U.S. patent application number 12/082076 was filed with the patent office on 2008-10-09 for novel b1 bradykinin receptor antagonists.
This patent application is currently assigned to Amgen Inc.. Invention is credited to Benny C. Askew, Jian J. Chen, Derin C. D'Amico, Thomas Nguyen, Kevin Yang.
Application Number | 20080249106 12/082076 |
Document ID | / |
Family ID | 35708834 |
Filed Date | 2008-10-09 |
United States Patent
Application |
20080249106 |
Kind Code |
A1 |
Askew; Benny C. ; et
al. |
October 9, 2008 |
Novel B1 bradykinin receptor antagonists
Abstract
The invention encompasses novel compounds and pharmaceutically
acceptable derivatives thereof, pharmaceutical compositions and
methods for treatment of diseases mediated by B1 bradykinin
receptor.
Inventors: |
Askew; Benny C.;
(Marshfield, MA) ; Chen; Jian J.; (Newbury Park,
CA) ; D'Amico; Derin C.; (Newbury Park, CA) ;
Nguyen; Thomas; (Thousand Oaks, CA) ; Yang;
Kevin; (San Gabriel, CA) |
Correspondence
Address: |
AMGEN INC.
1120 VETERANS BOULEVARD
SOUTH SAN FRANCISCO
CA
94080
US
|
Assignee: |
Amgen Inc.
|
Family ID: |
35708834 |
Appl. No.: |
12/082076 |
Filed: |
April 8, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11247050 |
Oct 11, 2005 |
7414134 |
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12082076 |
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60618367 |
Oct 12, 2004 |
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Current U.S.
Class: |
514/254.05 ;
514/326; 514/359; 544/366; 546/210; 548/255 |
Current CPC
Class: |
A61P 27/06 20180101;
A61P 3/10 20180101; C07D 249/04 20130101; C07D 405/14 20130101;
C07D 311/68 20130101; A61P 25/28 20180101; C07C 2603/18 20170501;
C07D 405/04 20130101; A61P 29/00 20180101; C07D 405/06 20130101;
A61P 19/02 20180101; C07C 271/22 20130101; C07D 295/135 20130101;
A61P 11/06 20180101 |
Class at
Publication: |
514/254.05 ;
548/255; 514/359; 544/366; 546/210; 514/326 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 249/06 20060101 C07D249/06; A61K 31/4192 20060101
A61K031/4192; A61K 31/454 20060101 A61K031/454; C07D 401/08
20060101 C07D401/08; C07D 403/08 20060101 C07D403/08 |
Claims
1. A compound of Formula (I): ##STR00064## wherein: A is a group of
formula (a) or (b): ##STR00065## where: R.sup.4 is selected from H,
C.sub.1-3alkyl, C.sub.1-4haloalkyl, F, Cl, Br or I; and R.sup.5 is
a saturated, partially saturated or unsaturated 8-, 9-, 10- or
11-membered bicyclic or 12-, 13-, 14- or 15-membered tricyclic
hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms
independently selected from N, O or S, wherein the carbon and
sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups
and the ring is substituted by R.sup.6, R.sup.7 or R.sup.8
independently selected from basic moieties, and additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from R.sup.6, R.sup.7 and R.sup.8 which are selected from R.sup.g,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 which
are independently selected from Br, Cl, F or I; X is --NR.sup.3--
or C(R.sup.3a)(R.sup.3b)-- where: R.sup.3 is H, phenyl, benzyl or
C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents independently selected
from R.sup.e, R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F
and I; R.sup.3a is H, R.sup.8, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl or C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2 or 3
substituents independently selected from R.sup.e, R.sup.g,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F or
I; and R.sup.3b is H, F, Cl, OCH.sub.3, C.sub.1-2alkyl or CF.sub.3;
or R.sup.3a and R.sup.3b together are C.sub.2-6alkylenyl to form a
spiroalkyl that is substituted by 0, 1, 2 or 3 substituents
independently selected from R.sup.e, R.sup.g, C.sub.1-4haloalkyl,
halo, cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)O R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b, --N(R.sup.a)
(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F
and I; R.sup.1 is selected from H, R.sup.g, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl or C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2, or 3
groups independently selected from R.sup.g, cyano, oxo, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F
or I; R.sup.1a is selected from H, F, Cl,
(C.sub.1-C.sub.3)haloalkyl, or (C.sub.1-C.sub.3)alkyl; R.sup.1b and
R.sup.1c are independently in each instance selected from H,
C.sub.1-3alkyl, C.sub.1-4haloalkyl, F, Cl, Br or I; R.sup.2 is a
saturated, partially saturated or unsaturated 5-, 6- or 7-membered
monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic
hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms selected
from N, O and S, wherein the carbon atoms of the ring are
substituted by 0, 1 or 2 oxo groups and the ring is substituted by
0, 1, 2 or 3 substituents independently selected from R.sup.e,
R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F or I; R.sup.a is independently, at each
instance, H or R.sup.b; R.sup.b is independently, at each instance,
phenyl, benzyl or C.sub.1-6alkyl, the phenyl, benzyl and
C.sub.1-6alkyl being substituted by 0, 1, 2 or 3 substituents
independently selected from halo, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, or --N(C.sub.1-4alkyl)C.sub.1-4alkyl; R.sup.d
is independently, at each instance, C.sub.1-8alkyl,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a; R.sup.e is independently, at each
instance, C.sub.1-6alkyl substituted by 0, 1, 2 or 3 substituents
independently selected from R.sup.d and additionally substituted by
0 or 1 substituents selected from R.sup.g; and R.sup.g is
independently at each instance a saturated, partially saturated or
unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-
or 11-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4
heteroatoms independently selected from N, O and S, wherein the
carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups
and the ring is substituted by 0, 1, 2 or 3 substituents
independently selected from C.sub.1-8alkyl, C.sub.1-4haloalkyl,
halo, cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F or I; or a pharmaceutically-acceptable salt
or hydrate thereof.
2. The compound of claim 1 wherein the basic moieties are
independently selected from amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
3. The compound of claim 1 wherein A is a group of formula (a).
4. The compound of claim 1 wherein A is a group of formula (b).
5. The compound of claim 2 wherein A is a group of formula (a).
6. The compound of claim 2 wherein A is a group of formula (b).
7. The compound of claim 2 wherein R.sup.1a, R.sup.1b, R.sup.1c are
hydrogen and X is --NH--
8. The compound of claim 5 wherein R.sup.1a, R.sup.1b, R.sup.1c are
hydrogen and X is --NH--.
9. The compound of claim 6 wherein R.sup.1a, R.sup.1b, R.sup.1c are
hydrogen and X is --NH--.
10. The compound of claim 2 wherein R.sup.1a, R.sup.1b, R.sup.1c
are hydrogen and X is --C(R.sup.3a)(R.sup.3b)--.
11. The compound of claim 5 wherein R.sup.1a, R.sup.1b, R.sup.1c
are hydrogen and X is --C(R.sup.3a)(R.sup.3b)--.
12. The compound of claim 6 wherein R.sup.1a, R.sup.1b, R.sup.1c
are hydrogen and X is --C(R.sup.3a)(R.sup.3b)--.
13. The compound of claim 2 wherein R.sup.1 is hydrogen, alkyl,
--COOR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a where R.sup.a is H, or
phenyl substituted with 0, 1, 2 or 3 substituents independently
selected from C.sub.1-8alkyl, C.sub.1-4haloalkyl, halo, cyano, or
nitro and R.sup.5 is a ring of formula: ##STR00066## wherein
X.sup.1 is Nor CR.sup.6; X.sup.2 is N or CR.sup.7; X.sup.3 is N or
CR.sup.8; X.sup.4 is N or CH; wherein no more than two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N; and the C ring is a saturated or
partially saturated 6- or 7-membered ring containing 0, 1 or 2
atoms selected from N, O and S, wherein the carbon and sulfur atoms
of the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0 or 1 substituents selected from R.sup.g,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
14. The compound of claim 7 wherein R.sup.1 is hydrogen, alkyl,
--COOR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a where R.sup.a is H, or
phenyl substituted with 0, 1, 2 or 3 substituents independently
selected from C.sub.1-8alkyl, C.sub.1-4haloalkyl, halo, cyano, or
nitro and R.sup.5 is a ring of formula: ##STR00067## wherein
X.sup.1 is N or CR.sup.6; X.sup.2 is N or CR.sup.7; X.sup.3 is N or
CR.sup.8; X.sup.4 is N or CH; wherein no more than two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N; and the C ring is a saturated or
partially saturated 6- or 7-membered ring containing 0, 1 or 2
atoms selected from N, O and S, wherein the carbon and sulfur atoms
of the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0 or 1 substituents selected from R.sup.g,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
15. The compound of claim 8 wherein R.sup.1 is hydrogen, alkyl,
--COOR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a where R.sup.a is H, or
phenyl substituted with 0, 1, 2 or 3 substituents independently
selected from C.sub.1-8alkyl, C.sub.1-4haloalkyl, halo, cyano, or
nitro and R.sup.5 is a ring of formula: ##STR00068## wherein
X.sup.1 is Nor CR.sup.6; X is N or CR.sup.7; X.sup.3 is N or
CR.sup.8; X.sup.4 is N or CH; wherein no more than two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N; and the C ring is a saturated or
partially saturated 6- or 7-membered ring containing 0, 1 or 2
atoms selected from N, O and S, wherein the carbon and sulfur atoms
of the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0 or 1 substituents selected from R.sup.g,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
16. The compound of claim 10 wherein R.sup.1 is hydrogen, alkyl,
--COOR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a where R.sup.a is H, or
phenyl substituted with 0, 1, 2 or 3 substituents independently
selected from C.sub.1-8alkyl, C.sub.1-4haloalkyl, halo, cyano, or
nitro and R.sup.5 is a ring of formula: ##STR00069## wherein
X.sup.1 is Nor CR.sup.6; X is N or CR.sup.7; X.sup.3 is N or
CR.sup.8; X.sup.4 is N or CH; wherein no more than two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N; and the C ring is a saturated or
partially saturated 6- or 7-membered ring containing 0, 1 or 2
atoms selected from N, O and S, wherein the carbon and sulfur atoms
of the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0 or 1 substituents selected from R.sup.1,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
17. The compound of claim 2 wherein R.sup.5 is a ring of formula:
##STR00070## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
18. The compound of claim 2 wherein R.sup.5 is a ring of formula:
##STR00071## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
19. The compound of claim 7 wherein R.sup.5 is a ring of formula:
##STR00072## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
20. The compound of claim 7 wherein R.sup.5 is a ring of formula:
##STR00073## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
21. The compound of claim 8 wherein R.sup.5 is a ring of formula:
##STR00074## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
22. The compound of claim 8 wherein R.sup.5 is a ring of formula:
##STR00075## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
23. The compound of claim 9 wherein R.sup.5 is a ring of formula:
##STR00076## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
24. The compound of claim 9 wherein R.sup.5 is a ring of formula:
##STR00077## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
25. The compound of claim 10 wherein R.sup.5 is a ring of formula:
##STR00078## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
26. The compound of claim 10 wherein R.sup.5 is a ring of formula:
##STR00079## where R.sup.7 is amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkyl-aminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6aminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl wherein each of
the basic moiety can be substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
diC.sub.1-6alkylamino, .dbd.NCN; and C.sub.1-6alkyl, aryl,
heteroaryl, cycloalkyl and heterocyclyl, each of which is
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, or
diC.sub.1-6alkylamino.
27. The compound of claim 17 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
28. The compound of claim 18 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
29. The compound of claim 19 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
30. The compound of claim 20 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
31. The compound of claim 21 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
32. The compound of claim 22 wherein R.sup.1 is hydrogen, methyl,
carboxy, --CONH.sub.2, phenyl or 4-fluorophenyl; R.sup.2 is phenyl
substituted with 0, 1, 2, or 3 substituents independently selected
from halo, alkoxy, alkyl, or haloalkyl, R.sup.4 is hydrogen and
R.sup.7 is isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methylethyl,
1-tert-butylaminoethyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
33. A compound selected from the group consisting of:
(R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic
acid;
(R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide;
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-ylmethyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic
acid;
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((r)-7-((pyridin-2-ylmethylamino)-
methyl)-3,4-dihydro-2h-chromen-4-yl)-1h-1,2,3-triazol-4-yl)propanoic
acid, tfa salt;
(2R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((neopentylamin-
o)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propano-
ic acid;
(R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-
-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanoic
acid tfa salt;
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-7-((piperidin-1-yl-
methyl)chroman-4-yl)-1H-1,2,3-triazol-4-yl)propanamide;
(R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1-
H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide;
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-ylmethyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide;
(2R)-3-(1-(6-((tert-butylamino)methyl)-1,2,3,4-tertahydronaphthalen-1-yl)-
-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide;
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((4-methylpiperazin-1-yl)m-
ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamid-
e;
(2R)-2-(4-methylphenylsulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide;
(2R)-3-(1-(6-((tert-butyl-amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl-
)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide;
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((4-methylpiperazin-1-yl)meth-
yl)-1,2,3,4-tetrahydro-naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide;
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide;
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-(piperidin-1-ylmethyl)-1,2,3,-
4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic acid;
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((neopentylamino)methyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic
acid;
N-((S)-1-(1-(6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-y-
l)-1H-1,2,3-triazol-4-yl)propan-2-yl)-4-methylbenzenesulfonamide;
4-methyl-N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-chroman-4-yl)-1H-1,2,3-
-triazol-4-yl)propan-2-yl)benzenesulfonamide;
4-methyl-N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaph-
thalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide;
N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-hydronaphthalen-1-
-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)-benzenesulfona-
mide;
N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-chromen-4-y-
l)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamid-
e;
N-((S)-1-(1-((R)-7-((tert-butylamino)methyl)-3,4-dihydro-2H-chromen-4-y-
l)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfonamid-
e;
N-((R)-2-(1-((R)-7-((tert-butylamino)methyl)-3,4-dihydro-2H-chromen-4-y-
l)-1H-1,2,3-triazol-4-yl)-1-(4-fluorophenyl)ethyl)-3-(trifluoromethyl)benz-
enesulfonamide;
N-((S)-1-(1-((R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydronaphthale-
n-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfo-
namide;
N-((S)-1-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2h-chrom-
en-4-yl)-1H-1,2,3-triazol-4-yl)-propan-2-yl)-3-(trifluoro-methyl)benzenesu-
lfonamide;
N-((S)-1-(1-((R)-6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tet-
rahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoro-me-
thyl)benzenesulfonamide;
N-((S)-1-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chrome-
n-4-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfo-
namide; or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1.
35. A method of treating a disease mediated by Bradykinin 1 in a
patient which method comprises treating the patient with a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of claim 1.
36. The method of claim 35 wherein the disease is inflammation,
rheumatoid arthritis, cystitis, post-traumatic and post ischemic
cerebral edema, liver cirrhosis, Alzheimer's disease,
cardiovascular disease, pain, common cold, allergies, asthma,
pancreatitis, burns, virus infection, head injury, multiple trauma,
rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis,
neovascularization, corneal haze, glaucoma, ocular pain, ocular
hypertension or angio edema.
37. The method of claim 35 wherein the disease is pain.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of application Ser. No.
11/247,050, filed on Oct. 11, 2005 which claims the benefit under
35 U.S.C. 119(e) of U.S. Provisional Application Ser. No.
60/618,367, filed on Oct. 12, 2004, the disclosure of which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention is in the field of pharmaceutical agents and
specifically relates to compounds, compositions, uses and methods
for treating inflammation-related disorders, including pain.
[0004] 2. State of the Art
[0005] More than two million people in the United States alone are
incapacitated by chronic pain on any given day (T. Jessell & D.
Kelly, Pain and Analgesia in PRINCIPLES OF NEURAL SCIENCE,
third-edition (E. Kandel, J. Schwartz, T. Jessell, eds., (1991)).
Unfortunately, current treatments for pain are only partially
effective, and many cause lifestyle altering, debilitating, and/or
dangerous side effects. For example, non-steroidal
anti-inflammatory drugs ("NSAIDs") such as aspirin, ibuprofen, and
indomethacin are moderately effective against inflammatory pain but
they are also renally toxic, and high doses tend to cause
gastrointestinal irritation, ulceration, bleeding, increased
cardiovascular risk, and confusion. Patients treated with opioids
frequently experience confusion and constipation, and long-term
opioid use is associated with tolerance and dependence. Local
anesthetics such as lidocaine and mixelitine simultaneously inhibit
pain and cause loss of normal sensation. In addition, when used
systemically, local anesthetics are associated with adverse
cardiovascular effects. Thus, there is currently an unmet need in
the treatment of chronic pain.
[0006] Pain is a perception based on signals received from the
environment and transmitted and interpreted by the nervous system
(for review, see M. Millan, Prog. Neurobiol. 57:1-164 (1999)).
Noxious stimuli such as heat and touch cause specialized sensory
receptors in the skin to send signals to the central nervous system
("CNS"). This process is called nociception, and the peripheral
sensory neurons that mediate it are nociceptors. Depending on the
strength of the signal from the nociceptor(s) and the abstraction
and elaboration of that signal by the CNS, a person may or may not
experience a noxious stimulus as painful. When one's perception of
pain is properly calibrated to the intensity of the stimulus, pain
serves its intended protective function. However, certain types of
tissue damage cause a phenomenon, known as hyperalgesia or
pronociception, in which relatively innocuous stimuli are perceived
as intensely painful because the person's pain thresholds have been
lowered. Both inflammation and nerve damage can induce
hyperalgesia. Thus, persons afflicted with inflammatory conditions,
such as sunburn, osteoarthritis, colitis, carditis, dermatitis,
myositis, neuritis, inflammatory bowel disease, collagen vascular
diseases (which include rheumatoid arthritis and lupus) and the
like, often experience enhanced sensations of pain. Similarly,
trauma, surgery, amputation, abscess, causalgia, collagen vascular
diseases, demyelinating diseases, trigeminal neuralgia, cancer,
chronic alcoholism, stroke, thalamic pain syndrome, diabetes,
herpes infections, acquired immune deficiency syndrome ("AIDS"),
toxins and chemotherapy cause nerve injuries that result in
pain.
[0007] As the mechanisms by which nociceptors transduce external
signals under normal and hyperalgesic conditions become better
understood, processes implicated in hyperalgesia can be targeted to
inhibit the lowering of the pain threshold and thereby lessen the
amount of pain experienced.
[0008] Bradykinin (BK) and the related peptide, kallidin (Lys-BK)
mediate the physiological actions of kinins on the cardiovascular
and renal systems. However, the active peptides, BK and kallidin,
are quickly degraded by peptidases in the plasma and other
biological fluids and by those released from a variety of cells, so
that the half-life of BK in plasma is reported to be approximately
17 seconds (1). BK and kallidin are rapidly metabolized in the body
by carboxypeptidase N, which removes the carboxyterminal arginine
residue to generate des-Arg BK or des-Arg kallidin.
Des-Arg-kallidin is among the predominant kinins in man and
mediates the pathophysiological actions of kinins in man. In
addition to being a very potent proinflammatory peptide, des-Arg-BK
or des-Arg-kallidin is known to induce vasodilation, vascular
permeability, and bronchoconstriction (for review, see Regoli and
Barabe, Pharmacological Rev, 32(1), 1-46 (1980)). In addition,
des-Arg-BK and des-Arg-kallidin appear to be particularly important
mediators of inflammation and inflammatory pain as well as being
involved in the maintenance thereof. There is also a considerable
body of evidence implicating the overproduction of des-Arg-kallidin
in conditions in which pain is a prominent feature such as septic
shock, arthritis, angina, and migraine.
[0009] The membrane receptors that mediate the pleiotropic actions
of kinins are of two distinct classes, designated B1 and B2. Both
classes of receptors have been cloned and sequenced from a variety
of species, including man (Menke, et al, J. Biol. Chem. 269,
21583-21586 (1994); Hess et al, Biochem. Biophys. Res. Commun. 184,
260-268 (1992)). They are typical G protein coupled receptors
having seven putative membrane spanning regions. In various
tissues, BK receptors are coupled to every known second messenger.
B2 receptors, which have a higher affinity for BK, appear to be the
most prevalent form of bradykinin receptor. Essentially all normal
physiological responses and many pathophysio-logical responses to
bradykinin are mediated by B2 receptors.
[0010] B1 receptors, on the other hand, have a higher affinity for
des-Arg-BK compared with BK, whereas des-Arg-BK is inactive at B2
receptors. In addition, B1 receptors are not normally expressed in
most tissues. Their expression is induced upon injury or tissue
damage as well as in certain kinds of chronic inflammation or
systemic insult (F. Marceau, et al., Immunopharmacology, 30, 1-26
(1995)). Furthermore, responses mediated by B1 receptors are
up-regulated from a null level following administration of
bacterial lipopolysaccharide (LPS) or inflammatory cytokines in
rabbits, rats, and pigs.
[0011] The pain-inducing properties of kinins coupled with the
inducible expression of B1 receptors make the B1 receptor an
interesting target in the development of anti-inflammatory,
antinociceptive, antihyperalgesic and analgesic agents that may be
directed specifically at injured tissues with minimal actions in
normal tissues.
[0012] Certain compounds have been described as bradykinin
antagonists. WO 03/07958, published 30 Jan. 2003, describes
tetrahydroquinoxalines. Dihydroquinoxalinones are described in a
JACS communication. Piperazine-2,3,5-triones are described in Tet.
Lett., 40, 7557-7560 (1999). European application 641779, published
8 Mar. 1995, describes 3,6-dioxopiperazines as platelet aggregation
inhibitors.
[0013] Clearly, there is a need for new, safe and effective
treatments for inflammation and pain. Such agents are provided in
the present invention.
SUMMARY OF THE INVENTION
[0014] In one aspect, this invention is directed to a compound of
Formula (I):
##STR00001##
[0015] wherein:
[0016] A is a group of formula (a) or (b):
##STR00002##
[0017] where:
[0018] R.sup.4 is selected from H, C.sub.1-3alkyl,
C.sub.1-4haloalkyl, F, Cl, Br or I; and
[0019] R.sup.5 is a saturated, partially saturated or unsaturated
8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15-membered
tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 heteroatoms
independently selected from N, O or S, wherein the carbon and
sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups
and the ring is substituted by R.sup.6, R.sup.7 or R.sup.8
independently selected from basic moieties, and additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from R.sup.6, R.sup.7 and R.sup.8 which are selected from R.sup.9,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.b, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 which
are independently selected from Br, Cl, F or I;
[0020] X is --NR.sup.3-- or --C(R.sup.3a)(R.sup.3b)-- where:
[0021] R.sup.3 is H, phenyl, benzyl or C.sub.1-6alkyl, the phenyl,
benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2 or 3
substituents independently selected from R.sup.e, R.sup.g,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F
and I;
[0022] R.sup.3a is H, R.sup.g, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl or C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2 or 3
substituents independently selected from R.sup.e, R.sup.g,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F or
I; and
[0023] R.sup.3b is H, F, Cl, OCH.sub.3, C.sub.1-2alkyl or CF.sub.3;
or
[0024] R.sup.3a and R.sup.3b together are C.sub.2-6alkylenyl to
form a spiroalkyl that is substituted by 0, 1, 2 or 3 substituents
independently selected from R.sup.e, R.sup.g, C.sub.1-4haloalkyl,
halo, cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atom independently selected from Br, Cl, F
and I;
[0025] R.sup.1 is selected from H, R.sup.g, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl or C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2, or 3
groups independently selected from R.sup.g, cyano, oxo, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F
or I;
[0026] R.sup.1a is selected from H, F, Cl,
(C.sub.1-C.sub.3)haloalkyl, or (C.sub.1-C.sub.3)alkyl;
[0027] R.sup.1b and R.sup.1c are independently in each instance
selected from H, C.sub.1-3alkyl, C.sub.1-4haloalkyl, F, Cl, Br or
I;
[0028] R.sup.2 is a saturated, partially saturated or unsaturated
5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or
11-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4
heteroatoms selected from N, O and S, wherein the carbon atoms of
the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from R.sup.e, R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F or I;
[0029] R.sup.a is independently, at each instance, H or
R.sup.b;
[0030] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl,
--NH.sub.2, --NHC.sub.1-4alkyl, or
--N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0031] R.sup.d is independently, at each instance, C.sub.1-8alkyl,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a.
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0032] R.sup.e is independently, at each instance, C.sub.1-6alkyl
substituted by 0, 1, 2 or 3 substituents independently selected
from R.sup.d and additionally substituted by 0 or 1 substituents
selected from R.sup.g; and
[0033] R.sup.g is independently at each instance a saturated,
partially saturated or unsaturated 5-, 6- or 7-membered monocyclic
or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic hydrocarbon ring
containing 0, 1, 2, 3 or 4 heteroatoms independently selected from
N, O and S, wherein the carbon atoms of the ring are substituted by
0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3
substituents independently selected from C.sub.1-8alkyl,
C.sub.1-4haloalkyl, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F or I; or
[0034] a pharmaceutically-acceptable salt or hydrate thereof.
[0035] In a second aspect, this invention is directed to a
pharmaceutical composition comprising a compound of Formula (I) and
a pharmaceutically acceptable excipient.
[0036] In a third aspect, this invention is directed to a method of
treating a disease in a patient mediated the B1 receptor comprising
administering to the patient a pharmaceutical composition
comprising a therapeutically effective amount of a compound of
Formula (I) and a pharmaceutically acceptable excipient.
Specifically, the compounds of the present invention are useful in
the treatment of a disorder such as acute pain, dental pain, back
pain, lower back pain, pain from trauma, surgical pain, pain
resulting from amputation or abscess, causalgia, fibromyalgia,
demyelinating diseases, trigeminal neuralgia, cancer, chronic
alcoholism, stroke, thalamic pain syndrome, diabetes, acquired
immune deficiency syndrome ("AIDS"), toxins and chemotherapy,
general-headache, migraine, cluster headache, mixed-vascular and
non-vascular syndromes, tension headache, general inflammation,
arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory
bowel disorders, inflammatory eye disorders, inflammatory or
unstable bladder disorders, psoriasis, skin complaints with
inflammatory components, sunburn, carditis, dermatitis, myositis,
neuritis, collagen vascular diseases, chronic inflammatory
conditions, inflammatory pain and associated hyperalgesia and
allodynia, neuropathic pain and associated hyperalgesia and
allodynia, diabetic neuropathy pain, sympathetically maintained
pain, deafferentation syndromes, asthma, vasomotor or allergic
rhinitis, epithelial tissue damage or dysfunction, herpes simplex,
post-herpetic neuralgia, disturbances of visceral motility at
respiratory, genitourinary, gastrointestinal or vascular regions,
wounds, burns, allergic skin reactions, pruritis, vitiligo, general
gastrointestinal disorders, colitis, inflammatory bowel disease,
gastric ulceration, duodenal ulcers, thalamic pain syndrome,
diabetes, toxins and chemotherapy, septic shock, and bronchial
disorders.
[0037] In a fourth aspect, this invention is directed to the use of
one or more of the compounds of the present invention in the
manufacture of a medicament. Preferably, the medicament is useful
in the treatment of a disorder such as acute pain, dental pain,
back pain, lower back pain, pain from trauma, surgical pain, pain
resulting from amputation or abscess, causalgia, fibromyalgia,
demyelinating diseases, trigeminal neuralgia, cancer, chronic
alcoholism, stroke, thalamic pain syndrome, diabetes, acquired
immune deficiency syndrome ("AIDS"), toxins and chemotherapy,
general headache, migraine, cluster headache, mixed-vascular and
non-vascular syndromes, tension headache, general inflammation,
arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory
bowel disorders, inflammatory eye disorders, inflammatory or
unstable bladder disorders, psoriasis, skin complaints with
inflammatory components, sunburn, carditis, dermatitis, myositis,
neuritis, collagen vascular diseases, chronic inflammatory
conditions, inflammatory pain and associated hyperalgesia and
allodynia, neuropathic pain and associated hyperalgesia and
allodynia, diabetic neuropathy pain, sympathetically maintained
pain, deafferentation syndromes, asthma, vasomotor or allergic
rhinitis, epithelial tissue damage or dysfunction, herpes simplex,
post-herpetic neuralgia, disturbances of visceral motility at
respiratory, genitourinary, gastrointestinal or vascular regions,
wounds, burns, allergic skin reactions, pruritis, vitiligo, general
gastrointestinal disorders, colitis, inflammatory bowel disease,
gastric ulceration, duodenal ulcers, thalamic pain syndrome,
diabetes, toxins and chemotherapy, septic shock, and bronchial
disorders. The present invention also comprises the use of a
compound of the invention, or pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for the treatment
either acutely or chronically of pain or an inflammation mediated
disease state, including those described previously. The compounds
of the present invention are also useful in the manufacture of an
anti-inflammatory medicament. The compounds of the present
invention are also useful in the manufacture of a medicament to
attenuate or prevent disorders through inhibition of bradykinin I.
The compounds of the present invention are also useful in the
manufacture of a medicament to treat pain.
[0038] The compounds of this invention may also act as inhibitors
of other receptors or kinases, and thus be effective in the
treatment of diseases associated with other protein kinases.
[0039] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like. More preferred animals include horses, dogs, and
cats.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0040] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0041] The term "C.sub..alpha.-.beta.alkyl" means an alkyl group
having a minimum of a and a maximum of .beta. carbon atoms in a
branched, cyclical or linear relationship or any combination of the
three, wherein .alpha. and .beta. represent integers as indicated
in the claims. The alkyl groups described in this section may also
contain one or two double or triple bonds. When the alkyl group has
a double or triple bond it is also referred to herein as alkenyl or
alkynyl respectively.
[0042] Examples of C.sub.1-6alkyl include, but are not limited to,
the following:
##STR00003##
methyl, and the like.
[0043] The terms "oxo''" represents the group .dbd.O (as in
carbonyl).
[0044] The term "alkoxy" embrace linear or branched oxy-containing
radical --OR where R is alkyl of one to ten carbon atoms. More
preferred alkoxy radicals are "lower alkoxy" radicals having alkyl
of one to six carbon atoms. Examples of such radicals include
methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more
preferred are lower alkoxy radicals with alkyl of one to three
carbon atoms. The "alkoxy" radicals may be further substituted at
the alkyl radical with one or more halo atoms, such as fluoro,
chloro or bromo, to provide "haloalkoxy" radicals. Even more
preferred are lower haloalkoxy radicals having one to three carbon
atoms. Examples of such radicals include fluoromethoxy,
chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and
fluoropropoxy.
[0045] The term "alkoxyalkyl" embraces linear or branched alkyl
radicals having one to ten carbon atoms any of which is substituted
with one or more alkoxy radical as defined above. More preferred
alkoxyalkyl radicals are "lower alkoxyalkyl" radicals respectively
having one to six carbon atoms. Examples of such radicals include
methoxymethyl, methoxyethyl, and the like. Even more preferred are
lower alkoxyalkyl radicals respectively having one to three carbon
atoms alkyl radicals.
[0046] The term "aryl", alone or in combination, means a
carbocyclic aromatic system of 6 to 12 carbon atoms containing one
or two rings wherein such rings may be attached together in a
pendent manner or may be fused provided that at least one of the
ring is aromatic. The term "aryl" embraces aromatic radicals such
as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More
preferred aryl is phenyl. Unless otherwise stated the "aryl" group
may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo,
haloalkyl, nitro, cyano, alkoxy, and lower alkylamino.
[0047] The term "aminoalkyl" embraces linear or branched alkyl
radicals having one to ten carbon atoms any one of which is
substituted with one or more amino radicals. More preferred
aminoalkyl radicals are "lower aminoalkyl" radicals having one to
six carbon atoms and one or more amino radicals. Examples of such
radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl
and aminohexyl. Even more preferred are lower aminoalkyl radicals
having one to three carbon atoms.
[0048] The term "alkylaminoalkyl" embraces aminoalkyl radical as
defined herein having the nitrogen atom independently substituted
with an alkyl radical. More preferred alkylaminoalkyl radicals are
"lower alkylaminoalkyl" radicals having alkyl radicals of one to
six carbon atoms. Even more preferred are lower alkylaminoalkyl
radicals having alkyl radicals of one to three carbon atoms.
Suitable alkylaminoalkyl radicals may be mono or dialkyl
substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl,
N,N-diethylaminomethyl and the like.
[0049] The term "aminoalkenyl" embraces linear or branched alkyl
radicals having two to six carbon atoms and at least a double bond
wherein any one of the carbon atom is substituted with one or more
amino radicals.
[0050] The term "C.sub.1-4alkylaminoalkenyl" embraces aminoalkenyl
radical as defined herein having the nitrogen atom independently
substituted with a C.sub.1-4alkyl radical.
[0051] The term "N-arylaminoalkyl" denotes aminoalkyl radical as
defined herein substituted with an aryl radical. More preferred
arylaminoalkyl radicals are "lower N-arylaminoalkyl" radicals
having alkyl radicals of one to six carbon atoms. Even more
preferred are phenylaminoalkyl radicals having one to three carbon
atoms. Examples of such radicals include N-phenylaminomethyl and
N-phenylaminoethyl.
[0052] The term "aralkylaminoalkyl" embraces aralkyl radicals as
described below, attached to an aminoalkyl radical as defined
herein. More preferred are lower arylalkylaminoalkyl radicals
independently having alkyl radicals of one to three carbon
atoms.
[0053] The term "aralkyl" embraces aryl-substituted alkyl radicals.
Preferable aralkyl radicals are "lower aralkyl" radicals having
aryl radicals attached to alkyl radicals having one to six carbon
atoms. Even more preferred are lower aralkyl radicals phenyl
attached to alkyl portions having one to three carbon atoms.
Examples of such radicals include benzyl, diphenylmethyl and
phenylethyl. The aryl in said aralkyl may be additionally
substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[0054] The term "alkylamino" denotes amino groups, which have been
substituted with one alkyl radical and with two alkyl radicals,
including terms "N-alkylamino" and "N,N-dialkylamino". More
preferred alkylamino radicals are "lower alkylamino" radicals
having one or two alkyl radicals of one to six carbon atoms,
attached to a nitrogen atom. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Suitable
"alkylamino" may be mono or dialkylamino such as N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
[0055] The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals
substituted with an alkylaminoalkoxy radical as defined below. More
preferred alkylaminoalkoxyalkoxy radicals are "lower
alkylaminoalkoxyalkoxy" radicals independently having alkoxy
radicals of one to six carbon atoms. Even more preferred are lower
alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to
three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be
mono or dialkyl substituted, such as N-methylaminoethoxymethoxy,
N,N-dimethylaminoethoxymethoxy, N,N-diethylaminomethoxymethoxy, and
the like.
[0056] The term "alkylaminoalkoxy" embraces alkoxy radicals
substituted with alkylamino radicals. More preferred
alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals
having alkoxy radicals of one to six carbon atoms. Even more
preferred are lower alkylaminoalkoxy radicals having alkyl radicals
of one to three carbon atoms. Suitable alkylaminoalkoxy radicals
may be mono or dialkyl substituted, such as N-methylaminoethoxy,
N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
[0057] The term "aminoalkoxy" embraces alkoxy radicals substituted
with an amino radical. More preferred aminoalkoxy radicals are
"lower aminoalkoxy" radicals having alkoxy radicals of one to six
carbon atoms. Suitable aminoalkoxy radicals may be aminoethoxy,
aminomethoxy, aminopropoxy and the like.
[0058] The term "basic moiety" or "basic moieties" means a chemical
moiety that has a measured or calculated pK.sub.a of from about 7
to about 13. The term also can include a chemical moiety that is
protonable, to some extent, between a pH range of from about 7 to
about 10. Examples of basic moieties include, but are not limited
to, amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkylaminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylamino-C.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl; more
specifically amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkylaminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 5-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclylC.sub.1-6alkyl. More
specifically, amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutylaminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)-piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl. Each basic moiety can be
substituted by 0, 1, 2 or 3 groups independently selected from
halo, --NH.sub.2, --OH, --CN, --CF.sub.3, C.sub.1-6alkylamino,
haloalkyl, oxo, C.sub.1-6alkoxy, C.sub.1-6alkoxyalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, diC.sub.1-6alkylamino,
.dbd.NCN; and C.sub.1-6alkyl, aryl, heteroaryl, cycloalkyl and
heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, --OH, --CN,
--CF.sub.3, C.sub.1-6alkylamino, haloalkyl, oxo, C.sub.1-6alkoxy,
--C.sub.1-6alkoxyalkyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, or diC.sub.1-6alkylamino.
[0059] In one embodiment, the basic moiety is selected from
cycloalkylaminoC.sub.1-6alkyl, cycloalkylC.sub.1-6
alkylaminoC.sub.1-6alkyl, heterocyclylaminoC.sub.1-6alkyl,
heterocyclyl-C.sub.1-6alkylaminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkyl aminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl. In another
embodiment, the basic moiety is selected from
cycloalkylaminoC.sub.1-6alkyl, cycloalkylC.sub.1-6
alkylaminoC.sub.1-6alkyl, heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkylaminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkoxy,
C.sub.1-6alkylaminoC.sub.1-6alkoxyC.sub.1-6alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4alkylamino-C.sub.2-6alkenyl, 4-8-membered
nitrogen-containing heterocyclylC.sub.2-6alkenyl,
heterocyclylC.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl any of which
are substituted by halo, C.sub.1-6alkyl or cycloalkyl.
[0060] The term "cycloalkyl" includes saturated carbocyclic groups.
Preferred cycloalkyl groups include C.sub.3-C.sub.6 rings. More
preferred compounds include cyclopentyl, cyclopropyl, and
cyclohexyl.
[0061] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, denotes --CO.sub.2H.
[0062] The term "cycloalkylaminoalkyl" refers to an aminoalkyl
radical substituted with one cycloalkyl radical, or two cycloalkyl
radicals i.e., it includes "N-cycloalkylaminoalkyl" and
"N,N-dicycloalkylaminoalkyl". More preferred cycloalkylaminoalkyl
radicals are "lower cycloalkylaminoalkyl" radicals having alkyl
radicals with one to six carbon atoms. Even more preferred are
lower cycloalkylaminoalkyl radicals having alkyl radicals with one
to three carbon atoms. Examples of such lower alkylaminoalkyl
radicals include N-cyclohexylaminomethyl, and
N-cyclopentylaminoethyl.
[0063] The term "cycloalkyl-alkylaminoalkyl" embraces cycloalkyl
radicals as described above, attached to an alkylaminoalkyl
radical. More preferred are lower cycloalkyl-alkylaminoalkyl
radicals independently having alkyl radicals of one to three carbon
atoms.
[0064] "Halo" or "halogen" means a halogen atoms selected from F,
Cl, Br and I.
[0065] "C.sub..alpha.-.beta.haloalkyl" means a straight or branched
alkyl group where .alpha. and .beta. are carbon atoms indicated in
the claims where--at least one--of the hydrogen atoms attached to
the alkyl chain are replaced by F, Cl, Br or I e.g.,
trifluoromethyl, difluoromethyl, pentafluoroethyl, and the
like.
[0066] The term "heterocyclyl" embraces saturated, partially
saturated and unsaturated heteroatom-containing ring radicals,
where the heteroatoms are selected from nitrogen, sulfur and
oxygen. It does not include rings containing --O--O-- or --S--S--
groups in the ring system. Preferred heterocyclic radicals include
five to ten membered fused or unfused radicals. Unless otherwise
stated the "heterocyclyl" group may have 1 to 3 substituents such
as hydroxyl, halo, haloalkyl, cyano, lower alkyl, lower aralkyl,
oxo, lower alkoxy, amino, and lower alkylamino.
[0067] Examples of saturated heterocyclic radicals include
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4
nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino,
piperazinyl]; saturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothiophene, dihydropyran, dihydrofuran and
dihydrothiazole.
[0068] Examples of unsaturated heterocyclic radicals, also termed
"heteroaryl" radicals, include unsaturated 5 to 6 membered
heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridinyl,
3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
2H-1,2,3-triazolyl]; unsaturated 3 to 6-membered heteromonocyclic
group containing an oxygen atom, for example, pyranyl, 2-furanyl,
3-furanyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group
containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;
unsaturated 5- to 6-membered heteromonocyclic group containing 1 to
2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0069] The term also embraces radicals where heterocyclic radicals
are fused/condensed with aryl radicals: unsaturated condensed
heterocyclic group containing 1 to 5 nitrogen atoms, for example,
indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolinyl,
isoquinolinyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl
[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed
heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated
condensed heterocyclic group containing 1 to 2 sulfur atoms and 1
to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl].
[0070] The term also includes bridged, spiro and oxo-containing
heterocyclic rings, such as 1,4-dioxa-8-aza-spiro[4.5]decyl,
phthalimidyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, and
(1-aza-bicyclo[2.2.2]oct-3-yl).
[0071] More preferred examples of heteroaryl radicals include
quinolinyl, isoquinolinyl, imidazolyl, pyridinyl, thienyl,
thiazolyl, oxazolyl, furanyl, and pyrazinyl. Even more preferred
heteroaryl radicals are 5- or 6-membered heteroaryl, containing one
or two heteroatoms selected from sulfur, nitrogen and oxygen,
selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl,
piperidinyl and pyrazinyl.
[0072] The term "heterocyclyloxy" refers to --OR radical where
heterocyclyl is as defined above.
[0073] The term "heterocyclylaminoalkyl" embraces heterocyclyl
radicals as described above, attached to an aminoalkyl radical.
[0074] The term "heterocyclylalkyl" embraces
heterocyclic-substituted alkyl radicals. More preferred
heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl"
radicals having alkyl portions of one to six carbon atoms and a 5-
or 6-membered heteroaryl radical. Even more preferred are lower
heteroarylalkyl radicals having alkyl portions of one to three
carbon atoms. Examples include such radicals as pyridinylmethyl and
thienylmethyl.
[0075] The term "heterocyclylalkenyl" embraces
heterocyclic-substituted alkenyl radicals wherein the alkenyl group
has two to six carbon atoms.
[0076] The term "heterocyclylC.sub.1-6alkylaminoC.sub.1-6alkyl"
embraces aminoalkyl radical wherein the alkyl radical has one to
six carbon atoms and further wherein the nitrogen atom of the amino
group is independently substituted with heterocyclylC.sub.1-6alkyl
radical as defined herein.
[0077] The term "unsaturated" used in the claims in conjunction
with the ring (i.e., in the definitions of R.sup.5, R.sup.2, and
R.sup.g) means that the ring(s) in the ring system are aromatic.
Representative examples of unsaturated ring include, but are not
limited to, napthyl, benzimidazole, indole, and the like.
[0078] The term "partially saturated" used in the claims in
conjunction with the ring (i.e., in the definitions of R.sup.5,
R.sup.2, and R.sup.g) means that at least one of the rings in the
ring system is not aromatic. Representative examples of partially
saturated rings include, but are not limited to, dihydronapthyl,
tetrahydronaphthyl, chromenyl, dihydroindole, and the like.
[0079] The phrase "therapeutically-effective" is intended to
qualify the amount of compound of the present invention, which will
achieve the goal of improvement in disorder severity and the
frequency of incidence over treatment of each agent by itself,
while avoiding adverse side effects typically associated with
alternative therapies. For example, effective pain therapeutic
agents relieve the pain sensation of the patient. Alternatively,
effective therapeutic agents for the treatment of inflammation
minimize the damage from the inflammation, and the like.
[0080] The term "treatment" includes therapeutic treatment as well
as prophylactic treatment (either preventing the onset of disorders
altogether or delaying the onset of a pre-clinically evident stage
of disorders in individuals).
[0081] The term "comprising" is meant to be open ended, including
the indicated component but not excluding other elements.
[0082] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups from the genus.
[0083] Compounds of the present invention can possess, in general,
one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or non-racemic mixtures thereof. Unless otherwise
indicated, the compounds of the present invention, as depicted or
named, may exist as the racemate, a single enantiomer, or any
uneven (i.e. non 50/50) mixture of enantiomers, and are all
included in the family of compounds of the invention. The optical
isomers can be obtained by resolution of the racemic mixtures
according to conventional processes, e.g., by formation of
diastereoisomeric salts, by treatment with an optically active acid
or base. Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and
camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column, such as, for example, a CHIRAL-AGP column,
optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of the invention
with an optically pure acid in an activated form or an optically
pure isocyanate. The synthesized diastereoisomers can be separated
by conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of
the invention can likewise be obtained by using optically active
starting materials. These isomers may be in the form of a free
acid, a free base, an ester or a salt. Preferred compounds of the
invention are those wherein the carbon attached to the nitrogen
atom of the triazole ring has an R configuration if it a chiral
carbon:
##STR00004##
[0084] Compounds of the present invention can possess, in general,
tautomeric forms, including any enolate anions such as cyclic and
acyclic amidine and guanidine groups, heteroatom substituted
heterocyclyl groups (Y'=O, S, NR), and the like, which are
illustrated in the following examples. All such forms are within
the scope of this invention.
##STR00005##
[0085] The compounds may also occur in cis- or trans- or E- or
Z-double bond isomeric forms. All such isomeric forms of such
compounds are included in the present invention. All crystal forms
of the compounds described herein are expressly included in the
present invention.
[0086] The term "pharmaceutically-acceptable salts" embraces salts
commonly used to form alkali metal salts and to form addition salts
of free acids or free bases. The nature of the salt is not
critical, provided that it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of the
invention may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, arylaliphatic, heterocyclic carboxylic
and sulfonic classes of organic acids, example of which are formic,
acetic, adipic, butyric, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,
cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,
glycerophosphonic, heptanoic, hexanoic, 2-hydroxyethanesulfonic,
nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,
persulfuric, 2-phenylpropionic, picric, pivalic propionic,
succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic,
algenic, .beta.-hydroxybutyric, salicylic, galactaric and
galacturonic acid. Suitable pharmaceutically-acceptable base
addition salts of compounds of the invention include metallic
salts, such as salts made from aluminum, calcium, lithium,
magnesium, potassium, sodium and zinc, or salts made from organic
bases including primary, secondary and tertiary amines, substituted
amines including cyclic amines, such as caffeine, arginine,
diethylamine, N-ethyl piperidine, histidine, glucamine,
isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine,
piperidine, triethylamine, trimethylamine. All of these salts may
be prepared by conventional means from the corresponding compound
of the invention by reacting, for example, the appropriate acid or
base with the compound of the invention.
[0087] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0088] Examples of acids that may be employed to from
pharmaceutically acceptable acid addition salts include such
inorganic acids as HCl, H.sub.2SO.sub.4 and H.sub.3PO.sub.4 and
such organic acids as oxalic acid, maleic acid, succinic acid and
citric acid. Other examples include salts with alkali metals or
alkaline earth metals, such as sodium, potassium, calcium or
magnesium or with organic bases.
[0089] A "pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes an excipient that is acceptable for
veterinary use as well as human pharmaceutical use. "A
pharmaceutically acceptable excipient" as used in the specification
and claims includes both one and more than one such excipient.
EMBODIMENTS
[0090] While the broadest definition of this invention is set forth
in the Summary of the Invention, certain compounds of Formula (I)
are preferred. For example,
[0091] In one embodiment, in conjunction with any of the below
embodiments, the basic moieties on R.sup.5 are independently
selected from amino, cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl,
heterocyclylaminoC.sub.1-6alkyl,
heterocyclylC.sub.1-6alkylaminoC.sub.1-6alkyl,
arylaminoC.sub.1-6alkyl, arylC.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
aminoC.sub.1-6alkoxy, aminoC.sub.1-6alkyl,
C.sub.1-6alkylaminoC.sub.1-6alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-C.sub.1-6alkylaminoC.sub.2-6alkyl, 5-6 membered
heterocyclyloxy, 4-6 membered nitrogen-containing heterocyclyl and
5-7 membered nitrogen-containing heterocyclyl-alkyl; and wherein
each of said basic moieties is substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
--CF.sub.3, C.sub.1-6alkylamino, oxo, C.sub.1-6alkoxy,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, diC.sub.1-6alkylamino,
C.sub.1-6alkyl, substituted C.sub.1-6alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, cycloalkyl, substituted
cycloalkyl, substituted saturated or partially saturated
heterocyclyl and unsubstituted saturated or partially saturated
heterocyclyl, wherein each substituted C.sub.1-6alkyl, substituted
aryl substituted heteroaryl and substituted saturated or partially
saturated heterocyclyl is substituted by 0, 1, 2 or 3 groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
C.sub.1-6alkylamino, C.sub.1-6haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, or diC.sub.1-6alkylamino.
[0092] In another embodiment, in conjunction with any of the above
or below embodiments, the basic moieties on R.sup.5 are
independently selected from amino,
mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl.
[0093] In another embodiment, in conjunction with any of the above
or below embodiments, the basic moieties on R.sup.5 are
independently selected from amino, aminomethyl,
isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)-aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl.
[0094] In another embodiment, in conjunction with any one of the
above and below embodiments, A is:
##STR00006##
[0095] In another embodiment, in conjunction with any one of the
above and below embodiments, A is:
##STR00007##
[0096] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is H.
[0097] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is selected from R.sup.g,
cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl and C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2, or 3
groups independently selected from R.sup.g, cyano, oxo, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I.
[0098] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is R.sup.g.
[0099] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is selected from cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkyOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, a R.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, benzyl and C.sub.1-6alkyl, with
the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2, or 3
groups independently selected from R.sup.g, cyano, oxo, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I.
[0100] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is --OR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a.
[0101] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is benzyl and C.sub.1-6alkyl,
with the benzyl and C.sub.1-6alkyl being substituted by 0, 1, 2, or
3 groups independently selected from R.sup.g, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I.
[0102] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is C.sub.1-6alkyl substituted
by 1, 2, or 3 groups independently selected from R.sup.g, cyano,
oxo, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aC.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.aC.sub.2-6alkylOR.sup.a, and
additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected
from Br, Cl, F and I.
[0103] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is C.sub.1-6alkyl.
[0104] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1 is phenyl.
[0105] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1a is H.
[0106] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1a is selected from F, Cl,
(C.sub.1-C.sub.3)haloalkyl, and (C.sub.1-C.sub.3)alkyl.
[0107] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1b is H.
[0108] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1c is H.
[0109] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1b is selected from H,
C.sub.1-3alkyl, C.sub.1-3haloalkyl, F, Cl, Br and I.
[0110] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.1c is selected from H,
C.sub.1-3alkyl, C.sub.1-3haloalkyl, F, Cl, Br and I.
[0111] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.2 is phenyl or napthyl, both of
which are substituted by 0, 1, 2 or 3 substituents selected from
R.sup.e, R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I.
[0112] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.2 is phenyl or napthyl, both of
which are substituted by 1, 2 or 3 substituents selected from
R.sup.e, R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I.
[0113] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.2 is a saturated, partially
saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-,
8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2, 3 or 4
atoms selected from N, O and S, wherein the carbon atoms of the
ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 0, 1, 2 or 3 substituents selected from R.sup.e,
R.sup.g, C.sub.1-4haloalkyl, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F and I.
[0114] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.2 is an unsaturated 5-, 6- or
7-membered monocyclic ring containing 1, 2 or 3 atoms selected from
N, O and S, wherein the carbon atoms of the ring are substituted by
0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3
substituents selected from R.sup.e, R.sup.g, C.sub.1-4haloalkyl,
halo, cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F and I.
[0115] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.2 is selected from 2-naphthyl,
1-naphthyl, phenyl, 3-chlorophenyl, 4-chlorophenyl,
3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4,6-trichlorophenyl,
3-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl,
3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 3-methylphenyl, 2,1,3-benzoxadiazol-4-yl,
thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl.
[0116] In another embodiment, in conjunction with any one of the
above and below embodiments, X is --NR.sup.3-- where R.sup.3 is
selected from H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, F, Cl, Br and
I.
[0117] In another embodiment, in conjunction with any one of the
above and below embodiments, X is --CR.sup.3aR.sup.3b-- where
R.sup.3a is selected from H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, F,
Cl, Br and I.
[0118] In another embodiment, in conjunction with any one of the
above and below embodiments, X is --CR.sup.3aR.sup.3b-- where
R.sup.3 and R.sup.3a together form oxo.
[0119] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.4 is selected from H,
C.sub.1-3alkyl, C.sub.1-3haloalkyl, F, Cl, Br and I.
[0120] In another embodiment, in conjunction with any one of the
above and below embodiments, --X is --NR.sup.3-- where R.sup.3 is
H.
[0121] In another embodiment, in conjunction with any one of the
above and below embodiments, X is --CR.sup.3aR.sup.3b-- where
R.sup.3a is H.
[0122] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.4 is H.
[0123] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.5 is a partially saturated 8-,
9-, 10- or 11-membered bicyclic containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, wherein the carbon and sulfur atoms of
the ring are substituted by 0, 1 or 2 oxo groups and the ring is
substituted by 1, 2 or 3 basic moieties, and additionally
substituted by 0, 1, 2 or 3 substituents selected from R.sup.g,
C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F and I, wherein R.sup.5 is attached via a
sp.sup.3 hybridized carbon atom in the bicyclic ring.
[0124] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.5 is:
##STR00008##
[0125] wherein:
[0126] X.sup.1 is N or CR.sup.6;
[0127] X.sup.2 is N or CR.sup.7;
[0128] X.sup.3 is N or CR.sup.8.
[0129] X.sup.4 is N or CH; wherein no more than two of X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is N; and
[0130] the C ring is a saturated or partially saturated 6- or
7-membered ring containing 0, 1 or 2 atoms selected from N, O and
S, wherein the carbon and sulfur atoms of the ring are substituted
by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1
substituents selected from R.sup.g, C.sub.1-8alkyl,
C.sub.1-4haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
[0131] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.5 is:
##STR00009##
[0132] wherein:
[0133] the C ring is a saturated or partially saturated 6- or
7-membered ring containing 0, 1 or 2 atoms selected from N, O and
S, wherein the carbon and sulfur atoms of the ring are substituted
by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1
substituents selected from R.sup.g, C.sub.1-8alkyl,
C.sub.1-4haloalkyl, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2 or 3 substituents independently selected
from Br, Cl, F and I provided that at least one of R.sup.6, R.sup.7
and R.sup.8 is a basic moiety.
[0134] In another embodiment, in conjunction with any one of the
above and below embodiments, R.sup.5 is:
##STR00010##
[0135] wherein the portion of the rings that is attached to the
triazole or oxazole ring is substituted by 0 or 1 substituents
selected from R.sup.g, C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a, and additionally substituted by
0, 1, 2 or 3 substituents independently selected from Br, Cl, F and
I provided that at least one of R.sup.6, R.sup.7 and R.sup.8 is a
basic moiety.
[0136] In another embodiment, in conjunction with any one of the
above and below embodiments,
[0137] R.sup.5 is:
##STR00011##
[0138] wherein portion of the rings that is attached to the
triazole or oxazole ring is substituted by 0 or 1 substituents
selected from R.sup.g, C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano,
nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aC.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.aC.sub.2-6alkylOR.sup.a, and
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from Br, Cl, F and I provided that at least one of
R.sup.6, R.sup.7 and R.sup.8 is a basic moiety.
[0139] In another embodiment, in conjunction with any one of the
above and below embodiments,
[0140] R.sup.5 is:
##STR00012##
[0141] wherein portion of the ring that is attached to the triazole
or oxazole ring is substituted by 0 or 1 substituents selected from
R.sup.g, C.sub.1-8alkyl, C.sub.1-4haloalkyl, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aC.sub.2-6
alkylNR.sup.aR.sup.a and --NR.sup.aC.sub.2-6alkylOR.sup.a, and
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from Br, Cl, F and I provided that at least one of
R.sup.6, R.sup.7 and R.sup.8 is a basic moiety.
[0142] In another embodiment, X is --NH-- and R.sup.1a, R.sup.1b
and R.sup.1c are hydrogen.
[0143] Within this embodiment, a preferred group of compounds is
that where A is a group of formula (a) where R.sup.4 is hydrogen
and R.sup.5 is tetrahydronaphthyl or 3,4-dihydro-2H-chromenyl,
preferably tetrahydronapthlen-1-yl or 3,4-dihydro-2H-chromen-4-yl,
substituted at the 6-position and 7-position respectively, with
cycloalkylaminoC.sub.1-6alkyl,
cycloalkylC.sub.1-6alkylaminoC.sub.1-6alkyl, 5-7 membered
nitrogen-containing heterocyclyl-alkyl, or
C.sub.1-6alkylaminoC.sub.1-6alkyl where heterocyclyl is substituted
by 0, 1, 2 or 3 groups independently selected from halo,
--NH.sub.2, hydroxyl, cyano, C.sub.1-6alkylamino,
C.sub.1-6haloalkyl, oxo, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, or diC.sub.1-6alkylamino. Preferably,
isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methylethyl, 1-tert-butylaminoethyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)-propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)-piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, or piperazin-1-ylmethyl.
[0144] Within the embodiment and more preferred groups contained
therein, an even more preferred group of compounds is that wherein
R.sup.1 is hydrogen, alkyl, --COOR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a where R.sup.a is H, or phenyl
substituted with 0, 1, 2 or 3 substituents independently selected
from C.sub.1-8alkyl, C.sub.1-4haloalkyl, halo, cyano, or nitro,
preferably hydrogen, methyl, carboxy, --CONH.sub.2, phenyl or
4-fluorophenyl; and
[0145] R.sup.2 is phenyl substituted by 0, 1, 2 or 3 substituents
independently selected from R.sup.e, R.sup.g, C.sub.1-4haloalkyl,
halo, cyano, nitro, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--OC.sub.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.b,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkylOR.sup.a, and the ring is additionally
substituted by 0, 1, 2, 3, 4 or 5 substituents independently
selected from Br, Cl, F or I.
[0146] Preferably, R.sup.2 is phenyl, 3-chlorophenyl,
4-chlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl,
2,4,6-trichlorophenyl, 3-fluorophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-biphenyl, 3-chloro-4-methylphenyl,
4-chloro-3-methylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, or
3-methylphenyl.
General Synthetic Procedures
[0147] Compounds of this invention can be made by the methods
depicted in the reaction schemes shown below.
[0148] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.),
or Sigma (St. Louis, Mo.) or are prepared by methods known to those
skilled in the art following procedures set forth in references
such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes
1-17 (John Wiley and Sons, 1994); Rodd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplementals (Elsevier Science
Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and
Sons, 2003), March's Advanced Organic Chemistry, (John Wiley and
Sons, 4th Edition) and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). These schemes are
merely illustrative of some methods by which the compounds of this
invention can be synthesized, and various modifications to these
schemes can be made and will be suggested to one skilled in the art
having referred to this disclosure.
[0149] The starting materials and the intermediates of the reaction
may be isolated and purified if desired using conventional
techniques, including but not limited to filtration, distillation,
crystallization, chromatography and the like. Such materials may be
characterized using conventional means, including physical
constants and spectral data.
[0150] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., more preferably
from about 0.degree. C. to about 125.degree. C. and most preferably
at about room (or ambient) temperature, e.g., about 20.degree.
C.
[0151] Compounds of Formula (I) where X is --NH--, A is a group of
formula (a) and other groups are as defined in the Summary of the
Invention can be prepared as shown in Scheme A below.
##STR00013##
[0152] Reaction of a sulfonyl chloride of formula 1 where R.sup.2
is as defined in the Summary of the Invention with an alkyne of
formula 2 where R.sup.1, R.sup.1a, R.sup.1b, and R.sup.1c are as
defined in the Summary of the Invention provides a compound of
formula 3. The reaction is carried out in the presence of a base
such as sodium carbonate, lithium hydroxide, cesium carbonate, and
the like and in a suitable organic solvent such as methanol,
ethanol, and the like. Compounds of formula 1 such as
benzenesulfonyl chloride, trifluorobenzenesulfonyl chloride, and
tolylsulfonyl chloride are commercially available. Compounds of
formula 2 are either commercially available or they can be prepared
by methods well known in the art. For example, propargylglycine is
commercially available and can be used to prepare other compounds
of formula 2 by methods well known in the art. Some such methods
are described in working examples below. Compounds of formula 3 can
also be prepared from alpha amino acids as described in detail in
working example below.
[0153] Treatment of compound 3 with an azido compound of formula
R.sup.5N.sub.3 where R.sup.5 is as defined in the Summary of the
Invention provides a compound of Formula (I). Compounds of formula
R.sup.5N.sub.3 can be prepared from the corresponding hydroxyl
compound of formula R.sup.5OH by treating it
diphenylphosphorylazide in the presence of
8-diazabicyclo[5.4.0]undec-7-ene in a suitable organic solvent such
as tetrahydrofuran, and the like.
[0154] Alternatively, compounds of Formula (I) where X is --NH--, A
is a group of formula (a) and other groups are as defined in the
Summary of the Invention can be prepared as shown in Scheme B
below.
##STR00014##
[0155] Alternatively, compounds of Formula (I) where X is --NH--, A
is a group of formula (a) and other groups are as defined in the
Summary of the Invention can be prepared by reacting an azido
compound of formula 4 with an amino-protected alkyne of formula 5
under reaction conditions described above to give a compound of
formula 6. Removal of the amino protecting group followed by
reaction of the resulting amino compound of formula 7 with sulfonyl
chloride compound of formula 1 as described above provides a
compound of Formula (I). Suitable amino protecting groups are Fmoc,
Boc, and the like. Other suitable amino protecting groups can be
found in T. Greene and P. Wuts, Protective Groups in Organic
Synthesis, 3rd. Ed., John Wiley and Sons (1999).
[0156] Compounds of Formula (I) where X is --C(R.sup.3aR.sup.3b)--,
A is a group of formula (a) and other groups are as defined in the
Summary of the Invention can be prepared as shown in Scheme C
below.
##STR00015##
[0157] Protection of the hydroxyl group in compound 8 where
R.sup.1, R.sup.1a, R.sup.3a and R.sup.3b are as defined in the
Summary of the Invention and R is an alkyl group, preferably
methyl, followed by reduction of the ester group in the resulting
hydroxyl protected compound with a suitable reducing agent such as
lithium aluminum hydride, and the like and in a suitable ethereal
solvent such as tetrahydrofuran, and the like provides a compound
of formula 9. Suitable hydroxyl protecting groups include benzyl,
and the like. Other suitable hydroxy protecting groups can be found
in T. Greene and P. Wuts, Protective Groups in Organic Synthesis,
3rd. Ed., John Wiley and Sons (11999). Activation of the alcohol OH
group in 9 with TsCl, followed by substitution with lithium
acetylide provides the alkyne compound of formula 11. Protection of
the alkyne with TMSCl after deprotonation with n-BuLi, followed by
deprotection of the hydroxy protecting group and treatment of the
resulting compound with iodine in the presence of triphenylphoshine
proves the compound of formula 11. Treatment of compound 11 with
R.sup.2SH where R.sup.2 is as defined in the Summary of the
Invention followed by oxidation of the sulfur group with a suitable
oxidizing agent such as oxone, Des Martin Peridanane, and the like
provides a compound of formula 12. Removal of the silyl group in 12
with tetrabutylammonium fluoride, followed by reaction with the
azido compound under the mediation of a copper-catalyzed "click"
reaction provides a compound of Formula (I).
Utility
[0158] The compound of Formula (I) are B1 receptor antagonists and
hence are useful in the treatment of a disorder such as acute pain,
dental pain, back pain, lower back pain, pain from trauma, surgical
pain, pain resulting from amputation or abscess, causalgia,
fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer,
chronic alcoholism, stroke, thalamic pain syndrome, diabetes,
acquired immune deficiency syndrome ("AIDS"), toxins and
chemotherapy, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases, lupus,
osteoarthritis, inflammatory bowel disorders, inflammatory eye
disorders, inflammatory or unstable bladder disorders, psoriasis,
skin complaints with inflammatory components, sunburn, carditis,
dermatitis, myositis, neuritis, collagen vascular diseases, chronic
inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain,
sympathetically maintained pain, deafferentation syndromes, asthma,
vasomotor or allergic rhinitis, epithelial tissue damage or
dysfunction, herpes simplex, post-herpetic neuralgia, disturbances
of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritis, vitiligo, general gastrointestinal disorders,
colitis, inflammatory bowel disease, gastric ulceration, duodenal
ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy,
septic shock, and bronchial disorders.
Biological Testing
[0159] The in vitro binding affinity of the compounds of the
invention to the human B1 and B2 bradykinin receptors can be tested
using the radioligand binding assay described in Biological Example
1 below. The antagonistic activity of the compounds of the
invention for the human B1 and B2 bradykinin receptors can be
tested using the calcium flux assay, Rabbit endothelial cell
B1-specific PGI.sub.2 secretion Assay, and umbilical vein Assay
described in Biological Examples 2 and 3 below. The antinociceptive
activity of the compounds of the invention was determined using the
rat and monkey pain models described in Example 4 below. The
antiinflammatory activity of the compounds of the invention was
determined using the Green Monkey LPS inflammation model described
in Example 5 below.
Pharmaceutical Compositions and Administration
[0160] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of the
invention in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention can be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The compounds and compositions of the present invention may, for
example, be administered orally, mucosally, topically, rectally,
pulmonarily such as by inhalation spray, or parentally including
intravascularly, intravenously, intraperitoneally, subcutaneously,
intramuscularly intrasternally and infusion techniques, in dosage
unit formulations containing conventional pharmaceutically
acceptable carriers, adjuvants, and vehicles.
[0161] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals.
[0162] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
For example, these may contain an amount of active ingredient from
about 1 to 2000 mg, preferably from about 1 to 500 mg or 5 to 1000
mg. A suitable daily dose for a human or other mammal may vary
widely depending on the condition of the patient and other factors,
but, once again, can be determined using routine methods.
[0163] The amount of compounds which are administered and the
dosage regimen for treating a disease condition with the compounds
and/or compositions of this invention depends on a variety of
factors, including the age, weight, sex and medical condition of
the subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.01 to 500 mg/kg, preferably between about 0.1 and about 50 mg/kg,
and more preferably about 0.1 and about 20 mg/kg body weight may be
appropriate. The daily dose can be administered in one to four
doses per day.
[0164] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants
appropriate to the indicated route of administration. If
administered, the compounds may be admixed with lactose, sucrose,
starch powder, cellulose esters of alkanoic acids, cellulose alkyl
esters, talc, stearic acid, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulfuric acids, gelatin,
acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropylmethyl cellulose.
[0165] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of compounds of this
invention to the affected area two to four times a day.
[0166] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin (e.g., liniments, lotions, ointments, creams, or pastes)
and drops suitable for administration to the eye, ear, or nose. A
suitable topical dose of active ingredient of a compound of the
invention is 0.1 mg to 150 mg administered one to four, preferably
one or two times daily. For topical administration, the active
ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2%
by weight of the formulation, although it may comprise as much as
10% w/w, but preferably not more than 5% w/w, and more preferably
from 0.1% to 1% of the formulation.
[0167] When formulated in an ointment, the active ingredients may
be employed with either paraffinic or a water-miscible ointment
base. Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound,
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include DMSO and related analogs.
[0168] The compounds of this invention can also be administered by
a transdermal device. Preferably transdermal administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0169] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier, which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base, which forms
the oily, dispersed phase of the cream formulations. Emulsifiers
and emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate,
glyceryl distearate alone or with a wax, or other materials well
known in the art.
[0170] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0171] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The active ingredients are preferably
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% and particularly about 1.5% w/w.
[0172] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (i.e. Captisol),
cosolvent solubilization (i.e., propylene glycol) or micellar
solubilization (i.e., Tween 80).
[0173] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0174] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[0175] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable non-irritating
excipient such as cocoa butter and polyethylene glycols that are
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum and release the drug.
[0176] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents.
[0177] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more compounds of the invention or other
agents. When administered as a combination, the therapeutic agents
can be formulated as separate compositions that are administered at
the same time or sequentially at different times, or the
therapeutic agents can be given as a single composition.
[0178] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[0179] The present compounds may also be used in combination
therapies with opioids and other anti-pain analgesics, including
narcotic analgesics, Mu receptor antagonists, Kappa receptor
antagonists, non-narcotic (i.e. non-addictive) analgesics,
monoamine uptake inhibitors, adenosine regulating agents,
cannabinoid derivatives, Substance P antagonists, neurokinin-1
receptor antagonists, COX-2 inhibitors such as celecoxib,
rofecoxib, valdecoxib, parecoxib, and darecoxib, NSAID's, and
sodium channel blockers, among others. More preferred would be
combinations with compounds selected from morphine, meperidine,
codeine, pentazocine, buprenorphine, butorphanol, dezocine,
meptazinol, hydrocodone, oxycodone, methadone,
tetrahydrocannibinol, pregabalin, Tramadol [(+) enantiomer], DuP
747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078,
ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine,
E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol
[(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,
GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,
SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.
[0180] Alternatively, the present compounds may also be used in
co-therapies with other treatments for inflammation, e.g. steroids,
NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors,
5-lipoxygenase inhibitors, LTB.sub.4 receptor antagonists and
LTA.sub.4 hydrolase inhibitors.
EXAMPLES
[0181] In order that the invention described herein may be more
readily understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner. Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. All
parts are by weight unless otherwise indicated, All compounds
showed NMR spectra consistent with their assigned structures.
Melting points were determined on a Buchi apparatus and are
uncorrected. Mass spectral data was determined by electrospray
ionization technique. All examples were purified to >90% purity
as determined by high-performance liquid chromatography. Unless
otherwise stated, reactions were run at RT.
[0182] Abbreviations used in the examples are defined as follows:
[0183] AcOH, HOAc--acetic acid [0184]
AIBN--2,2'-azobisisobutyronitrile [0185]
BH.sub.3SMe.sub.2--borane-methyl sulfide complex [0186]
BH.sub.3--borane [0187] Br.sub.2--bromine [0188]
CBS--Corey-Bakshi-Shibata Catalyst [0189] CCl.sub.4--carbon
tetrachloride [0190] CH.sub.2Cl.sub.2--dichloromethane; DCM
CH.sub.3CN--acetonitrile [0191] CHCl.sub.3--chloroform [0192]
DBU--1,8-diazabicyclo[5.4.0]undec-7-ene [0193]
DCE--1,2-dichloroethane [0194] DMAP--4-(dimethylamino)pyridine
[0195] DMF--dimethylformamide [0196] DMSO--dimethyl sulfoxide (also
known as methyl sulfoxide) [0197] DPPA--diphenylphosphoryl azide
[0198] EDC, EDCI--(3-dimethylamino-propyl)-ethyl carbodiimide-HCl
salt [0199] Et.sub.2O--diethyl ether [0200] EtOAc--ethyl acetate
[0201] EtOH--ethanol [0202] g--gram [0203] h--hour [0204]
H.sub.2--hydrogen [0205] H.sub.2O--water [0206]
H.sub.2SO.sub.4--sulfuric acid [0207] H.sub.3PO.sub.4-- phosphoric
acid [0208]
HATU--O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0209] HCl--hydrochloric acid [0210]
HCO.sub.2H--formic acid [0211] HOAt--1-hydroxy-7-azabenzotriazole
[0212] HOBt--1-hydroxybenzotriazole [0213] iPr.sub.2NEt, DIEA,
DIPEA--diisopropylethylamine [0214] IPA--isopropanol [0215]
iPrOH--isopropanol [0216] ISCO--ISCO liquid chromatography system
[0217] K.sub.2CO.sub.3--potassium carbonate [0218] KCN--potassium
cyanide [0219] KOH--potassium hydroxide [0220] LAH--lithium
aluminum hydride [0221] LDA--lithium diisopropylamide [0222]
LiOH--lithium hydroxide [0223] Me.sub.2NH --dimethylamine [0224]
MeOH--methanol [0225] MgSO.sub.4-- magnesium sulfate [0226]
min--minutes [0227] mL--milliliter [0228] MP-BH.sub.4-- macroporous
borohydride (Argonaut Technologies) [0229] N.sub.2--nitrogen [0230]
NaBH(OAc).sub.3--sodium triacetoxyborohydride [0231] NaBH.sub.4--
sodium borohydride [0232] NaHCO.sub.3-- sodium bicarbonate [0233]
NaN.sub.3-- sodium azide [0234] NaOAc--sodium acetate [0235]
NaOH--sodium hydroxide [0236] NBS--N-bromosuccinimide [0237]
NH.sub.3-- ammonia [0238] NH.sub.4Cl--ammonium chloride [0239]
NH.sub.4OH --ammonium hydroxide [0240] NMM--N-methylmorpholine
[0241] NMP--1-methyl-2-pyrrolidone [0242] Pd(OH).sub.2-- palladium
hydroxide [0243] Pd/C--palladium on carbon [0244]
PPh.sub.3--triphenylphosphine [0245]
(PPh.sub.3).sub.2NiBr.sub.2--bis(triphenylphosphine)nickel(II)
bromide [0246] RT--room temperature [0247] SiO.sub.2--silica [0248]
SOCl.sub.2--thionyl chloride [0249] TEA, Et.sub.3N--triethylamine
[0250] TFA--trifluoroacetic acid [0251] THF--tetrahydrofuran [0252]
TsCl--p-tosyl chloride [0253] TsOH--p-toluene sulfonic acid
Synthetic Examples
Example 1
Synthesis of methyl
(R)-5-azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylate and
(R)-methyl 4-azido-3,4-dihydro-2H-chromene-7-carboxylate
##STR00016##
[0255] Reagents and Conditions: a)
(R)-2-methyl-CBS-oxazaborolidine, BH.sub.3.DMS or (1S,2S)-TsDPEN,
[RuCl.sub.2(.eta..sup.6-p-cymene)].sub.2, TEA-Formic acid; b) DPPA,
DBU.
Step (i): Synthesis of methyl
(S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3)
[0256] To an oven-dried 2 L round-bottomed flask equipped with an
argon inlet/outlet and magnetic stirring was added
(R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1M solution in
toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the
reaction mixture was cooled in an ice-salt bath (bath
temp.=-10.degree. C.). BH.sub.3--SMe.sub.2 was added (17 mL, 180
mmol, Aldrich), then
5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
(30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over
5 h using a syringe pump. After the addition was complete, the
reaction mixture was stirred for an additional 1 h. The reaction
mixture was poured into an addition funnel, and then added to 200
mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate
that the internal temperature was kept below 0.degree. C. The
mixture was concentrated in vacuo. Et.sub.2O (1 L) was added, and
the mixture was washed with 1M H.sub.3PO.sub.4 (3.times.), 5%
NaHCO.sub.3, and brine (ca. 400 mL each wash). The organic layer
was dried over MgSO.sub.4, filtered and concentrated in vacuo. The
residue was dissolved in Et.sub.2O again (500 mL), and the mixture
was washed with 1M H.sub.3PO.sub.4 (3.times.200 mL), satd
NaHCO.sub.3, and brine. After drying the organic layer over
MgSO.sub.4, the mixture was filtered and concentrated in vacuo,
which gave the title compound as a white-yellow solid. MS (+ ion
ESI) m/z=207 (MH.sup.+), 189 (MH.sup.+--H.sub.2O).
Step (ii) Synthesis of (S)-methyl
4-hydroxy-3,4-dihydro-2H-chromene-7-carboxylate (4)
[0257] A solution of (1S,2S)-TsDPEN (1.709 g, 4.85 mmol) in
isopropanol (5 mL) was added to a 35 mL schlenk-flask and cooled to
0.degree. C. The solution was degassed by three cycles of
evacuation/nitrogen refill. Then,
[RuCl.sub.2(.eta..sup.6-p-cymene)].sub.2 (1.313 g, 2.425 mmol) was
added, followed by TEA (1.352 mL, 9.699 mmol). The reaction mixture
was heated to 80.degree. C. under N.sub.2 for 1 h and cooled. The
iso-propanol was removed under a stream of nitrogen, and dissolved
in 10 mL acetonitrile. The catalyst solution was added to nitrogen
filled 1 L 3-N flask equipped with overhead stirring.
7-Carbomethoxy-4-chromanone (100 g, 485 mmol) and 400 mL
acetonitrile was added to the flask, followed by 5:2 formic
acid-TEA (50 mL). The reaction mixture was incubated for 24 h at
30.degree. C. An additional portion of formic acid-TEA (5 mL) was
added and the reaction mixture stirred for an additional 24 h. The
solution was concentrated completely by rotary evaporation. The
product was purified by crystallization from 200 mL 2-propanol and
100 mL hexanes. The solids were collected by filtration and washed
with cold 2:1 iPrOH-Hex. Final drying of the solids afforded the
title compound. MS (m/z): 208.9 (m+H). Chiral HPLC showed the
enantiomeric purity to be greater than 98%, when compared to
racemic material.
Step (iii) Synthesis of methyl
(R)-5-azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylate (5)
[0258] To a 500 mL three-neck round-bottomed flask equipped with
argon inlet/outlet, thermometer, and magnetic stirring was added
5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid
methyl ester (29 g, 140 mmol) in 280 mL of toluene. The reaction
mixture was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol,
Aldrich) was added (internal temp.=-4.degree. C.). DBU (25 mL, 170
mmol, Aldrich) was added over 10 min at such a rate that the
internal temperature was kept below 1.degree. C. The ice in the
bath was allowed to melt, and the reaction continued for 12 h
during which time the mixture stopped stirring because a
precipitate had formed. Stirring was resumed, and the reaction
mixture was stirred at RT for another 11 h. The reaction contents
were poured into a 2 L sep funnel, and the lower dark-brown layer
was removed. Water (250 mL) was added to the remaining top layer,
and the mixture was extracted with Et.sub.2O (3.times.250 mL). The
combined organic layers were washed with 1M H.sub.3PO.sub.4, water,
satd NaHCO.sub.3, and brine. The organic layer was dried over
MgSO.sub.4, filtered and concentrated in vacuo. Purification by
silica gel chromatography (330 g Isco Redisep.RTM. column, 1:1
hexane-CH.sub.2Cl.sub.2) of the crude material provided the title
compound. MS (+ ion ESI) m/z=232 (MH.sup.+).
Step (iv): Synthesis of (R)-methyl
4-azido-3,4-dihydro-2H-chromene-7-carboxylate (6)
[0259] To a 3 L three-neck round-bottomed flask equipped with argon
inlet/outlet, thermometer, and magnetic stirring was added
(S)-methyl 4-hydroxychroman-7-carboxylate (71 g, 340 mmol) in 800
mL of toluene. The reaction vessel was cooled with a ice/salt bath,
and treated with a solution of diphenylphosphoryl azide (88 mL, 407
mmol, Aldrich) in 200 mL toluene (internal temp.=-4.degree. C.).
After 10 min, a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (61
mL, 407 mmol, Aldrich) in toluene (350 mL) was added over 30 min
(the internal temperature did not exceed 1.degree. C.). The
reaction mixture was warmed to room temp and stirred for 40 h. The
reaction mixture was diluted with 800 mL EtOAc and washed with 1M
H.sub.3PO.sub.4, water, 5% NaHCO.sub.3, and brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography (10:1
hexane-EtOAc) to provide the title compound. MS (+ ion ESI) m/z=234
(MH.sup.+).
Example 2
Synthesis of
(R)-1-((4-azidochroman-7-yl)methyl)-4-fluoropiperidine
##STR00017##
[0261] Reagents and Conditions: a) TBSCl, imidazole; b) Dibal; c)
MnO.sub.2, CHCl.sub.3; d) 4-fluoropiperidine, NaBH(OAc).sub.3; e)
TBAF; f) DPPA, DBU.
Step (i): Synthesis of (S)-methyl
4-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-chromene-7-carboxylate
(7)
[0262] A mixture of
(S)-methyl-4-hydroxyl-3,4-dihydro-2H-chromene-7-carboxylate (10.2
g, 49.0 mmol), imidazole (3.70 g, 53.9 mmol), and TBSCl (8.12 g,
53.9 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction
mixture was quenched with H.sub.2O and extracted with ether
(3.times.). The organic extracts were dried over MgSO.sub.4, and
concentrated to give a brown oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 0.74 (s, 15H), 1.81 (m, 1H), 1.91 (m, 1H),
3.87 (s, 3H), 4.02 (m, 1H), 4.11 (m, 1H), 4.67 (t, 5.2 Hz, 1H),
7.09 (s, 1H), 7.11 (d, 7.6 Hz, 1H), 7.23 (d, 7.6 Hz, 1H).
Step (ii): Synthesis of
(S)-(4-(tert-butyldimethyloxy)-3,4-dihydro-2H-chromen-7-yl)methanol
(8)
[0263] To a stirred solution of (S)-methyl
4-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-chromene-7-carboxylate
(32.2 g, 99.9 mmol) in 150 mL toluene was added 1.5M DIBAL-H in
toluene dropwise. After 1 h, the reaction mixture was cooled to
0.degree. C. and quenched by the slow addition of 2N HCl. The
solution was then extracted with EtOAc (3.times.), dried over
MgSO.sub.4, and concentrated to give a reddish oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 0.74 (s, 15H), 1.81 (m, 1H), 1.91
(m, 1H), 4.02 (m, 1H), 4.11 (m, 1H), 4.55 (s, 2H), 4.67 (t, 5.2 Hz,
1H), 7.09 (s, 1H), 7.11 (d, 7.6 Hz, 1H), 7.23 (d, 7.6 Hz, 1H).
Step (iii): Synthesis of
(S)-4-(tert-butyldimethyloxy)-3,4-dihydro-2H-chromene-7-yl-carbaldehyde
(9)
[0264] A mixture of
(S)-(4-(tert-butyldimethyloxy)-3,4-dihydro-2H-chromen-7-yl)methanol
(29.3 g, 99.57 mmol) and MnO.sub.2 in 150 mL CHCl.sub.3 was stirred
for 6 h at RT. The solid was removed by filtration. The filtrate
was concentrated to afford the title compound as a yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.74 (s, 15H), 1.81 (m,
1H), 1.91 (m, 1H), 4.02 (m, 1H), 4.11 (m, 1H), 4.55 (s, 2H), 4.67
(t, 5.2 Hz, 1H), 7.09 (s, 1H), 7.11 (d, 7.6 Hz, 1H), 7.23 (d, 7.6
Hz, 1H), 9.75 (s, 1H).
Step (iv): Synthesis of
(S)-1-((4-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-chromen-7-yl)methyl-
)-4-fluoropiperidine (10)
[0265] A mixture of
(S)-4-(tert-butyldimethyloxy)-3,4-dihydro-2H-chromene-7-yl-carbaldehyde
(3.65 g, 12.497 mmol), 4-fluoropiperidine.HBr (5 g, 12 mmol),
K.sub.2CO.sub.3 and NaBH(OAc).sub.3 in MeOH (50 mL) was stirred at
RT in 24 h. The methanol was evaporated in vacuo, and the residue
taken up in H.sub.2O. The solution was acidified to pH 3 with 1N
HCl and washed with EtOAc (discarded). The aqueous layer was
neutralized with 1N NaOH, and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic extracts were dried over
MgSO.sub.4, and concentrated afford the title compound. MS (m/z):
364.4 (m+H).
Step (v): Synthesis of
(S)-7-((4-fluoropiperidin-1-yl)methyl-3,4-dihydro-2H-chromen-4-ol
(11)
[0266] A mixture of
(S)-1-((4-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-chromen-7-yl)methyl-
)-4-fluoropiperidine (4.54 g, 12.5 mmol) and TBAF (7.92 g, 37.49
mmol) in THF (50 mL) was stirred for 16 h at RT. The reaction
mixture was taken up in H.sub.2O, and extracted with EtOAc
(3.times.). The organic layers were extracted with 10% aqueous HCl.
The combined aqueous extracts were neutralized with 2N NaOH, and
extracted with CH.sub.2Cl.sub.2 (3.times.). The combined organic
extracts were dried over MgSO.sub.4 and concentrated to give the
title compound as a yellow oil. MS (m/z, m+1): 282.4.
Step (vi): Synthesis of
(R)-1-((4-Azidochroman-7-yl)methyl)-4-fluoropiperidine (12)
[0267] A solution of
(S)-7-((4-fluoropiperidin-1-yl)methyl-3,4-dihydro-2H-chromen-4-ol
(1.9 g, 7.2 mmol) in 20 mL THF was cooled to 0.degree. C. DPPA
(2.56 g, 9.31 mmol) was then added dropwise. After 10 minutes, DBU
(1.42 g, 9.31 mmol) was added and the reaction mixture was stirred
overnight at RT. The THF was removed in vacuo and the residue taken
up in H.sub.2O. The aqueous solution was extracted with EtOAc
(3.times.), dried over MgSO.sub.4, and concentrated. The crude was
purified by SiO.sub.2 chromatography (30% EtOAc/Hexanes) afford the
title compound. MS (m/z, m+1): 291.4.
[0268] Starting from compounds 3 and 6 compounds 18-28 (Table 1)
were prepared as described below:
##STR00018##
[0269] Reagents and Conditions: a)
(R)-2-methyl-CBS-oxazaborolidine, BH3.DMS; b) MnO.sub.2; c) DPPA,
DBU; d) Dibal, THF, 0.degree. C.; e) substituted amine,
NaB(OAc).sub.3, HOAc.
TABLE-US-00001 TABLE 1 Compound X R 18 O ##STR00019## 19 CH.sub.2
##STR00020## 20 CH.sub.2 ##STR00021## 21 CH.sub.2 ##STR00022## 22
CH.sub.2 ##STR00023## 23 CH.sub.2 ##STR00024## 24 CH.sub.2
##STR00025## 25 CH.sub.2 ##STR00026## 26 O ##STR00027## 27 O
##STR00028## 28 O ##STR00029##
Step (i): Synthesis of
(S)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (13)
[0270] To an oven-dried 2 L round-bottomed flask equipped with an
argon inlet/outlet and magnetic stirring was added
(R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1M solution in
toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the
reaction mixture was cooled in an ice-salt bath (bath
temp.=-10.degree. C.). BH.sub.3--SMe.sub.2 was added (17 mL, 180
mmol, Aldrich), then
5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
(30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over
5 h using a syringe pump. After the addition was complete, the
reaction mixture was stirred for an additional 1 h. The reaction
mixture was allowed to stir for 72 h at RT. The reaction mixture
was poured into an addition funnel, and the mixture was added to
200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a
rate that the internal temperature was kept below 0.degree. C. The
mixture was concentrated in vacuo to get a solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.35-1.50 (m, 2H), 1.55-1.75 (m, 2H),
2.30 (s, 1H), 2.35-2.60 (m, 2H), 4.22 (s, 2H), 4.33 (s, 1H), 6.78
(s, 1H), 6.87 (d, 8.0 Hz, 1H), and 7.12 (d, 8.0 Hz, 1H).
Step (ii): Synthesis of
(S)-5-hydroxy-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (14)
[0271] To a stirred solution of
(S)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2.5 g, 14
mmol) in CH.sub.2Cl.sub.2/MeCN (1:1, 80 mL) was added MnO.sub.2
(6.1 g, 70. mmol). The reaction mixture was stirred for 16 h at RT.
The solid was filtered off, and the filtrate was concentrated to
afford the title compound. MS (m/z): 277.2 (M+H).
Step (iii): Synthesis of
(R)-(4-azido-3,4-dihydro-2H-chromen-7-yl)methanol (15)
[0272] (R)-Methyl 4-azido-3,4-dihydro-2H-chromene-7-carboxylate
(21.50 mmol, 1.0 eq) in 50 mL THF was cooled to 0.degree. C., and
treated with DIBAL (63.0 mmol, 3.0 eq). After 2.5 h, the reaction
mixture was quenched by adding 50% saturated K--Na tartrate (60
mL). After stirring 1 h at room temperature, the solution was
extracted with DCM (4.times.50 mL). The organic layers were then
washed with water (2.times.50 mL), dried over MgSO.sub.4 and
concentrated. The residue was purified using SiO.sub.2
chromatography (10.fwdarw.80% EtOAc/Hexanes) to afford the title
compound.
Step (iv): Synthesis of
(R)-5-azido-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (16)
[0273] (S)-5-Hydroxy-5,6,7,8-tetrahydronapthalene-2-carbaldehyde
(19.73 mmol) was dissolved in 50 mL of toluene and cooled to
0.degree. C. Diphenylphosphoryl azide (29.6 mmol, 1.5 eq) was
added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (23.07 mmol,
1.2 eq). After stirring at room temperature overnight, the solvent
was evaporated. The residue was purified by SiO.sub.2
chromatography (5.fwdarw.30% ethyl acetate in dichloromethane) to
afford the title compound. MS (m/z): 204.2 (M+H).
Step (v): Synthesis of
(R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde (17)
[0274] To a stirred solution of
(R)-(4-azido-3,4-dihydro-2H-chromen-7-yl)methanol (3.293 g, 16.05
mmol) in 50 mL DCM was added manganese dioxide (160.3 mmol, 10.0
eq). The reaction mixture was allowed to stir overnight. A second
portion of manganese dioxide (57.84 mmol, 3.5 eq) was added and
stirred an additional 4 h. The reaction mixture was filtered and
concentrated to yield the aldehyde.
Step (vi): Synthesis of
(R)-1-((5-azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)piperidine
(20)
[0275] To a 100 mL flame dry round bottom flask was added
(R)-5-azido-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (200 mg,
0.99 mmol), piperidine (0.5 mL, 5 mmol), dry DCM (10 mL), HOAc (1
drop), and CH(OMe).sub.3. The resulting mixture was stirred under
N.sub.2 for 3 h at RT. Then, NaBH(OAc).sub.3 (632 mg, 2.98 mmol)
was added and stirred for 20 h. The reaction mixture was quenched
with 5% NaHCO.sub.3 and concentrated in vacuo. The residue was
partitioned between EtOAc and H.sub.2O. The organic layer was
washed with H.sub.2O, brine, dried over MgSO.sub.4 and
concentrated. The residue was purified by SiO.sub.2 (95% DCM:5%
MeOH) to afford the title compound. MS (m/z): 271.2 (M+H) (Calc'd.
for C.sub.16H.sub.22N.sub.4: 270.37).
[0276]
(R)-1-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)piperidine (18)
was synthesized by the procedure described for (20);
[0277] Using the same procedure described for (20), and using
(R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde afforded
(R)-1-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)piperidine (26)
MS m/z: 273.6 (M+H) (Calc'd for C.sub.15H.sub.20N.sub.4O--272.35);
and
[0278] Using the same procedure described for (20), and using
(R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde afforded
(R)-N-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)-cyclopentylamine
(27) MS (m/z): 273.3 (M+H) (Calc'd for C.sub.15H.sub.20N.sub.4O:
272.35).
Synthesis of
(R)-N-((5-azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)cyclopentan-amin-
e (22)
[0279] (R)-5-Azido-5,6,7,8-tetrahydronapthalene-2-carbaldehyde (1
g, 5 mmol) in 10 mL DCM was treated with cyclopentylamine (14.9
mmol, 3 eq), acetic acid (14.9 mmol, 3 eq) and MgSO.sub.4. After
stirring for 3 d, sodium triacetoxy borohydride (14.9 mmol, 3 eq)
was added, and stirred overnight. A 5% solution of NaHCO.sub.3 was
then added to the thick immulsion, and extracted with DCM
(3.times.). The combined organic layers were washed with 5%
NaHCO.sub.3 (2.times.), dried over MgSO.sub.4 and concentrated. The
residue was purified by SiO.sub.2 chromatography (0.fwdarw.20%
Methanol, 60.fwdarw.40% DCM, 40% THF) to afford the product. MS
(m/z): 271.2 (m+H) (Calc'd. for C.sub.16H.sub.22N.sub.4: 270.37).
[0280]
(R)-N-((5-Azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-2-methylpropan--
2-amine (19) MS (m/z): 259.2 (m+H) and
(R)-N-((5-Azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-2,2-dimethylpro-
pan-1-amine (21) MS (m/z): 273.3 (m+H); [0281]
(R)-1-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine
(28) MS (m/z): 291.2 (M+H) (Calc'd for Cl.sub.5Hg.sub.9FN.sub.4O:
290.31); and [0282]
(R)-N-((5-Azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-2-methylpropan--
1-amine (23) MS (m/z): 259.2 (m+H) were prepared as described
above. [0283]
(R)-1-((5-Azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-4-methyl-
piperazine (24) was prepared using the same method described for
(22) except the product was purified using C18 chromatography
(10.fwdarw.100% acetonitrile water over 14 min). Removal of the
solvent afforded the product. MS (m/z): 286.2 (m+H); [0284]
(R)-1-((5-Azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-4-fluoropiperaz-
ine (25) was prepared using the same method described for (22)
except the product was purified using SiO.sub.2 (40% EtOAc in
hexanes) to afford the product. MS (m/z): 289.2 (m+H) (Calc'd for
C.sub.16H.sub.21FN.sub.4: 288.36).
Example 3
Synthesis of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynamide
##STR00030##
[0286] Reagents and Conditions: a) D-propargyl alanine,
Na.sub.2CO.sub.3, substituted benzenesulfonyl chloride; b) for 37,
MeOH, HCl, D-propargyl alanine, Na.sub.2CO.sub.3,
3-trifluoromethylbenzene-sulfonyl chloride, LiOH; c) HOAt, DIPEA,
EDC.sub.1, NH.sub.4Cl.
Synthesis of (R)-(2-benzenesulfonamido)pent-4-ynoic acid (33)
[0287] A mixture of d-propargylglycine (32.10 g, 88.46 mmol),
Na.sub.2CO.sub.3 (20.62 g, 194.6 mmol), and benzenesulfonyl
chloride (18.74 g, 106.2 mmol) in p-dioxane/H.sub.2O (1:1, 200 ml)
was stirred overnight at rt. The reaction mixture was concentrated
and the ph adjusted to 4.0 with 10% hcl. The aqueous layer was
extracted with CHCl.sub.3 (3.times.), dried over mgso.sub.4, and
concentrated to give the title compound. .sup.1H NMR (400 mhz,
CDCl.sub.3): .delta. 2.04 (s, 1h), 2.65 (s, 3h), 2.71 (m, 2h), 4.11
(m, 1h), 5.61 (d, 8.4 hz, 1h), 7.61 (m, 3h), 7.88 (m, 2h).
Synthesis of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynoic acid
(34)
[0288] Using the same procedure described for 33,
d-propargylglycine (5 g, 44 mmol), Na.sub.2CO.sub.3 (9.84 g, 92.9
mmol), and p-TsCl (10.62 g, 48.65 mmol) afforded the title
compound. .sup.1h nmr (400 mhz, cdcl.sub.3): .delta. 2.04 (s, 1 h),
2.65 (s, 3h), 2.71 (m, 2h), 4.11 (m, 1h), 5.61 (d, 8.4 hz, 1h),
7.31 (d, 8.0 hz, 2h), 7.77 (d, 8.0 hz, 2h).
Synthesis of (R)-4-(4-methoxylbenzenesulfonamido)pent-4-ynoic acid
(35)
[0289] Using the same procedure described for 33, and
4-methoxybenzenesulfonyl chloride afforded the title compound. MS
(m/z, m+1): 284.4.
Synthesis of (R)-4-(4-chlorobenzenesulfonamido)pent-4-ynoic acid
(36)
[0290] Using the same procedure described for 34, and
4-chlorobenzenesulfonyl chloride afforded the title compound. MS
(m/z, m+1): 289.3.
Synthesis of
(R)-4-(3-trifluoromethylbenzenesulfonamido)pent-4-ynoic acid
(37)
[0291] A mixture of D-propargylglycine (13 g, 115 mmol) and 4M HCl
in 100 mL p-dioxane and 150 mL MeOH was refluxed for 16 h. The
reaction mixture was cooled and concentrated to give a light yellow
oil. The crude methyl ester (9.45 g, 57.5 mmol) was dissolved in
150 mL CH.sub.2Cl.sub.2 and treated with pyridine (10.25 g, 126.5
mmol) and cooled to 0.degree. C. To the cooled solution was added
3-trifluoromethylphenylsulfonyl chloride (14.1 g, 57.5 mmol). After
stirring for 3 h, H.sub.2O was added and layers were separated. The
organic layer was dried over MgSO.sub.4 and concentrated to afford
the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 2.05
(s, 1H), 2.68 (m, 2H), 3.65 (s, 3H), 4.28 (m, 1H), 6.67 (d, 8.8 Hz,
1H), 7.75 (d, 7.8 Hz, 1H) 7.87 (t, 7.8 Hz, 1H), 8.05 (d, 7.8 Hz,
1H), 8.11 (s, 1H).
Synthesis of (R)-2-(3,4-dichlorobenzenesulfonamido)pent-4-ynoic
acid (38)
[0292] (R)-2-Aminopent-4-ynoic acid (16.0 g, 141 mmol) and
Na.sub.2CO.sub.3.H.sub.2O (36.8 g, 296 mmol) were dissolved in 500
mL H.sub.2O and 300 mL p-dioxane. To this solution was added
3,4-dichlorobenzene-1-sulfonyl chloride (33.0 g, 134 mmol) dropwise
over 25 min. The solution was stirred at RT for 19 h. The solution
was then acidified with 5N HCl to pH 1. EtOAc (400 mL) and sat'd
NaCl aq. (200 mL) were added and organic layer was separated. The
aqueous phase was extracted with EtOAc (200 mL.times.2), and the
combined EtOAc extracts were washed with brine (400 mL.times.4) and
dried over Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and dried in vacuo to yield 38.
Synthesis of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynamide
(39)
[0293] A mixture of (R)-2-(4-methylphenyl sulfonamido)pent-4-ynoic
acid (1.0 g, 3.7 mmol), HOAt (0.76 g, 5.6 mmol), iPr.sub.2NEt (2.17
g, 16.9 mmol), NH.sub.4Cl (0.6 g, 11 mmol), and EDCI (1.07 g, 5.61
mmol) in 20 mL DMF was stirred for 18 h at RT. Water was added,
which caused a precipitate to form. The white solid was filtered
and air dried to afford the title compound. MS (m/z, m+1):
267.3.
Example 4
Synthesis of (R)-methyl
2-(((9H-fluoren-9-yl)methoxy)carbonyl)pent-4-ynoate
##STR00031##
[0295] Reagents and Conditions: a) Methanol, HCl.
Synthesis of (R)-methyl
2-(((9H-fluoren-9-yl)methoxy)carbonyl)pent-4-ynoate (41)
[0296] A mixture of D-Fmoc-propargylglycine (40, 9.5 g, 28 mmol),
4M HCl in p-dioxane (10 mL) and 100 mL MeOH was refluxed for 24 h.
The reaction mixture was cooled and concentrated to afford the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 2.65
(m, 1H), 3.21 (s, 1H), 3.65 (s, 3H), 4.22 (m, 2H), 4.33 (d, 6.8 Hz,
2H), 7.32 (t, 7.6 Hz, 2H), 7.44 (t, 7.6 Hz, 2H), 7.73 (d, 7.6 Hz,
2H), 7.91 (d, 7.6 Hz, 2H), 7.97 (d, 1H).
Example 5
Synthesis of
(S)-N-(pent-4-yn-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
(S)-N-(pent-4-yn-2-yl)-3-(trifluoromethyl)benzenesulfonamide and
(R)-N-(1-(4-fluorophenyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamid-
e
##STR00032##
[0298] Reagents and Conditions: a) LiAlH.sub.4, THF, reflux; b)
substituted benzenesulfonyl chloride, pyridine; c) KO-t-Bu, THF; d)
lithium trimethylsilylacetylide; e) K.sub.2CO.sub.3, MeOH.
Step (i): Synthesis of (S)-2-Amino-2-(4-fluorophenyl)ethanol
(44)
[0299] To a 150 mL flame dry round bottom flask was added
LiAlH.sub.4 (1.14 g, 29.9 mmol) and 70 mL THF. The solution was
cooled to 0.degree. C. and (S)-2-amino-2-(4-fluorophenyl)acetic
acid (2.53 g, 15.0 mmol) was added portionwise. Following the
addition, the reaction mixture was heated to reflux under N.sub.2
for 20 h. The resulting mixture was then cooled to 0.degree. C. and
quenched slowly with 5% NaHCO.sub.3. The solvents were removed and
the residue was suspended in EtOAc. After-2 h, the white
precipitate was filtered and the filtrate concentrated to give the
title compound. MS (m/z): 156.3 (M+H) (Calc'd for
C.sub.8H.sub.10FNO: 155.17).
Step (ii): Synthesis of (S)-2-(4-Methylbenzenesulfonamido)propyl
4-methylbenzenesulfonate (45)
[0300] p-Toluenesulfonyl chloride (25.38 g, 133.1 mmol) was
dissolved in 70 mL dry pyridine and cooled to 0.degree. C.
(S)-2-Aminopropan-1-ol (43, 5.0 g, 66 mmol) in 20 mL dry pyridine
was added dropwise via an addition funnel and the resulting mixture
was stirred for 20 h at RT. The reaction mixture was concentrated
and the residue was partitioned between EtOAc and H.sub.2O. The
organic layer was washed with 1N HCl (4.times.50 mL), H.sub.2O, 5%
NaHCO.sub.3, brine, dried over MgSO.sub.4 and concentrated. The
residue was purified by SiO.sub.2 chromatography (80% Hex:20%
Acetone) to afford the title compound. MS (m/z): 384.2 (M+H)
(Calc'd for C.sub.17H.sub.21NO.sub.5S.sub.2: 383.48).
[0301] Proceeding as described for (45), but using
(S)-2-aminopropan-1-ol and 3-trifluoromethylbenzenesulfonyl
chloride afforded
(S)-2-(3-(trifluoromethyl)benzenesulfonamido)propyl
3-(trifluoromethyl)benzenesulfonate (46). MS (m/z): 492.1 (M+H)
(Calc'd for C.sub.17H.sub.15F.sub.6NO.sub.5S.sub.2: 491.03).
[0302] Proceeding as described for (45), but using
(S)-2-amino-2-(4-fluorophenyl)ethanol and
3-trifluoromethylbenzenesulfonyl chloride afforded
(S)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)benzenesulfonamido)ethyl
3-(trifluoromethyl)benzenesulfonate (47). MS m/z: 572.3 (M+H)
(Calc'd for C.sub.22H.sub.16F.sub.7NO.sub.5S.sub.2: 571.48).
Step (iii): Synthesis of
(S)-2-methyl-1-(3-(trifluoromethyl)benzenesulfonyl)-aziridine
(49)
[0303] (S)-2-(3-(Trifluoromethyl)benzenesulfonamido)propyl
3-(trifluoromethyl)benzenesulfonate (1.60 g, 3.26 mmol) was
dissolved in 25 mL dry THF and treated with KOtBu (5.0 g, 4.9
mmol). The resulting mixture was stirred for 20 h at RT. The
reaction mixture was quenched with sat. NH.sub.4Cl and the solvent
was removed. The residue was partitioned between EtOAc/H.sub.2O.
The organic layer was washed with sat. NH.sub.4C.sub.1, H.sub.2O,
brine, dried over MgSO.sub.4 and concentrated. The residue was
purified by SiO.sub.2 (90% hexanes:10% Acetone) to afford the final
compound. MS (m/z): 266.1 (M+H) (Calc'd for
C.sub.10H.sub.10F.sub.3NO.sub.2S: 265.25).
[0304] Proceeding as described for (49), but using
(S)-2-(4-methylbenzenesulfonamido)propyl 4-methylbenzenesulfonate
afforded (S)-2-methyl-1-(4-methylbenzene-sulfonyl)aziridine
(48).
[0305] MS m/z: 212.1 (M+H) (Calc'd for C.sub.10H.sub.13NO.sub.2S:
211.28).
[0306] Proceeding as described for (49), but using
(S)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)-benzenesulfonamido)ethyl
3-(trifluoromethyl)benzenesulfonate afforded
(S)-2-(4-Fluorophenyl)-1-(3-(trifluoromethyl)benzenesulfonyl)aziridine
(50). MS (m/z): 355.2 (M+H) (Calc'd for C.sub.15H,
F.sub.4NO.sub.2S: 354.31).
Step (iv): Synthesis of
(S)-4-methyl-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide
(51)
[0307] (Trimethylsilyl)acetylene (5.8 mL, 41.65 mmol) was dissolved
in 15 mL dry TMEDA and cooled to 0.degree. C. n-BuLi (12.50 mL,
31.24 mmol) was added dropwise via an addition funnel and the
resulting mixture was stirred for 20 min at RT. The solution was
recooled to 0.degree. C. and cannulated to a 0.degree. C. solution
of (S)-2-methyl-1-(4-methylbenzenesulfonyl)aziridine (2.2 g, 10.4
mmol) in 15 mL TMEDA. The resulting solution was stirred for 20 h
at RT. The reaction mixture was cooled to 0.degree. C. and quenched
with sat. NH.sub.4Cl and the organic solvent removed. The residue
was partitioned between EtOAc and H.sub.2O. The organic layer was
washed with sat. NaHCO.sub.3, brine, dried over MgSO.sub.4 and
concentrated. The residue was purified by SiO.sub.2 (90%
hexanes:10% acetone) to afford the title compound. MS (m/z): 310.2
(M+H) (Calc'd for C.sub.15H.sub.23NO.sub.2SSi: 309.5).
[0308] Proceeding as described for (51), but using
(S)-2-methyl-1-(3-(trifluoromethyl)-benzenesulfonyl)aziridine
afforded
(S)-3-(trifluoromethyl)-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfon-
amide (52). MS (m/z): 364.1 (M+H) (Calc'd for
C.sub.15H.sub.20F.sub.3NO.sub.2SSi: 363.47).
[0309] Proceeding as described for (51), but using
(S)-2-(4-fluorophenyl)-1-(3-(trifluoromethyl)benzenesulfonyl)aziridine
afforded
(R)-N-(1-(4-fluorophenyl)-4-(trimethylsilyl)but-3-ynyl)-3-(trifl-
uoromethyl)benzenesulfonamide (53). MS (m/z): 444.3 (M+H) (Calc'd
for C.sub.20H.sub.21F.sub.4NO.sub.2SSi: 443.54).
Step (v) Synthesis of
(S)-4-methyl-N-(pent-4-yn-2-yl)benzenesulfonamide (54)
[0310]
(S)-4-Methyl-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide
(2.0 g, 6.5 mmol) was dissolved in 15 mL MeOH and treated with
K.sub.2CO.sub.3 (1.3 g, 9.7 mmol). The resulting mixture was
stirred for 2 h at RT. The reaction mixture was quenched with sat.
NH.sub.4Cl and the solvent removed. The residue was partitioned
between EtOAc/H.sub.2O. The organic layer was washed with sat.
NaHCO.sub.3, H.sub.2O, brine, dried over MgSO.sub.4 and
concentrated. The residue was purified using SiO.sub.2 (80%
hexanes:20% acetone) to afford the title compound. MS (m/z): 238.3
(M+H) (Calc'd for C.sub.12H.sub.15NO.sub.2S: 237.32).
[0311] Proceeding as described for (54), but using
(S)-3-(trifluoromethyl)-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfon-
amide afforded
(S)-N-(pent-4-yn-2-yl)-3-(trifluoromethyl)-benzenesulfonamide (55).
MS (m/z): 292.1 (M+H) (Calc'd for C.sub.12H.sub.12F.sub.3NO.sub.2S:
291.29).
[0312] Proceeding as described for (54), but using
(R)-N-(1-(4-fluorophenyl)-4-(trimethylsilyl)but-3-ynyl)-3-(trifluoromethy-
l)benzenesulfonamide afforded
(R)-N-(1-(4-fluorophenyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamid-
e (56). MS (m/z): 372.1 (M+H) (Calc'd for
C.sub.17H.sub.13F.sub.4NO.sub.2S: 371.35).
Example 6
Synthesis of
(R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic
acid
##STR00033##
[0314] Reagents and conditions: a) Sodium ascorbate,
CuSO.sub.4.5H.sub.2O, t-BuOH/water; b) piperidine, DMF; c) TsCl,
pyr; d) LiOH.
Step (i): Synthesis of (R) methyl
2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-(1-((R)-7-((4-fluoropiperidin-1--
yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propanoate
(57)
[0315] To a stirred mixture of
(R)-1-((4-azido-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine
(0.83 g, 2.9 mmol) and (R)-methyl
2-(((9H-fluoren-9-yl)methoxy)-carbonyl)pent-4-ynoate (1.0 g, 2.9
mmol) in t-BuOH/H.sub.2O (1:1, 40 mL) was added a solution of
sodium ascorbate (30. mg, 0.14 mmole) in H.sub.2O (300 .mu.L),
followed by CuSO.sub.4.5H.sub.2O (7 mg, 0.03 mmol) in H.sub.2O (300
.mu.L). The reaction mixture was stirred for 72 h at RT. The
reaction mixture was concentrated, extracted with CH.sub.2Cl.sub.2
(3.times.), dried over MgSO.sub.4, and concentrated. The residue
was purified by SiO.sub.2 (2% MeOH/CH.sub.2Cl.sub.2) to give the
title compound. MS (m/z): 640.4 (m+H).
Step (ii) Synthesis of (R)
methyl-amino-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H--
chromen-4-yl)-1H-1,2,3-triazol-4-yl)propanoate (58)
[0316] To a stirred solution of (R)-methyl
2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-(1-(R)-7-((4-fluoropiperidin-1-y-
l)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propanoate
(0.45 g, 0.71 mmol) in 8 mL DMF was added 2 mL piperidine. Stirring
was continued for 10 min. The reaction mixture was concentrated,
taken up in H.sub.2O and acidified to pH 1 with 10% HCl. The
aqueous layer was washed with EtOAc. The aqueous layer was then
neutralized with 2N NaOH and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic extracts were dried over
MgSO.sub.4, concentrated and purified by SiO.sub.2 (5%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound. MS (m/z, m+1):
418.4.
Step (iii): Synthesis of (R)-methyl
3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-
-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoate
(59)
[0317] A mixture of (R)
methyl-amino-3-(1-(R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-c-
hromen-4-yl)-1H-1,2,3-triazol-4-yl)propanoate (0.165 g, 0.4 mmol),
i-Pr.sub.2NEt (61 mg, 0.47 mmol), and p-TsCl (90 mg, 0.47 mmol) in
4 mL CH.sub.2Cl.sub.2 was stirred for 24 h at RT. The reaction
mixture was concentrated, and stirred with H.sub.2O and hexane,
which caused a precipitate to form. The tan solid was filtered and
air-dried to afford the title compound. MS (m/z): 572.3 (m+1).
Step (iv): Synthesis of
(R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic
acid (60)
[0318] (R)-Methyl
3-(1-((R)-7-((4-Fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-yl)-
-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoate
(130. mg, 0.228 mmol), 1N LiOH (0.3 mL, 0.3 mmol) in 4 mL MeOH was
stirred for 14 h at RT. The reaction mixture was then stirred at
55.degree. C. for 24 h. The reaction mixture was cooled,
concentrated and neutralized with 1N HCl. A precipitate formed that
was filtered and washed with ether to afford the title compound. MS
(m/z): 558.4 (m+H).
Example 7
Synthesis of
(R)-3-(1-((R)-7-((4-fluoropiperidin-1-yl)methyl)-3,4-dihydro-2H-chromen-4-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide
##STR00034##
[0320] Reagents and conditions: a) Sodium ascorbate,
CUSO.sub.4.5H.sub.2O, t-BuOH/water.
[0321] To a stirred mixture of (R)-2-4-methylphenyl
sulfonamido)pent-4-ynamide (0.3 g, 1.1 mmol) and
(R)-1-((4-azido-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine
(0.33 g, 1.1 mmol) in 15 mL t-BuOH was successively treated with
sodium ascorbate (23 mg, 0.11 mmol in 300 .mu.L H.sub.2O) and
CuSO.sub.4.5H.sub.2O (30 mg, 0.113 mmol in 300 .mu.M H.sub.2O). An
additional portion of H.sub.2O (10 mL) was added. The reaction
mixture was stirred for 16 h at RT. The reaction mixture was
concentrated, taken up in H.sub.2O and extracted with CHCl.sub.3
(3.times.). The combined extracts were dried over MgSO.sub.4,
concentrated, and purified by SiO.sub.2 (5% MeOH/CH.sub.2Cl.sub.2)
to afford the title compound. MS (m/z): 557.4 (m+H).
Example 8
Synthesis of
(R)-3-(1-((R)-7-formyl-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl-
)-2-(4-methylbenzenesulfonamido)propanoic acid and
(R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazo-
l-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid
##STR00035##
[0323] Reagents and conditions: a) Sodium ascorbate,
CuSO.sub.4.5H.sub.2O, t-BuOH/water.
Synthesis of
(R)-3-(1-((R)-7-formyl-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl-
)-2-(4-methylbenzenesulfonamido)propanoic acid (62)
[0324] To a stirred mixture of
(R)-2-(4-methylbenezenesulfonamido)pent-4-ynoic acid (1.32 g, 4.92
mmol) and (R)-4-azido-3,4-dihydro-2H-chromen-7-carbaldehyde (1.01
g, 4.92 mmol) in 20 mL t-BuOH was added sodium ascorbate (0.10 g,
0.49 mmol in 500 .mu.L H.sub.2O) and CuSO.sub.4.5H.sub.2O (0.13 g,
0.49 mmol in 500 .mu.L H.sub.2O). An additional portion of H.sub.2O
(5 mL) was added, and the reaction mixture was stirred for 24 h at
RT. The reaction mixture was diluted with H.sub.2O, and a
precipitate had formed. The yellow solid was filtered and air-dried
to afford the product. MS (m/z): 472.3 (m+H).
[0325] Proceeding as described above, but using
(R)-5-azido-5,6,7,8-tetrahydronapthalene-2-carbaldehyde afforded
(R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazo-
l-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid (63).
Example 9
Synthesis of compounds 65-68
##STR00036##
[0327] Reagents and conditions: a. substituted amine,
NaBH(OAc).sub.3, HOAc;
TABLE-US-00002 TABLE 2 No. X R.sup.6 65 CH.sub.2 ##STR00037## 66 O
##STR00038## 67 CH.sub.2 ##STR00039## 68 O ##STR00040## 69 O
##STR00041##
Synthesis of
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-ylmethyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic
acid (65)
[0328]
(2R)-3-(1-(6-Formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-tri-
azol-4-yl)-2-(4-methylphenylsulfonamido)-propanoic acid (85.8
.mu.M, 1 eq) piperidine (3 eq) and HOAc (3 eq) were heated to
40.degree. C. for 3 d. Additional portions of piperidine (3 eq) and
HOAc (3 eq) were then added. After 2 h, MP-BH.sub.4 was added and
the reaction mixture was allowed to stir for 3 days. The reaction
mixture was concentrated and was purified using reverse phase
conditions C18 (0-100% acetonitrile/water) to afford the title
compound. MS (m/z): 538.2 (m+H).
Synthesis of
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-7-((pyridin-2-yl-methylamino-
)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)propanoic
acid, TFA salt (66)
[0329] A mixture of
(R)-3-(1-((R)-7-formyl-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl-
)-2-(4-methylbenzenesulfonamido)propanoic acid (0.30 g, 0.64 mmol),
2-aminomethylpyridine (0.083 g, 0.77 mmol), Na.sub.2CO.sub.3 (0.14
g, 1.3 mmol), and NaBH(OAc).sub.3 (0.7 g, 3.2 mmol) in 5 mL MeOH
was stirred for 16 h at RT. The reaction mixture was quenched with
H.sub.2O, and extracted with CHCl.sub.3 (3.times.). The combined
extracts were dried over MgSO.sub.4, concentrated and purified by
reverse phase HPLC to give an off white solid. MS (m/z): 563.4
(m+H).
Synthesis of
(2R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((neonentyl-amino)methyl)-
-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanoic
acid (67)
[0330] Using the procedure described for 65, neopentyl amine
afforded the title compound.
Synthesis of
(R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1-
H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanoic acid
TFA salt (68)
[0331] Using the procedure described in the synthesis of 66,
cyclopentylamine afforded the title compound. MS (m/z): 540.3
(m+H).
Synthesis of
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-7-((piperidin-1-ylmethyl)chr-
oman-4-yl)-1H-1,2,3-triazol-4-yl)propanamide (69)
[0332] A mixture of
(R)-3-(1-((R)-7-formyl-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl-
)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45 mmol) and
piperidine (0.20 g, 2.25 mmol) in 5 mL 1,2-dichloroethane was
heated to 60.degree. C. for 30 min. The reaction mixture was cooled
and treated with NaBH(OAc).sub.3 and a drop of HOAc. The resulting
slurry was stirred at 80.degree. C. for 16 h. The reaction mixture
was cooled, quenched with H.sub.2O, and extracted with CHCl.sub.3
(3.times.). The combined organic extracts were dried over
MgSO.sub.4, concentrated, and purified by SiO.sub.2 (5%
MeOH/CH.sub.2Cl.sub.2) to afford a white solid. MS (m/z): 537.4
(m+H).
Example 10
Synthesis of
(R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1-
H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide
##STR00042##
[0334] A mixture of
(R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1-
H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid
(61 mg, 0.11 mol), HOAt (18 mg, 0.12 mmol), i-Pr.sub.2NEt (60. mL,
0.45 mmol), NH.sub.4Cl (25 mg, 0.45 mmol), and EDCI (24 mg, 0.12
mmol) in 5 mL DMF was stirred for 24 h at RT. The reaction mixture
was concentrated, taken up in H.sub.2O, and the white solid was
filtered and air-dried to afford the title compound. MS (m/z, m+1):
539.4.
Example 11
Synthesis of Compounds 75-78
##STR00043## ##STR00044##
[0336] Reagents and conditions: a) Sodium ascorbate,
CuSO.sub.4.5H.sub.2O, t-BuOH/water; b) HOAt, DIPEA, NH.sub.4Cl; c)
LiOH; d) Dibal; e) MnO.sub.2; f) substituted amine,
NaBH(OAc).sub.3, HOAc.
Step (i): Synthesis of
(R)-3-(1-((R)-6-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1-
,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanoic acid
(70)
[0337] A solution of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynoic
acid (6.25 g, 23.4 mmol) and (R)-methyl
5-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylate (5.4 g, 23.4
mmol) in 80 mL t-BuOH was treated with sodium ascorbate (0.47 g,
2.34 mmole in 24 mL H.sub.2O) and CuSO.sub.4.5H.sub.2O (0.58 g,
2.34 mmol in 24 mL H.sub.2O). An additional portion of H.sub.2O (50
mL) was then added to the reaction mixture. After stirring for 48 h
at RT, the reaction mixture was diluted with H.sub.2O. A
precipitate had formed that was filtered and air-dried. MS (m/z):
499.4 (m+H).
[0338] Step (ii): Synthesis of (R)-methyl
5-(4-((R)-3-amino-2-(4-methylbenzenesulfonamido)-3-oxopropyl)-1H-1,2,3-tr-
iazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (71). Using
the same procedure described for (64) afforded the title compound
as a white solid. MS (m/z): 498.4 (m+H).
Step (iii): Synthesis of
(R)-5-(4-((R)-3-amino-2-(4-methylphenylsulfonamido)-3-oxopropyl)-1H-1,2,3-
-triazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
(72)
[0339] (R)-Methyl
5-(4-((R)-3-amino-2-(4-methylbenzenesulfonamido)-3-oxopropyl)-1H-1,2,3-tr-
iazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.2 g,
0.41 mmol) and 1N LiOH (1.9 mL, 1.9 mmol) in 5 mL THF was stirred
for 16 h at RT. The reaction mixture was concentrated, taken up in
H.sub.2O, and acidified with 10% HCl. A precipitate had formed,
that was filtered and air-dried to afford the title compound. MS
(m/z): 484.4 (m+H).
Step (iv): Synthesis of
(R)-3-(1-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl)-1H-1,-
2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide
(73)
[0340] To a stirred solution of
(R)-5-(4-((R)-3-amino-2-(4-methylbenzenesulfonamido)-3-oxopropyl)-1H-1,2,-
3-triazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
(1.63 g, 3.28 mmol) in 40 mL toluene was added a solution of 1.5M
DIBAL-H in toluene. The reaction mixture was stirred for 3 h and
then cooled to 0.degree. C. The reaction mixture was quenched by
the slow addition of 10% HCl and extracted with EtOAc (3.times.).
The extracts were dried over MgSO.sub.4, concentrated and purified
by SiO.sub.2 (5% MeOH/CH.sub.2Cl.sub.2) to afford a light yellow
solid. MS (m/z): 470.4 (m+H).
Step (v): Synthesis of
(R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazo-
l-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (74)
[0341] To a stirred solution of
(R)-3-(1-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2-
,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.66 g,
1.4 mmol) in DCE/MeCN (1:1, 30 mL) was added MnO.sub.2. The
reaction mixture was stirred overnight at RT. The solid was removed
by filtration, and the filtrate was concentrated to give a tan
solid. MS (m/z): 468.4 (m+H).
Synthesis of
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-(piperidin-1-yl-methyl)-1,-
2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide
(75)
[0342] A mixture of
(R)-3-(1-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazo-
l-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.21 g, 0.45
mmol) and piperidine (0.20 g, 2.2 mmol) in 5 mL 1,2-dichloroethane
was heated to 60.degree. C. for 30 min. The reaction mixture was
cooled and treated with NaBH(OAc).sub.3 and a drop of HOAc. The
resulting mixture was heated to 80.degree. C. for 16 h. The
reaction mixture was cooled, quenched with H.sub.2O, and extracted
with CHCl.sub.3 (3.times.). The combined extracts were dried over
MgSO.sub.4, concentrated and purified by SiO.sub.2 (5%
MeOH/CH.sub.2Cl.sub.2) to give a white solid. MS (m/z): 537.4
(m+H).
Synthesis of
(2R)-3-(1-(6-((tert-butylamino)methyl)-1,2,3,4-tertahydronaphthalen-1-yl)-
-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanamide
(76)
[0343]
(2R)-3-(1-(6-Formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-tri-
azol-4-yl)-2-(4-methylphenylsulfonamido)propanamide (0.09 mmol, 1
eq), t-Butyl amine (0.28 mol, 3.0 eq), HOAc (0.34 mmol, 3.0 eq) and
4 A molecular sieves were stirred in a 1: I solution of DMF and DCE
for 5.5 h. Then, NaBH(OAc).sub.3 (0.26 mmol, 3.0 eq) was added.
After 3 d, the reaction mixture was loaded onto an Agilent AccuBOND
SCX cartridge. The cartridge was washed DCM, MeOH, and 2M Ammonia
in MeOH. The product eluted in the NH.sub.3 wash. MS (m/z): 525.3
(m+H).
Synthesis of
(R)-2-(4-methylbenzenesulfonamido)-3-(1-((R)-6-((4-methylpiperazin-1-yl)m-
ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamid-
e (77)
[0344] Using the same procedure described for (76), but using
N-methylpiperazine afforded the title compound. MS (m/z): 552.3
(m+H).
Synthesis of
(2R)-2-(4-Methylphenylsulfonamido)-3-(1-(6-((neopentylamino)-methyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanamide
(78)
[0345] Using the same procedure described for 76, but using
neopentylamine afforded the title compound.
Example 12
Synthesis of Compounds of Formula (I) Using Parallel Synthesis
Method
##STR00045##
[0347] Parallel Synthesis of Triazoles Compounds.
[0348] Using the Bohdan Miniblock system, the azide-containing
compounds (1.0 eq) in 1 mL t-BuOH were charged to a 2-mL reaction
vessel. The alkyne-containing compounds (1.1 eq) were then added.
Sodium ascorbate (66.1 .mu.M in H.sub.2O) followed by an aqueous
solution of CuSO.sub.4.5H.sub.2O (66.1 .mu.M). The reactions were
placed on an orbital shaker and allowed to swirl for 3 days. The
reactions were purified by loading onto a Agilent AccuBOND II SCX
cartridge that had previously been rinsed with MeOH and H.sub.2O.
The cartridge was washed with MeOH, and the product eluted with 2M
ammonia in MeOH. The solvents were removed using a Genevac to
afford the desired product.
TABLE-US-00003 TABLE 4 No. Name Structure Mass 79
(2S)-3-(1-(6-(methoxy-carbonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl)-1H--
1,2,3-triazol-4-yl)-2-(4-methyl-phenylsulfonamido)propanoicacid
##STR00046## C.sub.24H.sub.26N.sub.4O.sub.6S,Calcd: 498.16Found:
499.4(M + H) 80
(2S)-3-(1-(7-methoxy-carbonyl)chroman-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-
-methylphenylsulfonamido)-propanoic acid ##STR00047##
C.sub.23H.sub.24N.sub.4O.sub.7S,Calcd: 500.14Found: 501.2(M + H) 81
(2R)-3-(1-(6-((tert-butyl-amino)methyl)-1,2,3,4-tetra-hydronaphthalen-1-
-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)-propanamide
##STR00048## C.sub.27H.sub.36N.sub.6O.sub.3S,Calcd: 524.26Found:
525.3(M + H) 82
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((4-methylpiperazin-1-yl)-m-
ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propanami-
de ##STR00049## C.sub.28H.sub.37N.sub.7O.sub.3S,Calcd: 551.27Found:
552.3(M + H) 83
(2R)-2-(4-methylphenyl-sulfonamido)-33-(1-(6-((neo-pentylamino)methyl)--
1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3,-triazol-4-yl)-propanamide
##STR00050## C.sub.28H.sub.38N.sub.6O.sub.3S,Calcd: 538.27Found:
539.1(M + H) 84
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-(piperidin-1-ylmethyl)-1,2,-
3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-propanoic
acid ##STR00051## C.sub.28H.sub.35N.sub.5O.sub.4S,Calcd:
537.24Found: 538.2(M + H) 85
(2R)-2-(4-methylphenyl-sulfonamido)-3-(1-(6-((neo-pentylamino)methyl)-1-
,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-propanoic
acid ##STR00052## C.sub.28H.sub.37N.sub.5O.sub.4S,Calcd:
539.26Found: 540.3(M + H) 86
N-((S)-1-(1-(6-((tert-butyl-amino)methyl)-1,2,3,4-tetrahydronaphthalen--
1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-4-methylbenzenesulfon-amide
##STR00053## C.sub.27H.sub.37N.sub.5O.sub.2S,Calcd: 497.25Found:
498.3(M + H) 87
4-methyl-N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-chroman-4-yl)-1H-1,2-
,3-triazol-4-yl)propan-2-yl)-benzenesulfonamide ##STR00054##
C.sub.27H.sub.35N.sub.5O.sub.3S,Calcd: 509.25Found: 510.3(M + H) 88
4-Methyl-N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydrona-
phthalen-1-yl)-1H-1,2,3-triazol-4-yl)-propan-2-yl)benzene-sulfonamide
##STR00055## C.sub.28H.sub.37N.sub.5O.sub.2SCalcd: 507.27Found:
549.3(M + H) 89
N-((S)-1-(1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-hydronaphthalen-
-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)-benzenesulfo-
namide ##STR00056## C.sub.28H.sub.34F.sub.3N.sub.5O.sub.2SCalcd:
561.24Found: 562.2(M + H) 90
N-((S)-1-(1-((R)-7-(piperidin-1-ylmethyl)-3,4-dihydro-2H-chromen-4-yl)--
1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzenesulfon-amide
##STR00057## C.sub.27H.sub.32F.sub.3N.sub.5O.sub.3SCalcd:
563.22Found: 564.2(M + H) 91
N-((S)-1-(1-((R)-7-((tert-butylamino)methyl)-3,4-di-hydro-2H-chromen-4--
yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)-benzenesulfonam-
ide ##STR00058## C.sub.26H.sub.32F.sub.3N.sub.5O.sub.3SCalcd:
551.22Found: 552.4(M + H) 92
N-((R)-2-(1-((R)-7-((tert-butylamino)methyl)-3,4-dihydro-2H-chromen-4-y-
l)-1H-1,2,3-triazol-4-yl)-1-(4-fluorophenyl)ethyl)-3-(trifluoromethyl)benz-
ene-sulfonamide ##STR00059##
C.sub.31H.sub.33F.sub.4N.sub.5O.sub.3SCalcd: 631.22Found: 632.4(M +
H) 93
N-((S)-1-(1-((R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydronaphtha-
len-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)-3-(trifluoromethyl)benzene-su-
lfonamide ##STR00060## C.sub.28H.sub.34F.sub.3N.sub.5O.sub.2SCalcd:
561.24Found: 562.5(M + H) 94
N-((S)-1-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4--
yl)-1H-1,2,3-triazol-4-yl)-propan-3-yl)-3-(trifluoro-methyl)benzenesulfona-
mide ##STR00061## C.sub.27H.sub.32F.sub.3N.sub.5O.sub.3SCalcd:
563.22Found: 564.1(M + H) 95
N-((S)-1-(1-((R)-6-((4-fluoro-piperidin-1-yl)methyl)-1,2,3,4-tetrahydro-
naphthalen-1-yl)-1H-1,2,3,-triazol-4-yl)-propan-2-yl)-3-(trifluoro-methyl)-
benzenesulfonamide ##STR00062##
C.sub.27H.sub.31F.sub.4N.sub.5O.sub.3SCalcd: 579.23Found: 580.5(M +
H) 96
N-((S)-1-(1-((R)-7-((4-fluoro-piperidin-1-yl)methyl)-3,4-di-hydro-2H-ch-
romen-4-yl)-1H-1,2,3-triazol-44-yl)propan-2-yl)-3-(trifluoromethyl)-benzen-
esulfonamide ##STR00063##
C.sub.27H.sub.31F.sub.4N.sub.5O.sub.3SCalcd: 581.21Found: 582.1(M +
H)
Formulations
[0349] The following are representative pharmaceutical formulations
containing a compound of formula (I).
Tablet Formulation
[0350] The following ingredients are mixed intimately and pressed
into single scored tablets.
TABLE-US-00004 Quantity per Ingredient tablet, mg compound of this
invention 400 corn starch 50 croscarmellose sodium 25 lactose 120
magnesium stearate 5
Capsule Formulation
[0351] The following ingredients are mixed intimately and loaded
into a hard-shell gelatin capsule.
TABLE-US-00005 Quantity per Ingredient capsule, mg compound of this
invention 200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation
[0352] The following ingredients are mixed to form a suspension for
oral administration.
TABLE-US-00006 Ingredient Amount compound of this invention 1.0 g
fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g
propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70%
solution 12.85 g Veegum K (Vanderbilt Co. 1.0 g flavoring 0.035 ml
colorings 0.5 mg distilled water q.s. to 100 ml
Injectable Formulation
[0353] The following ingredients are mixed to form an injectable
formulation.
TABLE-US-00007 Ingredient Amount compound of this invention 0.4 mg
sodium acetate buffer solution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N)
q.s. to suitable pH water (distilled, sterile) q.s. to 20 ml
Biological Testing
[0354] Although the pharmacological properties of the compounds of
the invention vary with structural change, in general, activity
possessed by compounds of the invention may be demonstrated in
vivo. The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological in vitro
assays. The exemplified pharmacological assays, which follow, have
been carried out with the compounds according to the invention and
their salts. Compounds of the present invention showed binding
IC.sub.50's for B1 at doses less than 20 .mu.M.
Human Bradykinin B1 Receptor and Human B2 Receptor In Vitro Binding
Assays
Example 1
Radioligand Binding Assay for Human B1 and Human B2 Bradykinin
Receptor
[0355] Step 1 Preparation of Membranes Expressing Human B1
Bradykinin Receptor:
[0356] Membranes were prepared from CHO-d.sup.-AQN cells stably
transfected with human bradykinin B1 receptor cDNA. For large-scale
production of membranes, cells were grown in 100 L suspension
culture to 1.0E8 cells/mL then harvested using the Viafuge at
continuous centrifugation of 1000 g. For pilot studies, cells were
grown in 2 L spinner culture and harvested by centrifugation (1900
g, 10 min, 4.degree. C.). The cell pellet was washed with PBS,
centrifuged (1900 g, 10 min, 4.degree. C.), then the cells
resuspended in lysis buffer (25 mM HEPES, pH 7.4, 5 mM EDTA, 5 mM
EGTA, 3 mM MgCl.sub.2, 10% (w/v) sucrose, Complete Protease
Inhibitor tablets (EDTA-free)) to a density of 14% w/v for passage
through a microfluidizer (Microfluidics 110S, 3 passes, 6,000 psi).
The resulting cell lysate was centrifuged (1900 g, 10 min,
4.degree. C.), and the crude particulate fraction isolated by
centrifugation (142,000 g, 1 h, 4.degree. C.) of the low-speed
supernatant. The resulting pellet was resuspended in 1/3 the
original lysis buffer volume, homogenized, and recentrifuged as
above. The membrane pellet was resuspended by homogenization in
storage buffer (25 mM HEPES, pH 7.4, 3 mM MgCl.sub.2, 10% (w/v)
sucrose and Complete Protease Inhibitor tablets (EDTA-free)).
Single-use aliquots were made and flash-frozen in liquid N.sub.2
prior to storage at -80.degree. C.
[0357] Membranes containing human bradykinin B2 receptor were
purchased from Receptor Biology (now Perkin Elmer Life Sciences).
They were derived from a CHO-K1 line stably expressing the human B2
receptor developed by Receptor Biology and subsequently purchased
by Amgen. For some studies, membranes were prepared in-house from
this same cell line using the method described for human B1
receptor membranes, except cells were grown in roller bottles and
harvested using Cellmate.
[0358] Step 2 Human B1 receptor binding assay was performed in
96-well polypropylene plates (Costar 3365) by adding 50 .mu.l
[.sup.3H] des-arg.sup.10 kallidin (NET1064; Perkin Elmer Life
Sciences) to 10 .mu.L test compound diluted in 90 .mu.L assay
buffer (24 mM TES, pH 6.8, 1 mM 1,10 o-phenanthroline, 0.3% BSA,
0.5 mM Pefabloc SC, 2 .mu.g/mL aprotinin, 5 .mu.g/mL leupeptin, and
0.7 .mu.g/mL pepstatin A). Membranes (50 .mu.L) were added last.
[.sup.3H] des-arg.sup.10 kallidin was diluted from stock into assay
buffer to yield a final concentration of 0.3 nM in the assay but
was adjusted as needed to ensure a concentration at or below the
K.sub.d determined for each batch of receptor membranes.
Nonspecific binding was defined with 2 .mu.M
des-Arg.sup.10Leu.sup.9 kallidin. Membranes were diluted in assay
buffer to yield a final concentration of 0.068 nM hB1 receptor in
the assay. Compounds were solubilized in either DMSO or ddH.sub.2O,
plated into polypropylene plates (Costar 3365), then serially
diluted in either DMSO or dilution buffer (20 mM Hepes, pH 7.6,
0.1% BSA) to yield a final concentration of either 5% DMSO or no
DMSO in the assay. The assay mixture was incubated with shaking for
1 h at RT and then filtered through GF/C plates presoaked in 0.5%
polyethyleneimine (Unifilter; Perkin Elmer Life Sciences) using a
Filtermate 96-well harvester (Perkin Elmer Life Sciences). Filter
plates were rapidly washed 6 times with 200 .mu.L ice-cold buffer
(50 mM Tris, pH 7.4), dried in a vacuum oven at 55.degree. C. for
15-20 min, backed, and 40 .mu.L per well of Microscint 20 was
added. The plates were sealed and activity read on Topcount (Perkin
Elmer Life Sciences) using a count time of 3 min per channel.
[0359] For human B2 bradykinin receptor, the same procedure was
followed with the following exceptions: [.sup.3H] bradykinin
(NET706; Perkin Elmer Life Sciences) was used at a final
concentration of .about.0.2 nM and non-specific binding was defined
with 2 .mu.M bradykinin. Human B2 receptor concentration was 0.068
nM final in the assay.
Data Analysis
[0360] Data was analyzed in XLFit with the four-parameter logistic
y=A+((B-A)/(1+((C/x) D))) and fit with the Levenburg-Marquardt
algorithm. Raw cpm were converted to percent of control values
prior to analysis (POC=((compound cpm-nonspecfic cpm)/(no-compound
cpm-nonspecific cpm)*100)). K.sub.i values were determined from the
IC.sub.50 using the Cheng-Prusoff equation and K.sub.d values
determined by direct saturation binding of the radioligands.
Example 2
In Vitro B1
Inhibition Activity
In vitro Assay of Human B1 Receptor Function Using Calcium Flux
[0361] Activation of the G.sub.q linked B1 receptor results in an
increase in intracellular calcium. The calcium sensitive
photoprotein aequorin can, therefore, be used as an indicator of B1
receptor activation. Aequorin is a 21-kDa photoprotein that forms a
bioluminescent complex when linked to the chromophore cofactor
coelenterazine. Following the binding of calcium to this complex,
an oxidation reaction of coelenterazine results in the production
of apoaequorin, coelenteramide, CO.sub.2, and light that can be
detected by conventional luminometry.
[0362] A stable CHO D-/hB1/Aequorin cell line was established and
the cells were maintained in suspension in spinner bottles
containing a 1:1 ratio of DMEM and HAM F12 (Gibco 11765-047), high
glucose (Gibco 11965-084), 10% Heat Inactivated Dialyzed serum
(Gibco 26300-061), 1.times. Non-Essential Amino Acids (Gibco
11140-050), 1.times. Glutamine-Pen-Strep (Gibco 10378-016), and
Hygromycin, 300 .mu.g/mL (Roche 843555). 15-24 h prior to the
luminometer assay, 25,000 cells/well (2.5E6 cells/10 mL/plate) were
plated in 96-well black-sided clear bottom assay plates (Costar
#3904).
[0363] Media was removed from the wells and replaced with 60 .mu.L
of serum free HAM's F12 with 30 mM HEPES (pH 7.5) and 15 .mu.M
coelenterazine (Coelenterazine h Luciferin #90608 from Assay
Designs). The plates were incubated for 1.5-2 h. Ten point
IC.sub.50 compound plates containing 1:3 or 1:5 dilutions of
antagonist compounds and an agonist activator plate (20 nM
des-Arg10-Kallidin final concentration, EC.sub.80) were prepared
using Ham's F12 with 30 mM HEPES, pH 7.5. Following coelenterazine
incubation, an automated flash-luminometer platform was used to
dispense the B1 antagonist compounds (dissolved in DMSO and diluted
with buffer to the desired concentration (final DMSO concentration
<1% DMSO)) to the cell plate, a CCD camera situated underneath
the cell plate took 12 images of the cell plate at 5 second
intervals to determine if there was any agonist activity with the
compounds. The hB1 agonist, des-Arg.sub.10-Kallidin, was added to
the cell plate and another 12 images were recorded to determine the
IC.sub.50 of the antagonist(s). The compounds of examples 3c, 7,
and 9-12 have binding IC.sub.50's to hB1 receptor function at a
level below 1 .mu.M.
In Vitro Assay of hB2 Receptor Function Using Calcium Flux
[0364] The intracellular calcium flux induced by hB2 receptor
activation was analyzed using an hB2 recombinant cell line (CHO-K1)
purchased from PerkinElmer (Catalog Number: RBHB2C000EA) on a
fluorometric imaging plate reader (FLIPR). The cells were cultured
in T225 flask containing Ham's F12 Nutrient Mixture (Invitrogen
Corp., Cat # 11765-047), 10% Fetal Clone II Bovine Serum (HyClone,
Cat # SH3006603), 1 mM Sodium pyruvate (100 mM stock, Invitrogen
Corp., Cat# 12454-013), and 0.4 mg/mL Geneticin (G418; 50 mg/mL
active geneticin, Invitrogen, Cat# 10131-207). Culture medium was
changed every other day. 24 h prior to the FLIPR assay, the hB2/CHO
cells were washed once with PBS (Invitrogen) and 10 mL of Versene
(1:5000, Invitrogen, Cat# 15040-066) was added to each flask. After
5 min incubation at 37.degree. C., Versene was removed and cells
were detached from the flask and resuspended in culture medium.
Cells were counted and 25,000 cells/well were plated in 96-well
black-sided clear bottom assay plates (Costar #3904). Cells were
incubated in a 37.degree. C. CO.sub.2 incubator overnight.
[0365] The media was aspirated from the cells and replaced with 65
.mu.L of dye-loading buffer. The loading buffer was prepared by
diluting a stock solution of 0.5 mM Fluo-4 AM (Molecular Probes,
dissolved in DMSO containing 10% [w/v] pluronic acid) to a
concentration of 1 .mu.M in Clear Dulbecco's Modified Eagle Medium
(DMEM) containing 0.1% BSA, 20 mM HEPES, and 2.5 mM probenecid. The
cells were dye-loaded for 1 h at RT. The excess dye was removed by
washing the cells 2.times. with assay buffer. The assay buffer
consists of Hank's Balanced Salt Solution (HBSS) containing 20 mM
HEPES, 0.1% BSA, and 2.5 mM probenecid. After the wash cycles, a
volume of 100 .mu.L was left in each well, and the plate was ready
to be assayed in the FLIPR System. Single point (10 .mu.M final
concentration) POC antagonist compound plates or ten point
IC.sub.50 compound plates containing 1:3 or 1:5 dilutions of
antagonist compounds (dissolved in DMSO and diluted with buffer to
the desired concentration (final DMSO concentration <1% DMSO))
and an agonist activator plate (0.3 nM bradykinin final
concentration, EC.sub.80) were prepared using assay buffer. The
cell plate and the compound plates were loaded onto the FLIPR and
during the assay, fluorescence readings are taken simultaneously
from all 96 wells of the cell plate. Ten 1-second readings were
taken to establish a stable baseline for each well, then 25 .mu.L
from the B1 antagonist plate was rapidly (50 .mu.L/sec.) added. The
fluorescence signal was measured in 1-second (1 min) followed by
6-second (2 min) intervals for a total of 3 min to determine if
there is any agonist activity with the compounds. The B2 agonist,
bradykinin, was added to the cell plate and another 3 min were
recorded to determine the percent inhibition at 10 .mu.M (POC
plates) or the IC.sub.50 of the antagonist.
Example 3
Cell and Tissue Based In Vitro Assays of hB1 Receptor Binding
[0366] These studies established the antagonist activity of several
compounds at the bradykinin B1 receptors in in vitro cell-based and
isolated organ assays.
[0367] Rabbit Endothelial Cell B1-Specific PGI.sub.2 Secretion
Assay
[0368] B1 and B2 Umbilical Vein Assay
In Vitro B1-Inhibition Activity:
[0369] The effectiveness of the compounds as inhibitors of B1
activity (i.e., B1 "neutralization") can be evaluated by measuring
the ability of each compound to block B1 stimulated CGRP and
substance P release and calcium signaling in Dorsal Root Ganglion
(DRG) neuronal cultures.
Dorsal Root Ganglion Neuronal Cultures:
[0370] Dorsal root ganglia are dissected one by one under aseptic
conditions from all spinal segments of embryonic 19-day old (E19)
rats that are surgically removed from the uterus of timed-pregnant,
terminally anesthetized Sprague-Dawley rats (Charles River,
Wilmington, Mass.). DRG are collected in ice-cold L-15 media
(GibcoBRL, Grand Island, N.Y.) containing 5% heat inactivated horse
serum (GibcoBRL), and any loose connective tissue and blood vessels
are removed. The DRG are rinsed twice in Ca.sup.2+- and
Mg.sup.2+-free Dulbecco's phosphate buffered saline (DPBS), pH 7.4
(GibcoBRL). The DRG are dissociated into single cell suspension
using a papain dissociation system (Worthington Biochemical Corp.,
Freehold, N.J.). Briefly, DRG are incubated in a digestion solution
containing 20 U/mL of papain in Earle's Balanced Salt Solution
(EBSS) at 37.degree. C. for fifty minutes. Cells are dissociated by
trituration through fire-polished Pasteur pipettes in a
dissociation medium consisting of MEM/Ham's F12, 1:1, 1 mg/mL
ovomucoid inhibitor and 1 mg/mL ovalbumin, and 0.005%
deoxyribonuclease I (DNase). The dissociated cells are pelleted at
200.times.g for 5 min and re-suspended in EBSS containing 1 mg/mL
ovomucoid inhibitor, 1 mg/mL ovalbumin and 0.005% DNase. Cell
suspension is centrifuged through a gradient solution containing 10
mg/mL ovomucoid inhibitor, 10 mg/mL ovalbumin at 200.times.g for 6
min to remove cell debris, then filtered through a 88-.mu.M nylon
mesh (Fisher Scientific, Pittsburgh, Pa.) to remove any clumps.
Cell number is determined with a hemocytometer, and cells are
seeded into poly-ornithine 100 .mu.g/mL (Sigma, St. Louis, Mo.) and
mouse laminin 1 .mu.g/mL (GibcoBRL)-coated 96-well plates at
10.times.10.sup.3 cells/well in complete medium. The complete
medium consists of minimal essential medium (MEM) and Ham's F12,
1:1, penicillin (100 U/mL), streptomycin (100 .mu.g/mL), and 10%
heat inactivated horse serum (GibcoBRL). The cultures are kept at
37.degree. C., 5% CO.sub.2 and 100% humidity. For controlling the
growth of non-neuronal cells, 5-fluoro-2'-deoxyuridine (75 .mu.M)
and uridine (180 .mu.M) are included in the medium.
[0371] Two hours after plating, cells are treated with recombinant
human .beta.-b1 or recombinant rat .beta.-b1 at a concentration of
10 mg/ml (0.38 nm). Positive controls comprising serial-diluted
anti-b1 antibody (r&d systems, Minneapolis, Minn.) are applied
to each culture plate. Compounds are added at ten concentrations
using 3.16-fold serial dilutions. All samples are diluted in
complete medium before being added to the cultures. Incubation time
is generally around 40 h prior to measurement of vr1
expression.
Measurement of VR1 Expression in DRG Neurons:
[0372] Cultures are fixed with 4% paraformaldehyde in Hanks'
balanced salt solution for 15 min, blocked with Superblock (Pierce,
Rockford, Ill.), and permeabilized with 0.25% Nonidet P-40 (Sigma)
in Tris.HCl (Sigma)-buffered saline (TBS) for 1 h at RT. Cultures
are rinsed once with TBS containing 0.1% Tween 20 (Sigma) and
incubated with rabbit anti-VR1 IgG (prepared at Amgen) for 1.5 h at
RT, followed by incubation of Eu-labeled anti-rabbit second
antibody (Wallac Oy, Turku, Finland) for 1 h at RT. Washes with TBS
(3.times. five min with slow shaking) are applied after each
antibody incubation. Enhance solution (150 mL/well, Wallac Oy) is
added to the cultures. The fluorescence signal is measured in a
time-resolved fluorometer (Wallac Oy). VR1 expression in samples
treated with the compounds is determined by comparing to a standard
curve of B1 titration from 0-1000 ng/mL. Percent inhibition
(compared to maximum possible inhibition) of B1 effect on VR1
expression in DRG neurons is determined by comparing to controls
that are not B1-treated.
Example 4
In Vivo Antinociceptive Activity in Rat and Monkey Pain Models
Rat Neuropathic Pain Model
[0373] Male Sprague-Dawley rats (200 g) are anesthetized with
isoflurane inhalant anesthesia and the left lumbar spinal nerves at
the level of L5 and L6 are tightly ligated (4-0 silk suture) distal
to the dorsal root ganglion and prior to entrance into the sciatic
nerve, as first described by Kim and Chung (Kim, S. H.; Chung, J.
M. An experimental model for peripheral neuropathy produced by
segmental spinal nerve ligation in the rat. Pain 50:355-363,
(1992)). The incisions are closed and the rats are allowed to
recover. This procedure results in mechanical (tactile) allodynia
in the left hind paw as assessed by recording the pressure at which
the affected paw (ipsilateral to the site of nerve injury) was
withdrawn from graded stimuli (von Frey filaments ranging from 4.0
to 148.1 mN) applied perpendicularly to the plantar surface of the
paw (between the footpads) through wire-mesh observation cages. A
paw withdrawal threshold (PWT) was determined by sequentially
increasing and decreasing the stimulus strength and analyzing
withdrawal data using a Dixon non-parametric test, as described by
Chaplan et al. (Chaplan, S. R.; Bach, F. W.; Pogrel, J. W.; Chung,
J. M.; Yaksh, T. L. Quantitative assessment of tactile allodynia in
the rat paw. J. Neurosci. Meth., 53:55-63 (1994)).
[0374] Normal rats and sham surgery rats (nerves isolated but not
ligated) withstand at least 148.1 mN (equivalent to 15 g) of
pressure without responding. Spinal nerve ligated rats respond to
as little as 4.0 mN (equivalent to 0.41 g) of pressure on the
affected paw. Rats are included in the study only if they did not
exhibit motor dysfunction (e.g., paw dragging or dropping) and
their PWT was below 39.2 mN (equivalent to 4.0 g). At least seven
days after surgery rats are treated with compounds (usually a
screening dose of 60 mg/kg) or control diluent (PBS) once by s.c.
injection and PWT was determined each day thereafter for 7
days.
Rat CFA Inflammatory Pain Model
[0375] Male Sprague-Dawley rats (200 g) are lightly anesthetized
with isoflurane inhalant anesthesia and the left hindpaw is
injected with complete Freund's adjuvant (CFA), 0.15 mL. This
procedure results in mechanical (tactile) allodynia in the left
hind paw as assessed by recording the pressure at which the
affected paw is withdrawn from graded stimuli (von Frey filaments
ranging from 4.0 to 148.1 mN) applied perpendicularly to the
plantar surface of the paw (between the footpads) through wire-mesh
observation cages. PWT is determined by sequentially increasing and
decreasing the stimulus strength and analyzing withdrawal data
using a Dixon non-parametric test, as described by Chaplan et al.
(1994). Rats are included in the study only if they do not exhibit
motor dysfunction (e.g., paw dragging or dropping) or broken skin
and their PWT is below 39.2 mN (equivalent to 4.0 g). At least
seven days after CFA injection rats are treated with compounds
(usually a screening dose of 60 mg/kg) or control solution (PBS)
once by s.c. injection and PWT is determined each day thereafter
for 7 days. Average paw withdrawal threshold (PWT) is converted to
percent of maximum possible effect (% MPE) using the following
formula: % MPE=100*(PWT of treated rats-PWT of control
rats)/(15-PWT of control rats). Thus, the cutoff value of 15 g
(148.1 mN) is equivalent to 100% of the MPE and the control
response is equivalent to 0% MPE.
[0376] At the screening dose of 60 mg/kg, compounds in vehicle are
expected to produce an antinociceptive effect with a PD
relationship.
Example 5
Green Monkey LPS Inflammation Model
[0377] The effectiveness of the compounds as inhibitors of B1
activity are evaluated in Male green monkeys (Cercopithaecus
aethiops St Kitts) challenged locally with B1 agonists essentially
as described by deBlois and Horlick (British Journal of
Pharmacology, 132:327-335 (2002), which is hereby incorporated by
reference in its entirety).
[0378] In order to determine whether compounds of the present
invention inhibit B1 induced oedema the studies described below are
conducted on male green monkeys (Cercopithaecus aethiops St Kitts)
at the Caribbean Primates Ltd. experimental farm (St Kitts, West
Indies). Procedures are reviewed and accepted by the Animal Care
Committees of the CR-CHUM (Montreal, Canada) and of Caribbean
Primates Ltd. (St Kitts, West Indies). Animals weighing 6.01.+-.0.5
kg (n=67) were anaesthetized (50 mg ketamine kg.sup.-1) and
pretreated with a single intravenous injection of LPS (90 .mu.g
kg.sup.-1) or saline (1 mL) via the saphenous vein.
Inflammation Studies
[0379] Kinin-induced oedema is evaluated by the ventral skin fold
assay (Sciberras et al., 1987). Briefly, anaesthetized monkeys were
injected with captopril (1 mg kg.sup.-1 30 min before assay). A
single subcutaneous injection of dKD, BK or the vehicle (2 mM
amastatin in 100 .mu.L Ringer's lactate) is given in the ventral
area and the increase in thickness of skin folds is monitored for
30-45 min using a calibrated caliper. The results are expressed as
the difference between the skin fold thickness before and after the
subcutaneous injection. Captopril and amastatin are used to reduce
degradation of kinins at the carboxyl- and amino-terminus,
respectively.
Antagonist Schild Analysis:
[0380] The dose-response relationship for dKD (1-100 nmol)-induced
oedema is determined at 24 h post-LPS in the absence or presence of
different concentrations of antagonist. BK (30 nmol) is used as a
positive control.
Antagonist Time Course
[0381] The time course of inhibition by antagonist is determined at
4, 24 and 48 h, 72 and/or 96 h after single bolus administration.
BK (30 nmol) is used as a positive control.
Drugs
[0382] Ketamine hydrochloride, LPS, amastatin and captopril are
from Sigma (MO, U.S.A.). All peptides are from Phoenix
Pharmaceuticals (CA, U.S.A.).
Statistics
[0383] Values are presented as mean .+-.standard error of the mean
(s.e. mean). In edema studies, the pre-injection thickness of the
skin folds was subtracted from the values after subcutaneous
challenge. Curve fitting and EC.sub.50 calculations were obtained
using the Delta Graph 4.0 software for Apple Computers. Data were
compared by two-way analysis of variance followed by unpaired, one
tail Student's t-test with Bonferroni correction. P<0.05 was
considered statistically significant.
[0384] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes, which are obvious to one skilled in the
art, are intended to be within the scope and nature of the
invention, which are defined, in the appended claims.
[0385] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions. All mentioned references, patents,
applications and publications, are hereby incorporated by reference
in their entirety, as if here written.
* * * * *