyl-benzamide
[0160] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 215. (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 7.4 (s, 1H) .delta. 7.15 (m, 1H) .delta. 6.65 (d, 1H)
.delta. 3.6 (s, 3H) .delta. 3.28 (s, 3H).
Procedure B (General Synthesis of Substituted
2-Aminobenzophenones):
[0161] A substituted Weinreb amide (10 mmol) and a substituted
bromobenzene (10 mmol) were dissolved in THF under nitrogen. The
reaction mixture was cooled to -100.degree. C. using a liquid
nitrogen/diethyl ether bath. n-BuLi (21 mmol, 1.6 M in
cyclohexanes) was introduced via syringe over a period of twenty
minutes. The reaction mixture was allowed to warm to -70.degree. C.
and then quenched by adding of 21 mL of 1 N HCl. The reaction
mixture was partitioned between ethyl acetate and saturated sodium
bicarbonate. The organic layer was washed with saturated sodium
chloride, then concentrated to a residue. The residue was
chromatographed on silica gel using 1:1 ethyl acetate:hexanes to
give the product. Typical yields are 30-60%.
The following compounds were prepared using Procedure B:
Example 4
(2-Amino-5-bromo-phenyl)-phenyl-methanone
[0162] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 276 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 7.2-7.8 (m, 6H) .delta. 6.85 (d, 2H) .delta. 6.2 (br s,
2H).
Example 5
(2-Amino-5-nitro-phenyl)-(3-trifluoromethyl-phenyl)-methanone
[0163] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 311 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 7.6-8.4 (m, 5H) .delta.6.75 (d, 2H) .delta. 7.0 (br s,
2H).
Example 6
(2-Amino-5-chloro-phenyl)-m-tolyl-methanone
[0164] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 246. (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 7.25-7.5 (m, 5H) .delta. 6.8 (d, 2H) .delta. 2.4 (s,
3H).
Procedure C (General Synthesis of
N-(2-benzoyl-phenyl)-benzenesulfonamides):
[0165] A substituted 2-aminobenzophenone (1 mmol) was dissolved in
5 mL of pyridine. A substituted sulfonyl chloride (1.3 mmol) and
dimethlaminopyridine (10 mg) were added to the 2-aminobenzophenone
solution. The reaction mixture was heated to 110.degree. C. for 2
hours. The solvent was evaporated under a stream of nitrogen and
the product was isolated by reverse phase HPLC using the method
given below. Typical yields are 60-80%.
General Method for HPLC Purification of
N-(2-benzoyl-phenyl)-benzenesulfonamides:
[0166] A crude N-(2-benzoyl-phenyl)-benzenesulfonamides was
dissolved in 1 mL of MeOH (or MeOH/DCM) and filtered through a 0.45
micron filter. The solution was then injected (50-75 mg/injection)
to a HPLC/MS system equipped with Waters 2700 Sample Manager
auto-injector, Waters 600 Controller and Pumps, Waters 996 Diode
Array detector, Micro Mass Platform LCZ mass spectrometer and
Gilson FC-204 fraction collector. Solvents A and B were used for
gradient elution of the purified compound using Phenomenex Luna 15
micron, C18(2) 100A, 100.times.21.2 mm column at 20 mL/min flow
rate.
Solvent A: 99% Water/1% CH.sub.3CN/0.1% Formic Acid
Solvent B: 95% CH.sub.3CN/5% Water/0.1% Formic Acid
The gradients were programmed according to their analytical scale
HPLC retention time (t.sub.ana) which was obtained by running a
linear gradient of 0% B to 100% B in A in 3.5 min on a Phenomenex
Luna 5 micron C18(2) 50.times.4.6 mm column at 3.5 mL/min.
[0167] Linear mixing of 0% of B to X % of B in A was used according
to the following formula with some adjustments for some compounds.
X=t.sub.ana.times.95/3.5+15
[0168] About 15 mL to 25 mL size fractions were collected based on
mass triggered collection. They were combined according to their
purities based on mass spectral pattern of the fractions.
The following examples were prepared using Procedure C:
Example 7
N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-4-nitro-benzenesulfonamide
[0169] ##STR31##
[0170] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 451 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.0 (s, 1H) .delta. 8.0-8.4 (dd, 4H) .delta. 7.8 (d, 1H)
.delta. 7.38-7.58 (m, 6H).
Example 8
Thiophene-2-sulfonic acid (2-benzoyl-4-chloro-phenyl)-amide
[0171] ##STR32##
[0172] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 378 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.0 (s, 1H) .delta. 7.85 (d, 1H) .delta. 7.4-7.7 (m, 9H)
.delta. 6.85 (d, 1H).
Example 9
N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide
[0173] ##STR33##
[0174] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 498 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.7 (s, 1H) .delta. 7.3-7.8 (m, 12H).
Example 10
N-(2-Benzoyl-4-chloro-phenyl)-4-chloro-benzenesulfonamide
[0175] ##STR34##
[0176] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 406 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.65 (s, 1H) .delta. 7.2-7.8 (m, 12H).
Example 11
N-(2-Benzoyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide
[0177] ##STR35##
[0178] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 428 (M+H.sup.+). .sup.1H NMR (CDCl.sub.3, shifts
relative to the solvent peak at 7.24 ppm) .delta. 9.9 (s, 1H)
.delta. 7.2-7.8 (m, 12H), .delta. 1.18 (s, 9H).
Example 12
N-(2-Benzoyl-4-chloro-phenyl)-4-propyl-benzenesulfonamide
[0179] ##STR36##
[0180] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 414 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.9 (s, 1H) .delta. 7.0-7.8 (m, 12H), .delta. 2.42 (m, 2H)
.delta. 1.5 (m, 2H) .delta. 0.92 (m, 3H).
Example 13
N-(2-Benzoyl-4-chloro-phenyl)-4-ethyl-benzenesulfonamide
[0181] ##STR37##
[0182] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 400 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.9 (s, 1H) .delta. 7.0-7.8 (m, 12H), .delta. 2.42 (t, 2H)
.delta. 0.92 (d, 3H).
Example 14
N-(2-Benzoyl-4-nitro-phenyl)-4-ethyl-benzenesulfonamide
[0183] ##STR38##
[0184] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 411 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.6 (s, 1H) .delta. 8.2-8.45 (m, 2H) .delta. 7.2-7.9 (m,
10H), .delta. 2.6 (q, 2H) .delta. 1.05 (t, 3H).
Example 15
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropyl-benzenesulfonamide
[0185] ##STR39##
[0186] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 414 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.85 (s, 1H) .delta. 7.0-7.8 (m, 12H), .delta. 2.8 (m, 1H)
.delta. 1.03 (d, 6H).
Example 16
N-(2-Benzoyl-4-bromo-phenyl)-4-ethyl-benzenesulfonamide
[0187] ##STR40##
[0188] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 444 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.8 (s, 1H), .delta. 7.38-7.8 (m, 10H) .delta. 7.08 (d, 2H)
.delta. 2.47 (q, 2H) .delta. 1,1 (t, 3H).
Example 17
N-(2-Benzoyl-4-bromo-phenyl)-4-methoxy-benzenesulfonamide
[0189] ##STR41##
[0190] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 446 (M+H.sup.+). .sup.1H NMR Bruker 300 MHz,
(CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.61 (s, 1H) .delta. 7.2-7.8 (m, 10H), .delta.6.64 (d, 2H)
.delta. 3.78 (s, 3H).
Example 18
N-(2-Benzoyl-4-bromo-phenyl)-4-isopropyl-benzenesulfonamide
[0191] ##STR42##
[0192] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 459 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.9 (s, 1H), .delta.7.28-7.8 (m, 10H) .delta. 7.16 (d, 2H),
.delta.2.8 (m, 1H) .delta. 1.08 (d, 1H).
Example 19
4-Ethyl-N-[4-nitro-2-(3-trifluoromethyl-benzoyl)-phenyl]-benzenesulfonamid-
e
[0193] ##STR43##
[0194] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 479 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.9 (s, 1H), .delta. 8.4 (m, 2H) .delta. 7.6-8.0 (m, 6H)
.delta. 7.28 (m, 2H) .delta. 2.62 (q, 2H) .delta. 1.09 (t, 3H).
Example 20
N-[4-Chloro-2-(3-methyl-benzoyl)-phenyl]-4-ethyl-benzenesulfonamide
[0195] ##STR44##
[0196] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 414 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.8 (s, 1H) .delta. 7.0-7.9 (m, 1H) .delta. 2.48 (q, 2H)
.delta. 2.39 (s, 3H) .delta. 1.13 (t, 3H).
Example 21
N-(2-Benzoyl-4-bromo-phenyl)-4-chloro-benzenesulfonamide
[0197] ##STR45##
[0198] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 450 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.7 (s, 1H), .delta. 7.2-8.0 (m, 12H).
Procedure D: (Alternate Synthesis of
N-(2-benzoyl-phenyl)-benzenesulfonamides):
[0199] A solution of substituted 2-aminobenzophenone (0.5 mmol),
sulfonyl chloride (0.7 mmol), and N-methylmorpholine (0.9 mmol) in
dichloromethane (5 mL) was stirred at 40.degree. C. for 20 hours.
The mixture was cooled to room temperature, washed with water
(2.times.5 mL), brine (5 mL) dried over Na.sub.2SO.sub.4, filtered,
and purified by silica gel chromatography using
dichloromethane:hexanes (1:1) to afford the desired
N-(2-benzoyl-phenyl)-benzenesulfonamides.
The following examples were prepared using Procedure D:
Example 22
N-(2-Benzoyl-4-chloro-phenyl)-4-ethoxy-benzenesulfonamide
[0200] ##STR46##
[0201] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 416 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 1.30-1.40 (t, 3H), .delta. 3.85-3.95 (m, 2H), .delta.
6.68-6.70 (d, 2H), .delta. 7.30-7.65 (m, 9H), .delta. 7.75-7.77 (d,
H), .delta. 9.65 (s, H).
Example 23
N-(2-Benzoyl-4-chloro-phenyl)-4-propoxy-benzenesulfonamide
[0202] ##STR47##
[0203] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 430 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 0.99-1.10 (t, 3H), .delta. 1.70-1.80 (m, 2H), .delta.
3.70-3.75 (t, 2H), .delta. 6.68-6.70 (d, 2H), .delta. 7.30-7.65 (m,
9H), .delta. 7.75-7.77 (d, H), .delta. 9.65 (s, H).
Example 24
N-(2-Benzoyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
[0204] ##STR48##
[0205] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 430 (M+H.sup.+). .sup.1H-NMR (CDCl.sub.3, Bruker
300 MHz): .delta. 1.25-1.26 (d, 6H), .delta. 4.30-4.48 (m, H),
.delta. 6.68-6.70 (d, 2H), .delta. 7.30-7.65 (m, 9H), .delta.
7.75-7.77 (d, H), .delta. 9.70 (s, H).
Example 25
N-(2-Benzoyl-4-chloro-phenyl)-4-butoxy-benzenesulfonamide
[0206] ##STR49##
[0207] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 444 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 0.95-1.00 (t, 3H), .delta. 1.40-1.60 (m, 2H), .delta.
1.70-1.80 (m, 2H), .delta. 3.75-3.80 (t, 2H), .delta. 6.68-6.70 (d,
2H), .delta. 7.30-7.65 (m, 9H), .delta. 7.75-7.77 (d, H), .delta.
9.70 (s, H).
Example 26
N-(2-Benzoyl-4-chloro-phenyl)-4-benzyloxy-benzenesulfonamide
[0208] ##STR50##
[0209] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 478 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 4.93 (s, 2H), .delta. 6.75-6.80 (d, 2H), .delta. 7.335-7.55
(m, 11H), .delta. 7.60-7.70 (m, 3H), .delta. 7.78-7.80 (d, H),
.delta. 9.70 (s, H).
Example 27
N-(2-Benzoyl-4-chloro-phenyl)-4-phenoxy-benzenesulfonamide
[0210] ##STR51##
[0211] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 464 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. (ppm)=6.78-6.80 (d, 2H), 6.90-6.93 (d, 2H), 7.20-7.24 (t,
H), 7.33-7.45 (m, 3H), 7.45-7.53 (m, 5H), 7.60-7.70 (m, 3H),
7.75-7.77 (d, H), 9.78 (s, H). III. General Synthesis of
2-Amino-Pyridophenone-Sulfonamides ##STR52## Procedure E: (BOC
protection of substituted 2-aminopyridines)
[0212] To a mixture of 2-amino-5-substituted-pyridine (0.10 mol),
4-dimethylaminopyridine (DMAP, 1.22 g, 0.01 mol), and triethylamine
(TEA, 20 mL, 0.15 mol) in dichloromethane (80 mL) and DMF (4 mL) at
0.degree. C. was added a solution of di-t-butyl dicarbonate (28.4
g, 0.13 mol) in dichloromethane (20 mL). The mixture was stirred at
room temperature overnight. The mixture was washed with water
(3.times.100 mL), brine (100 mL), dried with anhydrous
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated in
vacuo to afford a solid which was collected by filtration and
washed with small amount of DCM to give the expected product in
40-60% yield.
The following example was prepared using Procedure E:
Example 28
(5-Chloro-pyridin-2-yl)-carbamic acid tert-butyl ester
[0213] .sup.1H-NMR (Bruker 300 MHz, CDCl.sub.3, shifts relative to
the solvent peak at 7.24 ppm)1.54 (s, 9H), 7.59-7.64 (dd, H),
7.94-7.97 (d, H), 8.24-8.25 (dd, H), 8.39 (b, H). LC-MS showed the
product to be >95% pure. The molecular ion was not observed but
the fragment corresponding to loss of the t-butyl group was evident
(M.W. of 173/175).
Procedure F: (Synthesis 2-aminopyridin-3-yl)-phenyl-methanones or
2-aminopyridin-3-yl)-pyridin-4-yl-methanones)
[0214] A solution of BOC protected 5-substituted 2-aminopyridine
(10 mmol) in anhydrous tetrahydrofuran (THF, 5 mL) was cooled to
-78.degree. C. under nitrogen atmosphere with stirring. A solution
of n-butyl lithium in hexane (2.5 M, 8.8 mL) was added dropwise,
and the mixture was stirred at 0.degree. C. for 10 min. A Weinreb
amide (12 mmol) was prepared as in Procedure A and was dissolved in
anhydrous THF (5 mL) and added to the reaction mixture. The
reaction mixture was warmed to room temperature and stirred for 2
hours. The reaction was added to an ice-0.18 M aqueous citric acid
solution (100 g-130 mL) mixture, then extracted with ethyl acetate
(EtOAc, 150 mL and 50 mL). The combined organic layer was washed
with water (2.times.100 mL), brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, and filtered. The crude material concentrated
from the filtrate was purified by flash chromatography to give a
solid product. This compound was heated in 4 N HCl/dioxane (6 mL)
at 100.degree. C. for 2 hours, then cooled to room temperature. The
mixture was evaporated in vacuo and the residue was taken up into a
saturated aqueous NaHCO.sub.3 solution (50 mL) and extracted with
EtOAc (2.times.50 mL). The combined organic layer was washed with
water (2.times.50 mL), then with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was
evaporated and dried in vacuum to afford a pale yellow solid
product in yields of 40-60% for the two steps.
The following examples were prepared using Procedure F:
Example 29
(2-Amino-5-chloro-pyridin-3-yl)-pyridin-4-yl-methanone
[0215] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 234 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 6.96 (b, 2H), .delta. 7.40-7.44 (m, 2H), .delta. 7.62-7.63
(d, H), .delta. 8.25-8.26 (d, H), .delta. 8.81-8.84 (m, 2H).
Example 30
(2-Amino-5-chloro-pyridin-3-yl)-phenyl-methanone
[0216] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 233 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 6.69-6.84 (br s, 2H), 7.48-7.54 (m, 2H), 7.57-7.65 (m, 3H),
7.74-7.75 (d, H), 8.22-8.23 (d, H).
Procedure G: (Alternate Synthesis of Sulfonamides Using NaH)
[0217] To a solution of a 2-aminopyridophenone (0.5 mmol) in dry
DMF (1 mL) at 0.degree. C. was added NaH (60%, 20 mg, 0.5 mmol).
The mixture was stirred for 5 min. The a sulfonyl chloride (0.55
mmol) in dry DMF (1 mL) was added, and the mixture stirred at
0.degree. C. for 10 min. The second portion of NaH (0.25 mmol) was
added, and the mixture stirred at room temperature for 2 hours. The
mixture was quenched with ice water (20 mL) and extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
water (2.times.10 mL), brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated in vacuo to give crude
product. The crude product was purified by chromatography using
DCM:EtOAc (100:0 to 98:2) or hexane:EtOAc (9:1) as eluent to afford
the purified product in 10-24% yield.
The following examples were prepared using Procedure G:
Example 31
N-(3-Benzoyl-5-chloro-pyridin-2-yl)-4-isopropoxy-benzenesulfonamide
[0218] ##STR53##
[0219] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 431 (M+H.sup.+) .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 1.34-1.36 (d, 6H), .delta. 4.57-4.70 (m, H), .delta.
6.91-6.98 (d, 2H), .delta. 7.50-7.70 (m, 5H), .delta. 7.82-7.83 (d,
H), .delta. 8.08-8.12 (d, 2H), .delta. 8.38-8.39 (d, H), .delta.
10.70 (s, H). Elemental analysis: C=58.26%/cal. 58.53%,
H=4.65%/cal. 4.44%, N=6.26%/cal. 6.50%.
Example 32
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]4-ethoxy-benzenesulfonamide
[0220] ##STR54##
[0221] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 417 (M+H.sup.+); .sup.1H NMR (CDCl.sub.3, shifts
relative to the solvent peak at 7.24 ppm) .delta. 9.90 (1H, s),
.delta. 8.80 (2H, s), .delta. 7.79 (1H, d), .delta. 6.76 (2H, d),
.delta. 7.51 (1H, d), .delta. 7.33-7.20 (3H, m), .delta. 6.75 (2H,
d), .delta. 3.90 (2H, m), .delta. 1.5 (3H, m).
Example 33
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide
[0222] ##STR55##
[0223] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 415 (M+H.sup.+); .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.06 (1H, s), .delta. 8.77 (1H, s), .delta. 7.79 (1H, d),
.delta. 7.70-7.62 (3H, m), .delta. 7.56-7.51 (1H, m), .delta.
7.33-7.16 (5H, m), .delta. 1.19 (6H, m),.delta. 2.88 (1H, m).
Example 34
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]4-isobutyl-benzenesulfonamide
[0224] ##STR56##
[0225] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 429 (M+H.sup.+); .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.06 (1H, s), .delta. 7.77 (1H, s), .delta. 7.67-7.61 (3H,
m), .delta. 7.58-7.47 (1H, m), .delta. 7.33-7.24 (3H, m), .delta.
7.17-7.08 (3H, m), .delta. 2.42 (2H, m), .delta. 0.86 (6H, m).
[0226] Another example of a compound prepared using Procedure G is
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide.
LC-MS showed the product to be >95% pure and to have the
expected M.W. of 401 (M+H.sup.+).
Procedure H: (Alternate Synthesis of Sulfonamides Using
Na(TMS).sub.2N)
[0227] To a suspension of a 2-aminopyridophenone (1 mmol) in dry
DMF (5 mL) at 0.degree. C. was added a solution of sodium
bis(trimethylsilyl)amide in THF (1M, 2.2 mL). This mixture was
stirred at 0.degree. C. for 20 min. A solution of a sulfonyl
chloride (1.3 mmol) in dry DMF (2 mL) was added, and the reaction
mixture was stirred at room temperature overnight. The reaction was
quenched with ice water (60 mL), neutralized with 0.18 M aqueous
citric acid solution (3 mL) to about pH 7.5, then extracted with
EtOAc (60 mL, 2.times.20 mL). The combined organic layers were
washed with water (2.times.50 mL), brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered, and evaporated in vacuo to
give a crude product. The crude product was purified by
chromatography using DCM:EtOAc (6:4) as elute to afford a solid
product in 20-25% yield.
The following examples were prepared using Procedure H:
Example 35
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]4-ethoxy-benzenesulfonami-
de
[0228] ##STR57##
[0229] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 418 (M+H.sup.+). .sup.1H-NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 1.40-1.44 (t, 3H), .delta. 4.03-4.12 (m, 2H), .delta.
6.93-6.96 (d, 2H), .delta. 7.39-7.42 (d, 2H), .delta. 7.70-7.72 (d,
H), .delta. 8.08-8.11 (d, 2H), .delta. 8.39-8.40 (d, H), .delta.
8.84-8.86 (d, 2H), .delta. 10.73 (s, H).
Example 36
N-[5-Chloro-3-(pyridine-4-carbonyl)-pyridin-2-yl]-4-isopropoxy-benzenesulf-
onamide
[0230] ##STR58##
[0231] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 432 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm):
.delta. 1.35-1.36 (d, 6H), .delta. 4.57-4.67 (m, H), .delta.
6.92-6.95 (d, 2H), .delta. 7.42-7.44 (d, 2H), .delta. 7.72-7.73 (d,
H), .delta. 8.08-8.11 (d, 2H), .delta. 8.41-8.42 (d, H), .delta.
8.84-8.87 (d, 2H), .delta. 10.74 (s, H). IV. Synthesis of
(2-Amino-5-Chloro-Phenyl)-Pyridin-3-yl-Methanones ##STR59##
Procedure I: (Alternate Synthesis of
(2-amino-5-choro-phenyl)-pyridin-3-yl-methanones Using
BCl.sub.3)
[0232] To a solution of 85 mL BCl.sub.3 in 80 mL
1,1,2,2-tetrachloroethane, stirred in an ice bath, was added a
solution of 4 g of p-chloroaniline in 50 mL of tetrachloroethane.
After 5 min, 3 g of 3-cyanopyridine is added followed by 7 g of
aluminum chloride. The mixture was stirred at room temperature for
20 min and then heated at reflux for 6 hr. After cooling, 25 mL of
3N HCl was added and refluxing continued for 1 hr. After cooling,
the filtrate was concentrated, made basic with 6N NaOH, then
extraction with dichloromethane. The organic solution was dried
over MgSO.sub.4 and concentrated. The residue was flash
chromatographed on silica gel (Hexane/EtOAc=2:1) to give a 10-20%
yield of product.
[0233] The following Example was prepared using Procedure I:
Example 37
(2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone
[0234] ##STR60##
[0235] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 233. (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 8.95(s, 1H), .delta. 8.80 (d, 1H), .delta. 8.18 (d, 1H),
.delta. 7.40-7.45 (m, 1H), .delta. 7.20-7.30 (m, 2H) .delta. 7.10
(s, 1H), .delta. 6.30 (br s, 2H).
[0236] (2-Amino-5-choro-phenyl)-pyridin-3-yl-methanones prepared
using the method depicted in Scheme III can be converted to the
corresponding aryl sulfonamide or heteroaryl sulfonamide using
Procedure G or H. The following example was prepared using the
method depicted in Scheme III followed by Procedure G or H:
Example 38
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
[0237] ##STR61##
[0238] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 387 (M+H.sup.+); .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 9.66 (s, 1H), .delta. 7.87-7.76 (m, 3H), .delta. 7.56-7.50
(m, 4H), .delta. 7.43-7.40 (m, 1H), .delta. 7.28 (s, 1H), .delta.
7.08 (d, 2H), .delta. 3.50 (s, 3H). V. Synthesis of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanones ##STR62##
Procedure J: (Pivaloyl protection of 4-chloro aniline)
[0239] To a mixture of 2.3 g of 4-chloroaniline and 3 mL of
triethylamine in 20 mL of dichloromethane was added 2.3 g of
trimethylacetyl chloride. The reaction mixture was stirred
overnight at room temperature, then washed with 1 N HCl. The
organic layer was separated and dried over MgSO.sub.4. Removal of
the solvent afforded 4.5 g of pure product.
The following examples were prepared using Procedure J:
Example 39
N-(5-Chloro-pyridin-2-yl)-2,2-dimethyl-propionamide
[0240] ##STR63##
[0241] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 213 (M+H.sup.+).
Example 40
N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide
[0242] ##STR64##
[0243] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 212. (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm).delta.
10.51 (s, 1H), .delta. 7.25 (d, 2H), .delta.7.15 (d, 2H), .delta.
1.51 (s, 9H).
Procedure K:
[0244] A solution of 2 g of pivaloyl protected 4-chloroaniline in
50 mL of THF was cooled to -78.degree. C. under nitrogen. A
solution of n-butyl lithium (14 mL of 2 N in hexane) was added
dropwise. The mixture was allowed to warm 0.degree. C. and stirring
continued at 0.degree. C. for one hour. A pyridine 4-carboxaldehyde
was added to the solution and the reaction was stirred at 0.degree.
C. for one hour. The reaction mixture was poured into ethyl acetate
and washed with water. The organic layer was separated and dried
over MgSO.sub.4. Removal of the solvent followed by chromatography
on silica gel (hexane:ethyl acetate 2:1 as eluent) afforded 1 g of
the desired product.
The following example was prepared using Procedure K:
Example 41
N-[4-Chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-2,2-dimethyl-propionam-
ide
[0245] ##STR65##
[0246] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 319. (M+H.sup.+).
Procedure L:
[0247] The alcohol from Procedure K (1 g) was dissolved in 25 mL of
dichloromethane. Manganese dioxide (2 g) was added and the mixture
was heated to reflux for 2 hours. After cooling and filtration, the
solvent was evaporated to give 0.95 g of the desired ketone.
The following example was prepared using Procedure L:
Example 42
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-2,2-dimethyl-propionamide
[0248] ##STR66##
[0249] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 317 (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.06 (s, 1H), .delta. 8.87 (d, 2H), .delta. 8.8 (d, 1H),
.delta. 7.61(d, 1H), .delta. 7.50 (d, 2H), .delta. 7.47 (s, 1H),
.delta. 1.35 (s, 9H).
Procedure M:
[0250] A solution of the pivaloyl protected
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone from Procedure L
(2 g) was dissolved in 25 mL of ethanol along with 8 mL of 6 N HCl.
The mixture was brought to reflux for 7 hours. The ethanol was
removed by rotary evaporation and the solution neutralized with 6 N
NaOH. The precipitated solid was collected by filtration, washed
with water, and dried to yield
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone.
The following example was prepared using Procedure M:
Example 43
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone
[0251] ##STR67##
[0252] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 233. (M+H.sup.+). .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 8.80 (d, 2H), .delta. 7.45 (d, 2H), .delta. 7.29 (m, 2H),
.delta. 6.70 (d, 1H), .delta. 6.33 (br s, 2H).
[0253] (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanones prepared
using the method depicted in Scheme IV can be converted to the
corresponding aryl sulfonamide or heteroaryl sulfonamide using
Procedure G or H. The following example was prepared using the
procedure depicted in Scheme IV followed by Procedure G or H:
Example 44
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide
[0254] ##STR68##
[0255] LC-MS showed the product to be >95% pure and to have the
expected M.W. of 401 (M+H.sup.+); .sup.1H NMR (Bruker 300 MHz,
CDCl.sub.3, shifts relative to the solvent peak at 7.24 ppm)
.delta. 10.0 (s, 1H), .delta. 7.78 (d, 1H), .delta. 7.64-7.58 (m,
3H), .delta. 7.52 (d, 1H) .delta. 7.34-7.21 (m, 3H), .delta.
7.17-7.21 (m, 3H), .delta. 2.58 (m, 2H), .delta. 1.15 (m, 3H). VI.
Synthesis of Sulfones and Sulfoxides ##STR69## Procedure N:
Production of 4-Chloro-1-nitro-2-phenylsulfanyl-benzene
[0256] To a solution of 2 g of 2-fluoro-4-chloro-nitrobenzene in 50
ml DMF and 1.25 ml of thiophenol was added 1.9 ml triethylamine at
room temperature. The mixture was stirred for one hour. One hundred
mL of water was added and a yellow solid crashed out of solution.
The solid was collected by filtration and dried. Yield: 50-70%.
LC-MS showed a single peak with the expected (M+H.sup.+) of
267.
Procedure O: Production of
4-Chloro-2-phenylsulfanyl-phenylamine
[0257] To a suspension of 1.8 g of
2-benzylthio-4-chloro-nitrobenzene in 100 ml ethanol was added 2 g
powdered iron and 20 mL of 0.33N NH.sub.4Cl. The mixture was heated
at 70.degree. C. for 6 hr. The mixture was cooled and filtered
through a pad of Celite. The filtrate was condensed and purified by
flash chromatography (hexane/ethyl acetate 4:1 as eluent) to yield
1.25 g of an oil. LC-MS showed a single peak with the expected
(M+H.sup.+) of 236.
The following example was prepared by Procedure C:
Example 116
(4-Chloro-2-phenylsulfanyl-phenyl)-4-isopropoxy-benzenesulfonamide
[0258] ##STR70##
[0259] The product showed a single peak by LC-MS with the expected
(M+H.sup.+) of 434.
Procedure P:
[0260] To a solution of the 0.5 g of the sulfide from procedure C
in 20 ml DCM, was added one equivalent of m-chloro peroxybenzoic
acid (mCPBA). The mixture was stirred at room temperature
overnight. The mixture was concentrated and purified by flash
chromatography (hexane/ethyl acetate=2:1 as eluent) to give 0.12 g
of white solid as product.
The following example was prepared using Procedure P:
Example 63
N-(2-Benzenesulfinyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
[0261] ##STR71##
[0262] LC-MS showed a single peak with the expected (M+H.sup.+)
450.
Procedure Q:
[0263] To a solution of the 0.5 sulfide from procedure C in 20 ml
DCM, added two equivalents of mCPBA. The mixture was stirred at
room temperature overnight. The mixture is concentrated and
purified by flash chromatography (hexane/ethyl acetate=2:1 as
eluent) to give 0.14 g of white solid as product.
The following example was prepared using Procedure Q.
Example 117
N-(2-Benzenesulfonyl-4-chloro-phenyl)-4-isopropoxy-benzenesulfonamide
[0264] ##STR72##
[0265] LC-MS showed a single peak with the expected (M+H.sup.+)
466.
The following example was prepared using Procedure G:
Example 118
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamid-
e
[0266] ##STR73##
[0267] LC-MS showed a single peak with the expected (M+H.sup.+) of
431. ##STR74## Procedure R:
[0268]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzensul-
fonamide (60 mg) was dissolved in 5 mL of dichloromethane. 1.05 eq.
of mCPBA was added and the mixture stirred at room temperature
overnight. The solvent was removed by rotary evaporation and the
residue chromatographed on silica gel (hexane/ethyl acetate=1:1 as
eluent) to give the product. Yield: 95%.
The following example was prepared using Procedure R:
Example 119
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulf-
onamide
[0269] ##STR75##
[0270] LC-MS showed a single peak with the expected (M+H.sup.+) of
447.
[0271] Other examples listed herein can be made by the general
procedures outlined above.
Biological Data
I. FMAT Assay: FMAT Assay Determine Inhibitors of TECK Binding to
Human CCR9 receptors:
[0272] A CCR9 assay buffer was prepared by adding 5mL of 1M HEPES,
1.25 mL of 1M CaCl.sub.2,1.5 mL of 1M MgCl.sub.2,14 mL of 5M NaCl,
0.5 g fatty acid free bovine serum albumin, and 1 mL of 5% azide
were added to 400 mL of distilled, deionized water (ddH.sub.2O).
The solution was mixed until all the fatty acid free bovine serum
albumin was dissolved. After pH was adjusted to 7.4, the final
volume was adjusted to 500 mL, and the solution was filtered
through a 0.2 .mu.m filter.
[0273] A 1000 nM biotinylated human TECK in assay buffer was
prepared. A 14 .mu.M solution of Cy5-.alpha.-Biotin working
solution was prepared. Biotinylated TECK and Cy5-.alpha.-Biotin
working solutions were mixed right before cells were ready to be
added into wells. 13 mL of assay buffer was added to a 50 mL
polyethylene tube. 5.6 .mu.L of 1000 nM biotinylated TECK working
solution and 178 .mu.L of 14 .mu.g/mL Cy5-.alpha.-Biotin working
solution were added to the tube and mixed. The final biotinylated
TECK concentration was 0.4 nM and the final Cy5-.alpha.-Biotin
concentration 0.064 .mu.g/mL.
[0274] Cells were plated right before all other reagents are added
to wells. Cells were collected and centrifuged in a tabletop
centrifuge at 1200 rpm for 5 minutes. The supernatant was removed
by vacuum without disturbing cell pellet. The cells were
resuspended in 5 mL of assay buffer. The cells were counted by
adding 1 mL of a cell suspension to an eppendorf tube. Then 150
.mu.L of this suspension was added to 150 .mu.L of Trypan Blue.
Then 10 .mu.L of Trypan Blue suspension was added to hemocytometer,
and the cell number per mL was calculated. The cells were
resuspended with CCR9 assay buffer to final 0.2.times.10.sup.6
cells/mL for the assay. Approximately 2.6.times.10.sup.6 cells for
1 384 well plate was needed.
[0275] 20 .mu.L of a test compound dissolved in DMSO was added to a
well a polypropylene 384 well plate. Multiple compounds were tested
simultaneously by adding a different test compound to each well. A
control of 20 .mu.L of DMSO in assay buffer was prepared. 20 .mu.L
of the Biotin-Teck and Cy5-.alpha.-Biotin mixed solution was added
to each well of the polypropylene plate. 20 .mu.L of cells
suspension at 0.2.times.10.sup.6/mL was added to each well. The
assay plate was incubated on a rotator at room temperature for 1.5
hour. FMAT was read (PMT=490/518 or 537/568, threshold set a t 1
standard deviation).
II. FLIPR Assay: FLIPR Assay Determines Inhibitors of TECK Induced
Response in Chinese Hamster ovary (CHO) cells that over express
recombinant human CCR9 and the Gal6 protein.
[0276] The day before the assay was run, CHO cells were diluted to
give appropriately 10,000 cells/well (in a volume of 50 mL). Each
well of the 384 black/clear plate was then seeded with 50 mL of the
diluted cell suspension. The cell plates were placed in a
37.degree. C. tissue culture incubator at 6% CO.sub.2
overnight.
[0277] A wash buffer and a dye loading solution were prepared on
the day the assay was preformed. The wash buffer was prepared by
mixing 880 mL of Nanopure water, 100 mL of 10.times.HBSS and 20 mL
of 1M HEPES to give 1 L of a 1.times.HBSS and 20 mM HEPES solution.
1 g of BSA (bovine serum albumin) was added to the 1.times.HBSS/20
mM HEPES solution. A 250 mM probenecid stock solution was prepared
by dissolving 710 mg of probenecid in 5 mL of 1 N NaOH and 5 mL of
previously prepared 1.times.HBSS/20 mM HEPES/0.1% BSA buffer. 10 mL
of 250 mM probenecid was added to the 1.times.HBSS/20 mM HEPES/0.1%
BSA buffer to give a wash buffer having 1.times.HBSS/20 mM
HEPES/2.5 mM probenecid/0.1% BSA.
[0278] For each 384 well plate, 11 mL of 2.times.FLUO-3 dye loading
solution was required. The 2.times.FLUO-3 dye loading solution
prepared by adding 22 mL of DMSO (100%) to each of 2.times.50 mg
vials of FLUO-3. The vials were vortexed, then 22 mL of 20%
pluronic acid was added to each 50 mg vial of FLUO-3 and vortex. 88
mL of reconstituted FLUO-3 stock solution was added to 11 mL of
1.times.wash buffer.
[0279] Each cell plate was washed with the wash buffer. At the end
of the wash, there was 25 mL residual volume per well. 25 mL of dye
loading solution was added to each well of the 384 plate. The
plates were placed in an incubator for at least 1 hour. A
yellowplate calibration plate was run on a FLIPR 384, and a
standard deviation of less than 3.5% was obtained.
[0280] 10 mM stock concentrations of compounds in 100% DMSO were
prepared and stored at room temperature. Stock concentrations
(100.times.final assay concentration) 9.times.1:3 serial dilutions
in 100% DMSO were prepared in order to carry out 10 point
concentration response curves. 3.times.final assay concentration
were prepared by making 1 in 33.3 dilutions of the 100.times.stocks
in wash buffer and were plated into Greiner 384 well plates. 10
point concentration response curves started at 100 mM, 10 mM or 1
mM (final assay concentration). The 1st compound was added to wells
A1-A10 and other compounds were added down the plate to P1-P10.
Columns 11 and 12 were control wells, with FLIPR buffer (with 3%
DMSO) added to wells A11-H12. The remaining compounds were added to
A13-A22 down through P13-P22. Each compound was tested in
triplicate.
[0281] Ligand (rhTECK) plate at 4.times. ligand EC.sub.50 (final
assay concentration) in wash buffer was prepared and plated into a
Greiner 384 well plate. Appropriate amount of 4.times. ligand was
added to wells A1 through P10 and A13 through P22. In columns 11
and 12, FLIPR wash buffer was added to wells A11-D12 and 4.times.
ligand solution was added to wells E11-H12.
[0282] The cell plates were incubated at least a 1 hour with the
dye solution, then washed with wash buffer. At the end of the wash,
there was 25 mL residual volume per well. The cell plate were
loaded onto the stacker of FLIPR-384. Individual well activity
(IWA) was measured, using the max-min function between timepoints
88-145. Data was expressed as % inhibition of rhTECK induced
response, and IC.sub.50 values were calculated for compounds
displaying antagonist activity.
[0283] Inhibition of binding of human TECK to human CCR9 receptors
(FMAT assay) and inhibition of human TECK induced
response(FLIPR)
[0284] Of the compounds tested in the FMAT assay described above,
the following provided an IC.sub.50 value less than or equal to
about 1.0 .mu.M: 17-21, 31-34, 44, 70, 73, 74, and 115.
[0285] Of the compounds tested in the FLIPR assay described above,
the following provided an IC.sub.50 value less than or equal to
about 1.0 .mu.M: 8-13, 14-15, 17-20, 22-24, 31-36, 44, 49, 63, and
69-89, 116-143.
* * * * *