U.S. patent application number 10/342666 was filed with the patent office on 2003-12-25 for heterocyclo-alkylsulfonyl pyrazole derivatives as anti-inflammatory/analge- sic agents.
This patent application is currently assigned to Pfizer Inc.. Invention is credited to Cheng, Hengmiao, Li, Jin, Lundy, Kristin M., Minich, Martha L., Sakya, Subas M., Uchida, Chikara.
Application Number | 20030236258 10/342666 |
Document ID | / |
Family ID | 22612589 |
Filed Date | 2003-12-25 |
United States Patent
Application |
20030236258 |
Kind Code |
A1 |
Lundy, Kristin M. ; et
al. |
December 25, 2003 |
Heterocyclo-alkylsulfonyl pyrazole derivatives as
anti-inflammatory/analge- sic agents
Abstract
The present invention relates to compounds of the formula 1
wherein R.sup.2, R.sup.3, R.sup.6 and A are defined as in the
specification, to pharmaceutical compositions containing them and
to their medicinal use. The compounds of the invention are useful
in the treatment or alleviation of inflammation and other
inflammation associated disorders, such as osteoarthritis,
rheumatoid arthritis, colon cancer and Alzheimer's disease, in
mammals (preferably humans, dogs, cats and livestock).
Inventors: |
Lundy, Kristin M.; (Groton,
CT) ; Cheng, Hengmiao; (East Lyme, CT) ;
Sakya, Subas M.; (East Lyme, CT) ; Li, Jin;
(Pawcatuck, CT) ; Minich, Martha L.; (Gales Ferry,
CT) ; Uchida, Chikara; (Chita-Gun, JP) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc.
|
Family ID: |
22612589 |
Appl. No.: |
10/342666 |
Filed: |
January 14, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10342666 |
Jan 14, 2003 |
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09724446 |
Nov 28, 2000 |
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6531492 |
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Current U.S.
Class: |
514/242 ;
514/252.05; 514/255.05; 514/269; 514/406; 544/182; 544/238;
544/316; 544/405; 548/364.1 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 25/14 20180101; C07D 405/14 20130101; A61P 7/04 20180101; A61P
21/00 20180101; A61P 25/06 20180101; A61P 3/10 20180101; A61P 7/06
20180101; A61P 29/02 20180101; A61P 43/00 20180101; A61P 31/00
20180101; C07D 401/14 20130101; A61P 31/04 20180101; A61P 27/02
20180101; A61P 19/06 20180101; A61P 19/10 20180101; A61P 25/28
20180101; A61P 35/00 20180101; A61P 13/12 20180101; A61P 25/16
20180101; A61P 37/02 20180101; A61P 11/06 20180101; A61P 15/06
20180101; A61P 37/04 20180101; A61P 35/04 20180101; A61P 5/14
20180101; A61P 19/02 20180101; A61P 1/04 20180101; A61P 1/02
20180101; A61P 9/04 20180101; A61P 33/02 20180101; A61P 9/00
20180101; A61P 29/00 20180101; A61P 9/10 20180101; A61P 15/08
20180101; A61P 25/02 20180101; A61P 7/02 20180101; A61P 17/00
20180101; A61P 25/00 20180101; A61P 25/24 20180101; C07D 403/04
20130101; A61P 11/00 20180101; A61P 17/02 20180101 |
Class at
Publication: |
514/242 ;
514/252.05; 514/269; 514/255.05; 514/406; 544/182; 544/238;
544/405; 544/316; 548/364.1 |
International
Class: |
A61K 031/53; A61K
031/513; A61K 031/497; A61K 031/4439; A61K 031/416; C07D 43/04 |
Claims
1. A compound of the formula 119wherein A is a heterocycle selected
from the group consisting of 120121R.sup.2 is hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, formyl, formamidyl, cyano,
nitro, HO--(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxycarbony- l,
aminocarbonyl, N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)ar- ylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino; wherein said R.sup.2
(C.sub.1-C.sub.6)alkyl group may optionally be substituted with one
to three substitutents independently selected from halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, cyano, nitro, HO--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub- .2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino; R.sup.3 is hydrogen, halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, formyl, formamidyl, cyano,
nitro, --CO.sub.2H, (C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)ar- ylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino; wherein said R.sup.3
(C.sub.1-C.sub.6)alkyl group may optionally be substituted with one
to three substitutents independently selected from halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, cyano, nitro, HO--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub- .2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino; R.sup.4 is (C.sub.1-C.sub.6)
alkyl optionally substituted by one to three halo atoms; R.sup.5 is
hydrogen; halo; hydroxy; mercapto; (C.sub.1-C.sub.6)alkyl;
(C.sub.1-C.sub.6)alkoxy optionally substituted with one to three
halogen atoms; (C.sub.2-C.sub.6)alkenyl; (C.sub.2-C.sub.6)alkynyl;
cyano; formyl; (C.sub.1-C.sub.6)alkylcarbonyl;
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--; HO--(O.dbd.C)--;
(C.sub.1-C.sub.6)alkoxy-C(.dbd.O)--; aminocarbonyl;
N--(C.sub.1-C.sub.6)alkylaminocarbonyl;
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl; nitro; amino;
(C.sub.1-C.sub.6)alkylamino; [(C.sub.1-C.sub.6)alkyl].sub.2amino;
or (C.sub.1-C.sub.6)alkyl-S--; wherein said R.sup.5
(C.sub.1-C.sub.6)alkyl group may optionally be substituted with one
to three substitutents independently selected from halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, cyano, nitro, amino,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)dialkylamino,
HO--(O.dbd.C)--, (C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--,
aminocarbonyl, N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl, N,N--[(
C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(- C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylam- ino; R.sup.6 is selected from
the group consisting of: (a) phenyl optionally substituted by 1-3
substituents independently selected from the group consisting of
halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl- (C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (b) phenyl fused to a saturated, partially
saturated or aromatic (5- to 7-membered)-carbocyclic ring; wherein
either of said phenyl or said fused saturated, partially saturated
or aromatic (5- to 7-membered)-carbocyclic ring is optionally
substituted by 1 to 2 substituents per ring, wherein said
substituents are independently selected from the group consisting
of halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (c) phenyl fused to a saturated, partially
saturated or aromatic (5- to 6-membered)-heterocycli- c containing
1 to 2 ring heteroatoms independently selected from the group
consisting of --N.dbd., --NR'--, --S-- or --O--; wherein either of
said phenyl or said fused saturated, partially saturated or
aromatic (5- to 6-membered)-heterocyclic is optionally substituted
with one to two substituents per ring, wherein said substituents
are independently selected from the group consisting of halo,
hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (d) (5- to 7-membered)-carbocyclic
optionally containing one or two double bonds; wherein said (5- to
7-membered)-carbocyclic may also be optionally substituted by 1-3
substituents independently selected from the group consisting of
halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (e) (5- to 7-membered)-carbocyclic fused to
a saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein said (5- to
7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (f) (5- to 7-membered)-carbocyclic fused to
a saturated, partially unsaturated or aromatic (5- to
6-membered)-heterocyclic containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein said (5- to
7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially unsaturated or aromatic (5- to
6-membered)-heterocyclic is optionally substituted with one to two
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (g) saturated, partially unsaturated or
aromatic (5- to 6-membered)heterocyclic containing 1 to 4 ring
heteroatoms independently selected from --N.dbd., --NR--, --O--, or
--S--, wherein said (5- to 6-membered)heterocyclic is optionally
substituted by 1-3 substituents independently selected from the
group consisting of halo, hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3- substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; (h) saturated, partially unsaturated or
aromatic (5- to 6-membered)heterocyclic containing 1 to 2 ring
heteroatoms independently selected from the group consisting of
--N.dbd., --NR'--, --S-- or --O--; wherein said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic is
fused to a saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein either of said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic ring
or said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(Cl-C.sub.6)alkyl; and (i) saturated, partially unsaturated or
aromatic (5- to 6-membered)heterocyclic containing 1 to 2 ring
heteroatoms independently selected from the group consisting of
--N.dbd., --NR'--, --S--, or --O--; wherein said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic is
fused to a saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein either of said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic or
said fused saturated, partially unsaturated or aromatic (5- to
6-membered)-heterocyclic is optionally substituted with one to two
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; R.sup.7 is hydrogen or
(C.sub.1-C.sub.6)alkyl; R.sup.8 is hydrogen; halo; hydroxy;
mercapto; (C.sub.1-C.sub.6)alkyl; (C.sub.1-C.sub.6)alkoxy
optionally substituted with one to three halogen atoms;
(C.sub.2-C.sub.6)alkenyl; (C.sub.2-C.sub.6)alkynyl; cyano; formyl;
(C.sub.1-C.sub.6)alkylcarbonyl;
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--; HO--(O.dbd.C)--;
(C.sub.1-C.sub.6)alkoxy-C(.dbd.O)--; aminocarbonyl;
N--(C.sub.1-C.sub.6)alkylaminocarbonyl;
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl; nitro; amino;
(C.sub.1-C.sub.6)alkylamino; di[(C.sub.1-C.sub.6)alkyl]amino; or
(C.sub.1-C.sub.6)alkyl-S--; wherein said R.sup.8
(C.sub.1-C.sub.6)alkyl group may optionally be substituted with one
to three substitutents independently selected from halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, cyano, nitro, HO--(O.dbd.C)--,
(C.sub.1-C.sub.6)alkoxy-C(.dbd.O)--, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alk- yl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylam- ino; and a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1 wherein said compound has the
formula 122wherein X is CR.sup.8 or N and m is 2.
3. A compound according to claim 1 wherein said compound has the
formula 123wherein X is CR.sup.8 or N and m is 2.
4. A compound according to claim 1 wherein said compound has the
formula 124wherein m is 2.
5. A compound according to claim 1 wherein said compound has the
formula 125wherein m is 2.
6. A compound according to claim 1 wherein said compound has the
formula 126wherein m is 2.
7. A compound according to claim 1 wherein said compound has the
formula 127wherein m is 2.
8. A compound according to claim 1 wherein said compound has the
formula 128wherein m is 2.
9. A compound according to claim 1, wherein said compounds have the
formula 129wherein m is 2.
10. A compound according to claim 1, wherein said compounds have
the formula 130wherein m is 2.
11. A compound according to claim 1, wherein said compounds have
the formula 131wherein m is 2.
12. A compound according to claim 1 wherein R.sup.6 is phenyl
optionally substituted by 1-3 substituents independently selected
from the group consisting of halo, hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy- , --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-(S.dbd.O- )--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamin- o, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -: wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
13. A compound according to claim 1 wherein R.sup.6 is phenyl fused
to a saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein either of said phenyl or said
fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
14. A compound according to claim 1 wherein R.sup.6 is phenyl fused
to a saturated, partially saturated or aromatic (5- to
6-membered)-heterocycli- c ring containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein either of said phenyl or said
fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic ring is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo, hydroxy,
cyano, mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--;
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
15. A compound according to claim 1 wherein R.sup.6 is (5- to
7-membered)-carbocyclic optionally containing one or two double
bonds; wherein said (5- to 7-membered)-carbocyclic may also bed
optionally substituted by 1-3 substituents independently selected
from the group consisting of halo, hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
16. A compound according to claim 1 wherein R.sup.6 is (5- to
7-membered)-carbocyclic fused to a saturated, partially saturated
or aromatic (5- to 7-membered)-carbocyclic ring; wherein said (5-
to 7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
17. A compound according to claim 1 wherein R.sup.6 is (5- to
6-membered)-carbocyclic fused to a saturated, partially saturated
or aromatic (5- to 6-membered)-heterocyclic containing 1 to 2 ring
heteroatoms independently selected from the group consisting of
--N.dbd., --NR'--, --S-- or --O--; wherein said (5- to
7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic is optionally substituted with one to two
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
18. A compound according to claim 1 wherein R.sup.6 is saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic
containing 1 to 4 ring heteroatoms independently selected from
--N.dbd., --NR--, --O--, or --S--, wherein said (5- to
6-membered)heterocyclic is optionally substituted by 1-3
substituents independently selected from the group consisting of
halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
19. A compound according to claim 1 wherein R.sup.6 is saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic
containing 1 to 2 ring heteroatoms independently selected from the
group consisting of --N.dbd., --NR'--, --S-- or --O--; wherein said
saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic is fused to a saturated, partially
saturated or aromatic (5- to 7-membered)-carbocyclic ring; wherein
either of said saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic ring or said fused saturated, partially
saturated or aromatic (5- to 7-membered)-carbocyclic ring is
optionally substituted by 1 to 2 substituents per ring, wherein
said substituents are independently selected from the group
consisting of halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--,
nitro, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O), (C.sub.1-C.sub.6)alkyl-HN--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
20. A compound according to claim 1 wherein R.sup.6 is saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic
containing 1 to 2 ring heteroatoms independently selected from the
group consisting of --N.dbd., --NR'--, --S--, or --O--; wherein
said saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic is fused to a saturated, partially
saturated or aromatic (5- to 6-membered)-heterocycli- c containing
1 to 2 ring heteroatoms independently selected from the group
consisting of --N.dbd., --NR'--, --S-- or --O--; wherein either of
said saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic or said fused saturated, partially
saturated or aromatic (5- to 6-membered)-heterocyclic is optionally
substituted with one to two substituents per ring, wherein said
substituents are independently selected from the group consisting
of halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl.
21. A compound according to claim 1 wherein R.sup.2 is hydrogen,
halo or (C.sub.1-C.sub.6)alkyl.
22. A compound according to claim 1 wherein R.sup.2 is methyl or
hydrogen.
23. A compound according to claim 1 wherein R.sup.3 is cyano or
(C.sub.1-C.sub.6)alkyl optionally substituted with one to three
halo atoms.
24. A compound according to claim 1 wherein R.sup.3is --CF.sub.3 or
--CF.sub.2H.
25. A compound according to claim 1 wherein said compound is
selected from the group consisting of:
2-[5-(4-Bromo-phenyl)-3-trifluoromethyl-pyrazol--
1-yl]-5-methanesulfonyl-pyridine;
{4-[2-(6-Methanesulfonyl-pyridin-3-yl)-5-
-trifluoromethyl-2H-pyrazol-3-yl]-phenyl}-dimethyl-amine;
{4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-
-phenyl}-dimethyl-amine;
2-[3-Difluoromethyl-5-(3-fluoro-4-methoxy-phenyl)-
-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
2-[5-(3-Bromo-4-methoxy-phenyl)-
-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
2-[5-(3-Chloro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
2-(3-Difluoromethyl-5-p-tolyl-pyrazol-1-yl)-5-methanes-
ulfonyl-pyridine;
5-Methanesulfonyl-2-(5-o-tolyl-3-trifluoromethyl-pyrazol-
-1-yl)-pyridine;
5-Methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-pyrazol-1-
-yl)-pyridine;
2-[5-(3-Chloro-4-methoxy-phenyl)-3-difluoromethyl-pyrazol-1-
-yl]-5-methanesulfonyl-pyridine;
2-[5-(3-Fluoro-4-methoxy-phenyl)-3-triflu-
oromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
5-Methanesulfonyl-2-[5-(4-methoxy-3-methyl-phenyl)-3-trifluoromethyl-pyra-
zol-1-yl]-pyridine;
2-[3-Difluoromethyl-5-(4-methoxy-3-methyl-phenyl)-pyra-
zol-1-yl]-5-methanesulfonyl-pyridine;
2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-
-yl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
2-(5-Benzo[1,3]dioxol-5-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfo-
nyl-pyridine;
2-[5-(2-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-
-yl]-5-methanesulfonyl-pyridine;
2-[3-Difluoromethyl-5-(2-fluoro-4-methoxy-
-phenyl)-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
2-[3-Difluoromethyl-5-(-
3,4-dimethyl-phenyl)-pyrazol-1-yl]-5-methanesulfonyl-pyridine;
2-[5-(4-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl--
pyridine;
2-[5-(4-Fluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methane-
sulfonyl-pyridine;
2-[5-(4-Chloro-3-methyl-phenyl)-3-trifluoromethyl-pyraz-
ol-1-yl]-5-methanesulfonyl-pyridine;
2-(3-Difluoromethyl-5-phenyl-pyrazol--
1-yl)-5-methanesulfonylpyridine;
2-[3-Difluoromethyl-5-(4-fluoro-phenyl)-p-
yrazol-1-yl]-5-methanesulfonyl-pyridine;
5-Methanesulfonyl-2-[5-(6-methyl--
naphthalen-2-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine;
2-(5-Cyclohexyl-3-difluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine-
;
2-[3-Difluoromethyl-5-(2-fluoro-phenyl)-pyrazol-1-yl]-5-methanesulfonyl--
pyridine;
2-(4-Chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesu-
lfonyl-pyridine; and
2-(5-Cyclohexyl-3-trifluoromethyl-pyrazol-1-yl)-5-met-
hanesulfonyl-pyridine.
26. A pharmaceutical composition for the treatment of a condition
selected from the group consisting of arthritis, fever, common
cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease,
Crohn's disease, emphysema, acute respiratory distress syndrome,
asthma, bronchitis, chronic obstructive pulmonary disease,
Alzheimer's disease, organ transplant toxicity, cachexia, allergic
reactions, allergic contact hypersensitivity, cancer, tissue
ulceration, peptic ulcers, gastritis, regional enteritis,
ulcerative colitis, diverticulitis, recurrent gastrointestinal
lesion, gastrointestinal bleeding, coagulation, anemia, synovitis,
gout, ankylosing spondylitis, restenosis, periodontal disease,
epidermolysis bullosa, osteoporosis, loosening of artificial joint
implants, atherosclerosis, aortic aneurysm, periarteritis nodosa,
congestive heart failure, myocardial infarction, stroke, cerebral
ischemia, head trauma, spinal cord injury, neuralgia,
neuro-degenerative disorders, autoimmune disorders, Huntington's
disease, Parkinson's disease, migraine, depression, peripheral
neuropathy, pain, gingivitis, cerebral amyloid angiopathy,
nootropic or cognition enhancement, amyotrophic lateral sclerosis,
multiple sclerosis, ocular angiogenesis, corneal injury, macular
degeneration, conjunctivitis, abnormal wound healing, muscle or
joint sprains or strains, tendonitis, skin disorders, myasthenia
gravis, polymyositis, myositis, bursitis, burns, diabetes, tumor
invasion, tumor growth, tumor metastasis, corneal scarring,
scleritis, immunodeficiency diseases, sepsis, premature labor,
hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's
syndrome, hypersensitivity, kidney disease, Rickettsial infections,
Protozoan diseases, reproductive disorders and septic shock in a
mammal, comprising an amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof effective in such
treatments and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition for the treatment of a disorder or
condition that can be treated or prevented by selectively
inhibiting COX-2 in a mammal, comprising a COX-2 selective
inhibiting effective amount of a compound according to claim 1 or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
28. A method for treating a condition selected from the group
consisting of arthritis, fever, common cold, dysmenorrhea,
menstrual cramps, inflammatory bowel disease, Crohn's disease,
emphysema, acute respiratory distress syndrome, asthma, bronchitis,
chronic obstructive pulmonary disease, Alzheimer's disease, organ
transplant toxicity, cachexia, allergic reactions, allergic contact
hypersensitivity, cancer, tissue ulceration, peptic ulcers,
gastritis, regional enteritis, ulcerative colitis, diverticulitis,
recurrent gastrointestinal lesion, gastrointestinal bleeding,
coagulation, anemia, synovitis, gout, ankylosing spondylitis,
restenosis, periodontal disease, epidermolysis bullosa,
osteoporosis, loosening of artificial joint implants,
atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive
heart failure, myocardial infarction, stroke, cerebral ischemia,
head trauma, spinal cord injury, neuralgia, neuro- degenerative
disorders, autoimmune disorders, Huntington's disease, Parkinson's
disease, migraine, depression, peripheral neuropathy, pain,
gingivitis, cerebral amyloid angiopathy, nootropic or cognition
enhancement, amyotrophic lateral sclerosis, multiple sclerosis,
ocular angiogenesis, corneal injury, macular degeneration,
conjunctivitis, abnormal wound healing, muscle or joint sprains or
strains, tendonitis, skin disorders, myasthenia gravis,
polymyositis, myositis, bursitis, burns, diabetes, tumor invasion,
tumor growth, tumor metastasis, corneal scarring, scleritis,
immunodeficiency diseases, sepsis, premature labor,
hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's
syndrome, hypersensitivity, kidney disease, Rickettsial infections,
Protozoan diseases, reproductive disorders, and septic shock in a
mammal, comprising administering to said mammal an amount of a
compound according to claim 1 or a pharmaceutically acceptable salt
thereof effective in treating such a condition.
29. A method for treating a disorder or condition that can be
treated or prevented by selectively inhibiting COX-2 in a mammal,
comprising administering to a mammal requiring such treatment a
COX-2 selective inhibiting effective amount of a compound according
to claim 1 or a pharmaceutically acceptable salt thereof.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to heterocyclo-alkylsulfonyl pyrazole
derivatives and methods of treatment and pharmaceutical
compositions for the treatment of cyclooxygenase mediated diseases.
The compounds of this invention inhibit the biosynthesis of
prostaglandins by intervention of the action of the enzyme
cyclooxygenase on arachidonic acid, and are therefore useful in the
treatment or alleviation of inflammation and other inflammation
associated disorders, such as arthritis, neurodegeneration and
colon cancer, in mammals, preferably humans, dogs, cats or
livestock.
[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely
used in treating pain and the signs and symptoms of arthritis
because of their analgesic and anti-inflammatory activity. It is
accepted that common NSAIDs work by blocking the activity of
cyclooxygenase (COX), also known as prostaglandin G/H synthase
(PGHS), the enzyme that converts arachidonic acid into prostanoids.
Prostaglandins, especially prostaglandin E.sub.2 (PGE.sub.2), which
is the predominant eicosanoid detected in inflammation conditions,
are mediators of pain, fever and other symptoms associated with
inflammation. Inhibition of the biosynthesis of prostaglandins has
been a therapeutic target of anti-inflammatory drug discovery. The
therapeutic use of conventional NSAIDs is, however, limited due to
drug associated side effects, including life threatening ulceration
and renal toxicity. An alternative to NSAIDs is the use of
corticosteriods, however, long term therapy can also result in
severe side effects.
[0003] The use of NSAIDs in dogs and cats has been more limited
than that in humans, e.g., only three such NSAIDs have been
approved by the Food and Drug Administration, Committee on
Veterinary Medicine (FDA/CVM), for use in dogs in the United
States, i.e., ETOGESIC.RTM. (etodolac), ARQUEL.RTM. (meclofenamic
acid) and RIMADYL.RTM. (carprofen). Consequently, there is less
experience and knowledge in veterinary medicine about safety and
efficacy issues surrounding the use of NSAIDs in dogs. In
veterinary medicine, for example, the most common indication for
NSAIDs is the treatment of degenerative joint disease (DJD), which
in dogs often results from a variety of developmental diseases,
e.g., hip dysplasia and osteochondrosis, as well as from traumatic
injuries to joints. In addition to the treatment of chronic pain
and inflammation, NSAIDs are also useful in dogs for treating
post-surgical acute pain, as well as for treating clinical signs
associated with osteoarthritis.
[0004] Two forms of COX are now known, a constitutive isoform
(COX-1) and an inducible isoform (COX-2) of which expression is
upregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.;
Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll,
J.;Willoughby, D. A. Proc. Natl. Acad. Sci. USA, 1994, 91, 2046).
COX-1 is thought to play a physiological role and to be responsible
for gastrointestinal and renal protection. On the other hand, COX-2
appears to play a pathological role and is believed to be the
predominant isoform present in inflammation conditions. A
pathological role for prostaglandins has been implicated in a
number of human disease states including rheumatoid arthritis and
osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular
diseases, dysmenorrhea, premature labour, nephritis, nephrosis,
atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer
disease. It is believed that compounds that selectively inhibit the
biosynthesis of prostaglandins by intervention of the induction
phase of the inducible enzyme COX-2 and/or by intervention of the
activity of the enzyme COX-2 on arachidonic acid would provide
alternate therapy to the use of NSAIDs or corticosteriods in that
such compounds would exert anti-inflammatory effects without the
adverse side effects associated with COX-1 inhibition.
[0005] A variety of sulfonylbenzene compounds which inhibit COX
have been disclosed in patent publications (WO 97/16435, WO
97/14691, WO 96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO
97/727181, WO 96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO
95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP
0799523, EP 418845, and EP 554829). Especially important is
International Publication Number WO 97/11704, which discloses
pyrazole compounds substituted by optionally substituted aryl.
SUMMARY OF THE INVENTION
[0006] The present invention relates to compounds of the formula
2
[0007] wherein A is a heterocycle selected from the group
consisting of 34
[0008] R.sup.2 is hydrogen, halo (more preferably chloro or fluoro,
most preferably fluoro), (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, formyl
formamidyl, cyano, nitro, HO--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alk- yl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylam- ino;
[0009] wherein said R.sup.2 (C.sub.1-C.sub.6)alkyl group may
optionally be substituted with one to three substitutents
independently selected from halo, hydroxy, (C.sub.1-C.sub.6)alkoxy,
cyano, nitro, HO--(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl, N--(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub- .2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylam inocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino;
[0010] R.sup.3 is hydrogen, halo (more preferably chloro or fluoro,
most preferably fluoro), (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
formyl, formamidyl, cyano, nitro, HO--(O.dbd.C)--,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alk- yl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylam- ino;
[0011] wherein said R.sup.3 (C.sub.1-C.sub.6)alkyl group may
optionally be substituted with one to three substitutents
independently selected from halo, hydroxy, (C.sub.1-C.sub.6)alkoxy,
cyano, nitro, HO--(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxycarbonyl,
aminocarbonyl, N--(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub- .2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkylcarbonylamino;
[0012] R.sup.4 is (C.sub.1-C.sub.6)alkyl (preferably methyl)
optionally substituted by one to three halo atoms (preferably
fluoro);
[0013] R.sup.5 is hydrogen; halo (preferably fluoro or chloro);
hydroxy; mercapto; (C.sub.1-C.sub.6)alkyl; (C.sub.1-C.sub.6)alkoxy
optionally substituted with one to three halogen atoms (preferably
fluoro); (C.sub.2-C.sub.6)alkenyl; (C.sub.2-C.sub.6)alkynyl; cyano;
formyl; (C.sub.1-C.sub.6)alkylcarbonyl;
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--; HO--(O.dbd.C)--;
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; aminocarbonyl;
N--(C.sub.1-C.sub.6)alkylaminocarbonyl;
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl; nitro; amino;
(C.sub.1-C.sub.6)alkylamino; [(C.sub.1-C.sub.6)alkyl].sub.2amino;
or (C.sub.1-C.sub.6)alkyl-S--;
[0014] wherein said R.sup.5 (C.sub.1-C.sub.6)alkyl group may
optionally be substituted with one to three substitutents
independently selected from halo, hydroxy, (C.sub.1-C.sub.6)alkoxy,
cyano, nitro, amino, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)dialkylamino, HO--(O.dbd.C)--,
(C.sub.1-C.sub.6)alkoxycarbonyl, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkylaminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub- .2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub.2aminocarbonyl,
N--(C.sub.1-C.sub.6)alk- yl-N--(C.sub.6-C.sub.10)arylaminocarbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylam- ino;
[0015] R.sup.6 is selected from the group consisting of
[0016] (a) phenyl optionally substituted by 1-3 substituents
independently selected from the group consisting of halo
(preferably chloro, bromo or fluoro), hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy- , --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O- )--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino- , di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0017] (b) phenyl fused to a saturated, partially saturated or
aromatic (5- to 7-membered)-carbocyclic ring; wherein either of
said phenyl or said fused saturated, partially saturated or
aromatic (5- to 7-membered)-carbocyclic ring is optionally
substituted by 1 to 2 substituents per ring, wherein said
substituents are independently selected from the group consisting
of halo (preferably chloro, bromo or fluoro), hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0018] (c) phenyl fused to a saturated, partially saturated or
aromatic (5- to 6-membered)-heterocyclic ring containing 1 to 2
ring heteroatoms independently selected from the group consisting
of --N.dbd., --NR'--, --S-- or --O--; wherein either of said phenyl
or said fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic ring is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo
(preferably chloro, bromo or fluoro), hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0019] (d) (5- to 7-membered)-carbocyclic ring optionally
containing one or two double bonds; wherein said (5- to
7-membered)-carbocyclic may also be optionally substituted by 1-3
substituents independently selected from the group consisting of
halo (preferably chloro, bromo or fluoro), hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0020] (e) (5- to 7-membered)-carbocyclic ring fused to a
saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein said (5- to
7-membered)-carbocyclic ring may optionally contain one or two
double bonds; wherein either of said (5- to 7-membered)-carbocyclic
or said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo (preferably chloro,
bromo or fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0021] (f) (5- to 7-membered)-carbocyclic ring fused to a
saturated, partially unsaturated or aromatic (5- to
6-membered)-heterocyclic ring containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein said (5- to
7-membered)-carbocyclic ring may optionally contain one or two
double bonds; wherein either of said (5- to 7-membered)-carbocyclic
or said fused saturated, partially unsaturated or aromatic (5- to
6-membered)-heterocyclic ring is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo
(preferably chloro, bromo or fluoro), hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0022] (g) saturated, partially unsaturated or aromatic (5- to
6-membered)heterocyclic ring containing 1 to 4 ring heteroatoms
independently selected from --N.dbd., --NR--, --O--, or --S--,
wherein said (5- to 6-membered)heterocyclic ring is optionally
substituted by 1-3 substituents independently selected from the
group consisting of halo (preferably chloro, bromo or fluoro),
hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0023] (h) saturated, partially unsaturated or aromatic (5- to
6-membered)heterocyclic ring containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein said (5- to
6-membered)heterocyclic ring is fused to a saturated, partially
saturated or aromatic (5- to 7-membered)-carbocyclic ring; wherein
either of said (5- to 6-membered)heterocyclic ring or said fused
saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo (preferably chloro,
bromo or fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; and
[0024] (i) saturated, partially unsaturated or aromatic (5- to
6-membered)heterocyclic ring containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S--, or --O--; wherein said (5- to
6-membered)heterocyclic ring is fused to a saturated, partially
saturated or aromatic (5- to 6-membered)-heterocyclic containing 1
to 2 ring heteroatoms independently selected from the group
consisting of --N.dbd., --NR'--, --S-- or --O--; wherein either of
said saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic ring or said fused saturated, partially
unsaturated or aromatic (5- to 6-membered)-heterocyclic ring is
optionally substituted with one to two substituents per ring,
wherein said substituents are independently selected from the group
consisting of halo (preferably chloro, bromo or fluoro), hydroxy,
cyano, mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, )C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl;
[0025] R.sup.7 is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0026] R.sup.8 is hydrogen; halo (preferably fluoro or chloro);
hydroxy; mercapto; (C.sub.1-C.sub.6)alkyl; (C.sub.1-C.sub.6)alkoxy
optionally substituted with one to three halogen atoms (preferably
fluoro); (C.sub.2-C.sub.6)alkenyl; (C.sub.2-C.sub.6)alkynyl; cyano;
formyl; (C.sub.1-C.sub.6)alkylcarbonyl;
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--; HO--(O.dbd.C)--;
(C.sub.1-C.sub.6)alkoxy-C(.dbd.O)--; aminocarbonyl;
N--(C.sub.1-C.sub.6)alkylaminocarbonyl;
N,N--[(C.sub.1-C.sub.6)alkyl).sub- .2aminocarbonyl; nitro; amino;
(C.sub.1-C.sub.6)alkylamino; [(C.sub.1-C.sub.6)alkyl].sub.2amino;
or (C.sub.1-C.sub.6)alkyl-S--;
[0027] wherein said R.sup.8 (C.sub.1-C.sub.6)alkyl group may
optionally be substituted with one to three substitutents
independently selected from halo, hydroxy, (C.sub.1-C.sub.6)alkoxy,
cyano, nitro, HO--(O.dbd.C)--, (C.sub.1-C.sub.6)alkoxy-C(.dbd.O)--,
amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
N,N--[(C.sub.1-C.sub.6)alkyl].sub.2aminocarbonyl,
N--(C.sub.6-C.sub.10)arylaminocarbonyl,
N,N--[(C.sub.6-C.sub.10)aryl].sub- .2aminocarbonyl,
N--(C.sub.1-C.sub.6)alkyl-N--(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heteroaryloxy,
morpholino-carbonyl, (C.sub.1-C.sub.6)alkoxyaminocarbonyl or
(C.sub.1-C.sub.6)alkyl-carbonylamino;
[0028] and the pharmaceutically acceptable salts thereof.
[0029] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, acetate, lactate, citrate,
acid citrate, tartrate, bitartrate, succinate, maleate, fumarate,
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
[0030] The invention also relates to base addition salts of formula
I. The chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those compounds of
formula I that are acidic in nature are those that form non-toxic
base salts with such compounds. Such non-toxic base salts include,
but are not limited to those derived from such pharmacologically
acceptable cations such as alkali metal cations (e.g., potassium
and sodium) and alkaline earth metal cations (e.g., calcium and
magnesium), ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines.
[0031] The compounds of this invention include all stereoisomers
(e.g., cis and trans isomers) and all optical isomers of compounds
of the formula I (e.g., R and S enantiomers), as well as racemic,
diastereomeric and other mixtures of such isomers.
[0032] The compounds of the invention also exist in different
tautomeric forms. This invention relates to all tautomers of
formula I.
[0033] The compounds of this invention may contain olefin-like
double bonds. When such bonds are present, the compounds of the
invention exist as cis and trans configurations and as mixtures
thereof.
[0034] Unless otherwise indicated, the alkyl, referred to herein,
as well as the alkyl moieties of other groups referred to herein
(e.g., alkoxy), may be linear or branched (such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl,
tertiary-butyl), and they may also be cyclic (e.g., cyclopropyl, or
cyclobutyl); optionally substituted by 1 to 3 suitable substituents
as defined below such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl. The
phrase "each of said alkyl" as used herein refers to any of the
preceding alkyl moieties within a group such alkoxy, alkenyl or
alkylamino.
[0035] Unless otherwise indicated, halogen includes fluoro, chloro,
bromo or iodo, or fluoride, chloride, bromide or iodide.
[0036] As used herein, the term "halo-substituted alkyl" refers to
an alkyl radical as described above substituted with one or more
halogens included, but not limited to, chloromethyl,
dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
2,2,2-trichloroethyl, and the like; optionally substituted by 1 to
3 suitable substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0037] As used herein, the term "alkenyl" means straight or
branched chain unsaturated radicals of 2 to 6 carbon atoms,
including, but not limited to ethenyl, 1-propenyl, 2-propenyl
(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
and the like; optionally substituted by 1 to 3 suitable
substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0038] As used herein, the term "alkynyl" is used herein to mean
straight or branched hydrocarbon chain radicals of 2 to 6 carbon
atoms having one triple bond including, but not limited to,
ethynyl, propynyl, butynyl, and the like; optionally substituted by
1 to 3 suitable substituents as defined below such as fluoro,
chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0039] As used herein, the term "alkoxy" refers to O-alkyl groups,
wherein alkyl is as defined above.
[0040] As used herein, the term "alkoxycarbonyl" refers to an
alkoxy radical as described above connected to a carbonyl group
(>C.dbd.O), which, in turn, serves as the point of
attachment.
[0041] As used herein the term "aryl" means aromatic radicals such
as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like;
optionally substituted by 1 to 3 suitable substituents as defined
below such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
[0042] As used herein "heteroaryl" group usually has one heteroatom
selected from O, S and N in the ring. In addition to said
heteroatom, the aromatic group may optionally have up to four N
atoms in the ring. For example, heteroaryl group includes pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl,
pyranyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl,
1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl),
pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,
1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl),
thiadiazolyl (e.g., 1,3,4-thiadiazolyl), tetrazole, quinolyl,
isoquinolyl, benzothienyl, isobenzofuranyl, benzofuryl, indolyl,
quinoxalinyl and the like; optionally substituted by 1 to 3
suitable substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0043] The term "heterocyclic" as used herein refers to a cyclic
group containing 2-9 carbon atoms and 1-4 hetero atoms selected
from N, O, S or NR'. Examples of such rings include furyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl,
oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the
like. Examples of said monocyclic saturated or partially saturated
ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl,
pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl,
piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl,
piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,
thiomorpholine, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl and the like; optionally
substituted by 1 to 3 suitable substituents as defined below such
as fluoro, chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0044] The term "phenyl fused to a saturated, partially saturated
or aromatic (5- to 7-membered)-carbocyclic ring", as used herein,
unless otherwise indicated, means a bicyclic group having a first
phenyl ring covalently bound to the pyrazole nucleus and wherein
said first ring is fused to a second ring comprising a 5 to 7
membered carbocycle, wherein the 5 to 7 members include the carbon
atoms common to both rings. Examples of such rings include
tetralin-5-yl, tetralin-6-yl, 2,3-dihydro-inden-4-yl,
2,3-dihydro-inden-5-yl, inden-4-yl, inden-5-yl,
7,8-dihydro-naphthalen-1-yl, 7,8-dihydro-naphthalen-2-yl,
5,6-dihydro-naphthalen-1-yl, 5,6-dihydro-naphthalen-2-yl,
5,8-dihydro-naphthalen-1-yl, 5,8-dihydro-naphthalen-2-yl,
naphthalen-1-yl, naphthalen-2-yl,
5-(6,7,8,9-tetrahydro-5H-benzocyclohept- en-1-yl)-,
5-(8,9-dihydro-7H-benzocyclohepten-1-yl)-,
5-(6,7-dihydro-5H-benzocyclohepten-1-yl)-,
5-(7H-benzocyclohepten-1-yl)-, 5-(5H-benzocyclohepten-1-yl)-,
5-(9H-benzocyclohepten-1-yl)-,
5-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-,
5-(6,7-dihydro-5H-benzo- cyclohepten-2-yl)-,
5-(8,9-dihydro-7H-benzocyclohepten-2-yl)-,
5-(5H-benzocyclohepten-2-yl)-, 5-(9H-benzocyclohepten-2-yl)-,
5-(7H-benzocyclohepten-2-yl)-, and the like; optionally substituted
by 1 to 3 suitable substituents as defined below such as fluoro,
chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0045] The term "phenyl fused to a saturated, partially saturated
or aromatic (5- to 6-membered)-heterocyclic ring", as used herein,
unless otherwise indicated, means a bicyclic group having a first
phenyl ring covalently bound to the pyrazole nucleus and wherein
said first ring is fused to a second ring comprising a (5- to
6-membered)-heterocyclic ring, wherein the 5 to 6 members include
the carbon atoms common to both rings. Said second ring comprises a
saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic ring. Examples of such rings include
quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl,
isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl,
isoquinolin-8-yl, quinazolin-5-yl, quinazolin-6-yl,
quinazolin-7-yl, quinazolin-8-yl, cinnolin-5-yl, cinnolin-6-yl,
cinnolin-7-yl, cinnolin-8-yl, 4H-1,4-benzoxazin-5-yl,
4H-1,4-benzoxazin-6-yl, 4H-1,4-benzoxazin-7-yl,
4H-1,4-benzoxazin-8-yl, 4H-1,4-benzthiazin-5-yl,
4H-1,4-benzthiazin-6-yl, 4H-1,4-benzthiazin-7-yl,
4H-1,4-benzthiazin-8-yl, 1,4H-1,4-benzdiazin-5-y- l,
1,4H-1,4-benzdiazin-6-yl, 1,4H-1,4-benzdiazin-7-yl,
1,4H-1,4-benzdiazin-8-yl, indol-4-yl, indol-5-yl, indol-6-yl,
indol-7-yl, benzo(b)thiophen-4-yl, benzo(b)thiophen-5-yl,
benzo(b)thiophen-6-yl, benzo(b)thiophen-7-yl, benzofuran-4-yl,
benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl,
benzisoxazol-4-yl, benzisoxazol-5-yl, benzisoxazol-6-yl,
benzisoxazol-7-yl, benzoxazol-4-yl, benzoxazol-4-yl,
benzoxazol-5-yl, benzoxazol-6-yl and benzoxazol-7-yl. Preferred
fused phenylheteroaryl rings include quinolinyl, isoquinolinyl,
indolyl, benzo(b)thiophenyl, benzofuranyl and the like; optionally
substituted by 1 to 3 suitable substituents as defined below such
as fluoro, chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0046] The term "(5- to 7-membered)-carbocyclic", as used herein,
unless otherwise indicated, means a monocyclic group containing 5
to 7 carbon atoms and optionally containing 1 or 2 double bonds.
Examples of such rings include cyclopentyl, cyclohexyl,
cycloheptanyl, cyclopentenyl, cyclohexenyl and cycloheptenyl and
the like; optionally substituted by 1 to 3 suitable substituents as
defined below such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
[0047] The term "(5- to 7-membered)-carbocyclic fused to a
saturated or partially saturated (5- to 7-membered)-carbocyclic
ring", as used herein, unless otherwise indicated, means a bicyclic
group having a first carbocyclic ring covalently bound to the
pyrazole nucleus and wherein said first ring is fused to a second
ring comprising a 5 to 7 membered carbocycle, wherein the 5 to 7
members include the carbon atoms common to both rings and wherein
said second ring may contain 1, 2 or 3 double bonds. Examples of
such rings, wherein the fusion is so called ortho fused, include
tetralin-1-yl, tetralin-2-yl, hexahydronaphthalen-1-yl,
hexahydronaphthalen-2-yl, octahydronaphthalen-1-yl,
octahydronaphthalen-2-yl, decalin-1-yl, decalin-2-yl,
4,5,6,7-tetrahydro-indan4-yl, 4,5,6,7-tetrahydro-indan-5-yl,
4,5,6,7,8,9-hexahydro-indan-4-yl, 4,5,6,7,8,9-hexahydro-indan-5-yl,
4,5,6,7-tetrahydro-inden-4-yl, 4,5,6,7-tetrahydro-inden-5-yl,
4,5,6,7,8,9-hexahydro-inden-4-yl, 4,5,6,7,8,9-hexahydro-inden-5-yl,
pentalan-1-yl, pentalan-2-yl, 4,5 dihydro-pentalan-1-yl, 4,5
dihydro-pentalan-2-yl, 4,5,6,7 tetrahydro-pentalan-1-yl, 4,5,6,7
tetra-pentalan-2-yl, benzocycloheptan-5-yl, benzocycloheptan-6-yl
and the like. Examples of such bicyclic rings that are not ortho
fused include bicyclo[3.2.1]-octan-2-yl, bicyclo[3.2.1]-octan-3-yl,
bicyclo [5.2.0]nonan-2-yl, bicyclo [5.2.0]nonan-3-yl, bicyclo
[5.2.0]nonan-4-yl, bicyclo [4.3.2]undecan-7-yl, bicyclo
[4.3.2]undecan-8-yl, bicyclo [4.3.2]undecan-9-yl,
bicyclo[2.2.2]-octan-2-yl, bicyclo[2.2.2]-octan-3-yl- ,
bicyclo[2.2.1]-heptan-2-yl, bicyclo[3.1.1]-heptan-2-yl,
borneol-2-yl and the like; optionally substituted by 1 to 3
suitable substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0048] The term "(5- to 7-membered)carbocyclic fused to a
saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic", as used herein, unless otherwise
indicated, means a bicyclic group having a first carbocyclic ring
covalently bound to the pyrazole nucleus and wherein said first
ring is fused to a second ring comprising a 5 to 6 membered
heterocyclic ring, wherein said second 5 to 6 members include the
atoms common to both rings. Said second ring comprises a saturated,
partially saturated or aromatic (5- to 6-membered)-heterocyclic
ring. Examples of said bicyclic ring systems are 5,6,7,8
tetrahydro-quinolin-5-yl, 5,6,7,8 tetrahydro-quinolin-6-yl, 5,6,7,8
tetrahydro-quinolin-7-yl, 5,6,7,8 tetrahydro-quinolin-8-yl, 5,6,7,8
tetrahydro-isoquinolin-5-yl, 5,6,7,8 tetrahydro-isoquinolin-6-yl,
5,6,7,8 tetrahydro-isoquinolin-7-yl, 5,6,7,8
tetrahydro-isoquinolin-8-yl, 5,6,7,8 tetrahydro-quinazolin-5-yl,
5,6,7,8 tetrahydro-quinazolin-6-yl, 5,6,7,8
tetrahydro-quinazolin-7-yl, 5,6,7,8 tetrahydro-quinazolin-8-yl,
5,6,7,8 tetrahydro-4H-1,4-benzoxazin-5-yl, 5,6,7,8
tetrahydro-4H-1,4-benzoxazin-6-yl, 5,6,7,8
tetrahydro-4H-1,4-benzoxazin-7-yl, 5,6,7,8
tetrahydro-4H-1,4-benzoxazin-8- -yl, 5,6,7,8
tetrahydro-4H-1,4-benzthiazin-5-yl, 5,6,7,8
tetrahydro-4H-1,4-benzthiazin-6-yl, 5,6,7,8
tetrahydro-4H-1,4-benzthiazin- -7-yl, 5,6,7,8
tetrahydro-4H-1,4-benzthiazin-8-yl, 5,6,7,8
tetrahydro-1,4H-1,4-benzdiazin-5-yl, 5,6,7,8
tetrahydro-1,4H-1,4-benzdiaz- in-6-yl, 5,6,7,8
tetrahydro-1,4H-1,4-benzdiazin-7-yl, 5,6,7,8
tetrahydro-1,4H-1,4-benzdiazin-8-yl, 4,5,6,7 tetrahydro-indol-4-yl,
4,5,6,7 tetrahydro indol-5-yl, 4,5,6,7 tetrahydro-indol-6-yl,
4,5,6,7 tetrahydro-indol-7-yl, 4,5,6,7
tetrahydro-benzo(b)thiophen-4-yl, 4,5,6,7
tetrahydro-benzo(b)thiophen-5-yl, 4,5,6,7
tetrahydro-benzo(b)thiophen-6-y- l, 4,5,6,7
tetrahydro-benzo(b)thiophen-7-yl, 4,5,6,7
tetrahydro-benzofuran-4-yl, 4,5,6,7 tetrahydro-benzofuran-5-yl,
4,5,6,7 tetrahydro-benzofuran-6-yl, 4,5,6,7
tetrahydro-benzofuran-7-yl, 4,5,6,7 tetrahydro-benzisoxazol-4-yl,
4,5,6,7 tetrahydro-benzisoxazol-5-yl, 4,5,6,7
tetrahydro-benzisoxazol-6-yl, 4,5,6,7 tetrahydro-benzisoxazol-7-y-
l, 4,5,6,7 tetrahydro-benzoxazol-4-yl, 4,5,6,7
tetrahydro-benzoxazol-4-yl, 4,5,6,7 tetrahydro-benzoxazol-5-yl,
4,5,6,7 tetrahydro-benzoxazol-6-yl, 4,5,6,7
tetrahydro-benzoxazol-7-yl and the like; optionally substituted by
1 to 3 suitable substituents as defined below such as fluoro,
chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0049] The term "saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic containing 1 to 4 ring heteroatoms
independently selected from --N.dbd., --NR--, --O--, or --S--", as
used herein, unless otherwise indicated, means a monocyclic (5- to
6-membered)heterocyclic ring covalently bound to the pyrazole
nucleus. Said ring may contain optional double bonds so as to
include saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic rings. Examples of the monocyclic aromatic
ring systems are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, oxatriazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, and the like. Examples of said
monocyclic saturated or partially saturated ring systems are
piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,
piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,
isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,
1,3-pyrazolidin-1-yl, thiomorpholine, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl and the like; optionally
substituted by 1 to 3 suitable substituents as defined below such
as fluoro, chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0050] The term "saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic fused to a saturated, partially saturated
or aromatic (5- to 7-membered)-carbocyclic ring", as used herein,
unless otherwise indicated, means a bicyclic group having a first
(5- to 6-membered)heterocyclic ring covalently bound to the
pyrazole nucleus and wherein said first ring is fused to a second
ring comprising a 5 to 6 membered heterocyclic ring, wherein said
second 5 to 6 members include the atoms common to both rings. Said
first and second rings comprise saturated, partially saturated or
aromatic (5- to 6-membered)-heterocycli- c rings. Examples of said
bicyclic ring systems are indolidin-4-yl, indolidin-5-yl,
quinolidin-5-yl, quinolidin-6-yl, quinolidin-7-yl, quinolidin-8-yl,
isoquinolidin-5-yl, isoquinolidin-6-yl, isoquinolidin-7-yl,
isoquinolidin-8-yl, quinazolidin-5-yl, quinazolidin-6-yl,
quinazolidin-7-yl, quinazolidin-8-yl, benzofuran-2-yl,
benzofuran-3-yl, isobenzofuran-1-yl, isobenzofuran-3-yl,
benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl, indol-3-yl,
isoindol-1-yl, isoindol-3-yl, cyclopentapyrid-2-yl,
cyclopentapyrid-3-yl, benzoxazol-2-yl, cinnolin-4-yl and the like;
optionally substituted by 1 to 3 suitable substituents as defined
below such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
[0051] The term "saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic fused to a saturated, partially saturated
or aromatic (5- to 6-membered)-heterocyclic" as used herein, unless
otherwise indicated, means a bicyclic heterocyclic group having a
first ring covalently bound to the pyrazole nucleus and containing
five to six ring atoms comprising one to two heteroatoms each
independently selected from --N.dbd., --NH--,
--[N--(C.sub.1-C.sub.4)alkyl]-, --O-- and --S--; wherein said first
ring is fused to a second ring comprising a 5 to 6 membered
heterocyclic ring, wherein said second 5 to 6 members include the
atoms common to both rings. Said second ring comprises a saturated,
partially saturated or aromatic (5- to 6-membered)-heterocyclic
ring. Examples of said bicyclic ring systems are
pyrano[3,4b]pyrrolyl, pyrano[3,2b]pyrrolyl, pyrano[4,3b]pyrrolyl,
purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, pteridin-2-yl,
pyrido[3,4b]pyridyl, pyrido[3,2b]pyridyl, pyrido[4,3b]pyridyl,
naphthyridinyl and the like; optionally substituted by 1 to 3
suitable substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0052] "A suitable substituent" is intended to mean a chemically
and pharmaceutically acceptable functional group i.e., a moiety
that does not negate the inhibitory activity of the inventive
compounds. Such suitable substituents may be routinely selected by
those skilled in the art. Illustrative examples of suitable
substituents include, but are not limited to halo groups,
perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups,
hydroxy groups, oxo groups, mercapto groups, alkylthio groups,
alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy
groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy
groups, carboxy groups, amino groups, alkyl- and dialkylamino
groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl
groups, alkylaminocarbonyl groups dialkylamino carbonyl groups,
arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups,
arylsulfonyl groups and the like; optionally substituted by 1 to 3
suitable substituents as defined below such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0053] An embodiment and a preferred group of compounds of the
present invention includes compounds of formula I, referred to as
the IA(1) Group of compounds, wherein said compounds have the
formula 5
[0054] wherein X is CR.sup.8 or N.
[0055] Another embodiment and a preferred group of compounds of the
present invention includes compounds of formula I, referred to as
the IA(2) Group of compounds, wherein said compounds have the
formula 6
[0056] wherein X is CR.sup.8 or N.
[0057] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(3) Group of compounds, wherein
said compounds have the formula 7
[0058] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0059] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(4) Group of compounds, wherein
said compounds have the formula 8
[0060] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0061] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(5) Group of compounds, wherein
said compounds have the formula 9
[0062] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0063] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(6) Group of compounds, wherein
said compounds have the formula 10
[0064] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0065] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(7) Group of compounds, wherein
said compounds have the formula 11
[0066] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0067] An embodiment of the present invention includes compounds of
formula I, referred to as the IA(8) Group of compounds, wherein
said compounds have the formula 12
[0068] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0069] An embodiment of the present invention includes compounds of
formula I, referred to as the A(9) Group of compounds, wherein said
compounds have the formula 13
[0070] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0071] An embodiment of the present invention includes compounds of
formula I, referred to as the A(1 0) Group of compounds, wherein
said compounds have the formula 14
[0072] wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are
as defined above.
[0073] An embodiment and a particularily preferred group of
compounds of the present invention includes compounds of formula I,
referred to as the R.sup.6(a) Group of compounds, wherein R.sup.6
is phenyl optionally substituted by 1-3 substituents independently
selected from the group consisting of halo (preferably chloro,
bromo or fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O) and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--.
[0074] An embodiment of the present invention and a moderately
preferred group of compounds of the present invention includes
compounds of formula I, referred to as the R.sup.6(b) Group of
compounds, wherein R.sup.6 is phenyl fused to a saturated,
partially saturated or aromatic (5- to 7-membered)-carbocyclic
ring; wherein either of said phenyl or said fused saturated,
partially saturated or aromatic (5- to 7-membered)-carbocyclic ring
is optionally substituted by 1 to 2 substituents per ring, wherein
said substituents are independently selected from the group
consisting of halo (preferably chloro, bromo or fluoro), hydroxy,
cyano, mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--.
[0075] An embodiment and a preferred group of compounds of the
present invention includes compounds of formula I, referred to as
the R.sup.6(c) Group of compounds, wherein R.sup.6 is phenyl fused
to a saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic ring containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein either of said phenyl or said
fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic ring is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo
(preferably chloro, bromo or fluoro), hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0076] An embodiment of the present invention and a preferred group
of compounds includes compounds of formula I, referred to as the
R.sup.6(d) Group of compounds, wherein R.sup.6 is (5- to
7-membered)-carbocyclic optionally containing one or two double
bonds; wherein said (5- to 7-membered)-carbocyclic may also be
optionally substituted by 1-3 substituents independently selected
from the group consisting of halo (preferably chloro, bromo or
fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--.
[0077] An embodiment of the present invention includes compounds of
formula I, referred to as the R.sup.6(e) Group of compounds,
wherein R.sup.6 is (5- to 7-membered)-carbocyclic fused to a
saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein said (5- to
7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo (preferably chloro,
bromo or fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0078] An embodiment of the present invention includes compounds of
formula I, referred to as the R.sup.6(f) Group of compounds,
wherein R.sup.6 is (5- to 7-membered)-carbocyclic fused to a
saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein said (5- to
7-membered)-carbocyclic may optionally contain one or two double
bonds; wherein either of said (5- to 7-membered)-carbocyclic or
said fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocycli- c is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo, hydroxy,
cyano, mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkyny- l,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-S--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkymino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--.
[0079] An embodiment of the present invention includes compounds of
formula I, referred to as the R.sup.6(g) Group of compounds,
wherein R.sup.6 is saturated, partially saturated or aromatic (5-
to 6-membered)heterocyclic containing 1 to 4 ring heteroatoms
independently selected from --N.dbd., --NR--, --O--, or --S--,
wherein said saturated, partially saturated or aromatic (5- to
6-membered)heterocyclic is optionally substituted by 1-3
substituents independently selected from the group consisting of
halo (preferably chloro, bromo or fluoro), hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2-, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0080] An embodiment of the present invention includes compounds of
formula I, referred to as the R.sup.6(h) Group of compounds,
wherein R.sup.6 is saturated, partially saturated or aromatic (5-
to 6-membered)heterocyclic containing 1 to 4 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein said saturated, partially
saturated or aromatic (5- to 6-membered)heterocyclic is fused to a
saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring; wherein either of said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic ring
or said fused saturated, partially saturated or aromatic (5- to
7-membered)-carbocyclic ring is optionally substituted by 1 to 2
substituents per ring, wherein said substituents are independently
selected from the group consisting of halo (preferably chloro,
bromo or fluoro), hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy, --OCF.sub.3,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.- O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0081] An embodiment of the present invention includes compounds of
formula I, referred to as the R.sup.6(i) Group of compounds,
wherein R.sup.6 is saturated, partially saturated or aromatic (5-
to 6-membered)heterocyclic containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S--, or --O--; wherein said saturated, partially
saturated or aromatic (5- to 6-membered)heterocyclic is fused to a
saturated, partially saturated or aromatic (5- to
6-membered)-heterocyclic containing 1 to 2 ring heteroatoms
independently selected from the group consisting of --N.dbd.,
--NR'--, --S-- or --O--; wherein either of said saturated,
partially saturated or aromatic (5- to 6-membered)heterocyclic or
said fused saturated, partially saturated or aromatic (5- to
6-membered)-heterocycli- c is optionally substituted with one to
two substituents per ring, wherein said substituents are
independently selected from the group consisting of halo
(preferably chloro, bromo or fluoro), hydroxy, cyano, mercapto,
HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, --OCF.sub.3, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-S(.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
H.sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-NH--(C.dbd.O)--,
di[(C.sub.1-C.sub.6)alkyl]-N--(C.- dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.1-C.sub.6)alkyl-(C-
.dbd.O)--N(R')--, formyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, (C.sub.6-C.sub.10)aryl and
(C.sub.2-C.sub.9)heterocyclic; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--- N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--.
[0082] Subgeneric embodiments of the present invention of the "A"
(i.e. A1, A2, A3, A4, A5, A6, A7, A8 and A9) and R.sup.6 (i.e.
R.sup.6(a), R.sup.6(b), R.sup.6(c), R.sup.6(d), R.sup.6(e),
R.sup.6(f), R.sup.6(g), R.sup.6(h), R.sup.6(i)) Groups of compounds
are expressly contemplated by the present invention. Such
subgeneric embodiments within the A1 Group of compounds include the
A1 group in combination with each of the R.sup.6 groups (i.e.
A1-R.sup.6(a), A1-R.sup.6(b), A1-R.sup.6(c), A1-R.sup.6(d),
A1-R.sup.6(e), A1-R.sup.6(f), A1-R.sup.6(g), A1-R.sup.6(h) and
A1-R.sup.6(i)). Such subgeneric embodiments within the A2 Group of
compounds include the A2 group in combination with each of the
R.sup.6 groups (i.e. A2-R.sup.6(a), A2-R.sup.6(b), A2-R.sup.6(c),
A2-R.sup.6(d), A2-R.sup.6(e), A2-R.sup.6(f), A2-R.sup.6(g),
A2-R.sup.6(h) and A2-R.sup.6(i)). Such subgeneric embodiments
within the A3 Group of compounds include the A3 group in
combination with each of the R.sup.6 groups (i.e. A3-R.sup.6(a),
A3-R.sup.6(b), A3-R.sup.6(c), A3-R.sup.6(d), A3-R.sup.6(e),
A3-R.sup.6(f), A3-R.sup.6(g), A3-R.sup.6(h) and A3-R.sup.6(i)).
Such subgeneric embodiments within the A4 Group of compounds
include the A4 group in combination with each of the R.sup.6 groups
(i.e. A4-R.sup.6(a), A4-R.sup.6(b), A4-R.sup.6(c), A4-R.sup.6(d),
A4-R.sup.6(e), A4-R.sup.6(f), A4-R.sup.6(g), A4-R.sup.6(h) and
A4-R.sup.6(i)). Such subgeneric embodiments within the A5 Group of
compounds include the A5 group in combination with each of the
R.sup.6 groups (i.e. A5-R.sup.6(a), A5-R.sup.6(b), A5-R.sup.6(c),
A5-R.sup.6(d), A5-R.sup.6(e), A5-R.sup.6(f), A5-R.sup.6(g),
A5-R.sup.6(h) and A5-R.sup.6(i)). Such subgeneric embodiments
within the A6 Group of compounds include the A6 group in
combination with each of the R.sup.6 groups (i.e. A6-R.sup.6(a),
A6-R.sup.6(b), A6-R.sup.6(c), A6-R.sup.6(d), A6-R.sup.6(e),
A6-R.sup.6(f), A6-R.sup.6(g), A6-R.sup.6(h) and A6-R.sup.6(i)).
Such subgeneric embodiments within the A7 Group of compounds
include the A7 group in combination with each of the R.sup.6 groups
(i.e. A7-R.sup.6(a), A7-R.sup.6(b), A7-R.sup.6(c), A7-R.sup.6(d),
A7-R.sup.6(e), A7-R.sup.6(f), A7-R.sup.6(g), A7-R.sup.6(h) and
A7-R.sup.6(i)). Such subgeneric embodiments within the A8 Group of
compounds include the A8 group in combination with each of the
R.sup.6 groups (i.e. A8-R.sup.6(a), A8-R.sup.6(b), A8-R.sup.6(c),
A8-R.sup.6(d), A8-R.sup.6(e), A8-R.sup.6(f), A8-R.sup.6(g),
A8-R.sup.6(h) and A8-R.sup.6(i)). Such subgeneric embodiments
within the A9 Group of compounds include the A9 group in
combination with each of the R.sup.6 groups (i.e. A9-R.sup.6(a),
A9-R.sup.6(b), A9-R.sup.6(c), A9-R.sup.6(d), A9-R.sup.6(e),
A9-R.sup.6(f), A9-R.sup.6(g), A9-R.sup.6(h) and A9-R.sup.6(i)).
Such subgeneric embodiments within the A10 Group of compounds
include the A10 group in combination with each of the R.sup.6
groups (i.e. A10-R.sup.6(a), A10-R.sup.6(b), A10-R.sup.6(c),
A10-R.sup.6(d), A10-R.sup.6(e), A10-R.sup.6(f), A10-R.sup.6(g),
A10-R.sup.6(h) and A10 -R.sup.6(i)).
[0083] Preferred compounds of formula I are those compounds wherein
the "A" ring is optionally substituted pyridin-2-yl or
pyridin-3-yl; more preferably wherein m is 2.
[0084] Other preferred compounds of this invention are those of the
formula (I) wherein R.sup.6 is phenyl optionally substituted by 1-3
substituents independently selected from the group consisting of
halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-S--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0085] Other preferred compounds of this invention are those of the
formula (I) wherein R.sup.6 is cyclohexyl optionally substituted by
1 substituent independently selected from the group consisting of
halo, hydroxy, cyano, mercapto, HO--(C.dbd.O)--, nitro,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-S--, amino,
(C.sub.1-C.sub.6)alkylamino, di[(C.sub.1-C.sub.6)alkyl]amino,
amido, (C.sub.1-C.sub.6)alkylamido,
di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -; wherein R' is hydrogen or
(C.sub.1-C.sub.6)alkyl; wherein each of said (C.sub.1-C.sub.6)alkyl
is optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halo, hydroxy, cyano,
mercapto, HO--(C.dbd.O)--, nitro, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-S--, amino, (C.sub.1-C.sub.6)alkylamino,
di[(C.sub.1-C.sub.6)alkyl]amino, amido,
(C.sub.1-C.sub.6)alkylamido, di[(C.sub.1-C.sub.6)alkyl]amido,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--N(R')--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)-- and
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)-- -.
[0086] Other preferred compounds of this invention are those of the
formula (I) wherein R.sup.2 is hydrogen, halo (more preferably
chloro or fluoro, most preferably fluoro) or
(C.sub.1-C.sub.6)alkyl, more preferably wherein R.sup.2 is methyl
or hydrogen.
[0087] Other preferred compounds of this invention are those of the
formula (I) wherein R.sup.3 is cyano or (C.sub.1-C.sub.6)alkyl
optionally substituted with one to three halo atoms, more
preferably wherein R.sup.3 is --CF.sub.3 or --CF.sub.2H.
[0088] Other preferred compounds of this invention are those of the
formula (I) wherein R.sup.4 is methyl.
[0089] Examples of specific preferred compounds of the formula I
are the following:
[0090]
2-[5-(4-Bromo-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0091]
{4-[2-(6-Methanesulfonyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-
-3-yl]-phenyl}-dimethyl-amine;
[0092]
{4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-
-3-yl]-phenyl}-dimethyl-amine;
[0093]
2-[3-Difluoromethyl-5-(3-fluoro-4-methoxy-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0094]
2-[5-(3-Bromo-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0095]
2-[5-(3-Chloro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0096]
2-(3-Difluoromethyl-5-p-tolyl-pyrazol-1-yl)-5-methanesulfonyl-pyrid-
ine;
[0097]
5-Methanesulfonyl-2-(5-o-tolyl-3-trifluoromethyl-pyrazol-1-yl)-pyri-
dine;
[0098]
5-Methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-pyrid-
ine;
[0099]
2-[5-(3-Chloro-4-methoxy-phenyl)-3-difluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0100]
2-[5-(3-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0101]
5-Methanesulfonyl-2-[5-(4-methoxy-3-methyl-phenyl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0102]
2-[3-Difluoromethyl-5-(4-methoxy-3-methyl-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0103]
2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-trifluoromethyl-pyrazol--
1-yl]-5-methanesulfonyl-pyridine;
[0104]
2-(5-Benzo[1,3]dioxol-5-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methan-
esulfonyl-pyridine;
[0105]
2-[5-(2-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0106]
2-[3-Difluoromethyl-5-(2-fluoro-4-methoxy-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0107]
2-[3-Difluoromethyl-5-(3,4-dimethyl-phenyl)-pyrazol-1-yl]-5-methane-
sulfonyl-pyridine;
[0108]
2-[5-(4-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0109]
2-[5-(4-Fluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0110]
2-[5-(4-Chloro-3-methyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0111]
2-(3-Difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridin-
e;
[0112]
2-[3-Difluoromethyl-5-(4-fluoro-phenyl)-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0113]
5-Methanesulfonyl-2-[5-(6-methyl-naphthalen-2-yl)-3-trifluoromethyl-
-pyrazol-1-yl]-pyridine;
[0114]
2-(5-Cyclohexyl-3-difluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-py-
ridine;
[0115]
2-[3-Difluoromethyl-5-(2-fluoro-phenyl)-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0116]
2-(4-Chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfo-
nyl-pyridine; and
[0117]
2-(5-Cyclohexyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-p-
yridine.
[0118] Other compounds of formula I include the following:
[0119]
5-[3-Difluoromethyl-5-(3-fluoro-4-methoxy-phenyl)-pyrazol-1-yl)-2-m-
ethanesulfonyl-pyridine;
[0120]
2-[5-(4-Bromo-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0121]
4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-N-methyl-benzamide;
[0122]
{4-[2-(6-Methanesulfonyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-
-3-yl]-phenyl}-dimethyl-amine;
[0123]
2-Methanesulfonyl-5-(5-p-tolyl-3-trifluoromethyl-pyrazol-1-yl)-pyri-
dine;
[0124]
{4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-
-3-yl]-phenyl}-dimethyl-amine;
[0125]
2-[3-Difluoromethyl-5-(3-fluoro-4-methoxy-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0126]
2-[5-(3-Bromo-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0127]
2-[5-(3-Chloro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0128]
5-Methanesulfonyl-2-[5-(4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-
-1-yl]-pyridine;
[0129]
2-(3-Difluoromethyl-5-p-tolyl-pyrazol-1-yl)-5-methanesulfonyl-pyrid-
ine;
[0130]
2-[5-(4-Bromo-phenyl)-3-difluoromethyl-pyrazol-1-yl]-5-methanesulfo-
nyl-pyridine;
[0131]
5-Methanesulfonyl-2-(5-o-tolyl-3-trifluoromethyl-pyrazol-1-yl)-pyri-
dine;
[0132]
5-Methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-pyrid-
ine;
[0133]
5-[5-(3-Chloro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2--
methanesulfonyl-pyridine;
[0134]
5-[5-(3-Fluoro-4-methoxy-phenyl)-3,-trifluoromethyl-pyrazol-1-yl]-2-
-methanesulfonyl-pyridine;
[0135]
5-[5-(4-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methanesul-
fonyl-pyridine;
[0136]
5-[5-(4-Fluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methanesul-
fonyl-pyridine;
[0137]
5-[5-(4-Chloro-phenyl)-3-difluoromethyl-pyrazol-1-yl]-2-methanesulf-
onyl-pyridine;
[0138]
2-[5-(3-Chloro-4-methoxy-phenyl)-3-difluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0139]
2-[5-(3-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0140]
5-Methanesulfonyl-2-[5-(4-methoxy-3-methyl-phenyl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0141]
2-[3-Difluoromethyl-5-(4-methoxy-3-methyl-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0142]
2-Methanesulfonyl-5-(5-o-tolyl-3-trifluoromethyl-pyrazol-1-yl)-pyri-
dine;
[0143]
2-Methanesulfonyl-5-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-pyrid-
ine;
[0144]
5-[5-(2-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methanesul-
fonyl-pyridine;
[0145]
2-Methanesulfonyl-5-[5-(4-methylsulfanyl-phenyl)-3-trifluoromethyl--
pyrazol-1-yl]-pyridine;
[0146]
2-[5-(4-Chloro-phenyl)-3-difluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0147]
2-[5-(2,4-Dimethyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0148]
5-Methanesulfonyl-2-(5-naphthalen-2-yl-3-trifluoromethyl-pyrazol-1--
yl)-pyridine;
[0149]
2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-trifluoromethyl-pyrazol--
1-yl]-5-methanesulfonyl-pyridine;
[0150]
5-Methanesulfonyl-2-[3-trifluoromethyl-5-(3,4,5-trimethoxy-phenyl)--
pyrazol-1-yl]-pyridine;
[0151]
3-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-benzonitrile;
[0152]
2-(5-Biphenyl-4-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfony-
l-pyridine;
[0153]
2-Methanesulfonyl-5-[5-(4-methoxy-3-methyl-phenyl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0154]
5-[3-Difluoromethyl-5-(4-methoxy-3-methyl-phenyl)-pyrazol-1-yl]-2-m-
ethanesulfonyl-pyridine;
[0155]
2-(5-Benzo[1,3]dioxol-5-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methan-
esulfonyl-pyridine;
[0156]
2-(5-Benzo[1,3]dioxol-5-yl-3-difluoromethyl-pyrazol-1-yl)-5-methane-
sulfonyl-pyridine;
[0157]
2-[5-(2-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5--
methanesulfonyl-pyridine;
[0158]
2-[3-Difluoromethyl-5-(2-fluoro-4-methoxy-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0159]
2-[5-(3,4-Dimethyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0160]
2-[3-Difluoromethyl-5-(3,4-dimethyl-phenyl)-pyrazol-,1-yl]-5-methan-
esulfonyl-pyridine;
[0161]
2-[5-(2,3-Dihydro-benzofuran-6-yl)-3-trifluoromethyl-pyrazol-1-yl]--
5-methanesulfonyl-pyridine,
[0162]
2-[5-(3,5-Difluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0163]
2-[5-(4-tert-Butyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0164]
2-(3,5-Diphenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;
[0165]
4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-benzonitrile;
[0166]
1-(5-Methanesulfonyl-pyridin-2-yl)-5-methyl-3-trifluoromethyl-4,5-d-
ihydro-1H-benzo[g]indazole,
[0167]
1-(5-Methanesulfonyl-pyridin-2-yl)-8-methoxy-3-trifluoromethyl-4,5--
dihydro-1H-benzo[g]indazole;
[0168]
1-(5-Methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-4,5-dihydro-1H-
-benzo[g]indazole;
[0169]
2-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-pyrazine;
[0170]
2-(3-Difluoromethyl-5-naphthalen-2-yl-pyrazol-1-yl)-5-methanesulfon-
yl-pyridine;
[0171]
5-Methanesulfonyl-2-[5-(1-methanesulfonyl-piperidin-4-yl)-3-trifluo-
romethyl-pyrazol-1-yl]-pyridine;
[0172]
2-[5-(3-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0173]
2-{4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyraz-
ol-3-yl]-piperidin-1-yl}-benzothiazole;
[0174]
3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-7-methoxy-4,5-d-
ihydro-1H-benzo[g]indazole;
[0175]
5-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-pyrimidine;
[0176]
2-(5-Cyclohexyl-3-difluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-py-
ridine;
[0177]
2-(5-Cyclohexyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-p-
yridine;
[0178]
5-Methanesulfonyl-2-[4-methyl-3-trifluoromethyl-5-(2-trifluoromethy-
l-phenyl)-pyrazol-1-yl]-pyridine;
[0179]
2-(5-Difluoromethyl-3-phenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridi-
ne;
[0180]
5-Methanesulfonyl-2-(4-methyl-5-phenyl-3-trifluoromethyl-pyrazol-1--
yl)-pyridine;
[0181]
5-Methanesulfonyl-2-(5-naphthalen-1-yl-3-trifluoromethyl-pyrazol-1--
yl)-pyridine;
[0182]
5-[5-(4-Bromo-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methanesulf-
onyl-pyridine;
[0183]
1-(6-Methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-4,5-dihydro-1H-
-benzo[g]indazole;
[0184]
1-(5-Methanesulfonyl-pyridin-2-yl)-6-methoxy-3-trifluoromethyl-1,4--
dihydro-indeno[1,2-c]pyrazole;
[0185]
2-[3-Difluoromethyl-5-(2-fluoro-phenyl)-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0186]
2-[5-(2-Chloro-phenyl)-3-difluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0187]
2-(4-Chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfo-
nyl-pyridine;
[0188]
2-(4-Chloro-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;
[0189]
1-(5-Methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-3-carboxyli-
c acid;
[0190]
4-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-3--
carboxylic acid;
[0191]
5-(5-Benzo[1,3]dioxol-5-yl-3-difluoromethyl-pyrazol-1-yl)-2-methane-
sulfonyl-pyridine;
[0192]
5-[3-Difluoromethyl-5-(2-fluoro-4-methoxy-phenyl)-pyrazol-1-yl]-2-m-
ethanesulfonyl-pyridine;
[0193]
5-[5-(3,4-Dimethyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methan-
esulfonyl-pyridine;
[0194]
5-[3-Difluoromethyl-5-(3,4-dimethyl-phenyl)-pyrazol-1-yl]-2-methane-
sulfonyl-pyridine;
[0195]
5-(5-Benzo[1,3]dioxol-5-yl-3-trifluoromethyl-pyrazol-1-yl)-2-methan-
esulfonyl-pyridine;
[0196]
5-[5-(2-Fluoro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2--
methanesulfonyl-pyridine;
[0197]
2-Methanesulfonyl-5-(5-naphthalen-2-yl-3-trifluoromethyl-pyrazol-1--
yl)-pyridine;
[0198]
2-[5-(4-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0199]
2-[5-(4-Fluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0200]
2-[5-(2,5-Dichloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0201]
2-[5-(4-Chloro-3-methyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0202]
2-[5-(2,4-Dichloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0203]
2-[3-(Chloro-difluoro-methyl)-5-(4-chloro-phenyl)-pyrazol-1-yl]-5-m-
ethanesulfonyl-pyridine;
[0204]
5-Methanesulfonyl-2-[5-(4-methoxy-2-methyl-phenyl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0205]
2-[5-(3-Bromo-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0206]
2-[5-(2-Fluoro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesul-
fonyl-pyridine;
[0207]
2-[5-(3,4-Dichloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine;
[0208] 5-Methanesulfonyl-2-(5-phenyl-pyrazol-1-yl)-pyridine;
[0209]
5-Methanesulfonyl-2-[5-(2-methyl-2,3-dihydro-benzofuran-6-yl)-3-tri-
fluoromethyl-pyrazol-1-yl]-pyridine;
[0210]
5-Methanesulfonyl-2-[5-(4-piperidin-1-yl-phenyl)-3-trifluoromethyl--
pyrazol-1-yl]-pyridine;
[0211]
2-[5-(4-Isobutyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanes-
ulfonyl-pyridine;
[0212]
1-Ethyl-5-[2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H--
pyrazol-3-yl-2-methyl-1H-benzoimidazole;
[0213]
5-Methanesulfonyl-2-[5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-3-trifl-
uoromethyl-pyrazol-1-yl]-pyridine;
[0214]
5-Methanesulfonyl-2-[5-(4-trifluoromethoxy-phenyl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0215]
2-(3-Difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridin-
e;
[0216]
2-[3-Difluoromethyl-5-(4-fluoro-phenyl)-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine;
[0217]
5-Methanesulfonyl-2-[5-(6-methoxy-naphthalen-2-yl)-3-trifluoromethy-
l-pyrazol-1-yl]-pyridine;
[0218]
5-Methanesulfonyl-2-[5-(6-methyl-naphthalen-2-yl)-3-trifluoromethyl-
-pyrazol-1-yl]-pyridine;
[0219]
1-(5-Methanesulfonyl-pyridin-2-yl)-5-phenyl-1H-pyrazole-3-carboxyli-
c acid methyl ester;
[0220]
5-Methanesulfonyl-2-(5-p-tolyl-3-trifluoromethyl-pyrazol-1-yl)-pyri-
dine;
[0221]
4-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol--
3-yl]-2-methyl-benzonitrile;
[0222]
2-[5-(4-Bromo-3-methyl-phenyl)-4-ethyl-3-trifluoromethyl-pyrazol-1--
yl]-5-methanesulfonyl-pyridine;
[0223]
2-Chloro-4-[2-(6-methanesulfonyl-pyridin-3-yl)-5-trifluoromethyl-2H-
-pyrazol-3-yl-phenol;
[0224]
5-[5-(4-Chloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-2-methanesul-
fonyl-pyridine;
[0225]
5-Methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-pyrim-
idine;
[0226]
2-[5-(2,3-Dihydro-benzofuran-5-yl)-3-trifluoromethyl-pyrazol-1-yl]--
5-methanesulfonyl-pyrimidine;
[0227]
5-Methanesulfonyl-2-(5-naphthalen-2-yl-3-trifluoromethyl-pyrazol-1--
yl)-pyrimidine;
[0228]
5-Methanesulfonyl-2-[5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-3-trifl-
uoromethyl-pyrazol-1-yl]-pyrimidine;
[0229]
6-Methanesulfonyl-3-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-[1,2,-
4]triazine;
[0230]
3-[5-(2,3-Dihydro-benzofuran-5-yl)-3-trifluoromethyl-pyrazol-1-yl]--
6-methanesulfonyl-[1,2,4]triazine;
[0231]
6-Methanesulfonyl-3-(5-naphthalen-2-yl-3-trifluoromethyl-pyrazol-1--
yl)-[1,2,4]triazine; and
[0232]
6-Methanesulfonyl-3-[5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-3-trifl-
uoromethyl-pyrazol-1-yl]-[1,2,4]triazine.
[0233] The present invention also relates to a pharmaceutical
composition for the treatment of a condition selected from the
group consisting of arthritis (including osteoarthritis,
degenerative joint disease, spondyloarthropathies, gouty arthritis,
systemic lupus erythematosus, juvenile arthritis and rheumatoid
arthritis), fever (including rheumatic fever and fever associated
with influenza and other viral infections), common cold,
dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's
disease, emphysema, acute respiratory distress syndrome, asthma,
bronchitis, chronic obstructive pulmonary disease, Alzheimer's
disease, organ transplant toxicity, cachexia, allergic reactions,
allergic contact hypersensitivity, cancer (such as solid tumor
cancer including colon cancer, breast cancer, lung cancer and
prostrate cancer; hematopoietic malignancies including leukemias
and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and
familiar adenomatous polyposis), tissue ulceration, peptic ulcers,
gastritis, regional enteritis, ulcerative colitis, diverticulitis,
recurrent gastrointestinal lesion, gastrointestinal bleeding,
coagulation, anemia, synovitis, gout, ankylosing spondylitis,
restenosis, periodontal disease, epidermolysis bullosa,
osteoporosis, loosening of artificial joint implants,
atherosclerosis (including atherosclerotic plaque rupture), aortic
aneurysm (including abdominal aortic aneurysm and brain aortic
aneurysm), periarteritis nodosa, congestive heart failure,
myocardial infarction, stroke, cerebral ischemia, head trauma,
spinal cord injury, neuralgia, neuro-degenerative disorders (acute
and chronic), autoimmune disorders, Huntington's disease,)
Parkinson's disease, migraine, depression, peripheral neuropathy,
pain (including low back and neck pain, headache and toothache),
gingivitis, cerebral amyloid angiopathy, nootropic or cognition
enhancement, amyotrophic lateral sclerosis, multiple sclerosis,
ocular angiogenesis, corneal injury, macular degeneration,
conjunctivitis, abnormal wound healing, muscle or joint sprains or
strains, tendonitis, skin disorders (such as psoriasis, eczema,
scleroderma and dermatitis), myasthenia gravis, polymyositis,
myositis, bursitis, burns, diabetes (including types I and II
diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor
invasion, tumor growth, tumor metastasis, corneal scarring,
scleritis, immunodeficiency diseases (such as AIDS in humans and
FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia,
hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome,
hypersensitivity, kidney disease, Rickettsial infections (such as
Lyme disease, Erlichiosis), Protozoan diseases (such as malaria,
giardia, coccidia), reproductive disorders (preferably in
livestock), and septic shock in a mammal, preferably a human, cat
livestock or a dog, comprising an amount of a compound of formula I
or a pharmaceutically acceptable salt thereof effective in such
treatment and a pharmaceutically acceptable carrier.
[0234] The present invention also relates to a pharmaceutical
composition for the treatment of a disorder or condition that can
be treated by selectively inhibiting COX-2 in a mammal, preferably
a human, cat, livestock or dog, comprising a COX-2 selective
inhibiting effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0235] The present invention also relates to a method for treating
a condition selected from the group consisting of arthritis
(including osteoarthritis, degenerative joint disease,
spondyloarthropathies, gouty arthritis, systemic lupus
erythematosus, juvenile arthritis and rheumatoid arthritis), fever
(including rheumatic fever and fever associated with influenza and
other viral infections), common cold, dysmenorrhea, menstrual
cramps, inflammatory bowel disease, Crohn's disease, emphysema,
acute respiratory distress syndrome, asthma, bronchitis, chronic
obstructive pulmonary disease, Alzheimer's disease, organ
transplant toxicity, cachexia, allergic reactions, allergic contact
hypersensitivity, cancer (such as solid tumor cancer including
colon cancer, breast cancer, lung cancer and prostrate cancer;
hematopoietic malignancies including leukemias and lymphomas;
Hodgkin's disease; aplastic anemia, skin cancer and familiar
adenomatous polyposis), tissue ulceration, peptic ulcers,
gastritis, regional enteritis, ulcerative colitis, diverticulitis,
recurrent gastrointestinal lesion, gastrointestinal bleeding,
coagulation, anemia, synovitis, gout, ankylosing spondylitis,
restenosis, periodontal disease, epidermolysis bullosa,
osteoporosis, loosening of artificial joint implants,
atherosclerosis (including atherosclerotic plaque rupture), aortic
aneurysm (including abdominal aortic aneurysm and brain aortic
aneurysm), periarteritis nodosa, congestive heart failure,
myocardial infarction, stroke, cerebral ischemia, head trauma,
spinal cord injury, neuralgia, neuro-degenerative disorders (acute
and chronic), autoimmune disorders, Huntington's disease,
Parkinson's disease, migraine, depression, peripheral neuropathy,
pain (including low back and neck pain, headache and toothache),
gingivitis, cerebral amyloid angiopathy, nootropic or cognition
enhancement, amyotrophic lateral sclerosis, multiple sclerosis,
ocular angiogenesis, corneal injury, macular degeneration,
conjunctivitis, abnormal wound healing, muscle or joint sprains or
strains, tendonitis, skin disorders (such as psoriasis, eczema,
scleroderma and dermatitis), myasthenia gravis, polymyositis,
myositis, bursitis, burns, diabetes (including types I and II
diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor
invasion, tumor growth, tumor metastasis, corneal scarring,
scleritis, immunodeficiency diseases (such as AIDS in humans and
FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia,
hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome,
hypersensitivity, kidney disease, Rickettsial infections (such as
Lyme disease, Erlichiosis), Protozoan diseases (such as malaria,
giardia, coccidia), reproductive disorders (preferably in
livestock) and septic shock in a mammal, preferably a human, cat
livestock or a dog, comprising administering to said mammal an
amount of a compound of formula I or a pharmaceutically acceptable
salt thereof effective in treating such a condition.
[0236] The present invention also relates to a method for treating
a disorder or condition that can be treated or prevented by
selectively inhibiting COX-2 in a mammal, preferably a human, cat
livestock or a dog, comprising administering to a mammal requiring
such treatment a COX-2 selective inhibiting effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof.
[0237] This invention also relates to a method of or a
pharmaceutical composition for treating inflammatory processes and
diseases comprising administering a compound of formula I of this
invention or its salt to a mammal including a human, cat, livestock
or dog, wherein said inflammatory processes and diseases are
defined as above, and said inhibitory compound is used in
combination with one or more other therapeutically active agents
under the following conditions:
[0238] A.) where a joint has become seriously inflammed as well as
infected at the same time by bacteria, fungi, protozoa, and/or
virus, said inhibitory compound is administered in combination with
one or more antibiotic, antifungal, antiprotozoal, and/or antiviral
therapeutic agents;
[0239] B.) where a multi-fold treatment of pain and inflammation is
desired, said inhibitory compound is administered in combination
with inhibitors of other mediators of inflammation, comprising one
or more members independently selected from the group consisting
essentially of:
[0240] (1) NSAIDs;
[0241] (2) H.sub.1-receptor antagonists;
[0242] (3) kinin-B.sub.1- and B.sub.2-receptor antagonists;
[0243] (4) prostaglandin inhibitors selected from the group
consisting of PGD-, PGF- PGI.sub.2-, and PGE-receptor
antagonists;
[0244] (5) thromboxane A.sub.2 (TXA.sub.2-) inhibitors;
[0245] (6) 5-, 12- and 15-lipoxygenase inhibitors;
[0246] (7) leukotriene LTC.sub.4-, LTD.sub.4/LTE.sub.4-, and
LTB.sub.4-inhibitors;
[0247] (8) PAF-receptor antagonists;
[0248] (9) gold in the form of an aurothio group together with one
or more hydrophilic groups;
[0249] (10) immunosuppressive agents selected from the group
consisting of cyclosporine, azathioprine, and methotrexate;
[0250] (11) anti-inflammatory glucocorticoids;
[0251] (12) penicillamine;
[0252] (13) hydroxychloroquine;
[0253] (14) anti-gout agents including colchicine; xanthine oxidase
inhibitors including allopurinol; and uricosuric agents selected
from probenecid, sulfinpyrazone, and benzbromarone;
[0254] C. where older mammals are being treated for disease
conditions, syndromes and symptoms found in geriatric mammals, said
inhibitory compound is administered in combination with one or more
members independently selected from the group consisting
essentially of:
[0255] (1) cognitive therapeutics to counteract memory loss and
impairment;
[0256] (2) anti-hypertensives and other cardiovascular drugs
intended to offset the consequences of atherosclerosis,
hypertension, myocardial ischemia, angina, congestive heart
failure, and myocardial infarction, selected from the group
consisting of:
[0257] a. diuretics;
[0258] b. vasodilators;
[0259] c. .beta.-adrenergic receptor antagonists;
[0260] d. angiotensin-II converting enzyme inhibitors
(ACE-inhibitors), alone or optionally together with neutral
endopeptidase inhibitors;
[0261] e. angiotensin II receptor antagonists;
[0262] f. renin inhibitors;
[0263] g. calcium channel blockers;
[0264] h. sympatholytic agents;
[0265] i. .alpha..sub.2-adrenergic agonists;
[0266] j. .alpha.-adrenergic receptor antagonists; and
[0267] k. HMG-CoA-reductase inhibitors
(anti-hypercholesterolemics);
[0268] (3) antineoplastic agents selected from:
[0269] a. antimitotic drugs selected from:
[0270] i. vinca alkaloids selected from:
[0271] [1] vinblastine, and
[0272] [2] vincristine;
[0273] (4) growth hormone secretagogues;
[0274] (5) strong analgesics;
[0275] (6) local and systemic anesthetics; and
[0276] (7) H.sub.2-receptor antagonists, proton pump inhibitors,
and other gastroprotective agents.
[0277] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. The term "treatment", as used herein,
refers to the act of treating, as "treating" is defined immediately
above.
[0278] The term "livestock animals" as used herein refers to
domesticated quadrupeds, which includes those being raised for meat
and various byproducts, e.g., a bovine animal including cattle and
other members of the genus Bos, a porcine animal including domestic
swine and other members of the genus Sus, an ovine animal including
sheep and other members of the genus Ovis, domestic goats and other
members of the genus Capra; domesticated quadrupeds being raised
for specialized tasks such as use as a beast of burden, e.g., an
equine animal including domestic horses and other members of the
family Equidae, genus Equus, or for searching and sentinel duty,
e.g., a canine animal including domestic dogs and other members of
the genus Canis; and domesticated quadrupeds being raised primarily
for recreational purposes, e.g., members of Equus and Canis, as
well as a feline animal including domestic cats and other members
of the family Felidae, genus Felis.
[0279] "Companion animals" as used herein refers to cats and dogs.
As used herein, the term "dog(s)" denotes any member of the species
Canis familiaris, of which there are a large number of different
breeds. While laboratory determinations of biological activity may
have been carried out using a particular breed, it is contemplated
that the inhibitory compounds of the present invention will be
found to be useful for treating pain and inflammation in any of
these numerous breeds. Dogs represent a particularly preferred
class of patients in that they are well known as being very
susceptible to chronic inflammatory processes such as
osteoarthritis and degenerative joint disease, which in dogs often
results from a variety of developmental diseases, e.g., hip
dysplasia and osteochondrosis, as well as from traumatic injuries
to joints. Conventional NSAIDs, if used in canine therapy, have the
potential for serious adverse gastrointestinal reactions and other
adverse reactions including kidney and liver toxicity.
Gastrointestinal effects such as single or multiple ulcerations,
including perforation and hemorrhage of the esophagus, stomach,
duodenum or small and large intestine, are usually debilitating,
but can often be severe or even fatal.
[0280] The term "treating reproductive disorders (preferably in
livestock)" as used herein refers to the use of the COX-2
inhibitors of the invention in mammals, preferably livestock
animals (cattle, pigs, sheep, goats or horses), during the estrus
cycle to control the time of onset of estrus by blocking the
uterine signal for lysis of the corpus luteum, i.e. F-series
prostaglandins, then removing the inhibition when the onset of
estrus is desired. There are settings where it is useful to control
or synchronize the time of estrus, especially when artificial
insemination or embryo transfer are to be performed. Such use also
includes enhancing the rate of embryo survival in pregnant
livestock animals. Blocking F-series prostaglandin release can have
several beneficial actions including reducing uterine contractions,
enhancing uteroplacental bloodflow, supporting recognition of
pregnancy, and postponing lysis of the corpus luteum at the time
when estrus would have occurred had the animal not become pregnant
(around Day 21 of pregnancy). Such treatment also abrogates the
effects of stress on reproduction. For example reductions in
fertility caused by excessive heat, negative energy balance and
other stresses which have a COX-2 mediated component, as does
abortion induced by stress such as heat, transportation,
co-mingling, palpation, infection, etc. Such treatment is also
useful to control the time of parturition, which is accompanied by
release of F-series prostaglandins that lead to lysis of the corpus
luteum. Inhibition of COX-2 would block the onset of premature
labor in livestock animals, allowing the offspring time to mature
before birth. Also there are settings where controlling the time of
parturition is a useful tool for management of pregnant
animals.
[0281] The subject invention also includes isotopically-labelled
compounds, which are identical to those recited in Formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Compounds of the present invention,
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
Formula I of this invention and prodrugs thereof can generally be
prepared by carrying out the procedures disclosed in the Schemes
and/or in the Examples and Preparations below, by substituting, a
readily available isotopically labelled reagent for a
non-isotopically labelled reagent.
[0282] This invention also encompasses pharmaceutical compositions
containing prodrugs of compounds of the formula I. This invention
also encompasses methods of treating or preventing disorders that
can be treated or prevented by the selective inhibition of COX-2
comprising administering prodrugs of compounds of the formula I.
Compounds of formula I having free amino, amido, hydroxy,
carboxylic acid ester, sulfonamide or carboxylic groups (especially
alkyl-S-- and alkyl-(S.dbd.O)--) can be converted into prodrugs.
Prodrugs include compounds wherein an amino acid residue, or a
polypeptide chain of two or more (e.g., two, three or four) amino
acid residues which are covalently joined through peptide bonds to
free amino, hydroxy or carboxylic acid groups of compounds of
formula I. The amino acid residues include the 20 naturally
occurring amino acids commonly designated by three letter symbols
and also include, 4-hydroxyproline, hydroxylysine, demosine,
isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine,
ornithine and methionine sulfone. Prodrugs also include compounds
wherein carbonates, carbamates, amides and alkyl esters are
covalently bonded to the above substituents of formula I through
the carbonyl carbon prodrug sidechain. Prodrugs also include
metabolically labile groups such as ethers, acetates, mercaptans
and sulfoxides.
[0283] One of ordinary skill in the art will appreciate that the
compounds of the invention are useful in treating a diverse array
of diseases. One of ordinary skill in the art will also appreciate
that when using the compounds of the invention in the treatment of
a specific disease that the compounds of the invention may be
combined with various existing therapeutic agents used for that
disease.
[0284] For the treatment of rheumatoid arthritis, the compounds of
the invention may be combined with agents such as TNF-.alpha.
inhibitors such as anti-TNF monoclonal antibodies and TNF receptor
immunoglobulin molecules (such as Enbrel.RTM.), low dose
methotrexate, lefunimide, hydroxychloroquine, d-penicilamine,
auranofin or parenteral or oral gold.
[0285] The compounds of the invention can also be used in
combination with existing therapeutic agents for the treatment of
osteoarthritis. Suitable agents to be used in combination include
standard non-steroidal anti-inflammatory agents (hereinafter
NSAID's) such as piroxicam, diclofenac, propionic acids such as
naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen,
fenamates such as mefenamic acid, indomethacin, sulindac, apazone,
pyrazolones such as phenylbutazone, salicylates such as aspirin,
COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and
intraarticular therapies such as corticosteroids and hyaluronic
acids such as hyalgan and synvisc.
[0286] The active ingredient of the present invention may be
administered in combination with inhibitors of other mediators of
inflammation, comprising one or more members selected from the
group consisting essentially of the classes of such inhibitors and
examples thereof which include, matrix metalloproteinase
inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene
receptor antagonists, IL-1 processing and release inhibitors, ILra,
H.sub.1-receptor antagonists; kinin-B.sub.1- and B.sub.2-receptor
antagonists; prostaglandin inhibitors such as PGD-, PGF-
PGI.sub.2-, and PGE-receptor antagonists; thromboxane A.sub.2
(TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene
LTC.sub.4-, LTD.sub.4/LTE.sub.4-, and LTB.sub.4-inhibitors;
PAF-receptor antagonists; gold in the form of an aurothio group
together with various hydrophilic groups; immunosuppressive agents,
e.g., cyclosporine, azathioprine, and methotrexate;
anti-inflammatory glucocorticoids; penicillamine;
hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine
oxidase inhibitors, e.g., allopurinol, and uricosuric agents, e.g.,
probenecid, sulfinpyrazone, and benzbromarone.
[0287] The compounds of the present invention may also be used in
combination with anticancer agents such as endostatin and
angiostatin or cytotoxic drugs such as adriamycin, daunomycin,
cis-platinum, etoposide, taxol, taxotere and alkaloids, such as
vincristine, and antimetabolites such as methotrexate.
[0288] The compounds of the present invention may also be used in
combination with anti-hypertensives and other cardiovascular drugs
intended to offset the consequences of atherosclerosis, including
hypertension, myocardial ischemia including angina, congestive
heart failure, and myocardial infarction, selected from
vasodilators such as hydralazine, .beta.-adrenergic receptor
antagonists such as propranolol, calcium channel blockers such as
nifedipine, .alpha..sub.2-adrenergic agonists such as clonidine,
.alpha.-adrenergic receptor antagonists such as prazosin, and
HMG-CoA-reductase inhibitors (anti-hypercholesterolemics- ) such as
lovastatin or atorvastatin.
[0289] The active ingredient of the present invention may also be
administered in combination with one or more antibiotic,
antifungal, antiprotozoal, antiviral or similar therapeutic
agents.
[0290] The compounds of the present invention may also be used in
combination with CNS agents such as antidepressants (such as
sertraline), anti-Parkinsonian drugs (such as L-dopa, requip,
mirapex, MAOB inhibitors such as selegine and rasagiline, comP
inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake
inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists
and inhibitors of neuronal nitric oxide synthase), and
anti-Alzheimer's drugs such as donepezil, tacrine, COX-2
inhibitors, propentofylline or metryfonate.
[0291] The compounds of the present invention may also be used in
combination with osteoporosis agents such as roloxifene,
lasofoxifene, droloxifene or fosomax and immunosuppressant agents
such as FK-506 and rapamycin.
[0292] The present invention also relates to the formulation of the
active agents of the present invention alone or with one or more
other therapeutic agents which are to form the intended
combination, including wherein said different drugs have varying
half-lives, by creating controlled-release forms of said drugs with
different release times which achieves relatively uniform dosing;
or, in the case of non-human patients, a medicated feed dosage form
in which said drugs used in the combination are present together in
admixture in said feed composition. There is further provided in
accordance with the present invention co-administration in which
the combination of drugs is achieved by the simultaneous
administration of said drugs to be given in combination; including
co-administration by means of different dosage forms and routes of
administration; the use of combinations in accordance with
different but regular and continuous dosing schedules whereby
desired plasma levels of said drugs involved are maintained in the
patient being treated, even though the individual drugs making up
said combination are not being administered to said patient
simultaneously.
DETAILED DESCRIPTION OF THE INVENTION
[0293] Compounds of the formula I may be prepared according to the
following reaction schemes and discussion. Unless otherwise
indicated, R.sup.2 through R.sup.8, A, X and m in the reaction
schemes and discussion that follow are as defined above. 15 16 17
18 19
[0294] Scheme 1 illustrates a method of synthesizing compounds of
the formula I. Referring to Scheme 1, a compound of the formula I
is prepared from a compound of formula II by reaction with a
compound of the formula 20
[0295] under acidic, neutral or basic conditions, preferably in the
presence of acid or the acid salt of the compound of formula V in a
suitable solvent or solvent mixture. Suitable solvents include
alcohols, such as ethanol, trifluoroethanol, methanol, propanol,
isopropanol or butanol; dimethyl sulfoxide (DMSO),
N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),
N-methyl-2-pyrrolidinone (NMP), benzene, toluene or chloroform,
preferably an alcohol, most preferably ethanol or isopropanol.
Preferred acids are hydrochloric acid, acetic acid, trifluoroacetic
acid, p-toluenesulfonic acid and sulfuric acid. This reaction is
generally carried out at a temperature from about 0.degree. C. to
about 140.degree. C., preferably at about the reflux temperature of
the polar solvent.
[0296] The compound of formula II is prepared from a compound of
the formula III by reaction with a compound of the formula 21
[0297] wherein L is a leaving group, in the presence of a base and
a solvent. Suitable reagents of formula IV include ester or ester
equivalents such as acylimidazole, dialkylamide, dialkylacetal,
halides and thioesters, preferably acylimidazole. Suitable bases
include potassium carbonate (K.sub.2CO.sub.3), sodium carbonate
(Na.sub.2CO.sub.3), sodium hydride (NaH), sodium methoxide,
potassium-tert.-butoxide, lithium diisopropylamide, pyrrolidine and
piperidine, preferably sodium methoxide. These reactions can be
carried out in a solvent such as di-(alkyl)ether (preferably
dimethoxyethane), tetrahydrofuran (THF), methanol, dichloromethane,
methyl tert-butyl ether, dimethylformamide (DMF), dimethylacetamide
(DMA) or DMSO, preferably dimethoxyethane. Reaction temperatures
can range from about 0.degree. C. to about 150.degree. C.,
preferably from about 20.degree. C. to about 25.degree. C.
[0298] Compounds of formula III are commercially available or can
be made by methods well known to those of ordinary skill in the
art. Compounds of formula III can be prepared by the methods
described in Aust. J. Chem., 1977, 30, 229 and Heterocycles, 1990,
31, 1951 and methods which are incorporated by reference. The regio
isomeric pyrazole (la') can be also prepared from the corresponding
1,3-diketone and an appropriate heteroaryl hydrazine according to
other methods well known in the art.
[0299] Scheme 2 refers to the preparation of compounds of the
formula V in a multi-step process from compounds of the formula
VIII, wherein L.sup.1 and L.sup.2 are leaving groups such as halo.
Referring to Scheme 2, compounds of the formula V are prepared from
compounds of the formula VI by reaction with hydrazine (preferably
anhydrous) in the presence of a polar solvent. Suitable solvents
include alcohols, such as ethanol, methanol, propanol or butanol;
dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),
preferably an alcohol, most preferably ethanol. This reaction is
generally carried out at a temperature from about 0.degree. C. to
about 140.degree. C., preferably at about the reflux temperature of
the polar solvent. Preferably the product is isolated as a salt,
such as a hydrobromide or hydrochoride salt. The hydrochloride salt
is preferred.
[0300] The compound of formula VI is prepared from a compound of
the formula VII by reaction with an oxidizing reagent in the
presence of a solvent. Suitable oxidants include
meta-chloroperbenzoic acid, hydrogen peroxide, sodium perborate, or
Oxone.RTM.. Suitable solvents or solvent mixtures include
methanol-water, dioxane-water, tetrahydrofuran-water, methylene
chloride, or chloroform, preferably methanol-water. Suitable
temperatures for the aforesaid reaction range from about 0.degree.
C. to about 60.degree. C., preferably the temperature may range
from about 20.degree. C. to about 25.degree. C. (i.e. room
temperature). The reaction is complete within about 0.5 hours to
about 24 hours, preferably about 16 hours.
[0301] The compound of the formula VII is prepared from a compound
of formula VIII by nucleophilic substitution reaction using a
sulfur nucleophilic reagent such as alkylthiols, dialkyldisulfide,
alkylsulfonate, sodium thioalkoxide or potassium thioalkoxide, in
the presence or absence of a base in a polar solvent. Suitable
bases include sodium hydroxide, triethylamine; alkyllithiums such
as n-butyllithium, sec-butyllithium, and tert-butyllithium; and
lithium diisopropylamide, and suitable solvents include ethers such
as dimethylether; alkanols such as methanol, ethanol and
tert-butanol; a mixture of an alkanol and water; THF; benzene;
toluene; xylene; DMF; DMSO; dioxane; and 1,2-dimethoxyethane. This
reaction is generally carried out at a temperature from about
-78.degree. C. to 200.degree. C. for from about 1 minute to 1
day.
[0302] Alternatively, compounds of the formula V may also be
prepared from a compound of the formula IX by nitrosation followed
by reduction as illustrated in Scheme 3. Referring to Scheme 3, a
compound of the formula V is prepared by reacting a compound of
formula X, wherein P is --NH--NO or --N.ident.N.sup.+, with a
reducing agent or catalytic hydrogenation in an inert solvent.
Suitable reducing agents include metal halides such as TiCl.sub.3,
SnCl.sub.2, zinc powder-acetic acid, sodium-ethanol, sodium-aqueous
ammonia, lithium aluminum hydride and the like. Catalytic
hydrogenation may be carried out using a catalyst such as palladium
on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO.sub.4),
platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium
chloride (Wilkinson's catalyst), in an appropriate solvent such as
methanol, ethanol, THF, dioxane or ethyl acetate, at a pressure
from about 1 to about 5 atmospheres and a temperature from about
10.degree. C. to about 60.degree. C. The following conditions are
preferred: Pd on carbon, methanol at 25.degree. C. and 50 psi of
hydrogen gas pressure. This method also provides for introduction
of hydrogen isotopes (i.e., deuterium, or tritium) by replacing
.sup.1H.sub.2 with .sup.2H.sub.2 or .sup.3H.sub.2 in the above
procedure. Compounds of formula V thus obtained may be isolated as
an acid addition salt such as hydrochloride.
[0303] A compound of the formula X, wherein P is --NH--NO or
--N.ident.N.sup.+, can be prepared by reaction of a compound of the
formula IX with a suitable reagent. Typical reagents include sodium
nitrite in an aqueous medium (e.g., hydrochloric acid in water);
others include nitrosyl chloride, nitrogen oxides and nitrite
ethers. This reaction is typically carried out at about 0.degree.
C. for from about 1 minute to 10 hours.
[0304] Compounds of formula IX are commercially available or can be
prepared by methods well known to those of ordinary skill in the
art (e.g., F. Walker et al., J. Chem. Soc. 1939, 1948).
[0305] Compounds of the formula V may be also prepared according to
known methods disclosed in Collection Czechoslov. Chem. Common.
Vol. 37, p. 1721, 1972 by J. Vavrina et al.
[0306] Scheme 4 illustrates preparation methods for synthesizing
compounds of formula XIV (i.e., pyrimidine compounds of formula
VIII which can be used in Scheme 2) wherein X and Y are
independently NH or CR.sup.8; and both L.sup.1 and L.sup.2 are
leaving groups. Referring to Scheme 4, a diketone compound of
formula XII may be subjected to substitution reaction to introduce
L.sup.1 to give the compound of formula XIII followed by reduction
to give the compound of formula XIV. A typical leaving group is
halo, which can be introduced by halogenation according to methods
known in the art. For example, chlorination of a compound of
formula XII can be carried out using a chlorinating reagent such as
an excess amount of phosphoryl chloride in the presence or absence
of a base such as N,N-diethylaniline. This reaction can typically
be carried out under reflux for from about 30 minutes to about 10
hours. The subsequent reduction may be carried out using a reducing
reagent such as a metal catalyst in the presence of a base in a
reaction inert solvent according to known methods in the art. For
example, this reaction can typically be carried out using zinc
powder in the presence of ammonia in a reaction inert solvent such
as benzene at about room temperature for from about 1 hour to about
1 day. Compounds of formula XIV thus obtained can be subjected to
the reactions illustrated in Scheme 2.
[0307] Compounds of the formula XII are commercially available or
can be made by methods well known to those of ordinary skill in the
art. See for example Pharmazie, 17, 135 (1961), Pharmazie, 17, 209
(1962) and J.O.C., 63, 6329 (1998).
[0308] Scheme 5 illustrates the methods for preparing compounds of
formula V', wherein R.sup.9 is alkyl, which can be converted to
compounds of the formula I according to Scheme 1. Referring to
Scheme 5, a compound of formula V' is prepared from a compound of
formula XV by reaction with hydrazine in a polar solvent. Suitable
solvents include alcohols, such as ethanol, methanol, propanol or
butanol; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),
preferably an alcohol, most preferably ethanol. This reaction is
generally carried out at a temperature from about 0.degree. C. to
about 140.degree. C., preferably at about the reflux temperature of
the polar solvent. Preferably the product is isolated as a salt,
such as a hydrobromide or hydrochoride salt. The hydrochloride salt
is preferred.
[0309] The compound of formula XV can be prepared from a compound
of formula XVI by reaction with an oxidizing reagent in the
presence of a solvent. Suitable solvents or solvent mixtures
include methanol-water, dioxane-water, tetrahydrofuran-water,
methylene chloride, or chloroform, preferably methanol-water.
Suitable temperatures for the aforesaid reaction range from about
0.degree. C. to about 60.degree. C., preferably the temperature may
range from about 20.degree. C. to about 25.degree. C. (i.e. room
temperature). The reaction is complete within about 0.5 hours to
about 24 hours, preferably about 16 hours.
[0310] The compound of formula XVI is prepared from a compound of
formula XVII by reaction with a hydride reagent in a solvent.
Suitable hydride reagents include sodiumborohydride or
lithiumaluminumhydride. Suitable solvents include ether, THF,
dimethylformamid, preferably ether. The aforementioned reaction is
run at a temperature of about 0.degree. C. to about 25.degree. C.,
preferably about 0.degree. C. The reaction is run for a period from
about 5 minutes to about 2 hours.
[0311] The compound of formula XVII, wherein Tf is a leaving group
such as CF.sub.3--SO.sub.2, is prepared from a compound of formula
XVIII by reaction with an activating reagent in the presence of a
base. Suitable activating agents include triflic anhydride or
phosphorous oxychloride. Suitable solvents include pyridine. The
aforementioned reaction is run at a temperature of about
-20.degree. C. to about O.degree. C. for a period from about 5
minutes to about 2 hours.
[0312] The compound of formula XVIII can be prepared by methods
well known to those of ordinary skill in the art such as those
described in J. Org. Chem., Vol. 63, p. 6329 (1998).
[0313] Other methods of preparing the compounds of Formula I are
well known to those skilled in the art such as those described in
Heterocycles, 31,1041 (1990). The compounds of formula (I) can also
be synthesized by using the method of Kharash, Negishi, Stille, or
Suzuki et. al., which are well known in the art. In general,
aryl/heteroaryl compounds are synthesized by a number of catalytic
cross-coupling reactions from aryl/heteroaryl halides or triflates
and aryl/heteroaryl metal reagents, [for example, Grignard reagent
(the so-called Kharasch reaction), aryl/heteroaryl zinc reagent
(the so-called Negishi reaction), aryl/heteroaryl tin reagent (the
so-called Stille reaction), arylboron reagent (the so-called Suzuki
reaction), aryl/heteroaryl silyl reagent, etc. (see for example S.
P. Stanforth, Tetrahedron, 1998, 54, 263-303].
[0314] Unless indicated otherwise, the pressure of each of the
above reactions is not critical. Generally, the reactions will be
conducted at a pressure of about one to about three atmospheres,
preferably at ambient pressure (about one atmosphere).
[0315] Those skilled in the art will appreciate that the above
schemes describe general methods for preparing the compounds of the
invention. Specific compounds of formula I may possess sensitive
functional groups that require protecting groups when prepared with
the intermediates described. Examples of suitable protecting groups
may be found in T. W. Greene and P. Wuts, Protecting Groups in
Organic Synthesis, John Wiley & Sons, 2nd Edition, New York,
1991.
[0316] The compounds of the formula I which are basic in nature are
capable of forming a wide variety of different salts with various
inorganic and organic acids. Although such salts must be
pharmaceutically acceptable for administration to animals, it is
often desirable in practice to initially isolate a compound of the
formula I from the reaction mixture as a pharmaceutically
unacceptable salt and then simply convert the latter back to the
free base compound by treatment with an alkaline reagent, and
subsequently convert the free base to a pharmaceutically acceptable
acid addition salt. The acid addition salts of the base compounds
of this invention are readily prepared by treating the base
compound with a substantially equivalent amount of the chosen
mineral or organic acid in an aqueous solvent medium or in a
suitable organic solvent such as methanol or ethanol. Upon careful
evaporation of the solvent, the desired solid salt is obtained.
[0317] The acids which are used to prepare the pharmaceutically
acceptable acid addition salts of the base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or
bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
or acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate and
pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-napht- hoate)]
salts.
[0318] Those compounds of the formula I which are also acidic in
nature, e.g., wherein A or R.sup.6 include a COOH or tetrazole or
other acidic moiety, are capable of forming base salts with various
pharmacologically acceptable cations. Examples of such salts
include the alkali metal or alkaline-earth metal salts and
particularly, the sodium and potassium salts. These salts are all
prepared by conventional techniques. The chemical bases which are
used as reagents to prepare the pharmaceutically acceptable base
salts of this invention are those which form non-toxic base salts
with the herein described acidic compounds of formula I. These
non-toxic base salts include those derived from such
pharmacologically acceptable cations as sodium, potassium, calcium
and magnesium, etc. These salts can easily be prepared by treating
the corresponding acidic compounds with an aqueous solution
containing the desired pharmacologically acceptable cations, and
then evaporating the resulting solution to dryness, preferably
under reduced pressure. Alternatively, they may also be prepared by
mixing lower alkanolic solutions of the acidic compounds and the
desired alkali metal alkoxide together, and then evaporating the
resulting solution to dryness in the same manner as before. In
either case, stoichiometric quantities of reagents are preferably
employed in order to ensure completeness of reaction and maximum
product yields.
[0319] Method for Assisting Biological Activities:
[0320] The activity of the compounds of the formula (I) of the
present invention was demonstrated by the following assays.
[0321] Human In vitro Assays
[0322] Human Cell-Based COX-1 Assay
[0323] Human peripheral blood obtained from healthy volunteers was
diluted to 1/10 volume with 3.8% sodium citrate solution. The
platelet-rich plasma immediately obtained was washed with 0.14 M
sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA.
Platelets were then washed with platelet buffer (Hanks buffer (Ca
free) containing 0.2% BSA and 20 mM Hepes). Finally, the human
washed platelets (HWP) were suspended in platelet buffer at the
concentration of 2.85.times.10.sup.8 cells/ml and stored at room
temperature until use. The HWP suspension (70 .mu.l aliquots, final
2.0.times.10.sup.7 cells/ml) was placed in a 96-well U bottom plate
and 10 .mu.l aliquots of 12.6 mM calcium chloride added. Platelets
were incubated with A23187 (final 10 .mu.M, Sigma) with test
compound (0.1-100 .mu.M) dissolved in DMSO (final concentration;
less than 0.01%) at 37.degree. C. for 15 minutes. The reaction was
stopped by addition of EDTA (final 7.7 mM) and TxB2 in the
supernatant quantitated by using a radioimmunoassay kit (Amersham)
according to the manufacturer's procedure.
[0324] Human Cell-Based COX-2 Assay
[0325] The human cell based COX-2 assay was carried out as
previously described (Moore et a., Inflam. Res., 45, 54, 1996).
Confluent human umbilical vein endothelial cells (HUVECs, Morinaga)
in a 96-well flat bottom plate were washed with 80 ml of RPMI1640
containing 2% FBS and incubated with hIL-1.beta. (final
concentration 300 U/ml, R & D Systems) at 37.degree. C. for 24
hours. After washing, the activated HUVECs were incubateed with
test compound (final concentration; 0.1 nM-1 .mu.M) dissolved in
DMSO (final concentration; less than 0.01%) at 37.degree. C. for 20
minutes and stimulated with A23187 (final concentration 30 mM) in
Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37.degree. C. for
15 minutes. 6-Keto-PGF.sub.1.alpha., stable metabolite of PGI2, in
the supernatant was quantitated by using a radioimmunoassay method
(antibody; Preseptive Diagnostics, SPA; Amersham).
[0326] Canine In vitro Assays
[0327] The following canine cell based COX 1 and COX-2 assays have
been reported in Ricketts et al., Evaluation of Selective
Inhibition of Canine Cyclooxygenase 1 and 2 by Carprofen and Other
Nonsteroidal Anti-inflammatory Drugs, American Journal of
Veterinary Research, 59 (11), 1441-1446.
[0328] Protocol for Evaluation of Canine COX-1 Activity
[0329] Test drug compounds were solubilized and diluted the day
before the assay was to be conducted with 0.1 mL of DMSO/9.9 mL of
Hank's balanced salts solution (HBSS), and stored overnight at
4.degree. C. On the day that the assay was carried out, citrated
blood was drawn from a donor dog, centrifuged at 190.times.g for 25
minutes at room temperature, and the resulting platelet-rich plasma
was then transferred to a new tube for further procedures. The
platelets were washed by centrifuging at 1500.times.g for 10
minutes at room temperature. The platelets were washed with
platelet buffer comprising Hank's buffer (Ca free) with 0.2% bovine
serum albumin (BSA) and 20 mM HEPES. The platelet samples were then
adjusted to 1.5.times.10.sup.7/mL, after which 50 .mu.l of calcium
ionophore (A23187) together with a calcium chloride solution were
added to 50 .mu.l of test drug compound dilution in plates to
produce final concentrations of 1.7 .mu.M A23187 and 1.26 mM Ca.
Then, 100 .mu.l of canine washed platelets were added and the
samples were incubated at 37.degree. C. for 15 minutes, after which
the reaction was stopped by adding 20 .mu.l of 77 mM EDTA. The
plates were then centrifuged at 2000.times.g for 10 minutes at
4.degree. C., after which 50 .mu.l of supernatant was assayed for
thromboxane B.sub.2 (TXB.sub.2) by enzyme-immunoassay (EIA). The
pg/mL of TXB.sub.2 was calculated from the standard line included
on each plate, from which it was possible to calculate the percent
inhibition of COX-1 and the IC.sub.50 values for the test drug
compounds.
[0330] Protocol for Evaluation of Canine COX-2 Activity
[0331] A canine histocytoma (macrophage-like) cell line from the
American Type Culture Collection designated as DH82, was used in
setting up the protocol for evaluating the COX-2 inhibition
activity of various test drug compounds. There was added to flasks
of these cells 10 .mu.g/mL of LPS, after which the flask cultures
were incubated overnight. The same test drug compound dilutions as
described above for the COX-1 protocol were used for the COX-2
assay and were prepared the day before the assay was carried out.
The cells were harvested from the culture flasks by scraping, and
were then washed with minimal Eagle's media (MEM) combined with 1%
fetal bovine serum, centrifuged at 1500 rpm for 2 minutes, and
adjusted to a concentration of 3.2.times.10.sup.5 cells/mL. To 50
.mu.l of test drug dilution there was added 50 .mu.l of arachidonic
acid in MEM to give a 10 .mu.M final concentration, and there was
added as well 100 .mu.l of cell suspension to give a final
concentration of 1.6.times.10.sup.5 cells/mL. The test sample
suspensions were incubated for 1 hour and then centrifuged at 1000
rpm for 10 minutes at 4.degree. C., after which 50 .mu.l aliquots
of each test drug sample were delivered to EIA plates. The EIA was
performed for prostaglandin E.sub.2 (PGE.sub.2), and the pg/mL
concentration of PGE.sub.2 was calculated from the standard line
included on each plate. From this data it was possible to calculate
the percent inhibition of COX-2 and the IC.sub.50 values for the
test drug compounds. Repeated investigations of COX-1 and COX-2
inhibition were conducted over the course of several months. The
results are averaged, and a single COX-1:COX-2 ratio is
calculated.
[0332] Whole blood assays for COX-1 and COX-2 are known in the art
such as the methods described in C. Brideau, et al., A Human Whole
Blood Assay for Clinical Evaluation of Biochemical Efficacy of
Cyclooxygenase Inhibitors, Inflammation Research, Vol. 45, pp.
68-74 (1996). These methods may be applied with feline, canine or
human blood as needed.
[0333] In vivo Assays
[0334] Carrageenan Induced Foot Edema in Rats
[0335] Male Sprague-Dawley rats (5 weeks old, Charles River Japan)
were fasted overnight. A line was drawn using a marker above the
ankle on the right hind paw and the paw volume (V0) was measured by
water displacement using a plethysmometer (Muromachi). Animals were
given orally either vehicle (0.1% methyl cellulose or 5% Tween 80)
or a test compound (2.5 ml per 100 g body weight). One hour later,
the animals were then injected intradermally with
.lambda.-carrageenan (0.1 ml of 1% w/v suspension in saline,
Zushikagaku) into right hind paw (Winter et al., Proc. Soc. Exp.
Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch.,
25, 1629, 1975) and three hours later, the paw volume (V3) was
measured and the increase in volume (V3-V0) calculated. Since
maximum inhibition attainable with classical NSAIDs is 60-70%,
ED.sub.30 values were calculated.
[0336] Gastric Ulceration in Rats
[0337] The gastric ulcerogenicity of test compound was assessed by
a modification of the conventional method (Ezer et al., J. Pharm.
Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,
330 -336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles
River Japan), fasted overnight, were given orally either vehicle
(0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per
100 g body weight). Six hours after, the animals were sacrificed by
cervical dislocation. The stomachs were removed and inflated with
1% formalin solution (10 ml). Stomachs were opened by cutting along
the greater curvature. From the number of rats that showed at least
one gastric ulcer or haemorrhaging erosion (including ecchymosis),
the incidence of ulceration was calculated. Animals did not have
access to either food or water during the experiment.
[0338] Canine Whole Blood ex vivo Determinations of COX-1 and COX-2
Activity Inhibition
[0339] The in vivo inhibitory potency of a test compound against
COX-1 and COX-2 activity may be evaluated using an ex vivo
procedure on canine whole blood. Three dogs were dosed with 5 mg/kg
of the test compound administered by oral gavage in 0.5%
methylcellulose vehicle and three dogs were untreated. A zero-hour
blood sample was collected from all dogs in the study prior to
dosing, followed by 2- and 8-hour post-dose blood sample
collections. Test tubes were prepared containing 2 .mu.L of either
(A) calcium ionophore A23187 giving a 50 .mu.M final concentration,
which stimulates the production of thromboxane B.sub.2 (TXB.sub.2)
for COX-1 activity determination; or of (B) lipopolysaccharide
(LPS) to give a 10 .mu.g/mL final concentration, which stimulates
the production of prostaglandin E.sub.2 (PGE.sub.2) for COX-2
activity determination. Test tubes with unstimulated vehicle were
used as controls. A 500 .mu.L sample of blood was added to each of
the above-described test tubes, after which they were incubated at
37.degree. C. for one hour in the case of the calcium
ionophore-containing test tubes, and overnight in the case of the
LPS-containing test tubes. After incubation, 10 .mu.L of EDTA was
added to give a final concentration of 0.3%, in order to prevent
coagulation of the plasma which sometimes occurs after thawing
frozen plasma samples. The incubated samples were centrifuged at
4.degree. C. and the resulting plasma sample of .about.200 .mu.L
was collected and stored at .mu.20.degree. C. in polypropylene
96-well plates. In order to determine endpoints for this study,
enzyme immunoassay (EIA) kits available from Cayman were used to
measure production of TXB.sub.2 and PGE.sub.2, utilizing the
principle of competitive binding of tracer to antibody and endpoint
determination by colorimetry. Plasma samples were diluted to
approximate the range of standard amounts which would be supplied
in a diagnostic or research tools kit, i.e., 1/500 for TXB.sub.2
and 1/750 for PGE.sub.2.
[0340] The data set out in Table 2 below show how the percent
inhibition of COX-1 and COX-2 activity is calculated based on their
zero hour values. The data is expressed as treatment group averages
in pg/ml of TXB.sub.2 and PGE.sub.2 produced per sample. Plasma
dilution was not factored in said data values.
[0341] The data in Table 2 show that, in this illustration, at the
5 mg/kg dose there was significant COX-2 inhibition at both
timepoints. The data in Table 2 also show that at the 5 mg/kg dose
there was no significant inhibition of COX-1 activity at the
timepoints involved. Accordingly, the data in Table 2 clearly
demonstrates that at the 5 mg/kg dosage concentration this compound
possesses good COX-2 selectivity.
1TABLE 2 COX-1 ACTIVITY INHIBITION - Group Averages TXB.sub.2
Pg/mL/Well Percent Inhibition Hour 0-hour 2-hour 8-hour 2-hour
8-hour Untreated 46 45 140 2% 0% 5 mg/kg 41 38 104 7% 0% COX-2
ACTIVITY INHIBITION - Group Averages PGE.sub.2 Pg/mL/Well Percent
inhibition Hour 0-hour 2-hour 8-hour 2-hour 8-hour Untreated 420
486 501 0% 0% 5 mg/kg 711 165 350 77% 51%
[0342] COX inhibition is observed when the measured percent
inhibition is greater than that measured for untreated controls.
The percent inhibition in the above table is calculated in a
straightforward manner in accordance with the following equation: 1
% lnhibition ( 2 - hour ) = ( PGE 2 at t = 0 ) - ( PGE 2 at t = 2 )
( PGE 2 at t = 0 )
[0343] Data Analysis
[0344] Statistical program packages, SYSTAT (SYSTAT, INC.) and
StatView (Abacus Cencepts, Inc.) for Macintosh were used.
Differences between test compound treated group and control group
were tested for using ANOVA. The IC.sub.50 (ED.sub.30) values were
calculated from the equation for the log-linear regression line of
concentration (dose) versus percent inhibition.
[0345] Most compounds prepared in the Working Examples as described
hereinafter were tested by at least one of the methods described
above, and showed IC.sub.50 values of 0.001 .mu.M to 3 .mu.M with
respect to inhibition of COX-2 in either the canine or human
assays.
[0346] COX-2 selectivity can be determined by ratio in terms of
IC.sub.50 value of COX-1 inhibition to COX-2 inhibition. In
general, it can be said that a compound showing a COX-2/COX-1
inhibition ratio of more than 5 has good COX-2 selectivity.
[0347] The compounds of the formula (I) of this invention can be
administered via oral, parenteral, anal, buccal or topical routes
to mammals (including humans, dogs, cats, horses and
livestock).
[0348] In general, these compounds are most desirably administered
to humans in doses ranging from 0.01 mg to 100 mg per kg of body
weight per day, although variations will necessarily occur
depending upon the weight, sex and condition of the subject being
treated, the disease state being treated and the particular route
of administration chosen. However, a dosage level that is in the
range of from 0.1 mg to 10 mg per kg of body weight per day, single
or divided dosage is most desirably employed in humans for the
treatment of abovementioned diseases.
[0349] These compounds are most desirably administered to said
non-human mammals, e.g. dogs, cats, horses or livestock in an
amount, expressed as mg per kg of body weight of said member per
day, ranging from about 0.01 mg/kg to about 20.0 mg/kg/day,
preferably from about 0.1 mg/kg to, about 12.0 mg/kg/day, more
preferably from about 0.5 mg/kg to about 10.0 mg/kg/day, and most
preferably from about 0.5 mg/kg to about 8.0 mg/kg/day.
[0350] The compounds of the present invention may be administered
alone or in combination with pharmaceutically acceptable carriers
or diluents by either of the above routes previously indicated, and
such administration can be carried out in single or multiple doses.
More particularly, the novel therapeutic agents of the invention
can be administered in a wide variety of different dosage forms,
i.e., they may be combined with various pharmaceutically acceptable
inert carriers in the form of tablets, capsules, lozenges,
trochees, hard candies, powders, sprays, creams, salves,
suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like.
Such carriers include solid diluents or fillers, sterile aqueous
media and various nontoxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective compounds of
this invention are present in such dosage forms at concentration
levels ranging 5% to 70% by weight, preferably 10% to 50% by
weight.
[0351] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dipotassium phosphate and glycine may be
employed along with various disintegrants such as starch and
preferably corn, potato or tapioca starch, alginic acid and certain
complex silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatine capsules; preferred materials in this
connection also include lactose or milk sugar as well as high
molecular weight polyethylene glycols. When aqueous suspensions
and/or elixirs are desired for oral administration, the active
ingredient may be combined with various sweetening or flavoring
agents, coloring matter or dyes, and, if so desired, emulsifying
and/or suspending agents as well, together with such diluents as
water, ethanol, propylene glycol, glycerin and various combinations
thereof.
[0352] A preferred composition for dogs comprises an ingestible
liquid peroral dosage form selected from the group consisting of a
solution, suspension, emulsion, inverse emulsion, elixir, extract,
tincture, and concentrate, optionally to be added to the drinking
water of the dog being treated. Any of these liquid dosage forms,
when formulated in accordance with methods well known in the art,
can either be administered directly to the dog being treated, or
may be added to the drinking water of the dog being treated. The
concentrate liquid form, on the other hand, is formulated to be
added first to a given amount of water, from which an aliquot
amount may be withdrawn for administration directly to the dog or
addition to the drinking water of the dog.
[0353] A preferred composition provides delayed-, sustained-,
and/or controlled-release of said anti-inflammatory selective COX-2
inhibitor. Such preferred compositions include all such dosage
forms which produce .gtoreq.80% inhibition of COX-2 isozyme
activity and result in a plasma concentration of said inhibitor of
at least 3 fold the COX-2 IC.sub.50 for at least 4 hours;
preferably for at least 8 hours; more preferably for at least 12
hours; more preferably still for at least 16 hours; even more
preferably still for at least 20 hours; and most preferably for at
least 24 hours. Preferably, there is included within the
above-described dosage forms those which produce .gtoreq.80%
inhibition of COX-2 isozyme activity and result in a plasma
concentration of said inhibitor of at least 5 fold the COX-2
IC.sub.50 for at least 4 hours, preferably for at least 8 hours,
more preferably for at least 12 hours, still more preferably for at
least 20 hours, and most preferably for at least 24 hours. More
preferably, there is included the above-described dosage forms
which produce .gtoreq.90% inhibition of COX-2 isozyme activity and
result in a plasma concentration of said inhibitor of at least 5
fold the COX-2 IC.sub.50 for at least 4 hours, preferably for at
least 8 hours, more preferably for at least 12 hours, still more
preferably for at least 20 hours, and most preferably for at least
24 hours.
[0354] For parenteral administration, solutions of a compound of
the present invention in either sesame or peanut oil or in aqueous
propylene glycol may be employed. The aqueous solutions should be
suitably buffered (preferably pH>8) if necessary and the liquid
diluent first rendered isotonic. These aqueous solutions are
suitable for intravenous injection purposes. The oily solutions are
suitable for intra-articular, intramuscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well-known to those skilled in the art.
Additionally, it is also possible to administer the compounds of
the present invention topically when treating inflammatory
conditions of the skin and this may preferably be done by way of
creams, jellies, gels, pastes, ointments and the like, in
accordance with standard pharmaceutical practice.
[0355] The compounds of formula (I) may also be administered in the
form of suppositories for rectal or vaginal administration of the
active ingredient. These compositions can be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at room temperature (for example, 10.degree. C. to 32.degree.
C.) but liquid at the rectal temperature and will melt in the
rectum or vagina to release the active ingredient. Such materials
are polyethylene glycols, cocoa butter, suppository and wax.
[0356] For buccal administration, the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0357] For transdermal administration, transdermal patches prepared
in accordance with well known drug delivery technology may be
prepared and applied to the skin of a mammal, preferably a human or
a dog, to be treated, whereafter the active agent by reason of its
formulated solubility characteristics migrates across the epidermis
and into the dermal layers of the skin where it is taken up as part
of the general circulation, ultimately providing systemic
distribution of the active ingredient over a desired, extended
period of time. Also included are implants which are placed beneath
the epidermal layer of the skin, i.e. between the epidermis and the
dermis of the skin of the patient being treated. Such an implant
will be formulated in accordance with well known principles and
materials commonly used in this delivery technology, and may be
prepared in such a way as to provide controlled-, sustained-,
and/or delayed-release of the active ingredient into the systemic
circulation of the patient. Such subepidermal (subcuticular)
implants provide the same facility of installation and delivery
efficiency as transdermal patches, but without the limitation of
being subject to degradation, damage or accidental removal as a
consequence of being exposed on the top layer of the patient's
skin.
EXAMPLES
[0358] The following examples contain detailed descriptions of the
methods of the preparation of compounds of formula (I). These
detailed descriptions fall within the scope of the invention and
serve to exemplify the above described general synthetic procedures
which form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended to
restrict the scope of the present invention.
[0359] The invention is illustrated in the following non-limiting
examples in which, unless stated otherwise: all operations were
carried out at room or ambient temperature, that is, in the range
of 18-25.degree. C.; evaporation of solvent was carried out using a
rotary evaporator under reduced pressure with a bath of up to
60.degree. C.; reactions were monitored by thin layer
chromatography (tlc) and reaction times are given for illustration
only; melting points (m.p.) given are uncorrected (polymorphism may
result in different melting points); structure and purity of all
isolated compounds were assured by at least one of the following
techniques: tic (Merck silica gel 60 F-254 precoated plates), mass
spectrometry, nuclear magnetic resonance (NMR) or infrared
spectroscopy (IR). IR data were obtained on a FTIR 8200 (SHIMAZU
Spectrometer). Yields are given for illustrative purposes only.
Flash column chromatography was carried out using Merck silica gel
60 (230-400 mesh ASTM). Low-resolution mass spectral data (EI) were
obtained on a Automass 120 (JEOL) mass spectrometer. Liquid
Chromatography data was collected on a Hewlett Packard 1100 Liquid
Chromatography/ Mass Selective Detector (LC/MSD). Analysis was
performed on a Luna C-18 column with dimensions of 3.0.times.150
mm. The flow rate was 0.425 ml/minute running a gradient of 50%
0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile
in 15 minutes. The ionization type for the mass detector of the
Mass Spectrophotometer was atmospheric pressure electrospray in the
positive ion mode with a fragmentor voltage of 50 volts. NMR data
was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) using
deuterated chloroform (99.8% D), methanol (99.8% D) or
dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise,
relative to tetramethylsilane (TMS) as internal standard in parts
per million (ppm); conventional abbreviations used are: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc.
[0360] The following abbrevation are used:
2 THF: tetrahydrofuran CH.sub.2Cl.sub.2: dichloromethane
NaHCO.sub.3: sodium bicarbonate HCl: hydrogen chloride MgSO.sub.4:
magnesium sulfate Na.sub.2SO.sub.4: sodium sulfate DME:
dimethoxyethane n-BuLi: n-butyllithium DMF: dimethylformamide
Example 1
[0361]
2-[5-(2,3-dihydro-benzofuran-6-yl)-3-trifluoromethyl-pyrazol-1-yl]--
5-methanesulfonyl-pyridine
[0362] 5-Hydrazino-2-(methylsulfonyl)pyridine hydrochloride (66 mg,
0.30 mmol) was added to a solution of
4,4,4-Trifluoro-1-[4-(benzodihydrofur-4-- yl)butane-1,3-dione from
Preparation 4 (0.91 mg, 0.35 mmol) in ethanol (3.5 mL). The mixture
was heated at reflux temperature for 18 hours and cooled down to
room temperature. The reaction mixture was concentrated in vacuo
and the crude mixture was subjected to preparative thin layer
chromatographic (TLC) (1000 um plate) purification with
dichloromethane as eluant. The desired product was isolated after
the band containing the product was washed with ethyl acetate and
concentrated in vacuo to provide 40.7 mg of a white solid.
Example 2
[0363] 5-methanesulfonyl-2-(5-phenyl-pyrazol-1-yl)-pyridine
[0364] 5-Hydrazino-2-(methylsulfonyl)pyridine hydrochloride (105.5
mg, 0.47 mmol) was added to a solution of 3-phenyl-2-propynal
(commercially available)(73.3 mg, 0.56 mmol) in trifluoroethanol
(3.5 mL). The mixture was heated at reflux temperature for 18 hours
and cooled down to room temperature. The reaction mixture was
concentrated in vacuo and the crude mixture was subjected to
preparative thin layer chromatographic (TLC) (1000 um plate)
purification with dichloromethane as eluant. The desired product
was isolated after the band containing the product was washed with
ethyl acetate and concentrated in vacuo to provide 28 mg of a pale
white solid.
Example 3
[0365]
2-[5-(2,4-dichloro-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methan-
esulfonyl-pyridine
[0366] To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine
(106 mg, 4.05 mmol) and
4,4,4-trifluoro-1-(2,4-dichlorophenyl)-1,3-butanedione (105 mg,
3.68 mmol) in dry trifluoroethanol (6 ml) was added a catalytic
amount of concentrated sulfuric acid ( about 0.25 ml) and the
mixture was refluxed overnight. The reaction mixture was cooled to
room temperture, concentrated, and diluted with water (25 ml) and
neutralized with saturated NaHCO.sub.3 to pH about 7 and then
extracted with EtOAc (50ml.times.3). The organic layer was washed
with brine (100 ml), dried (MgSO.sub.4) and concentrated to give
the crude solid. The solid was purified by flash chromatography
eluting with ethyl acetate/hexane (1/4) to give the desired product
as a white solid (134 mg, 83% yield).
[0367] Liquid chromatography yielded product eluting at 12.022
minutes with major mass spectra fragment peaks at 438.2, 436.2 and
400.2 AMU.
Example 4
[0368] 4,4,4-trifluoro-1-cyclohexyl-1,3-butanedione (Step 1)
[0369] To a stirred solution of cyclohexylmethylketone (2.75 g,
21.8 mmol) in DME (200 mL) was added ethyl trifluoroacetate (7.79
ml, 65.4 mmol) and sodium methoxide (7.71 g, 131 mmol), and the
resulting reaction mixture was stirred at room temperature
overnight. EtOAc (500 ml) and water (50 ml) were added, and the pH
of the aqueous layer was adjusted to 6 by addition of 1 N HCl
solution. The organic layer was washed with brine (50 ml), dried
over MgSO.sub.4, and concentrated in vacuo to give the title
compound in quantitative yield. This was used for the next coupling
step without further purification.
[0370]
2-(5-cyclohexyl-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-p-
yridine (Step 2)
[0371] 2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (425.2
mg, 1.9 mmol) and TFA (0.44 mL, 5.7 mmol) were mixed in
trifluoroethanol (15 mL) and heated at reflux temperature for 15
minutes 4,4,4-trifluoro-1-cyclohe- xyl-1,3-butanedione (422 mg, 1.9
mmol) in trifluoroethanol (5 ml) was added. The resulting reaction
mixture was heated at reflux temperature for 3 hours. The solvent
was then removed in vacuo, and the residue was partitioned between
EtOAc and water. The organic layer was washed with brine and
concentrated in vacuo. The product was purified by flash
chromatography using 7:2:0.5 of hexane:diethylamine:methanol to
give the title compound (305 mg, 43%).
Example 5
[0372] 4,4-difluoro-1-cyclohexyl-1,3-butanedione (Step 1)
[0373] To a stirred solution of cyclohexylmethylketone (2.52 g, 20
mmol) in DME (50 mL) at -20.degree. C. was added ethyl
difluoroacetate (7.44 g, 60 mmol) and sodium methoxide (6.48 g, 120
mmol), and the resulting reaction mixture was then stirred at room
temperature for 1 hour. EtOAc (500 ml) and water (50 ml) were
added, and the pH of the aqueous layer was adjusted to 6 by
addition of 1 N HCl solution. The organic layer was washed with
brine (50 ml), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo to give the title (3.8 g, 93%). This was used for the next
coupling step without further purification.
[0374]
2-(5-cyclohexyl-3-difluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-py-
ridine (Step 2)
[0375] 2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (448
mg, 2 mmol) and TFA (1.38 mL, 18 mmol) were mixed in
trifluoroethanol (10 mL) and stirred for 5 minutes
4,4-Difluoro-1-cyclohexyl-1,3-butanedione (408 mg, 2 mmol) was
added. The resulting reaction mixture was heated at reflux
temperature for 60 hours. The solvent was then removed in vacuo,
and the residue was partitioned between EtOAc and water. The
organic layer was washed with brine and concentrated in vacuo. The
product was purified by recrystallization from 3:1 of
isooctane:methylene chloride to give the title compound (346 mg,
49%).
Example 6
[0376] 1-(3-chloro-4-methoxyphenyl)ethanone (Step 1)
[0377] To a stirred solution of
1-(3-chloro-4-hydroxylphenyl)ethanone (1.7 g, 10 mmol) in DMF was
added K.sub.2CO.sub.3 (1.52 g, 11 mmol), 2 N NaOH solution (5 ml),
and Mel (0.68 ml). The reaction mixture was stirred at room
temperature for 2 hours. Another 1.24 ml of Mel was added, and the
reaction mixture was stirred for an additional 30 minutes. Water
(50 ml) was added, and the product was extracted with 200 ml of
EtOAc and 100 ml of benzene. The organic layer was washed with
brine (50 ml), and dried with MgSO.sub.4, and the solvent was
removed in vacuo to give the title compound in quantitative
yield.
[0378]
4,4,4-trifluoro-1-(3-chloro-4-methoxylphenyl)-1,3-butanedione (Step
2)
[0379] To stirred solution of 1-(3-chloro-4-methoxyphenyl)ethanone
(2.2 g, 12 mmol) in DME was added ethyl trifluoroacetate (4.28 ml,
36 mmol) and sodium methoxide (4.25 g, 72 mmol), and the resulting
reaction mixture was stirred at room temperature for 1 hour. EtOAc
(200 ml) and water (50 ml) were added, and the pH of the aqueous
layer was adjusted to 6 by addition of 1 N HCl solution. The
organic layer was washed with brine (50 ml), dried over MgSO.sub.4,
and concentrated in vacuo to give the title compound in
quantitative yield. This was used for the next coupling step
without further purification.
[0380]
2-[5-(3-chloro-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]5-m-
ethanesulfonylpyridine (Step 3)
[0381]
4,4,4-Trifluoro-1-(3-chloro-4-methoxylphenyl)-1,3-butanedione (1.2
g, 4.29 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine
hydrochloride (1.00 g, 4.46 mmol) were mixed in ethanol (60 ml),
and the resulting reaction mixture was heated at reflux temperature
overnight. The reaction mixture was then cooled to room
temperature, and the solvent was removed in vacuo. The residue was
dissolved in EtOAc (250 ml), and the organic layer was washed with
saturated NaHCO.sub.3 solution, brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by flash
chromatography first using 7:3:1 of hexane:diethylamine:methanol
and then 20% hexand in methylene chloride to give the title
compound (570 mg, 31%).
Example 7
[0382] 1-(3-methyl-4-methoxyphenyl)ethanone (Step 1)
[0383] To a stirred solution of
1-(3-methyl-4-hydroxylphenyl)ethanone (15.02 g, 100 mmol) in MeOH
was added K.sub.2CO.sub.3 (41.5 g, 300 mmol), and Mel (28.4 g, 200
mmol). The reaction mixture was stirred at room temperature for 2
hours. Another 56.7 g of Mel was added, and the reaction mixture
was stirred for an additional 2 hours. Water (50 ml) was added, and
the product was extracted with 600 ml of EtOAc. The organic layer
was washed with brine (250 ml), and dried with Na.sub.2SO.sub.4,
and the solvent was removed in vacuo to give the title compound
(10.2 g, 62%).
[0384]
4,4,4-trifluoro-1-(3-methyl-4-methoxylphenyl)-1,3-butanedione (Step
2)
[0385] To stirred solution of 1-(3-methyl-4-methoxyphenyl)ethanone
(3.29 g, 20 mmol) in DME was added ethyl trifluoroacetate (5.68 g,
40 mmol) and sodium methoxide (4.32 g, 80 mmol), and the resulting
reaction mixture was stirred at room temperature overnight. EtOAc
(200 ml) and water (50 ml) were added, and the pH of the aqueous
layer was adjusted to 6 by addition of 1 N HCl solution. The
organic layer was washed with brine (50 ml), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude
product which was recrystallized from isooctane to give the title
compound (3.2 g, 62%).
[0386]
2-[5-(3-methyl-4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]5-m-
ethanesulfonylpyridine (Step 3)
[0387]
4,4,4-Trifluoro-1-(3-methyl-4-methoxylphenyl)-1,3-butanedione (0.78
g, 3 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride
(0.671 g, 3 mmol) were mixed in ethanol (60 ml), and the resulting
reaction mixture was heated at reflux temperature for 72 hours. The
reaction mixture was then cooled to room temperature, and the
solvent was removed in vacuo. The residue was dissolved in EtOAc
(250 ml), and the organic layer was washed with saturated
NaHCO.sub.3 solution, brine, dried (MgSO.sub.4), and concentrated
in vacuo. The residue was purified first by flash chromatography
using 40% hexane in methylene chlorideto and then by
recrystallization from 3:1 of isooctane:methylene chloride, to give
the title compound (535 mg, 43%).
Example 8
[0388] 4,4,4-trifluoro-1-(1-cyclohexenyl)-1,3-butanedione (Step
1)
[0389] To a stirred solution of 1-cyclohexenylmethylketone (1 ml,
7.8 mmol) in DME (60 ml) was added ethyl trifluoroacetate (2.8 ml,
23.4 mmol) and sodium methoxide (2.2 g, 39 mmol), and the resulting
reaction mixture was stirred at room temperature overnight. EtOAc
(200 ml) and water (50 ml) were added, and the pH of the aqueous
layer was adjusted to 6 by addition of 2 N HCl solution. The
organic layer was washed with brine (50 ml), dried over MgSO.sub.4,
and concentrated in vacuo to give the title compound in
quantitative yield. This was used for the next coupling step
without further purification.
[0390]
2-[5-(1-cyclohexenyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulf-
onyl-pyridine (Step 2)
[0391] 2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (128
mg, 0.54 mmol) and
4,4,4-trifluoro-1-(1-cyclohexenyl)-1,3-butanedione (100 mg, 0.45
mmol) were mixed in ethanol (8 ml). The resulting reaction mixture
was heated at reflux temperature for 35 hours. The solvent was then
removed in vacuo, and the residue was partitioned between EtOAc and
water. The organic layer was washed with brine and concentrated in
vacuo. The product was purified by flash chromatography using
methylene chloride to give the title compound (30.6 mg, 18%).
Example 9
[0392]
5-methylsulfonyl-2-[5-phenyl-3-trifluoromethyl-1H-pyrazol-1-yl]pyri-
dine
[0393] To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (
456 mg, 2.04 mmol) and 4,4,4-trifluoro-1-phenyl-1,3-butanedione
(441 mg, 2.04 mmol) in dry trifluoroethanol (30 ml) was added a
catalytic amount of concentrated sulfuric acid (.about.0.5 ml) and
the mixture was refluxed overnight. The reaction mixture was cooled
to room temperature and diluted with water 50 ml and neutralized
with saturated NaHCO.sub.3 to PH.about.7 and then extracted with
EtOAc (50 ml.times.3). The organic layer was washed with brine (25
ml), dried (MgSO.sub.4) and concentrated to give the crude solid.
The crude solid was recrystallized in ethanol to provide a desired
product as a crystalline white solid (337 mg, 45% yield).
[0394] The following examples were prepared by an analogous
procedure to that of Example 1, except where indicated. LC refers
to liquid chromatography elution time (minutes)and MS refers to
mass spectral peaks (AMU). The particular apparatus and data
acquisition parameters are as defined above.
3TABLE 1 Example Structure LC HRMS 10 22 10.846 446.2, 448.2 11 23
4.407 425.3 12 24 9.871 411.3 13 25 9.617 382.3 14 26 9.565 411.3
15 27 6.888 398.3 16 28 7.030 398.3 17 29 10.344 476.2, 478.2 18 30
9.979 432.3 19 31 8.779 398.3 20 32 8.161 364.3 21 33 9.226 428.2,
430.2 22 34 10.021 382.3 23 35 8.650 368.2 24 36 9.458 432.3 25 37
8.581 416.3 26 38 9.605 402.2, 404.2 27 39 8.413 386.2 28 40 8.081
384.2, 386.2 29 41 8.061 414.2, 416.2 30 42 8.881 416.3 31 43
10.271 412.3 32 44 8.435 394.3 33 45 9.233 382.3 34 46 8.247 368.2
35 47 9.103 402.2, 404.2 36 48 9.689 414.3 37 49 8.685 384.2 38 50
11.405 396.3 39 51 8.389 426.3 40 52 8.063 393.2 41 53 42 54 10.234
412.3 43 55 8.398 394.3 44 56 8.364 412.3 45 57 9.556 416.3 46 58
7.688 398.3 47 59 10.993 396.3 48 60 9.110 378.3 49 61 8.740 410.3
50 62 51 63 12.989 424.3 52 64 10.178 376.3 53 65 8.164 393.2 54 66
55 67 56 68 57 69 7.082 334.2 58 70 2.934 344.2 59 71 3.960 378.2
60 72 6.413 394.3 61 73 7.262 398.3 62 74 10.745 396.3 63 75 8.998
378.3 64 76 10.625 418.3 65 77 10.399 402.2, 404.2 66 78 9.049
386.2 67 79 11.880 436.6, 400.3 68 80 11.703 416.3 69 81 11.167
418.2, 420.2 70 82 9.852 412.3 71 83 9.131 386.2, 366.2 72 84
11.945 436.2, 438.2 73 85 4.744 300.2 74 86 9.857 424.3 75 87
10.339 451.4 76 88 13.616 424.3 77 89 1.139 450.3 78 90 12.790
422.3 79 91 11.297 452.3 80 92 6.837 350.2 81 93 7.260 368.2 82 94
11.190 448.3 83 95 12.607 432.3 84 96 5.198 358.3 85 97 10.042
382.3 86 98 9.356 400.3 87 99 10.370 402.2, 404.2 88 100 11.184
356.3 89 101 13.025 .74.3 90 102 11.951 450.3 91 103 9.615 350.2 92
104 10.100 382.3 93 105 11.052 418.3 94 106 9.961 446.2, 448.2 95
107 5.651 370.2 96 108 6.517 453.3 97 109 98 110 99 111 100 112 101
113 102 114
[0395]
4TABLE 2 Ex Structure MP MS(M+). C, H, N NMR 103 115 191.degree. C.
(EI) 406 C 53.16%;nl H 3.42%; N 13.55%. .sup.1H-NMR (270 MHz,
CDCl3) .delta.8.69 (1 H, d, J = 2.5 Hz), 8.39 (1 H, dd, J = 2.5 and
8.5 Hz), 8.16 (1 H, d, J = 8.6 Hz), 7.61 (1 H, d, J = 8.2 Hz), 7.35
(1 H, s), 7.18 (1 H, d, J = 7.9 Hz), 6.79 (1 H, s), 3.11 (3 H, s),
2.59 (3 H, s). 104 116 149.degree. C. C 46.73; H 3.752; N, 8.56.
(CDCl.sub.3): 8.66 (dd, J = 0.7, 2.3 Hz, 1H), 8.28 (dd, J = 2.5,
8.7 Hz, 1H), 8.00 (dd, J = 0.7, 8.7 Hz, 1H), 7.57 (d, J = 8.1 Hz,
1H), 7.14 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 1.8, 8.1 Hz, 1H), 3.08
(s, 3H), 2.49 (q, J = 7.4 Hz, 2H), 2.42 (s, 3H), 1.09 (t, J =7.6
Hz, 3H). 105 117 (DMSO-d.sub.6) .delta.: 8.79.quadrature.dd, J =
1.1, 2.0 Hz, 1H.quadrature., 8.18-8.12 (m, 2H), 7.49 (d, J = 2.2
Hz, 1 H), 7.27 (s, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1 H), 6.95 (d, J
= 8.4 Hz, 1H), 3.24 (s, 3H). 106 118 138.degree. C. (EI) 401 C
47.76%; H 2.97%; N 10.39%. (300 MHz, CDCl3) .delta.8.69 (1 H, dd, J
= 0.7 and 2.6 Hz), 8.12 (1 H, dd, J = 0.6 and 8.4 Hz), 7.94 (1 H,
dd, J = 2.6 and 8.4 Hz), 7.46-7.40 (2 H, m), 7.24-7.18 (2 H, m),
6.83 (1 H, s), 3.25 (3 H, s).
Example 107
[0396]
5-methanesulfonyl-2-(5-naphthalen-2-yl-3-trifluoromethyl-pyrazol-1--
yl)-pyridine
[0397] 5-Hydrazino-2-(methylsulfonyl)pyridine hydrochloride (63 mg,
0.34 mmol) was added to a solution of
1-(2-napthoyl)-3,3,3-trifluoroacetone (98 mg, 0.37 mmol) in
trifluoroethanol (3.5 mL) with two drops of conc sulfuric acid. The
mixture was heated at reflux temperature (85-90.degree. C. bath
temperature) for 18 hours and cooled down to room temperature. The
reaction mixture was poured into a saturated aqueous sodium
bicarbonate (20 ml) and extracted with ethyl acetate (20
ml.times.2), dried (MgSO.sub.4), filtered and concentrated in
vacuo. The resulting crude mixture was subjected to preparative
thin layer chromatographic (TLC) (1000 um plate) purification with
dichloromethane as eluant. The desired product was isolated after
the band containing the product was washed with ethyl acetate and
concentrated in vacuo to provide 28 mg of a pale white solid.
[0398] Liquid chromatography yielded product eluting at 11.277
minutes with major mass spectral fragment peaks at 418.3 AMU.
Example 108
[0399]
2-methylsulfonyl-5-[5-phenyl-3-trifluoromethyl-1H-pyrazol-1-yl]pyri-
midine
[0400] 5-Fluoro-4-thiouracil can be prepared from 5-fluorouracil as
described (J. Med. Chem., Vol. 6, pp. 697-701 (1963)).
5-Fluoro-2(1H)-pyrimidinone can be subsequently prepared as
described (Acta Chem. Scand., Vol. 23, pp. 294-299 (1969)).
5-Fluoro-2(1H)-pyrimidi- none can then be converted to
2-methanesulfonyl-5-fluoropyrimidine by treatment with phosphorus
oxychloride, followed by reaction with sodium methanethiolate and
oxidation with m-chloroperbenzoic acid as described (Acta Chem.
Scand., Vol. B39, pp. 696-696 (1985)). Conversion to the hydrazine
is then effected by treatment of 2-methylsulfonyl-5-fluoropyrim-
idine with hydrazine hydrate in ethanol (Coll. Czech. Chem.
Commun., Vol. 37, pp. 1721-17330 (1972)). Subsequent reaction of
2-methylsulfonyl-5-hydrazinopyrimidine with
4,4,4-trifluoro-1-phenyl-1,3-- butanedione will then produce the
title compound.
Example 109
[0401]
5-methylsulfonyl-2-[5-(4-methoxy)phenyl-3-trifluoromethyl-1H-pyrazo-
l-1-yl]pyrazine
[0402] 2-Amino-5-bromopyrazine can be prepared from aminopyrazine
as described (Tetrahedron, Vol. 44, pp. 2977-2984 (1988)). Reaction
of 2-amino-5-bromopyrazine with sodium methanethiolate proceeds to
form 2-amino-5-methylthiopyrazine (J. Het. Chem., Vol. 28, pp.
1131-1137 (1991)). Oxidation of 2-amino-5-methylthiopyrazine with
m-chloroperbenzoic acid produces 2-amino-5-methanesulfonylpyrazine.
2-Hydrazino-5-methanesulfonylpyrazine can be prepared by known
procedures (J. Het. Chem., Vol. 27, pp. 2151-2163 (1990)).
Subsequent reaction of 2-Hydrazino-5-methanesulfonylpyrazine with
4,4,4-trifluoro-1-(4-methoxyph- enyl)-1,3-butanedione (made from
4-methoxyacetophenone and ethyl trifluoroacetate via Scheme 1) can
then produce the title compound.
Example 110
[0403]
1-methylsulfonyl-3-[5-(4-fluoro)phenyl-3-trifluoromethyl-1H-pyrazol-
-1-yl]pyrrole
[0404] 1-Methylsulfonyl-3-nitropyrrole can be prepared from pyrrole
as described (Can. J. Chem., Vol 63, pp. 896-902 (1985)).
1-Methylsulfonyl-3-aminopyrrole can then be prepared from
1-Methanesulfonyl-3-nitropyrrole and further reacted to
1-methylsulfonyl-3-hydrazinopyrrole by known procedures (J. Het.
Chem., Vol. 27, pp. 2151-2163 (1990)). Subsequent reaction of
1-methylsulfonyl-3-hydrazinopyrrole with
4,4,4-trifluoro-1-(4-fluoro)phen- yl-1,3-butanedione (made from
4'-fluoroacetophenone and ethyl trifluoroacetate via Scheme I) can
then produce the title compound.
Example 111
[0405]
1-methyl-2-methylsulfonyl-4-[5-(4-chloro)phenyl-3-trifluoromethyl-1-
H-pyrazol-1-yl]pyrrole
[0406] 1-Methyl-2-methylsulfonyl-4-nitropyrrole can be prepared
from pyrrole by modification of a known procedure (J. Chem. Res.
Miniprint, Vol. 3, pp. 0725-0754 (1983)).
1-Methyl-2-methylsulfonyl-4-aminopyrrole can then be prepared from
1-methyl-2-methylsulfonyl-4-nitropyrrole and further reacted to
1-methyl-2-methylsulfonyl-4-hydrazinopyrrole by known procedures
(J. Het. Chem., Vol. 27, pp. 2151-2163 (1990)). Subsequent reaction
of 1-methyl-2-methylsulfonyl-4-hydrazinopyrrole with
4,4,4-trifluoro-1-(4-chloro)phenyl-1,3-butanedione (made from
4'-chloroacetophenone and ethyl trifluoroacetate via Scheme I) can
then produce the title compound.
Example 112
[0407]
1-methyl-3-methylsulfonyl-5-[5-(4-methyl)phenyl-3-trifluoromethyl-1-
H-pyrazol-1-yl]pyrrole
[0408] 1-Methyl-3-methylsulfonyl-5-nitropyrrole can be prepared
from pyrrole by modification of a known procedure (J. Chem. Res.
Miniprint, Vol. 3, pp. 0725-0754 (1983)).
1-Methyl-3-methylsulfonyl-5-aminopyrrole can then be prepared from
1-methyl-3-methylsulfonyl-5-nitropyrrole and further reacted to
1-methyl-3-methylsulfonyl-5-hydrazinopyrrole by known procedures
(J. Het. Chem., Vol. 27, pp. 2151-2163 (1990)). Subsequent reaction
with 4,4,4-trifluoro-1-(4-methyl)phenyl-1,3-butanedione (made from
4'-methylacetophenone and ethyl trifluoroacetate via Scheme I) can
then produce the title compound.
Example 113
[0409]
2-methylsulfonyl-5-[5-(3-methyl)phenyl-3-trifluoromethyl-1H-pyrazol-
-1-yl]pyrrole
[0410] 2-Methylthiopyrrole can be prepared from pyrrole as
described (J. Org. Chem., Vol. 47, pp. 1682-1688 (1982)).
5-Chloro-2-methylthiopyrrole can then be prepared from
2-methylthiopyrrole by known procedures (J.Het. Chem., Vol. 22, pp.
281-285 (1985)). 5-Hydrazino-2-methylthiopyrrole can then be
prepared as in Scheme 2. Subsequent reaction of
5-Hydrazino-2-methylthiopyrrole with
4,4,4-trifluoro-1-(3-methyl)phenyl-1- ,3-butanedione (made from
3'-methylacetophenone and ethyl trifluoroacetate via Scheme I)
followed by oxidation can produce the title compound.
Example 114
[0411] Tablet Formulation of the Product of Example 6.
5 Tablet Formulation Ingredients Weight per Tablet Example 6 25.00
mg Lactose, U.S.P. 64.50 mg Corn Starch 10.00 mg Magnesium Stearate
0.50 mg
Example 115
[0412] Capsule Formulation of Example 15
6 Capsule Formulation Ingredients Weight per Capsule Example 15 50
mg Lactose, U.S.P. 124 mg Corn Starch, U.S.P. 30 mg Talc, U.S.P. 5
mg Total Weight: 210 mg
Example 116
[0413] Parenteral Formulation of 30
7 Parenteral Formulation Ingredients per 1 cc ampule Weight per
Ampule Example 30 10.2 mg Methyl Paraben, U.S.P. 1.8 mg Propyl
Paraben, U.S.P. 0.2 mg Sodium Hydroxide, U.S.P. q.s. ph 9.0 mg
Water for Injection, U.S.P. q.s. ad 1.0 cc
Preparations
[0414] Preparation 1
[0415] Step 1: 3-nitro-6-(methylthio)pyridine
[0416] 2-Mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended
in water/ethanol (43 mL/13 mL). Sodium carbonate monohydrate (17.49
g, 141 mmol, dissolved in 86 mL of water) was added to the above
slurry dropwise. Methyl iodide (20.0 g, 141 mmol) was added to the
above mixture and the mixture was stirred at room temperature for
one hour. The solid was filtered and washed with water and ethanol
to provide the title compound in quantitative yield.
[0417] Step 2A: 3-nitro-6-(methylsulfonyl)pyridine
[0418] 3-Nitro-6-(methylthio)pyridine (22.0 g, 129.3 mmol) was
dissolved in acetone (140 mL). Sulfuric acid (2N, 230 mL) was then
added dropwise to above solution to form a slurry. Potassium
permanganate (KMnO.sub.4) (26.5 g, 168.1 mmol, dissolved in 500 mL
of H.sub.2O) was added to the above mixture dropwise. The mixture
that resulted was stirred at room temperature overnight. The solid
was filtered and stirred with a warm mixture of ethanol/methanol
(10/1). The insoluble salt was filtered, the filtrate was
concentrated to provide a pale yellow solid. The crude product was
recrystallized from ethanol to furnish the title compound (17.8 g,
70%).
[0419] Step 2B: 3-nitro-6-(methylsulfonyl)pyridine
[0420] Alternatively, 3-nitro-6-(methylsulfonyl)pyridine was
prepared by dissolving of 3-nitro-6-(methylthio)pyridine (1
equivalent) and sodium methane sulfinate in DMSO and heating at
100.degree. C. for 2 hours. The reaction was diluted with a large
excess of water and extracted with ethyl acetate. The organic layer
was concentrated in vacuo to give the desired
3-nitro-6-(methylsulfonyl)pyridine.
[0421] Step 3: 3-amino-6-(methylsulfonyl)pyridine
[0422] 3-Nitro-6-(methylsulfonyl)pyridine (10 g, 49.5 mmol) was
suspended in water (200 mL). Iron powder (5.0 g, 89.3 mmol) and
acetic acid (0.5 mL) were added to the above mixture. The mixture,
which resulted, was heated to reflux for 2 hours. The reaction was
monitored by thin layer chromatography (ethyl acetate/hexane, 1/1).
The reaction mixture was then cooled to room temperature and a
saturated solution of sodium bicarbonate (NaHCO.sub.3) (100 mL) was
added to the mixture. Ethyl acetate (200 mL) was added to the above
mixture and the mixture which resulted was stirred at room
temperature for 30 minutes. The mixture was filtered through
Celite.RTM. and the organic layer was collected. The aqueous layer
was extracted with ethyl acetate (200 mL.times.3). The organic
extractions were combined and dried over sodium sulfate. The
solvent was removed under reduced pressure to provide the
3-amino-6-(methylsulfonyl)pyridine (6 g, 70.5%).
[0423] Step 4: 5-hydrazino-2-(methylsulfonyl)pyridine
hydrochloride
[0424] To a solution of 3-amino-6-(methylsulfonyl)pyridine (3.72 g,
21.6 mmol) in concentrated hydrochloric acid (30 mL), sodium
nitrite (1.78 g, 25.7 mmol) in water (20 mL) was added dropwise at
-10 to -15.degree. C. and the mixture was stirred for 2 hours at
-10 to -5.degree. C. (note: the reaction was monitored by thin
layer chromatography to make sure all the starting material was
consumed). Tin(II) chloride dihydrate (20 g, 88.6 mmol) in
concentrated hydrochloric acid (30 mL) was added dropwise at
-5.degree. C. The mixture was stirred 1 hour at -5.degree. C. and
then left overnight. The mixture was basified with aqueous sodium
hydroxide (pH=9) with ice cooling and tetrahydrofuran (200 mL) was
added and stirred for 30 minutes. The mixture was filtered through
Celite.RTM. and the filtrate was extracted with tetrahydrofuran
(200 mL.times.3). The organic extraction was combined and dried
over magnesium sulfate and concentrated under reduced pressure to
provide the title compound (3.2 g, 78.8%).
[0425] 5-Hydrazino-2-(methylsulfonyl)pyridine was dissolved in
HCl-methanol (10%, 30 mL) and volatiles were removed under reduced
pressure. The residue was washed with ether and employed directly
to next step without further purification.
[0426] Preparation 2
[0427] 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride
[0428] STEP 1: 5-methylthio-2-bromopyridine
[0429] To a solution of 2,5-dibromopyridine (23.4 g, 0.099 mol) in
ether (500 mL), was added dropwise n-butyl lithium (n-BuLi) (1.52 M
in n-hexane, 68 mL, 0.10 mmol) at -78.degree. C. and the mixture
was stirred for 1 hour at the temperature. Dimethyldisulfide (9.8
mL, 0.11 mol) was added slowly at -78.degree. C. and the mixture
was stirred for 1 hour at that temperature and further 1 hour at
0.degree. C. The mixture was quenched with aqueous 1N hydrochloric
acid (200 mL) and extracted with ether (100 mL.times.2), dried over
MgSO.sub.4, and concentrated in vacuo to yield the title compound
(18.9 g, 94%).
[0430] .sup.1H-NMR (CDCl.sub.3) .delta.:8.24 (dd, J=0.8, 2.5 Hz,
1H), 7.43 (dd, J=2.8, 8.4 Hz, 1H), 7.38 (dd, J=0.8, 8.4 Hz, 1H),
2.50 (s, 3H).
[0431] Step 2: 5-methylsulfonyl-2-bromopyridine
[0432] To a solution of 5-methylthio-2-bromopyridine from step 1
(18.9 g, 0.093 mol) in methylene chloride (600 mL), was added
portionwise m-chloroperbenzoic acid (48 g, 0.19 mol) at 0.degree.
C. and the mixture was stirred for 2 hours at room temperature.
Aqueous saturated sodium sulfate (Na.sub.2SO.sub.3) (200 mL) was
added and stirred for 15 minutes and organic phase was separated
and washed with aqueous saturated sodium bicarbonate (NaHCO.sub.3)
(200 mL), dried over MgSO.sub.4, and concentrated in vacuo gave the
title compound (20.9 g, 96%).
[0433] .sup.1H-NMR (CDCl.sub.3) .delta.:8.91 (d, J=2.6 Hz, 1H),
8.06 (dd, J=2.6, 8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 3.12 (s,
3H).
[0434] Step 3: 2-hydrazino-5-(methylsulfonyl)pyridine
hydrochloride
[0435] A mixture of 5-methylsulfonyl-2-bromopyridine from step 2
(20.9 g, 0.088 mol) and anhydrous hydrazine (5.6 mL, 0.18 mol) in
ethanol (200 mL) was refluxed for 4 hours. After cooling to room
temperature the mixture was concentrated. The residual solid was
washed with aqueous saturated NaHCO.sub.3 (100 mL) and water (100
mL) and collected by filtration to give a pale yellow solid (9.6
g). The solid was treated with 10% methanolic HCl (80 mL) and the
precipitate was collected by filtration to give the title compound
(9.8 g, 50%).
[0436] .sup.1H-NMR (DMSO-d.sub.6) .delta.:8.54 (s, 1H), 7.99 (d,
J=8.9 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 3.20 (s, 3H). (hydrazine
proton was not detected).
[0437] Alternative Preparation 2
[0438] 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride
[0439] Step 1: 2.5-bis-methylsulfanyl-pyridine
[0440] A solution of the 2,5-dichloropyridine and sodium methane
thiolate in DMSO was heated at 100-120.degree. C. for 3 days. The
reaction mixture was cooled down and diluted with water and then
extracted with ether. The organic layer was concentrated in vacuo
to give the title compound (52%).
[0441] Step 2: 2,5-bis-methanesulfonyl-pyridine
[0442] The 2,5-bis-methylsulfanyl-pyridine in dry methylene
chloride at 0.degree. C. was treated with mCPBA (.about.4 equiv.)
and allowed to react overnight, while warming to room temperature.
The reaction mixture was washed with saturated bicarbonate and
extracted with ethyl acetate or ether. The organic layer was dried
and concentrated in vacuo to give the title compound in
quantitative yield.
[0443] Step 3: 2-hydrazino-5-(methanesulfonyl)pyridine
hydrochloride
[0444] The 2,5-bis-methanesulfonyl-pyridine and anhydrous hydrazine
are stirred in ethanol for two hours between room temperature and
reflux temperature. After cooling to room temperature the mixture
is concentrated. The residual solid is washed with aqueous
saturated NaHCO.sub.3 and water and collected by filtration to give
a pale yellow solid. The solid is treated with 10% methanolic HCl
and the precipitate is collected by filtration to give the title
compound.
[0445] Preparation 3
[0446] 2-methylsulfonyl-5-hydrazinopyrimidine hydrochloride
[0447] 2-Methylsulfonyl-5-hydrazinopyrimidine (2.0 g, 0.011 mol, J.
Vavrina et al., Collection Czechoslov. Chem. Commun., 37, 1721
(1972)) was treated with 10% methanolic HCl, and volatiles were
removed by evaporation. The precipitate was collected by filtration
to give 1.8 g (78%) of the title compound.
[0448] .sup.1H-NMR (DMSO-d.sub.6) .delta.:9.43 (br, 1H), 8.50 (s,
2H), 3.48 (br, 2H), 3.22 (s, 3H).
[0449] Preparation of Diketones
[0450] Preparation 4
[0451]
4,4,4-trifluoro-1-[4-(benzodihydrofur-4-yl)butane-1,3-dione
[0452] A solution mixture of the
1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one (212 mg, 1.31 mmol) and
ethyltrifluoroacetate (428 mg, 3.0 mmol) in dry dimethoxyethane (4
ml) at room temperature was treated with sodium methoxide (0.69 ml,
3.0 mmol) and the reaction mixture vigorously stirred at room
temperature for 18 hours. The reaction mixture was poured into
aqueous 1N hydrochloric acid (20 ml) and extracted with ethyl
acetate (20 ml.times.2), dried (MgSO4), filtered, and concentrated
in vacuo to give the desired diketone.
[0453] Preparation 5
[0454] 4,4,4-trifluoro-1-(2,4-dichlorophenyl)-1,3-butanedione
[0455] To a mixture of 1-(2,4-dichlorophenyl) ethanone (19.3 g,
0.102 mol) and 1,1,1-trifluoroacetic acid ethyl ester (21.8 g,
0.1531 mol) in anhydrous ethylene glycol dimthyl ether (200 mL) was
added sodium methoxide (44.12 g, 25 wt. % sodium methoxide in
methanol, 0.204 mol) and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into a flask
containing 200 mL of ethyl acetate (EtOAc) and ice, pH was adjusted
to 4-5 using 3N hydrochloric acid and then layers were separated.
The aqueous layer was extracted with EtOAc (200 mL). The organic
layers were combined, dried (MgSO.sub.4) and concentrated to give
the crude solid. The crude solid was recrystallized from isooctane
to provide the desired product as a pale yellow solid (15.2 g, 52%
yield).
[0456] Preparation 6
[0457] 4,4-difluoro-1-(4-fluorophenyl)-1,3-butanedione
[0458] To a mixture of 1-(4-fluorophenyl) ethanone (5 g, 0.036 mol)
and 1,1-difluoroacetic acid ethyl ester (4.94 g, 0.040 mol) in
anhydrous ethylene glycol dimthyl ether (100 mL) was added sodium
methoxide ( 15.6 g, 25 wt. % sodium methoxide in methanol, 0.072
mol) and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into a flask containing 200 mL of EtOAc
and ice, pH was adjusted to 4-5 using 3N HCl and then layers were
separated. The aqueous layer was extracted with EtOAc (200 mL). The
organic layers were combined, dried (MgSO.sub.4) and concentrated
to give the crude solid. The crude solid was directly used in next
step without further purification.
* * * * *