U.S. patent application number 10/313433 was filed with the patent office on 2003-06-05 for prostaglandin endoperoxide h synthase biosynthesis inhibitors.
Invention is credited to Black, Lawrence A..
Application Number | 20030105101 10/313433 |
Document ID | / |
Family ID | 26735560 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105101 |
Kind Code |
A1 |
Black, Lawrence A. |
June 5, 2003 |
Prostaglandin endoperoxide H synthase biosynthesis inhibitors
Abstract
The present invention describes pyridazinone compounds which are
cyclooxygenase (COX) inhibitors, and in particular, are selective
inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible
isoform associated with inflammation, as opposed to the
constitutive isoform, cyclooxygenase-1 (COX-1) which is an
important "housekeeping" enzyme in many tissues, including the
gastrointestinal (GI) tract and the kidneys. The selectivity of
these compounds for COX-2 minimizes the unwanted GI and renal
side-effects seen with currently marketed non-steroidal anti
inflammatory drugs (NSAIDs).
Inventors: |
Black, Lawrence A.;
(Libertyville, IL) |
Correspondence
Address: |
STEVEN F. WEINSTOCK
ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
26735560 |
Appl. No.: |
10/313433 |
Filed: |
December 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10313433 |
Dec 6, 2002 |
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09137403 |
Aug 20, 1998 |
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60056652 |
Aug 22, 1997 |
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Current U.S.
Class: |
514/247 ;
514/252.01; 514/85; 544/238; 544/239 |
Current CPC
Class: |
A61K 31/50 20130101;
C07D 237/14 20130101 |
Class at
Publication: |
514/247 ; 514/85;
514/252.01; 544/238; 544/239 |
International
Class: |
A61K 031/675; A61K
031/501; C07D 49/02 |
Claims
We claim:
1. A compound of formula I: 11where X is selected from the group
consisting of O, S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c,
wherein R.sup.4 is selected from the group consisting of alkyl,
alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,
cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and
arylalkyl; and R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of alkyl, cycloalkyl,
cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl,
alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl,
heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy),
heterocyclic (oxy), --C(O)R.sup.5, --(CH.sub.2).sub.nC(O)R.sup.5,
--R.sup.6--R.sup.7, --(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nCH(OR.sup.d)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nC(NR.sup.d)R.sup- .5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NR.sup.dR- .sup.e)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(C H.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.2).sub.n--R.sup.8,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).sub.nR.sup.8,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--R.sup.8, and --(C
H.sub.2).sub.n--R.sup.20, wherein R.sup.5 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl,
heterocyclic, and heterocyclic (alkyl); wherein R.sup.6 is alkylene
or alkenylene; R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic,
and heterocyclic (alkyl); R.sup.20 is selected from the group
consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl,
aryl, heterocyclic, and heterocyclic (alkyl); R.sup.d and R.sup.e
are independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl,
arylalkyl, heterocyclic, and heterocyclic (alkyl); X' is halogen; n
is from 0 to about 10, and m is 0 to about 5; at least one of
R.sup.1, R.sup.2 and R.sup.3 is a group, substituted with a
substituent having a group --X.sup.1--R.sup.9, having the formula:
12where X.sup.1 is selected from the group consisting of
--SO.sub.2--, --SO(NR.sup.10)--, --PO(OR.sup.11)--, and
--PO(NR.sup.12R.sup.13)--, R.sup.9 is selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
amino, --NHNH.sub.2, alkylamino, dialkylamino, alkoxy, thiol,
alkylthiol, and protecting groups, X.sup.2 is selected from the
group consisting of hydrogen or halogen; R.sup.10, R.sup.11,
R.sup.12, and R.sup.13 are independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl, or R.sup.12 and
R.sup.13 can be taken together, with the nitrogen to which they are
attached, to form a heterocyclic ring having from 3 to 6 atoms. The
remaining two of the groups of R.sup.1, R.sup.2, and R.sup.3, are
independently selected from the group consisting of hydrogen,
hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy,
alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino,
aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclic,
heterocyclic (alkyl), cyano, nitro, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --C(R.sup.16)
(R.sup.17)--, C(O)NR.sup.21--, --C(O)--, --C(O)O--, --NH--,
--NC(O)--, and --NR.sup.19-. R.sup.14 is selected from the group
consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy,
cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl,
heterocyclic, and heterocyclic (alkyl), R.sup.16, R.sup.17, and
R.sup.19 are independently selected from the group consisting of
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; and R.sup.21 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic,
heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
2. A compound of the formula II: 13wherein Z is a group having the
formula: 14where X.sup.1 is selected from the group consisting of
--SO.sub.2--, and SO(NR.sup.10)--, and R.sup.9 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, amino, alkylamino, dialkylamino; X.sup.2 is selected
from the group consisting of hydrogen or halogen; X is selected
from the group consisting of O, S, NR.sup.4, N--OR.sup.a, and
N--NR.sup.bR.sup.c, wherein R.sup.4 is selected from the group
consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, hetrocyclic
(alkyl), and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl,
alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl,
heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy),
heterocyclic (oxy), --C(O)R.sup.5, --(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.2).sub.n--R.sup.8,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).sub.nR.sup.8,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--R.sup.8, and
--(CH.sub.2).sub.n--R.sup.20, 0wherein R.sup.5 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl); R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl,
heterocyclic, and heterocyclic (alkyl), R.sup.20 is selected from
the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl,
cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl); X' is
halogen; n is from 0 to about 10, m is from 0 to about 5; R.sup.1
and R.sup.2 are independently selected from the group consisting of
hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
amino, alkylamino, dialkylamino, arylamino, arylalkylamino,
diarylamino, aryl, heterocyclic, hetreocyclic (alkyl), cyano,
nitro, and --Y--R.sup.14, wherein Y is selected from the group
consisting of, --O--, --S--, --CH.sub.2--, --C(R.sup.16)
(R.sup.17)--, --C(O)--, --C(O)O--, --NH--, and --NR.sup.19-.
R.sup.14 is selected from the group consisting of hydrogen,
halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl), and R.sup.16, R.sup.17, and R.sup.19 are
independently selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, hetrocyclic,
heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
3. A compound according to claim 1 having the formula III:
15wherein X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.3, and R.sup.9 are
as defined above in Formula I; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
4. A compound of the formula III: 16wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and arylalkyl; and R.sup.a,
R.sup.b, and R.sup.c. are independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and
arylalkyl; R is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,
arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.2).sub.n--R.sup.8
and --(CH.sub.2).sub.n--R.sup.20; wherein R.sup.5 is selected from
the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl); R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl,
heterocyclic, and heterocyclic (alkyl), R.sup.20 is selected from
the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl,
cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl); X' is
halogen; n is from 0 to about 10, m is from 0 to about 5; R.sup.1
and R.sup.3 are independently selected from the group consisting of
hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, amino, alkylamino, dialkylamino, arylamino,
arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic
(alkyl), cyano, and --Y--R.sup.14, wherein Y is selected from the
group consisting of, --O--, --S--, --C(R.sup.16) (R.sup.17)--,
--C(O)--, --C(O)O--, --NH--, --NC(O)--, and --NR.sup.19-. R.sup.14
is selected from the group consisting of hydrogen, halogen, alkyl,
alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano,
aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and
R.sup.16, R.sup.17, and R.sup.19 are independently selected from
the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl,
alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or
cyano; or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
5. A compound according to claim 4 wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen; X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl,
heteroaryl, and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl; R is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl,
carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic,
heterocyclic (alkyl), arylalkyl, --(CH.sub.2).sub.nC(O)R.sup.5, and
--(CH.sub.2).sub.n--R.sup.20; wherein R.sup.5 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl); R.sup.20 is selected from the group
consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl,
aryl, heterocyclic, and heterocyclic (alkyl); n is from 0 to about
10; R.sup.1 and R.sup.2 are independently selected from the group
consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --C(R.sup.16)
(R.sup.17)--, --C(O)--, --C(O)O--, --NH--, --NC(O)--, and
--NR.sup.19-. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl), and R.sup.16, R.sup.17, and R.sup.19 are
independently selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic,
heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
6. A compound according to claim 4 wherein X.sup.1 is selected from
the group consisting of --SO.sub.2-, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl,
heteroaryl, and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl; R is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl,
carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkynyl, heterocyclic, heterocyclic
(alkyl), arylalkyl, and --(CH.sub.2).sub.nC(O)R.sup.5,; wherein
R.sup.5 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl,
heterocyclic, and heterocyclic (alkyl); and n is from 0 to about
10; R.sup.1 and R.sup.2 are independently selected from the group
consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and --Y--R.sup.14, wherein Y is selected from the group
consisting of, --O--, --S--, --C(R.sup.16) (R.sup.17)--, --C(O)--,
--C(O)O--, --NH--, --NC(O)--, and --NR.sup.19-. R.sup.14 is
selected from the group consisting of hydrogen, halogen, alkyl,
alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano,
aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and
R.sup.16, R.sup.17, and R.sup.19 are independently selected from
the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl,
alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or
cyano; or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
7. A compound according to claim 4 wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl,
heteroaryl, and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl; R is selected
from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
--Y--R.sup.14, wherein Y is selected from the group consisting of,
--O--, --S--, --C(R.sup.16) (R.sup.17)--, --C(O)--, --C(O)O--,
--NH--, --NC(O)--, and --NR.sup.19-. R.sup.14 is selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl,
heterocyclic, and heterocyclic (alkyl), and R.sup.16, R.sup.17, and
R.sup.19 are independently selected from the group consisting of
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
8. A compound according to claim 4 wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl,
heteroaryl, and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl; R is selected
from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
9. A compound according to claim 4 wherein X.sup.1 is --SO.sub.2--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, X is selected from the group consisting of O,
S, NR.sup.4, N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4
is selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl,
heteroaryl, and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are
independently selected from the group consisting of alkyl,
cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl; R is selected
from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
unsubstituted aryl and substituted aryl with one, two, or three
substituents selected from the group consisting of alkyl, alkoxy,
fluorine and chlorine; or a pharmaceutically acceptable salt,
ester, or prodrug thereof.
10. A compounds of formula IV: 17wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl,
carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl,
haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic,
heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy),
--(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].s-
ub.m--(CH.sub.2).sub.n--R.sup.8 and --(CH.sub.2).sub.n--R.sup.20;
wherein R.sup.5 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl); R.sup.7 and
R.sup.8 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl),
R.sup.20 is selected from the group consisting of alkyl, alkenyl,
haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and
heterocyclic (alkyl); X' is halogen; n is from 0 to about 10, m is
from 0 to about 5; R.sup.1 and R.sup.2 are independently selected
from the group consisting of hydrogen, hydroxy, halogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino,
dialkylamino, arylamino, arylalkylamino, diarylamino, aryl,
heterocyclcic, heterocyclic (alkyl), cyano, nitro, and
--Y--R.sup.14, wherein Y is selected from the group consisting of,
--O--, --S--, --C(R.sup.16) (R.sup.17)--, --C(O)--, --C(O)O--,
--NH--, --NC(O)--, and --NR.sup.19-. R.sup.14 is selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl,
heterocyclic, and heterocyclic (alkyl), and R.sup.16, R.sup.17, and
R.sup.19 are independently selected from the group consisting of
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
11. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl,
cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl),
arylalkyl, --(CH.sub.2).sub.nC(O)R.sup.5, and --(C
H.sub.2).sub.n--R.sup.20; wherein R.sup.5 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl); R.sup.20 is selected from the group
consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl,
aryl, heterocyclic, and heterocyclic (alkyl); n is from 0 to about
10; R.sup.1 is hydrogen and R.sup.2 is selected from the group
consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, nitro, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --C(R.sup.16)
(R.sup.17)--, --C(O)--, --C(O)O--, --NH--, --NC(O)--, and
--NR.sup.19-. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl), and R.sup.16, R.sup.17, and R.sup.19 are
independently selected from the group consisting of alkyl, alkenyl,
cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic,
heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
12. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl,
cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
and --(CH.sub.2).sub.nC(O)R.sup.5,; wherein R.sup.5 is selected
from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl); and n is from 0 to about 10; R.sup.1 is
hydrogen and R.sup.2 is selected from the group consisting of
hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
--Y--R.sup.14, wherein Y is selected from the group consisting of,
--O--, --S--, --C(R.sup.16) (R.sup.17)--, --C(O)--, --C(O)O--,
--NH--, --NC(O)--, and --NR.sup.19-. R.sup.14 is selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl,
heterocyclic, and heterocyclic (alkyl), and R.sup.16, R.sup.17, and
R.sup.19 are independently selected from the group consisting of
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
13. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from haloalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 is
hydrogen and R.sup.2 is selected from the group consisting of
hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
--Y--R.sup.14, wherein Y is selected from the group consisting of,
--O--, --S--, --C(R.sup.16) (R.sup.17)--, --C(O)--, --C(O)O--,
--NH--, --NC(O)--, and --NR.sup.19-. R.sup.14 is selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl,
heterocyclic, and heterocyclic (alkyl), and R.sup.16, R.sup.17, and
R.sup.19 are independently selected from the group consisting of
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
14. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from haloalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 is
hydrogen and R.sup.2 is selected from the group consisting of
hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
15. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--,
and R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino; X.sup.2 is selected from the group consisting of
hydrogen and halogen, R is selected from haloalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and
--(CH.sub.2).sub.n--R.sup.20 where is R.sup.20 is substituted and
unsubstituted aryl wherein the substituted aryl compounds are
substituted with halogen; n is from 0 to about 10; R.sup.1 is
hydrogen and R.sup.2 is selected from the group consisting of
hydrogen, aryl substituted with one, two, or three substituents
selected from the group consisting of alkyl, alkoxy, fluorine and
chlorine including, but not limited to, p-chlorophenyl,
p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and
the like; or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
16. A compound according to claim 10 wherein X.sup.1 is
--SO.sub.2--, and R.sup.9 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino,
alkylamino, or dialkylamino; X.sup.2 is selected from the group
consisting of hydrogen and halogen, R is haloalkyl and R.sup.1 is
hydrogen and R.sup.2 is selected from the group consisting of
unsubstituted aryl and aryl substituted with one, two, or three
substituents selected from the group consisting of alkyl, alkoxy,
fluorine and chlorine; or a pharmaceutically acceptable salt,
ester, or prodrug thereof.
17. A compound according to claim 10 wherein X.sup.1 is selected
from the group consisting of --SO.sub.2, and R.sup.9 is selected
from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, amino, alkylamino, or dialkylamino; X.sup.2 is
selected from the group consisting of hydrogen and halogen, R is
substituted and unsubstituted aryl and R.sup.1 is hydrogen and
R.sup.2 is selected from the group consisting of unsubstituted aryl
and aryl substituted with one, two, or three substituents selected
from the group consisting of alkyl, alkoxy, fluorine and chlorine;
or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
18. A compound according to claim 10 wherein X' is SO.sub.2,
R.sup.9 is selected from alkyl and amino, X.sup.2 is selected from
the group consisting of hydrogen and halogen, R is substituted and
unsubstituted aryl and R.sup.1 is hydrogen and R.sup.2 is selected
unsubstituted aryl and aryl substituted with one, two, or three
substituents selected from the group consisting of alkyl, alkoxy,
fluorine and chlorine; or a pharmaceutically acceptable salt,
ester, or prodrug thereof.
19. A compound according to claim 10, selected from the group
consisting of:
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-Benzyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone-
;
2-Methyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinon-
e;
2-Ethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinon-
e;
2-(4-Fluorobenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)--
pyridazinone;
2-(n-Butyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(-
2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-5-(4-methylsulfonylphenyl)-6-(4-
-flurophenyl)-3(2H)-pyridazinone;
2-(4-Fluoro-.alpha.-methylbenzyl)-5-(4-m-
ethylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(n-Propyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazi-
none;
2-(n-Pentyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyr-
idazinone;
2-Cyclohexylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl-
)-3(2H)-pyridazinone;
2-Phenacyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophe-
nyl)-3(2H)-pyridazinone;
2-Propargyl-5-(4-methylsulfonylphenyl)-6-(4-fluor-
ophenyl)-3(2H)-pyridazinone;
2-Cyclohexyl-5-(4-methylsulfonylphenyl)-6-(4--
fluorophenyl)-3(2H)-pyridazinone;
2-(2-Butynyl)-5-(4-methylsulfonylphenyl)-
-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(Cyclobutanylmethyl)-5-(4-methyl-
sulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone; and
2-(3-Methylbuten-2-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H-
)-pyridazinone; or a pharmaceutically acceptable salt or ester
thereof.
20. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 1 and a pharmaceutrically acceptable carrier.
21. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 2 and a pharmaceutrically acceptable carrier.
22. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 4 and a pharmaceutrically acceptable carrier.
23. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 10 and a pharmaceutrically acceptable
carrier.
24. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of claim 1.
25. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of claim 2.
26. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal a therapeutically effective amount of a
compound of claim 4.
27. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal a therapeutically effective amount of a
compound of claim 10.
28. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, and cancer comprising administering to a
therapeutically effective amount of a compound of claim 1.
29. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, and cancer comprising administering to a
mammal in need of such teratment a therapeutically effective amount
of a compound of claim 1.
30. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, and cancer comprising administering to a
mammal a therapeutically effective amount of a compound of claim
2.
31. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, and cancer comprising administering to a
mammal a therapeutically effective amount of a compound of claim
4.
32. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, and cancer comprising administering to a
mammal a therapeutically effective amount of a compound of claim
10.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/056,652, filed Aug. 22, 1997.
TECHNICAL FIELD
[0002] The present invention encompasses novel pyridazinone
compounds useful in the treatment of cyclooxygenase-2 mediated
diseases. More particularly, this invention concerns a method of
inhibiting prostaglandin biosynthesis, particularly the induced
prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2,
COX-2) protein.
BACKGROUND OF THE INVENTION
[0003] The prostaglandins are extremely potent substances which
produce a wide variety of biological effects, often in the
nanomolar to picomolar concentration range. The discovery of two
forms of prostaglandin endoperoxide H synthase, isoenzymes PGHS-1
and PGHS-2, that catalyze the oxidation of arachidonic acid leading
to prostaglandin biosynthesis has resulted in renewed research to
delineate the role of these two isozymes in physiology and
pathophysiology. These isozymes have been shown to have different
gene regulation and represent distinctly different prostaglandin
biosynthesis pathways. The PGHS-1 pathway is expressed
constitutively in most cell types. It responds to produce
prostaglandins that regulate acute events in vascular homeostasis
and also has a role in maintaining normal stomach and renal
function. The PGHS-2 pathway involves an induction mechanism which
has been linked to inflammation, mitogenesis and ovulation
phenomena.
[0004] Prostaglandin inhibitors provide therapy for pain, fever,
and inflammation, and are useful therapies, for example in the
treatment of rheumatoid arthritis and osteoarthritis. The
non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen,
naproxen and fenamates inhibit both isozymes. Inhibition of the
constitutive enzyme PGHS-1 results in gastrointestinal side effects
including ulcers and bleeding and incidence of renal problems with
chronic therapy. Inhibitors of the induced isozyme PGHS-2 may
provide anti-inflammatory activity without the side effects of
PGHS-1 inhibitors.
[0005] The problem of side-effects associated with NSAID
administration has never completely been solved in the past.
Enteric coated tablets and co-administration with misoprostol, a
prostaglandin derivative, have been tried in an attempt to minimize
stomach toxicity. It would be advantageous to provide compounds
which are selective inhibitors of the induced isozyme PGHS-2.
[0006] The present invention discloses novel compounds which are
selective inhibitors of PGHS-2.
SUMMARY OF THE INVENTION
[0007] The present invention discloses pyridazinone compounds which
are selective inhibitors of cyclooxygenase-2 (COX-2). The the
compounds of the present invention have the formula 1: 1
[0008] where
[0009] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and arylalkyl; and R.sup.a,
R.sup.b, and R.sup.c are independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and
arylalkyl;
[0010] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl,
cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic
(alkoxy), heterocyclic (oxy), --C(O)R.sup.5,
--(CH.sub.2).sub.nC(O)R.sup.- 5, --R.sup.6--R.sup.7,
--(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nCH(OR.sup.d)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.su- p.5,
--(CH.sub.2).sub.nC(NR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)- R.sup.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].s-
ub.m--(CH.sub.2).sub.n--CX'.sub.3, --(CH.sub.2).sub.m--(C
X'.sub.2).sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n[CH(CX'.s-
ub.3)].sub.m--(CH.sub.2).sub.n--R.sup.8,
--(CH.sub.2).sub.n(CX'.sub.2).sub- .m--(CH.sub.2).sub.nR.sup.8,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).su- b.n--CX'.sub.3,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--R.sup.8, and
--(CH.sub.2).sub.n--R.sup.20,
[0011] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic
(alkyl);
[0012] wherein R.sup.6 is alkylene or alkenylene;
[0013] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl);
[0014] R.sup.20 is selected from the group consisting of alkyl,
alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic,
and heterocyclic (alkyl);
[0015] R.sup.d and R.sup.e are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl);
[0016] X' is halogen;
[0017] n is from 0 to about 10, and m is 0 to about 5; at least one
of R.sup.1, R.sup.2 and R3 is a group, substituted with a
substituent having a group --X.sup.1--R.sup.9, having the formula:
2
[0018] where X.sup.1 is selected from the group consisting of
--SO.sub.2--, --SO(NR.sup.10)--, --PO(OR.sup.11)--, and
--PO(NR.sup.12R.sup.13)--,
[0019] R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, --NHNH.sub.2,
alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting
groups,
[0020] X.sup.2 is selected from the group consisting of hydrogen or
halogen;
[0021] R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrogen, alkyl, and
cycloalkyl, or R.sup.12 and R.sup.13 can be taken together, with
the nitrogen to which they are attached, to form a heterocyclic
ring having from 3 to 6 atoms.
[0022] The remaining two of the groups of R.sup.1, R.sup.2, and
R.sup.3, are independently selected from the group consisting of
hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl,
alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino,
aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclic,
heterocyclic (alkyl), cyano, nitro, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --C(R.sup.16)
(R.sup.17)--,
[0023] C(O)NR.sup.21--, --C(O)--, --C(O)O--, --NH--, --NC(O)--, and
--NR.sup.19--. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl),
[0024] R.sup.16, R.sup.17, and R.sup.19 are independently selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; and
[0025] R.sup.21 is selected from the group consisting of hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0026] All patents, patent applications, and literature references
cited in the specification are hereby incorporated by reference in
their entirety. In the case of inconsistencies, the present
disclosure, including definitions, will prevail.
[0027] The present invention discloses pyridazinone compounds which
are cyclooxygenase (COX) inhibitors and are selective inhibitors of
cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated
with inflammation, as opposed to the constitutive isoform,
cyclooxygenase-1 (COX-1) which is an important "housekeeping"
enzyme in many tissues, including the gastrointestinal (GI) tract
and the kidneys.
[0028] In one embodiment, the compounds of the present invention
have the formula I: 3
[0029] where
[0030] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and arylalkyl; and R.sup.a,
R.sup.b, and R.sup.c are independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and
arylalkyl;
[0031] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl,
cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic
(alkoxy), heterocyclic (oxy), --C(O)R.sup.5,
--(CH.sub.2).sub.nC(O)R.sup.- 5, --R.sup.6--R.sup.7,
--(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nCH(OR.sup.d)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.su- p.5,
--(CH.sub.2).sub.nC(NR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)- R.sup.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub-
.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.- sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH.sub.-
2).sub.n--R.sup.8,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).sub.nR.- sup.8,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--R.sup.8, and
--(CH.sub.2).sub.n--R.sup.20,
[0032] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic
(alkyl);
[0033] wherein R.sup.6 is alkylene or alkenylene;
[0034] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl);
[0035] R.sup.20 is selected from the group consisting of alkyl,
alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic,
and heterocyclic (alkyl);
[0036] R.sup.d and R.sup.e are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl);
[0037] X' is halogen;
[0038] n is from 0 to about 10, and m is 0 to about 5;
[0039] at least one of R.sup.1, R.sup.2 and R.sup.3 is a group,
substituted with a substituent having a group --X.sup.1--R.sup.9,
having the formula: 4
[0040] where X.sup.1 is selected from the group consisting of
--SO.sub.2--, --SO(NR.sup.10)--, --PO(OR.sup.11)--, and
--PO(NR.sup.12R.sup.13)--,
[0041] R.sup.9 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, --NHNH.sub.2,
alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting
groups,
[0042] X.sup.2 is selected from the group consisting of hydrogen or
halogen;
[0043] R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrogen, alkyl, and
cycloalkyl, or R.sup.12 and R.sup.13 can be taken together, with
the nitrogen to which they are attached, to form a heterocyclic
ring having from 3 to 6 atoms.
[0044] The remaining two of the groups of R.sup.1, R.sup.2, and
R.sup.3, are independently selected from the group consisting of
hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl,
alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino,
aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclic,
heterocyclic (alkyl), cyano, nitro, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --C(R.sup.16)
(R.sup.17)--,
[0045] C(O)NR.sup.21--, --C(O)--, --C(O)O--, --NH--, --NC(O)--, and
--NR.sup.19--. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl),
[0046] R.sup.16, R.sup.17, and R.sup.19 are independently selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; and
[0047] R.sup.21 is selected from the group consisting of hydrogen,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl,
heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
[0048] In another embodiment, compounds of the present invention
have the formula II: 5
[0049] wherein Z is a group having the formula: 6
[0050] where X.sup.1 is selected from the group consisting of
--SO.sub.2--, and SO(NR.sup.10)--, and R.sup.9 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, amino, alkylamino, dialkylamino;
[0051] X.sup.2 is selected from the group consisting of hydrogen or
halogen;
[0052] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,
heterocyclic, hetrocyclic (alkyl), and arylalkyl; and R.sup.a,
R.sup.b, and R.sup.c. are independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and
arylalkyl;
[0053] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl,
cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic
(alkoxy), heterocyclic (oxy), --C(O)R.sup.5, --(C
H.sub.2).sub.nC(O)R.sup- .5, --(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)-
].sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m-- -(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m--(CH-
.sub.2).sub.n--R.sup.8,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m--(CH.sub.2).su- b.nR.sup.8,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--CX'.sub.3,
--(CH.sub.2).sub.n(CHX').sub.m--(CH.sub.2).sub.n--R.sup.8, and
--(CH.sub.2).sub.n--R.sup.20,
[0054] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl);
[0055] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl),
[0056] R.sup.20 is selected from the group consisting of alkyl,
alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic,
and heterocyclic (alkyl);
[0057] X' is halogen;
[0058] n is from 0 to about 10, m is from 0 to about 5;
[0059] R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
cycloalkenylalkyl, amino, alkylamino, dialkylamino, arylamino,
arylalkylamino, diarylamino, aryl, heterocyclic, hetreocyclic
(alkyl), cyano, nitro, and --Y--R.sup.14, wherein Y is selected
from the group consisting of, --O--, --S--, --CH.sub.2--,
--C(R.sup.16) (R.sup.17)--, --C(O)--, --C(O)O--, --NH--, and
--NR.sup.19--. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl), and
[0060] R.sup.16, R.sup.17, and R.sup.19 are independently selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, hetrocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0061] In yet another embodiment, compounds of the present
invention have the formula III: 7
[0062] wherein X, X.sup.1, R, R.sup.1, R.sup.3, and R.sup.9 are as
defined in Formula I; or a pharmaceutically acceptable salt, ester,
or prodrug thereof.
[0063] In a preferred embodiment, compounds of the present
invention have the formula III, wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0064] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,
heterocyclic, heterocyclic (alkyl), and arylalkyl; and R.sup.a,
R.sup.b, and R.sup.c. are independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and
arylalkyl;
[0065] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,
arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.mCX'.sub.3,
--(CH.sub.2).sub.n(CX'R.sup- .e).sub.mCX'.sub.3,
--(CH.sub.2).sub.n(CX'.sub.2).sub.mR.sup.8,
--(CH.sub.2).sub.n(CX'R.sup.e).sub.mR.sup.8, and
--(CH.sub.2).sub.n--R.su- p.20;
[0066] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl);
[0067] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl), R.sup.20 is selected from the group
consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl,
aryl, heterocyclic, and heterocyclic (alkyl);
[0068] X' is halogen;
[0069] R.sup.e is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, hydroxy, and haloalkyl;
[0070] n is from 0 to about 10, m is from 0 to about 5;
[0071] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --CH.sub.2--,
--CHR.sup.15--, --C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and
--NR.sup.19--. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and
[0072] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0073] In another preferred embodiment, compounds of the present
invention have the formula III, wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0074] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl,
and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are independently
selected from the group consisting of alkyl, cycloalkyl,
alkylcycloalkyl, aryl, and arylalkyl;
[0075] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,
arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5, and
--(CH.sub.2).sub.n--R.sup.20;
[0076] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl);
[0077] R.sup.20 is selected from the group consisting of alkyl,
alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic,
and heterocyclic (alkyl);
[0078] n is from 0 to about 10;
[0079] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --CH.sub.2--,
--CHR.sup.15-, --C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and
--NR.sup.19-. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and
[0080] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0081] In another preferred embodiment, compounds of the present
invention have the formula II, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0082] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl,
and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are independently
selected from the group consisting of alkyl, cycloalkyl,
alkylcycloalkyl, aryl, and arylalkyl;
[0083] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl,
heterocyclic, heterocyclic (alkyl), arylalkyl, and
--(CH.sub.2).sub.nC(O)R.sup.5,;
[0084] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl); and
[0085] n is from 0 to about 10;
[0086] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, aryl, arylalkyl, heterocyclic,
heterocyclic (alkyl), and --Y--R.sup.14, wherein Y is selected from
the group consisting of, --O--, --S--, --CH.sub.2--, --CHR.sup.15-,
--C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and --NR.sup.19-.
R.sup.14 is selected from the group consisting of hydrogen,
halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano,
aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
[0087] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0088] In another preferred embodiment, compounds of the present
invention have the formula III, wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0089] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl,
and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are independently
selected from the group consisting of alkyl, cycloalkyl,
alkylcycloalkyl, aryl, and arylalkyl;
[0090] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sub.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0091] n is from 0 to about 10;
[0092] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, aryl, arylalkyl, heterocyclic,
heterocyclic (alkyl), and --Y--R.sup.14, wherein Y is selected from
the group consisting of, --O--, --S--, --CH.sub.2--, --CHR.sup.15-,
--C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and --NR.sup.19-.
R.sup.14 is selected from the group consisting of hydrogen,
halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano,
aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
[0093] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0094] In another preferred embodiment, compounds of the present
invention have the formula III, wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0095] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl,
and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are independently
selected from the group consisting of alkyl, cycloalkyl,
alkylcycloalkyl, aryl, and arylalkyl;
[0096] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sub.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0097] n is from 0 to about 10;
[0098] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester,
or prodrug thereof.
[0099] In another preferred embodiment, compounds of the present
invention have the formula III, wherein X.sup.1 is selected from
the group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0100] X is selected from the group consisting of O, S, NR.sup.4,
N--OR.sup.a, and N--NR.sup.bR.sup.c, wherein R.sup.4 is selected
from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl,
and arylalkyl; and R.sup.a, R.sup.b, and R.sup.c. are independently
selected from the group consisting of alkyl, cycloalkyl,
alkylcycloalkyl, aryl, and arylalkyl;
[0101] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sup.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0102] n is from 0 to about 10;
[0103] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, phenyl substituted with one, two, or
three substituents selected from the group consisting of alkyl,
alkoxy, fluorine and chlorine including, but not limited to,
p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl,
3-chloro-4-fluoro-phenyl, and the like; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
[0104] In yet another embodiment, compounds of the present
invention have formula IV: 8
[0105] where R, R.sup.1, X.sup.1, X.sup.2, R.sup.9, and R.sup.3 are
as described in Formula I; or a pharmaceutically acceptable salt or
ester thereof.
[0106] In a preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0107] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,
arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.C--R.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.mCX'.sub.3,
--(CH.sub.2).sub.n(CX'R.sup- .e).sub.mCX'.sub.3, --(CH.sub.2).sub.n
(CX'.sub.2).sub.mR.sup.8,
--(CH.sub.2).sub.n(CX'R.sup.e).sub.mR.sup.8, and
--(CH.sub.2).sub.n--R.su- p.20;
[0108] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl);
[0109] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and
heterocyclic (alkyl), R.sup.20 is selected from the group
consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl,
aryl, heterocyclic, and heterocyclic (alkyl);
[0110] X' is halogen;
[0111] R.sup.e is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, hydroxy, and haloalkyl;
[0112] n is from 0 to about 10, m is from 0 to about 5;
[0113] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --CH.sub.2--,
--CHR.sup.15-, --C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and
--NR.sup.19-. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and
[0114] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0115] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0116] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,
arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5, and
--(CH.sub.2).sub.n--R.sup.20;
[0117] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl);
[0118] R.sup.20 is selected from the group consisting of alkyl,
alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic,
and heterocyclic (alkyl);
[0119] n is from 0 to about 10;
[0120] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino,
arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic,
heterocyclic (alkyl), cyano, and --Y--R.sup.14, wherein Y is
selected from the group consisting of, --O--, --S--, --CH.sub.2--,
--CHR.sup.15-, --C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and
--NR.sup.19-. R.sup.14 is selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and
[0121] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0122] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0123] R is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl,
alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl,
heterocyclic, heterocyclic (alkyl), arylalkyl, and
--(CH.sub.2).sub.nC(O)R.sup.5,;
[0124] wherein R.sup.5 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
haloalkyl, heterocyclic, and heterocyclic (alkyl); and
[0125] n is from 0 to about 10;
[0126] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and --Y--R.sup.14, wherein Y is selected from the group
consisting of, --O--, --S--, --CH.sub.2--, --CHR.sup.15-,
--C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and --NR.sup.19-.
R.sup.14 is selected from the group consisting of hydrogen,
halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano,
aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
[0127] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0128] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0129] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sub.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0130] n is from 0 to about 10;
[0131] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), and --Y--R.sup.14, wherein Y is selected from the group
consisting of, --O--, --S--, --CH.sub.2--, --CHR.sup.15-,
--C(R.sup.16) (R.sup.17)--, --C(O)--, --NH--, and --NR.sup.19-.
R.sup.14 is selected from the group consisting of hydrogen,
halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano,
aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
[0132] R.sup.15, R.sup.16, R.sup.17, and R.sup.19 are independently
selected from the group consisting of alkyl, alkenyl, cycloalkyl,
cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic
(alkyl), or cyano.
[0133] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0134] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sub.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0135] n is from 0 to about 10;
[0136] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, aryl, arylalkyl, heterocyclic, and
heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester,
or prodrug thereof.
[0137] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0138] R is selected from hydrogen, haloalkyl, aryl, heterocyclic,
heterocyclic (alkyl), and --(CH.sub.2).sub.n--R.sup.20 where is
R.sup.20 is substituted and unsubstituted aryl wherein the
substituted aryl compounds are substituted with halogen;
[0139] n is from 0 to about 10;
[0140] R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen, phenyl substituted with one, two, or three
substituents selected from the group consisting of alkyl, alkoxy,
fluorine and chlorine including, but not limited to,
p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl,
3-chloro-4-fluoro-phenyl, and the like; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
[0141] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0142] R is haloalkyl, R.sup.1 is hydrogen and R.sup.3 is selected
from the group consisting of hydrogen and phenyl substituted with
one, two, or three substituents selected from the group consisting
of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
[0143] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X.sup.1 is selected from the
group consisting of --SO.sub.2--, and --SO(NR.sup.10)--, and
R.sup.9 is selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or
dialkylamino;
[0144] R is substituted and unsubstituted aryl and R.sup.1 is
hydrogen and R.sup.3 is selected from the group consisting of
hydrogen and phenyl substituted with one, two, or three
substituents selected from the group consisting of alkyl, alkoxy,
fluorine and chlorine; or a pharmaceutically acceptable salt,
ester, or prodrug thereof.
[0145] In another preferred embodiment, compounds of the present
invention have the formula IV, wherein X' is SO.sub.2, R.sup.9 is
selected from alkyl and amino, R is substituted and unsubstituted
aryl and R.sup.1 is hydrogen and R.sup.3 is selected from the group
consisting of hydrogen and phenyl substituted with one, two, or
three substituents selected from the group consisting of alkyl,
alkoxy, fluorine and chlorine; or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
[0146] Preferred Embodiments
[0147] Compounds useful in practicing the present invention
include, but are not limited to:
[0148]
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
[0149]
2-Benzyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyrida-
zinone;
[0150]
2-Methyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyrida-
zinone;
[0151]
2-Ethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridaz-
inone;
[0152]
2-(4-Fluorobenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(-
2H)-pyridazinone;
[0153]
2-(n-Butyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyr-
idazinone;
[0154]
2-(2,2,2-Trifluroethyl)-5-(4-methylsulfonylphenyl)-6-(4-flurophenyl-
)-3(2H)-pyridazinone;
[0155]
2-(4-Fluoro-.alpha.-methylbenzyl)-5-(4-methylsulfonylphenyl)-6-(4-f-
luorophenyl)-3(2H)-pyridazinone;
[0156]
2-(n-Propyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone;
[0157]
2-(n-Pentyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone;
[0158]
2-Cyclohexylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(-
2H)-pyridazinone;
[0159]
2-Phenacyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyri-
dazinone;
[0160]
2-Propargyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyr-
idazinone;
[0161]
2-Cyclohexyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone;
[0162]
2-(2-Butynyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-p-
yridazinone;
[0163]
2-(Cyclobutanylmethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl-
)-3(2H)-pyridazinone; and
[0164]
2-(3-Methylbuten-2-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl-
)-3(2H)-pyridazinone; or a pharmaceutically acceptable salt, ester,
or prodrug thereof.
[0165] Preparation of Compounds of the Invention
[0166] The compounds of the invention may be prepared by a variety
of synthetic routes. Representative procedures are outlined in
Scheme 1 below.
[0167] A general route to the compounds of the invention having
Formula III, where the aryl group at the 5-position on the
pyridazinone ring is substituted with a sulfonyl group ring
(R.sup.2 is aminosulfonyl, or methylsulfonyl, shown as
methylsulfonyl) is described in Scheme 1, below. Phenyl acetic
acid, optionally substituted, was. condensed with a benzaldehyde to
form the corresponding 2-phenyl-trans-cinnamic acid. The
trans-cinnamic acid was converted to the corresponding acid
chloride which was then decarbonylated to provide the benzyl-aryl
ketone. The ketone was then alkylated with ethyl bromoacetate in
the presence of a strong base such as sodium
bis(trimethylsilyl)amide. Treatment of the ketoester product with
hydrazine, in an alcohol solvent, such as ethanol, provided
dihydropyridazinone. The dihydropyridazinone was dehydrogenated to
form the pyridazinone by treatment with Bromine in acetic acid. If
desired, the R' group can be added via substitution using an
appropriate alkylating agent. In Scheme 1, X is defined as in
R.sup.3 and R' is defined as in R. 9
[0168] Definitions of Terms
[0169] As used throughout this specification and the appended
claims, the following terms have the meanings specified.
[0170] The term "protecting groups includes "carboxy protecting
group" and "N-protecting groups". "Carboxy protecting group" as
used herein refers to a carboxylic acid protecting ester group
employed to block or protect the carboxylic acid functionality
while the reactions involving other functional sites of the
compound are carried out. Carboxy protecting groups are disclosed
in Greene, "Protective Groups in Organic Synthesis" pp. 152-186
(1981), which is hereby incorporated herein by reference. In
addition, a carboxy protecting group can be used as a prodrug
whereby the carboxy protecting group can be readily cleaved in
vivo, for example by enzymatic hydrolysis, to release the
biologically active parent. T. Higuchi and V. Stella provide a
thorough discussion of the prodrug concept in "Pro-drugs as Novel
Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American
Chemical Society (1975), which is hereby incorporated herein by
reference. Such carboxy protecting groups are well known to those
skilled in the art, having been extensively used in the protection
of carboxyl groups in the penicillin and cephalosporin fields, as
described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures
of which are hereby incorporated herein by reference. Examples of
esters useful as prodrugs for compounds containing carboxyl groups
can be found on pages 14-21 of "Bioreversible Carriers in Drug
Design: Theory and Application", edited by E. B. Roche, Pergamon
Press, New York (1987), which is hereby incorporated herein by
reference. Representative carboxy protecting groups are C.sub.1 to
C.sub.8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like);
haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof
such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and
substituted derivatives thereof such as cyclohexylmethyl,
cylcopentylmethyl and the like; arylalkyl, for example, phenethyl
or benzyl and substituted derivatives thereof such as alkoxybenzyl
or nitrobenzyl groups and the like; arylalkenyl, for example,
phenylethenyl and the like; aryl and substituted derivatives
thereof, for example, 5-indanyl and the like; dialkylaminoalkyl
(e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups
such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl,
isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl,
1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-(propionyloxy)-1-ethyl,
pivaloyloxymethyl, propionyloxymethyl and the like;
cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl,
cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl,
cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as
benzoyloxymethyl, benzoyloxyethyl and the like;
arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl,
2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as
methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl,
1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl,
such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl,
1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and
the like; alkoxycarbonylaminoalkyl, such as
t-butyloxycarbonylaminomethyl and the like;
alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminom-
ethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl
and the like; heterocycliccarbonyloxyalkyl, such as
4-methylpiperazinylcarbonylox- ymethyl and the like;
dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl,
diethylaminocarbonylmethyl and the like;
(5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as
(5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and
(5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as
(5-phenyl-2-oxo-1,3-diox- olen-4-yl)methyl and the like.
[0171] The term "N-protecting group" or "N-protected" as used
herein refers to those groups intended to protect the N-terminus of
an amino acid or peptide or to protect an amino group against
undersirable reactions during synthetic procedures. Commonly used
N-protecting groups are disclosed in Greene, "Protective Groups In
Organic Synthesis," (John Wiley & Sons, New York (1981)), which
is hereby incorporated by reference. N-protecting groups comprise
acyl groups such as formyl, acetyl, propionyl, pivaloyl,
t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,
trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,
.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
4-nitrobenzoyl, and the like; sulfonyl groups such as
benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming
groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl- ,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
.alpha.,.alpha.-dimethyl-3,5-di- methoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,
phenoxycarbonyl, 4-nitrophenoxycarbonyl,
fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and
the like; alkyl groups such as benzyl, triphenylmethyl,
benzyloxymethyl and the like; and silyl groups such as
trimethylsilyl and the like. Preferred N-protecting groups are
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl,
benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).
[0172] The term "alkanoyl" as used herein refers to an alkyl group
as previously defined appended to the parent molecular moiety
through a carbonyl (--C(O)--) group. Examples of alkanoyl include
acetyl, propionyl and the like.
[0173] The term "alkanoylamino" as used herein refers to an
alkanoyl group as previously defined appended to an amino group.
Examples alkanoylamino include acetamido, propionylamido and the
like.
[0174] The term "alkenyl" as used herein refers to a straight or
branched chain hydrocarbon radical containing from 2 to 15 carbon
atoms and also containing at least one carbon-carbon double bond.
Alkenyl groups include, for example, vinyl (ethenyl), allyl
(propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
[0175] The term "alkenylene" denotes a divalent group derived from
a straight or branched chain hydrocarbon containing from 2 to 15
carbon atoms and also containing at least one carbon-carbon double
bond. Examples of alkenylene include --CH.dbd.CH--,
--CH.sub.2CH.dbd.CH--, --C(CH.sub.3).dbd.CH--,
--CH.sub.2CH.dbd.CHCH.sub.2--,
--CH.sub.2CH.dbd.CHCH.sub.2CH.dbd.CHCH.sub.2--, and the like.
[0176] The term "alkenyloxy" as used herein refers to an alkenyl
group, as previously defined, connected to the parent molecular
moiety through an oxygen (--O--) linkage. Examples of alkenyloxy
include allyloxy, butenyloxy and the like.
[0177] The term "alkoxy" as used herein refers to R.sub.41O--
wherein R.sub.41 is a loweralkyl group, as defined herein. Examples
of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and
the like.
[0178] The term "alkoxyalkoxy" as used herein refers to
R.sub.80O--R.sub.81O-- wherein R.sub.80 is loweralkyl as defined
above and R.sub.81 is alkylene. Representative examples of
alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy,
t-butoxymethoxy and the like.
[0179] The term "alkoxycarbonyl" as used herein refers to an
alkoxyl group as previously defined appended to the parent
molecular moiety through a carbonyl group. Examples of
alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl and the like.
[0180] The term "alkoxyalkoxyalkenyl" as used herein refers to an
alkoxyalkoxy group as previously defined appended to an alkenyl
radical. Representative examples of alkoxyalkoxyalkenyl groups
include methoxyethoxyethenyl, methoxymethoxymethenyl, and the
like.
[0181] The term "alkoxyalkyl" as used herein refers to an alkoxy
group as previously defined appended to an alkylene as previously
defined. Examples of alkoxyalkyl include, but are not limited to,
methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
[0182] The term "(alkoxycarbonyl)thioalkoxy" as used herein refers
to an alkoxycarbonyl group as previously defined appended to a
thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include
methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the
like.
[0183] The terms "alkyl" and "loweralkyl" as used herein refer to
straight or branched chain alkyl radicals containing from 1 to 15
carbon atoms including, but not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl,
n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,
2,2-dimethylpropyl, n-hexyl and the like.
[0184] The term "alkylamino" as used herein refers to R.sub.51NH--
wherein R.sub.51 is a loweralkyl group, for example, ethylamino,
butylamino, and the like.
[0185] The term "alkylcarbonylalkyl" as used herein refers to
R.sub.40--C(O)--R.sub.41-- wherein R.sub.40 is an alkyl group and
R.sub.41 is alkylene.
[0186] The term "alkylene" denotes a divalent group derived from a
straight or branched chain saturated hydrocarbon having from 1 to
15 carbon atoms by the removal of two hydrogen atoms, for example
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2C(CH.sub.3).sub.2CH.sub.2--
and the like.
[0187] The term "alkylsulfonyl" as used herein refers to an alkyl
group as previously defined appended to the parent molecular moiety
through a sulfonyl (--S(O).sub.2--) group. Examples of
alkylsulfonyl include methylsulfonyl, ethylsulfonyl,
isopropylsulfonyl and the like.
[0188] The term "alkylsulfonylalkyl" as used herein refers to an
alkyl group as previously defined appended to the parent molecular
moiety through a sulfonylalkyl (--S(O).sub.2--R.sub.52--) group
wherein R.sub.52 is alkylene. Examples of alkylsulfonylalkyl
include methylsulfonylmethyl (CH.sub.3--S(O).sub.2--CH.sub.2--),
ethylsulfonylmethyl, isopropylsulfonylethyl and the like.
[0189] The term "alkylsulfonylamino" as used herein refers to an
alkyl group as previously defined appended to the parent molecular
moiety through a sulfonylamino (--S(O).sub.2--NH--) group. Examples
of alkylsulfonylamino include methylsulfonylamino,
ethylsulfonylamino, isopropylsulfonylamino and the like.
[0190] The term "alkylsulfonylarylalkyl" as used herein refers to
an alkyl group as previously defined appended to the parent
molecular moiety through a sulfonylalkyl
(--S(O).sub.2--R.sub.45R.sub.33--) group wherein R.sub.45 is aryl
and R.sub.33 is alkylene. Examples of alkylsulfonylarylalkyl
include methylsulfonylphenylmethyl ethylsulfonylphenylmethyl,
isopropylsulfonylphenylethyl and the like.
[0191] The term "alkylthio" as used herein refers to R.sub.53S--
wherein R.sub.53 is alkyl.
[0192] The term "alkynyl" as used herein refers to a straight or
branched chain hydrocarbon radical containing from 2 to 15 carbon
atoms and also containing at least one carbon-carbon triple bond.
Examples of alkynyl include --C.ident.C--H,
H--C.ident.C--CH.sub.2--, H--C.ident.C--CH(CH.sub- .3)-- and the
like.
[0193] The term "amido" as used herein refers to
R.sub.54--C(O)--NH-- wherein R.sub.54 is an alkyl group.
[0194] The term "amidoalkyl" as used herein refers to
R.sub.34--C(O)--NHR.sub.35-- wherein R.sub.34 is alkyl and R.sub.35
is alkylene.
[0195] The term "amino" as used herein refers --NH.sub.2.
[0196] The term "aminocarbonyl" as used herein refers to
H.sub.2N--C(O)--.
[0197] The term "aminocarbonylalkyl" as used herein refers to an
aminocarbonyl as described above appended to the parent molecular
moiety through an alkylene.
[0198] The term "aminocarbonylalkoxy" as used herein refers to
H.sub.2N--C(O)--O--R.sub.55--, wherein R55 is an alkyl radical
group. Examples of aminocarbonylalkoxy include
aminocarbonylmethoxy, aminocarbonylethoxy and the like.
[0199] The term "aryl" as used herein refers to a mono- or bicyclic
carbocyclic ring system having one or two aromatic rings including,
but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl,
indenyl and the like. Aryl groups can be unsubstituted or
substituted with one, two or three substituents independently
selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo
(.dbd.O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy,
alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy,
thioalkoxy, alkylimino (R*N=wherein R* is a loweralkyl group),
amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl,
aminocarbonylalkoxy, alkanoylamino, aryl, arylalkyl, arylalkoxy,
aryloxy, mercapto, cyano, nitro, mercapto, carboxy, carboxaldehyde,
carboxamide, cycloalkyl, carboxyalkenyl, carboxyalkoxy,
alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, --SO.sub.3H,
hydroxalkoxy, phenyl and tetrazolylalkoxy. Examples of substituted
aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,
4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl;
4-methylsulfonylphenyl, and the like.
[0200] The term "arylalkenyl" as used herein refers to an
alkenylene to which is appended an aryl group, for example,
phenylethenyl and the like.
[0201] The term "arylalkynyl" as used herein refers to an alkynyl
radical to which is appended an aryl group, for example,
phenylethynyl and the like
[0202] The term "arylalkoxy" as used herein refers to R.sub.42O--
wherein R.sub.42 is an arylalkyl group, for example, benzyloxy, and
the like.
[0203] The term "arylalkyl" as used herein refers to an aryl group
as previously defined, appended to a loweralkyl radical, for
example, benzyl and the like.
[0204] The term "arylalkylamino" as used herein refers to an
arylalkyl group as previously defined, appended to the parent
molecular moiety through an amino group.
[0205] The term "arylamino" as used herein refers to
R.sub.45NH.sub.2-- wherein R.sub.45 is an aryl.
[0206] The term "arylcarbonylalkyl" as used herein refers to
R.sub.45C(O)R.sub.33-- wherein R.sub.45 is an aryl group and
R.sub.33 is an alkylene group.
[0207] The term "aryloxy" as used herein refers to R.sub.45O--
wherein R.sub.45 is an aryl group, for example, phenoxy, and the
like.
[0208] The term "carboxaldehyde" as used herein refers to a
formaldehyde radical, --C(O)H.
[0209] The term "carboxamide" as used herein refers to
--C(O)NH.sub.2.
[0210] The term "carboxy" as used herein refers to a carboxylic
acid radical, --C(O)OH.
[0211] The term "carboxyalkenyl" as used herein refers to a carboxy
group as previously defined appended to an alkenyl radical as
previously defined. Examples of carboxyalkenyl include
2-carboxyethenyl, 3-carboxy-1-ethenyl and the like.
[0212] The term "carboxyalkyl" as used herein refers to a carboxy
group as previously defined appended to an alkyl radical as
previously defined. Examples of carboxyalkyl include
2-carboxyethyl, 3-carboxy-1-propyl and the like.
[0213] The term "carboxyalkoxy" as used herein refers to a carboxy
group as previously defined appended to an alkoxy radical as
previously defined. Examples of carboxyalkoxy include
carboxymethoxy, carboxyethoxy and the like.
[0214] The term "cyano" as used herein refers a cyano (--CN)
group.
[0215] The term "cyanoalky" as used herein refers to a cyano (--CN)
group appended to the parent molecular moiety through an alkyl.
Examples of cyanoalkyl include 3-cyanopropyl, 4-cyanobutyl, and the
like.
[0216] The term "cyanoalkoxy" as used herein refers to a cyano
(--CN) group appended to the parent molecular moiety through an
alkoxy radical. Examples of cyanoalkoxy include 3-cyanopropoxy,
4-cyanobutoxy and the like.
[0217] The term "cycloalkyl" as used herein refers to an aliphatic
ring system having 3 to 10 carbon atoms and 1 to 3 rings including,
but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the
like. Cycloalkyl groups can be unsubstituted or substituted with
one, two or three substituents independently selected from hydroxy,
halo, oxo (.dbd.O), alkylimino (R*N=wherein R* is a loweralkyl
group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy,
alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy,
carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl,
--SO.sub.3H, nitro, cyano and loweralkyl.
[0218] The term "cycloalkenyl" as used herein refers to an
aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings
containing at least one double bond in the ring structure.
Cycloalkenyl groups can be unsubstituted or substituted with one,
two or three substituents independently selected hydroxy, halo, oxo
(.dbd.O), alkylimino (R*N=wherein R* is a loweralkyl group), amino,
alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl,
thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde,
carboxamide, cycloalkyl, aryl, arylalkyl, --SO.sub.3H, nitro, cyano
and loweralkyl.
[0219] The term "cycloalkylalkyl" as used herein refers to a
cycloalkyl group appended to a loweralkyl radical, including but
not limited to cyclohexylmethyl.
[0220] The term "cycloalkenylalkyl" as used herein refers to a
cycloalkenyl group appended to a loweralkyl radical, including but
not limited to cyclohexenylmethyl.
[0221] The term "dialkylamino" as used herein refers to
(R.sub.56)(R.sub.57)N-- wherein R.sub.56 and R.sub.57 are
independently selected from loweralkyl, for example diethylamino,
methyl propylamino, and the like.
[0222] The term "diarylamino" as used herein refers to
(R.sub.45)(R.sub.46)N-- wherein R.sub.45 and R.sub.46 are
independently aryl, for example diphenylamino and the like.
[0223] The term "halo" or "halogen" as used herein refers to 1, Br,
Cl or F.
[0224] The term "haloalkyl" as used herein refers to an alkyl
radical, as defined above, which has at least one halogen
substituent, for example, chloromethyl, fluoroethyl,
trifluoromethyl or pentafluoroethyl, 2,3-difluropentyl, and the
like.
[0225] The term "haloalkenyl" as used herein refers to an alkenyl
radical has at least one halogen substituent.
[0226] The term "haloalkynyl" as used herein refers to an alkynyl
radical has at least one halogen substituent.
[0227] The term "haloalkoxy" as used herein refers to an alkoxy
radical as defined above, bearing at least one halogen substituent,
for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,
trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
[0228] The term "heterocyclic ring" or "heterocyclic" or
"heterocycle" as used herein refers to any 3- or 4-membered ring
containing a heteroatom selected from oxygen, nitrogen and sulfur;
or a 5-, 6- or 7-membered ring containing one, two or three
nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and
one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms
in non-adjacent positions; one oxygen and one sulfur atom in
non-adjacent positions; or two sulfur atoms in non-adjacent
positions. Examples of heterocycles include, but are not limited
to, thiophene, pyrrole, and furan. The 5-membered ring has 0-2
double bonds and the 6- and 7-membered rings have 0-3 double bonds.
The nitrogen heteroatoms can be optionally quaternized. The term
"heterocyclic" also includes bicyclic groups in which any of the
above heterocyclic rings is fused to a benzene ring or a
cycloalkane ring or another heterocyclic ring (for example,
indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,
benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,
homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl,
oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl,
thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl,
tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl,
tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl,
pyrimidyl and benzothienyl. Heterocyclics also include compounds of
the formula 10
[0229] where X* is --CH.sub.2-- or --O-- and Y* is --C(O)-- or
[--C(R").sub.2--].sub.v where R" is hydrogen or
C.sub.1-C.sub.4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl,
1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic
rings such as quinuclidinyl and the like.
[0230] Heterocyclics can be unsubstituted or be substituted with
one, two, or three substituents independently selected from
hydroxy, halo, oxo (.dbd.O), alkylimino (R*N=wherein R* is a
loweralkyl group), amino, alkylamino, dialkylamino, alkoxy,
alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto,
carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl,
--SO.sub.3H, nitro, cyano and loweralkyl. In addition, nitrogen
containing heterocycles can be N-protected.
[0231] The term "heterocyclic(alkoxy)" as used herein refers to a
heterocyclic group as defined above appended to an alkoxy radical
as defined above. Examples of (heterocyclic)alkoxy include
4-pyridylmethoxy, 2-pyridylmethoxy and the like.
[0232] The term "heterocyclic(alkyl)" as used herein refers to a
heterocyclic group as defined above appended to the parent
molecular moiety through a loweralkyl radical as defined above.
[0233] The term "heterocyclic(oxy)" as used herein refers to a
heterocyclic group as defined above appended to the parent
molecular moiety through an oxygen. Examples of (heterocyclic)oxy
include 4-pyridyloxy, 2-pyridyloxy and the like.
[0234] The term "hydroxy" as used herein refers to --OH.
[0235] The term "hydroxyalkoxy" as used herein refers to an alkoxy
radical as previously defined to which is appended a hydroxy (--OH)
group. Examples of hydroxyalkoxy include 3-hydroxypropoxy,
4-hydroxybutoxy and the like.
[0236] The term "hydroxyalkyl" as used herein refers to a
loweralkyl radical to which is appended a hydroxy group.
[0237] The term "mercapto" or "thiol" as used herein refers to
--SH.
[0238] The term "nitro" as used herein refers to --NO.sub.2.
[0239] The term "thioalkoxy" as used herein refers to R.sub.70S--
wherein R.sub.70 is alkoxy. Examples of thioalkoxy include, but are
not limited to, methylthio, ethylthio and the like.
[0240] The compounds of the present invention can be used in the
form of salts derived from inorganic or organic acids. These salts
include but are not limited to the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as loweralkyl halides, such as methyl,
ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides, and others. Water or oil-soluble or dispersible
products are thereby obtained.
[0241] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulphuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid.
[0242] Basic addition salts can be prepared in situ during the
final isolation and purification of the compounds of formula (I),
or separately by reacting a carboxylic acid function with a
suitable base such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia, or an
organic primary, secondary or tertiary amine. Such pharmaceutically
acceptable salts include, but are not limited to, cations based on
the alkali and alkaline earth metals, such as sodium, lithium,
potassium, calcium, magnesium, aluminum salts and the like, as well
as nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. Other representative
organic amines useful for the formation of base addition salts
include diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like.
[0243] The term "pharmaceutically acceptable ester" as used herein
refers to esters which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters includes formates, acetates, propionates,
butyates, acrylates and ethylsuccinates.
[0244] The term "pharmaceutically acceptable prodrug" as used
herein refers to those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to provide the parent compound having the above formula, for
example by hydrolysis in blood. A thorough discussion is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,
ed., Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[0245] As used throughout this specification and the appended
claims, the term metabolically cleavable group denotes a moiety
which is readily cleaved in vivo from the compound bearing it,
wherein said compound, after cleavage remains or becomes
pharmacologically active. Metabolically cleavable groups form a
class of groups reactive with the carboxyl group of the compounds
of this invention are well known to practitioners of the art. They
include, but are not limited to groups such as, for example,
alkanoyl, such as acetyl, propionyl, butyryl, and the like;
unsubstituted and substituted aroyl, such as benzoyl and
substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl;
trialkylsilyl, such as trimethyl- and triethysilyl; monoesters
formed with dicarboxylic acids, such as succinyl, and the like.
Because of the ease with which the metabolically cleavable groups
of the compounds of this invention are cleaved in vivo, the
compounds bearing such groups act as pro-drugs of other
prostaglandin biosynthesis inhibitors. The compounds bearing the
metabolically cleavable groups have the advantage that they may
exhibit improved bioavailability as a result of enhanced solubility
and/or rate of absorption conferred upon the parent compound by
virtue of the presence of the metabolically cleavable group.
[0246] Asymmetric centers may exist in the compounds of the present
invention. The present invention contemplates the various
stereoisomers and mixtures thereof. Individual stereoisomers of
compounds of the present invention are made by synthesis from
starting materials containing the chiral centers or by preparation
of mixtures of enantiomeric products followed by separation as, for
example, by conversion to a mixture of diastereomers followed by
separation by recrystallization or chromatographic techniques, or
by direct separation of the optical enantiomers on chiral
chromatographic columns. Starting compounds of particular
stereochemistry are either commercially available or are made by
the methods detailed below and resolved by techniques well known in
the organic chemical arts.
[0247] The following examples illustrate the process of the
invention, without limitation.
EXAMPLE 1
[0248] 2-(4-Fluorophenyl)-4-methylthio-trans-cinnamic Acid
[0249] To a stirred solution of 4-fluorophenylacetic acid (48.8 g,
0.31 mol.) and 4-(methylthio)benzaldehyde (50 g, 0.31 mol.) in
acetic anhydride (50 mL) was added sodium methoxide (18.8 g, 0.33
mol.). The solution was stirred at reflux for 18 hours. The
reaction mixture was allowed to cool to room temperature and a
yellow precipitate formed. The yellow precipitate was filtered,
stirred in water (550 mL) for 3 hours, and refiltered. The product
was purified by recrystallization (ethanol) to provide yellow
crystals (yield: 51.55 g; 57%). M.p.=163-167.degree. C.
[0250] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 2.42 (s, 3H),
6.97 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.2 (d, J=7 Hz, 4H),
7.72 (s, 1H), 12.68 (bs, 1H).
[0251] MS (DCl/NH.sub.3) m/e 289 (M+H).sup.+.
EXAMPLE 2
[0252] 4-Fluorophenyl-4'-methylthiobenzylketone
[0253] A solution of 2-(4-fluorophenyl)-4-methylthio-trans-cinnamic
acid, prepared in Example 1, (51.48 g, 0.179 mol.) in thionyl
chloride (115 mL) was heated at reflux for 1.5 hours and then
stirred at room temperature for an additional 18 hours. The
reaction mixture was concentrated in vacuo, dissolved in acetone,
and added dropwise to a solution of sodium azide (12.8 g, 0.197
mol.) in water (95 mL) maintained at 0.degree. C. The mixture was
allowed to warm to room temperature, diluted with water (730 mL),
and extracted with toluene (1 L). The organic extract was washed
with brine, dried over MgSO.sub.4, and filtered. The filtrate was
heated at reflux for 1.5 hours, concentrated in vacuo, and
dissolved in acetic acid:water (127 mL:63 mL). The solution was
heated at reflux for 2 hours, allowed to cool to room temperature,
diluted with water (180 mL), whereafter a yellow solid
precipitated, and was filtered. The yellow precipitate was purified
by recrystallization (ethanol) to provide yellow crystals (yield:
27.85 g; 59%).
[0254] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.05 (s, 3H), 5.43
(s, 2H), 6.95 (m, 3H), 7.1 (m, 2H), 7.3 (d, J=9 Hz, 2H), 7.37 (m,
3H), 7.55 (m, 2H), 7.9 (d, J=9 Hz, 2H).
[0255] MS (DCl/NH.sub.3) m/e 435 (M+H).sup.+, 452
(M+NH.sub.4).sup.+.
[0256] Elemental analysis, calculated for
C.sub.24H.sub.19FN.sub.2O.sub.3S- : C, 66.34; H, 4.40; N, 6.44.
Found: C, 66.21; H, 4.35; N, 6.43.
EXAMPLE 3
[0257] 3-(4-Fluorobenzoyl)-3-(4-methylthiophenyl)propionic Acid,
Ethyl Ester
[0258] A solution of 4-fluorophenyl-4'-methylthiobenzylketone,
prepared in Example 2, (10 g, 38.45 mmol.) in THF (300 mL), was
prepared and maintained at -78.degree. C. A 1 M THF solution of
sodium bis(trimethylsilyl)amide (38.45 mL, 38.45 mmol.) was added
dropwise. The reaction mixture was stirred at -78.degree. C. for 45
minutes and ethyl bromoacetate (4.26 mL, 38.45 mmol.) was added
dropwise maintaining the temperature at -78.degree. C. The mixture
was allowed to warm to room temperature and stirred for 18 hours.
The solution was acidified with a 10% citric acid solution,
extracted with ether (3.times.50 mL), washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 5% ethyl acetate/hexane) to provide an
oil (yield: 8.7 g; 65%).
[0259] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 1.1 (s, 3H),
2.41 (s, 3H), 2.66 & 2.71 (2d, j=5 Hz, 1H), 3.14 & 3.20
(2d, J=5 Hz, 1H), 4.02 (q, J=7 Hz, 2H), 5.19 & 5.23 (2d, J=5
Hz, 1H), 7.18 (d, J=9 Hz, 2H), 7.29 (m, 4H), 8.1 (m, 2H).
[0260] MS (DCl/NH.sub.3) m/e 347 (M+H).sup.+.
EXAMPLE 4
[0261] 3-(4-Fluorobenzoyl)-3-(4-methylsulfonylphenyl)propionic
Acid, Ethyl Ester
[0262] To a stirred solution of ethyl
3-(4-fluorobenzoyl)-3-(4'-methylthio- phenyl)propionate, prepared
in Example 3 (8.7 g, 25.11 mmol.), in CH.sub.2Cl.sub.2 (450 mL) at
0.degree. C. was added 3-chloroperoxybenzoic acid (17.3 g, 50.22
mmol.). The reaction mixture was warmed to room temperature and
stirred for 45 minutes. The solution was quenched with a saturated
aqueous solution of sodium sulfite. The organic layer was washed
with 1 N aqueous NaOH (2.times.50 mL), brine, and dried over
MgSO.sub.4. The solution was concentrated in vacuo to provide an
oil (yield: 9.45 g; 99%).
[0263] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 1.1 (t, J=7 Hz,
3H), 2.76 & 2.82 (2d, J=5 Hz, 1H), 3.17 (s, 3H), 3.18-3.32 (m,
1H), 4.03 (q, J=7 Hz, 2H), 5.42 & 5.45 (2d, J=5 Hz, 1H), 7.32
(t, J=9 Hz, 3H), 7.65 (d, J=9 Hz, 2H), 7.84 (d, J=9 Hz, 2H), 8.16
(dd, J=9 Hz, 7 Hz, 2H).
[0264] MS (DCl/NH.sub.3) m/e 379 (M+H).sup.+.
EXAMPLE 5
[0265]
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-4.5-dihydro-3(2H)-pyr-
idazinone
[0266] To a stirred solution of ethyl
3-(4-fluorobenzoyl)-3-(4-methylsulfo- nylphenyl)propionate,
prepared in Example 3 (9.7 g, 26.99 mmol.), in ethanol (140 mL) was
added hydrazine monohydrate (40 mL, 0.824 mol.). The reaction
vessel was equipped with a soxhelet extractor, heated at reflux for
7 hours. The reaction mixture was concentrated in vacuo, quenched
with ice water (100 mL) and concentrated HCl (10 mL), extracted
with ethyl acetate (3.times.50 mL). The combined extracts were
washed with brine, dried over MgSO.sub.4, and concentrated in
vacuo. The product was purified by recrystallization (MeOH) to
provide a yellow solid (yield: 3.79 g; 41%). M.p.=240-241.degree.
C.
[0267] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.8 (m, 1H), 3.05
(s, 3H), 3.1 (m, 1H), 4.58 (m, 1H), 7.05 (t, J=9 Hz, 2H), 7.42 (d,
J=9 Hz, 2H), 7.65 (m, 2H), 7.91 (d, J=9 Hz, 2H), 8.88 (bs, 1H).
[0268] MS (DCl/NH.sub.3) m/e 347 (M+H).sup.+.
EXAMPLE 6
[0269]
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone
[0270] To a stirred solution of
5-(4-methylsulfonylphenyl)-6-(4-fluorophen-
yl)-4,5-dihydro-3(2H)-pyridazinone, prepared in Example 5 (2.6 g,
7.51 mmol.), in glacial acetic acid (250 mL) maintained at
95.degree. C. was added bromine (0.386 mL, 7.51 mmol.). The
reaction mixture was stirred at 95.degree. C. for 30 minutes,
concentrated in vacuo, quenched with water, and extracted with
ethyl acetate (2.times.25 mL). The combined extracts were washed
with brine, dried over MgSO.sub.4, concentrated in vacuo, and
filtered to provide a yellow solid (yield: 2.13 g; 82%).
M.p.=260-262.degree. C.
[0271] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.08 (s, 3H), 6.98
(m, 3H), 7.13 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H),
11.1 (bs, 1H).
[0272] MS (DCl/NH.sub.3) m/e 345 (M+H).sup.+.
EXAMPLE 7
[0273]
2-Benzyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyrida-
zinone
[0274] A solution of
5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-p- yridazinone,
prepared in Example 6 (600 mg, 1.74 mmol.), K.sub.2CO.sub.3 (264
mg, 1.91 mmol.), benzyl bromide (0.207 mL, 1.74 mmol.) and NaI
(about 0.1 eq., catalytic) in about 40 mL of dimethylformamide was
stirred at room temperature for 18 hours. The reaction mixture was
quenched with 2N HCl, and extracted with ethyl acetate (2.times.20
mL). The combined extracts were washed with brine, water, and dried
over MgSO.sub.4. The dried extracts were concentrated in vacuo and
the residue purified by recrystallization (MeOH) to provide a white
solid (yield: 601 mg; 79%). M.p.=172-174.degree. C.
[0275] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.05 (s, 3H), 5.43
(s, 2H), 6.95 (m, 3H), 7.1 (m, 2H), 7.3 (d, J=9 Hz, 2H), 7.37 (m,
3H), 7.55 (m, 2H), 7.9 (d, J=9 Hz, 2H).
[0276] MS (DCl/NH.sub.3) m/e 435 (M+H).sup.+, 452
(M+NH.sub.4).sup.+.
[0277] Elemental analysis, calculated for
C.sub.24H.sub.19FN.sub.2O.sub.3S- : C, 66.34; H, 4.40; N, 6.44.
Found: C, 66.21; H, 4.35; N, 6.43.
EXAMPLE 8
[0278]
2-Methyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyrida-
zinone
[0279] The title compound was prepared according to the method of
Example 7, substituting methyl iodide for benzyl bromide.
M.p.=181-182.degree. C.
[0280] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.08 (s, 3H), 3.92
(s, 3H), 6.98 (m, 3H), 7.13 (m, 2H), 7.32 (d, J=9 Hz, 2H), 7.9 (d,
J=9 Hz, 2H).
[0281] MS (DCl/NH.sub.3) m/e 359 (M+H).sup.+, 376
(M+NH.sub.4).sup.+.
[0282] Elemental Analysis: calculated for
C.sub.18H.sub.15FN.sub.2O.sub.3S- : C, 60.32; H, 4.21; N, 7.81.
Found: C, 60.26; H, 3.93; N, 7.81.
EXAMPLE 9
[0283]
2-Ethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridaz-
inone
[0284] The title compound was prepared according to the method of
Example 7, substituting ethyl bromide for benzyl bromide.
M.p.=177-179.degree. C.
[0285] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.47 (t, J=7 Hz,
3H), 3.05 (s, 3H), 4.33 (q, J=7 Hz, 2H), 6.96 (m, 3H), 7.13 (m,
2H), 7.32 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H).
[0286] MS (DCl/NH.sub.3) m/e 373 (M+H).sup.+, 390
(M+NH.sub.4).sup.+.
[0287] Elemental analysis, calculated for
C.sub.19H.sub.17FN.sub.2O.sub.3S- .0.25M H.sub.2O C, 60.54; H,
4.67; N, 7.43; Found: C, 60.40; H, 4.55; N, 7.43.
EXAMPLE 10
[0288]
2-(4-Fluorobenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(-
2H)-pyridazinone
[0289] The title compound was prepared according to the method of
Example 7, substituting 4-fluorobenzyl bromide for benzyl bromide.
M.p.=150-151.degree. C.
[0290] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.05 (s, 3H), 5.4
(s, 2H), 6.92-7.14 (m, 7H), 7.3 (d, J=9 Hz, 2H), 7.52 (m, 2H), 7.9
(d, J=9 Hz, 2H).
[0291] MS (DCl/NH.sub.3) m/e 453 (M+H).sup.+, 470
(M+NH.sub.4).sup.+.
[0292] Elemental Analysis: calculated for
C.sub.24H.sub.18F.sub.2N.sub.2O.- sub.3S: C, 63.70; H, 4.00; N,
6.19. Found: C, 63.46; H, 3.86; N, 5.92.
EXAMPLE 11
[0293]
2-(n-Butyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyr-
idazinone
[0294] The title compound was prepared according to the method of
Example 7, substituting n-butyl bromide for benzyl bromide.
M.p.=111-113.degree. C.
[0295] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.0 (t, J=7 Hz,
3H), 1.47 (m, 2H), 1.9 (m, 2H), 3.08 (s, 3H), 4.28 (t, J=7 Hz, 2H),
6.96 (m, 3H), 7.14 (m, 2H), 7.33 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz,
2H).
[0296] MS (DCl/NH.sub.3) m/e 401 (M+H).sup.+, 418
(M+NH.sub.4).sup.+.
[0297] Elemental Analysis: calculated for
C.sub.21H.sub.21FN.sub.2O.sub.3S- : C, 62.98; H, 5.28; N, 6.99.
Found: C, 62.95; H, 4.67; N, 6.90.
EXAMPLE 12
[0298]
2-(4-Fluoro-.alpha.-methylbenzyl)-5-(4-methylsulfonylphenyl)-6-(4-f-
luorophenyl)-3(2H)-pyridazinone
[0299] The title compound was prepared according to the method of
Example 7, substituting 4-fluoro-.alpha.-methyl benzyl bromide
(synthesized from 4-fluoro-.alpha.-methyl benzyl alcohol) for
benzyl bromide. M.p.=185-186.degree. C.
[0300] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.84 (d, J=7 Hz,
3H), 3.07 (s, 3H), 6.43 (q, J=7 Hz, 1H), 6.91-7.11 (m, 7H), 7.31
(d, J=9 Hz, 2H), 7.52 (m, 2H), 7.9 (d, J=9 Hz, 2H).
[0301] MS (DCl/NH.sub.3) m/e 467 (M+H).sup.+, 484
(M+NH.sub.4).sup.+.
[0302] Elemental Analysis: calculated for
C.sub.25H.sub.20F.sub.2N.sub.2O.- sub.3S: C, 64.36; H, 4.32; N,
6.00. Found: C, 64.38; H, 4.07; N, 5.93.
EXAMPLE 13
[0303]
2-(n-Propyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone
[0304] The title compound was prepared according to the method of
Example 7, substituting propyl bromide for benzyl bromide.
M.p.=155-157.degree. C.
[0305] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.04 (t, J=7 Hz,
3H), 1.94 (m, 2H), 3.08 (s, 3H), 4.23 (t, J=7 Hz, 2H), 6.96 (m,
3H), 7.13 (m, 2H), 7.33 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H);
[0306] MS (DCl/NH.sub.3) m/e 387 (M+H).sup.+, 404
(M+NH.sub.4).sup.+.
[0307] Elemental Analysis: calculated for
C.sub.20H.sub.19FN.sub.2O.sub.3S- : C, 62.16; H, 4.95; N, 7.24.
Found: C, 62.15; H, 4.78; N, 7.22.
EXAMPLE 14
[0308]
2-(n-Pentyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone
[0309] The title compound was prepared according to the method of
Example 7, substituting n-pentyl bromide for benzyl bromide.
M.p.=65-670C.
[0310] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.93 (m, 3H), 1.2
(m, 4H), 1.9 (m, 2H), 3.08 (s, 3H), 4.28 (t, J=7 Hz, 2H), 6.97 (m,
3H), 7.14 (m, 2H), 7.33 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H).
[0311] MS (DCl/NH.sub.3) m/e 415 (M+H).sup.+, 432
(M+NH.sub.4).sup.+.
[0312] Elemental Analysis: calculated for
C.sub.22H.sub.23FN.sub.2O.sub.3S- .0.75M H.sub.2O: C, 61.73; H,
5.76; N, 6.54. Found: C, 61.97; H, 6.00; N, 6.36.
EXAMPLE 15
[0313]
2-Cyclohexylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(-
2H)-pyridazinone
[0314] The title compound was prepared according to the method of
Example 7, substituting cyclohexylmethyl bromide for benzyl
bromide. M.p.=175-176.degree. C.
[0315] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.03-1.38 (m, 5H),
1.63-1.8 (m, 5H), 2.05 (m, l H), 3.08 (s, 3H), 4.13 (d, J=7 Hz,
2H), 6.97 (m, 3H), 7.14 (m, 2H), 7.33 (d, J=9 Hz, 2H), 7.9 (d, J=9
Hz, 2H).
[0316] MS (DCl/NH.sub.3) m/e 441 (M+. H).sup.+, 458
(M+NH.sub.4).sup.+.
[0317] Elemental Analysis: calculated for
C.sub.24H.sub.25FN.sub.2O.sub.3S- .0.25M H.sub.2O: C, 64.77; H,
5.77; N, 6.29. Found: C, 64.63; H, 5.85; N, 6.16.
EXAMPLE 16
[0318]
2-Phenacyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyri-
dazinone
[0319] The title compound was prepared according to the method of
Example 7, substituting 2-bromoacetophenone for benzyl bromide.
M.p.=178-180.degree. C.
[0320] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.08 (s, 3H), 5.75
(s, 2H), 6.96 (t, J=9 Hz, 2H), 7.03 (s, 1H), 7.15 (dd, J=9 Hz, 7
Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.55 (t, J=7 Hz, 2H), 7.68 (t, J=7
Hz, 1H), 7.94 (d, J=9 Hz, 2H), 8.05 (d, J=7 Hz, 2H).
[0321] MS (DCl/NH.sub.3) m/e 463 (M+H).sup.+, 480
(M+NH.sub.4).sup.+.
[0322] Elemental Analysis: calculated for
C.sub.25H.sub.19FN.sub.2O.sub.4S- .0.75 M H.sub.2O: C, 63.08; H,
4.34; N, 5.88. Found: C, 63.01; H, 4.12; N, 5.85.
EXAMPLE 17
[0323]
2-Propargyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyr-
idazinone
[0324] The title compound was prepared according to the method of
Example 7, substituting propargyl bromide for benzyl bromide.
M.p.=168-169.degree. C.
[0325] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.4 (t, J=3 Hz,
1H), 3.08 (s, 3H), 5.05 (d, J=3 Hz, 2H), 6.97 (t, J=9 Hz, 2H), 6.99
(s, 1H), 7.16 (dd, J=9 Hz, 7 Hz, 2H), 7.34 (d, J=9 Hz, 2H), 7.91
(d, J=9 Hz, 2H).
[0326] MS (DCl/NH.sub.3) m/e 383 (M+H).sup.+, 400
(M+NH.sub.4).sup.+.
[0327] Elemental Analysis: calculated for
C.sub.20H.sub.15FN.sub.2O.sub.3S- .0.25 M H.sub.2O: C, 62.08; H,
4.03; N, 7.24. Found: C, 62.15; H, 4.18; N, 7.05.
EXAMPLE 18
[0328]
2-Cyclohexyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-py-
ridazinone
[0329] The title compound was prepared according to the method of
Example 7, substituting cyclohexyl bromide for benzyl bromide.
M.p.=86-90.degree. C.
[0330] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 1.5 (m, 10H),
3.24 (s, 3H), 4.85 (m, 1H), 7.04 (s, 1H), 7.19 (m, 4H), 7.46 (d,
J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H).
[0331] MS (DCl/NH.sub.3) m/e 427 (M+H).sup.+.
[0332] Elemental Analysis calculated. for
C.sub.23H.sub.23FN.sub.2O.sub.3S- : C, 64.77; H, 5.43; N, 6.56.
Found: C, 64.52; H, 5.4; N, 6.38.
EXAMPLE 19
[0333]
2-(2-Butyn-1-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H-
)-pyridazinone
[0334] The title compound was prepared according to the method of
Example 7, substituting 1-bromo-2-butyne for benzyl bromide.
M.p.=81-82.degree. C.
[0335] .sup.1H NMR (300 MHz, d.sub.6-DMSO) 61.81 (t, J=3 Hz, 3H),
3.24 (s, 3H), 4.93 (d, J=3,2H), 7.10 (s, 1H), 7.19 (m, 4H), 7.48
(d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H).
[0336] MS (DCl/NH.sub.3) m/e 397 (M+H).sup.+.
[0337] Elemental analysis, calculated for
C.sub.21H.sub.17FN.sub.2O.sub.3S- : C, 63.62; H, 4.32; N, 7.06.
Found: C, 64.22; H, 4.36; N, 6.61.
EXAMPLE 20
[0338]
2-(Cyclobutylmethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)3-
(2)-pyridazinone
[0339] The title compound was prepared according to the method of
Example 7, substituting chloromethylcyclobutane for benzyl bromide.
M.p.=74-76.degree. C.
[0340] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 1.98 (m, 4H),
2.05 (m, 2H), 2.84 (p, J=7.5 Hz, 1H), 3.24 (s, 3H), 4.22 (d, J=7.5
Hz, 2H), 7.05 (s, 1H), 7.16 (m, 4H), 7.45 (d, J=9 Hz, 2H), 7.87 (d,
J=9 Hz, 2H).
[0341] MS (DCl/NH.sub.3) m/e 413 (M+H).sup.+.
[0342] Elemental analysis, calculated for
C.sub.22H.sub.21FN.sub.2O.sub.3S- : C, 64.06; H, 5.13; N, 6.79.
Found: C, 64.37; H, 5.26; N, 6.73.
EXAMPLE 21
[0343]
2-(3-Methylbuten-2-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl-
)-3(2H)-pyridazinone
[0344] The title compound was prepared according to the method of
Example 7, substituting 4-bromo-2-methyl-2-butene for benzyl
bromide. M.p.=71-72.degree. C.
[0345] .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 1.72 (s, 3H),
1.79 (s, 3H), 3.24 (s, 3H), 4.76 (d, J=7.5 Hz, 2H), 5.42 (m, 1H),
7.04 (s, 1H), 7.17 (m, 4H), 7.46 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz,
2H).
[0346] MS (DCl/NH.sub.3) m/e 413 (M+H).sup.+.
[0347] Elemental analysis, calculated for
C.sub.22H.sub.21FN.sub.2O.sub.3S- : C, 64.06; H, 5.13; N, 6.79.
Found: C, 64.34; H, 4.87; N, 6.51.
EXAMPLE 22
[0348]
2-(2.2.2-Trifluoroethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophen-
yl)-3(2H)-pyridazinone
[0349] The title compound is prepared according to the method of
Example 7, substituting 2-iodo-1,1,1-trifluoroethane for benzyl
bromide. M.p.=177-179.degree. C.
[0350] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.08 (s, 3H), 4.90
(q, 2H), 6.98 (t, J=9 Hz, 2H), 7.01 (s, 1H), 7.13 (dd, J=9 Hz, 7
Hz, 2H), 7.34 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H).
[0351] MS (DCl/NH.sub.3) m/e 427 (M+H).sup.+, 444
(M+NH.sub.4).sup.+.
[0352] Elemental analysis, calculated for
C.sub.19H.sub.14F.sub.3N.sub.2O.- sub.3S (0.25 hydrate): C, 52.96;
H, 3.39; N, 6.50. Found: C, 52.89; H, 3.35; N, 6.27.
EXAMPLE 23
[0353]
2-(Cyclopropylmethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-
-3(2H)-pyridazinone
[0354] The title compound was prepared according to the method of
Example 7, substituting cyclopropylmethyl bromide for benzyl
bromide. M.p.=130-132.degree. C.
[0355] .sup.1H NMR (300 MHz, CDCl.sub.3) 0.5 (m, 2H), 0.6 (m, 2H),
1.46 (m, 1H), 3.08 (s, 3H), 4.15 (d, J=7 Hz, 2H), 6.97 (s, 1H),
6.98 (d, J=9 Hz, 2H), 7.14 (dd, J=9 Hz, 7 Hz, 2H),7.35 (d, J=9 Hz,
2H),7.9 (d, J=9 Hz, 2H).
[0356] MS m/e 399 (M+H).sup.+, 416 (M+NH.sub.4).sup.+.
[0357] Elemental analysis, calculated for
C.sub.21H.sub.19FN.sub.2O.sub.3S- : C, 63.30; H, 4.80; N, 7.03.
Found: C, 63.13; H, 4.75; N, 6.94.
EXAMPLE 24
[0358]
2-Cyclopentylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3-
(2H)-pyridazinone
[0359] The title compound was prepared according to the method of
Example 7, substituting chloromethylcyclopentane for benzyl
bromide. M.p.=76-77.degree. C.
[0360] .sup.1H NMR (d.sub.6-DMSO, 300 MHz) .delta. 1.38 (m, 2H),
1.6 (m, 7H), 3.23 (s, 3H), 4.11 (d, J=7.5 Hz, 2H), 7.05 (s, 1H),
7.17 (m, 4H), 7.47 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H).
[0361] MS (DCl/NH.sub.3) m/e 427 (M+H).sup.+.
[0362] Elemental analysis, calculated for
C.sub.23H.sub.23FN.sub.2O.sub.3S- : C, 64.77; H, 5.43; N, 6.56.
Found: C, 63.96; H, 5.11; N, 6.44.
EXAMPLE 25
[0363]
2-Cyclopentyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-p-
yridazinone
[0364] The title compound was prepared according to the method of
Example 7, substituting chlorocyclopentane for benzyl bromide.
M.p.=191-192.degree. C.
[0365] .sup.1H NMR (d.sub.6-DMSO, 300 MHz) .delta. 1.65 (m, 2H),
1.85 (m, 4H), 2.05 (m, 2H), 3.24 (s, 3H), 5.39 (p, J=7.5 Hz, 1H),
7.02 (s, 1H), 7.18 (m, 4H), 7.46 (d, J=9 Hz, 2H), 7.89 (d, J=9 Hz,
2H).
[0366] MS (DCl/NH.sub.3) m/e 413 (M+H).sup.+.
[0367] Elemental analysis, calculated for
C.sub.22H.sub.21FN.sub.2O.sub.3S- : C, 64.06; H, 5.13; N, 6.79.
Found: C, 64.14; H, 5.11; N, 6.69
Prostaglandin Inhibition Determination
[0368] Compound Preparation and Administration
[0369] For oral administration, test compounds were suspended on
the day of use in 100% polyethyleneglycol (PEG 400) with a
motorized homogenizer equipped with a Teflon-coated pestle (TRI-R
Instrument, Jamaica, N.Y.).
[0370] To compare the mean responses of the treatment groups,
analysis of variance was applied. Percent inhibition values were
determined by comparing the individual treatment mean values to the
mean of the control group. Linear regression was used to estimate
IC.sub.50's/ED.sub.50's in appropriate assays.
[0371] EIA Determination of Prostaglandins
[0372] EIA reagents for prostaglandin determination were purchased
from Perseptive Diagnostics, (Cambridge, Mass.). PGE.sub.2 levels
in lavage fluids were determined after the samples were dried under
nitrogen and reconstituted with assay buffer. PGE.sub.2 levels in
enzyme assays or cell culture media were measured against standards
prepared in the same milieu. The immunoassays were conducted as
recommended by the manufacturer. The EIA was conducted in 96 well
microtiter plates (Nunc Roskilde, Denmark) and optical density was
measured using a microplate reader (Vmax, Molecular Devices Corp.,
Menlo Park, Calif.).
[0373] Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays
[0374] Inhibition of prostaglandin biosynthesis in vitro was
evaluated using recombinant human Cox-1 (r-hu Cox1) and Cox-2 (r-hu
Cox2) enzyme assays. Representative compounds dissolved in DMSO
(3.3% v/v) were preincubated with microsomes from recombinant human
Cox-1 or Cox-2 expressed in the baculovirus/Sf9 cell system
(Gierse, J. K., Hauser, S. D., Creely, D. P., Koboldt, C.,
Rangwala, S., H., Isakson, P. C., and Seibert, K. Expression and
selective inhibition of the constituitive and inducible forms of
cyclooxygenase, Biochem J. 1995, 305: 479.), together with the
cofactors phenol (2 mM) and hematin (1 .mu.M) for 60 minutes prior
to the addition of 10 .mu.M arachidonic acid. The reaction was
allowed to run for 2.5 minutes at room temperature prior to
quenching with HCl and neutralization with NaOH. PGE.sub.2
production in the presence and absence of the drug was determined
by EIA analysis. The EIA was conducted in 96 well microtiter plates
(Nunc Roskilde, Denmark) and optical density was measured using a
microplate reader (Vmax, Molecular Devices Corp., Menlo Park,
Calif.). EIA reagents for prostaglandin determination were
purchased from Perseptive Diagnostics (Cambridge, Mass.). PGE.sub.2
levels were measured against standards prepared in the same milieu.
The immunoassays were conducted as recommended by the
manufacturer.
[0375] The data illustrating the inhibition of prostaglandin
biosynthesis in vitro by compounds of this invention is shown in
Table 1. The compounds are designated by the Example Number. Column
2 shows Cox-1 percent inhibition at the particular micromolar dose
level. Column 3 shows Cox-2 percent inhibition at the particular
nanomolar dose level. Values for Cox-2 inhibition that are
parenthetical indicate IC.sub.50 values.
1TABLE 1 RHUCX1 RHUCX2 Example No. (.mu.M) (nM) 7 4 @ 100 (20) 10 2
@ 100 65 @ 100 11 19 @ 100 51 @ 100 12 8 @ 100 (740) 14 23 @ 100 66
@ 100 15 52 @ 100 (5) 17 0 @ 100 (850) 18 16 @ 100 49 @ 100 19 3 @
100 66 @ 1000 21 62 @ 100 92 @ 100 22 0 @ 100 46 @ 1000 23 24 @ 100
(250) 24 23 @ 100 87 @ 100 25 7 @ 100 42 @ 100
[0376] IL-1.beta. Induced PGE.sub.2 Production in WISH Cells
[0377] Human amnionic WISH cells were grown to 80% confluence in 48
well plates. Following removal of the growth medium and two
washings with Gey's Balanced Salt Solution, 5 ng IL-1.beta./ml
(UBI, Lake Placid, N.Y.) was added to the cells with or without
test compound in DMSO (0.01% v/v) in Neuman-Tytell Serumless Medium
(GIBCO, Grand Island, N.Y.). Following an 18 hour incubation to
allow for the maximal induction of PGHS-2, the conditioned medium
was removed and assayed for PGE.sub.2 activity by EIA analysis as
described above.
[0378] U937 (ATCC, Rockville, Md.) cells were grown in a similar
fashion to the WISH cells. After incubation, the conditioned medium
was removed and assayed for Cox-1 activity by EIA analysis as
described above.
[0379] The data illustrating the inhibition of prostaglandin
biosynthesis in vitro by compounds of this invention is shown in
Table 2. U937 values indicate percent inhibition at the particular
micromolar dose level while parenthetical values indicate IC.sub.50
values. Wish cell values indicate Cox-2 pecent inhibition at the
particular micromolar dose level.
2TABLE 2 Example No. U937 (.mu.M) Wish (mM) 7 (0.87) (0.02) 10 62 @
10 (0.11) 14 42 @ 1 34 @ 0.00001 15 33 @ 0.01 43 @ 0.001 17 41 @ 10
54 @ 1 20 60 @ 10 (0.13) 21 80 @ 10 (0.00004) 23 30 @ 10 62 @ 1
[0380] Carrageenan Induced Paw Edema (CPE) in Rats
[0381] Hindpaw edema was induced in male rats as described by
Winter et al, Proc. Soc. Exp. Biol. Med., 1962, 111, 544. Briefly,
male Sprague-Dawley rats weighing between 170 and 190 g were
administered test compounds orally 1 hour prior to the subplantar
injection of 0.1 ml of 1% sodium carrageenan (lambda carrageenan,
Sigma Chemical Co., St Louis, Mo.) into the right hindpaw. Right
paw volumes (ml) were measured immediately following injection of
carrageenan for baseline volume measurements using a Buxco
plethysmograph (Buxco Electronics, Inc., Troy, N.Y.). Three hours
after the injection of carrageenan, right paws were remeasured and
paw edema calculated for each rat by subtracting the zero time
reading from the 3 hour reading. Data are reported as mean percent
inhibition +/-SEM. Statistical significance of results was analyzed
by Dunnetts multiple comparison test where p<0.05 was considered
statistically significant.
[0382] Rat Carrageenan Pleural Inflammation Model (CIP)
[0383] Pleural inflammation was induced in male adrenalectomized
Sprague-Dawley rats following the method of Vinegar et al., Fed.
Proc. 1976, 35, 2447-2456. Animals were orally dosed with
experimental compounds, in 0.2% HPMC, 30 minutes prior to the
intrapleural injection of 2% lambda carrageenan (Sigma Chemical
Co., St. Louis Mo.). Four hours later the animals were euthanized
and the pleural cavities ravaged with ice cold saline. The lavage
fluid was then added to two volumes of ice cold methanol (final
methanol concentration 66%) to lyse cells and precipitate protein.
Eicosanoids were determined by EIA as described above. The data
illustrating the inhibition of prostaglandin biosynthesis in vivo
by the compounds of this invention is shown in Table 3. Values
reported are percent inhibition at 10 milligrams per kilogram body
weight.
3 TABLE 3 CIP Inh @ Example No. 10 mpk 7 22 23 41
[0384] Pharmaceutical Compositions
[0385] The present invention also provides pharmaceutical
compositions which comprise compounds of the present invention
formulated together with one Or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions of the present
invention comprise a therapeutically effective amount of a compound
of the present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the procedures and
judgements well known to one skilled in the art. The pharmaceutical
compositions of this invention can be administered to humans and
other animals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally, topically (as by powders,
ointments, or drops), bucally, or as an oral or nasal spray.
[0386] The compounds of the present invention may be potentially
useful in the treatment of several illness or disease states such
as inflammatory diseases, dysmennorhea, asthma, premature labor,
osteoporosis, and ankylosing spondolitis. Current Drugs Ltd, ID
Patent Fast Alert, AG16, May 9, 1997.
[0387] The compounds of the present invention may also be
potentially useful in the treatment of cancers, and in particular,
colon cancer. Proc. Natl. Acad. Sci., 94, pp. 3336-3340, 1997.
[0388] The compounds of the present invention may be useful by
providing a pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt, ester,
or prodrug thereof, and a pharmaceutrically acceptable carrier.
[0389] The compounds of the present invention may be useful by
providing a pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of a
compound of formula 11 or a pharmaceutically acceptable salt,
ester, or prodrug thereof, and a pharmaceutrically acceptable
carrier.
[0390] The compounds of the present invention may be useful by
providing a pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of a
compound of formula III or a pharmaceutically acceptable salt,
ester, or prodrug thereof, and a pharmaceutrically acceptable
carrier.
[0391] The compounds of the present invention may be useful by
providing pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of a
compound of formula IV or a pharmaceutically acceptable salt,
ester, or prodrug thereof, and a pharmaceutrically acceptable
carrier.
[0392] In addition, the compounds of the present invention may be
useful by providing a method for inhibiting prostaglandin
biosynthesis comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
[0393] The compounds of the present invention may be useful by
providing a method for inhibiting prostaglandin biosynthesis
comprising administering to a mammal in need of such treatment a
therapeutically effective amount a compound of formula II or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0394] The compounds of the present invention may be useful by
providing a method for inhibiting prostaglandin biosynthesis
comprising administering to a mammal in need of such treatment a
therapeutically effective amount compound of formula III or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0395] The compounds of the present invention may be useful by
providing a method for inhibiting prostaglandin biosynthesis
comprising administering to a mammal in need of such treatment a
therapeutically effective amount a compound of formula IV or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0396] In addition, the compounds of the present invention may be
useful by providing a method for treating pain, fever, inflamation,
rheumatoid arthritis, osteoarthritis, and cancer comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of formula I.
[0397] In addition, the compounds of the present invention may be
useful by providing a method for treating pain, fever, inflamation,
rheumatoid arthritis, osteoarthritis, and cancer comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of formula II.
[0398] In addition, the compounds of the present invention may be
useful by providing a method for treating pain, fever, inflamation,
rheumatoid arthritis, osteoarthritis, and cancer comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of formula III.
[0399] In addition, the compounds of the present invention may be
useful by providing a method for treating pain, fever, inflamation,
rheumatoid arthritis, osteoarthritis, and cancer comprising
administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of formula IV.
[0400] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (such as, for example, cottonseed,
groundnut, corn, germ, olive, castor, sesame oils, and the like),
glycerol, tetrahydrofurfuryl alcohol, poly-ethyl-ene glycols and
fatty acid esters of sorbitan, and mixtures thereof. Besides inert
diluents, the oral compositions can also include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and perfuming agents.
[0401] Injectable preparations, such as, for example, sterile
injectable aqueous or oleaginous suspensions may be formulated
according to the known art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution, suspension or emulsion
in a nontoxic parenterally acceptable diluent or solvent, such as,
for example, a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, isotonic sodium chloride solution, and the like. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
can be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid are used in the
preparation of injectable preparations.
[0402] The injectable formulations can be sterilized by any method
known in the art, such as, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents
in the form of sterile solid compositions which can be dissolved or
dispersed in sterile water or other sterile injectable medium prior
to use.
[0403] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsulated matrices of the
drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides) Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions which are compatible with body tissues.
[0404] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and thus melt in the rectum or vaginal cavity
and release the active compound.
[0405] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is usually mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as, for
example, sodium citrate or dicalcium phosphate and/or a) fillers or
extenders such as, for example, starches, lactose, sucrose,
glucose, mannitol, and silicic acid, b) binders such as, for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as,
for example, glycerol, d) disintegrating agents such as, for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents such as, for example, paraffin, f) absorption
accelerators such as, for example, quaternary ammonium compounds,
g) wetting agents such as, for example, cetyl alcohol and glycerol
monostearate, h) absorbents such as, for example, kaolin and
bentonite clay, and) lubricants such as, for example, talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering
agents.
[0406] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients such as, for example, lactose or milk sugar as well as
high molecular weight polyethylene glycols and the like.
[0407] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using excipients
such as, for example, lactose or milk sugar as well as high
molecular weight polethylene glycols and the like.
[0408] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulation art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as, for example, sucrose, lactose or starch. Such dosage forms may
also comprise, as is normal practice, additional substances other
than inert diluents, e.g., tableting lubricants and other tableting
aids such as, for example, magnesium stearate and microcrystalline
cellulose. In the case of capsules, tablets and pills, the dosage
forms may also comprise buffering agents. They may optionally
contain opacifying agents and can also be of a composition that
they release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0409] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0410] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as, for example, animal and vegetable fats, oils, waxes, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene glycols,
silicones, bentonites, silicic acid, talc and zinc oxide, or
mixtures thereof.
[0411] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as, for example, lactose, talc,
silicic acid, aluminum hydroxide, calcium silicates and polyamide
powder, or mixtures of these substances. Sprays can additionally
contain customary propellants such as chlorofluorohydrocarbons.
[0412] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in a suitable
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0413] According to the methods of treatment of the present
invention, a patient, such as a human or mammal, is treated by
administering to the patient a therapeutically effective amount of
a compound of the invention, in such amounts and for such time as
is necessary to achieve the desired result. By a therapeutically
effective amount" of a compound of the invention is meant a
sufficient amount of the compound to provide the relief desired, at
a reasonable benefit/risk ratio applicable to any medical
treatment. It will be understood, however, that the total daily
usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of
sound medical judgment. The specific therapeutically effective dose
level for any particular patient will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed;
and like factors well known in the medical arts.
[0414] The total daily dose of the compounds of this invention
administered to a human or other mammal in single or in divided
doses can be in amounts, for example, from 0.001 to about 1000
mg/kg body weight daily or more preferably from about 0.1 to about
100 mg/kg body weight for oral administration or 0.01 to about 10
mg/kg for parenteral administration daily. Single dose compositions
may contain such amounts or submultiples thereof to make up the
daily dose.
[0415] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0416] The reagents required for the synthesis of the compounds of
the invention are readily available from a number of commercial
sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma
Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp.
(Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, Mass. 01835-9953);
Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster
Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical
Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901);
Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not
commercially available can be prepared by employing known methods
from the chemical literature.
* * * * *