U.S. patent application number 12/631360 was filed with the patent office on 2010-04-08 for heterotricyclic metalloprotease inhibitors.
This patent application is currently assigned to ALANTOS PHARMACEUTICALS HOLDINGS, INC.. Invention is credited to Harald Bluhm, Carine Chevrier, Hongbo Deng, Brian M. Gallagher, JR., Christian Gege, Matthias Hochgurtel, Matthias Schneider, Irving Sucholeiki, Arthur G. Taveras.
Application Number | 20100087420 12/631360 |
Document ID | / |
Family ID | 39161115 |
Filed Date | 2010-04-08 |
United States Patent
Application |
20100087420 |
Kind Code |
A1 |
Gege; Christian ; et
al. |
April 8, 2010 |
Heterotricyclic Metalloprotease Inhibitors
Abstract
The present invention relates generally to azatriocyclic
containing pharmaceutical agents, and in particular, to
azatricyclic metalloprotease inhibiting compounds. More
particularly, the present invention provides a new class of
azatricyclic MMP-3, MMP-8 and/or MMP-13 inhibiting compounds, that
exhibit an increased potency and selectivity in relation to
currently known MMP-13, MMP-8 and MMP-3 inhibitors.
Inventors: |
Gege; Christian; (Mauer,
DE) ; Chevrier; Carine; (Muchen, DE) ;
Schneider; Matthias; (Offenburg, DE) ; Bluhm;
Harald; (Arnsberg-Neheim, DE) ; Hochgurtel;
Matthias; (Schriesheim, DE) ; Deng; Hongbo;
(Southborough, MA) ; Gallagher, JR.; Brian M.;
(Merrimac, MA) ; Sucholeiki; Irving; (Winchester,
MA) ; Taveras; Arthur G.; (Southborough, MA) |
Correspondence
Address: |
AMGEN INC.
MAIL STOP 28-2-C, ONE AMGEN CENTER DRIVE
THOUSAND OAKS
CA
91320-1799
US
|
Assignee: |
ALANTOS PHARMACEUTICALS HOLDINGS,
INC.
Thousand Oaks
CA
|
Family ID: |
39161115 |
Appl. No.: |
12/631360 |
Filed: |
December 4, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11986603 |
Nov 20, 2007 |
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12631360 |
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60860195 |
Nov 20, 2006 |
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Current U.S.
Class: |
514/211.09 ;
514/215; 514/230.5; 514/232.8; 514/257; 514/267; 540/552; 540/586;
544/105; 544/115; 544/247; 544/250 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 471/04 20130101; A61P 9/10 20180101; A61P 19/02 20180101; C07D
413/12 20130101; C07D 487/04 20130101; C07D 495/22 20130101; C07D
239/88 20130101; C07D 491/04 20130101; C07D 513/04 20130101; C07D
401/12 20130101; C07D 495/04 20130101; C07D 498/04 20130101; C07D
495/14 20130101 |
Class at
Publication: |
514/211.09 ;
544/250; 544/247; 540/586; 544/115; 544/105; 540/552; 514/215;
514/232.8; 514/230.5; 514/267; 514/257 |
International
Class: |
A61K 31/553 20060101
A61K031/553; C07D 495/04 20060101 C07D495/04; C07D 495/14 20060101
C07D495/14; C07D 495/22 20060101 C07D495/22; A61K 31/55 20060101
A61K031/55; A61K 31/5377 20060101 A61K031/5377; A61K 31/519
20060101 A61K031/519 |
Claims
1. A compound having Formula (I): ##STR01297## wherein R.sup.1 in
each occurrence is independently selected from hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl,
heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl,
cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl
fused heteroaryl, heterocycloalkyl fused heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl,
heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl,
arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl,
heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl,
and heterocycloalkyl fused heteroarylalkyl, wherein R.sup.1 is
optionally substituted one or more times, or wherein R.sup.1 is
optionally substituted by one R.sup.16 group and optionally
substituted by one or more R.sup.9 groups; R.sup.2 is selected from
hydrogen and alkyl, wherein alkyl is optionally substituted one or
more times or R.sup.1 and R.sup.2 when taken together with the
nitrogen to which they are attached complete a 3- to 8-membered
ring containing carbon atoms and optionally containing a heteroatom
selected from O, S(O).sub.x, or NR.sup.50 and which is optionally
substituted one or more times; R.sup.4 in each occurrence is
independently selected from R.sup.10, hydrogen, alkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF.sub.3,
(C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.10,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl, wherein each R.sup.4 group
is optionally substituted one or more times, or wherein each
R.sup.4 group is optionally substituted by one or more R.sup.14
groups, or wherein optionally two R.sup.4 groups, when taken
together with the nitrogen or carbon to which they are attached
complete a 3- to 8-membered saturated ring or multicyclic ring or
unsaturated ring containing carbon atoms and optionally containing
one or more heteroatom independently selected from O, S(O).sub.x,
N, or NR.sup.50 and which is optionally substituted one or more
times, or optionally two R.sup.4 groups together at one saturated
carbon atom form .dbd.O, .dbd.S, .dbd.NR.sup.10 or .dbd.NOR.sup.10;
R.sup.5 is independently selected from hydrogen, alkyl,
C(O)NR.sup.10R.sup.11, aryl, arylalkyl, SO.sub.2NR.sup.10R.sup.11
and C(O)OR.sup.10 wherein alkyl, aryl and arylalkyl are optionally
substituted one or more times; R.sup.8 is independently selected
from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, R.sup.10 and NR.sup.10R.sup.11 wherein alkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally
substituted one or more times; R.sup.9 in each occurrence is
independently selected from R.sup.10, hydrogen, alkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, halo, CHF.sub.2, CF.sub.3,
OR.sup.10, SR.sup.10, COOR.sup.10, CH(CH.sub.3)CO.sub.2H,
(C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-P(O).sub.2OH,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
S(O).sub.2NR.sup.10-alkyl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.11,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl, wherein each R.sup.9 group
is optionally substituted, or wherein each R.sup.9 group is
optionally substituted by one or more R.sup.14 groups; R.sup.19 and
R.sup.11 in each occurrence are independently selected from
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl,
aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl,
wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl,
heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl,
fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are
optionally substituted one or more times, or R.sup.10 and R.sup.11
when taken together with the nitrogen to which they are attached
complete a 3- to 8-membered ring containing carbon atoms and
optionally containing a heteroatom selected from O, S(O).sub.x, or
NR.sup.50 and which is optionally substituted one or more times;
R.sup.14 is independently selected from hydrogen, alkyl, arylalkyl,
cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo,
wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and
heterocyclylalkyl are optionally substituted one or more times.
R.sup.16 is selected from cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused
aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl,
spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused
arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused
heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and
(ii): ##STR01298## wherein cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused
aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl,
spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused
arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused
heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are
optionally substituted one or more times; R.sup.17 is selected from
R.sup.1, R.sup.4 and R.sup.21; R.sup.21 is a bicyclic or tricyclic
fused ring system, wherein at least one ring is partially
saturated, and wherein R.sup.21 is optionally substituted one or
more times, or wherein R.sup.21 is optionally substituted by one or
more R.sup.9 groups; R.sup.30 is selected from alkyl and
(C.sub.0-C.sub.6)-alkyl-aryl, wherein alkyl and aryl are optionally
substituted; R.sup.50 in each occurrence is independently selected
from hydrogen, alkyl, aryl, heteroaryl, C(O)R.sup.80,
C(O)NR.sup.80R.sup.81, SO.sub.2R.sup.80 and
SO.sub.2NR.sup.80R.sup.81, wherein alkyl, aryl, and heteroaryl are
optionally substituted one or more times; R.sup.80 and R.sup.81 in
each occurrence are independently selected from hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,
heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein
alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,
heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl,
arylalkyl, heteroarylalkyl and aminoalkyl are optionally
substituted, or R.sup.80 and R.sup.81 when taken together with the
nitrogen to which they are attached complete a 3- to 8-membered
ring containing carbon atoms and optionally a heteroatom selected
from O, S(O).sub.x, --NH, and --N(alkyl) and which is optionally
substituted one or more times; E is selected from a bond,
CR.sup.10R.sup.11, O, NR.sup.5, S, S.dbd.O, S(.dbd.O).sub.2,
C(.dbd.O), N(R.sup.10)(C.dbd.O),
(C.dbd.O)N(R.sup.10)N(R.sup.10)S(.dbd.O).sub.2,
S(.dbd.O).sub.2N(R.sup.10), C.dbd.N--OR.sup.11,
--C(R.sup.10R.sup.11)C(R.sup.10R.sup.11, CH.sub.2--W.sup.1-- and
##STR01299## L.sub.a is independently selected from CR.sup.9 and N;
L.sub.b is independently selected from C and N with the proviso,
that both L.sub.b are not N, and that the bond between L.sub.b and
L.sub.b is optionally a double bond only if both L.sub.b are C;
L.sub.c is selected from a single bond or an acyclic, straight or
branched, saturated or unsaturated hydrocarbon chain having 1 to 10
carbon atoms, optionally containing 1 to 3 groups independently
selected from --S--, --O--, NR.sup.10--, --NR.sup.10CO--,
--CONR.sup.10--, --S(O).sub.x--, --SO.sub.2NR.sup.10--,
--NR.sup.10SO.sub.2--, NR.sup.10SO.sub.2NR.sup.10--,
--NR.sup.10CONR.sup.10--, --NR.sup.10C(O)O--, which replace a
corresponding number of non-adjacent carbon atoms, and wherein the
hydrocarbon chain is optionally substituted one or more times; Q is
a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl
or a 5- or 6-membered ring selected from aryl and heteroaryl,
wherein Q is optionally substituted one or more times, or wherein Q
is optionally substituted one or more times with R.sup.4, or
wherein Q is fused via two of its adjacent atoms, which are
selected from N and C with a further cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which
is optionally independently substituted one or more times; U is
selected from)C(R.sup.5R.sup.10, NR.sup.5, O, S, S.dbd.O and
S(.dbd.O).sub.2; W.sup.1 is selected from O, NR.sup.5, S, S.dbd.O,
S(.dbd.O).sub.2, N(R.sup.10)(C.dbd.O), N(R.sup.10)S(.dbd.O).sub.2
and S(.dbd.O).sub.2N(R.sup.10); X is selected from a bond and
(CR.sup.10R.sup.11).sub.wE(CR.sup.10R.sup.11).sub.w; X.sup.1 is
independently selected from O, S, NR.sup.10, N--CN, NCOR.sup.10,
N--NO.sub.2, or N--SO.sub.2R.sup.10; g and h are independently
selected from 0-2; w is selected from 0-4; x is selected from 0 to
2; y is selected from 1 and 2; the dotted line optionally
represents a double bond; and N-oxides, pharmaceutically acceptable
salts, prodrugs, formulations, polymorphs, tautomers, racemic
mixtures and stereoisomers thereof.
2. A compound according to claim 1, wherein Q is phenyl or
thiophene that is fused via two of its adjacent atoms with a
further cycloalkyl, heterocycloalkyl, bicycloalkyl,
hetero-bicycloalkyl, aryl and heteroaryl system, which is
optionally independently substituted one or more times.
3. A compound according to claim 2, wherein L.sub.a is N.
4. A compound according to claim 2, wherein: L.sub.a is N; and
L.sub.b is C.
5. A compound according to claim 1, selected from: ##STR01300##
##STR01301## ##STR01302##
6. A compound according to claim 5, wherein R.sup.8 is H.
7. A compound according to claim 5, wherein R.sup.17 is selected
from ##STR01303## wherein: R.sup.6 is selected from R.sup.9,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR.sup.10,
CH(CH.sub.3)CO.sub.2H, (C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-P(O).sub.2OH,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.11CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
S(O).sub.2NR.sup.10-alkyl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.11,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl, wherein each R.sup.6 group
is optionally substituted by one or more R.sup.14 groups; R.sup.9
is independently selected from hydrogen, alkyl, halo, CHF.sub.2,
CF.sub.3, OR.sup.10, NR.sup.10R.sup.11, NO.sub.2, and CN, wherein
alkyl is optionally substituted one or more times.
8. A compound according to claim 5, wherein R.sup.1 is selected
from: ##STR01304## wherein: R.sup.18 is independently selected from
hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl,
aryl, heteroaryl, OH, halo, CN, C(O)NR.sup.10R.sup.11,
CO.sub.2R.sup.10, OR.sup.10, OCF.sub.3, OCHF.sub.2,
NR.sup.10CONR.sup.10R.sup.11, NR.sup.10 COR.sup.11,
NR.sup.10SO.sub.2NR.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11 and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl
are optionally substituted one or more times; R.sup.25 is selected
from hydrogen, alkyl, cycloalkyl, C(O)NR.sup.10R.sup.11 and
haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally
substituted one or more times; B.sub.1 is selected from NR.sup.10,
O and S; D.sup.2, G.sup.2, L.sup.2, M.sup.2 and T.sup.2 are
independently selected from CR.sup.18 and N; and Z is a 5- to
8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl
and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and
heteroaryl are optionally substituted one or more times.
9. The compound according to claim 6, wherein R.sup.1 is selected
from: ##STR01305## ##STR01306## ##STR01307## ##STR01308##
##STR01309## ##STR01310## ##STR01311##
10. A compound according to claim 5, wherein R.sup.1 is selected
from: ##STR01312## ##STR01313## wherein: R.sup.12 and R.sup.13 are
independently selected from hydrogen, alkyl and halo, wherein alkyl
is optionally substituted one or more times, or optionally R.sup.12
and R.sup.13 together form .dbd.O, .dbd.S, .dbd.NR.sup.10 or
.dbd.NOR.sup.10; R.sup.18 is independently selected from hydrogen,
alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl,
heteroaryl, OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10,
OR.sup.10, OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
NR.sup.10SO.sub.2NR.sup.10R.sup.11, SO.sub.2NR.sup.10R.sup.11 and
NR.sup.10R.sup.11, wherein alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally
substituted one or more times; R.sup.19 is independently selected
from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,
alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR.sup.10R.sup.11,
CO.sub.2R.sup.10, OR.sup.10, OCF.sub.3, OCHF.sub.2,
NR.sup.10CONR.sup.10R.sup.11, NR.sup.10COR.sup.11,
NR.sup.10SO.sub.2R.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11 and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and
heteroaryl are optionally substituted one or more times, or
optionally two R.sup.19 groups together at one carbon atom form
.dbd.O, .dbd.S, .dbd.NR.sup.10 or .dbd.NOR.sup.10; R.sup.25 is
selected from hydrogen, alkyl, cycloalkyl, C(O)NR.sup.10R.sup.11
and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are
optionally substituted one or more times; J and K are independently
selected from CR.sup.10R.sup.18, NR.sup.10, O and S(O).sub.x;
A.sub.1 is selected from NR.sup.10, O and S(O).sub.x; and D.sup.2,
G.sup.2, J.sup.2, L.sup.2, M.sup.2 and T.sup.2 are independently
selected from CR.sup.18 and N.
11. A compound according to claim 6, wherein R.sup.1 is selected
from: ##STR01314## ##STR01315## ##STR01316## ##STR01317##
##STR01318##
12. A compound according to claim 5, wherein R.sup.1 is selected
from: ##STR01319## ##STR01320## wherein: R.sup.18 is independently
selected from hydrogen, alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN,
C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10, OCF.sub.3,
OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11, NR.sup.10COR.sup.11,
NR.sup.10SO.sub.2R.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11, and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and
heteroaryl are optionally substituted one or more times; R.sup.19
is independently selected from hydrogen, alkyl, haloalkyl,
cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo,
CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10, OCF.sub.3,
OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11, NR.sup.10COR.sup.11,
NR.sup.10SO.sub.2R.sup.11, NR.sup.10SO.sub.2NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11 and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and
heteroaryl are optionally substituted one or more times, or
optionally two R.sup.19 groups together at one carbon atom form
.dbd.O, .dbd.S, .dbd.NR.sup.10 or .dbd.NOR.sup.10; R.sup.25 is
selected from hydrogen, alkyl, cycloalkyl, CONR.sup.10R.sup.11 and
haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally
substituted one or more times; L.sup.2, M.sup.2, and T.sup.2 are
independently selected from CR.sup.18 and N; D.sup.3, G.sup.3,
L.sup.3, M.sup.3, and T.sup.3 are independently selected from N,
CR.sup.18, (i) and (ii) ##STR01321## with the proviso that one of
L.sup.3, M.sup.3, T.sup.3, D.sup.3, and G.sup.3 is (i) or (ii);
B.sub.1 is selected from the group consisting of NR.sup.10, O and
S(O).sub.x; and Q.sup.2 is a 5- to 8-membered ring selected from
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is
optionally substituted one or more times with R.sup.19.
13. A compound according to claim 6, wherein R.sup.1 is selected
from: ##STR01322## ##STR01323## ##STR01324##
14. A compound according to claim 6, wherein R.sup.1 is selected
from: ##STR01325## ##STR01326## ##STR01327##
15. A compound according to claim 6, wherein R.sup.1 is selected
from: ##STR01328##
16. A compound according to claim 1, having the structure:
##STR01329## ##STR01330## ##STR01331## ##STR01332## ##STR01333##
##STR01334## or N-oxides, pharmaceutically acceptable salts,
prodrugs, formulations, polymorphs, tautomers, racemic mixtures and
stereoisomers thereof.
17. A pharmaceutical composition comprising an effective amount of
a compound according to claim 1.
18. A method of treating a metalloprotease mediated disease,
comprising administering to a subject in need of such treatment an
effective amount of a compound according to claim 1.
19. The method according to claim 18, wherein the disease is
selected from rheumatoid arthritis, osteoarthritis, inflammation,
atherosclerosis and multiple sclerosis.
20. A pharmaceutical composition comprising: A) an effective amount
of a compound selected from: a compound according to claim 1; B) a
pharmaceutically acceptable carrier; and C) a drug, agent or
therapeutic selected from: (a) a disease modifying antirheumatic
drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2
selective inhibitor; (d) a COX-1 inhibitor; (e) an
immunosuppressive; (f) a steroid; (g) a biological response
modifier; and (h) a small molecule inhibitor of pro-inflammatory
cytokine production.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. Non
Provisional application Ser. No. 11/986,603, filed Nov. 20, 2007,
which claims the benefit of U.S. Provisional Application No.
60/860,195, filed Nov. 20, 2006.
FIELD OF THE INVENTION
[0002] The present invention relates generally to amide containing
azatricyclic metalloprotease inhibiting compounds, and more
particularly to azatricyclic amide MMP-13, MMP-8, MMP-3 and MMP-2
inhibiting compounds.
BACKGROUND OF THE INVENTION
[0003] Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a
disintegrin and metalloproteinase with thrombospondin motif) are a
family of structurally related zinc-containing enzymes that have
been reported to mediate the breakdown of connective tissue in
normal physiological processes such as embryonic development,
reproduction, and tissue remodelling. Over-expression of MMPs and
aggrecanases or an imbalance between extracellular matrix synthesis
and degradation has been suggested as factors in inflammatory,
malignant and degenerative disease processes. MMPs and aggrecanases
are, therefore, targets for therapeutic inhibitors in several
inflammatory, malignant and degenerative diseases such as
rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis,
multiple sclerosis, gingivitis, corneal epidermal and gastric
ulceration, atherosclerosis, neointimal proliferation (which leads
to restenosis and ischemic heart failure) and tumor metastasis.
[0004] The ADAMTSs are a group of proteases that are encoded in 19
ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain
enzymes whose functions include collagen processing, cleavage of
the matrix proteoglycans, inhibition of angiogenesis and blood
coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis
Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory
Anti-Allergy Agents 2005, 4, 251-264).
[0005] The mammalian MMP family has been reported to include at
least 20 enzymes (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3
(MMP-13) is among three collagenases that have been identified.
Based on identification of domain structures for individual members
of the MMP family, it has been determined that the catalytic domain
of the MMPs contains two zinc atoms; one of these zinc atoms
performs a catalytic function and is coordinated with three
histidines contained within the conserved amino acid sequence of
the catalytic domain. MMP-13 is over-expressed in rheumatoid
arthritis, osteoarthritis, abdominal aortic aneurysm, breast
carcinoma, squamous cell carcinomas of the head and neck, and
vulvar squamous cell carcinoma. The principal substrates of MMP-13
are fibrillar collagens (types I, II, III) and gelatins,
proteoglycans, cytokines and other components of ECM (extracellular
matrix).
[0006] The activation of the MMPs involves the removal of a
propeptide, which features an unpaired cysteine residue complexed
with the catalytic zinc (II) ion. X-ray crystal structures of the
complex between MMP-3 catalytic domain and TIMP-1 and MMP-14
catalytic domain and TIMP-2 also reveal ligation of the catalytic
zinc (II) ion by the thiol of a cysteine residue. The difficulty in
developing effective MMP inhibiting compounds comprises several
factors, including choice of selective versus broad-spectrum MMP
inhibitors and rendering such compounds bioavailable via an oral
route of administration.
[0007] MMP-3 (stromelysin-1; transin-1) is another member of the
MMP family (FASEB J. 1991, 5, 2145-2154). Human MMP-3 was initially
isolated from cultured human synoviocytes. It is also expressed by
chondrocytes and has been localized in OA cartilage and synovial
tissues (Am. J. Pathol. 1989, 135, 1055-64).
[0008] MMP-3 is produced by basal keratinocytes in a variety of
chronic ulcers. MMP-3 mRNA and Protein were detected in basal
keratinocytes adjacent to but distal from the wound edge in what
probably represents the sites of proliferating epidermis. MMP-3 may
thus prevent the epidermis from healing (J. Clin. Invest. 1994, 94,
79-88).
[0009] MMP-3 serum protein levels are significantly elevated in
patients with early and long-term rheumatoid arthritis (Arthritis
Rheum. 2000, 43, 852-8) and in osteoarthritis patients (Clin.
Orthop. Relat. Res. 2004, 428, 272-85) as well as in other
inflammatory diseases like systemic lupus erythematosis and
ankylosing spondylitis (Rheumatology 2006, 45, 414-20).
[0010] MMP-3 acts on components of the ECM as aggrecan,
fibronectin, gelatin, laminin, elastin, fibrillin and others and on
collagens of type III, IV, V, VII, IX, X (Clin. Orthop. Relat. Res.
2004, 428, 272-85). On collagens of type II and IX, MMP-3 exhibits
telopeptidase activity (Arthritis Res. 2001, 3, 107-13; Clin.
Orthop. Relat. Res. 2004, 427, S118-22). MMP-3 can activate other
MMP family members such as MMP-1, MMP-7, MMP-8, MMP-9 and MMP-13
(Ann. Rheum. Dis. 2001, 60 Suppl 3:iii62-7).
[0011] MMP-3 is involved in the regulation of cytokines and
chemokines by releasing TGF.beta.1 from the ECM, activating
TNF.alpha., inactivating IL-1.beta. and releasing IGF (Nat. Rev.
Immunol. 2004, 4, 617-29). A potential role for MMP-3 in the
regulation of macrophage infiltration is based on the ability of
the enzyme to convert active MCP species into antagonistic peptides
(Blood 2002, 100, 1160-7).
[0012] MMP-8 (collagenase-2; neutrophil collagenase; EC 3.4.24.34)
is another member of the MMP family (Biochemistry 1990, 29,
10628-34). Human MMP-8 was initially located in human neutrophils
(Biochemistry 1990, 29, 10620-7). It is also expressed by
macrophages, human mucosal keratinocytes, bronchial epithelial
cells, ginigival fibroblasts, resident synovial and articular
chondrodrocytes mainly in the course of inflammatory conditions
(Cytokine & Growth Factor Rev. 2006, 17, 217-23).
[0013] The activity of MMP-8 is tightly regulated and mostly
limited to the sites of inflammation. MMP-8 is expressed and stored
as an inactive pro-enzyme in the granules of the neutrophils. Only
after the activation of the neutrophils by proinflammatory
mediators, MMP-8 is released and activated to exert its
function.
[0014] MMP-8 plays a key role in the migration of immune cells to
the sites of inflammation. MMP-8 degrades components of the
extracellular matrix (ECM) such as collagen type I, II, III, VII,
X, cartilage aggrecan, laminin-5, nidogen, fibronectin,
proteoglycans and tenascin, thereby facilitating the cells
migration through the ECM barrier. MMP-8 also influences the
biological activity of its substrates. Through proteolytic
processing of the chemokines IL-8, GCP-2, ENA-78, MMP-8 increases
the chemokines ability to activate the infiltrating immune cells.
While MMP-8 inactivates the serine protease inhibitor alpha-1
antitrypsin through its cleavage (Eur. J. Biochem. 2003, 270,
3739-49; PloS One 2007, 3, 1-10; Cytokine & Growth Factor Rev.
2006, 17, 217-23).
[0015] MMP-8 has been implicated in the pathogenesis of several
chronic inflammatory diseases characterized by the excessive influx
and activation of neutrophils, including cystic fibrosis (Am. J.
Resprir. Critic. Care Med. 1994, 150, 818-22), rheumatoid arthritis
(Clin. Chim. Acta 1996, 129-43), chronic periodontal disease
(Annals Med. 2006, 38, 306-321) and chronic wounds (J. Surg. Res.
1999, 81, 189-195).
[0016] In osteoarthritis patients, MMP-8 protein expression is
significantly elevated in inflamed human articular cartilage in the
knee and ankle joints (Lab Invest. 1996, 74, 232-40; J. Biol. Chem.
1996, 271, 11023-6).
[0017] The levels of activated MMP-8 in BALF is an indicator of the
disease severity and correlates with the airway obstruction in
patients with asthma, COPD, pulmonary emphysema and bronchiectasis
(Lab Invest. 2002, 82, 1535-45; Am. J. Respir. Crit. Care Med.
1999, 159, 1985-91; Respir. Med. 2005, 99, 703-10; J. Pathol. 2001,
194, 232-38).
SUMMARY OF THE INVENTION
[0018] The present invention relates to a new class of azatricyclic
amide containing pharmaceutical agents which inhibits
metalloproteases. In particular, the present invention provides a
new class of metalloprotease inhibiting compounds that exhibit
potent MMP-13 inhibiting activity and/or activity towards MMP-8,
MMP-3 and MMP-2.
[0019] The present invention provides several new classes of amide
containing azatricyclic metalloprotease compounds, which are
represented by the following general formula:
##STR00001##
[0020] wherein all variables in the preceding Formula (I) are as
defined hereinbelow.
[0021] The azatricyclic metalloprotease inhibiting compounds of the
present invention may be used in the treatment of metalloprotease
mediated diseases, such as rheumatoid arthritis, osteoarthritis,
abdominal aortic aneurysm, cancer (e.g. but not limited to
melanoma, gastric carcinoma or non-small cell lung carcinoma),
inflammation, atherosclerosis, multiple sclerosis, chronic
obstructive pulmonary disease, ocular diseases (e.g. but not
limited to ocular inflammation, retinopathy of prematurity, macular
degeneration with the wet type preferred and corneal
neovascularization), neurologic diseases, psychiatric diseases,
thrombosis, bacterial infection, Parkinson's disease, fatigue,
tremor, diabetic retinopathy, vascular diseases of the retina,
aging, dementia, cardiomyopathy, renal tubular impairment,
diabetes, psychosis, dyskinesia, pigmentary abnormalities,
deafness, inflammatory and fibrotic syndromes, intestinal bowel
syndrome, allergies, Alzheimers disease, arterial plaque formation,
oncology, periodontal, viral infection, stroke, atherosclerosis,
cardiovascular disease, reperfusion injury, trauma, chemical
exposure or oxidative damage to tissues, chronic wound healing,
wound healing, hemorroid, skin beautifying, pain, inflammatory
pain, bone pain and joint pain, acne, acute alcoholic hepatitis,
acute inflammation, acute pancreatitis, acute respiratory distress
syndrome, adult respiratory disease, airflow obstruction, airway
hyperresponsiveness, alcoholic liver disease, allograft rejections,
angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic
dermatitis, bronchiectasis, bronchiolitis, bronchiolitis
obliterans, burn therapy, cardiac and renal reperfusion injury,
celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS
vasculitis, colds, contusions, cor pulmonae, cough, Crohn's
disease, chronic bronchitis, chronic inflammation, chronic
pancreatitis, chronic sinusitis, crystal induced arthritis, cystic
fibrosis, delayted type hypersensitivity reaction, duodenal ulcers,
dyspnea, early transplantation rejection, emphysema, encephalitis,
endotoxic shock, esophagitis, gastric ulcers, gingivitis,
glomerulonephritis, glossitis, gout, graft vs. host reaction, gram
negative sepsis, granulocytic ehrlichiosis, hepatitis viruses,
herpes, herpes viruses, HIV, hypercapnea, hyperinflation,
hyperoxia-induced inflammation, hypoxia, hypersensitivity,
hypoxemia, inflammatory bowel disease, interstitial pneumonitis,
ischemia reperfusion injury, kaposi's sarcoma associated virus,
liver fibrosis, lupus, malaria, meningitis, multi-organ
dysfunction, necrotizing enterocolitis, osteoporosis, chronic
periodontitis, periodontitis, peritonitis associated with continuos
ambulatory peritoneal dialysis (CAPD), pre-term labor,
polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic
arthritis, pulmatory fibrosis, pulmatory hypertension, renal
reperfusion injury, respiratory viruses, restinosis, right
ventricular hypertrophy, sarcoidosis, septic shock, small airway
disease, sprains, strains, subarachnoid hemorrhage, surgical lung
volume reduction, thrombosis, toxic shock syndrome, transplant
reperfusion injury, traumatic brain injury, ulcerative colitis,
vasculitis, ventilation-perfusion mismatching, and wheeze.
[0022] In particular, the azatricyclic metalloprotease inhibiting
compounds of the present invention may be used in the treatment of
MMP-13, MMP-8, MMP-3 and MMP-2 mediated osteoarthritis and may be
used for other MMP-13, MMP-8, MMP-3 and MMP-2 mediated symptoms,
inflammatory, malignant and degenerative diseases characterized by
excessive extracellular matrix degradation and/or remodelling, such
as cancer, and chronic inflammatory diseases such as arthritis,
rheumatoid arthritis, osteoarthritis, atherosclerosis, abdominal
aortic aneurysm, inflammation, multiple sclerosis, and chronic
obstructive pulmonary disease, and pain, such as inflammatory pain,
bone pain and joint pain.
[0023] The present invention also provides azatricyclic
metalloprotease inhibiting compounds that are useful as active
ingredients in pharmaceutical compositions for treatment or
prevention of metalloprotease--especially MMP-13, MMP-8, MMP-3 and
MMP-2 mediated diseases. The present invention also contemplates
use of such compounds in pharmaceutical compositions for oral or
parenteral administration, comprising one or more of the
azatricyclic metalloprotease inhibiting compounds disclosed
herein.
[0024] The present invention further provides methods of inhibiting
metalloproteases, by administering formulations, including, but not
limited to, oral, rectal, topical, intravenous, parenteral
(including, but not limited to, intramuscular, intravenous), ocular
(ophthalmic), transdermal, inhalative (including, but not limited
to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous
or intraarticular formulations, comprising the azatricyclic
metalloprotease inhibiting compounds by standard methods known in
medical practice, for the treatment of diseases or symptoms arising
from or associated with metalloprotease, especially MMP-13, MMP-8,
MMP-3 and MMP-2, including prophylactic and therapeutic treatment.
Although the most suitable route in any given case will depend on
the nature and severity of the conditions being treated and on the
nature of the active ingredient. The compounds from this invention
are conveniently presented in unit dosage form and prepared by any
of the methods well-known in the art of pharmacy.
[0025] The azatricyclic metalloprotease inhibiting compounds of the
present invention may be used in combination with a disease
modifying antirheumatic drug, a nonsteroidal anti-inflammatory
drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an
immunosuppressive, a steroid, a biological response modifier or
other anti-inflammatory agents or therapeutics useful for the
treatment of chemokines mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0026] One aspect of the invention relates to a compound of Formula
(I):
##STR00002##
[0027] wherein
[0028] R.sup.1 in each occurrence is independently selected from
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused
aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl,
spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused
arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused
heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,
[0029] wherein R.sup.1 is optionally substituted one or more times,
or
[0030] wherein R.sup.1 is optionally substituted by one R.sup.16
group and optionally substituted by one or more R.sup.9 groups;
[0031] R.sup.2 is selected from hydrogen and alkyl, wherein alkyl
is optionally substituted one or more times or R.sup.1 and R.sup.2
when taken together with the nitrogen to which they are attached
complete a 3- to 8-membered ring containing carbon atoms and
optionally containing a heteroatom selected from O, S(O).sub.x, or
NR.sup.50 and which is optionally substituted one or more
times;
[0032] R.sup.4 in each occurrence is independently selected from
R.sup.10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, halo, haloalkyl, CF.sub.3,
(C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.10,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
[0033] wherein each R.sup.4 group is optionally substituted one or
more times, or
[0034] wherein each R.sup.4 group is optionally substituted by one
or more R.sup.14 groups, or
[0035] wherein optionally two R.sup.4 groups, when taken together
with the nitrogen or carbon to which they are attached complete a
3- to 8-membered saturated ring or multicyclic ring or unsaturated
ring containing carbon atoms and optionally containing one or more
heteroatom independently selected from O, S(O).sub.x, N, or
NR.sup.50 and which is optionally substituted one or more times,
or
[0036] optionally two R.sup.4 groups together at one saturated
carbon atom form .dbd.O, .dbd.S, .dbd.NR.sup.10 or
.dbd.NOR.sup.10;
[0037] R.sup.5 is independently selected from hydrogen, alkyl,
C(O)NR.sup.10R.sup.11, aryl, arylalkyl, SO.sub.2NR.sup.10R.sup.11
and C(O)OR.sup.10 wherein alkyl, aryl and arylalkyl are optionally
substituted one or more times;
[0038] R.sup.8 is independently selected from hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R.sup.10 and
NR.sup.10R.sup.11 wherein alkyl, cycloalkyl, heterocycloalkyl,
aryl, and heteroaryl is optionally substituted one or more
times;
[0039] R.sup.9 in each occurrence is independently selected from
R.sup.10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, halo, CHF.sub.2, CF.sub.3, OR.sup.10, SR.sup.10,
COOR.sup.10, CH(CH.sub.3)CO.sub.2H,
(C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-P(O).sub.2OH,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.19R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.19--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
S(O).sub.2NR.sup.10-alkyl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.11,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
[0040] wherein each R.sup.9 group is optionally substituted, or
[0041] wherein each R.sup.9 group is optionally substituted by one
or more R.sup.14 groups;
[0042] R.sup.10 and R.sup.11 in each occurrence are independently
selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl,
spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,
alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and
aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl,
alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and
aminoalkyl are optionally substituted one or more times, or
R.sup.10 and R.sup.11 when taken together with the nitrogen to
which they are attached complete a 3- to 8-membered ring containing
carbon atoms and optionally containing a heteroatom selected from
O, S(O).sub.x, or NR.sup.50 and which is optionally substituted one
or more times;
[0043] R.sup.14 is independently selected from hydrogen, alkyl,
arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and
halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl
and heterocyclylalkyl are optionally substituted one or more
times.
[0044] R.sup.16 is selected from cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl,
aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused
aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl,
bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl,
spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused
arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused
heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and
(ii):
##STR00003##
[0045] wherein cycloalkyl, heterocycloalkyl, bicycloalkyl,
heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl,
cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl
fused heteroaryl, heterocycloalkyl fused heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl,
heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl,
arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl,
heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl,
and heterocycloalkyl fused heteroarylalkyl are optionally
substituted one or more times;
[0046] R.sup.17 is selected from R.sup.1, R.sup.4 and R.sup.21;
[0047] R.sup.21 is a bicyclic or tricyclic fused ring system,
wherein at least one ring is partially saturated, and
[0048] wherein R.sup.21 is optionally substituted one or more
times, or
[0049] wherein R.sup.21 is optionally substituted by one or more
R.sup.9 groups;
[0050] R.sup.30 is selected from alkyl and
(C.sub.0-C.sub.6)-alkyl-aryl, wherein alkyl and aryl are optionally
substituted;
[0051] R.sup.50 in each occurrence is independently selected from
hydrogen, alkyl, aryl, heteroaryl, C(O)R.sup.80,
C(O)NR.sup.80R.sup.81, SO.sub.2R.sup.80 and
SO.sub.2NR.sup.80R.sup.81, wherein alkyl, aryl, and heteroaryl are
optionally substituted one or more times;
[0052] R.sup.80 and R.sup.81 in each occurrence are independently
selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,
alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and
aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl,
alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and
aminoalkyl are optionally substituted, or R.sup.80 and R.sup.81
when taken together with the nitrogen to which they are attached
complete a 3- to 8-membered ring containing carbon atoms and
optionally a heteroatom selected from O, S(O).sub.x, --NH, and
--N(alkyl) and which is optionally substituted one or more
times;
[0053] E is selected from a bond, CR.sup.10R.sup.11, O, NR.sup.5,
S, S.dbd.O, S(.dbd.O).sub.2, C(.dbd.O), N(R.sup.10)(C.dbd.O),
(C.dbd.O)N(R.sup.10), N(R.sup.10)S(.dbd.O).sub.2,
S(.dbd.O).sub.2N(R.sup.10), C.dbd.N--OR.sup.11,
--C(R.sup.10R.sup.11)C(R.sup.10R.sup.11)--, --CH.sub.2--W.sup.1--
and
##STR00004##
[0055] L.sub.a is independently selected from CR.sup.9 and N;
[0056] L.sub.b is independently selected from C and N with the
proviso, that both L.sub.b are not N, and that the bond between
L.sub.b and L.sub.b is optionally a double bond only if both
L.sub.b are C;
[0057] L.sub.c is selected from a single bond or an acyclic,
straight or branched, saturated or unsaturated hydrocarbon chain
having 1 to 10 carbon atoms, optionally containing 1 to 3 groups
independently selected from --S--, --O--, NR.sup.10CO--,
--S(O).sub.x--, --SO.sub.2NR.sup.10--, --NR.sup.10SO.sub.2--,
NR.sup.10SO.sub.2NR.sup.10--, --NR.sup.10CONR.sup.10--,
--OC(O)NR.sup.10--, --NR.sup.10C(O)O--, which replace a
corresponding number of non-adjacent carbon atoms, and wherein the
hydrocarbon chain is optionally substituted one or more times;
[0058] Q is a 4- to 8-membered ring selected from cycloalkyl,
heterocycloalkyl or a 5- or 6-membered ring selected from aryl and
heteroaryl,
[0059] wherein Q is optionally substituted one or more times,
or
[0060] wherein Q is optionally substituted one or more times with
R.sup.4, or
[0061] wherein Q is fused via two of its adjacent atoms, which are
selected from N and C with a further cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which
is optionally independently substituted one or more times;
[0062] U is selected from C(R.sup.5R.sup.10), NR.sup.5, O, S,
S.dbd.O and S(.dbd.O).sub.2;
[0063] W.sup.1 is selected from O, NR.sup.5, S, S.dbd.O,
S(.dbd.O).sub.2, N(R.sup.10)(C.dbd.O), N(R.sup.10)S(.dbd.O).sub.2
and) S(.dbd.O).sub.2N(R.sup.10);
[0064] X is selected from a bond and
(CR.sup.10R.sup.11).sub.wE(CR.sup.10R.sup.11).sub.w;
[0065] X.sup.1 is independently selected from O, S, NR.sup.10,
N--CN, NCOR.sup.10, N--NO.sub.2, or N--SO.sub.2R.sup.10;
[0066] g and h are independently selected from 0-2;
[0067] w is selected from 0-4;
[0068] x is selected from 0 to 2;
[0069] y is selected from 1 and 2;
[0070] the dotted line optionally represents a double bond; and
[0071] N-oxides, pharmaceutically acceptable salts, prodrugs,
formulations, polymorphs, tautomers, racemic mixtures and
stereoisomers thereof.
[0072] In one embodiment, in conjunction with any above or below
embodiments, Q is phenyl or thiophene that is fused via two of its
adjacent atoms with a further cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which
is optionally independently substituted one or more times.
[0073] In another embodiment, in conjunction with any above or
below embodiments, L.sub.a is N.
[0074] In another embodiment, in conjunction with any above or
below embodiments, L.sub.a is N; and L.sub.b is C.
[0075] In another embodiment, in conjunction with any above or
below embodiments, the compound has the structure:
##STR00005##
[0076] wherein Q' is a fused cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
[0077] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused cycloalkyl.
[0078] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused heterocycloalkyl.
[0079] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused heterobicycloalkyl.
[0080] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused cycloalkyl, heterocycloalkyl,
bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
[0081] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused phenyl.
[0082] In another embodiment, in conjunction with any above or
below embodiments, Q' is a fused heteroaryl.
[0083] In another embodiment, in conjunction with any above or
below embodiments, the compound is selected from:
##STR00006## ##STR00007## ##STR00008##
[0084] In another embodiment, in conjunction with any above or
below embodiments, R.sup.8 is H.
[0085] In another embodiment, in conjunction with any above or
below embodiments, R.sup.17 is selected from
##STR00009##
[0086] wherein:
[0087] R.sup.6 is selected from R.sup.9, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, C(O)OR.sup.10,
CH(CH.sub.3)CO.sub.2H, (C.sub.0-C.sub.6)-alkyl-COR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NO.sub.2, (C.sub.0-C.sub.6)-alkyl-CN,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yOR.sup.10,
(C.sub.0-C.sub.6)-alkyl-P(O).sub.2OH,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10CONR.sup.11SO.sub.2R.sup.30,
(C.sub.0-C.sub.6)-alkyl-S(O).sub.xR.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-OC(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.NR.sup.10)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.NR.sup.11)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--CN)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(.dbd.N--NO.sub.2)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10SO.sub.2R.sup.11,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2NR.sup.10--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
S(O).sub.2NR.sup.10-alkyl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-aryl,
S(O).sub.2--(C.sub.0-C.sub.6)-alkyl-heteroaryl,
(C.sub.0-C.sub.6)-alkyl-C(O)--NR.sup.11--CN,
O--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)OR.sup.10,
S(O).sub.x--(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-C(O)NR.sup.10--(C.sub.0-C.sub.6)-alkyl-NR.sup.10R-
.sup.11, (C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)R.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)OR.sup.10,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--C(O)--NR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yNR.sup.10R.sup.11,
(C.sub.0-C.sub.6)-alkyl-NR.sup.10--S(O).sub.yR.sup.11,
O--(C.sub.0-C.sub.6)-alkyl-aryl and
O--(C.sub.0-C.sub.6)-alkyl-heteroaryl, wherein each R.sup.6 group
is optionally substituted by one or more R.sup.14 groups;
[0088] R.sup.9 is independently selected from hydrogen, alkyl,
halo, CHF.sub.2, CF.sub.3, OR.sup.16, NR.sup.16R.sup.11, NO.sub.2,
and CN, wherein alkyl is optionally substituted one or more
times.
[0089] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00010##
[0090] wherein:
[0091] R.sup.18 is independently selected from hydrogen, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl,
OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10,
OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
SO.sub.2NR.sup.10R.sup.11 and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl
are optionally substituted one or more times;
[0092] R.sup.25 is selected from hydrogen, alkyl, cycloalkyl,
C(O)NR.sup.10R.sup.11 and haloalkyl, wherein alkyl, cycloalkyl, and
haloalkyl are optionally substituted one or more times;
[0093] B.sub.1 is selected from NR.sup.10, O and S;
[0094] D.sup.2, G.sup.2, L.sup.2, M.sup.2 and T.sup.2 are
independently selected from CR.sup.18 and N; and
[0095] Z is a 5- to 8-membered ring selected from cycloalkyl,
heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl,
heterocycloalkyl, aryl and heteroaryl are optionally substituted
one or more times.
[0096] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017##
[0097] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00018## ##STR00019##
[0098] wherein:
[0099] R.sup.12 and R.sup.13 are independently selected from
hydrogen, alkyl and halo, wherein alkyl is optionally substituted
one or more times, or optionally R.sup.12 and
[0100] R.sup.13 together form .dbd.O, .dbd.S, .dbd.NR.sup.10 or
.dbd.NOR.sup.10;
[0101] R.sup.18 is independently selected from hydrogen, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl,
OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10,
OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
SO.sub.2NR.sup.10R.sup.11 and NR.sup.10R.sup.11, wherein alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and
heteroaryl are optionally substituted one or more times;
[0102] R.sup.19 is independently selected from hydrogen, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl,
OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10,
OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
NR.sup.10SO.sub.2NR.sup.10R.sup.11, SO.sub.2NR.sup.10R.sup.11 and
NR.sup.10R.sup.11, wherein alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally
substituted one or more times, or optionally two R.sup.19 groups
together at one carbon atom form .dbd.O, .dbd.S, .dbd.NR.sup.10 or
.dbd.NOR.sup.10;
[0103] R.sup.25 is selected from hydrogen, alkyl, cycloalkyl,
C(O)NR.sup.10R.sup.11 and haloalkyl, wherein alkyl, cycloalkyl, and
haloalkyl are optionally substituted one or more times;
[0104] J and K are independently selected from CR.sup.10R.sup.18,
NR.sup.10, O and S(O).sub.x; and
[0105] A.sub.1 is selected from NR.sup.10, O and S(O).sub.x;
and
[0106] D.sup.2, G.sup.2, J.sup.2, L.sup.2, M.sup.2 and T.sup.2 are
independently selected from CR.sup.18 and N.
[0107] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024##
[0108] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00025## ##STR00026##
[0109] wherein:
[0110] R.sup.18 is independently selected from hydrogen, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl,
OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10,
OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
NR.sup.10SO.sub.2NR.sup.10R.sup.11, SO.sub.2NR.sup.10R.sup.11 and
NR.sup.10R.sup.11, wherein alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally
substituted one or more times;
[0111] R.sup.19 is independently selected from hydrogen, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl,
OH, halo, CN, C(O)NR.sup.10R.sup.11, CO.sub.2R.sup.10, OR.sup.10,
OCF.sub.3, OCHF.sub.2, NR.sup.10CONR.sup.10R.sup.11,
NR.sup.10COR.sup.11, NR.sup.10SO.sub.2R.sup.11,
NR.sup.10SO.sub.2NR.sup.10R.sup.11, SO.sub.2NR.sup.10R.sup.11 and
NR.sup.10R.sup.11, wherein alkyl, haloalkyl, cycloalkyl,
heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally
substituted one or more times, or optionally two R.sup.19 groups
together at one carbon atom form .dbd.O, .dbd.S, .dbd.NR.sup.10 or
.dbd.NOR.sup.10;
[0112] R.sup.25 is selected from hydrogen, alkyl, cycloalkyl,
CONR.sup.10R.sup.11 and haloalkyl, wherein alkyl, cycloalkyl and
haloalkyl are optionally substituted one or more times;
[0113] L.sup.2, M.sup.2, and T.sup.2 are independently selected
from CR.sup.18 and N;
[0114] D.sup.3, G.sup.3, L.sup.3, M.sup.3, and T.sup.3 are
independently selected from N, CR.sup.18, (i) and (ii)
##STR00027##
[0115] with the proviso that one of L.sup.3, M.sup.3, T.sup.3,
D.sup.3, and G.sup.3 is (i) or (ii);
[0116] B.sub.1 is selected from the group consisting of NR.sup.10,
O and S(O).sub.x; and
[0117] Q.sup.2 is a 5- to 8-membered ring selected from cycloalkyl,
heterocycloalkyl, aryl, and heteroaryl, which is optionally
substituted one or more times with R.sup.19.
[0118] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00028## ##STR00029## ##STR00030##
[0119] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00031## ##STR00032## ##STR00033##
[0120] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is selected from:
##STR00034##
[0121] In another embodiment, in conjunction with any above or
below embodiments, the compounds have the structure:
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049##
and N-oxides, pharmaceutically acceptable salts, prodrugs,
formulations, polymorphs, tautomers, racemic mixtures and
stereoisomers thereof.
[0122] Another aspect of the invention relates to a pharmaceutical
composition comprising an effective amount of the compound
according to any of the above or below embodiments.
[0123] Another aspect of the invention relates to a method of
treating a metalloprotease mediated disease, comprising
administering to a subject in need of such treatment an effective
amount of a compound according to any of the above or below
embodiments.
[0124] In another embodiment, in conjunction with any above or
below embodiments, the disease is selected from rheumatoid
arthritis, osteoarthritis, inflammation, atherosclerosis and
multiple sclerosis.
[0125] Another aspect of the invention relates to a pharmaceutical
composition comprising:
[0126] A) an effective amount of a compound according to any of the
above or below embodiments;
[0127] B) a pharmaceutically acceptable carrier; and
[0128] C) a drug, agent or therapeutic selected from: (a) a disease
modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory
drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e)
an immunosuppressive; (f) a steroid; (g) a biological response
modifier; and (h) a small molecule inhibitor of pro-inflammatory
cytokine production.
[0129] Another aspect of the invention relates to a method of
inhibiting a metalloprotease enzyme, comprising administering a
compound according to any of the above or below embodiments.
[0130] In another embodiment, in conjunction with any above or
below embodiments, the metalloproteinase is selected from MMP-2,
MMP-3, MMP-8, and MMP-13.
[0131] In another embodiment, in conjunction with any above or
below embodiments, the disease is selected from the group
consisting of: rheumatoid arthritis, osteoarthritis, abdominal
aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric
carcinoma or non-small cell lung carcinoma), inflammation,
atherosclerosis, chronic obstructive pulmonary disease, ocular
diseases (e.g. but not limited to ocular inflammation, retinopathy
of prematurity, macular degeneration with the wet type preferred
and corneal neovascularization), neurologic diseases, psychiatric
diseases, thrombosis, bacterial infection, Parkinson's disease,
fatigue, tremor, diabetic retinopathy, vascular diseases of the
retina, aging, dementia, cardiomyopathy, renal tubular impairment,
diabetes, psychosis, dyskinesia, pigmentary abnormalities,
deafness, inflammatory and fibrotic syndromes, intestinal bowel
syndrome, allergies, Alzheimers disease, arterial plaque formation,
oncology, periodontal, viral infection, stroke, atherosclerosis,
cardiovascular disease, reperfusion injury, trauma, chemical
exposure or oxidative damage to tissues, wound healing, hemorroid,
skin beautifying, pain, inflammatory pain, bone pain and joint
pain, acne, acute alcoholic hepatitis, acute inflammation, acute
pancreatitis, acute respiratory distress syndrome, adult
respiratory disease, airflow obstruction, airway
hyperresponsiveness, alcoholic liver disease, allograft rejections,
angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic
dermatitis, bronchiectasis, bronchiolitis, bronchiolitis
obliterans, burn therapy, cardiac and renal reperfusion injury,
celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS
vasculitis, colds, contusions, cor pulmonae, cough, Crohn's
disease, chronic bronchitis, chronic inflammation, chronic
pancreatitis, chronic sinusitis, crystal induced arthritis, cystic
fibrosis, delayted type hypersensitivity reaction, duodenal ulcers,
dyspnea, early transplantation rejection, emphysema, encephalitis,
endotoxic shock, esophagitis, gastric ulcers, gingivitis,
glomerulonephritis, glossitis, gout, graft vs. host reaction, gram
negative sepsis, granulocytic ehrlichiosis, hepatitis viruses,
herpes, herpes viruses, HIV, hypercapnea, hyperinflation,
hyperoxia-induced inflammation, hypoxia, hypersensitivity,
hypoxemia, inflammatory bowel disease, interstitial pneumonitis,
ischemia reperfusion injury, kaposi's sarcoma associated virus,
lupus, malaria, meningitis, multi-organ dysfunction, necrotizing
enterocolitis, osteoporosis, chronic periodontitis, periodontitis,
peritonitis associated with continuos ambulatory peritoneal
dialysis (CAPD), pre-term labor, polymyositis, post surgical
trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory
fibrosis, pulmatory hypertension, renal reperfusion injury,
respiratory viruses, restinosis, right ventricular hypertrophy,
sarcoidosis, septic shock, small airway disease, sprains, strains,
subarachnoid hemorrhage, surgical lung volume reduction,
thrombosis, toxic shock syndrome, transplant reperfusion injury,
traumatic brain injury, ulcerative colitis, vasculitis,
ventilation-perfusion mismatching, and wheeze.
[0132] Another aspect of the invention relates to the use of a
compound according to any of the above or below embodiments for the
manufacture of a medicament for treating an metalloprotease
mediated disease.
[0133] In another embodiment, in conjunction with any of the above
or below embodiments, the metalloprotease mediated disease is
selected from the group consisting of MMP-2, MMP-3, MMP-8 and
MMP-13 mediated diseases.
[0134] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups as needed.
[0135] The terms "alkyl" or "alk", as used herein alone or as part
of another group, denote optionally substituted, straight and
branched chain saturated hydrocarbon groups, preferably having 1 to
10 carbons in the normal chain, most preferably lower alkyl groups.
Exemplary unsubstituted such groups include methyl, ethyl, propyl,
isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl and the like. Exemplary substituents may
include, but are not limited to, one or more of the following
groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to
form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or
protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl,
alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH.sub.2--CO--),
substituted carbamoyl ((R.sup.10)(R.sup.11)N--CO-- wherein R.sup.10
or R.sup.11 are as defined below, except that at least one of
R.sup.10 or R.sup.11 is not hydrogen), amino, heterocyclo, mono- or
dialkylamino, or thiol (--SH).
[0136] The terms "alkyl" or "alk", as used herein alone or as part
of another group, denote optionally substituted, straight and
branched chain saturated hydrocarbon groups, preferably having 1 to
10 carbons in the normal chain, most preferably lower alkyl groups.
Exemplary unsubstituted such groups include methyl, ethyl, propyl,
isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl and the like. Exemplary substituents may
include, but are not limited to, one or more of the following
groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to
form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or
protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl,
alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH.sub.2--CO--),
substituted carbamoyl ((R.sup.10)(R.sup.11)N--CO-- wherein R.sup.10
or R.sup.11 are as defined below, except that at least one of
R.sup.10 or R.sup.11 is not hydrogen), amino, heterocyclo, mono- or
dialkylamino, or thiol (--SH).
[0137] The terms "lower alk" or "lower alkyl" as used herein,
denote such optionally substituted groups as described above for
alkyl having 1 to 4 carbon atoms in the normal chain.
[0138] The term "alkoxy" denotes an alkyl group as described above
bonded through an oxygen linkage (--O--).
[0139] The term "alkenyl", as used herein alone or as part of
another group, denotes optionally substituted, straight and
branched chain hydrocarbon groups containing at least one carbon to
carbon double bond in the chain, and preferably having 2 to 10
carbons in the normal chain. Exemplary unsubstituted such groups
include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl,
heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary
substituents may include, but are not limited to, one or more of
the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl,
aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy,
carboxyl (--COOH), alkyloxycarbonyl, alkylcarbonyloxy,
alkylcarbonyl, carbamoyl (NH.sub.2--CO--), substituted carbamoyl
((R.sup.10)(R.sup.11)N--CO-- wherein R.sup.10 or R.sup.11 are as
defined below, except that at least one of R.sup.10 or R.sup.11 is
not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol
(--SH).
[0140] The term "alkynyl", as used herein alone or as part of
another group, denotes optionally substituted, straight and
branched chain hydrocarbon groups containing at least one carbon to
carbon triple bond in the chain, and preferably having 2 to 10
carbons in the normal chain. Exemplary unsubstituted such groups
include, but are not limited to, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the
like. Exemplary substituents may include, but are not limited to,
one or more of the following groups: halo, alkoxy, alkylthio,
alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or
protected hydroxy, carboxyl (--COOH), alkyloxycarbonyl,
alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH.sub.2--CO--),
substituted carbamoyl ((R.sup.10)(R.sup.11)N--CO-- wherein R.sup.10
or R.sup.11 are as defined below, except that at least one of
R.sup.10 or R.sup.11 is not hydrogen), amino, heterocyclo, mono- or
dialkylamino, or thiol (--SH).
[0141] The term "cycloalkyl", as used herein alone or as part of
another group, denotes optionally substituted, saturated cyclic
hydrocarbon ring systems, containing one ring with 3 to 9 carbons.
Exemplary unsubstituted such groups include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents
include, but are not limited to, one or more alkyl groups as
described above, or one or more groups described above as alkyl
substituents.
[0142] The term "bicycloalkyl", as used herein alone or as part of
another group, denotes optionally substituted, saturated cyclic
bridged hydrocarbon ring systems, desirably containing 2 or 3 rings
and 3 to 9 carbons per ring. Exemplary unsubstituted such groups
include, but are not limited to, adamantyl, bicyclo[2.2.2]octane,
bicyclo[2.2.1]heptane and cubane. Exemplary substituents include,
but are not limited to, one or more alkyl groups as described
above, or one or more groups described above as alkyl
substituents.
[0143] The term "spiroalkyl", as used herein alone or as part of
another group, denotes optionally substituted, saturated
hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per
ring are bridged via one carbon atom. Exemplary unsubstituted such
groups include, but are not limited to, spiro[3.5]nonane,
spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents
include, but are not limited to, one or more alkyl groups as
described above, or one or more groups described above as alkyl
substituents.
[0144] The term "spiroheteroalkyl", as used herein alone or as part
of another group, denotes optionally substituted, saturated
hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per
ring are bridged via one carbon atom and at least one carbon atom
is replaced by a heteroatom independently selected from N, O and S.
The nitrogen and sulfur heteroatoms may optionally be oxidized.
Exemplary unsubstituted such groups include, but are not limited
to, 1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents
include, but are not limited to, one or more alkyl groups as
described above, or one or more groups described above as alkyl
substituents.
[0145] The terms "ar" or "aryl", as used herein alone or as part of
another group, denote optionally substituted, homocyclic aromatic
groups, preferably containing 1 or 2 rings and 6 to 12 ring
carbons. Exemplary unsubstituted such groups include, but are not
limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents
include, but are not limited to, one or more nitro groups, alkyl
groups as described above or groups described above as alkyl
substituents.
[0146] The term "heterocycle" or "heterocyclic system" denotes a
heterocyclyl, heterocyclenyl, or heteroaryl group as described
herein, which contains carbon atoms and from 1 to 4 heteroatoms
independently selected from N, O and S and including any bicyclic
or tricyclic group in which any of the above-defined heterocyclic
rings is fused to one or more heterocycle, aryl or cycloalkyl
groups. The nitrogen and sulfur heteroatoms may optionally be
oxidized. The heterocyclic ring may be attached to its pendant
group at any heteroatom or carbon atom which results in a stable
structure. The heterocyclic rings described herein may be
substituted on carbon or on a nitrogen atom.
[0147] Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl,
benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,
4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,
oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,
4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
[0148] Further examples of heterocycles include, but not are not
limited to, "heterobicycloalkyl" groups such as
7-oxa-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, and
1-aza-bicyclo[2.2.2]octane.
[0149] "Heterocyclenyl" denotes a non-aromatic monocyclic or
multicyclic hydrocarbon ring system of about 3 to about 10 atoms,
desirably about 4 to about 8 atoms, in which one or more of the
carbon atoms in the ring system is/are hetero element(s) other than
carbon, for example nitrogen, oxygen or sulfur atoms, and which
contains at least one carbon-carbon double bond or carbon-nitrogen
double bond. Ring sizes of rings of the ring system may include 5
to 6 ring atoms. The designation of the aza, oxa or thia as a
prefix before heterocyclenyl define that at least a nitrogen,
oxygen or sulfur atom is present respectively as a ring atom. The
heterocyclenyl may be optionally substituted by one or more
substituents as defined herein. The nitrogen or sulphur atom of the
heterocyclenyl may also be optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. "Heterocyclenyl" as used herein
includes by way of example and not limitation those described in
Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.
A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; "The Chemistry of Heterocyclic Compounds, A series of
Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.",
82:5566 (1960), the contents all of which are incorporated by
reference herein. Exemplary monocyclic azaheterocyclenyl groups
include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine,
1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,
1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,
2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary
oxaheterocyclenyl groups include, but are not limited to,
3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An
exemplary multicyclic oxaheterocyclenyl group is
7-oxabicyclo[2.2.1]heptenyl.
[0150] "Heterocyclyl," or "heterocycloalkyl," denotes a
non-aromatic saturated monocyclic or multicyclic ring system of
about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in
which one or more of the carbon atoms in the ring system is/are
hetero element(s) other than carbon, for example nitrogen, oxygen
or sulfur. Ring sizes of rings of the ring system may include 5 to
6 ring atoms. The designation of the aza, oxa or thia as a prefix
before heterocyclyl define that at least a nitrogen, oxygen or
sulfur atom is present respectively as a ring atom. The
heterocyclyl may be optionally substituted by one or more
substituents which may be the same or different, and are as defined
herein. The nitrogen or sulphur atom of the heterocyclyl may also
be optionally oxidized to the corresponding N-oxide, S-oxide or
S,S-dioxide.
[0151] "Heterocyclyl" as used herein includes by way of example and
not limitation those described in Paquette, Leo A.; "Principles of
Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of
Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,
19, and 28; and "J. Am. Chem. Soc.", 82:5566 (1960). Exemplary
monocyclic heterocyclyl rings include, but are not limited to,
piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0152] "Heteroaryl" denotes an aromatic monocyclic or multicyclic
ring system of about 5 to about 10 atoms, in which one or more of
the atoms in the ring system is/are hetero element(s) other than
carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings
of the ring system include 5 to 6 ring atoms. The "heteroaryl" may
also be substituted by one or more substituents which may be the
same or different, and are as defined herein. The designation of
the aza, oxa or thia as a prefix before heteroaryl define that at
least a nitrogen, oxygen or sulfur atom is present respectively as
a ring atom. A nitrogen atom of a heteroaryl may be optionally
oxidized to the corresponding N-oxide. Heteroaryl as used herein
includes by way of example and not limitation those described in
Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.
A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; "The Chemistry of Heterocyclic Compounds, A series of
Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.",
82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl
groups include, but are not limited to, pyrazinyl, thienyl,
isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl,
1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl,
imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl,
azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl,
dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl,
isoquinolinyl, isothiazolyl, oxadiazolyl, oxazinyl, oxiranyl,
piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl,
pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl,
quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl,
1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl,
5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl,
triazolyl and triazolonyl.
[0153] The phrase "fused" means, that the group, mentioned before
"fused" is connected via two adjacent atoms to the ring system
mentioned after "fused" to form a bicyclic system. For example,
"heterocycloalkyl fused aryl" includes, but is not limited to,
2,3-dihydro-benzo[1,4]dioxine, 4H-benzo[1,4]oxazin-3-one,
3H-Benzooxazol-2-one and
3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one.
[0154] The term "amino" denotes the radical --NH.sub.2 wherein one
or both of the hydrogen atoms may be replaced by an optionally
substituted hydrocarbon group. Exemplary amino groups include, but
are not limited to, n-butylamino, tert-butylamino,
methylpropylamino and ethyldimethylamino.
[0155] The term "cycloalkylalkyl" denotes a cycloalkyl-alkyl group
wherein a cycloalkyl as described above is bonded through an alkyl,
as defined above. Cycloalkylalkyl groups may contain a lower alkyl
moiety. Exemplary cycloalkylalkyl groups include, but are not
limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,
cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl,
cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
[0156] The term "arylalkyl" denotes an aryl group as described
above bonded through an alkyl, as defined above.
[0157] The term "heteroarylalkyl" denotes a heteroaryl group as
described above bonded through an alkyl, as defined above.
[0158] The term "heterocyclylalkyl," or "heterocycloalkylalkyl,"
denotes a heterocyclyl group as described above bonded through an
alkyl, as defined above.
[0159] The terms "halogen", "halo", or "hal", as used herein alone
or as part of another group, denote chlorine, bromine, fluorine,
and iodine.
[0160] The term "haloalkyl" denotes a halo group as described above
bonded though an alkyl, as defined above. Fluoroalkyl is an
exemplary group.
[0161] The term "aminoalkyl" denotes an amino group as defined
above bonded through an alkyl, as defined above.
[0162] The phrase "bicyclic fused ring system wherein at least one
ring is partially saturated" denotes an 8- to 13-membered fused
bicyclic ring group in which at least one of the rings is
non-aromatic. The ring group has carbon atoms and optionally 1-4
heteroatoms independently selected from N, O and S. Illustrative
examples include, but are not limited to, indanyl,
tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
[0163] The phrase "tricyclic fused ring system wherein at least one
ring is partially saturated" denotes a 9- to 18-membered fused
tricyclic ring group in which at least one of the rings is
non-aromatic. The ring group has carbon atoms and optionally 1-7
heteroatoms independently selected from N, O and S. Illustrative
examples include, but are not limited to, fluorene,
10,11-dihydro-5H-dibenzo[a,d]cycloheptene and
2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
[0164] The term "pharmaceutically acceptable salts" refers to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. Examples therefore may be, but are not limited
to, sodium, potassium, choline, lysine, arginine or
N-methyl-glucamine salts, and the like.
[0165] The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as, but not limited
to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,
nitric and the like; and the salts prepared from organic acids such
as, but not limited to, acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0166] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two. Organic solvents include, but are not limited
to, nonaqueous media like ethers, ethyl acetate, ethanol,
isopropanol, or acetonitrile. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing
Company, Easton, Pa., 1990, p. 1445, the disclosure of which is
hereby incorporated by reference.
[0167] The phrase "pharmaceutically acceptable" denotes those
compounds, materials, compositions, and/or dosage forms which are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication commensurate with a reasonable benefit/risk
ratio.
[0168] The phrase "pharmaceutically acceptable carrier" denotes
media generally accepted in the art for the delivery of
biologically active agents to mammals, e.g., humans. Such carriers
are generally formulated according to a number of factors well
within the purview of those of ordinary skill in the art to
determine and account for. These include, without limitation: the
type and nature of the active agent being formulated; the subject
to which the agent-containing composition is to be administered;
the intended route of administration of the composition; and, the
therapeutic indication being targeted. Pharmaceutically acceptable
carriers include both aqueous and non-aqueous liquid media, as well
as a variety of solid and semi-solid dosage forms. Such carriers
can include a number of different ingredients and additives in
addition to the active agent, such additional ingredients being
included in the formulation for a variety of reasons, e.g.,
stabilization of the active agent, well known to those of ordinary
skill in the art. Non-limiting examples of a pharmaceutically
acceptable carrier are hyaluronic acid and salts thereof, and
microspheres (including, but not limited to
poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic
acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin
(BSA)). Descriptions of suitable pharmaceutically acceptable
carriers, and factors involved in their selection, are found in a
variety of readily available sources, e.g., Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton,
Pa., 1985, the contents of which are incorporated herein by
reference.
[0169] Pharmaceutically acceptable carriers particularly suitable
for use in conjunction with tablets include, for example, inert
diluents, such as celluloses, calcium or sodium carbonate, lactose,
calcium or sodium phosphate; disintegrating agents, such as
croscarmellose sodium, cross-linked povidone, maize starch, or
alginic acid; binding agents, such as povidone, starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets may be uncoated or may be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax may be employed.
[0170] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example celluloses, lactose, calcium phosphate
or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with non-aqueous or oil medium, such as
glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid
paraffin or olive oil.
[0171] The compositions of the invention may also be formulated as
suspensions including a compound of the present invention in
admixture with at least one pharmaceutically acceptable excipient
suitable for the manufacture of a suspension. In yet another
embodiment, pharmaceutical compositions of the invention may be
formulated as dispersible powders and granules suitable for
preparation of a suspension by the addition of suitable
excipients.
[0172] Carriers suitable for use in connection with suspensions
include suspending agents, such as sodium carboxymethylcellulose,
methylcellulose, hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or
wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycethanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate); and
thickening agents, such as carbomer, beeswax, hard paraffin or
cetyl alcohol. The suspensions may also contain one or more
preservatives such as acetic acid, methyl and/or n-propyl
p-hydroxy-benzoate; one or more coloring agents; one or more
flavoring agents; and one or more sweetening agents such as sucrose
or saccharin.
[0173] Cyclodextrins may be added as aqueous solubility enhancers.
Preferred cyclodextrins include hydroxypropyl, hydroxyethyl,
glucosyl, maltosyl and maltotriosyl derivatives of .alpha.-,
.beta.-, and .gamma.-cyclodextrin. The amount of solubility
enhancer employed will depend on the amount of the compound of the
present invention in the composition.
[0174] The term "formulation" denotes a product comprising the
active ingredient(s) and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical formulations of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutical carrier.
[0175] The term "N-oxide" denotes compounds that can be obtained in
a known manner by reacting a compound of the present invention
including a nitrogen atom (such as in a pyridyl group) with
hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic
acid, in an inert solvent, such as dichloromethane, at a
temperature between about -10-80.degree. C., desirably about
0.degree. C.
[0176] The term "polymorph" denotes a form of a chemical compound
in a particular crystalline arrangement. Certain polymorphs may
exhibit enhanced thermodynamic stability and may be more suitable
than other polymorphic forms for inclusion in pharmaceutical
formulations.
[0177] The compounds of the invention can contain one or more
chiral centers and/or double bonds and, therefore, exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers, or diastereomers. According to the
invention, the chemical structures depicted herein, and therefore
the compounds of the invention, encompass all of the corresponding
enantiomers and stereoisomers, that is, both the stereomerically
pure form (e.g., geometrically pure, enantiomerically pure, or
diastereomerically pure) and enantiomeric and stereoisomeric
mixtures.
[0178] The term "racemic mixture" denotes a mixture that is about
50% of one enantiomer and about 50% of the corresponding enantiomer
relative to all chiral centers in the molecule. Thus, the invention
encompasses all enantiomerically-pure, enantiomerically-enriched,
and racemic mixtures of compounds of Formulas (I) and (II).
[0179] Enantiomeric and stereoisomeric mixtures of compounds of the
invention can be resolved into their component enantiomers or
stereoisomers by well-known methods. Examples include, but are not
limited to, the formation of chiral salts and the use of chiral or
high performance liquid chromatography "HPLC" and the formation and
crystallization of chiral salts. See, e.g., Jacques, J., et al.,
Enantiomers, Racemates and Resolutions (Wiley-Interscience, New
York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);
Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill,
N.Y., 1962); Wilen, S. H., Tables of Resolving Agents and Optical
Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press,
Notre Dame, Ind., 1972); Stereochemistry of Organic Compounds,
Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John
Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical
Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.).
Enantiomers and stereoisomers can also be obtained from
stereomerically- or enantiomerically-pure intermediates, reagents,
and catalysts by well-known asymmetric synthetic methods.
[0180] "Substituted" is intended to indicate that one or more
hydrogens on the atom indicated in the expression using
"substituted" is replaced with a selection from the indicated
group(s), provided that the indicated atom's normal valency is not
exceeded, and that the substitution results in a stable compound.
When a substituent is keto (i.e., .dbd.O) group, then 2 hydrogens
on the atom are replaced.
[0181] Unless moieties of a compound of the present invention are
defined as being unsubstituted, the moieties of the compound may be
substituted. In addition to any substituents provided above, the
moieties of the compounds of the present invention may be
optionally substituted with one or more groups independently
selected from:
[0182] C.sub.1-C.sub.4 alkyl;
[0183] C.sub.2-C.sub.4 alkenyl;
[0184] C.sub.2-C.sub.4 alkynyl;
[0185] CF.sub.3;
[0186] halo;
[0187] OH;
[0188] O--(C.sub.1-C.sub.4 alkyl);
[0189] OCH.sub.2F;
[0190] OCHF.sub.2;
[0191] OCF.sub.3;
[0192] ONO.sub.2;
[0193] OC(O)--(C.sub.1-C.sub.4 alkyl);
[0194] OC(O)--(C.sub.1-C.sub.4 alkyl);
[0195] OC(O)NH--(C.sub.1-C.sub.4 alkyl);
[0196] OC(O)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0197] OC(S)NH--(C.sub.1-C.sub.4 alkyl);
[0198] OC(S)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0199] SH;
[0200] S--(C.sub.1-C.sub.4 alkyl);
[0201] S(O)--(C.sub.1-C.sub.4 alkyl);
[0202] S(O).sub.2--(C.sub.1-C.sub.4 alkyl);
[0203] SC(O)--(C.sub.1-C.sub.4 alkyl);
[0204] SC(O)O--(C.sub.1-C.sub.4 alkyl);
[0205] NH.sub.2;
[0206] N(H)--(C.sub.1-C.sub.4 alkyl);
[0207] N(C.sub.1-C.sub.4 alkyl).sub.2;
[0208] N(H)C(O)--(C.sub.1-C.sub.4 alkyl);
[0209] N(CH.sub.3)C(O)--(C.sub.1-C.sub.4 alkyl);
[0210] N(H)C(O)--CF.sub.3;
[0211] N(CH.sub.3)C(O)--CF.sub.3;
[0212] N(H)C(S)--(C.sub.1-C.sub.4 alkyl);
[0213] N(CH.sub.3)C(S)--(C.sub.1-C.sub.4 alkyl);
[0214] N(H)S(O).sub.2--(C.sub.1-C.sub.4 alkyl);
[0215] N(H)C(O)NH.sub.2;
[0216] N(H)C(O)NH--(C.sub.1-C.sub.4 alkyl);
[0217] N(CH.sub.3)C(O)NH--(C.sub.1-C.sub.4 alkyl);
[0218] N(H)C(O)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0219] N(CH.sub.3)C(O)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0220] N(H)S(O).sub.2NH.sub.2);
[0221] N(H)S(O).sub.2NH--(C.sub.1-C.sub.4 alkyl);
[0222] N(CH.sub.3)S(O).sub.2NH--(C.sub.1-C.sub.4 alkyl);
[0223] N(H)S(O).sub.2N(C.sub.1-C.sub.4 alkyl).sub.2;
[0224] N(CH.sub.3)S(O).sub.2N(C.sub.1-C.sub.4 alkyl).sub.2;
[0225] N(H)C(O)O--(C.sub.1-C.sub.4 alkyl);
[0226] N(CH.sub.3)C(O)O--(C.sub.1-C.sub.4 alkyl);
[0227] N(H)S(O).sub.2O--(C.sub.1-C.sub.4 alkyl);
[0228] N(CH.sub.3)S(O).sub.2O--(C.sub.1-C.sub.4 alkyl);
[0229] N(CH.sub.3)C(S)NH--(C.sub.1-C.sub.4 alkyl);
[0230] N(CH.sub.3)C(S)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0231] N(CH.sub.3)C(S)O--(C.sub.1-C.sub.4 alkyl);
[0232] N(H)C(S)NH.sub.2;
[0233] NO.sub.2;
[0234] CO.sub.2H;
[0235] CO.sub.2--(C.sub.1-C.sub.4 alkyl);
[0236] C(O)N(H)OH;
[0237] C(O)N(CH.sub.3)OH:
[0238] C(O)N(CH.sub.3)OH;
[0239] C(O)N(CH.sub.3)O--(C.sub.1-C.sub.4 alkyl);
[0240] C(O)N(H)--(C.sub.1-C.sub.4 alkyl);
[0241] C(O)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0242] C(S)N(H)--(C.sub.1-C.sub.4 alkyl);
[0243] C(S)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0244] C(NH)N(H)--(C.sub.1-C.sub.4 alkyl);
[0245] C(NH)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0246] C(NCH.sub.3)N(H)--(C.sub.1-C.sub.4 alkyl);
[0247] C(NCH.sub.3)N(C.sub.1-C.sub.4 alkyl).sub.2;
[0248] C(O)--(C.sub.1-C.sub.4 alkyl);
[0249] C(NH)--(C.sub.1-C.sub.4 alkyl);
[0250] C(NCH.sub.3)--(C.sub.1-C.sub.4 alkyl);
[0251] C(NOH)--(C.sub.1-C.sub.4 alkyl);
[0252] C(NOCH.sub.3)--(C.sub.1-C.sub.4 alkyl);
[0253] CN;
[0254] CHO;
[0255] CH.sub.2OH;
[0256] CH.sub.2O--(C.sub.1-C.sub.4 alkyl);
[0257] CH.sub.2NH.sub.2;
[0258] CH.sub.2N(H)--(C.sub.1-C.sub.4 alkyl);
CH.sub.2N(C.sub.1-C.sub.4 alkyl).sub.2;
[0259] aryl;
[0260] heteroaryl;
[0261] cycloalkyl; and
[0262] heterocyclyl.
[0263] In some cases, a ring substituent may be shown as being
connected to the ring by a bond extending from the center of the
ring. The number of such substituents present on a ring is
indicated in subscript by a number. Moreover, the substituent may
be present on any available ring atom, the available ring atom
being any ring atom which bears a hydrogen which the ring
substituent may replace. For illustrative purposes, if variable
R.sup.X were defined as being:
##STR00050##
[0264] this would indicate a cyclohexyl ring bearing five R.sup.X
substituents. The R.sup.X substituents may be bonded to any
available ring atom. For example, among the configurations
encompassed by this are configurations such as:
##STR00051##
[0265] These configurations are illustrative and are not meant to
limit the scope of the invention in any way.
Biological Activity
[0266] The inhibiting activity towards different metalloproteases
of the heterocyclic metalloprotease inhibiting compounds of the
present invention may be measured using any suitable assay known in
the art. A standard in vitro assay for measuring the
metalloprotease inhibiting activity is described in Examples 1700
to 1706. The heterocyclic metalloprotease inhibiting compounds show
activity towards MMP-2, MMP-3, MMP-8, MMP-12, MMP-13, ADAMTS-4
and/or ADAMTS-5.
[0267] The heterocyclic metalloprotease inhibiting compounds of the
invention have an MMP-13 inhibition activity (IC.sub.50 MMP-13)
ranging from below 0.2 nM to about 20 .mu.M, and typically, from
about 0.2 nM to about 1 .mu.M. Heterocyclic metalloprotease
inhibiting compounds of the invention desirably have an MMP
inhibition activity ranging from about 0.2 nM to about 20 nM. Table
1 lists typical examples of heterocyclic metalloprotease inhibiting
compounds of the invention that have an MMP-13 activity lower than
100 nM (Group A) and from 100 nM to 20 .mu.M (Group B).
TABLE-US-00001 TABLE 1 SUMMARY OF MMP-13 ACTIVITY FOR COMPOUNDS
Group Ex. # A 1, 2/25, 2/29, 2/33, 2/52, 2/67, 2/89, 2/90, 2/94,
2/95, 2/103, 2/104, 2/107, 2/108, 2/113, 2/114, 2/117, 2/118,
2/119, 2/120, 2/121, 2/122, 2/125, 2/126, 2/129, 2/131, 2/132,
2/145, 2/152, 2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/173,
2/174, 2/175, 2/176, 2/188, 2/208, 2/209, 2/210, 2/211, 2/219,
2/224, 2/231, 2/240, 2/245, 2/246, 2/251, 2/255, 2/267, 2/290,
2/309, 2/313, 2/316, 2/332, 2/354, 2/359, 2/367, 3/382, 2/413,
2/417, 2/526, 2/528, 3, 4/14, 4/15, 15, 15/2, 15/4, 15/5, 19, 22,
22/1, 22/2, 26, 28, 41, 42/2, 43 B 2/24, 2/34, 2/130, 2/143, 2/144,
2/146, 2/291, 2/292, 2/294, 2/302, 2/305, 2/307, 2/319, 2/323,
2/327, 2/328, 2/333, 2/344, 2/352, 2/355, 2/368, 2/383, 2/384,
2/428, 2/433, 2/530, 2/538, 39/7, 39/20
[0268] Some heterocyclic metalloprotease inhibiting compounds of
the invention have an MMP-8 inhibition activity (IC.sub.50 MMP-8)
ranging from below 5 nM to about 20 .mu.M, and typically, from
about 10 nM to about 2 .mu.M. Heterocyclic metalloprotease
inhibiting compounds of the invention desirably have an MMP
inhibition activity ranging below 100 nM. Table 2 lists typical
examples of heterocyclic metalloprotease inhibiting compounds of
the invention that have an MMP-8 activity lower than 250 nM (Group
A) and from 250 nM to 20 .mu.M (Group B).
TABLE-US-00002 TABLE 2 SUMMARY OF MMP-8 ACTIVITY FOR COMPOUNDS
Group Ex. # A 1, 2/25, 2/33, 2/52, 2/94, 2/95, 2/103, 2/104, 2/107,
2/113, 2/114, 2/117, 2/118, 2/121, 2/122, 2/125, 2/126, 2/131,
2/132, 2/152, 2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/174,
2/175, 2/176, 2/188, 2/209, 2/211, 2/218, 2/223, 2/224, 2/230,
2/240, 2/251, 2/255, 2/267, 2/269, 2/313, 2/413, 4/14, 4/15, 15,
15/2, 19, 22/1, 26, 42/2, 43/1 B 2/129, 2/130, 2/173, 2/290, 2/292,
2/316, 2/382, 2/383, 2/384, 2/387, 2/417, 2/428, 2/433, 2/528,
2/529, 2/538, 3, 15/3, 22, 22/2, 39/7, 39/20, 41, 42, 42/1
[0269] Some heterocyclic metalloprotease inhibiting compounds of
the invention have an MMP-3 inhibition activity (IC.sub.50 MMP-3)
ranging from below 10 nM to about 20 .mu.M, and typically, from
about 50 nM to about 2 .mu.M. Heterocyclic metalloprotease
inhibiting compounds of the invention desirably have an MMP
inhibition activity ranging below 100 nM.
[0270] Table 3 lists typical examples of heterocyclic
metalloprotease inhibiting compounds of the invention that have an
MMP-3 activity lower than 250 nM (Group A) and from 250 nM to 20
.mu.M (Group B).
TABLE-US-00003 TABLE 3 SUMMARY OF MMP-3 ACTIVITY FOR COMPOUNDS
Group Ex. # A 2/103, 2/104, 28, 42/2, 43 B 2/95, 2/107, 2/108,
2/132, 2/171, 2/188, 2/208, 2/209, 2/210, 2/211, 2/212, 2/231,
2/232, 2/236, 2/240, 2/245, 3, 4/15, 15, 15/2, 19, 22, 22/1, 22/2,
26, 39/7, 42/1
[0271] The synthesis of metalloprotease inhibiting compounds of the
invention and their biological activity assay are described in the
following examples which are not intended to be limiting in any
way.
Schemes
[0272] Provided below are schemes according to which compounds of
the present invention may be prepared.
[0273] In some embodiments the compounds of Formula (I) and (II)
are synthesized by the general methods shown in Scheme 1 to Scheme
3.
##STR00052##
Route A
[0274] An carbonic acid and amino substituted compound (e.g.
4-amino-nicotinic acid) is condensed (e.g. EtOH/reflux) with
chloro-oxo-acetic acid ethyl ester as previously described e.g. in
WO2005/105760 in pyridine to give an oxazine ethyl ester (Scheme
1). This intermediate is then converted into the corresponding
pyrimidine derivative using a suitable reagent (e.g. NH.sub.4OAc,
HOAc, EtOH/80.degree. C.). For example, when ring Q is a pyridine
ring. the compound can be obtained according this route A.
Route B
[0275] An ester and amino substituted compound (e.g.
2-amino-benzoic acid ethyl ester) is condensed (e.g. 4N HCl,
dioxane/50.degree. C.) with ethyl cyanoformate as previously
described e.g. in WO2005/105760, to give a 1,3-pyrimidine-4-one
ethyl ester (Scheme 1).
Route C
[0276] An carboxamide and amino substituted compound (e.g.
2-amino-benzamide) is condensed with an suitable reagent (e.g
oxalic acid diethyl ester or acetic acid anhydride as described in
DD272079A1 or chloro-oxo-acetic acid ethyl ester as described in J.
Med. Chem. 1979, 22(5), 505-510) to give a 1,3-pyrimidine-4-one
ethyl ester (Scheme 1).
##STR00053##
[0277] Saponification (e.g. aqueous LiOH) of the
1,3-pyrimidine-4-one derivative of Scheme 1 above gives the
corresponding bicyclic carboxylic acid (Scheme 2). Activated acid
coupling (e.g. EDCI/HOAt) with R.sup.1R.sup.2NH (e.g.
6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solvent
gives the desired amide. The saponification/coupling step can be
combined by stirring the ester with the free amine at elevated
temperature (e.g. 200.degree. C., 15 min) under microwave
irradiation.
##STR00054##
[0278] A substituted ketone (e.g. tetrahydrothiophen-3-one) is
condensed (e.g. toluene/reflux with Dean-Stark apparatus) with
ethyl cyanoacetate, acetic acid and ammonium acetate to afford the
desired ethyl ester-cyano substituted double bond. (Scheme 3). This
intermediate is then converted into the corresponding thiophene
derivative using suitable reagents (e.g. sulphur, Et.sub.2NH,
EtOH/50.degree. C.) as previously described e.g. in J. prakt. Chem.
1973, 315, 39-43 or Monatsh. Chem. 2001, 132, 279-293.
[0279] The Knoevenagel/cyclisation step can be combined by stirring
the ketone with ethyl cyanoacetate, sulphur and a base (e.g.
Et.sub.3N) in a suitable solvent (e.g EtOH/50.degree. C.),
following the Gewald type reaction as described e.g. in J. prakt.
Chem. 1973, 315, 39-43 or Bioorg. Med. Chem. 2002, 10,
3113-3122.
[0280] In compounds, where the one L.sub.b in formula (I) is a
nitrogen atom, the following procedure can be applied (Scheme
4).
##STR00055##
[0281] For example, N-(pyrazol-3-yl)acetamide acetate can be
cyclizised with carbonic acid diethyl ester to
2-methylpyrazolo[1,5a]-s-triazine-4-one (J. Heterocycl. Chem. 1985,
22, 601-634) and further oxidized to the corresponding acid (e.g.
by SeO.sub.2 and then oxone).
[0282] In ring Q of the product in Scheme 1 to Scheme 4, further
functional group manipulation can be applied (e.g. J. March,
Advanced Organic Chemistry, Wiley&Sons), e.g. palladium
catalyzed halogen-cyanide exchange or nucleophilic
substitution.
EXAMPLES AND METHODS
[0283] All reagents and solvents were obtained from commercial
sources and used without further purification. Proton spectra
('H-NMR) were recorded on a 400 MHz and a 250 MHz NMR spectrometer
in deuterated solvents. Purification by column chromatography was
performed using silica gel, grade 60, 0.06-0.2 mm (chromatography)
or silica gel, grade 60, 0.04-0.063 mm (flash chromatography) and
suitable organic solvents as indicated in specific examples.
Preparative thin layer chromatography was carried out on silica gel
plates with UV detection.
[0284] Preparative Examples are directed to intermediate compounds
useful in preparing the compounds of the present invention.
Preparative Example 4
##STR00056##
[0285] Step A
[0286] 2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic
acid methyl ester (1 g) was dissolved in a 4M solution of HCl in
1,4-dioxane (20 mL) and cyanoacetic acid ethyl ester (0.6 mL) was
added. The mixture was stirred at 40.degree. C. overnight,
concentrated and purified by extraction with ethyl acetate from an
aqueous solution to afford the title compound (1.3 g, 99%).
[MH].sup.+=265.
Preparative Examples 5/7 to 5/106
[0287] Following similar procedures as described in the Preparative
Examples 4 except using the amines indicated in Table I.2 below,
the following compounds were prepared.
TABLE-US-00004 TABLE I.2 Ex. # amine product yield 5/7 ##STR00057##
##STR00058## 59% [MH].sup.+ = 275 5/10 ##STR00059## ##STR00060##
n.d. [MH].sup.+ = 294 5/35 ##STR00061## ##STR00062## 74% [MH].sup.+
= 306 5/36 ##STR00063## ##STR00064## 36% [MH].sup.+ = 322 5/41
##STR00065## ##STR00066## 88% [MH].sup.+ = 329 5/43 ##STR00067##
##STR00068## 46% [MH].sup.+ = 357 5/45 ##STR00069## ##STR00070##
89% [MH].sup.+ = 337 5/47 ##STR00071## ##STR00072## 100% [MH].sup.+
= 293 5/48 ##STR00073## ##STR00074## 27% [MH].sup.+ = 297 5/49
##STR00075## ##STR00076## 100% [MH].sup.+ = 283 5/51 ##STR00077##
##STR00078## 95% [MH].sup.+ = 307 5/53 ##STR00079## ##STR00080##
100% [MH].sup.+ = 297 5/59 ##STR00081## ##STR00082## 84% [MH].sup.+
= 331 5/60 ##STR00083## ##STR00084## 96% [MH].sup.+ = 355 5/63
##STR00085## ##STR00086## 7% [MH].sup.+ = 281 5/64 ##STR00087##
##STR00088## 28% [MH].sup.+ = 394 5/69 ##STR00089## ##STR00090##
n.d. [MH].sup.+ = 406 5/71 ##STR00091## ##STR00092## 97% [MH].sup.+
= 351 5/72 ##STR00093## ##STR00094## 96% [MH].sup.+ = 337 5/73
##STR00095## ##STR00096## 35% [MH].sup.+ = 295 5/74 ##STR00097##
##STR00098## 30% (cryst from, CH.sub.2Cl.sub.2-- cyclohexane)
[MH].sup.+ = 311 5/76 ##STR00099## ##STR00100## 38% [MH].sup.+ =
365 5/87 ##STR00101## ##STR00102## 100% [MH].sup.+ = 351 5/88
##STR00103## ##STR00104## 69% [MH].sup.+ = 351 5/89 ##STR00105##
##STR00106## n.d. [MH].sup.+ = 323 5/91 ##STR00107## ##STR00108##
100% [MH].sup.+ = 351 5/95 ##STR00109## ##STR00110## 35% [MH].sup.+
= 400 5/106 ##STR00111## ##STR00112## n.d. [MH].sup.+ = n.d.
Preparative Example 9
##STR00113##
[0288] Step A
[0289] A solution of the commercially available
4-Isopropyl-phenylamine (1.35 g) and N-Bromosuccinimide (2.0 g) in
benzene (20 mL) was stirred at room temperature. After 12h, the
precipitated solid was filtered off, and the filtrate was
concentrated and purified by chromatography (silica, hexane/EtOAc)
to afford the title compound (1.8 g, 89%). [MH].sup.+=214.
Step B
[0290] A solution of the intermediate from Step A above (800 mg),
xantphos (36 mg), Pd.sub.2(dba).sub.3 (20 mg), triethylamine (1.4
mL) in methanol (10 mL) was heated in autoclave under carbon
monoxide at 50 psi at 100.degree. C. for 6 h. The solution was
concentrated and purified by chromatography (silica, hexane/EtOAc)
to afford the title compound (360 mg, 49%). [MH].sup.+=194.
Preparative Example 10/4
[0291] Following similar procedures as described in the Preparative
Example 9 except using the aniline derivative indicated in Table
1.4 below, the following compounds were prepared.
TABLE-US-00005 TABLE I.4 Ex. # Aniline Product yield 10/4
##STR00114## ##STR00115## 10% [MH].sup.+ = 259
Preparative Example 11
##STR00116##
[0292] Step A
[0293] To a solution of the Preparative Example 4 above (503 mg) in
THF (20 mL) was added 1M aqueous LiOH (5 mL). The resulting mixture
was stirred at room temperature for 1 h, concentrated and
neutralized with 1M aqueous HCl. The residue was filtered off and
used without further purification (420 mg, 87%).
[MH].sup.+=237.
Preparative Examples 12/9-12/104
[0294] Following a similar procedure as described in the
Preparative Example 11 except using the ester indicated in Table
1.5 below, the following compounds were prepared.
TABLE-US-00006 TABLE I.5 Ex. # Ester Product yield 12/9
##STR00117## ##STR00118## >99% [MH].sup.+ = 247 12/12
##STR00119## ##STR00120## n.d. [MH].sup.+ = 266 12/13 ##STR00121##
##STR00122## 83% [MH].sup.+ = 251 12/43 ##STR00123## ##STR00124##
n.d. [MH].sup.+ = 278 12/44 ##STR00125## ##STR00126## 92%
[MH].sup.+ = 294 12/49 ##STR00127## ##STR00128## 31% [MH].sup.+ =
301 12/51 ##STR00129## ##STR00130## 78% [MH].sup.+ = 329 12/54
##STR00131## ##STR00132## 56% [MH].sup.+ = 309 12/56 ##STR00133##
##STR00134## 68% [MH].sup.+ = 265 12/57 ##STR00135## ##STR00136##
100% [MH].sup.+ = 269 12/58 ##STR00137## ##STR00138## 69%
[MH].sup.+ = 255 12/60 ##STR00139## ##STR00140## 84% [MH].sup.+ =
279 12/62 ##STR00141## ##STR00142## 65% [MH].sup.+ = 269 12/68
##STR00143## ##STR00144## 89% [MH].sup.+ = 303 12/69 ##STR00145##
##STR00146## 100% [MH].sup.+ = 327 12/73 ##STR00147## ##STR00148##
100% [MH].sup.+ = 253 12/77 ##STR00149## ##STR00150## 45%
[MH].sup.+ = 366 12/84 ##STR00151## ##STR00152## n.d. [MH].sup.+ =
378 12/85 ##STR00153## ##STR00154## 63% [MH].sup.+ = 323 12/86
##STR00155## ##STR00156## 18% [MH].sup.+ = 309 12/87 ##STR00157##
##STR00158## 74% [MH].sup.+ = 267 12/89 ##STR00159## ##STR00160##
93% [MH].sup.+ = 283 12/91 ##STR00161## ##STR00162## 63% [MH].sup.+
= 337 12/92 ##STR00163## ##STR00164## 91% [MH].sup.+ = 323 12/93
##STR00165## ##STR00166## 70% [MH].sup.+ = 323 12/94 ##STR00167##
##STR00168## 21% (2 steps) [MH].sup.+ = 295 12/96 ##STR00169##
##STR00170## 47% [MH].sup.+ = 323 12/97 ##STR00171## ##STR00172##
68% [MH].sup.+ = 352 12/104 ##STR00173## ##STR00174## 92%
[MH].sup.+ = 372
Preparative Example 13
##STR00175##
[0295] Step A
[0296] A degassed suspension of commercially available
6-Bromo-4H-benzo[1,4]oxazin-3-one (8.39 g), Zn(CN).sub.2 (3.46 g)
and Pd(PPh.sub.3).sub.4 (2.13 g) in DMF (70 mL) was stirred in a
oil bath (80.degree. C.) overnight. The mixture was cooled to room
temperature and then poured into water (500 mL). The precipitate
was collected by suction, air dried, washed with pentane, dissolved
in CH.sub.2Cl.sub.2/MeOH (1:1), filtered through an silica pad and
concentrated to yield a yellow solid (5.68 g, 89%).
[MH].sup.+=175.
Step B
[0297] To an ice cooled solution of the title compound from Step A
above (5.6 g), di-tent-butyl dicarbonate (14.06 g) and
NiCl.sub.2.6H.sub.2O (1.53 g) in MeOH, NaBH.sub.4 (8.51 g) was
added in portions. The mixture was vigorously stirred for 1 h at
0.degree. C. and 1 h at room temperature. After the addition of
diethylenetriamine (3.5 mL) the mixture was concentrated, diluted
with EtOAc, washed subsequently with 1N HCl, saturated aqueous
NaHCO.sub.3 and saturated aqueous NaCl, dried (MgSO.sub.4),
concentrated to afford the title compound as an off-white solid
(7.91 g, 88%). [M+Na].sup.+=397.
Step C
[0298] The title compound from Step B above (7.91 g) was dissolved
in a 4M solution of HCl in 1,4-dioxane (120 mL), stirred for 14 h,
concentrated, suspended in Et.sub.2O, filtered and dried to afford
the title compound as an off-white solid (5.81 g, 96%).
[M-NH.sub.3Cl].sup.+=162.
Preparative Example 14
##STR00176##
[0299] Step A
[0300] A solution of commercially available
7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K.sub.2CO.sub.3
(3.60 g) and benzylchloroformate (2.7 mL) in THF/H.sub.2O was
stirred overnight and then concentrated. The residue was diluted
with EtOAc, washed with 10% aqueous citric acid, saturated aqueous
NaHCO.sub.3 and brine, dried (MgSO.sub.4) and concentrated. The
residue was dissolved in MeOH (100 mL) and di-tent-butyl
dicarbonate (7.60 g) and NiCl.sub.2.6H.sub.2O (400 mg) was added.
The solution was cooled to 0.degree. C. and NaBH.sub.4 (2.60 g) was
added in portions. The mixture was allowed to reach room
temperature and then vigorously stirred overnight. After the
addition of diethylenetriamine (2 mL) the mixture was concentrated,
diluted with EtOAc, washed subsequently with 10% aqueous citric
acid, saturated aqueous NaHCO.sub.3 and saturated aqueous NaCl,
dried (MgSO.sub.4), concentrated and purified by chromatography
(silica, CH.sub.2Cl.sub.2/MeOH) to afford the title compound as a
colorless oil (1.81 g, 26%). [MH].sup.+=397.
Preparative Example 15
##STR00177##
[0301] Step A
[0302] A mixture of the title compound from the Preparative Example
14 (1.81 g) and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was
hydrogenated at atmospheric pressure overnight, filtered and
concentrated to a volume of .about.20 mL.
3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt.sub.3 (0.5
mL) were added and the mixture was heated to reflux for 4 h.
Concentration and purification by chromatography (silica,
cyclohexane/EtOAc) afforded a slowly crystallizing colorless oil.
This oil was dissolved in EtOH (20 mL) and a 28% solution of
NH.sub.3 in H.sub.2O (100 mL) was added. The mixture was stirred
for 3 h, concentrated, slurried in H.sub.2O, filtered and dried
under reduced pressure. The remaining residue was dissolved in a 4M
solution of HCl in 1,4-dioxane (20 mL), stirred for 14 h,
concentrated, suspended in Et.sub.2O, filtered and dried to afford
the title compound as an off-white solid (1.08 g, 92%).
[M--Cl].sup.+=258.
Preparative Example 16
##STR00178##
[0303] Step A
[0304] Tetrahydrothiophen-3-one (1 g), ethyl cyanoacetate (1.44 g),
acetic acid (70 .mu.L) and ammonium acetate (30 mg) in toluene were
heated to reflux in presence of a Dean-Stark overnight. After
concentration of the mixture, a purification by chromatography
(silica cyclohexane/EtOAc 9/1) afforded a yellow oil (1.04 g, 54%).
[MH].sup.+=198.
Preparative Examples 17/1 to 17/20
[0305] Following similar procedures as described in the Preparative
Examples 16 except using the ketones indicated in Table 1.6 below,
the following compounds were prepared.
TABLE-US-00007 TABLE I.6 Ex. # Ketone Product yield 17/1
##STR00179## ##STR00180## 27% [MH].sup.+ = 212 17/2 ##STR00181##
##STR00182## n.d [MH].sup.+ = 309 17/5 ##STR00183## ##STR00184##
n.d [MH].sup.+ = n.d. 17/7 ##STR00185## ##STR00186## 93% [MH].sup.+
= 266 17/8 ##STR00187## ##STR00188## 83% [MH].sup.+ = 252 17/9
##STR00189## ##STR00190## 37% [MH].sup.+ = 210 17/10 ##STR00191##
##STR00192## n.d. [MH].sup.+ = 226 17/12 ##STR00193## ##STR00194##
n.d. [MH].sup.+ = 280 17/13 ##STR00195## ##STR00196## 40%
[MH].sup.+ = 266 17/14 ##STR00197## ##STR00198## n.d. [MH].sup.+ =
266 17/15 ##STR00199## ##STR00200## n.d. [MH].sup.+ = 238 17/17
##STR00201## ##STR00202## 41% [MH].sup.+ = 266 17/20 ##STR00203##
##STR00204## n.d. [MH].sup.+ = n.d.
Preparative Example 18
##STR00205##
[0306] Step A
[0307] A mixture of the title compound from the Preparative Example
16 (0.5 g) and sulfur (86 mg) in MeOH (5 mL) were heated at
50.degree. C. Diethylamine (135 .mu.L) was added slowly and the
mixture was stirred at 50.degree. C. for 2 h. After concentration
of the mixture, a purification by chromatography (silica
cyclohexane/EtOAc 9/1) afforded a orange solid (345 mg, 59%).
[MH].sup.+=230.
Preparative Examples 18/1 to 18/21
[0308] Following similar procedures as described in the Preparative
Examples 18 except using the adduct indicated in Table 1.7 below,
the following compounds were prepared.
TABLE-US-00008 TABLE I.7 Ex. # Adduct Product yield 18/1
##STR00206## ##STR00207## 43% [MH].sup.+ = 244 18/2 ##STR00208##
##STR00209## 62% (2 steps) [MH].sup.+ = 341 18/5 ##STR00210##
##STR00211## 98% (2 steps) [MH].sup.+ = 353 18/7 ##STR00212##
##STR00213## 82% [MH].sup.+ = 298 18/8 ##STR00214## ##STR00215##
65% [MH].sup.+ = 284 18/9 ##STR00216## ##STR00217## 80% [MH].sup.+
= 242 18/10 ##STR00218## ##STR00219## 92% (2 steps) [MH].sup.+ =
258 18/12 ##STR00220## ##STR00221## 47% (2 steps) [MH].sup.+ = 312
18/13 ##STR00222## ##STR00223## 79% [MH].sup.+ = 298 18/14
##STR00224## ##STR00225## 38% (2 steps) [MH].sup.+ = 298 18/15
##STR00226## ##STR00227## 62% (2 steps) [MH].sup.+ = 270 18/17
##STR00228## ##STR00229## 61% [MH].sup.+ = 298 18/21 ##STR00230##
##STR00231## 30% (2 steps). [MH].sup.+ = 347
Preparative Example 19
##STR00232##
[0309] Step A
[0310]
Ethyl-2-amino-6-terbutoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]py-
ridine-3-carboxylate (0.5 g) was dissolved in a 4M solution of HCl
in 1,4-dioxane (20 mL) and nitriloacetic acid ethyl ester (0.25 mL)
was added. The mixture was stirred at 50.degree. C. for 3 h and
concentrated. The decarboxylation of the ester was observed. This
product was used in the following step without further
purification. [MH].sup.+=280.
Step B
[0311] The title compound of Step A above was dissolved in DMF and
triethylamine (0.32 mL) was added. Di-tent-butyl dicarbonate (0.5
g) was added and the mixture was stirred at room temperature for 1
h. The solvent was removed by evaporation. The residue was
dissolved in dichloromethane and washed with water, dried and
evaporated to give the title compound (580 mg) as a yellow solid.
[MH].sup.+=380.
Preparative Example 20
##STR00233##
[0312] Step A
[0313] Tetrahydro-2H-pyran-4-one (1 g) was placed in methanol in
presence of barium oxide (0.1 g). Nitrosomethylurethane (1.3 g) was
added slowly to the reaction mixture. During the addition, barium
oxide (0.2 g) was added by small portion. The reaction was stirred
3 hours at room temperature and then filtrated. The methanol was
evaporated, diethyl ether was then added to the residue, a
precipitate was formed. The mixture was filtrated and diethyl ether
evaporated to afford the title compound (790 mg, 70%) as a yellow
oil. [MH].sup.+=115.
Preparative Example 20/1
[0314] Following similar procedures as described in the Preparative
Examples 20, except using the educt indicated in Table 1.13 below,
the following compounds were prepared.
TABLE-US-00009 TABLE I.13 Ex. # Educt Product yield 20/1
##STR00234## ##STR00235## 76% [MH].sup.+ = 143
Example 1
##STR00236##
[0315] Step A
[0316] To a solution of the title compound from Preparative Example
11 above (30 mg), EDCI (50 mg) and HOAt (22 mg) in DMF (10 mL) were
added N-methylmorpholine (50 .mu.L) and the title compound from the
Preparative Example 13 (50 mg). The mixture was stirred overnight
and then concentrated. The remaining residue was suspended in 10%
aqueous citric acid and the residue was filtered to afford the
title compound as an off white solid (38 mg, 74%).
[MH].sup.+=397.
Example 1A
##STR00237##
[0317] Step A
[0318] To a solution of the title compound from Preparative Example
12/16 above (9.5 mg), HATU (23.3 mg) and HOAt (8.2 mg) in DMA (200
.mu.L) was added a 0.1 M solution of morpholine in
DMA/pyridine(1:1, 440 .mu.L). The resulting mixture was agitated
(.about.600 rpm) at room temperature for 4 h, concentrated and
purified by HPLC (RP-C18, ACN/H.sub.2O) to afford the title
compound. [MH].sup.+=305.
Examples 2/24-2/547
[0319] Following similar procedures as described in the Examples 1
(method A) or 1a (method B), except using the amines and acids
indicated in Table II.1 below, the following compounds were
prepared.
TABLE-US-00010 TABLE II.1 Ex. # amine, acid Product method, yield
2/24 ##STR00238## ##STR00239## ##STR00240## A, 95% [MH].sup.+ = 407
2/25 ##STR00241## ##STR00242## ##STR00243## A, 26% [MH].sup.+ = 407
2/29 ##STR00244## ##STR00245## ##STR00246## A, 12% [MH].sup.+ = 426
2/30 ##STR00247## ##STR00248## ##STR00249## A, n.d. [MH].sup.+ =
426 2/33 ##STR00250## ##STR00251## ##STR00252## A, 29% [MH].sup.+ =
411 2/34 ##STR00253## ##STR00254## ##STR00255## A, 77% [MH].sup.+ =
411 2/52 ##STR00256## ##STR00257## ##STR00258## A, 85% [MH].sup.+ =
476 2/67 ##STR00259## ##STR00260## ##STR00261## A, 76% [MH].sup.+ =
486 2/89 ##STR00262## ##STR00263## ##STR00264## A, 27% [MH].sup.+ =
438 2/90 ##STR00265## ##STR00266## ##STR00267## A, 63% [MH].sup.+ =
517 2/94 ##STR00268## ##STR00269## ##STR00270## A, 83% [MH].sup.+ =
454 2/95 ##STR00271## ##STR00272## ##STR00273## A, 70% [MH].sup.+ =
533 2/103 ##STR00274## ##STR00275## ##STR00276## A, 81% [MH].sup.+
= 461 2/104 ##STR00277## ##STR00278## ##STR00279## A, 64%
[MH].sup.+ = 540 2/107 ##STR00280## ##STR00281## ##STR00282## A,
85% [MH].sup.+ = 489 2/108 ##STR00283## ##STR00284## ##STR00285##
A, quant. [MH].sup.+ = 489 2/113 ##STR00286## ##STR00287##
##STR00288## A, 40% [MH].sup.+ = 469 2/114 ##STR00289##
##STR00290## ##STR00291## A, 88% [MH].sup.+ = 548 2/117
##STR00292## ##STR00293## ##STR00294## A, 93% [MH].sup.+ = 425
2/118 ##STR00295## ##STR00296## ##STR00297## A, 98% [MH].sup.+ =
504 2/119 ##STR00298## ##STR00299## ##STR00300## A, 65% [MH].sup.+
= 429 2/120 ##STR00301## ##STR00302## ##STR00303## A, 76%
[MH].sup.+ = 508 2/121 ##STR00304## ##STR00305## ##STR00306## A,
86% [MH].sup.+ = 415 2/122 ##STR00307## ##STR00308## ##STR00309##
A, 91% [MH].sup.+ = 494 2/125 ##STR00310## ##STR00311##
##STR00312## A, 68% [MH].sup.+ = 439 2/126 ##STR00313##
##STR00314## ##STR00315## A, 43% [MH].sup.+ = 518 2/129
##STR00316## ##STR00317## ##STR00318## A, 31% [MH].sup.+ = 420
2/130 ##STR00319## ##STR00320## ##STR00321## A, 10% [MH].sup.+ =
422 2/131 ##STR00322## ##STR00323## ##STR00324## A, 77% [MH].sup.+
= 429 2/132 ##STR00325## ##STR00326## ##STR00327## A, 31%
[MH].sup.+ = 508 2/143 ##STR00328## ##STR00329## ##STR00330## A,
80% [MH].sup.+ = 463 2/144 ##STR00331## ##STR00332## ##STR00333##
A, 5% [MH].sup.+ = 542 2/145 ##STR00334## ##STR00335## ##STR00336##
A, 27% [MH].sup.+ = 487 2/146 ##STR00337## ##STR00338##
##STR00339## A, 74% [MH].sup.+ = 566 2/152 ##STR00340##
##STR00341## ##STR00342## A, 45% [MH].sup.+ = 413 2/153
##STR00343## ##STR00344## ##STR00345## A, 60% [MH].sup.+ = 492
2/166 ##STR00346## ##STR00347## A, 75% [MH].sup.+ = 440 2/167
##STR00348## ##STR00349## ##STR00350## A,99% [MH].sup.+ = 530 2/168
##STR00351## ##STR00352## ##STR00353## A, 40% [MH].sup.+ = 620
2/169 ##STR00354## ##STR00355## ##STR00356## A, 34% [MH].sup.+ =
587 2/170 ##STR00357## ##STR00358## ##STR00359## A, 50% [MH].sup.+
= 608 2/171 ##STR00360## ##STR00361## ##STR00362## A, 78%
[MH].sup.+ = 526 2/172 ##STR00363## ##STR00364## A, 26% [MH].sup.+
= 454 2/173 ##STR00365## ##STR00366## ##STR00367## A, 23%
[MH].sup.+ = 468 2/174 ##STR00368## ##STR00369## ##STR00370## A,
80% [MH].sup.+ = 548 2/175 ##STR00371## ##STR00372## ##STR00373##
A, 39% [MH].sup.+ = 544 2/176 ##STR00374## ##STR00375##
##STR00376## A, 36% [MH].sup.+ = 562 2/177 ##STR00377##
##STR00378## ##STR00379## A, 86% [MH].sup.+ = 562 2/178
##STR00380## ##STR00381## ##STR00382## A, 76% [MH].sup.+ = 562
2/188 ##STR00383## ##STR00384## ##STR00385## A, n.d. [MH].sup.+ =
538 2/208 ##STR00386## ##STR00387## ##STR00388## A, 25% [MH].sup.+
= 483 2/209 ##STR00389## ##STR00390## ##STR00391## A, 22%
[MH].sup.+ = 562 2/210 ##STR00392## ##STR00393## ##STR00394## A, 7%
[MH].sup.+ = 469 2/211 ##STR00395## ##STR00396## ##STR00397## A,
79% [MH].sup.+ = 427 2/212 ##STR00398## ##STR00399## ##STR00400##
A, 87% [MH].sup.+ = 506 2/218 ##STR00401## ##STR00402##
##STR00403## A, 66% [MH].sup.+ = 443 2/219 ##STR00404##
##STR00405## ##STR00406## A, 56% [MH].sup.+ = 522 2/223
##STR00407## ##STR00408## ##STR00409## A, 61% [MH].sup.+ = 478
2/224 ##STR00410## ##STR00411## ##STR00412## A, 58% [MH].sup.+ =
554 2/225 ##STR00413## ##STR00414## ##STR00415## A, 34% [MH].sup.+
= 482 2/230 ##STR00416## ##STR00417## ##STR00418## A, 48%
[MH].sup.+ = 534 2/231 ##STR00419## ##STR00420## ##STR00421## A,
87% [MH].sup.+ = 496 2/232 ##STR00422## ##STR00423## A, 70%
[MH].sup.+ = 519 2/236 ##STR00424## ##STR00425## ##STR00426## A,
98% [MH].sup.+ = 497 2/237 ##STR00427## ##STR00428## A, 78%
[MH].sup.+ = 482 2/238 ##STR00429## ##STR00430## ##STR00431## A,
80% [MH].sup.+ = 582 2/239 ##STR00432## ##STR00433## ##STR00434##
A, 79% [MH].sup.+ = 468 2/240 ##STR00435## ##STR00436## A, 69%
[MH].sup.+ = 468 2/245 ##STR00437## ##STR00438## ##STR00439## A,
26% [MH].sup.+ = 391 2/246 ##STR00440## ##STR00441## ##STR00442##
A, 10% [MH].sup.+ = 391 2/249 ##STR00443## ##STR00444##
##STR00445## A, 67% [MH].sup.+ = 526 2/250 ##STR00446##
##STR00447## ##STR00448## A, 69% [MH].sup.+ = 526 2/251
##STR00449## ##STR00450## ##STR00451## A, 90% [MH].sup.+ = 506
2/252 ##STR00452## ##STR00453## ##STR00454## A, 96% [MH].sup.+ =
483 2/253 ##STR00455## ##STR00456## A, 16% [MH].sup.+ = 454 2/254
##STR00457## ##STR00458## A, 26% [MH].sup.+ = 468 2/255
##STR00459## ##STR00460## A, 25% [MH].sup.+ = 497 2/256
##STR00461## ##STR00462## A, 86% [MH].sup.+ = 525 2/257
##STR00463## ##STR00464## ##STR00465## A, 85% [MH].sup.+ = 483
2/258 ##STR00466## ##STR00467## A, 43% [MH].sup.+ = 454 2/259
##STR00468## ##STR00469## A, 20% [MH].sup.+ = 468 2/260
##STR00470## ##STR00471## A, 30% [MH].sup.+ = 482 2/261
##STR00472## ##STR00473## ##STR00474## A, 14% [MH].sup.+ = 492
2/262 ##STR00475## ##STR00476## A, 78% [MH].sup.+ = 454 2/263
##STR00477## ##STR00478## A, 60% [MH].sup.+ = 468 2/264
##STR00479## ##STR00480## ##STR00481## A, 23% [MH].sup.+ = 455
2/266 ##STR00482## ##STR00483## ##STR00484## A, 95% [MH].sup.+ =
483 2/267 ##STR00485## ##STR00486## A, 96% [MH].sup.+ = 468
2/268 ##STR00487## ##STR00488## A, 57% [MH].sup.+ = 482 2/269
##STR00489## ##STR00490## A, 72% [MH].sup.+ = 496 2/270
##STR00491## ##STR00492## ##STR00493## A, 85% [MH].sup.+ = 512
2/289 ##STR00494## ##STR00495## ##STR00496## B, n.d. [MH].sup.+ =
315 2/290 ##STR00497## ##STR00498## ##STR00499## B, n.d. [MH].sup.+
= 343 2/291 ##STR00500## ##STR00501## ##STR00502## B, n.d.
[MH].sup.+ = 289 2/292 ##STR00503## ##STR00504## ##STR00505## B,
n.d. [MH].sup.+ = 343 2/293 ##STR00506## ##STR00507## ##STR00508##
B, n.d. [MH].sup.+ = 303 2/294 ##STR00509## ##STR00510##
##STR00511## B, n.d. [MH].sup.+ = 277 2/295 ##STR00512##
##STR00513## ##STR00514## B, n.d. [MH].sup.+ = 303 2/296
##STR00515## ##STR00516## ##STR00517## B, n.d. [MH].sup.+ = 325
2/297 ##STR00518## ##STR00519## ##STR00520## B, n.d. [MH].sup.+ =
331 2/298 ##STR00521## ##STR00522## ##STR00523## B, n.d. [MH].sup.+
= 334 2/299 ##STR00524## ##STR00525## ##STR00526## B, n.d.
[MH].sup.+ = 263 2/300 ##STR00527## ##STR00528## ##STR00529## B,
n.d. [MH].sup.+ = 317 2/301 ##STR00530## ##STR00531## ##STR00532##
B, n.d. [M - TFA].sup.+ = 306 2/302 ##STR00533## ##STR00534##
##STR00535## B, n.d. [MH].sup.+ = 403 2/303 ##STR00536##
##STR00537## ##STR00538## B, n.d. [MH].sup.+ = 249 2/304
##STR00539## ##STR00540## ##STR00541## B, n.d. [MH].sup.+ = 339
2/305 ##STR00542## ##STR00543## ##STR00544## B, n.d. [MH].sup.+ =
357 2/306 ##STR00545## ##STR00546## ##STR00547## B, n.d. [M -
TFA].sup.+ = 318 2/307 ##STR00548## ##STR00549## ##STR00550## B,
n.d. [MH].sup.+ = 365 2/308 ##STR00551## ##STR00552## ##STR00553##
B, n.d. [MH].sup.+ = 292 2/309 ##STR00554## ##STR00555##
##STR00556## B, n.d. [M - TFA].sup.+ = 326 2/310 ##STR00557##
##STR00558## ##STR00559## B, n.d. [MH].sup.+ = 339 2/311
##STR00560## ##STR00561## ##STR00562## B, n.d. [MH].sup.+ = 339
2/312 ##STR00563## ##STR00564## ##STR00565## B, n.d. [MH].sup.+ =
318 2/313 ##STR00566## ##STR00567## ##STR00568## B, n.d. [MH].sup.+
= 357 2/314 ##STR00569## ##STR00570## ##STR00571## B, n.d.
[MH].sup.+ = 404 2/315 ##STR00572## ##STR00573## ##STR00574## B,
n.d. [MH].sup.+ = 409 2/316 ##STR00575## ##STR00576## ##STR00577##
B, n.d. [MH].sup.+ = 383 2/317 ##STR00578## ##STR00579##
##STR00580## B, n.d. [M - TFA].sup.+ = 506 2/318 ##STR00581##
##STR00582## ##STR00583## B, n.d. [MH].sup.+ = 383 2/319
##STR00584## ##STR00585## ##STR00586## B, n.d. [MH].sup.+ = 357
2/320 ##STR00587## ##STR00588## ##STR00589## B, n.d. [MH].sup.+ =
357 2/321 ##STR00590## ##STR00591## ##STR00592## B, n.d. [MH].sup.+
= 401 2/322 ##STR00593## ##STR00594## ##STR00595## B, n.d.
[MH].sup.+ = 365 2/323 ##STR00596## ##STR00597## ##STR00598## B,
n.d. [MH].sup.+ = 346 2/324 ##STR00599## ##STR00600## ##STR00601##
B, n.d. [MH].sup.+ = 365 2/325 ##STR00602## ##STR00603##
##STR00604## B, n.d. [MH].sup.+ = 351 2/326 ##STR00605##
##STR00606## ##STR00607## B, n.d. [MH].sup.+ = 351 2/327
##STR00608## ##STR00609## ##STR00610## B, n.d. [MH].sup.+ = 368
2/328 ##STR00611## ##STR00612## ##STR00613## B, n.d. [M -
TFA].sup.+ = 402 2/329 ##STR00614## ##STR00615## ##STR00616## B,
n.d. [MH].sup.+ = 368 2/330 ##STR00617## ##STR00618## ##STR00619##
B, n.d. [MH].sup.+ = 332 2/331 ##STR00620## ##STR00621##
##STR00622## B, n.d. [MH].sup.+ = 376 2/332 ##STR00623##
##STR00624## ##STR00625## B, n.d. [MH].sup.+ = 427 2/333
##STR00626## ##STR00627## ##STR00628## B, n.d. [MH].sup.+ = 381
2/334 ##STR00629## ##STR00630## ##STR00631## B, n.d. [MH].sup.+ =
393 2/335 ##STR00632## ##STR00633## ##STR00634## B, n.d. [MH].sup.+
= 399 2/336 ##STR00635## ##STR00636## ##STR00637## B, n.d.
[MH].sup.+ = 393 2/337 ##STR00638## ##STR00639## ##STR00640## B,
n.d. [M - TFA].sup.+ = 368 2/338 ##STR00641## ##STR00642##
##STR00643## B, n.d. [MH].sup.+ = 375 2/339 ##STR00644##
##STR00645## ##STR00646## B, n.d. [MH].sup.+ = 393 2/340
##STR00647## ##STR00648## ##STR00649## B, n.d. [MH].sup.+ = 343
2/341 ##STR00650## ##STR00651## ##STR00652## B, n.d. [MH].sup.+ =
345 2/342 ##STR00653## ##STR00654## ##STR00655## B, n.d. [MH].sup.+
= 345 2/343 ##STR00656## ##STR00657## ##STR00658## B, n.d.
[MH].sup.+ = 319 2/344 ##STR00659## ##STR00660## ##STR00661## B,
n.d. [MH].sup.+ = 331 2/345 ##STR00662## ##STR00663## ##STR00664##
B, n.d. [M - TFA].sup.+ = 410 2/346 ##STR00665## ##STR00666##
##STR00667## B, n.d. [MH].sup.+ = 367 2/347 ##STR00668##
##STR00669## ##STR00670## B, n.d. [MH].sup.+ = 353 2/348
##STR00671## ##STR00672## ##STR00673## B, n.d. [MH].sup.+ = 353
2/349 ##STR00674## ##STR00675## ##STR00676## B, n.d. [MH].sup.+ =
353 2/350 ##STR00677## ##STR00678## ##STR00679## B, n.d. [MH].sup.+
= 345 2/351 ##STR00680## ##STR00681## ##STR00682## B, n.d.
[MH].sup.+ = 319 2/352 ##STR00683## ##STR00684## ##STR00685## B,
n.d. [MH].sup.+ = 381 2/353 ##STR00686## ##STR00687## ##STR00688##
B, n.d. [M - TFA].sup.+ = 410 2/354 ##STR00689## ##STR00690##
##STR00691## B, n.d. [MH].sup.+ = 365 2/355 ##STR00692##
##STR00693## ##STR00694## B, n.d. [M - TFA].sup.+ = 424 2/356
##STR00695## ##STR00696## ##STR00697## B, n.d. [MH].sup.+ = 409
2/357 ##STR00698## ##STR00699## ##STR00700## B, n.d. [M -
TFA].sup.+ = 326 2/358 ##STR00701## ##STR00702## ##STR00703## B,
n.d. [M - TFA].sup.+ = 340 2/359 ##STR00704## ##STR00705##
##STR00706## B, n.d. [M - TFA].sup.+ = 410 2/360 ##STR00707##
##STR00708## ##STR00709## B, n.d. [M - (TFA).sub.2].sup.+ = 423
2/361 ##STR00710## ##STR00711## ##STR00712## B, n.d. [MH].sup.+ =
409 2/362 ##STR00713## ##STR00714## ##STR00715## B, n.d. [MH].sup.+
= 333 2/363 ##STR00716## ##STR00717## ##STR00718## B, n.d.
[MH].sup.+ = 367 2/364 ##STR00719## ##STR00720## ##STR00721## B,
n.d. [M - TFA].sup.+ = 315 2/365 ##STR00722## ##STR00723##
##STR00724## B, n.d. [MH].sup.+ = 331 2/366 ##STR00725##
##STR00726## ##STR00727## B, n.d. [MH].sup.+ = 317 2/367
##STR00728## ##STR00729## ##STR00730## B, n.d. [MH].sup.+ = 410
2/368 ##STR00731## ##STR00732## ##STR00733## B, n.d. [M -
TFA].sup.+ = 394 2/369 ##STR00734## ##STR00735## ##STR00736## B,
n.d. [MH].sup.+ = 332 2/370 ##STR00737## ##STR00738## ##STR00739##
B, n.d. [MH].sup.+ =
374 2/371 ##STR00740## ##STR00741## ##STR00742## B, n.d. [MH].sup.+
= 374 2/372 ##STR00743## ##STR00744## ##STR00745## B, n.d.
[MH].sup.+ = 389 2/376 ##STR00746## ##STR00747## ##STR00748## A,
87% [MH].sup.+ = 532 2/382 ##STR00749## ##STR00750## ##STR00751##
B, n.d. [MH].sup.+ = 370 2/383 ##STR00752## ##STR00753##
##STR00754## B, n.d. [MH].sup.+ = 340 2/384 ##STR00755##
##STR00756## ##STR00757## B, n.d. [MH].sup.+ = 356 2/385
##STR00758## ##STR00759## ##STR00760## B, n.d. [MH].sup.+ = 348
2/386 ##STR00761## ##STR00762## ##STR00763## B, n.d. [MH].sup.+ =
356 2/387 ##STR00764## ##STR00765## ##STR00766## B, n.d. [MH].sup.+
= 356 2/388 ##STR00767## ##STR00768## ##STR00769## B, n.d.
[MH].sup.+ = 354 2/389 ##STR00770## ##STR00771## ##STR00772## B,
n.d. [MH].sup.+ = 384 2/390 ##STR00773## ##STR00774## ##STR00775##
B, n.d. [MH].sup.+ = 426 2/391 ##STR00776## ##STR00777##
##STR00778## B, n.d. [MH].sup.+ = 368 2/392 ##STR00779##
##STR00780## ##STR00781## B, n.d. [MH].sup.+ = 356 2/393
##STR00782## ##STR00783## ##STR00784## B, n.d. [MH].sup.+ = 356
2/394 ##STR00785## ##STR00786## ##STR00787## B, n.d. [MH].sup.+ =
384 2/395 ##STR00788## ##STR00789## ##STR00790## B, n.d. [MH].sup.+
= 384 2/396 ##STR00791## ##STR00792## ##STR00793## B, n.d.
[MH].sup.+ = 384 2/397 ##STR00794## ##STR00795## ##STR00796## B,
n.d. [MH].sup.+ = 356 2/398 ##STR00797## ##STR00798## ##STR00799##
B, n.d. [MH].sup.+ = 400 2/399 ##STR00800## ##STR00801##
##STR00802## B, n.d. [MH].sup.+ = 372 2/400 ##STR00803##
##STR00804## ##STR00805## B, n.d. [MH].sup.+ = 455 2/401
##STR00806## ##STR00807## ##STR00808## B, n.d. [MH].sup.+ = 384
2/402 ##STR00809## ##STR00810## ##STR00811## B, n.d. [MH].sup.+ =
384 2/403 ##STR00812## ##STR00813## ##STR00814## B, n.d. [MH].sup.+
= 383 2/404 ##STR00815## ##STR00816## ##STR00817## B, n.d.
[MH].sup.+ = 383 2/405 ##STR00818## ##STR00819## ##STR00820## B,
n.d. [MH].sup.+ = 340 2/406 ##STR00821## ##STR00822## ##STR00823##
B, n.d. [MH].sup.+ = 406 2/407 ##STR00824## ##STR00825##
##STR00826## B, n.d. [MH].sup.+ = 382 2/408 ##STR00827##
##STR00828## ##STR00829## B, n.d. [MH].sup.+ = 396 2/409
##STR00830## ##STR00831## ##STR00832## B, n.d. [MH].sup.+ = 383
2/410 ##STR00833## ##STR00834## ##STR00835## B, n.d. [MH].sup.+ =
397 2/411 ##STR00836## ##STR00837## B, n.d. [MH].sup.+ = 397 2/412
##STR00838## ##STR00839## B, n.d. [MH].sup.+ = 410 2/413
##STR00840## ##STR00841## ##STR00842## B, n.d. [MH].sup.+ = 450
2/414 ##STR00843## ##STR00844## B, n.d. [MH].sup.+ = 478 2/415
##STR00845## ##STR00846## ##STR00847## B, n.d. [MH].sup.+ = 394
2/416 ##STR00848## ##STR00849## ##STR00850## B, n.d. [MH].sup.+ =
464 2/417 ##STR00851## ##STR00852## ##STR00853## B, n.d. [MH].sup.+
= 468 2/418 ##STR00854## ##STR00855## ##STR00856## B, n.d.
[MH].sup.+ = 482 2/419 ##STR00857## ##STR00858## ##STR00859## B,
n.d. [MH].sup.+ = 482 2/420 ##STR00860## ##STR00861## ##STR00862##
B, n.d. [MH].sup.+ = 416 2/421 ##STR00863## ##STR00864##
##STR00865## B, n.d. [MH].sup.+ = 490 2/422 ##STR00866##
##STR00867## ##STR00868## B, n.d. [MH].sup.+ = 372 2/423
##STR00869## ##STR00870## ##STR00871## B, n.d. [MH].sup.+ = 351
2/424 ##STR00872## ##STR00873## ##STR00874## B, n.d. [M -
TFA].sup.+ = 368 2/425 ##STR00875## ##STR00876## ##STR00877## B,
n.d. [MH].sup.+ = 390 2/426 ##STR00878## ##STR00879## ##STR00880##
B, n.d. [MH].sup.+ = 412 2/427 ##STR00881## ##STR00882##
##STR00883## B, n.d. [MH].sup.+ = 412 2/428 ##STR00884##
##STR00885## ##STR00886## B, n.d. [MH].sup.+ = 384 2/429
##STR00887## ##STR00888## ##STR00889## B, n.d. [MH].sup.+ = 400
2/430 ##STR00890## ##STR00891## ##STR00892## B, n.d. [MH].sup.+ =
400 2/431 ##STR00893## ##STR00894## ##STR00895## B, n.d. [MH].sup.+
= 388 2/432 ##STR00896## ##STR00897## ##STR00898## B, n.d.
[MH].sup.+ = 368 2/433 ##STR00899## ##STR00900## ##STR00901## B,
n.d. [MH].sup.+ = 378 2/434 ##STR00902## ##STR00903## ##STR00904##
B, n.d. [MH].sup.+ = 342 2/435 ##STR00905## ##STR00906##
##STR00907## B, n.d. [MH].sup.+ = 420/422 2/436 ##STR00908##
##STR00909## ##STR00910## B, n.d. [MH].sup.+ = 425 2/437
##STR00911## ##STR00912## ##STR00913## B, n.d. [MH].sup.+ = 395
2/438 ##STR00914## ##STR00915## ##STR00916## B, n.d. [MH].sup.+ =
402 2/439 ##STR00917## ##STR00918## ##STR00919## B, n.d. [MH].sup.+
= 412 2/440 ##STR00920## ##STR00921## ##STR00922## B, n.d. [M -
TFA].sup.+ = 365 2/441 ##STR00923## ##STR00924## ##STR00925## B,
n.d. [MH].sup.+ = 392 2/442 ##STR00926## ##STR00927## ##STR00928##
B, n.d. [MH].sup.+ = 392 2/443 ##STR00929## ##STR00930##
##STR00931## B, n.d. [MH].sup.+ = 351 2/444 ##STR00932##
##STR00933## ##STR00934## B, n.d. [MH].sup.+ = 388 2/445
##STR00935## ##STR00936## ##STR00937## B, n.d. [MH].sup.+ = 404
2/446 ##STR00938## ##STR00939## ##STR00940## B, n.d. [MH].sup.+ =
455 2/447 ##STR00941## ##STR00942## ##STR00943## B, n.d. [MH].sup.+
= 384 2/448 ##STR00944## ##STR00945## ##STR00946## B, n.d.
[MH].sup.+ = 419 2/449 ##STR00947## ##STR00948## ##STR00949## B,
n.d. [MH].sup.+ = 384 2/450 ##STR00950## ##STR00951## ##STR00952##
B, n.d. [M - TFA].sup.+ = 357 2/451 ##STR00953## ##STR00954## B,
n.d. [MH].sup.+ = 294 2/452 ##STR00955## ##STR00956## ##STR00957##
B, n.d. [MH].sup.+ = 360 2/453 ##STR00958## ##STR00959##
##STR00960## B, n.d. [MH].sup.+ = 306 2/454 ##STR00961##
##STR00962## ##STR00963## B, n.d. [MH].sup.+ = 462 2/455
##STR00964## ##STR00965## ##STR00966## B, n.d. [M - TFA].sup.+ =
347 2/456 ##STR00967## ##STR00968## ##STR00969## B, n.d. [MH].sup.+
= 306 2/457 ##STR00970## ##STR00971## ##STR00972## B, n.d.
[MH].sup.+ = 370 2/458 ##STR00973## ##STR00974## ##STR00975## B,
n.d. [MH].sup.+ = 320 2/459 ##STR00976## ##STR00977## ##STR00978##
B, n.d. [MH].sup.+ = 280 2/460 ##STR00979## ##STR00980##
##STR00981## B, n.d. [MH].sup.+ = 446 2/461 ##STR00982##
##STR00983## ##STR00984## B, n.d. [MH].sup.+ = 320 2/462
##STR00985## ##STR00986## ##STR00987## B, n.d. [MH].sup.+ = 320
2/463 ##STR00988## ##STR00989## ##STR00990## B, n.d. [MH].sup.+
=
330 2/464 ##STR00991## ##STR00992## ##STR00993## B, n.d. [MH].sup.+
= 320 2/465 ##STR00994## ##STR00995## ##STR00996## B, n.d.
[MH].sup.+ = 394 2/466 ##STR00997## ##STR00998## ##STR00999## B,
n.d. [MH].sup.+ = 419 2/467 ##STR01000## ##STR01001## ##STR01002##
B, n.d. [MH].sup.+ = 308 2/468 ##STR01003## ##STR01004##
##STR01005## B, n.d. [MH].sup.+ = 364 2/469 ##STR01006##
##STR01007## ##STR01008## B, n.d. [MH].sup.+ = 376 2/470
##STR01009## ##STR01010## ##STR01011## B, n.d. [MH].sup.+ = 337
2/471 ##STR01012## ##STR01013## ##STR01014## B, n.d. [MH].sup.+ =
405 2/472 ##STR01015## ##STR01016## ##STR01017## B, n.d. [MH].sup.+
= 418/420 2/473 ##STR01018## ##STR01019## ##STR01020## B, n.d. [M -
TFA].sup.+ = 328 2/474 ##STR01021## ##STR01022## ##STR01023## B,
n.d. [MH].sup.+ = 294 2/475 ##STR01024## ##STR01025## ##STR01026##
B, n.d. [MH].sup.+ = 322 2/476 ##STR01027## ##STR01028##
##STR01029## B, n.d. [MH].sup.+ = 418/420 2/477 ##STR01030##
##STR01031## ##STR01032## B, n.d. [M - TFA].sup.+ = 407 2/478
##STR01033## ##STR01034## ##STR01035## B, n.d. [M - TFA].sup.+ =
321 2/479 ##STR01036## ##STR01037## ##STR01038## B, n.d. [MH].sup.+
= 294 2/480 ##STR01039## ##STR01040## ##STR01041## B, n.d.
[MH].sup.+ = 274 2/481 ##STR01042## ##STR01043## ##STR01044## B,
n.d. [MH].sup.+ = 368 2/482 ##STR01045## ##STR01046## ##STR01047##
B, n.d. [MH].sup.+ = 386 2/483 ##STR01048## ##STR01049##
##STR01050## B, n.d. [M - TFA].sup.+ = 452 2/484 ##STR01051##
##STR01052## ##STR01053## B, n.d. [MH].sup.+ = 466 2/485
##STR01054## ##STR01055## ##STR01056## B, n.d. [MH].sup.+ = 320
2/486 ##STR01057## ##STR01058## ##STR01059## B, n.d. [M -
TFA].sup.+ = 411 2/487 ##STR01060## ##STR01061## ##STR01062## B,
n.d. [M - TFA].sup.+ = 411 2/488 ##STR01063## ##STR01064##
##STR01065## B, n.d. [MH].sup.+ = 404/406 2/489 ##STR01066##
##STR01067## ##STR01068## B, n.d. [MH].sup.+ = 348 2/490
##STR01069## ##STR01070## ##STR01071## B, n.d. [MH].sup.+ = 315
2/491 ##STR01072## ##STR01073## ##STR01074## B, n.d. [M -
TFA].sup.+ = 355 2/492 ##STR01075## ##STR01076## ##STR01077## B,
n.d. [MH].sup.+ = 292 2/493 ##STR01078## ##STR01079## ##STR01080##
B, n.d. [MH].sup.+ = 368 2/494 ##STR01081## ##STR01082##
##STR01083## B, n.d. [MH].sup.+ = 462 2/495 ##STR01084##
##STR01085## ##STR01086## B, n.d. [MH].sup.+ = 422/424 2/496
##STR01087## ##STR01088## ##STR01089## B, n.d. [MH].sup.+ = 342
2/497 ##STR01090## ##STR01091## ##STR01092## B, n.d. [MH].sup.+ =
399 2/498 ##STR01093## ##STR01094## ##STR01095## B, n.d. [MH].sup.+
= 362 2/499 ##STR01096## ##STR01097## ##STR01098## B, n.d.
[MH].sup.+ = 362 2/500 ##STR01099## ##STR01100## ##STR01101## B,
n.d. [MH].sup.+ = 306 2/501 ##STR01102## ##STR01103## ##STR01104##
B, n.d. [MH].sup.+ = 306 2/502 ##STR01105## ##STR01106##
##STR01107## B, n.d. [MH].sup.+ = 292 2/503 ##STR01108##
##STR01109## ##STR01110## B, n.d. [MH].sup.+ = 292 2/504
##STR01111## ##STR01112## ##STR01113## B, n.d. [M - TFA].sup.+ =
375 2/505 ##STR01114## ##STR01115## ##STR01116## B, n.d. [M -
TFA].sup.+ = 319 2/506 ##STR01117## ##STR01118## ##STR01119## B,
n.d. [MH].sup.+ = 447 2/507 ##STR01120## ##STR01121## ##STR01122##
B, n.d. [M - TFA].sup.+ = 333 2/508 ##STR01123## ##STR01124##
##STR01125## B, n.d. [MH].sup.+ = 390 2/509 ##STR01126##
##STR01127## ##STR01128## B, n.d. [M - TFA].sup.+ = 423 2/510
##STR01129## ##STR01130## ##STR01131## B, n.d. [MH].sup.+ = 336
2/511 ##STR01132## ##STR01133## ##STR01134## B, n.d. [MH].sup.+ =
383 2/512 ##STR01135## ##STR01136## ##STR01137## B, n.d. [MH].sup.+
= 383 2/513 ##STR01138## ##STR01139## ##STR01140## B, n.d.
[MH].sup.+ = 333 2/514 ##STR01141## ##STR01142## ##STR01143## B,
n.d. [MH].sup.+ = 358 2/515 ##STR01144## ##STR01145## ##STR01146##
B, n.d. [MH].sup.+ = 433 2/516 ##STR01147## ##STR01148##
##STR01149## B, n.d. [MH].sup.+ = 304 2/517 ##STR01150##
##STR01151## ##STR01152## B, n.d. [MH].sup.+ = 318 2/518
##STR01153## ##STR01154## ##STR01155## B, n.d. [M - TFA].sup.+ =
345 2/519 ##STR01156## ##STR01157## ##STR01158## B, n.d. [M -
TFA].sup.+ = 328 2/520 ##STR01159## ##STR01160## ##STR01161## B,
n.d. [MH].sup.+ = 447 2/521 ##STR01162## ##STR01163## ##STR01164##
B, n.d. [M - TFA].sup.+ = 330 2/522 ##STR01165## ##STR01166##
##STR01167## B, n.d. [MH].sup.+ = 382 2/523 ##STR01168##
##STR01169## ##STR01170## B, n.d. [MH].sup.+ = 410 2/524
##STR01171## ##STR01172## ##STR01173## B, n.d. [MH].sup.+ = 410
2/525 ##STR01174## ##STR01175## ##STR01176## B, n.d. [MH].sup.+ =
410 2/526 ##STR01177## ##STR01178## ##STR01179## B, n.d. [MH].sup.+
= 390 2/527 ##STR01180## ##STR01181## ##STR01182## B, n.d. [M -
(TFA).sub.2].sup.+ = 396 2/528 ##STR01183## ##STR01184##
##STR01185## B, n.d. [M - (TFA).sub.2].sup.+ = 428 2/529
##STR01186## ##STR01187## ##STR01188## B, n.d. [M -
(TFA).sub.2].sup.+ = 412 2/530 ##STR01189## ##STR01190##
##STR01191## B, n.d. [MH].sup.+ = 419 2/531 ##STR01192##
##STR01193## ##STR01194## B, n.d. [MH].sup.+ = 358 2/532
##STR01195## ##STR01196## ##STR01197## B, n.d. [MH].sup.+ = 358
2/533 ##STR01198## ##STR01199## ##STR01200## B, n.d. [MH].sup.+ =
346 2/534 ##STR01201## ##STR01202## ##STR01203## B, n.d. [MH].sup.+
= 358 2/535 ##STR01204## ##STR01205## ##STR01206## B, n.d.
[MH].sup.+ = 340 2/536 ##STR01207## ##STR01208## ##STR01209## B,
n.d. [M - TFA].sup.+ = 349 2/537 ##STR01210## ##STR01211##
##STR01212## B, n.d. [MH].sup.+ = 415 2/538 ##STR01213##
##STR01214## ##STR01215## B, n.d. [MH].sup.+ = 459 2/539
##STR01216## ##STR01217## ##STR01218## B, n.d. [MH].sup.+ = 411
2/540 ##STR01219## ##STR01220## ##STR01221## B, n.d. [MH].sup.+ =
415 2/541 ##STR01222## ##STR01223## ##STR01224## B, n.d. [MH].sup.+
= 433 2/542 ##STR01225## ##STR01226## ##STR01227## B, n.d.
[MH].sup.+ = 411 2/543 ##STR01228## ##STR01229## ##STR01230## B,
n.d. [MH].sup.+ = 436 2/544 ##STR01231## ##STR01232## ##STR01233##
B, n.d. [MH].sup.+ = 454 2/545 ##STR01234## ##STR01235##
##STR01236## B, n.d. [MH].sup.+ = 383 2/546 ##STR01237##
##STR01238## ##STR01239## B, n.d. [MH].sup.+ = 426
2/547 ##STR01240## ##STR01241## ##STR01242## B, n.d. [MH].sup.+ =
416
Example 3
##STR01243##
[0320] Step A
[0321] To a solution of the title compound from Step A above (200
mg) in THF (3 mL) was added 1M aqueous LiOH (1.2 mL). The resulting
mixture was stirred at room temperature 3h, concentrated and
suspended in 1M aqueous HCl. The residue was filtered off and used
without further purification (150 mg, 80%). [MH].sup.+=469.
Examples 4/4-4/19
[0322] Following a similar procedure as described in Example 3,
except using the ester indicated in Table II.2 below, the following
compounds were prepared.
TABLE-US-00011 TABLE II.2 Ex. # Ester 4/4 ##STR01244## 4/9
##STR01245## 4/10 ##STR01246## 4/11 ##STR01247## 4/14 ##STR01248##
4/15 ##STR01249## 4/17 ##STR01250## 4/18 ##STR01251## 4/19
##STR01252## Ex. # Product Yield 4/4 ##STR01253## 70% [MH].sup.+ =
441 4/9 ##STR01254## 66% [MH].sup.+ = 606 4/10 ##STR01255## 68%
[MH].sup.+ = 574 4/11 ##STR01256## 99% [MH].sup.+ = 455 4/14
##STR01257## 65% [MH].sup.+ = 520 4/15 ##STR01258## 65% [MH].sup.+
= 441 4/17 ##STR01259## 40% [MH].sup.+ = 455 4/18 ##STR01260## 72%
[MH].sup.+ = 455 4/19 ##STR01261## 66% [MH].sup.+ = 467
Example 15
##STR01262##
[0323] Step A
[0324] To the title compound from Step A above (55 mg) was added a
4M solution of HCl in 1,4-dioxane (3 mL). The reaction mixture was
stirred at room temperature overnight and concentrated to afford
the title compound (29 mg, 58%). [MH].sup.+=526.
Examples 15/2-15/5
[0325] Following a similar procedure as described in the Example
15, except using the protected product indicated in Table II.7
below, the following compounds were prepared.
TABLE-US-00012 TABLE II.7 Ex. # educt 15/2 ##STR01263## 15/3
##STR01264## 15/4 ##STR01265## 15/5 ##STR01266## Ex. # Product
Yield 15/2 ##STR01267## 50% [MH].sup.+ = 498 15/3 ##STR01268## 16%
[MH].sup.+ = 426 15/4 ##STR01269## 69% [MH].sup.+ = 426 15/5
##STR01270## 46% [MH].sup.+ = 412
Example 19
##STR01271##
[0326] Step A
[0327] To DMF (5 mL) was added 2M oxalylchloride in dichloromethane
(250 .mu.L) at 0.degree. C. Then a solution of the title compound
from Example 2/166 (200 mg) in DMF (2 mL) was added and the mixture
was stirred for 6 h at 0.degree. C. After adding pyridine (150
.mu.L) the mixture was stirred for additional 2h at room
temperature. The mixture was concentrated and the remaining residue
was suspended in 1M HCl and filtered to afford the title compound
as an off white solid (192 mg, 99%). [MH].sup.+=422.
Example 22
##STR01272##
[0328] Step A
[0329] The title compound from example 2/119 (9 mg) was placed in a
mixture acetic acid/acetic acid anhydride (1:1). Hydrogen peroxide
(6 .mu.L) was added and the reaction mixture was heated at
100.degree. C. for 4 h and then stirred at room temperature
overnight. After evaporation, water was added and the residual
product was filtrated and dried to afford the title compound (7 mg,
72%). [MH].sup.+=461.
Example 22/1 and 22/2
[0330] Following a similar procedure as described in Example 22,
except using the educt indicated in Table II.9 below, the following
compounds were prepared.
TABLE-US-00013 TABLE II.9 Ex. # Educt product Yield 22/1
##STR01273## ##STR01274## 80% [MH].sup.+ = 475 22/2 ##STR01275##
##STR01276## 89% [MH].sup.+ = 461
Example 26
##STR01277##
[0331] Step A
[0332] The title compound from Example 2/218 (15.8 mg) was
dissolved in DMSO, then H.sub.2O.sub.2 (.about.1 mL) was added and
the mixture was stirred at room temperature for 3 h, evaporated,
slurried with water and filtered to afford the title compound (13.8
mg, 84%) as a colourless solid. [MH].sup.+=459.
Example 28
##STR01278##
[0333] Step A
[0334] To a solution of
9-oxo-8,9-dihydro-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalene-7-carboxyl-
ic acid ethyl ester (32 mg) in ethanol (1 mL) were added triethyl
amine (40 .mu.L) and the title compound from the Preparative
Example 13 (30 mg). The mixture was heated at 180.degree. C. in a
microwave oven for 1 h and then concentrated. The remaining residue
was purified by silica gel chromatography (10% methanol in
methylene chloride) to give a yellow solid (45 mg, 95%).
[MH].sup.+=395.
Example 39/7 and 39/20
[0335] Following similar procedures as described in Examples 28
except using the amines and the ester indicated in Table II.14
below, the following compounds were prepared.
TABLE-US-00014 TABLE II.14 Ex. # amine; ester 39/7 ##STR01279##
##STR01280## 39/20 ##STR01281## ##STR01282## Ex. # product Yield
39/7 ##STR01283## 20% [MH].sup.+ = 428 39/20 ##STR01284## 19%
[MH].sup.+ = 401
Example 41
##STR01285##
[0336] Step A
[0337] The title compound from Example 2/376 above was stirred in a
solution of HBr in glacial acid (33 wt %) at room temperature for 2
h. Evaporation afford the title compound. [MH].sup.+=398.
Example 42
##STR01286##
[0338] Step A
[0339] To a solution of the title compound from Example 41 (9.6 mg)
in pyridine (200 .mu.L) was added acetyl chloride (3 .mu.L) at room
temperature. The mixture was stirred for 2 h at room temperature
and evaporated. The resulting residue was purified by HPLC to
afford the title compound. (2.2 mg; 25%, [MH].sup.+=440).
Example 42/1 and 42/2
[0340] Following a similar procedure as described in Example 42
above, except using amines and acid chlorides as indicated in the
Table II.15 below, the following compounds were prepared.
TABLE-US-00015 TABLE II.15 Ex. # Amine; acid chloride 42/1
##STR01287## ##STR01288## 42/2 ##STR01289## ##STR01290## Ex. #
product Yield 42/1 ##STR01291## 9% [MH].sup.+ = 508 42/2
##STR01292## 29% [MH].sup.+ = 476
Example 43
##STR01293##
[0341] Step A
[0342] To a solution of the title compound from Example 41 (15 mg)
above in DMA (5004) was added 2-bromo-pyrimidine (10 mg). The
mixture was heated in a sealed tube at 100.degree. C. (microwave)
for 5 min. Purification by HPLC afforded the title compound. (6.1
mg; 33%, [MH].sup.+=476).
Example 43/1
[0343] Following a similar procedure as described in Example 43
above, except using amine and benzyl bromide as indicated in the
Table 11.16 below, the following compound was prepared.
TABLE-US-00016 TABLE II.16 Ex. # Amine; benzyl bromide 43/1
##STR01294## ##STR01295## Ex. # product yield 43/1 ##STR01296## 14%
[MH].sup.+ = 488
Example 1700
Assay for Determining MMP-13 Inhibition
[0344] The typical assay for MMP-13 activity is carried out in
assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM
CaCl.sub.2 and 0.05% Brij-35. Different concentrations of tested
compounds are prepared in assay buffer in 50 .mu.L aliquots. 10
.mu.L of a 50 nM stock solution of catalytic domain of MMP-13
enzyme (produced by Alantos or commercially available from Invitek
(Berlin), Cat.# 30100812) is added to the compound solution. The
mixture of enzyme and compound in assay buffer is thoroughly mixed
and incubated for 10 min at room temperature. Upon the completion
of incubation, the assay is started by addition of 40 .mu.L of a
12.5 .mu.M stock solution of MMP-13 fluorescent substrate
(Calbiochem, Cat. No. 444235). The time-dependent increase in
fluorescence is measured at the 320 nm excitation and 390 nm
emission by automatic plate multireader. The IC.sub.50 values are
calculated from the initial reaction rates.
Example 1701
Assay for Determining MMP-3 Inhibition
[0345] The typical assay for MMP-3 activity is carried out in assay
buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl.sub.2 and 0.05%
Brij-35. Different concentrations of tested compounds are prepared
in assay buffer in 50 .mu.L aliquots. 10 .mu.L of a 100 nM stock
solution of the catalytic domain of MMP-3 enzyme (Biomol, Cat. No.
SE-109) is added to the compound solution. The mixture of enzyme
and compound in assay buffer is thoroughly mixed and incubated for
10 min at room temperature. Upon the completion of incubation, the
assay is started by addition of 40 .mu.L of a 12.5 .mu.M stock
solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No.
480-455). The time-dependent increase in fluorescence is measured
at the 330 nm excitation and 390 nm emission by an automatic plate
multireader. The IC.sub.50 values are calculated from the initial
reaction rates.
Example 1702
Assay for Determining MMP-8 Inhibition
[0346] The typical assay for MMP-8 activity is carried out in assay
buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM
CaCl.sub.2 and 0.05% Brij-35. Different concentrations of tested
compounds are prepared in assay buffer in 50 .mu.L aliquots. 10
.mu.L of a 50 nM stock solution of activated MMP-8 enzyme
(Calbiochem, Cat. No. 444229) is added to the compound solution.
The mixture of enzyme and compound in assay buffer is thoroughly
mixed and incubated for 10 min at 37.degree. C. Upon the completion
of incubation, the assay is started by addition of 40 .mu.L of a 10
.mu.M stock solution of OmniMMP fluorescent substrate (Biomol, Cat.
No. P-126). The time-dependent increase in fluorescence is measured
at the 320 nm excitation and 390 nm emission by an automatic plate
multireader at 37.degree. C. The IC.sub.50 values are calculated
from the initial reaction rates.
Example 1703
Assay for Determining MMP-12 Inhibition
[0347] The typical assay for MMP-12 activity is carried out in
assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM
CaCl.sub.2 and 0.05% Brij-35. Different concentrations of tested
compounds are prepared in assay buffer in 50 .mu.L aliquots. 10
.mu.L of a 50 nM stock solution of the catalytic domain of MMP-12
enzyme (Biomol, Cat. No. SE-138) is added to the compound solution.
The mixture of enzyme and compound in assay buffer is thoroughly
mixed and incubated for 10 min at room temperature. Upon the
completion of incubation, the assay is started by addition of 40
.mu.L of a 12.5 .mu.M stock solution of OmniMMP fluorescent
substrate (Biomol, Cat. No. P-126). The time-dependent increase in
fluorescence is measured at the 320 nm excitation and 390 nm
emission by automatic plate multireader at 37.degree. C. The
IC.sub.50 values are calculated from the initial reaction
rates.
Example 1704
Assay for Determining Aggrecanase-1 Inhibition
[0348] The typical assay for aggrecanase-1 activity is carried out
in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM
CaCl.sub.2 and 0.05% Brij-35. Different concentrations of tested
compounds are prepared in assay buffer in 50 .mu.L aliquots. 10
.mu.L of a 75 nM stock solution of aggrecanase-1 (Invitek) is added
to the compound solution. The mixture of enzyme and compound in
assay buffer is thoroughly mixed. The reaction is started by
addition of 40 .mu.L of a 250 nM stock solution of aggrecan-IGD
substrate (Invitek) and incubation at 37.degree. C. for exact 15
min. The reaction is stopped by addition of EDTA and the samples
are analysed by using aggrecanase ELISA (Invitek, InviLISA, Cat.
No. 30510111) according to the protocol of the supplier. Shortly:
100 .mu.L of each proteolytic reaction are incubated in a
pre-coated micro plate for 90 min at room temperature. After 3
times washing, antibody-peroxidase conjugate is added for 90 min at
room temperature. After 5 times washing, the plate is incubated
with TMB solution for 3 min at room temperature. The peroxidase
reaction is stopped with sulfurous acid and the absorbance is red
at 450 nm. The IC.sub.50 values are calculated from the absorbance
signal corresponding to residual aggrecanase activity.
Example 1705
Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan
Degradation
[0349] The assay for MMP-3 activity is carried out in assay buffer
comprised of 50 mM MES, pH 6.0, 10 mM CaCl.sub.2 and 0.05% Brij-35.
Articular cartilage is isolated fresh from the first phalanges of
adult cows and cut into pieces (.about.3 mg). Bovine cartilage is
incubated with 50 nM human MMP-3 (Chemikon, cat.# 25020461) in
presence or absence of inhibitor for 24 h at 37.degree. C. Sulfated
glycosaminoglycan (aggrecan) degradation products (sGAG) are
detected in supernatant, using a modification of the colorimetric
DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al.,
2000, Arthritis & Rheumatism, 43 (3), 664). 10 .mu.L of the
samples or standard are added to 190 .mu.L of the dye reagent in
microtiter plate wells, and the absorbance is measured at 525 nm
immediately. All data points are performed in triplicates.
Example 1706
Assay for Determining Inhibition of MMP-3 Mediated Pro-Collagenase
3 Activation
[0350] The assay for MMP-3 mediated activation of pro-collagenase 3
(pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES,
pH 6.0, 10 mM CaCl.sub.2 and 0.05% Brij-35 (Nagase; J. Biol. Chem.
1994 Aug. 19; 269(33):20952-7).
[0351] Different concentrations of tested compounds are prepared in
assay buffer in 5 .mu.L aliquots. 10 .mu.L of a 100 nM stock
solution of trypsin-activated (Knauper V., et al., 1996 J. Biol.
Chem. 271, 1544-1550) human pro-MMP-3 (Chemicon; CC1035) is added
to the compound solution. To this mixture, 35 .mu.L of a 286 nM
stock solution of pro-collagenase 3 (Invitek; 30100803) is added to
the mixture of enzyme and compound. The mixture is thoroughly mixed
and incubated for 5 h at 37.degree. C. Upon the completion of
incubation, 10 .mu.L of the incubation mixture is added to 50 .mu.L
assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM
CaCl.sub.2 and 0.05% Brij-35 and the mixture is thoroughly
mixed.
[0352] The assay to determine the MMP-13 activity is started by
addition of 40 .mu.L of a 10 .mu.M stock solution of MMP-13
fluorogenic substrate (Calbiochem, Cat. No. 444235) in assay buffer
comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl.sub.2 and
0.05% Brij-35 (Knauper, V., et al., 1996. J. Biol. Chem. 271,
1544-1550). The time-dependent increase in fluorescence is measured
at 320 nm excitation and 390 nm emission by an automatic plate
multireader at room temperature. The IC.sub.50 values are
calculated from the initial reaction rates.
* * * * *